JP6980665B2 - Pemetrexed preparation - Google Patents

Description

The present invention relates to a composition (pharmaceutical composition) containing pemetrexed.

Pemetrexed is a folic acid metabolism antagonist, and as a pharmaceutical product, "Alimta injection preparation" (100 mg and 500 mg preparations) is commercially available from Eli Lilly Japan K.K. for use as an anticancer drug.
Alimta injectable formulations require a lysis procedure for use, which increases the risk of exposure to the anti-cancer drug to healthcare professionals. Therefore, it is desired to make pemetrexed into a liquid.

However, an isotonic physiological saline solution containing pemetrexed forms a related substance derived from pemetrexed by decomposing pemetrexed, which causes a problem that is not pharmaceutically acceptable. Further, in the aqueous solution in which pemetrexed is dissolved, the change in properties due to coloring is also a problem.

Under these circumstances, the development of a pemetrexed preparation stable in an aqueous solution is desired, and several formulations have been reported.
For example, Japanese Patent Application Laid-Open No. 2003-521518 (Patent Document 1) describes pemetrexto, at least one antioxidant selected from the group consisting of monothioglycerol, L-cysteine, and thioglycolic acid, and pharmaceutically acceptable. Pharmaceutical compositions containing possible excipients are disclosed.

Further, in Japanese Patent Application Laid-Open No. 2013-540104 (Patent Document 2), an anti-antioxidant selected from the group consisting of a) pemetrexed or a pharmaceutically acceptable salt thereof, b) lipoic acid, dihydrolipoic acid, methionine and a mixture thereof. A pharmaceutical composition comprising an oxidizing agent, c) a chelating agent selected from the group consisting of lactobionic acid, trisodium citrate, and a mixture thereof, and d) a pharmaceutically acceptable fluid having a specific pH. The thing is disclosed.

Further, Japanese Patent Application Laid-Open No. 2014-237607 (Patent Document 3) describes a liquid composition for injection containing pemetrexed and an antioxidant, wherein the antioxidants are ethylenediaminetetraacetic acid disodium and citric acid. , And a composition comprising at least one compound selected from the group consisting of ascorbic acid. This document describes that the antioxidant may further contain at least one compound selected from the group consisting of cysteine hydrochloride, thioglycolic acid, alpha thioglycerin, citric acid in the examples. And formulations containing cysteine hydrochloride are disclosed.

However, even with the formulations described in these documents, sufficient stability may not be obtained, and the development of further excellent formulations is desired.

Japanese Patent Publication No. 2003-521518 (Claims) Japanese Patent Application Laid-Open No. 2013-540104 (Claims) Japanese Unexamined Patent Publication No. 2014-237607 (Claims, Examples)

An object of the present invention is to provide a novel pemetrexed composition (pemetrexed preparation) having excellent stability.
Another object of the present invention is to provide a pemetrexed composition capable of achieving both suppression of coloring and excellent stability.

As a result of diligent research, the present inventors have obtained a pemetrexed preparation having excellent stability by combining at least two specific components (that is, ascorbic acids and thioglycerols) with respect to pemetrexeds. In addition, even though such a pemetrexed preparation contains pemetrexed, which is easily colored, as an active ingredient, it has been found that it does not have extreme coloring and can achieve both suppression of coloring and excellent stability, and further studies have been conducted. , The present invention has been completed.

That is, the composition (or preparation or pharmaceutical composition) of the present invention contains pemetrexeds, ascorbic acids and thioglycerols.

In such a composition, the ratio of ascorbic acids and thioglycerols may be, for example, the former / the latter (weight ratio) = 1 / 0.1 to 1/10.

Further, in the composition of the present invention, even if the ratio of ascorbic acids is about 0.1 to 10 parts by weight and the ratio of thioglycerols is about 0.3 to 20 parts by weight with respect to 100 parts by weight of pemetrexeds. good.

The composition of the present invention may be a liquid preparation having a pH of about 5 to 9.

A typical composition of the present invention contains pemetrexeds at a concentration of 5 to 80 mg / mL, ascorbic acids at a concentration of 0.15 to 3 mg / mL, thioglycerols at a concentration of 0.2 to 5 mg / mL, and the ascorbic acids. The ratio with the thioglycerols is the former / the latter (weight ratio) = 1 / 0.3 to 1/5 (for example, 1/1 to 1/5), and a liquid agent having a pH of 6 to 8 is included.

In particular, the composition of the present invention may be an injection containing an aqueous solvent as a solvent component.

