JP2018012660A - Pharmaceutical composition containing bortezomib - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a formulation that has high storage stability and can retain the efficacy and stability of bortezomib over a long period of time to solve the problems of generation and increase of an analogous substance accompanying decomposition of bortezomib.SOLUTION: According to the present invention, there is provided a pharmaceutical composition comprising: (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib; and (B) a pharmaceutical composition containing a compound having a guanidino group and/or a compound having a ureido group, and optionally a pharmaceutical additive to achieve the above object. Preferably, as the pharmaceutical additive, one or more additives selected from (C) a pH adjuster and (D) a pyridine derivative may be comprised. The pharmaceutical composition has a pH of 4.0 to 7.0.SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition containing bortezomib, which retains the stability of bortezomib and suppresses the formation of related substances.

  Bortezomib is an antineoplastic agent having a proteasome inhibitory action with the chemical name (N- (2-pyrazinecarbonyl) -L-phenylalanine-L-leucine boronic acid), and is currently used in multiple myeloma and mantle cell lymphoma It is used as a therapeutic agent. A pharmaceutical preparation of bortezomib used in clinical practice is a lyophilized preparation containing bortezomib as an active ingredient and D-mannitol as an additive, and is provided as a bortezomib injectable preparation (Velcade (registered trademark)). ing. The preparation is approved for intravenous administration and subcutaneous administration, and the amount of the solution varies depending on the administration method. In the case of intravenous administration, it is dissolved in 3 mL of physiological saline, and in the case of subcutaneous administration, it is dissolved in 1.2 mL of physiological saline.

Bortezomib, an aminoalkylboronic acid, is known to be unstable and susceptible to oxidation and chemical degradation. In addition, the boronic acid itself reacts dehydratingly to form an acid anhydride and multimerize. For this reason, when preparing a pharmaceutical preparation containing bortezomib as an active ingredient, it is necessary to take measures to stabilize against oxidation and decomposition and to prevent multimerization due to acid anhydride formation.
For example, Patent Document 1 discloses a boronic acid ester derivative of a bortezomib boronic acid and a saccharide such as mannitol, and a pharmaceutical preparation using the boronic acid ester derivative is taught. This is prepared by freeze-drying a tert-butanol solution or an aqueous solution containing tert-butanol of bortezomib and mannitol. Patent Document 2 describes a lyophilized preparation containing bortezomib and tromethamine. This is described as a tromethamine salt of bortezomib with a strong BN bond. Patent Document 3 describes a lyophilized preparation of bortezomib derivative, which is a pharmaceutical preparation selected from the group consisting of a bulking agent having a cyclodextrin and a monosaccharide and a surfactant.
Since bortezomib has a problem in stability, a freeze-dried preparation is usually studied. However, Patent Document 4 discloses an aqueous solution preparation stabilized by adding propylene glycol. Patent Document 5 discloses an acid anhydride-ester derivative of α-hydroxy-β-carboxylic acid such as citric acid and bortezomib, and describes that it can be used as a pharmaceutical preparation.
Thus, it is known that boronic acid reacts with alcohol or carboxylic acid to form boronic acid ester or acid anhydride. Such boronic acid esters and acid anhydrides undergo hydrolysis in an aqueous solution to reconstitute bortezomib. Thus, an attempt has been made to use a bortezomib derivative that can regenerate bortezomib at the time of administration as a chemical species at the time of formulation by utilizing the physical properties of boronic acid.

Japanese Patent No. 4162491 Japanese Patent No. 5689816 Japanese Patent No. 5722871 Japanese Patent No. 5661912 International Publication No. WO2009 / 154737

  An object of the present invention is to provide a pharmaceutical composition containing bortezomib in which production of related substances is suppressed.

