WO2018221487A1 - Injection containing eribulin and pharmaceutically acceptable salt thereof - Google Patents

Injection containing eribulin and pharmaceutically acceptable salt thereof Download PDF

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Publication number
WO2018221487A1
WO2018221487A1 PCT/JP2018/020456 JP2018020456W WO2018221487A1 WO 2018221487 A1 WO2018221487 A1 WO 2018221487A1 JP 2018020456 W JP2018020456 W JP 2018020456W WO 2018221487 A1 WO2018221487 A1 WO 2018221487A1
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Prior art keywords
eribulin
pharmaceutically acceptable
acceptable salt
injection
solution
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PCT/JP2018/020456
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French (fr)
Japanese (ja)
Inventor
奈生 小野
雅博 北川
敬三 中本
青木　茂
Original Assignee
エーザイ・アール・アンド・ディー・マネジメント株式会社
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Priority to JP2019521220A priority Critical patent/JPWO2018221487A1/en
Priority to CN201880024121.6A priority patent/CN110545808A/en
Publication of WO2018221487A1 publication Critical patent/WO2018221487A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an injection containing eribulin or a pharmaceutically acceptable salt thereof.
  • Eribulin mesylate is known as a therapeutic agent for inoperable or recurrent breast cancer and malignant soft tissue tumor (Non-patent Document 1).
  • the therapeutic agent is a colorless and clear injection containing eribulin mesylate, absolute ethanol, hydrochloric acid and sodium hydroxide, and its pH is in the range of 6.0 to 9.0. It is described.
  • Patent Document 1 discloses a preparation adjusted to pH 5.5 to 7.0 by adding citrate buffer and sodium chloride to eribulin mesylate.
  • Patent Document 1 neither discloses nor suggests whether or not the disclosed preparation can suppress an increase in impurity X.
  • the problem to be solved by the present invention is to provide an injection containing eribulin or a pharmaceutically acceptable salt thereof that suppresses the generation of impurities, particularly impurity X, even after long-term storage. is there.
  • the present invention is as follows.
  • An injectable preparation comprising eribulin or a pharmaceutically acceptable salt thereof and a pH adjuster and having a pH of 8.0 to 10.0.
  • the pH adjusting agent is one or more selected from the group consisting of sodium citrate, sodium tartrate, sodium gluconate, sodium hydrogen carbonate, trometamol, monoethanolamine and meglumine.
  • the injection of the present invention contains eribulin or a pharmaceutically acceptable salt thereof and a pH adjuster, and the pH of the injection is 8.0 to 10.0.
  • the eribulin in the present invention is a compound having a structure that is a free form that is an active substance of eribulin mesylate described in Non-Patent Document 1.
  • Examples of the pharmaceutically acceptable salt of eribulin in the present invention include sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, hydrofluoride, hydrochloride, and hydrogen bromide.
  • Inorganic acid salts such as acid salts and hydroiodide salts; acetate, oxalate, maleate, tartrate, fumarate, citrate, methanesulfonate, trifluoromethanesulfonate, ethanesulfonic acid Salts, organic salts such as benzenesulfonate, toluenesulfonate and camphorsulfonate; amino acid salts such as aspartate and glutamate; quaternary ammonium salts; sodium, potassium, magnesium and calcium salts, etc.
  • the metal salt is preferably a mesylate.
  • the pH adjuster in the present invention is not particularly limited as long as it is a compound that suppresses the generation of impurity X and has a function or buffering ability to adjust pH in a pharmaceutical preparation.
  • sodium phosphate, sodium acetate examples thereof include sodium acid, sodium tartrate, sodium gluconate, sodium hydrogen carbonate, trometamol, monoethanolamine and meglumine.
  • the pH adjuster is preferably trometamol, sodium tartrate or sodium citrate.
  • the pH regulator may be used alone or in combination of two or more.
  • the pH adjuster in the present invention may be contained in the injection of the present invention in the form described as a component in a package insert or an interview form, or may be a component produced in the injection.
  • Ingredients generated in injection include components that are present in injections by mixing two or more components, although they are not included in injections as components in package inserts and interview forms .
  • phosphoric acid, acetic acid, citric acid, tartaric acid and / or gluconic acid and sodium hydroxide are included in the injection, sodium phosphate, sodium acetate, sodium citrate and / or sodium gluconate are contained in the injection. Produced and functioning as a pH regulator.
  • Phosphoric acid, acetic acid, citric acid, tartaric acid and / or gluconic acid and sodium hydroxide are the molar ratio of acid to alkali so as to form sodium phosphate, sodium acetate, sodium citrate and / or sodium gluconate There is no need to add it. That is, when sodium acetate is described as an example, it can be considered that sodium acetate is produced when acetic acid and sodium hydroxide are contained at a molar ratio of 1: 1 in the injection, but the molar ratio is 1: It need not be 1. When an injection contains an acetic acid and sodium hydroxide in arbitrary ratios, it will contain sodium acetate in an injection.
  • the injection of the present invention preferably does not contain liposomes.
  • the content of the pH adjusting agent is not particularly limited, and may be any content as long as the pH in the injection is within the range of 8.0 to 10.0.
  • the content of the pH adjuster is preferably 1 to 80, more preferably 2 to 40 in terms of weight ratio when the content of eribulin or a pharmaceutically acceptable salt thereof is 1.
  • the injection according to the present invention may be adjusted to a pH within the range of 8.0 to 10.0 using an acid such as hydrochloric acid or a base such as sodium hydroxide.
  • an acid such as hydrochloric acid or a base such as sodium hydroxide.
  • the pH of the injection is preferably 8.0 to 9.0, more preferably 8.5 to 9.0.
  • the pH of the injection can be measured using a pH meter.
  • an injection containing eribulin or a pharmaceutically acceptable salt thereof in which the content of impurity X in the drug substance is 0.4% or less after storage under accelerated test or long-term storage test conditions also provide.
  • the content of the impurity X is preferably 0.2% or less.
  • the accelerated test means that the test is conducted for 6 months under the conditions of 40 ⁇ 2 ° C. and 75 ⁇ 5% RH, and the long-term storage test is 25 ⁇ 2 ° C., 60 ⁇ 5. It means that the test is conducted for at least 3 years under the condition of% RH.
  • the injection of the present invention is appropriately prepared in accordance with the Japanese Pharmacopoeia 16th revised formulation general rules, and may contain other additives as necessary as long as the object of the present invention is achieved.
  • an acid such as hydrochloric acid or a base such as sodium hydroxide may be added as appropriate in order to adjust the pH to a predetermined value.
  • the injection of the present invention may not contain an alcohol such as methanol, ethanol and / or isopropanol, preferably does not contain an alcohol having 1 to 4 carbon atoms, and more preferably has 1 to 3 carbon atoms. Of alcohol, and more preferably ethanol and / or isopropanol.
  • the injection of the present invention preferably does not contain ethanol.
  • Example 1 To 1573.4 mg of eribulin mesylate (amount to be 1500 mg as eribulin mesylate after correcting the content and moisture), ethanol (99.5) was added and dissolved, and 150 mL of solution A (10 mg / mL eribulin mesylate) Of ethanol solution) was prepared. An aqueous solution in which a pH adjusting agent was dissolved was added to 10 mL of this solution A, and sodium hydroxide or hydrochloric acid for adjusting the pH was further added to make 200 mL to obtain a 0.5 mg / mL eribulin mesylate solution.
