JP6665057B2 - Pharmaceutical preparation containing bortezomib - Google Patents

Description

  TECHNICAL FIELD The present invention relates to a pharmaceutical preparation containing bortezomib, which maintains the stability of bortezomib and has good resolubility.

  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. Pharmaceutical preparations of bortezomib for clinical use are lyophilized preparations containing bortezomib as an active ingredient and D-mannitol as an additive, and are provided as bortezomib injection preparations (Velcade (registered trademark)). ing. The formulation has been approved for intravenous administration and subcutaneous administration, and the amount of the lysate varies depending on the administration method. It is used by dissolving it in 3 mL of physiological saline for intravenous administration and 1.2 mL of physiological saline for subcutaneous administration.

Bortezomib, an aminoalkylboronic acid, is susceptible to oxidation and chemical decomposition and is known to have unstable physical properties. Further, the boronic acid itself reacts in a dehydrating manner to form an acid anhydride to form a polymer. For this reason, when preparing a pharmaceutical preparation containing bortezomib as an active ingredient, it is necessary to take measures for stabilizing oxidation and decomposition and suppressing multimerization due to acid anhydride.
For example, Patent Literature 1 discloses a boronic acid ester derivative of a boronic acid of bortezomib and a saccharide such as mannitol, and a pharmaceutical preparation using the same is suggested. This is prepared by freeze-drying a tert-butanol solution of bortezomib and mannitol or an aqueous solution containing tert-butanol. Patent Literature 2 discloses a lyophilized preparation containing bortezomib and tromethamine. It is described to be a tromethamine salt of bortezomib with a strong BN bond. Patent Document 3 describes a freeze-dried preparation of a bortezomib derivative, which is a pharmaceutical preparation selected from the group consisting of a bulking agent having cyclodextrin and a monosaccharide and a surfactant.
Since bortezomib has a problem in stability, lyophilized preparations are usually studied. Patent Document 4 discloses an aqueous 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 the derivative can be used as a pharmaceutical preparation.
As described above, it is known that boronic acid reacts with an alcohol or a carboxylic acid to form a boronic ester or an acid anhydride. Such boronic ester or acid anhydride undergoes hydrolysis in an aqueous solution to reconstitute bortezomib. Further, currently available freeze-dried bortezomib preparations have poor wettability of freeze-dried cakes, and Non-Patent Document 1 describes that dissolution requires a maximum of about 120 seconds. Therefore, a pharmaceutical preparation which is stable and has good resolubility is desired.

Japanese Patent No. 4162491 Japanese Patent No. 5689816 Japanese Patent No. 5722871 Japanese Patent No. 5666112 International Publication WO2009 / 154737

Pharmaceutical Interview Form Antineoplastic Agent (Proteasome Inhibitor) Velcade Injection 3 mg January 2016 (10th edition) p. 6

  An object of the present invention is to provide a pharmaceutical preparation containing bortezomib, which suppresses generation of related substances and has good resolubility.

The present inventors have found that by using glycerin together with bortezomib or a pharmaceutically acceptable salt thereof, or a bortezomib derivative, a pharmaceutical preparation containing bortezomib, which suppresses the production of related substances and further has good resolubility. Can be provided. The gist of the present application is the invention described in the following [1] to [5].
[1] A pharmaceutical preparation comprising (A) bortezomib or a pharmaceutically acceptable salt thereof, or a bortezomib derivative, and (B) glycerin.
[2] The pharmaceutical preparation according to [1], containing (C) nicotinamide.
[3] It contains (D) a pH adjuster, and the (D) pH adjuster comprises a basic compound and an acidic compound, and when the basic compound is 1 equivalent, the equivalent of the acidic compound is 1 to 4 equivalents [1] ] Or the pharmaceutical preparation according to [2].
[4] [1] to [1] to [1] to [1], which contain (D) a pH adjuster and (A) the pH of the aqueous pharmaceutical preparation solution is 4.0 to 7.0 when the concentration of bortezomib is 1 to 2.5 mg / mL. The pharmaceutical preparation according to 3).
[5] The pharmaceutical preparation according to any one of [1] to [4], which is a lyophilized preparation.