The present inventors suppressed the degradation of bortezomib, which is an active ingredient, by using a compound having a guanidino group and / or a compound having a ureido group together with bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib. It has been found that a pharmaceutical preparation can be provided. The gist of the present application is the invention described in [1] to [7] below.
[1] A pharmaceutical composition comprising (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib, (B) a compound having a guanidino group and / or a compound having a ureido group.
[2] The pharmaceutical according to [1] above, wherein the pharmaceutical composition aqueous solution contains (C) a pH adjuster, and (A) the aqueous pharmaceutical composition solution has a pH of 4 to 7 when the bortezomib concentration is 1 to 2.5 mg / mL. Composition.
[3] (B) Bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of Bortezomib is 0.1 to 25 parts of (B) a compound having a guanidino group and / or a compound having a ureido group. Pharmaceutical composition as described in said [1] or [2] containing a mass part.
[4] The pharmaceutical composition according to any one of [1] to [3], wherein (B) the compound having a guanidino group is arginine and the compound having a ureido group is urea.
[5] The pharmaceutical composition according to any one of [1] to [4], which comprises (D) a pyridine derivative.
[6] A pharmaceutical preparation containing the pharmaceutical composition according to any one of [1] to [5].
[7] The pharmaceutical preparation according to [6], which is a lyophilized preparation.

  The pharmaceutical composition comprising the bortezomib of the present invention or a pharmaceutically acceptable salt thereof or a derivative of bortezomib as an active ingredient can suppress the production of related substances accompanying the degradation of bortezomib and has excellent storage stability. A pharmaceutical composition of bortezomib can be provided. Therefore, it is possible to provide a pharmaceutical preparation that can maintain the efficacy and safety of bortezomib over a long period of time.

  The present invention is a pharmaceutical composition comprising (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib, (B) a compound having a guanidino group and / or a compound having a ureido group. The details will be described below.

The present invention relates to a pharmaceutical composition comprising bortezomib or a derivative thereof as an active ingredient. Bortezomib is a chemical name (N- (2-pyrazinecarbonyl) -L-phenylalanine-L-leucine boronic acid) having proteasome inhibitory activity. The compound is a boronic acid derivative disclosed in Japanese Patent No. 3717934, and can be obtained by the method described therein.
Bortezomib of the present invention may be a suitable pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include alkali metal salts (sodium, potassium, etc.), alkaline earth metal salts (magnesium, calcium, etc.), ammonium salts, and pharmaceutically acceptable amine salts (tetramethylammonium salt). , Triethylamine, methylamine, diethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine monoethanolamine, tris (hydroxymethyl) amine, lysine, arginine and N-methyl-D-glucan).

The present invention may also be a derivative of bortezomib as an active ingredient. The derivative is an ester derivative, an acid anhydride derivative, or an acid anhydride-ester mixed derivative of bortezomib with a boronic acid functional group, and has physical properties to regenerate bortezomib by hydrolysis in an aqueous solution. Is a derivative. That is, a polyol compound containing 1,2-diol, an α-hydroxy-β-carboxylic acid compound, a reaction product of a dicarboxylic acid compound and bortezomib can be mentioned. For example, boronate ester derivatives of bortezomib and glycerin, mannitol, sorbitol, xylitol, glucose, maltose, sucrose, trehalose, lactose, fructose, meglumine, inositol, sodium gluconate, cyclodextrin and the like. Citric acid, tartaric acid, malic acid, salicylic acid, mandelic acid, acid anhydride-ester mixed derivatives of α-hydroxy-β-carboxylic acid and bortezomib such as 3-hydroxybutyric acid, dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, etc. An acid anhydride with an acid, etc. are mentioned.
In the present invention, bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib (A) may be any one chemical species of bortezomib, a salt of bortezomib, or a derivative of bortezomib. A mixture of the above may also be used. Further, a part may contain a self-dehydrating condensate such as a trimer of bortezomib. However, since the trimer is hardly soluble and becomes an insoluble foreign substance when administered as an aqueous solution, it is preferable not to contain a self-dehydrating condensate such as the trimer. The component (A) is preferably a quality level that can be used as an active ingredient for pharmaceuticals.

The present invention uses (B) a compound (b-1) having a guanidino group and / or a compound (b-2) having a ureido group.
Examples of the compound (b-1) having a guanidino group include guanidine or a salt thereof, creatine, creatinine, arginine and the like. Arginine is preferable.

  Examples of the compound (b-2) having a ureido group include urea and ethylurea. Preferably it is urea.