  • solution A 10 mg / mL eribulin mesylate
  • sodium hydroxide or hydrochloric acid for adjusting the pH was further added to make 200 mL to obtain a 0.5 mg / mL eribulin mesylate solution.
  • Example 1-1 20 mg / mL Sodium Citrate, pH 8.5
  • Example 1-2 3.6 mg / mL Trometamol (30 mM), pH 8.5
  • Example 1-3 3.6 mg / mL Trometamol (30 mM), pH 9.0
  • Example 1-4 1 mg / mL monoethanolamine, pH 8.5
  • Comparative Example 1 In the same manner as in Example 1, 150 mL of Solution A (10 mg / mL eribulin mesylate in ethanol) was prepared. To 10 mL of this solution A, water was added to 200 mL to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 ⁇ m membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
  • Example 1 For each sample of Example 1 and Comparative Example 1 stored at 40 ° C. and 75% RH for 3 months and 6 months, the content of impurity X in the drug substance was measured by liquid chromatography. The ratio of the amount of impurity X after storage when the prescription amount of eribulin mesylate was 100% was determined. The results are shown in Table 1.
  • Example 2 An appropriate amount of water was added to and mixed with 2.5 mL of an ethanol solution of 10 mg / mL eribulin mesylate, 1 mL of a 1 mol / L bicarbonate buffer prepared in advance was added, and an appropriate amount of water was further added. Before measuring up, the pH was adjusted to 9.0 using hydrochloric acid or sodium hydroxide, and water was further added to make a total volume of 50 mL to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 ⁇ m membrane filter, and 2.2 mL was filled in a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap. The final concentration and pH of the pH adjuster (sodium bicarbonate) were as follows. Example 2 1.7 mg / mL Bicarbonate Buffer (20 mM), pH 9.0
  • Example 3 Example 3-1 1952 mg of meglumine and 9.0012 g of sodium chloride were placed in a 1 L volumetric flask, and 900 mL of water was added and dissolved therein. Further, 0.8 mL of hydrochloric acid and 1 mL of 1 mol / L sodium hydroxide solution were added, the pH was adjusted to 9.0, water was added to 1000 mL, and a pH 9.0 meglumine buffer was prepared. Eribulin mesylate 37.0 mg (concentration and moisture correction to give 35 mg as eribulin mesylate) was dissolved in 70.0053 g of pH 9.0 meglumine buffer, 0.5 mg / mL eribulin mesylate It was set as the solution. This solution was filtered using a 0.22 ⁇ m membrane filter, and 2.2 mL was filled in a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
  • Example 3-2 1952 mg of meglumine and 9.0008 g of sodium chloride were placed in a 1 L volumetric flask, and 900 mL of water was added and dissolved therein. Further, 0.25 mL of hydrochloric acid and 1.6 mL of 1 mol / L sodium hydroxide solution were added, the pH was adjusted to 10.0, water was added to 1000 mL, and a pH 10.0 meglumine buffer was prepared. 37.1 mg of eribulin mesylate (amount to be 35 mg as eribulin mesylate after correcting for content and moisture) was dissolved in 69.994 g of pH 10.0 meglumine buffer, and 0.5 mg / mL eribulin mesylate was dissolved. It was set as the solution. This solution was filtered using a 0.22 ⁇ m membrane filter, and 2.2 mL was filled in a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
  • Example 3-1 2.0 mg / mL meglumine buffer, pH 9.0
  • Example 3-2 2.0 mg / mL meglumine buffer, pH 10.0
  • Comparative Example 3 7 mL of ethanol (99.5) was added to 73.2 mg of eribulin mesylate (amount to be 67.5 mg as eribulin mesylate after correcting the content and moisture), and 50.0066 g of water was further added. Further, 85.503 g of water was added to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 ⁇ m membrane filter, and 2.2 mL was filled in a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
  • Example 3 and Comparative Example 3 were stored at 40 ° C. for 84 days and at 60 ° C. for 42 days, and the content of impurity X in the drug substance was measured by liquid chromatography, and eribulin mesyl was measured. The ratio of the area of the amount of impurities X after storage when the prescription amount of the acid salt was 100% was determined. The results are shown in Table 3.
  • Example 4-1 A suspension of 10 mg / mL eribulin mesylate was prepared by adding 100 mL of water to 104.24 mg of eribulin mesylate (amount that would be 1000 mg as eribulin mesylate after correcting the content and moisture). Separately, 2.40933 g of trometamol was dissolved in 1000 mL of water, and hydrochloric acid was added to adjust the pH to 8.5.
  • Example 4-2 A suspension of 10 mg / mL eribulin mesylate was prepared by adding 100 mL of water to 1039.28 mg of eribulin mesylate (amount that would be 1000 mg as eribulin mesylate after correcting the content and moisture). Separately, 7.30058 g of trometamol was dissolved in 1000 mL of water, and hydrochloric acid was added to adjust the pH to 8.5. 85.0113 g of D-sorbitol was dissolved therein, dissolved by adding a suspension of 10 mg / mL eribulin mesylate, and further added with water to 2000 mL to obtain a 0.5 mg / mL eribulin mesylate solution.
  • Example 4-1 1.2 mg / mL trometamol (about 10 mM), pH 8.5
  • Example 4-2 3.65 mg / mL trometamol (about 30 mM), pH 8.5
  • Comparative Example 4 A suspension of 10 mg / mL eribulin mesylate was prepared by adding 100 mL of water to 1041.20 mg of eribulin mesylate (content and moisture corrected to an amount of 1000 mg as eribulin mesylate). Separately, 100.0092 g of D-sorbitol was dissolved in 1000 mL of water, dissolved by adding a suspension of 10 mg / mL eribulin mesylate, and further water was added to 2000 mL to give a 0.5 mg / mL eribulin mesylate solution. It was. This solution was filtered using a 0.22 ⁇ m membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
  • Example 4 For each sample of Example 4 and Comparative Example 4 stored at 40 ° C. and 75% RH for 3 months and 6 months, the content of impurity X in the drug substance was measured by liquid chromatography. The ratio of the amount of impurity X after storage when the prescription amount of eribulin mesylate was 100% was determined. The results are shown in Table 4.
  • Example 5-1 30 ml of water was added to 312.22 mg of eribulin mesylate (the amount and water content were corrected to 300 mg as eribulin mesylate) to prepare a suspension of 10 mg / mL eribulin mesylate.
  • eribulin mesylate the amount and water content were corrected to 300 mg as eribulin mesylate
  • 0.72004 g of trometamol was dissolved in 280 mL of water, and hydrochloric acid for adjusting the pH was further added to adjust the pH to 9.0.
  • 29.10005 g of D-sorbitol was dissolved, a suspension of 10 mg / mL eribulin mesylate was added to dissolve, and water was further added to make 480 mL. This solution was designated as Solution B.
  • Hydrochloric acid was added to 80 mL of Solution B to adjust the pH to 8.0, and the total volume was adjusted to 100 mL with water to obtain a 0.5 mg / mL eribulin mesylate solution.
  • This solution was filtered using a 0.22 ⁇ m membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
  • Example 5-2 In the same manner as in Example 5-1, hydrochloric acid was added to 80 mL of the solution B to adjust the pH to 8.2, and the total amount was adjusted to 100 mL with water to obtain a 0.5 mg / mL eribulin mesylate solution.