The composition of the present invention is excellent in stability, and for example, the ratio of related substances when stored at 60 ° C. for 1 week may be 1% or less.

The present invention includes a container (or pharmaceutical product) containing (or hermetically sealed) the composition. In such a container, the voids in the container may be filled with an inert gas. Further, in the container of the present invention, the oxygen concentration with respect to the entire volume inside the container may be 2.5% by volume or less.
In addition, the present invention also treats (or improves) a method of administering the composition and cancer (malignant pleural mesothelioma, non-small cell lung cancer, etc.) using the composition (administering the composition). ) Is also included. The form of administration may be injection (intravenous drip infusion).

According to the present invention, by combining pemetrexeds and a specific component, a stabilized pemetrexed preparation with less production (by-product) of related substances can be obtained. In addition, the pemetrexed preparation of the present invention can achieve both suppression of coloring and excellent stability.

Therefore, according to the present invention, it is possible to efficiently obtain a stable pemetrexed preparation that does not impair the appearance and quality even after long-term storage.

The composition of the present invention (pemetrexed composition, pemetrexed preparation, pharmaceutical composition) contains pemetrexeds, ascorbic acids and thioglycerols.

[Pemetrexeds]
Pemetrexeds include pemetrexed, salts of pemetrexed (particularly pharmacologically acceptable salts), hydrates thereof and the like.
The formula for pemetrexed is as follows.

で表される構造を有し、化学名は、Ｎ−｛４−［２−（２−アミノ−４，７−ジヒドロ−４−オキソ−１Ｈ−ピロロ［２，３−ｄ］ピリミジン−５−イル）エチル］ベンゾイル｝−Ｌ−グルタミン酸である。

It has a structure represented by N- {4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidine-5-). Il) ethyl] benzoyl} -L-glutamic acid.

In addition, pemetrexed may be in the form of liberated acid or base.

The salt is not particularly limited, and is, for example, a metal salt [for example, an alkali metal salt (for example, lithium salt, sodium salt, potassium salt, etc.), an alkaline earth metal salt (for example, magnesium salt, calcium salt, etc.), a periodic table. Group 13 metal salts (eg, aluminum salts), transition metal salts (eg, salts of zinc, iron, cobalt, copper, etc.), ammonium salts, amine salts [eg, alkylamine salts (eg, trimethylamine salts, triethylamine) Trialkylamine salt of salt), alkanolamine salt (eg, monoethanolamine salt, triethanolamine salt), cyclic amine salt (eg, pyridine salt, substituted pyridine salt)], amino acid salt (eg, histidine, arginine, etc.) And salt) and so on. The salt may be a single salt or a double salt. It may also form a salt with the same or different acids or bases.

Typical pemetrexeds include pemetrexed, alkali metal salts of pemetrexed [sodium salt of pemetrexed (such as pemetrexed 2-sodium), potassium salt of pemetrexed], and hydrates thereof [for example, hydrate of pemetrexed 2-sodium (2). .5 hydrate, hepatic hydrate, etc.)] and the like.

Pemetrexeds may be used alone or in combination of two or more.

[Ascorbic acids]
Examples of ascorbic acids include ascorbic acid (L-ascorbic acid and the like), ascorbic acid derivatives, salts thereof (particularly pharmacologically acceptable salts) and hydrates thereof.

The ascorbic acid derivative is not particularly limited, but is, for example, an ascorbic acid ester {for example, an ester of ascorbic acid and a carboxylic acid [for example, a fatty acid ester (for example, mono or ascorbyl distearate, mono or ascorbyl dipalmitate, mono or _{Saturated or unsaturated C 1-40} carboxylic acid esters such as dioleic acid ascorbyl, more preferably saturated or unsaturated C _1-20 carboxylic acid esters), etc.], esters of ascorbic acid and phosphoric acid (ascorbic acid mono-triphosphate). Esters, etc.)}, ascorbic acid ethers {eg, ascorbic acid alkyl ethers (eg, ascorbic acid C _1-10 alkyl ethers such as ascorbic acid methyl ether, ascorbic acid ethyl ether, etc.)}, ascorbic acid glycosides (eg, eg. Ascorbic acid glucoside, etc.) and the like.