  In the present invention, (B) a compound having a guanidino group and / or a compound having a ureido group is applied in an amount of 1 mass of (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib, which is an active ingredient. It is preferable that the compound which has (B) the guanidino group and / or the compound which has a ureido group contains 0.1-25 mass parts with respect to a part. When the amount of the component (B) is less than 0.1 parts by mass relative to 1 part by mass of the component (A), there is a concern that the desired effect of inhibiting the formation of related substances of bortezomib cannot be achieved. On the other hand, the compound (B) having a guanidino group and / or a compound having a ureido group can be used within a range acceptable as a pharmaceutical product. More preferably, (B) component is 0.25-20 mass parts with respect to (A) component 1 mass part. The application amount of the component (b-1) having a guanidino group is more preferably 0.25 to 5 parts by mass. The application amount of the component (b-2) component having a ureido group is more preferably 1 to 20 parts by mass.

  The pharmaceutical composition of the present invention preferably contains (C) a pH adjuster. In addition, the pharmaceutical composition whose pH is 4-7 in the pharmaceutical composition aqueous solution of this invention made into 1.0-2.5 mg / mL as a density | concentration of the active ingredient bortezomib (A) including a pH adjuster. It is preferable that Since the bortezomib derivative has physical properties such that bortezomib is regenerated in an aqueous solution, the pH of the bortezomib derivative is 4.0 to 7. It is preferably a pharmaceutical composition that is zero. Preferably, it is a pharmaceutical composition having a pH of 4.5 to 6.5 as the aqueous solution. More preferably, the pH is particularly preferably adjusted within the range of 5.0 to 6.0.

(C) The pH adjuster is generally used in pharmaceutical preparations and is not particularly limited as long as it does not adversely affect the pharmaceutical composition of the present invention. For example, acidic agents such as inorganic acids such as hydrochloric acid, phosphoric acid, boric acid, and carbonic acid, and organic acids such as citric acid, tartaric acid, ascorbic acid, lactic acid, and acetic acid can be used. In addition, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, inorganic acids such as sodium dihydrogen phosphate, disodium monohydrogen phosphate, sodium carbonate and sodium hydrogen carbonate An alkaline agent such as an alkaline earth metal salt can be used. Moreover, you may use the buffer agent which mixed the said acidic agent and the alkaline agent and adjusted pH. Examples of the buffer include a phosphate buffer, an acetate buffer, a citrate buffer, a tartaric acid buffer, a lactic acid buffer, a succinic acid buffer, a TRIS buffer, a glycine buffer, and a histidine buffer. These pH adjusters may be used alone or in combination of two or more.
(C) The pH adjuster in the present invention is preferably hydrochloric acid, phosphoric acid or a salt thereof (sodium dihydrogen phosphate, disodium monohydrogen phosphate, etc.) and sodium hydroxide. That is, it is preferable to use phosphate or phosphate buffer.
(C) When manufacturing a pharmaceutical composition, (C) pH adjuster should just adjust pH of a solution to the target pH, and is used in an appropriate quantity. The blending amount of the pH adjuster used for producing the pharmaceutical composition of the present invention is not particularly limited as long as the pH can be adjusted to the above range. Usually, the pH adjuster is used in an appropriate amount so that the pH can be adjusted to the target range.

The pharmaceutical composition of the present invention preferably contains a pyridine derivative (D). The pyridine derivative can improve the solubility of the active ingredient (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib. For example, when the pharmaceutical composition of the present invention is in the form of a lyophilized preparation, and the aqueous solution is reconstituted using, for example, physiological saline at the time of administration, the preparation containing the pyridine derivative (D) has improved water solubility. Therefore, it can be dissolved quickly and an aqueous solution for administration can be easily prepared.
Examples of the pyridine derivative (D) include nicotine, nicotinic acid, nicotinic acid amide, pyridoxine, pyridoxal, and pyridoxamine. Preferred are nicotinic acid and nicotinic acid amide. More preferred is nicotinamide.
When the pyridine derivative (D) is used in the pharmaceutical composition of the present invention, the active ingredient (A) bortezomib or a pharmaceutically acceptable salt thereof, or 1 part by weight of the bortezomib derivative is (D) the pyridine derivative. It is preferable that 0.1-30 mass parts is contained. Preferably, (A) component is 1-15 parts by mass, and (D) the pyridine derivative is 1-15 parts by mass.