  • Example 5-3 In the same manner as in Example 5-1, hydrochloric acid was added to 80 mL of the solution B to adjust the pH to 8.5, and the total volume was adjusted to 100 mL with water to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 ⁇ m membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
  • Example 5-4 In the same manner as in Example 5-1, hydrochloric acid was added to 80 mL of the solution B to adjust the pH to 9.0, and the total amount was adjusted to 100 mL with water to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 ⁇ m membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
  • Example 5-1 1.2 mg / mL trometamol (about 10 mM), pH 8.0
  • Example 5-2 1.2 mg / mL trometamol (about 10 mM), pH 8.2
  • Example 5-3 1.2 mg / mL trometamol (about 10 mM), pH 8.5
  • Example 5-4 1.2 mg / mL trometamol (about 10 mM), pH 9.0
  • Comparative Example 5-1 In the same manner as in Example 5-1, hydrochloric acid was added to 80 mL of the solution B to adjust the pH to 7.5, and the total amount was adjusted to 100 mL with water to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 ⁇ m membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap. Comparative Example 5-2 5 mL of ethanol (99.5) was added and dissolved in 52.18 mg of eribulin mesylate (amount to give 50 mg as eribulin mesylate after correcting the content and moisture).
  • Example 5 For each sample of Example 5 and Comparative Example 5 stored at 40 ° C. and 75% RH for 3 months and 6 months, the content of impurity X in the drug substance was measured by liquid chromatography. The ratio of the amount of impurity X after storage when the prescription amount of eribulin mesylate was 100% was determined. The results are shown in Table 5.

Abstract

Provided is an injection containing: eribulin or a pharmaceutically acceptable salt thereof; and a pH modifier. The pH of the injection is 8.0 to 10.0.

Description

エリブリンまたはその薬剤学的に許容される塩を含む注射剤Injection containing eribulin or a pharmaceutically acceptable salt thereof
　本発明は、エリブリンまたはその薬剤学的に許容される塩を含む注射剤に関する。 The present invention relates to an injection containing eribulin or a pharmaceutically acceptable salt thereof.
　エリブリンメシル酸塩は、手術不能または再発乳癌、および悪性軟部腫瘍の治療剤として知られている（非特許文献１）。
　非特許文献１には、当該治療剤が、エリブリンメシル酸塩、無水エタノール、塩酸および水酸化ナトリウムを含有する無色澄明な注射剤であり、そのｐＨは６．０～９．０の範囲であると記載されている。 Eribulin mesylate is known as a therapeutic agent for inoperable or recurrent breast cancer and malignant soft tissue tumor (Non-patent Document 1).
In Non-Patent Document 1, the therapeutic agent is a colorless and clear injection containing eribulin mesylate, absolute ethanol, hydrochloric acid and sodium hydroxide, and its pH is in the range of 6.0 to 9.0. It is described.
　また、特許文献１には、エリブリンメシル酸塩にクエン酸バッファーおよび塩化ナトリウムを加え、ｐＨ５．５～７．０に調整された製剤が開示されている。 Patent Document 1 discloses a preparation adjusted to pH 5.5 to 7.0 by adding citrate buffer and sodium chloride to eribulin mesylate.
中国特許公開公報第１０５６４０９３５号Chinese Patent Publication No. 105640935
　本発明者らが検討した結果、非特許文献１に開示される製剤を長期保存した場合、製剤内で、不純物である下記式で示される化合物またはその塩（以下、「不純物Ｘ」と称す）が増加していることが判明した。 As a result of investigations by the present inventors, when the preparation disclosed in Non-Patent Document 1 is stored for a long time, the compound represented by the following formula, which is an impurity, or a salt thereof (hereinafter referred to as “impurity X”) in the preparation Turned out to be increasing.
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
　また、特許文献１には、開示される製剤が、不純物Ｘの増加を抑制できるか否かについては開示も示唆もなされてない。 Further, Patent Document 1 neither discloses nor suggests whether or not the disclosed preparation can suppress an increase in impurity X.
　そこで、本発明が解決しようとする課題は、長期保存した後においても、不純物、とりわけ不純物Ｘの発生を抑制する、エリブリンまたはその薬剤学的に許容される塩を含む注射剤を提供することである。 Therefore, the problem to be solved by the present invention is to provide an injection containing eribulin or a pharmaceutically acceptable salt thereof that suppresses the generation of impurities, particularly impurity X, even after long-term storage. is there.
　本発明者らが、鋭意検討した結果、エリブリンまたはその薬剤学的に許容される塩と、ｐＨ調節剤を含み、ｐＨが８．０～１０．０である、注射剤とすることにより、上記課題を解決し、本願発明を完成するに至った。 As a result of intensive studies by the present inventors, the above-mentioned injectable preparation containing eribulin or a pharmaceutically acceptable salt thereof and a pH adjuster and having a pH of 8.0 to 10.0 is described above. The problem has been solved and the present invention has been completed.
すなわち、本発明は以下のとおりである。
（１）
　エリブリンまたはその薬剤学的に許容される塩と、ｐＨ調節剤を含み、ｐＨが８．０～１０．０である、注射剤。
（２）
　ｐＨ調節剤が、クエン酸ナトリウム、酒石酸ナトリウム、グルコン酸ナトリウム、炭酸水素ナトリウム、トロメタモール、モノエタノールアミンおよびメグルミンからなる群から選択される１種又はそれ以上である、（１）記載の注射剤。
（３）
　ｐＨ調節剤が、トロメタモール、酒石酸ナトリウムまたはクエン酸ナトリウムである、（１）記載の注射剤。
（４）
　エリブリンまたはその薬剤学的に許容される塩に対して、重量比で１～８０のｐＨ調節剤を含む、（１）～（３）のいずれかに記載の注射剤。
（５）
　エリブリンまたはその薬剤学的に許容される塩に対して、重量比で２～４０のｐＨ調節剤を含む、（１）～（４）のいずれかに記載の注射剤。
（６）
　エリブリンまたはその薬剤学的に許容される塩が、エリブリンメシル酸塩である、（１）～（５）のいずれかに記載の注射剤。
（７）
　加速試験もしくは長期試験条件下保管後、原薬中の下記式で示される化合物の含有率が、０．４％以下である、エリブリンまたはその薬剤学的に許容される塩を含む注射剤。
Figure JPOXMLDOC01-appb-C000003
 （８）
　含有率が、０．２％以下である、（７）記載の注射剤。
（９）
　エリブリンまたはその薬剤学的に許容される塩が、エリブリンメシル酸塩である、（７）または（８）記載の注射剤。
（１０）
　加速試験もしくは長期試験条件下保管後、原薬中の下記式で示される化合物の含有率が、０．４％以下であり、好ましくは、０．２％以下である、（１）～（６）のいずれかに記載の注射剤。
（１１）
　アルコールを含まないことを特徴とする、（１）～（１０）のいずれかに記載の注射剤。 That is, the present invention is as follows.
(1)
An injectable preparation comprising eribulin or a pharmaceutically acceptable salt thereof and a pH adjuster and having a pH of 8.0 to 10.0.
(2)
The injection according to (1), wherein the pH adjusting agent is one or more selected from the group consisting of sodium citrate, sodium tartrate, sodium gluconate, sodium hydrogen carbonate, trometamol, monoethanolamine and meglumine.
(3)
The injection according to (1), wherein the pH adjusting agent is trometamol, sodium tartrate or sodium citrate.