  The pharmaceutical preparation containing bortezomib or a pharmaceutically acceptable salt thereof or a derivative of bortezomib of the present invention as an active ingredient can provide a pharmaceutical preparation of bortezomib which retains the stability of bortezomib and has good resolubility. . Therefore, it is possible to provide a pharmaceutical preparation which can maintain the efficacy and safety of bortezomib for a long period of time and can easily re-dissolve the lyophilized preparation.

  The present invention is a pharmaceutical preparation containing (A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib, and (B) glycerin. The details will be described below.

The present invention relates to a pharmaceutical preparation containing 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. Pharmaceutically acceptable salts include, for example, alkali metal salts (eg, sodium, potassium), alkaline earth metal salts (eg, magnesium, calcium), ammonium salts, and pharmaceutically acceptable amine salts (eg, tetramethylammonium). , Triethylamine, methylamine, diethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine monoethanolamine, tris (hydroxymethyl) amine, lysine, arginine and N-methyl-D-glucan).

In the present invention, a bortezomib derivative may be used as an active ingredient. The derivative is an ester derivative with a boronic acid functional group of bortezomib, an acid anhydride derivative, an acid anhydride-ester mixed derivative, and has a property of hydrolytic cleavage in an aqueous solution to regenerate bortezomib. It is a derivative. That is, a reaction product of a polyol compound containing 1,2-diol, an α-hydroxy-β-carboxylic acid compound, and a dicarboxylic acid compound with bortezomib can be mentioned. For example, a boronic acid ester derivative of bortezomib with a polyol compound such as glycerin, mannitol, sorbitol, xylitol, glucose, maltose, sucrose, trehalose, lactose, fructose, meglumine, inositol, sodium gluconate, and cyclodextrin. Acid anhydride-ester mixed derivatives of α-hydroxy-β-carboxylic acid such as citric acid, tartaric acid, malic acid, salicylic acid, mandelic acid, and 3-hydroxybutyric acid with bortezomib; dicarboxylic acids such as oxalic acid, malonic acid, and succinic acid And acid anhydrides with acids.
In the present invention, the bortezomib or a pharmaceutically acceptable salt thereof, or the bortezomib derivative (A) may be any one of bortezomib, a bortezomib salt, and a bortezomib derivative, and may be two kinds. A mixture of the above may be used. Further, a part thereof may contain a self-dehydrated 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 that a self-dehydrated condensate such as the trimer is not contained. The component (A) preferably has a quality level that can be used as an active ingredient for pharmaceuticals.

  In the present invention, (A) bortezomib or a pharmaceutically acceptable salt thereof, or a bortezomib derivative preferably contains at least bortezomib, and more preferably has a bortezomib content of 50% by mass or more. . It is even more preferred that component (A) be bortezomib.

The pharmaceutical preparation of the present invention contains (B) glycerin. Glycerin 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 preparation of the present invention is in the form of a lyophilized preparation and the aqueous solution is reconstituted with, for example, physiological saline at the time of administration, the preparation containing glycerin (B) has improved water solubility. In addition, the wettability of the freeze-dried preparation is improved, and the preparation is easily dissolved to easily prepare an aqueous solution for administration.
When glycerin (B) is used in the pharmaceutical preparation of the present invention, (B) glycerin is added in an amount of 1 part by mass of the active ingredient (A) bortezomib or a pharmaceutically acceptable salt thereof, or bortezomib derivative. It is preferable to contain from 0.01 to 10 parts by mass. Preferably, (A) component is 1 part by mass, and (B) glycerin is 0.1 to 2 parts by mass.

  The wettability in the present specification indicates the affinity of a liquid for a solid surface. The solid surface is, for example, the surface of a freeze-dried cake, and the liquid is a liquid used for re-dissolving a freeze-dried preparation, such as physiological saline. When the liquid is physiological saline, it is considered that the wettability is improved by improving the hydrophilicity of the freeze-dried cake.