The pharmaceutical composition comprising (A) bortezomib or a pharmaceutically acceptable salt thereof or a derivative of bortezomib of the present invention as an active ingredient comprises (B) a compound (b-1) having a guanidino group and / or a ureido group. In addition to the compound (b-2), the optional additive component (C) pH adjuster, and (D) a pyridine derivative, other additives used in normal pharmaceutical preparations may be contained. As other additives, isotonic agents, excipients, solubilizers, antioxidants and the like used in ordinary pharmaceutical preparations may be added as long as the stability of bortezomib is maintained.
Examples of isotonic agents include salts such as sodium chloride, sugars such as mannitol, lactose, sucrose, maltose, and trehalose, or sugar alcohols.
As the excipient, salts such as sodium chloride, saccharides such as mannitol, lactose, sucrose, maltose, trehalose or sugar alcohols can be used.
Examples of the solubilizer include polyols such as glycerin, thioglycerin, and propylene glycol, and polyether compounds such as polysorbate, polyethylene glycol, polypropylene glycol, and polyoxyethylene castor oil.
Antioxidants include butylated hydroxytoluene, propyl gallate, α-tocopherol, tocopherol polyethylene glycol succinate, L-cysteine and the like.
The content of the other additives is appropriately set in consideration of the stability of bortezomib, and is used in an appropriate amount, but 30 parts by mass with respect to 1 part by mass of bortezomib or its derivative (A) as an active ingredient It is preferable to add and use in the following. More preferably, the application amount is 15 parts by mass or less per 1 part by mass of bortezomib.

  The pharmaceutical composition of the present invention can be provided as a pharmaceutical preparation by preparing it in a suitable pharmaceutical preparation form containing it. Since pharmaceuticals containing bortezomib as an active ingredient are provided as antitumor agents by intravenous or subcutaneous administration in the form of injections, the pharmaceutical preparations of the present invention are also preferably injectable preparations. That is, it is preferable that it is a formulation type such as a lyophilized formulation or an injection solution formulation.

The pharmaceutical preparation of the present invention comprises a predetermined amount of (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib, (B) a compound having a guanidino group (b-1) and / or a compound having a ureido group Prepare a solution containing (b-2) and optional additive components (C) pH adjuster, (D) pyridine derivative, and other additives, and filter this with a membrane filter. Can be prepared by dispensing into In the case of an injection solution formulation, it can be prepared by aseptically sealing it, and in the case of a lyophilized formulation, the vial into which the solution has been dispensed may be lyophilized and aseptically sealed.
The solvent for preparing a solution containing the components (A) and (B) and the optional components (C), (D) and other additives can dissolve these components and is pharmaceutically acceptable. The solvent is not particularly limited, and an appropriate solvent may be used by appropriately selecting. For example, water, ethanol, isopropanol, tert-butanol, glycerin, propylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, polyethylene glycol (macrogol), polysorbate (Tween), cremophor and the like can be mentioned. You may use as a mixed solvent of a seed or more.

The pharmaceutical preparation of the present invention includes a lyophilized preparation.
When preparing a freeze-dried preparation, the solvent for preparing the solution containing the pharmaceutical composition of the present invention preferably has a melting point of −40 ° C. or higher in consideration of the preparation process. For example, it is preferable to use water, tert-butanol, glycerin, N-methylpyrrolidone, dimethyl sulfoxide, or the like. It is more preferable to use water or an aqueous mixed solvent of water and an organic solvent. A freeze-dried preparation can be prepared by freeze-drying the solution using this solvent and sealing aseptically.

  In the pharmaceutical composition of the present invention and the pharmaceutical preparation using the same, multimer formation due to bortezomib self-condensation is suppressed. Therefore, even if the pharmaceutical preparation is prepared as a solution for administration, the problem of generation of insoluble components such as bortezomib trimer can be solved. Therefore, it is possible to provide a safe pharmaceutical preparation that solves the problem of solution preparation at the time of administration.