(4)
The injection according to any one of (1) to (3), comprising a pH adjusting agent in a weight ratio of 1 to 80 with respect to eribulin or a pharmaceutically acceptable salt thereof.
(5)
The injection according to any one of (1) to (4), comprising a pH regulator in a weight ratio of 2 to 40 with respect to eribulin or a pharmaceutically acceptable salt thereof.
(6)
The injection according to any one of (1) to (5), wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.
(7)
An injection containing eribulin or a pharmaceutically acceptable salt thereof in which the content of the compound represented by the following formula in the drug substance is 0.4% or less after storage under accelerated test or long-term test conditions.
Figure JPOXMLDOC01-appb-C000003
 (8)
The injection according to (7), wherein the content is 0.2% or less.
(9)
The injection according to (7) or (8), wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.
(10)
After storage under accelerated test or long-term test conditions, the content of the compound represented by the following formula in the drug substance is 0.4% or less, preferably 0.2% or less. (1) to (6 The injection according to any one of the above.
(11)
The injection according to any one of (1) to (10), which does not contain alcohol.
　本発明の注射剤は、エリブリンまたはその薬剤学的に許容される塩と、ｐＨ調節剤を含み、注射剤のｐＨが８．０～１０．０である。 The injection of the present invention contains eribulin or a pharmaceutically acceptable salt thereof and a pH adjuster, and the pH of the injection is 8.0 to 10.0.
　本発明におけるエリブリンは、非特許文献１に記載されるエリブリンメシル酸塩の活性原体となるフリー体である構造を有する化合物である。
　本発明における、エリブリンの薬剤学的に許容できる塩として、例えば、硫酸塩、硝酸塩、過塩素酸塩、リン酸塩、炭酸塩、重炭酸塩、フッ化水素酸塩、塩酸塩、臭化水素酸塩およびヨウ化水素酸塩などの無機酸塩；酢酸塩、シュウ酸塩、マレイン酸塩、酒石酸塩、フマル酸塩、クエン酸塩、メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩およびカンファースルホン酸塩などの有機酸塩；アスパラギン酸塩およびグルタミン酸塩などのアミノ酸塩；四級アンモニウム塩；ナトリウム塩、カリウム塩、マグネシウム塩およびカルシウム塩などの金属塩等が挙げられるが、好ましくはメシル酸塩である。 The eribulin in the present invention is a compound having a structure that is a free form that is an active substance of eribulin mesylate described in Non-Patent Document 1.
Examples of the pharmaceutically acceptable salt of eribulin in the present invention include sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, hydrofluoride, hydrochloride, and hydrogen bromide. Inorganic acid salts such as acid salts and hydroiodide salts; acetate, oxalate, maleate, tartrate, fumarate, citrate, methanesulfonate, trifluoromethanesulfonate, ethanesulfonic acid Salts, organic salts such as benzenesulfonate, toluenesulfonate and camphorsulfonate; amino acid salts such as aspartate and glutamate; quaternary ammonium salts; sodium, potassium, magnesium and calcium salts, etc. The metal salt is preferably a mesylate.
　本発明における、ｐＨ調節剤は、不純物Ｘの発生を抑え、かつ医薬製剤中のｐＨを調節する機能または緩衝能がある化合物であれば特に限定されないが、例えば、リン酸ナトリウム、酢酸ナトリウム、クエン酸ナトリウム、酒石酸ナトリウム、グルコン酸ナトリウム、炭酸水素ナトリウム、トロメタモール、モノエタノールアミンおよびメグルミン等が挙げられる。
　ｐＨ調節剤としては、好ましくは、トロメタモール、酒石酸ナトリウムまたはクエン酸ナトリウムである。
　ｐＨ調節剤は、１種単独でも、２種以上を使用してもよい。 The pH adjuster in the present invention is not particularly limited as long as it is a compound that suppresses the generation of impurity X and has a function or buffering ability to adjust pH in a pharmaceutical preparation. For example, sodium phosphate, sodium acetate, Examples thereof include sodium acid, sodium tartrate, sodium gluconate, sodium hydrogen carbonate, trometamol, monoethanolamine and meglumine.
The pH adjuster is preferably trometamol, sodium tartrate or sodium citrate.
The pH regulator may be used alone or in combination of two or more.
　本発明におけるｐＨ調節剤は、添付文書やインタビューフォームにおいて成分として記載される態様で本発明の注射剤に含まれていてもよく、また、注射剤中で生成する成分であってもよい。
　注射剤中で生成する成分とは、添付文書やインタビューフォームにおける成分としては注射剤に含まれていないものの、２成分以上の混合により、注射剤中で存在していることになる成分が含まれる。
　例えば、リン酸、酢酸、クエン酸、酒石酸および／またはグルコン酸と、水酸化ナトリウムを注射剤に含む場合、注射剤中で、リン酸ナトリウム、酢酸ナトリウム、クエン酸ナトリウムおよび／またはグルコン酸ナトリウムが生成し、ｐＨ調節剤として機能していると考えらえる。
　リン酸、酢酸、クエン酸、酒石酸および／またはグルコン酸と、水酸化ナトリウムとは、リン酸ナトリウム、酢酸ナトリウム、クエン酸ナトリウムおよび／またはグルコン酸ナトリウムを形成するように、酸とアルカリのモル比で加えられている必要はない。すなわち、酢酸ナトリウムを例示して説明すると、注射剤中に、酢酸と水酸化ナトリウムがモル比で１：１で含む場合、酢酸ナトリウムが生成されると考えることができるが、モル比が１：１である必要はない。注射剤が、酢酸と水酸化ナトリウムとを、任意の割合で含むことにより、注射剤中に、酢酸ナトリウムを含むこととなる。 The pH adjuster in the present invention may be contained in the injection of the present invention in the form described as a component in a package insert or an interview form, or may be a component produced in the injection.
Ingredients generated in injection include components that are present in injections by mixing two or more components, although they are not included in injections as components in package inserts and interview forms .
For example, when phosphoric acid, acetic acid, citric acid, tartaric acid and / or gluconic acid and sodium hydroxide are included in the injection, sodium phosphate, sodium acetate, sodium citrate and / or sodium gluconate are contained in the injection. Produced and functioning as a pH regulator.
Phosphoric acid, acetic acid, citric acid, tartaric acid and / or gluconic acid and sodium hydroxide are the molar ratio of acid to alkali so as to form sodium phosphate, sodium acetate, sodium citrate and / or sodium gluconate There is no need to add it. That is, when sodium acetate is described as an example, it can be considered that sodium acetate is produced when acetic acid and sodium hydroxide are contained at a molar ratio of 1: 1 in the injection, but the molar ratio is 1: It need not be 1. When an injection contains an acetic acid and sodium hydroxide in arbitrary ratios, it will contain sodium acetate in an injection.
　本発明の注射剤は、リポソームを含まないことが好ましい。 The injection of the present invention preferably does not contain liposomes.
　本発明における、ｐＨ調節剤の含有量は特に限定されるものではなく、注射剤においてｐＨが８．０～１０．０の範囲内となる含有量であればよい。
　ｐＨ調節剤の含有量は、エリブリンまたはその薬剤学的に許容される塩の含有量を１とした場合に、重量比で、好ましくは１～８０であり、より好ましくは２～４０である。 In the present invention, the content of the pH adjusting agent is not particularly limited, and may be any content as long as the pH in the injection is within the range of 8.0 to 10.0.