The pharmaceutical preparation of the present invention preferably contains nicotinamide (C). Nicotinamide 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 preparation 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 nicotinamide (C) has improved water solubility. Therefore, the aqueous solution for administration can be easily prepared by dissolving quickly.
When nicotinamide (C) is used in the pharmaceutical preparation of the present invention, the active ingredient (A) bortezomib or a pharmaceutically acceptable salt thereof or a derivative of bortezomib is added to 1 part by mass of (C) nicotinic acid. It is preferred that the amide contains 0.1 to 30 parts by mass. Preferably, (C) nicotinamide is 1 to 15 parts by mass with respect to 1 part by mass of the component (A).

The pharmaceutical preparation of the present invention contains (D) a pH adjuster, and the pH adjuster preferably comprises a basic compound and an acidic compound.
The basic compound and the acidic compound used in the (D) pH adjuster are commonly used in pharmaceutical preparations, and are not particularly limited as long as they do not adversely affect the pharmaceutical preparation of the present invention. . Examples of the basic compound include hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, sodium dihydrogen phosphate, disodium monohydrogen phosphate, sodium carbonate, sodium hydrogen carbonate, and the like. And alkaline earth metal salts of inorganic acids. An additive may be used as the basic compound. Examples of the additive include a compound having a guanidino group, such as guanidine or a salt thereof, creatine, creatinine, and arginine. Examples of the acidic compound include 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. Further, a buffering agent whose pH is adjusted by mixing the basic compound and the acidic compound may be used. Examples of the buffer include a phosphate buffer, an acetate buffer, a citrate buffer, a tartrate buffer, a lactate buffer, a succinate 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.
The (D) pH adjuster in the present invention is preferably sodium hydroxide, arginine, hydrochloric acid, phosphoric acid or a salt thereof (sodium dihydrogen phosphate, disodium monohydrogen phosphate, etc.).
(D) The pH adjuster is only required to be able to adjust the pH of the solution to a target pH when producing a pharmaceutical preparation, and is used in an appropriate amount. The amount of the pH adjuster used in the production of the pharmaceutical preparation of the present invention is not particularly limited as long as the pH can be adjusted within the above range. Usually, an appropriate amount of the pH adjuster is used so that the pH can be adjusted to a target range.

  The pH adjusting agent comprising the basic compound and the acidic compound is preferably such that the equivalent of the acidic compound is 1 to 4 equivalents when the basic compound is 1 equivalent, and the equivalent of the acidic compound is 1 equivalent when the basic compound is 1 equivalent. More preferably, it is 1 to 3.5 equivalents.

The equivalent is the amount of a substance when a certain substance reacts without excess or deficiency, and includes a chemical equivalent, an electrochemical equivalent, and a work equivalent of heat. Usually means chemical equivalent. The chemical equivalent includes an element equivalent, an acid-base equivalent, and an oxidation-reduction equivalent. The equivalent in the present specification refers to an equivalent of acid-base. That is, when the amount of the basic compound is 1 equivalent and the amount of the acidic compound is 1 equivalent, the numbers of H ⁺ and OH ⁻ are equal, and when the amount of the basic compound is 1 equivalent and the amount of the acidic compound is 2 equivalents, the number of H ⁺ is equal. There OH ^- means that it is twice the number of.

  The pharmaceutical preparation of the present invention contains a pH adjuster and has a pH of 4 in an aqueous solution of the pharmaceutical preparation of the present invention in which the active ingredient bortezomib or a derivative of bortezomib (A) has a concentration of 1.0 to 2.5 mg / mL. It is preferably a pharmaceutical preparation having a pH of from 0.0 to 7.0. Since the bortezomib derivative has the property of regenerating bortezomib in an aqueous solution, the pH of the active ingredient bortezomib in an aqueous solution of 1.0 to 2.5 mg / mL as a concentration of 1.0 to 2.5 mg / mL is 4.0 to 7.0. It is preferably a pharmaceutical preparation which is 0. Preferably, the aqueous solution is a pharmaceutical preparation having a pH of 4.5 to 6.5. More preferably, it is particularly preferable to adjust the pH to the range of 5.0 to 6.0.