  The pharmaceutical preparation of the present invention can be used as a medicine containing bortezomib as an active ingredient. Since bortezomib preparations are used as therapeutic agents for malignant tumors such as multiple myeloma and mantle cell lymphoma based on proteasome inhibitory action, they can be similarly applied as antitumor agents.

  In the following, the present invention will be further illustrated by examples. However, the present invention is not limited to these examples.

[Example 1]
Nicotinamide 500 mg was dissolved in 24 mL of water for injection, 40 mg of arginine was added and dissolved, and 60 mg of bortezomib was dissolved in a solution having a pH of 10.5. This aqueous solution was adjusted to pH 5.5 using an appropriate amount of phosphoric acid solution and an appropriate amount of sodium hydroxide solution, and water for injection was added to make a total volume of 60 mL. The solution had a pH of 5.5.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, filled with 3 mL of the filtered solution in a vial, freeze-dried, and a freeze-dried preparation according to Example 1 was prepared.

[Example 2]
18 mg of glycerin and 460 mg of nicotinamide were dissolved in 24 mL of water for injection, dissolved by adding 40 mg of arginine, and dissolved by adding 60 mg of bortezomib to a solution whose pH was about 10.5. The pH was adjusted to 5.6 with an appropriate amount of phosphoric acid solution and sodium hydroxide solution, and water for injection was added to make a total volume of 60 mL. The solution was pH 5.6.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, filled with 3 mL of the filtered solution in a vial, freeze-dried, and a freeze-dried preparation according to Example 2 was prepared.

[Example 3]
18 mg of glycerin and 1000 mg of urea were dissolved in 24 mL of water for injection, and 60 mg of bortezomib was dissolved in a solution in which an appropriate amount of sodium hydroxide was added to adjust the pH of the aqueous solution to 11.0. This aqueous solution was adjusted to pH 5.3 using an appropriate amount of phosphoric acid solution and an appropriate amount of sodium hydroxide solution, and water for injection was added to make a total volume of 60 mL. The solution had a pH of 5.3.
This solution was aseptically filtered using a membrane filter having a pore diameter of 0.22 μm, filled with 3 mL of the filtered solution in a vial, freeze-dried, and a freeze-dried preparation according to Example 3 was prepared.

[Comparative Example 1]
Nicotinamide 420 mg was dissolved in 24 mL of water for injection, histidine 40 mg was added and dissolved, and sodium hydroxide was added to adjust the pH of the aqueous solution to about 11.0, and bortezomib 60 mg was added and dissolved. The pH was adjusted to 5.5 with appropriate amounts of phosphoric acid solution and sodium hydroxide solution, and water for injection was added to make the total volume 60 mL. The solution had a pH of 5.5.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, filled with 3 mL of the filtered solution in a vial, freeze-dried, and a freeze-dried preparation according to Comparative Example 1 was prepared.

[Comparative Example 2]
Nicotinamide 420 mg was dissolved in 24 mL of water for injection, 40 mg of sodium glutamate was added and dissolved, and sodium hydroxide was added to adjust the pH of the aqueous solution to about 11.0, and 60 mg of bortezomib was added and dissolved. The pH was adjusted to 5.5 with appropriate amounts of phosphoric acid solution and sodium hydroxide solution, and water for injection was added to make the total volume 60 mL. The solution had a pH of 5.5.
This solution was aseptically filtered using a membrane filter having a pore diameter of 0.22 μm, filled with 3 mL of the filtered solution in a vial, freeze-dried, and a freeze-dried preparation according to Comparative Example 2 was prepared.

[Comparative Example 3]
Nicotinamide 500 mg was dissolved in 24 mL of water for injection, threonine 200 mg was added and dissolved, and sodium hydroxide was added to adjust the pH of the aqueous solution to about 11.0, and bortezomib 60 mg was added and dissolved. The pH was adjusted to 5.5 with appropriate amounts of phosphoric acid solution and sodium hydroxide solution, and water for injection was added to make the total volume 60 mL. The solution had a pH of 5.5.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, filled with 3 mL of the filtered solution in a vial, freeze-dried, and a freeze-dried preparation according to Comparative Example 3 was prepared.

＊１；生理食塩水１．２ｍＬで再溶解した時のｐＨ値。 The composition of each component per vial of the pharmaceutical preparations according to Examples 1 to 3 is summarized in Table 1.