The content of the pH adjuster is preferably 1 to 80, more preferably 2 to 40 in terms of weight ratio when the content of eribulin or a pharmaceutically acceptable salt thereof is 1.
　本発明にかかる注射剤は、塩酸などの酸や、水酸化ナトリウムなどの塩基を用いて、ｐＨが８．０～１０．０の範囲内に調整されてもよい。ｐＨが８．０未満では、長期保管後、不純物Ｘの増加が大きく、ｐＨが１０．０より大きいと、エリブリンまたはその薬剤学的に許容される塩の溶解性が下がり溶けにくくなるためである。注射剤のｐＨは、好ましくは８．０～９．０、より好ましくは８．５～９．０である。
　注射剤のｐＨは、ｐＨ測定器を用いて測定することができる。 The injection according to the present invention may be adjusted to a pH within the range of 8.0 to 10.0 using an acid such as hydrochloric acid or a base such as sodium hydroxide. When the pH is less than 8.0, the increase of the impurity X is large after long-term storage, and when the pH is more than 10.0, the solubility of eribulin or a pharmaceutically acceptable salt thereof is lowered and is difficult to dissolve. . The pH of the injection is preferably 8.0 to 9.0, more preferably 8.5 to 9.0.
The pH of the injection can be measured using a pH meter.
　本願発明においては、加速試験もしくは長期保存試験条件下保管後、原薬中の不純物Ｘの含有率が、０．４％以下である、エリブリンまたはその薬剤学的に許容される塩を含む注射剤をも提供する。
　不純物Ｘの含有率は、好ましくは、０．２％以下である。 In the present invention, an injection containing eribulin or a pharmaceutically acceptable salt thereof in which the content of impurity X in the drug substance is 0.4% or less after storage under accelerated test or long-term storage test conditions Also provide.
The content of the impurity X is preferably 0.2% or less.
　本発明において、加速試験とは、４０±２℃、７５±５％ＲＨの条件で、６か月行われる試験であることを意味し、長期保存試験とは、２５±２℃、６０±５％ＲＨの条件で、最低３年以上行われる試験であることを意味する。 In the present invention, the accelerated test means that the test is conducted for 6 months under the conditions of 40 ± 2 ° C. and 75 ± 5% RH, and the long-term storage test is 25 ± 2 ° C., 60 ± 5. It means that the test is conducted for at least 3 years under the condition of% RH.
　本発明の注射剤は、日本薬局方第１６改正製剤総則に従い、適宜調製され、本発明の目的を達成する限り、必要に応じて他の添加剤を含んでもよい。例えば、ｐＨを所定の数値に調整するために、塩酸などの酸や、水酸化ナトリウムなどの塩基を適宜加えてもよい。 The injection of the present invention is appropriately prepared in accordance with the Japanese Pharmacopoeia 16th revised formulation general rules, and may contain other additives as necessary as long as the object of the present invention is achieved. For example, an acid such as hydrochloric acid or a base such as sodium hydroxide may be added as appropriate in order to adjust the pH to a predetermined value.
　本発明の注射剤は、メタノール、エタノールおよび／またはイソプロパノールなどのアルコールを含まなくてもよく、好ましくは、炭素数１～４のアルコールを含まなくてもよく、より好ましくは、炭素数１～３のアルコールを含まなくてもよく、さらに好ましくは、エタノールおよび／またはイソプロパノールを含まない。本発明の注射剤は、好ましくは、エタノールを含まない。 The injection of the present invention may not contain an alcohol such as methanol, ethanol and / or isopropanol, preferably does not contain an alcohol having 1 to 4 carbon atoms, and more preferably has 1 to 3 carbon atoms. Of alcohol, and more preferably ethanol and / or isopropanol. The injection of the present invention preferably does not contain ethanol.
　本発明を、実施例を用いてさらに具体的に説明するが、これらの実施例は例示的なものであって、本発明は、これらの実施例のみに限定されるものではない。 The present invention will be described more specifically with reference to examples. However, these examples are illustrative, and the present invention is not limited only to these examples.
実施例１
　エリブリンメシル酸塩１５７３．４ｍｇ（含量及び水分補正を行いエリブリンメシル酸塩として１５００ｍｇとなる量）に、エタノール（９９．５）を加えて溶解し、１５０ｍＬの溶液Ａ（１０ｍｇ／ｍＬエリブリンメシル酸塩のエタノール溶液）を調製した。この溶液Ａ　１０ｍＬに、ｐＨ調節剤を溶解した水溶液を加え、さらにｐＨを調整するための水酸化ナトリウムまたは塩酸を加えて２００ｍＬとし、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。
　ｐＨ調節剤の最終濃度とｐＨは、以下の通りであった。
実施例１－１　２０ｍｇ／ｍＬ　クエン酸ナトリウム，ｐＨ８．５
実施例１－２　３．６ｍｇ／ｍＬ　トロメタモール（３０ｍＭ），ｐＨ８．５
実施例１－３　３．６ｍｇ／ｍＬ　トロメタモール（３０ｍＭ），ｐＨ９．０
実施例１－４　１ｍｇ／ｍＬ　モノエタノールアミン，ｐＨ８．５ Example 1
To 1573.4 mg of eribulin mesylate (amount to be 1500 mg as eribulin mesylate after correcting the content and moisture), ethanol (99.5) was added and dissolved, and 150 mL of solution A (10 mg / mL eribulin mesylate) Of ethanol solution) was prepared. An aqueous solution in which a pH adjusting agent was dissolved was added to 10 mL of this solution A, and sodium hydroxide or hydrochloric acid for adjusting the pH was further added to make 200 mL to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 μm membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
The final concentration and pH of the pH regulator were as follows:
Example 1-1 20 mg / mL Sodium Citrate, pH 8.5
Example 1-2 3.6 mg / mL Trometamol (30 mM), pH 8.5
Example 1-3 3.6 mg / mL Trometamol (30 mM), pH 9.0
Example 1-4 1 mg / mL monoethanolamine, pH 8.5
比較例１
　実施例１と同様にして、１５０ｍＬの溶液Ａ（１０ｍｇ／ｍＬエリブリンメシル酸塩のエタノール溶液）を調製した。この溶液Ａ　１０ｍＬに、水を加えて２００ｍＬとし、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。 Comparative Example 1
In the same manner as in Example 1, 150 mL of Solution A (10 mg / mL eribulin mesylate in ethanol) was prepared. To 10 mL of this solution A, water was added to 200 mL to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 μm membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
　実施例１及び比較例１の各検体を４０℃、７５％ＲＨの条件で３箇月間及び６箇月間保管したものにつき、原薬中の不純物Ｘの含有率として、液体クロマトグラフィーにより測定して、エリブリンメシル酸塩の処方量を１００％としたときの保管後の不純物Ｘ量の割合を求めた。結果を表１に示す。 For each sample of Example 1 and Comparative Example 1 stored at 40 ° C. and 75% RH for 3 months and 6 months, the content of impurity X in the drug substance was measured by liquid chromatography. The ratio of the amount of impurity X after storage when the prescription amount of eribulin mesylate was 100% was determined. The results are shown in Table 1.