The pharmaceutical preparation (A) of the present invention containing bortezomib or a pharmaceutically acceptable salt thereof or a derivative of bortezomib as an active ingredient is (B) glycerin, and (C) nicotinamide, which is an optional additive ingredient, D) In addition to the pH adjuster, it may contain other additives used in ordinary pharmaceutical preparations. As other additives, an isotonic agent, an excipient, a solubilizing agent, an antioxidant, and the like, which are used in ordinary pharmaceutical preparations, may be added as long as the stability of bortezomib is maintained.
Examples of the tonicity agent include salts such as sodium chloride, mannitol, lactose, sucrose, maltose, trehalose, xylitol, sorbitol, inositol, sodium gluconate, meglumine, cyclodextrin, and other sugars or sugar alcohols, and urea.
Further, as an excipient, salts such as sodium chloride, saccharides such as mannitol, lactose, sucrose, maltose, trehalose, xylitol, sorbitol, inositol, sodium gluconate, meglumine, and cyclodextrin can be used.
Examples of the dissolution aid include polyols such as thioglycerin and propylene glycol, and polyether compounds such as polysorbate, polyethylene glycol, polypropylene glycol, and polyoxyethylene castor oil.
Antioxidants include propyl gallate, ascorbic acid, 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 appropriately. Each part is 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 the following. More preferably, the application amount is 15 parts by mass or less for 1 part by mass of bortezomib.

  The present invention relates to pharmaceutical formulations. Since the pharmaceutical preparation containing bortezomib as an active ingredient is provided as an antitumor agent by intravenous administration or subcutaneous administration in the form of an injection, the pharmaceutical preparation of the present invention is also preferably an injection preparation. That is, it is preferably in the form of a preparation such as a lyophilized preparation or an injection liquid preparation.

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) glycerin, and (C) nicotinamide, ) It can be prepared by preparing a solution containing a pH adjuster and other additives, filtering the solution with a membrane filter, and dispensing the solution into glass vials. In the case of an injection liquid preparation, it can be prepared by aseptically sealing it. In the case of a lyophilized preparation, the vial into which the solution has been dispensed may be lyophilized and sealed aseptically.
The solvent for preparing a solution containing the components (A) and (B) and the optional components (C) and (D) and other additives can dissolve these components and be pharmaceutically acceptable. The solvent is not particularly limited as long as the solvent is used, and an appropriate solvent may be appropriately selected and used. For example, water, ethanol, isopropanol, tert-butanol, glycerin, propylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, polyethylene glycol (macrogol), polysorbate (Tween), cremophor, etc., and these can be used alone or It may be used as a mixed solvent of more than one kind.

The pharmaceutical preparation of the present invention includes being a freeze-dried preparation.
When preparing a freeze-dried preparation, the solvent for preparing the solution containing the pharmaceutical preparation of the present invention preferably has a melting point of −40 ° C. or higher in consideration of the preparation step. For example, it is preferable to use water, tert-butanol, glycerin, N-methylpyrrolidone, dimethylsulfoxide and 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 aseptically sealing the solution.

  In the pharmaceutical preparation of the present invention, multimer formation due to the self-condensation of bortezomib is suppressed. Therefore, even if the pharmaceutical preparation is prepared as a solution for administration, the problem of formation of insoluble components such as bortezomib trimer can be solved. Therefore, it is possible to provide a safe pharmaceutical preparation which has solved 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.

  Hereinafter, the present invention will be further described with reference to Examples. However, the present invention is not limited to these examples.

[Example 1]
Glycerin (18 mg) and nicotinamide (460 mg) were dissolved in 24 mL of water for injection, arginine (40 mg) was added and dissolved, and the solution was adjusted to a pH of about 10.5, and bortezomib (60 mg) was added and dissolved. 480 μL of a 0.5 M phosphoric acid solution was added to adjust the pH to 5.6, and water for injection was added to adjust the total volume to 60 mL. The solution had a pH of 5.6.
This solution was subjected to aseptic filtration using a membrane filter having a pore size of 0.22 μm, and 3 mL of the filtered solution was filled in a vial, and lyophilized to prepare a lyophilized preparation according to Example 1.

