WO2016024369A1 - Medicinal composition for treating cancer - Google Patents

Abstract

Provided is a liquid medicinal composition formed by containing: (A) pemetrexed, a pharmaceutically acceptable salt or solvate thereof; (B) cysteine, a pharmaceutically acceptable salt or solvate thereof; and (C) a chelating agent. The liquid medicinal composition containing pemetrexed according to the present invention exhibits a suppressed increase of related substances and also suppressed coloring even after long-term storage, so that the composition may be appropriately applied to the treatment of, for example, malignant pleural mesothelioma and non-small cell lung cancer.

Description

Pharmaceutical composition for cancer treatment

The present invention relates to a pharmaceutical composition for treating cancer. More particularly, it relates to a liquid pharmaceutical composition containing pemetrexed.

Pemetrexed is a folate antimetabolite that exhibits antitumor activity by simultaneously inhibiting multiple folate metabolizing enzymes, and is used in the treatment of malignant pleural mesothelioma and non-small cell lung cancer. The currently marketed pemetrexed formulation (Alimta®) is a lyophilized formulation. However, the freeze-dried preparation takes time and effort to dissolve the preparation before use before administration to a patient. Moreover, there is a problem that the possibility that the operator is exposed increases due to the complicated preparation for administration for dissolving the preparation. In order to avoid such a problem, studies have been made on preparations in solution.

For example, Patent Document 1 includes a) pemetrex (synonymous with pemetrexed); b) at least one antioxidant selected from the group consisting of monothioglycerol, L-cysteine, and thioglycolic acid; and c) a pharmaceutical agent. A pharmaceutical composition comprising a pharmaceutically acceptable excipient is disclosed to be stable as a liquid formulation. Moreover, as an antioxidant, only the above-mentioned three kinds of compounds are effective, and it is described that an effect cannot be obtained with a normal antioxidant.

Patent Document 2 includes a) pemetrexed or a pharmaceutically acceptable salt thereof; b) an antioxidant selected from the group consisting of lipoic acid, dihydrolipoic acid, methionine, and mixtures thereof; c) lactobionic acid, tribasic A chelating agent selected from the group consisting of sodium citrate, and mixtures thereof; and d) a liquid composition comprising a pharmaceutically acceptable fluid and exhibiting a particular pH has long-term storage stability It is disclosed.

Special Table 2003-521518 Special table 2013-540104 gazette

However, although it is described that the composition of Patent Document 1 can be stored at 4 degrees Celsius in a highly concentrated state (see [0003] of Patent Document 1), the specific storage test method and results are as follows. Not disclosed.

The composition of Patent Document 2 is said to have long-term storage stability by suppressing the generation of impurities for at least 18 months when stored at about 5 ° C to about 25 ° C. There is a need for a liquid composition having.

Also, it is known that pemetrexed may be colored in an aqueous solution.

An object of the present invention is to provide a liquid pharmaceutical composition containing pemetrexed that is excellent in long-term storage stability.

As a result of repeated investigations to solve the above problems, the present inventors combined cysteine and a chelating agent with pemetrexed to suppress the generation of related substances, and unexpectedly to suppress coloring. Thus, the inventors have found that long-term storage is possible, and have completed the present invention.

That is, the present invention relates to (A) pemetrexed, a pharmaceutically acceptable salt thereof, or a solvate thereof, (B) cysteine, a pharmaceutically acceptable salt thereof, or a solvate thereof, and (C) The present invention relates to a liquid pharmaceutical composition containing a chelating agent.

The pemetrexed-containing liquid pharmaceutical composition of the present invention has an excellent effect that there is little increase in related substances after long-term storage. In addition to the above-described effects, there are some which have an excellent effect that coloring is suppressed.

The pharmaceutical composition of the present invention comprises (A) pemetrexed, a pharmaceutically acceptable salt thereof, or a solvate thereof, (B) cysteine, a pharmaceutically acceptable salt thereof, or a solvate thereof, and ( C) It contains a chelating agent such as sodium edetate or a solvate thereof and is a liquid. In the present specification, the “liquid” includes a fluid liquid, and includes a general liquid or a slightly viscous liquid.

The pharmaceutical composition of the present invention exhibits the effect of excellent long-term storage stability of pemetrexed in a liquid by using cysteine, a pharmaceutically acceptable salt thereof, or a solvate thereof and a chelating agent in combination. Is. Although the detailed reason is unknown, it is speculated that it is caused by the antioxidant action of cysteine and the production of metal chelate by the chelating agent. However, these assumptions do not limit the present invention.