In the salt of ascorbic acid or an ascorbic acid derivative, the salt may be, for example, a metal salt [for example, an alkali metal salt (for example, a lithium salt, a sodium salt, a potassium salt, etc.), an alkaline earth metal salt (for example, a magnesium salt, calcium). Salts), Periodic Table Group 13 metal salts (eg, aluminum salts), transition metal salts (eg, salts of zinc, iron, cobalt, copper, etc.), ammonium salts, amine salts [eg, alkylamine salts (eg, alkylamine salts). , Trimethylamine salt, trialkylamine salt of triethylamine salt), alkanolamine salt (eg monoethanolamine salt, triethanolamine salt), cyclic amine salt (eg pyridine salt, substituted pyridine salt)], amino acid salt (eg , Salt with histidine, arginine, etc.). The salt may be a single salt or a double salt. It may also form a salt with the same or different acids or bases.

Typical ascorbic acids include ascorbic acid, ascorbic acid metal salt (eg, alkaline or alkaline earth metal salt of ascorbic acid such as sodium ascorbate, potassium ascorbate, magnesium ascorbate, calcium ascorbate), phosphorus ascorbic acid. Examples thereof include acid esters, ascorbic acid phosphate metal salts (for example, alkaline or alkaline earth metal salts of ascorbic acid phosphate such as sodium ascorbic acid phosphate and magnesium ascorbic acid phosphate).

Ascorbic acids may be used alone or in combination of two or more.

[Thioglycerols]
Examples of thioglycerols include thioglycerol [for example, monothioglycerol (α-monothioglycerol, thioglycerin), etc.]. The thioglycerol may form a salt or may be derivatized.
As the thioglycerols, thioglycerol (monothioglycerol) can be preferably used.

The thioglycerols may be used alone or in combination of two or more.

[Ratio of each component]
In the composition of the present invention, the ratio of ascorbic acids is, for example, 0.01 to 100 parts by weight (for example, 0.03 to 80 parts by weight), preferably 0.05 to 50 parts by weight, based on 100 parts by weight of pemetrexeds. By weight (eg, 0.07 to 20 parts by weight), more preferably 0.1 to 10 parts by weight (eg, 0.15 to 8 parts by weight), especially 0.2 to 7 parts by weight (eg, 0.5). It may be about 5 parts by weight), usually about 1 to 5 parts by weight (for example, 1 to 3 parts by weight), or 2 parts by weight or more (for example, 2.3 to 5 parts by weight, 2). It may be 1.5 parts by weight or more, 2.8 parts by weight or more, 2.8 to 3.5 parts by weight, etc.).

When the pemetrexeds are pemetrexed salts, hydrates, etc., the above ratio may be a pemetrexed-equivalent ratio (hereinafter, the same applies to the description of the ratio). Similarly, when the ascorbic acids are derivatives or salts of ascorbic acid, the above ratio may be the ratio in terms of ascorbic acid (hereinafter, the same applies to the description of the ratio).

The ratio of thioglycerols is, for example, 0.01 to 200 parts by weight (for example, 0.03 to 120 parts by weight), preferably 0.1 to 100 parts by weight (for example, 0) with respect to 100 parts by weight of pemetrexeds. 2 to 50 parts by weight), more preferably 0.3 to 20 parts by weight (for example, 0.5 to 15 parts by weight), particularly about 1 to 12 parts by weight (for example, 1.5 to 10 parts by weight). It may be usually about 2 to 5 parts by weight (for example, 2 to 4 parts by weight, 2 to 3.5 parts by weight, 2 to 3 parts by weight, etc.).

When the thioglycerols are salts of thioglycerol or the like, the above ratio may be a ratio in terms of thioglycerol (hereinafter, the same applies to the description of the ratio).

The ratio of the total amount of ascorbic acids and thioglycerols is, for example, 0.02 to 300 parts by weight (for example, 0.05 to 200 parts by weight), preferably 0.15 to 150 parts by weight, based on 100 parts by weight of pemetrexeds. Parts (eg, 0.3 to 80 parts by weight), more preferably 0.5 to 30 parts by weight (eg, 1 to 25 parts by weight), particularly 1.5 to 20 parts by weight (eg, 2 to 15 parts by weight). It may be about 2.5 to 8 parts by weight (for example, 3 to 7 parts by weight), and may be 4 parts by weight or more (for example, 4.2 to 10 parts by weight, 4.5 to 5 parts by weight). It may be 8 parts by weight, 5 parts by weight or more, 5 to 7 parts by weight, etc.).

In the present invention, the ratio of ascorbic acids to thioglycerols is the former / the latter (weight ratio) = 1 / 0.01 to 1/100 (for example, 1 / 0.03 to 1/80), preferably 1 /. 0.05 to 1/50 (eg 1 / 0.07 to 1/30), more preferably 1 / 0.1 to 1/10 (eg 1 / 0.2 to 1/8), especially 1 / It may be about 0.3 to 1/7 (for example, 1 / 0.5 to 1/6), and usually 1 / 0.3 to 1/5 [preferably 1/1 to 1/5 (for example, 1/1 to 1/5). 1 / 1.2 to 3)], and may be about 1 / 0.3 to 1 / 1.5 (for example, 1 / 0.4 to 1 / 1.2, 1 / 0.5 to 1 /). 1, 1 / 0.6 to 1 / 0.9, etc.).