表１
Figure JPOXMLDOC01-appb-T000004
 Table 1
Figure JPOXMLDOC01-appb-T000004
実施例２
　１０ｍｇ／ｍＬエリブリンメシル酸塩のエタノール溶液２．５ｍＬに、適量の水を加え混和したのち、予め調製した１ｍｏｌ／Ｌの重炭酸緩衝液１ｍＬを添加し、さらに適量の水を加えた。メスアップ前に塩酸または水酸化ナトリウムを用いてｐＨ９．０に調整し、さらに水を加えて全量５０ｍＬとし、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２．２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。
　ｐＨ調節剤（炭酸水素ナトリウム）の最終濃度とｐＨは、以下の通りであった。
実施例２　１．７ｍｇ／ｍＬ　重炭酸緩衝液（２０ｍＭ），ｐＨ９．０ Example 2
An appropriate amount of water was added to and mixed with 2.5 mL of an ethanol solution of 10 mg / mL eribulin mesylate, 1 mL of a 1 mol / L bicarbonate buffer prepared in advance was added, and an appropriate amount of water was further added. Before measuring up, the pH was adjusted to 9.0 using hydrochloric acid or sodium hydroxide, and water was further added to make a total volume of 50 mL to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 μm membrane filter, and 2.2 mL was filled in a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
The final concentration and pH of the pH adjuster (sodium bicarbonate) were as follows.
Example 2 1.7 mg / mL Bicarbonate Buffer (20 mM), pH 9.0
比較例２
　エリブリンメシル酸塩３９．１４ｍｇ（含量及び水分補正を行いエリブリンメシル酸塩として３７．５ｍｇとなる量）をエタノール（９９．５）３．７５ｍＬに溶解し、水を加えて全量７５ｇとし、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２．２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。
　実施例２及び比較例２を４０℃、７５％ＲＨの条件で３箇月間及び６箇月間保管したものにつき、原薬中の不純物Ｘの含有率として、液体クロマトグラフィーにより測定して、エリブリンメシル酸塩の処方量を１００％としたときの保管後の不純物Ｘ量の面積の割合を求めた。結果を表２に示す。 Comparative Example 2
Eribulin mesylate 39.14 mg (adjusted for content and moisture to give 37.5 mg as eribulin mesylate) was dissolved in 3.75 mL of ethanol (99.5), and water was added to make a total amount of 75 g. A 5 mg / mL eribulin mesylate solution was prepared. This solution was filtered using a 0.22 μm membrane filter, and 2.2 mL was filled in a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
Example 2 and Comparative Example 2 were stored for 3 months and 6 months under the conditions of 40 ° C. and 75% RH, and the content of impurity X in the drug substance was measured by liquid chromatography to determine eribulin mesyl. The ratio of the area of the amount of impurities X after storage when the prescription amount of the acid salt was 100% was determined. The results are shown in Table 2.
表２
Figure JPOXMLDOC01-appb-T000005
 Table 2
Figure JPOXMLDOC01-appb-T000005
実施例３
実施例３－１
　メグルミン１９５２ｍｇと塩化ナトリウム９．００１２ｇを１Ｌのメスフラスコに入れ、そこに９００ｍＬの水を入れ溶解した。さらに塩酸０．８ｍＬと１ｍｏｌ／Ｌの水酸化ナトリウム溶液１ｍＬを入れ、ｐＨを９．０に調整し、水を加えて１０００ｍＬとし、ｐＨ９．０のメグルミン緩衝液とした。エリブリンメシル酸塩３７．０ｍｇ（含量及び水分補正を行いエリブリンメシル酸塩として３５ｍｇとなる量）を、ｐＨ９．０のメグルミン緩衝液７０．００５３ｇに溶解し、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２．２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。 Example 3
Example 3-1
1952 mg of meglumine and 9.0012 g of sodium chloride were placed in a 1 L volumetric flask, and 900 mL of water was added and dissolved therein. Further, 0.8 mL of hydrochloric acid and 1 mL of 1 mol / L sodium hydroxide solution were added, the pH was adjusted to 9.0, water was added to 1000 mL, and a pH 9.0 meglumine buffer was prepared. Eribulin mesylate 37.0 mg (concentration and moisture correction to give 35 mg as eribulin mesylate) was dissolved in 70.0053 g of pH 9.0 meglumine buffer, 0.5 mg / mL eribulin mesylate It was set as the solution. This solution was filtered using a 0.22 μm membrane filter, and 2.2 mL was filled in a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
実施例３－２
　メグルミン１９５２ｍｇと塩化ナトリウム９．０００８ｇを１Ｌのメスフラスコに入れ、そこに９００ｍＬの水を入れ溶解した。さらに塩酸０．２５ｍＬと１ｍｏｌ／Ｌの水酸化ナトリウム溶液１．６ｍＬを入れ、ｐＨを１０．０に調整し、水を加えて１０００ｍＬとし、ｐＨ１０．０のメグルミン緩衝液とした。エリブリンメシル酸塩３７．１ｍｇ（含量及び水分補正を行いエリブリンメシル酸塩として３５ｍｇとなる量）を、ｐＨ１０．０のメグルミン緩衝液６９．９９９４ｇに溶解し、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２．２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。 Example 3-2
1952 mg of meglumine and 9.0008 g of sodium chloride were placed in a 1 L volumetric flask, and 900 mL of water was added and dissolved therein. Further, 0.25 mL of hydrochloric acid and 1.6 mL of 1 mol / L sodium hydroxide solution were added, the pH was adjusted to 10.0, water was added to 1000 mL, and a pH 10.0 meglumine buffer was prepared. 37.1 mg of eribulin mesylate (amount to be 35 mg as eribulin mesylate after correcting for content and moisture) was dissolved in 69.994 g of pH 10.0 meglumine buffer, and 0.5 mg / mL eribulin mesylate was dissolved. It was set as the solution. This solution was filtered using a 0.22 μm membrane filter, and 2.2 mL was filled in a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
　添加物の最終濃度とｐＨは、以下の通りであった。
実施例３－１　２．０ｍｇ／ｍＬ　メグルミン緩衝液，ｐＨ９．０
実施例３－２　２．０ｍｇ／ｍＬ　メグルミン緩衝液，ｐＨ１０．０ The final concentration and pH of the additive were as follows:
Example 3-1 2.0 mg / mL meglumine buffer, pH 9.0
Example 3-2 2.0 mg / mL meglumine buffer, pH 10.0
比較例３
　エリブリンメシル酸塩７３．２ｍｇ（含量及び水分補正を行いエリブリンメシル酸塩として６７．５ｍｇとなる量）にエタノール（９９．５）７ｍＬを加え溶解し、更に水を５０．００６６ｇ添加した。更に水８５．５０３ｇを加えて０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２．２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。 Comparative Example 3
7 mL of ethanol (99.5) was added to 73.2 mg of eribulin mesylate (amount to be 67.5 mg as eribulin mesylate after correcting the content and moisture), and 50.0066 g of water was further added. Further, 85.503 g of water was added to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 μm membrane filter, and 2.2 mL was filled in a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
　実施例３及び比較例３の各検体を４０℃にて８４日間、６０℃にて４２日間保管したものにつき、原薬中の不純物Ｘの含有率として、液体クロマトグラフィーにより測定して、エリブリンメシル酸塩の処方量を１００％としたときの保管後の不純物Ｘ量の面積の割合を求めた。結果を表３に示す。 The samples of Example 3 and Comparative Example 3 were stored at 40 ° C. for 84 days and at 60 ° C. for 42 days, and the content of impurity X in the drug substance was measured by liquid chromatography, and eribulin mesyl was measured. The ratio of the area of the amount of impurities X after storage when the prescription amount of the acid salt was 100% was determined. The results are shown in Table 3.