[Component (A)]
Pemetrexed used in the present invention is N- {4- [2- (2-amino-4-oxo-4,7-dihydro-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl. } -L-glutamate, a pharmaceutically acceptable salt thereof, or a solvate thereof, and has an activity of inhibiting folate metabolic enzyme.

In this specification, examples of the pharmaceutically acceptable salt include basic salts and acidic salts. Basic salts include alkali metal salts, alkaline earth metal salts, transition metal salts, ammonium salts, aliphatic amine salts, aralkylamine salts, heterocyclic aromatic amine salts, quaternary ammonium salts, basic amino acid salts, etc. Is mentioned. Specifically, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, zinc salt, iron salt, ammonium salt, trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, Ethanolamine salt, ethylenediamine salt, meglumine salt, procaine salt, N, N-dibenzylethylenediamine, pyridine salt, picoline salt, quinoline salt, isoquinoline salt, tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt Salt, benzyltributylammonium salt, methyltrioctylammonium salt, tetrabutylammonium salt, arginine salt, lysine salt and the like are used. Examples of the acid salt include inorganic acid salts, organic acid salts, sulfonate salts, and acidic amino acid salts. Specifically, hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, hydrobromide, hydroiodide, perchlorate, formate, acetate, propionate , Trifluoroacetate, citrate, lactate, tartrate, oxalate, maleate, fumarate, mandelate, glutarate, malate, benzoate, phthalate, ascorbic acid Salts, methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, aspartate, glutamate and the like are used.

Further, the solvate includes an organic solvate that coordinates an arbitrary number of organic solvent molecules and a hydrate that coordinates an arbitrary number of water molecules. The “solvate” in the present specification means, for example, a solvate of the above-mentioned pemetrexed or a pharmaceutically acceptable salt thereof, for example, 1 organic solvate, 2 organic solvate, 1 hydrate. A dihydrate, a 2.5 hydrate, a heptahydrate etc. are mentioned.

Pemetrexed, pharmaceutically acceptable salts thereof, and solvates thereof can be synthesized according to known methods. In the present invention, for example, pemetrexed disodium 2.5 hydrate is preferably used. Can do.

The content of the component (A) in the liquid pharmaceutical composition of the present invention (content as pemetrexed) is preferably 0.1 mg / mL or more, more preferably 1 mg / mL or more, still more preferably 10 mg / mL or more. Moreover, it is preferably 100 mg / mL or less, more preferably 75 mg / mL or less, and still more preferably 50 mg / mL or less.

[Component (B)]
Examples of the cysteine used in the present invention include L-cysteine, D-cysteine, racemate, pharmaceutically acceptable salts thereof, and solvates thereof. Preferably, L-cysteine, a pharmaceutically acceptable salt thereof, or a solvate thereof is used, and more preferably, L-cysteine hydrochloride or a solvate thereof is used. In the present invention, for example, L-cysteine hydrochloride hydrate can be preferably used. The content of L-cysteine hydrochloride or a solvate thereof in component (B) is not particularly limited, but is preferably 80% by weight or more, more preferably 90% by weight or more, and still more preferably substantially 100% by weight. It is. Note that the content of L-cysteine hydrochloride or a solvate thereof means the total content when a plurality of compounds are contained.

The content of the component (B) in the liquid pharmaceutical composition of the present invention (content as cysteine) is preferably 0.01 mg / mL or more, more preferably 0.05 mg / mL or more, still more preferably 0.1 mg / mL. It is not less than mL, preferably not more than 100 mg / mL, more preferably not more than 10 mg / mL, still more preferably not more than 5 mg / mL, and still more preferably not more than 1 mg / mL. In the present specification, the content as cysteine refers to the content as L-cysteine when, for example, L-cysteine, a pharmaceutically acceptable salt thereof, or a solvate thereof is used. Means.

The amount as cysteine is preferably 0.05 parts by weight or more, more preferably 0.5 parts by weight or more, and further preferably 0.1 parts by weight or more with respect to 100 parts by weight as pemetrexed. The amount is preferably 100 parts by weight or less, more preferably 10 parts by weight or less, and still more preferably 5 parts by weight or less with respect to 100 parts by weight as pemetrexed.