In the composition of the present invention (such as a liquid preparation), the concentration of pemetrexeds is, for example, 0.1 to 1000 mg / mL (for example, 0.3 to 500 mg / mL), preferably 0.5 to 300 mg / mL (for example, for example). It may be 0.7 to 200 mg / mL), more preferably 1 to 100 mg / mL (for example, 3 to 90 mg / mL), particularly 5 to 80 mg / mL (for example, 7 to 60 mg / mL), and is usually used. It may be about 10 to 50 mg / mL (for example, 15 to 40 mg / mL).

The concentration of ascorbic acids is, for example, 0.001 to 100 mg / mL (for example, 0.005 to 80 mg / mL), preferably 0.01 to 50 mg / mL (for example, 0.03 to 30 mg / mL). More preferably, it may be about 0.05 to 10 mg / mL (for example, 0.1 to 5 mg / mL), particularly 0.15 to 3 mg / mL (for example, 0.2 to 3 mg / mL), and is usually 0. It may be on the order of .25 to 2 mg / mL (for example, 0.3 to 1.5 mg / mL, preferably 0.3 to 1 mg / mL), and may be about 0.5 to 1.5 mg / mL (for example, 0. It may be 55 to 1.3 mg / mL, 0.6 to 1.2 mg / mL, 0.65 to 1.1 mg / mL, 0.7 to 1 mg / mL, etc.).

Further, the concentration of thioglycerols is, for example, 0.001 to 200 mg / mL (for example, 0.005 to 80 mg / mL), preferably 0.01 to 50 mg / mL (for example, 0.03 to 40 mg / mL). More preferably, it may be about 0.05 to 20 mg / mL (for example, 0.1 to 10 mg / mL), particularly 0.2 to 5 mg / mL (for example, 0.3 to 4 mg / mL), and is usually used. It may be about 0.4 to 3 mg / mL (for example, 0.5 to 1.5 mg / mL).

[PH regulator]
The composition of the present invention may contain a pH adjuster.

The pH adjuster can be appropriately selected according to the desired pH and is not particularly limited. The pH adjuster may have a buffering action (or function as a buffering agent).
Examples of the pH adjuster include inorganic acids (eg, hydrochloric acid, phosphoric acid, boric acid, etc.) and organic acids [eg, carboxylic acids (citrate, tartaric acid, fumaric acid, lactic acid, maleic acid, acetic acid, oxalic acid, adipine). Acids, gluconic acids, etc.), sulfonic acids (methanesulfonic acid, etc.)], hydroxides (eg, alkali hydroxides or alkaline earth metal salts such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide) Etc.), amines [eg, alkanolamines (eg, monoethanolamine, triethanolamine, diisopropanolamine, trishydroxymethylaminomethane, etc.)], amino acids (eg, glycine, etc.), chelating agents (eg, ethylenediaminetetraacetic acid). Etc.), these salts and the like.

Examples of the salt include the above-exemplified salts. Specific salts include, for example, inorganic salts [eg, phosphates (such as disodium dihydrogen phosphate)] and carboxylates [eg, citrates (eg, trisodium citrate, disodium citrate, etc.). )], Ethylenediamine tetraacetate (for example, disodium ethylenediamine tetraacetate) and the like.
In addition, these compounds may be a hydrate or an anhydrate.

The pH adjuster may be used alone or in combination of two or more.

The ratio of the pH adjuster can be appropriately selected according to the desired pH.

[Other ingredients]
The composition of the present invention may or may not further contain other components (other components not in the category of ascorbic acids and thioglycerols), if necessary. The other components are not particularly limited, and are, for example, an isotonic agent {for example, an alkali or alkaline earth metal salt (for example, a halogenated alkali metal salt such as sodium chloride, potassium chloride, sodium bromide, magnesium bromide, etc.). And alkaline earth metal salts), sugars (eg, glucose, fructose, lactose, sucrose), sugar alcohols (mannitol, sorbitol, etc.), pyrophosphates (sodium pyrophosphate, etc.), carbonates or bicarbonates (sodium hydrogen carbonate, etc.) Etc.)}, solubilizers, stabilizers, surfactants, defoaming agents, solubilizers, solubilizers, dispersants, preservatives and the like.