* 1: pH value when redissolved in 1.2 mL of physiological saline.

＊２；生理食塩水１．２ｍＬで再溶解した時のｐＨ値。 The composition of each component per vial of the pharmaceutical preparations according to Comparative Examples 1 to 3 is summarized in Table 1.

* 2: pH value when redissolved in 1.2 mL of physiological saline.

[Test Example 1] 60 ° C. Storage Stability Test The lyophilized preparations for injection of Examples 1 to 3 and Comparative Examples 1 to 3 were stored at 60 ° C. for 1 week. For each formulation, bortezomib-derived related substances were analyzed by HPLC. The HPLC analysis conditions for bortezomib-related substances are shown below. The analysis results are shown in Tables 4 and 5.

[Analysis conditions for related substances derived from bortezomib]
The related substances derived from the degradation of bortezomib in Examples and Comparative Examples were analyzed under the following liquid chromatography (HPLC) conditions.
Column: Waters Symmetry Shield RP18 5μm, 4.6mm x 250mm
Column temperature: 35 ° C
Mobile phase A: water / acetonitrile / formic acid mixture (715: 285: 1)
Mobile phase B: methanol / water / formic acid mixture (800: 200: 1)
Liquid feeding amount: 1.0 mL / min.
Wavelength: 270nm
Liquid feeding of mobile phase: Liquid feeding was carried out under the conditions shown in Table 3.

＊３ 不純物Ａ、Ｂ、Ｅ以外の個々の類縁物質の最大値。 Table 4 summarizes the content of each related substance in the 60 ° C. storage stability test of the freeze-dried preparations of Examples 1 to 3.

* 3 Maximum values of individual related substances other than impurities A, B, and E.

＊３ 不純物Ａ、Ｂ、Ｅ以外の個々の類縁物質の最大値。 Table 5 summarizes the content of each related substance in the 60 ° C. storage stability test of the freeze-dried preparations of Comparative Examples 1 to 3.

* 3 Maximum values of individual related substances other than impurities A, B, and E.

In Examples 1 to 3, the production amounts of the related substances A and E were small even at the initial value, and the generation of the related substances was suppressed in the preparation process. Furthermore, even if it preserve | saved for one week at 60 degreeC, a total related substance was 0.5% (w / w) or less, and the production | generation of the related substance was suppressed on storage conditions. On the other hand, Comparative Examples 1 to 3 contained the total related substances in an amount exceeding 1% (w / w) even in the initial stage, and a clear increase in the related substances was recognized even during the preparation manufacturing process. Further, when stored at 60 ° C. for 1 week, the total related substances contained 1% (w / w) or more, and generation of related substances could not be suppressed under storage conditions. Comparison of the above results revealed that the pharmaceutical preparation of the present invention can inhibit the production of bortezomib-related substances from the preparation manufacturing process to the preparation storage period.
Usually, bortezomib produces the related substance E by oxidation with oxygen, peroxide, etc., and when this further decomposes, the related substance A is produced. By using arginine having a guanidino group or urea having a ureido group as a pharmaceutical formulation additive, it is possible to suppress the oxidation of bortezomib and suppress the production of the related substance E, and hence the formation of the related substance A. it is conceivable that.

Claims (7)

A pharmaceutical composition comprising (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib, (B) a compound having a guanidino group and / or a compound having a ureido group. The pharmaceutical composition according to claim 1, comprising (C) a pH adjuster, wherein (A) the aqueous pharmaceutical composition solution has a pH of 4 to 7 when the bortezomib concentration is 1 to 2.5 mg / mL. (A) Bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of Bortezomib is 0.1 part by mass of (B) a compound having a guanidino group and / or a compound having a ureido group. The pharmaceutical composition according to claim 1 or 2, which is contained. (B) The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound having a guanidino group is arginine and the compound having a ureido group is urea. (D) The pharmaceutical composition according to any one of claims 1 to 4, comprising a pyridine derivative. The pharmaceutical formulation containing the pharmaceutical composition as described in any one of Claims 1-5. The pharmaceutical preparation according to claim 6, which is a lyophilized preparation.