表３
Figure JPOXMLDOC01-appb-T000006
 Table 3
Figure JPOXMLDOC01-appb-T000006
実施例４－１
　エリブリンメシル酸塩１０４１．２４ｍｇ（含量及び水分補正を行いエリブリンメシル酸塩として１０００ｍｇとなる量）に、１００ｍＬの水を加え１０ｍｇ／ｍＬエリブリンメシル酸塩の懸濁液を調製した。別に水１０００ｍＬにトロメタモール２．４０９３３ｇを溶解し、さらにｐＨを調整するための塩酸を加えてｐＨ８．５とした。そこへＤ－ソルビトール９７．００１６ｇを溶解し、１０ｍｇ／ｍＬエリブリンメシル酸塩の懸濁液を加えて溶解し、さらに水を加えて２０００ｍＬとし、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。
実施例４－２
　エリブリンメシル酸塩１０３９．２８ｍｇ（含量及び水分補正を行いエリブリンメシル酸塩として１０００ｍｇとなる量）に、１００ｍＬの水を加え１０ｍｇ／ｍＬエリブリンメシル酸塩の懸濁液を調製した。別に水１０００ｍＬにトロメタモール７．３００５８ｇを溶解し、さらにｐＨを調整するための塩酸を加えてｐＨ８．５とした。そこへＤ－ソルビトール８５．０１１３ｇを溶解し、１０ｍｇ／ｍＬエリブリンメシル酸塩の懸濁液を加えて溶解し、さらに水を加えて２０００ｍＬとし、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。
　ｐＨ調節剤の最終濃度とｐＨは、以下の通りであった。
実施例４－１　１．２ｍｇ／ｍＬ　トロメタモール（約１０ｍＭ），ｐＨ８．５
実施例４－２　３．６５ｍｇ／ｍＬ　トロメタモール（約３０ｍＭ），ｐＨ８．５ Example 4-1
A suspension of 10 mg / mL eribulin mesylate was prepared by adding 100 mL of water to 104.24 mg of eribulin mesylate (amount that would be 1000 mg as eribulin mesylate after correcting the content and moisture). Separately, 2.40933 g of trometamol was dissolved in 1000 mL of water, and hydrochloric acid was added to adjust the pH to 8.5. 97.0016 g of D-sorbitol was dissolved therein, dissolved by adding a suspension of 10 mg / mL eribulin mesylate, and further added with water to 2000 mL to obtain a 0.5 mg / mL eribulin mesylate solution. . This solution was filtered using a 0.22 μm membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
Example 4-2
A suspension of 10 mg / mL eribulin mesylate was prepared by adding 100 mL of water to 1039.28 mg of eribulin mesylate (amount that would be 1000 mg as eribulin mesylate after correcting the content and moisture). Separately, 7.30058 g of trometamol was dissolved in 1000 mL of water, and hydrochloric acid was added to adjust the pH to 8.5. 85.0113 g of D-sorbitol was dissolved therein, dissolved by adding a suspension of 10 mg / mL eribulin mesylate, and further added with water to 2000 mL to obtain a 0.5 mg / mL eribulin mesylate solution. . This solution was filtered using a 0.22 μm membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
The final concentration and pH of the pH regulator were as follows:
Example 4-1 1.2 mg / mL trometamol (about 10 mM), pH 8.5
Example 4-2 3.65 mg / mL trometamol (about 30 mM), pH 8.5
比較例４
　エリブリンメシル酸塩１０４１．２０ｍｇ（含量及び水分補正を行いエリブリンメシル酸塩として１０００ｍｇとなる量）に、１００ｍＬの水を加え１０ｍｇ／ｍＬエリブリンメシル酸塩の懸濁液を調製した。別に水１０００ｍＬにＤ－ソルビトール１００．００９２ｇを溶解し、１０ｍｇ／ｍＬエリブリンメシル酸塩の懸濁液を加えて溶解し、さらに水を加えて２０００ｍＬとし、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。 Comparative Example 4
A suspension of 10 mg / mL eribulin mesylate was prepared by adding 100 mL of water to 1041.20 mg of eribulin mesylate (content and moisture corrected to an amount of 1000 mg as eribulin mesylate). Separately, 100.0092 g of D-sorbitol was dissolved in 1000 mL of water, dissolved by adding a suspension of 10 mg / mL eribulin mesylate, and further water was added to 2000 mL to give a 0.5 mg / mL eribulin mesylate solution. It was. This solution was filtered using a 0.22 μm membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
　実施例４及び比較例４の各検体を４０℃、７５％ＲＨの条件で３箇月間及び６箇月間保管したものにつき、原薬中の不純物Ｘの含有率として、液体クロマトグラフィーにより測定して、エリブリンメシル酸塩の処方量を１００％としたときの保管後の不純物Ｘ量の割合を求めた。結果を表４に示す。 For each sample of Example 4 and Comparative Example 4 stored at 40 ° C. and 75% RH for 3 months and 6 months, the content of impurity X in the drug substance was measured by liquid chromatography. The ratio of the amount of impurity X after storage when the prescription amount of eribulin mesylate was 100% was determined. The results are shown in Table 4.
表４
Figure JPOXMLDOC01-appb-T000007
 Table 4
Figure JPOXMLDOC01-appb-T000007
実施例５－１
　エリブリンメシル酸塩３１２．２２ｍｇ（含量及び水分補正を行いエリブリンメシル酸塩として３００ｍｇとなる量）に、３０ｍＬの水を加え１０ｍｇ／ｍＬエリブリンメシル酸塩の懸濁液を調製した。別に水２８０ｍＬにトロメタモール０．７２００４ｇを溶解し、さらにｐＨを調整するための塩酸を加えてｐＨ９．０とした。そこへＤ－ソルビトール２９．１０００５ｇを溶解し、１０ｍｇ／ｍＬエリブリンメシル酸塩の懸濁液を加えて溶解し、さらに水を加えて４８０ｍＬとした。この液を溶液Ｂとした。溶液Ｂ　８０ｍＬに塩酸を加えてｐＨ８．０とし全量を水で１００ｍＬとし、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。
実施例５－２
　実施例５－１と同様にして、溶液Ｂ　８０ｍＬに塩酸を加えてｐＨ８．２とし全量を水で１００ｍＬとし、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。
実施例５－３
　実施例５－１と同様にして、溶液Ｂ　８０ｍＬに塩酸を加えてｐＨ８．５とし全量を水で１００ｍＬとし、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。
実施例５－４
　実施例５－１と同様にして、溶液Ｂ　８０ｍＬに塩酸を加えてｐＨ９．０とし全量を水で１００ｍＬとし、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。
　ｐＨ調節剤の最終濃度とｐＨは、以下の通りであった。
実施例５－１　１．２ｍｇ／ｍＬ　トロメタモール（約１０ｍＭ），ｐＨ８．０
実施例５－２　１．２ｍｇ／ｍＬ　トロメタモール（約１０ｍＭ），ｐＨ８．２
実施例５－３　１．２ｍｇ／ｍＬ　トロメタモール（約１０ｍＭ），ｐＨ８．５
実施例５－４　１．２ｍｇ／ｍＬ　トロメタモール（約１０ｍＭ），ｐＨ９．０ Example 5-1
30 ml of water was added to 312.22 mg of eribulin mesylate (the amount and water content were corrected to 300 mg as eribulin mesylate) to prepare a suspension of 10 mg / mL eribulin mesylate. Separately, 0.72004 g of trometamol was dissolved in 280 mL of water, and hydrochloric acid for adjusting the pH was further added to adjust the pH to 9.0. Thereto, 29.10005 g of D-sorbitol was dissolved, a suspension of 10 mg / mL eribulin mesylate was added to dissolve, and water was further added to make 480 mL. This solution was designated as Solution B. Hydrochloric acid was added to 80 mL of Solution B to adjust the pH to 8.0, and the total volume was adjusted to 100 mL with water to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 μm membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
Example 5-2
In the same manner as in Example 5-1, hydrochloric acid was added to 80 mL of the solution B to adjust the pH to 8.2, and the total amount was adjusted to 100 mL with water to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 μm membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