Further, the composition of the present invention may contain an antioxidant (another antioxidant) that does not belong to the category of ascorbic acids and thioglycerols as long as the effect of the present invention is not impaired. You don't have to. Examples of such antioxidants include amino acids (cysteine, methionine, etc.), thioglycolic acid, lipoic acid, dihydrolipoic acid, chelate-forming compounds (citrate, ethylenediamine tetraacetic acid, lactobionic acid, etc.), sulfite, hydrogen sulfite. , Pyrosulfate, thiosulfate, nitrite, sulfur dioxide, salts thereof (eg, cysteine hydrochloride, sodium citrate, disodium ethylenediamine tetraacetate, sulfite, hydrogen sulfite, pyrosulfate, nitrite, thiosulfate, etc. ) Is included.

The compositions of the present invention include such other components (eg, sugar alcohols such as mannitol) and other antioxidants [eg, cysteine or salts thereof (such as cysteine hydrochloride), citric acid or salts thereof (citrate tri). Even if it does not contain [such as sodium)], excellent stability and suppression of coloring can be achieved.

These components may be used alone or in combination of two or more.

[Aspects and properties of the composition]
The composition of the present invention may be a composition (liquid agent) containing a solvent. The solvent usually includes an aqueous solvent [for example, water, a solvent miscible with water (alcohol, etc.), a mixed solvent thereof], and the solvent may be water in particular.

In the liquid preparation, the ratio of the solvent (aqueous solvent) may be, for example, 70% by weight or more, preferably 80% by weight or more, and more preferably 90% by weight or more.

The pH of the composition (liquid) containing the solvent can be selected from acidic, neutral and alkaline, for example, 4 to 10 (for example, 5 to 9), preferably 5.5 to 8.5, and further. It may be preferably about 6 to 8 (for example, 6.5 to 7.5).

The liquid agent of the present invention can realize excellent stability and color suppression effect even in a weak acid to weak alkaline region, particularly in a neutral region.

The viscosity of the liquid agent can be selected from, for example, in the range of 500 mPa · s or less, and may be, for example, 300 mPa · s or less, preferably 200 mPa · s or less, and more preferably 100 mPa · s or less.

The oxygen concentration in the composition (liquid agent) is preferably as low as possible (for example, 10% by volume or less), for example, 5% by volume or less (for example, 3% by volume or less), preferably 2.5. It may be 5% by volume or less, more preferably 2% by volume or less (for example, 1.5% by volume or less), and particularly 1% by volume or less.

The oxygen concentration (dissolved oxygen concentration) in the composition can be adjusted (reduced) by a conventional method (such as bubbling with an inert gas).

The composition of the present invention can be selected depending on the administration method, but may be in the form of an injection (or intravenous drip infusion) in particular. Specific administration methods include intravenous injection (intravenous injection), intramuscular injection, subcutaneous injection and the like. More specifically, it may be administered intravenously into an artery, peritoneum, submeninges, intraventricular, intraurethral, intrasternal, intracranial, or the like, or may be administered by intravenous drip infusion.

The concentration of each component in the liquid preparation can be selected from the same range as described above, but in particular, when administered by intravenous drip infusion, the composition is mixed with the infusion solution and dissolved to prepare an intravenous drip infusion solution. May be good. In this embodiment, the ratio when the composition is mixed with the infusion solution is appropriately selected according to the body surface area, age, sex, application site, degree of medical condition, etc. of the subject such as the patient to whom the intravenous infusion solution is administered. It is not particularly limited.

The infusion solution is not particularly limited, and examples thereof include physiological saline solution, sugar aqueous solution (dextrose aqueous solution, fructose aqueous solution, etc.), sugar alcohol aqueous solution (D-sorbitol aqueous solution, xylitol aqueous solution, etc.), amino acid aqueous solution, Ringer solution, and the like.

The composition of the present invention may be usually enclosed in a container for storage or the like.
Therefore, the present invention also includes a container containing the composition inside. Such a container may usually be sealed or hermetically sealed with the composition.

The container can be appropriately selected depending on the administration mode and the like, and examples thereof include bottles (vial bottles), ampoules, and syringes.

The container may be externally packaged (for example, packaged with a plastic film).

The inside of the container may be composed only of the composition (liquid agent) or may have a void (space). Such voids are particularly preferably filled (or substituted) with an inert gas (such as nitrogen gas).

Further, it is preferable that the amount of dissolved oxygen contained in the composition (liquid agent) contained in the container is as small as possible.