[Example 2]
18 mg of glycerin and 1000 mg of urea were dissolved in 24 mL of water for injection, and 60 mg of bortezomib was added to a solution whose pH was adjusted to 11.0 by adding 100 μL of 5 M sodium hydroxide. This aqueous solution was adjusted to pH 5.3 by adding 400 μL of a 0.5 M phosphoric acid 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 subjected to aseptic filtration using a membrane filter having a pore size of 0.22 μm, filled with 3 mL of the filtered solution in a vial, and lyophilized to prepare a lyophilized preparation according to Example 2.

[Comparative Example 1]
Nicotinamide (500 mg) was dissolved in 24 mL of water for injection, arginine (40 mg) was added to dissolve the solution, and the aqueous solution having a pH of 10.5 was dissolved by adding bortezomib (60 mg). The aqueous solution was adjusted to pH 5.5 by adding 480 μL of a 0.5 M phosphoric acid solution, and water for injection was added to make the total volume 60 mL. The solution had a pH of 5.5.
The solution was subjected to aseptic filtration using a membrane filter having a pore size of 0.22 μm, and 3 mL of the filtered solution was filled in a vial, and lyophilized to prepare a lyophilized preparation according to Comparative Example 1.

[Comparative Example 2]
800 mg of PEG 4000 and 420 mg of nicotinamide were dissolved in 24 mL of water for injection, 40 mg of arginine was added and dissolved, and 60 mg of bortezomib was added and dissolved in a solution whose pH of the aqueous solution was about 10.5. The aqueous solution was adjusted to pH 5.6 by adding 450 μL of a 0.5 M phosphoric acid solution, and water for injection was added to make a total volume of 60 mL. The solution had a pH of 5.6.
This solution was subjected to aseptic filtration using a membrane filter having a pore size of 0.22 μm, and 3 mL of the filtered solution was filled in a vial, and lyophilized to prepare a lyophilized preparation according to Comparative Example 2.

[Comparative Example 3]
180 mg of EDTA2Na and 420 mg of nicotinamide were dissolved in 24 mL of water for injection, 40 mg of arginine was added and dissolved, and 60 mg of bortezomib was added and dissolved in a solution adjusted to pH 11.5 by adding 200 μL of 5M sodium hydroxide solution. This solution was adjusted to pH 5.0 by adding 1.5 mL of a 0.5 M phosphoric acid solution, and water for injection was added to adjust the total volume to 60 mL. The solution had a pH of 5.0.
This solution was subjected to aseptic filtration using a membrane filter having a pore size of 0.22 μm, and 3 mL of the filtered solution was filled in a vial, and lyophilized to prepare a lyophilized preparation according to Comparative Example 3.

[Comparative Example 4]
6 mg of Na benzoate and 420 mg of nicotinamide were dissolved in 24 mL of water for injection, 40 mg of arginine was added and dissolved, and 60 mg of bortezomib was added and dissolved in a solution adjusted to pH 10.5. The solution was adjusted to pH 5.2 by adding 480 μL of a 0.5 M phosphoric acid solution, and water for injection was added to adjust the total volume to 60 mL. The solution had a pH of 5.6.
This solution was subjected to aseptic filtration using a membrane filter having a pore size of 0.22 μm, filled with 3 mL of the filtered solution in a vial, and lyophilized to prepare a lyophilized preparation according to Comparative Example 4.

[Comparative Example 5]
60 mg of polysorbate 80 and 420 mg of nicotinamide were dissolved in 24 mL of water for injection, 40 mg of arginine was added and dissolved, and 60 mg of bortezomib was added and dissolved in a solution adjusted to pH 10.5. This solution was adjusted to pH 5.6 by adding 480 μL of a 0.5 M phosphoric acid solution, and water for injection was added to make a total volume of 60 mL. The solution had a pH of 5.7.
This solution was subjected to aseptic filtration using a membrane filter having a pore size of 0.22 μm, and 3 mL of the filtered solution was filled in a vial, and lyophilized to prepare a lyophilized preparation according to Comparative Example 5.