Example 5-3
In the same manner as in Example 5-1, hydrochloric acid was added to 80 mL of the solution B to adjust the pH to 8.5, and the total volume was adjusted to 100 mL with water to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 μm membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
Example 5-4
In the same manner as in Example 5-1, hydrochloric acid was added to 80 mL of the solution B to adjust the pH to 9.0, and the total amount was adjusted to 100 mL with water to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 μm membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
The final concentration and pH of the pH regulator were as follows:
Example 5-1 1.2 mg / mL trometamol (about 10 mM), pH 8.0
Example 5-2 1.2 mg / mL trometamol (about 10 mM), pH 8.2
Example 5-3 1.2 mg / mL trometamol (about 10 mM), pH 8.5
Example 5-4 1.2 mg / mL trometamol (about 10 mM), pH 9.0
比較例５－１
　実施例５－１と同様にして、溶液Ｂ　８０ｍＬに塩酸を加えてｐＨ７．５とし全量を水で１００ｍＬとし、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。
比較例５－２
　エリブリンメシル酸塩５２．１８ｍｇ（含量及び水分補正を行いエリブリンメシル酸塩として５０ｍｇとなる量）に、エタノール（９９．５）５ｍＬを加え溶解した。さらに水を加えて全量を１００ｍＬとし、０．５ｍｇ／ｍＬのエリブリンメシル酸塩溶液とした。この液を０．２２μｍメンブランフィルターを用いてろ過し、５ｍＬガラスバイアルに２ｍＬ充てんした。充てんされたガラスバイアルにゴム栓をした後、さらにアルミキャップを被せた。 Comparative Example 5-1
In the same manner as in Example 5-1, hydrochloric acid was added to 80 mL of the solution B to adjust the pH to 7.5, and the total amount was adjusted to 100 mL with water to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 μm membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
Comparative Example 5-2
5 mL of ethanol (99.5) was added and dissolved in 52.18 mg of eribulin mesylate (amount to give 50 mg as eribulin mesylate after correcting the content and moisture). Further, water was added to make a total volume of 100 mL to obtain a 0.5 mg / mL eribulin mesylate solution. This solution was filtered using a 0.22 μm membrane filter, and 2 mL was filled into a 5 mL glass vial. The filled glass vial was sealed with a rubber stopper and then covered with an aluminum cap.
　実施例５及び比較例５の各検体を４０℃、７５％ＲＨの条件で３箇月間及び６箇月間保管したものにつき、原薬中の不純物Ｘの含有率として、液体クロマトグラフィーにより測定して、エリブリンメシル酸塩の処方量を１００％としたときの保管後の不純物Ｘ量の割合を求めた。結果を表５に示す。 For each sample of Example 5 and Comparative Example 5 stored at 40 ° C. and 75% RH for 3 months and 6 months, the content of impurity X in the drug substance was measured by liquid chromatography. The ratio of the amount of impurity X after storage when the prescription amount of eribulin mesylate was 100% was determined. The results are shown in Table 5.
表５
Figure JPOXMLDOC01-appb-T000008
  
 
  Table 5
Figure JPOXMLDOC01-appb-T000008

Claims (10)

  1. 　エリブリンまたはその薬剤学的に許容される塩と、ｐＨ調節剤を含み、ｐＨが８．０～１０．０である、注射剤。 An injection containing eribulin or a pharmaceutically acceptable salt thereof and a pH adjusting agent, and having a pH of 8.0 to 10.0.
  2. 　ｐＨ調節剤が、クエン酸ナトリウム、酒石酸ナトリウム、グルコン酸ナトリウム、炭酸水素ナトリウム、トロメタモール、モノエタノールアミンおよびメグルミンからなる群から選択される１種又はそれ以上である、請求項１記載の注射剤。 The injection according to claim 1, wherein the pH adjuster is one or more selected from the group consisting of sodium citrate, sodium tartrate, sodium gluconate, sodium bicarbonate, trometamol, monoethanolamine and meglumine.
  3. 　ｐＨ調節剤が、トロメタモール、酒石酸ナトリウムまたはクエン酸ナトリウムである、請求項１記載の注射剤。 The injection according to claim 1, wherein the pH adjusting agent is trometamol, sodium tartrate or sodium citrate.
  4. 　エリブリンまたはその薬剤学的に許容される塩に対して、重量比で１～８０のｐＨ調節剤を含む、請求項１～３のいずれか１項に記載の注射剤。 The injection according to any one of claims 1 to 3, comprising a pH adjusting agent having a weight ratio of 1 to 80 with respect to eribulin or a pharmaceutically acceptable salt thereof.
  5. 　エリブリンまたはその薬剤学的に許容される塩に対して、重量比で２～４０のｐＨ調節剤を含む、請求項１～４のいずれか１項に記載の注射剤。 The injection according to any one of claims 1 to 4, comprising a pH adjuster having a weight ratio of 2 to 40 with respect to eribulin or a pharmaceutically acceptable salt thereof.
  6. 　エリブリンまたはその薬剤学的に許容される塩が、エリブリンメシル酸塩である、請求項１～５のいずれか１項に記載の注射剤。 The injection according to any one of claims 1 to 5, wherein the eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.
  7. 　加速試験もしくは長期試験条件下保管後、原薬中の下記式で示される化合物の含有率が、０．４％以下である、エリブリンまたはその薬剤学的に許容される塩を含む注射剤。
    Figure JPOXMLDOC01-appb-C000001
         An injection containing eribulin or a pharmaceutically acceptable salt thereof in which the content of the compound represented by the following formula in the drug substance is 0.4% or less after storage under accelerated test or long-term test conditions.
    Figure JPOXMLDOC01-appb-C000001
  8. 　含有率が、０．２％以下である、請求項７記載の注射剤。 The injection according to claim 7, wherein the content is 0.2% or less.
  9. 　エリブリンまたはその薬剤学的に許容される塩が、エリブリンメシル酸塩である、請求項７または８記載の注射剤。 The injection according to claim 7 or 8, wherein the eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.
  10. 　アルコールを含まないことを特徴とする、請求項１～９のいずれか１項に記載の注射剤。 The injection according to any one of claims 1 to 9, which does not contain alcohol.
PCT/JP2018/020456 2017-05-31 2018-05-29 Injection containing eribulin and pharmaceutically acceptable salt thereof WO2018221487A1 (en)

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Publication number Priority date Publication date Assignee Title
WO2021200823A1 (en) * 2020-03-31 2021-10-07 ニプロ株式会社 Eribulin-containing parenteral pharmaceutical solution
WO2022248361A1 (en) * 2021-05-26 2022-12-01 Almirall, S.A. Pharmaceutical composition comprising a centella asiatica extract

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