Typically, the oxygen concentration with respect to the entire volume in the container is preferably, for example, 10% by volume or less, for example, 5% by volume or less (for example, 3% by volume or less), preferably 2.5% by volume or less. More preferably, it may be 2% by volume or less (for example, 1.5% by volume or less), particularly 1% by volume or less.

The oxygen is the total amount of dissolved oxygen contained in the composition when there is no void in the container, and the dissolved oxygen contained in the composition and oxygen contained in the void when the container has voids. Is.

The oxygen concentration can be adjusted by a conventional method, for example, a method of bubbling the inert gas inside the composition and / or the container, a method of degassing the inside of the composition and / or the container, a method combining these, and the like. ..

The composition of the present invention (or the composition in a container) is excellent in stability, and for example, the ratio (production rate) of related substances when stored at 60 ° C. for 1 week is 3% or less, preferably 2 It may be% or less (for example, 1.5% or less), more preferably 1% or less (for example, 0.8% or less), and particularly 0.7% or less (for example, 0.6% or less).

Further, the composition of the present invention (or the composition in the container) is less colored and may be, for example, a colorless clear liquid, a pale yellow (or slightly yellow) clear liquid, or the like.

Next, the present invention will be described in more detail with reference to experimental examples and examples, but the present invention is not limited to these examples, and many modifications are made within the technical idea of the present invention. It is possible by a person who has ordinary knowledge in this field.

[Purity test / quantification]
2 mL of the sample was accurately weighed and water was added to make exactly 250 mL, which was used as a sample solution.
Separately, about 24 mg of pemetrexed disodium 2.5 hydrate (20 mg as pemetrexed) was precisely weighed and dissolved by adding water to make exactly 100 mL, which was used as a standard solution.

Accurately 20 μL each of the sample solution and the standard solution were taken and measured by liquid chromatography (HPLC) under the following conditions.

(Measurement condition)
Detector: Ultraviolet absorptiometer (measurement wavelength: 250 nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm filled with 3.5 μm of octadecylsilylated silica gel for liquid chromatography was used.
Column temperature: Constant temperature around 30 ° C Flow rate: 1.0 mL / min
Mobile phase A: Ammonium formate solution (pH 3.5) / acetonitrile mixed solution (19: 1)
Mobile phase B: Ammonium formate solution (pH 3.5) / acetonitrile mixed solution (7: 3)
Liquid transfer of mobile phase: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.

(a formula)
Quantitative:
Content (%) = MS x 427.41 / 471.37 x AT / AS x 5

Related substances:
Amount of related substances (%) = MS × 427.41 / 471.37 × AT / AS × 1/200

impurity A to D:
Amount of impedance A to D (%)
= MS x 427.41 / 471.37 x AT / AS x 1/200
(Same as the analysis method for related substances above)
Specific method:
impurityA retention time 0.81
impurityB retention time 0.87
impurityC retention time 0.88
impurityD retention time 0.91

MS: Weighed amount of pemetrexed 2-sodium 2.5 hydrate for quantification converted to dehydrated product (mg)
427.41: Molecular weight of pemetrexed 471.37: Molecular weight of pemetrexed 2 sodium AT: Peak area of the substance to be measured in the sample solution AS: Peak area of pemetrexed in the standard solution

(Measurement method of oxygen concentration)
The oxygen concentration in the container space was measured with a residual oxygen meter.

(Severe test method)
It was stored at 60 ° C./Nariyuki humidity, and after 1 week, various test items were analyzed.