＊１；生理食塩水１．２ｍＬで再溶解したときのｐＨ値。
Table 1 summarizes the composition of each component per vial of the pharmaceutical preparation according to Example 1 and Example 2, and Comparative Examples 1 to 5.
[Table 1]

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

[Test Example 1] (Solubility test)
A solubility test was performed using the lyophilized preparations obtained in Example 1 and Comparative Examples 1 to 5.
To each sample, 1.2 mL of physiological saline was added to the vial, and the freeze-dried cake was gently shaken so as to adjust to the liquid, allowed to stand, and the time until complete dissolution was measured. Table 2 shows the results.
[Table 2]

  The freeze-dried preparation of Example 1 containing glycerin has better wettability and a dissolution time of 4 compared to the freeze-dried preparations of Comparative Example 1 containing no glycerin and Comparative Examples 2 to 5 containing other additives. Reduced by more than a minute. From the test results, it was confirmed that the addition of glycerin improved the resolubility of a pharmaceutical preparation containing bortezomib as an active ingredient.

[Test Example 2] Storage stability test at 60 ° C The freeze-dried preparations for injection of Examples 1 and 2, and Comparative Examples 1 to 5 were stored at 60 ° C for one week. For each formulation, bortezomib-related analogs were analyzed by HPLC. HPLC analysis conditions for bortezomib analogs are shown below.

[Analysis conditions for related substances derived from bortezomib]
Analogous substances derived from bortezomib degradation in Examples and Comparative Examples were analyzed under the following liquid chromatography (HPLC) conditions.
Column: Waters Symmetry Shield RP18 5μm, 4.6mm × 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 sending amount: 1.0 mL / min.
Wavelength: 270 nm
Liquid sending of mobile phase: Liquid was sent under the conditions shown in Table 3.

[Table 3]

＊２ 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 and 2 and Comparative Examples 1 to 5.
[Table 4]

* 2 Maximum value of each related substance other than impurities A, B, and E.

  In Examples 1 and 2, the amounts of generation 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 of the preparation. Furthermore, even after storage at 60 ° C. for one week, the total amount of related substances was 0.5% (w / w) or less, and the generation of related substances was suppressed even under storage conditions. On the other hand, in Comparative Example 1, even when the amount of the related substance produced was the initial value, the total related substance was 0.5% (w / w) or less even after storage at 60 ° C. for one week, indicating that it was stable. . However, since the time required for re-dissolution was 5 minutes or more, it was considered unsuitable as a preparation. In Comparative Examples 2 to 5, even in the initial stage, the total related substances were contained in an amount exceeding that of Example 1, and a clear increase in the related substances was observed even during the preparation process. Further, storage at 60 ° C. for 1 week contained 1% or more of all related substances, and could not suppress the formation of related substances under storage conditions. Comparison of the above results revealed that the pharmaceutical preparation of the present invention can suppress the formation of bortezomib analogs from the preparation manufacturing process to the storage period of the preparation.

Claims (3)

(A) bortezomib or a pharmaceutically acceptable salt thereof, or a derivative of bortezomib , (B) glycerin , and (D) a pH adjuster, wherein the pH adjuster comprises a basic compound and an acidic compound, A pharmaceutical preparation , wherein the equivalent of the acidic compound is 1 to 4 equivalents when the compound is 1 equivalent, and the compound is a freeze-dried preparation. The pharmaceutical preparation according to claim 1, which comprises (C) nicotinamide. (D) comprises a pH adjusting agent, pH of the pharmaceutical formulation aqueous solution when the 1 - 2.5 mg / mL as (A) bortezomib concentration is 4.0-7.0, according to claim 1 or 2 Pharmaceutical formulations.