(Example 1)
Pemetrexed disodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 121.4 mg (100.0 mg in terms of pemetrexed), ascorbic acid (manufactured by Nacalai Tesque Co., Ltd.) 1.5 mg, monothioglycerol (Nacalai Tesque (Nacalai Tesque) Co., Ltd.) 2.5 mg, an appropriate amount of sodium hydroxide, and an appropriate amount of hydrochloric acid were dissolved in water to make 4 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Example 2)
Pemetrexed disodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 121.4 mg (100.0 mg in terms of pemetrexed), ascorbic acid (manufactured by Nacalai Tesque Co., Ltd.) 3.0 mg, monothioglycerol (Nacalai Tesque (Nacalai Tesque) Co., Ltd.) 2.5 mg, an appropriate amount of sodium hydroxide, and an appropriate amount of hydrochloric acid were dissolved in water to make 4 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Example 3)
Pemetrexed disodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 121.4 mg (100.0 mg in terms of pemetrexed), ascorbic acid (manufactured by Nacalai Tesque Co., Ltd.) 4.5 mg, monothioglycerol (Nacalai Tesque (Nacalai Tesque) Co., Ltd.) 2.5 mg, an appropriate amount of sodium hydroxide, and an appropriate amount of hydrochloric acid were dissolved in water to make 4 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Comparative Example 1)
Pemetrexed disodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 130.5 mg (108.5 mg in terms of pemetrexed), monothioglycerol (manufactured by Nakaraitesk Co., Ltd.) 0.12 mg, appropriate amount of sodium hydroxide, An appropriate amount of hydrochloric acid was dissolved in water to make 4.2 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Comparative Example 2)
Pemetrexed 2 sodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 121.4 mg (100.0 mg in terms of pemetrexed), monothioglycerol (manufactured by Nacalai Tesque Co., Ltd.) 2.5 mg, appropriate amount of sodium hydroxide, An appropriate amount of hydrochloric acid was dissolved in water to make 4 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Comparative Example 3)
Pemetrexed 2 sodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 130.5 mg (108.5 mg in terms of pemetrexed), ascorbic acid (manufactured by Nakaraitesk Co., Ltd.) 7 mg, appropriate amount of sodium hydroxide, appropriate amount of hydrochloric acid Was dissolved in water to make 4.2 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Comparative Example 4)
Pemetrexed 2 sodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 130.5 mg (108.5 mg in terms of pemetrexed), ascorbic acid (manufactured by Nakaraitesk Co., Ltd.) 14 mg, appropriate amount of sodium hydroxide, appropriate amount of hydrochloric acid Was dissolved in water to make 4.2 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Comparative Example 5)
Pemetrexed disodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 130.5 mg (108.5 mg in terms of pemetrexed), sodium bisulfite (manufactured by Nakaraitesk Co., Ltd.) 8 mg, appropriate amount of sodium hydroxide, appropriate amount Sodium hydroxide was dissolved in water to make 4.2 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Comparative Example 6)
Pemetrexed disodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 130.5 mg (108.5 mg in terms of pemetrexed), sodium bisulfite (manufactured by Nakaraitesk Co., Ltd.) 16 mg, appropriate amount of sodium hydroxide, appropriate amount Sodium hydroxide was dissolved in water to make 4.2 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Comparative Example 7)
Pemetrexed 2 sodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 130.5 mg (108.5 mg in terms of pemetrexed), sodium bisulfite (manufactured by Nakaraitesk Co., Ltd.) 32 mg, appropriate amount of sodium hydroxide, appropriate amount Sodium hydroxide was dissolved in water to make 4.2 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Comparative Example 8)
Pemetrexed disodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 130.5 mg (108.5 mg in terms of pemetrexed), thioglycolic acid (manufactured by Nakaraitesk Co., Ltd.) 9.6 mg, appropriate amount of sodium hydroxide, An appropriate amount of hydrochloric acid was dissolved in water to make 4.2 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Comparative Example 9)
Pemetrexed 2 sodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 130.5 mg (108.5 mg in terms of pemetrexed), L-cysteine (manufactured by Nacalai Tesque Co., Ltd.) 0.12 mg, appropriate amount of sodium hydroxide, An appropriate amount of hydrochloric acid was dissolved in water to make 4.2 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Comparative Example 10)
Pemetrexed 2 sodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 121.4 mg (100.0 mg in terms of pemetrexed), citric acid monohydrate (manufactured by Nakaraitesk Co., Ltd.) 2 mg, appropriate amount of sodium hydroxide , An appropriate amount of hydrochloric acid was dissolved in water to make 4 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Comparative Example 11)
Pemetrexed 2 sodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 121.4 mg (100.0 mg in terms of pemetrexed), citric acid monohydrate (manufactured by Nakaraitesk Co., Ltd.) 2 mg, monothioglycerol (Nakarai) (Manufactured by Tesk Co., Ltd.) 2.5 mg, an appropriate amount of sodium hydroxide, and an appropriate amount of hydrochloric acid were dissolved in water to make 4 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

For each sample solution obtained in Examples 1 to 3 and Comparative Examples 1 to 11, the properties, pH, residual oxygen concentration, the ratio of all the components, and the ratio of related substances were observed or measured before and after the harsh test. The results are shown in the table below.
The properties were visually evaluated.

As is clear from the above table, Examples 1 to 3 in which ascorbic acid and monothioglycerol are combined with respect to pemetrexed have high stability even after a harsh test, and the coloring is also extreme. It was not a thing, but was suppressed to a light tan or a light yellow that maintained its clarity.

On the other hand, in the comparative example using various antioxidants, a large amount of related substances were produced, and the stability was inferior.

Moreover, among the antioxidants used in the present invention, when monothioglycerol is used, there is not much coloring (Comparative Examples 2, 11 and the like), whereas when ascorbic acid is used, it is brown. The more strongly it was colored (Comparative Examples 3 and 4).

Therefore, in order to confirm whether the amount of ascorbic acid can be reduced or the coloring can be suppressed by combining ascorbic acid with other antioxidants other than monothioglycerol, the following two sample solutions (Comparative Examples 12 and 13) Was prepared and subjected to a harsh test to confirm its properties (coloring).

(Comparative Example 12)
Pemetrexed 2 sodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 130.5 mg (108.5 mg in terms of pemetrexed), ascorbic acid (manufactured by Nakaraitesk Co., Ltd.) 3.5 mg, appropriate amount of sodium hydroxide, appropriate amount Hydrochloric acid was dissolved in water to make 4.2 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

(Comparative Example 13)
Pemetrexed disodium 2.5 hydrate (Chongqing Taihao Pharmaceutical Co. Ltd) 121.4 mg (100.0 mg in terms of pemetrexed), ascorbic acid (manufactured by Nakaraitesk Co., Ltd.) 1.5 mg, citric acid monohydrate ( 2 mg of Nakaraitesk Co., Ltd., an appropriate amount of sodium hydroxide, and an appropriate amount of citric acid were dissolved in water to make 4 mL, and a solution was obtained.
The obtained solution was filled in a glass vial and sealed in a space having an oxygen concentration of 2% or less by nitrogen substitution to obtain a sample solution.

However, even with the formulation in which the amount of ascorbic acid was reduced to 3.5 mg (Comparative Example 12), the properties after the harsh test were still brown, and no improvement in coloring was observed.
Further, in the formulation in which citric acid monohydrate was selected as the antioxidant to be combined with 1.5 mg of ascorbic acid as a comparison with Example 1 (Comparative Example 13), the properties after the harsh test became black, and more. The coloring became terrible.

As described above, it can be seen that in the present invention, excellent stability can be realized in the pemetrexed preparation while suppressing coloring.

According to the present invention, a stable pemetrexed composition can be obtained.

Claims (9)

A composition comprising pemetrexeds, ascorbic acids and thioglycerols , wherein the pemetrexeds are at least one selected from pemetrexed, salts of pemetrexed and hydrates thereof.
Ascorbic acids are at least one selected from ascorbic acid, ascorbic acid ester, ester of ascorbic acid and phosphoric acid, ascorbic acid ether, glycosyl of ascorbic acid, salts thereof, and hydrates thereof. ,
Thioglycerols are thioglycerols,
The ratio of ascorbic acid to 100 parts by weight of pemetrexed (pemetrexed equivalent) is 1.5 to 20 parts by weight in terms of ascorbic acid, and the ratio of thioglycerols is 1.5 to 10 parts by weight in terms of thioglycerol. ,
The ratio of ascorbic acids and thioglycerols is 1 / 0.3 to 1 / 1.5 in terms of ascorbic acid and thioglycerol, the former / the latter (weight ratio).
A composition free of cysteine, citric acid and salts thereof. The composition according to claim 1, wherein the ratio of ascorbic acids and thioglycerols is 1 / 0.5 to 1/1 in terms of ascorbic acid and thioglycerol, the former / the latter (weight ratio). Claim 1 or 2 in which the ratio of ascorbic acid is 2 to 10 parts by weight in terms of ascorbic acid and the ratio of thioglycerols is 2 to 5 parts by weight in terms of thioglycerol with respect to 100 parts by weight of pemetrexeds (pemetrexed equivalent). The composition described. The composition according to any one of claims 1 to 3, which is a liquid preparation having a pH of 5 to 9. Pemetrexed such a 5-80 mg / mL in pemetrexed terms, 0.15~3mg / mL ascorbic acid with ascorbic acid terms, at a concentration of 0.2~5mg / mL thio glycerols with thioglycerol terms, p H is The composition according to any one of claims 1 to 4, which is a liquid preparation of 6 to 8. The composition according to any one of claims 1 to 5, which is an injectable preparation containing an aqueous solvent as a solvent component. The composition according to any one of claims 1 to 6, wherein the proportion of related substances when stored at 60 ° C. for 1 week is 1% or less. A container in which the composition according to any one of claims 1 to 7 is enclosed, in which the voids in the container are filled with an inert gas. The container according to claim 8, wherein the oxygen concentration with respect to the total volume in the container is 2.5% by volume or less.