[Component (C)]
Examples of the chelating agent used in the present invention include EDTA, NTA, DTPA, HEDTA, TTHA, PDTA, metal salts thereof, and solvates thereof. Preferably, sodium edetate (hereinafter sometimes referred to as “EDTA-Na”) or a solvate thereof is used. In the present invention, for example, sodium edetate hydrate can be suitably used. The content of sodium edetate or a solvate thereof in component (C) is not particularly limited, but is preferably 80% by weight or more, more preferably 90% by weight or more, and still more preferably substantially 100% by weight. . In addition, content of sodium edetate or its solvate means a total content, when a several compound is contained.

The content of component (C) in the liquid pharmaceutical composition of the present invention (for example, content as sodium edetate) is preferably 0.01 mg / mL or more, more preferably 0.05 mg / mL or more, and still more preferably It is 0.1 mg / mL or more, preferably 100 mg / mL or less, more preferably 10 mg / mL or less, still more preferably 1 mg / mL or less, and still more preferably 0.5 mg / mL or less.

The content of component (C) is preferably 0.01 parts by weight or more, more preferably 0.1 parts by weight or more, and still more preferably 0.5 parts by weight or more with respect to 100 parts by weight as pemetrexed. is there. Moreover, it is preferably 10 parts by weight or less, more preferably 5 parts by weight or less, and still more preferably 2 parts by weight or less with respect to 100 parts by weight as pemetrexed.

The ratio of the amount as cysteine and the amount as sodium edetate (cysteine / sodium edetate) is preferably 20/1 to 1/20, more preferably 10/1 to 1/10, and 5/1 to 1/5. Is more preferable.

The liquid pharmaceutical composition of the present invention contains a carrier generally used for the preparation of liquids and the like in addition to the components (A) to (C). Such carriers include, for example, purified water, water for injection, physiological saline, absolute ethanol, vegetable oil, macrogol 400, polysorbate 20, polysorbate 80, propylene glycol, lactic acid, glycerin, mixtures thereof and the like.

The liquid pharmaceutical composition of the present invention contains the components (A) to (C) and the above carrier, but the liquid pharmaceutical composition of the present invention is in a liquid form within the range not impairing the effects of the present invention. Therefore, according to a conventional method, other raw materials can be appropriately selected, and one kind or a combination of two or more kinds can be contained. Other raw materials include, for example, thickeners, sugars, surfactants, preservatives, bactericides or antibacterial agents, pH adjusters, tonicity agents, fragrances or cooling agents, antioxidants other than cysteine, etc. Can be mentioned. These contents can be set as appropriate.

Examples of typical components used in the liquid pharmaceutical composition of the present invention are illustrated below, but are not limited thereto. Specifically, examples of the saccharide include lactose, purified sucrose, mannitol, sorbitol, and maltose. Examples of the surfactant include Macrogol 400, polysorbate 20, polysorbate 80, and propylene glycol. Examples of pH regulators include hydrochloric acid, sodium hydroxide, tartaric acid, sodium hydrogen phosphate hydrate, anhydrous sodium dihydrogen phosphate, anhydrous citric acid, citric acid, sodium citrate, acetic acid, sodium acetate, glycine, etc. Can do. Examples of isotonic agents include sodium chloride and glucose.

The liquid pharmaceutical composition of the present invention needs to be adjusted to an osmotic pressure ratio within a range that is acceptable to a living body, if necessary. For example, it is usually about 0.8 to 1.2, preferably about 0.9 to 1.1 with respect to physiological saline. The osmotic pressure ratio can be adjusted using a buffer, a pH adjuster, an isotonic agent, salts, and the like.

In addition, the liquid pharmaceutical composition of the present invention preferably has a pH of 7.0 to 10.0, more preferably a pH of 7.5 to 9.5, and even more preferably a pH of 8.0 to 9.0.

The preparation method of the liquid pharmaceutical composition of the present invention is not particularly limited as long as it contains the components (A) to (C). For example, in water for injection, (A) pemetrexed, a pharmaceutically acceptable salt thereof, or a solvate thereof, (B) cysteine, a pharmaceutically acceptable salt thereof, or a solvate thereof, and (C) A chelating agent can be uniformly mixed and dissolved, adjusted to a predetermined osmotic pressure and pH, filtered and sterilized if necessary, and filled into a container. When filling the container, the inside of the container can be brought into a low oxygen state using an inert gas (nitrogen, argon, etc.).

The container filled with the liquid pharmaceutical composition of the present invention is not particularly limited, and a container usually used in this field can be used. Examples include vials made of glass, cyclic polyolefin polymer, and cyclic polyolefin copolymer; glass ampules; polyethylene, polypropylene, and cyclic polyolefin bags; polypropylene, cyclic polyolefin polymer, and cyclic polyolefin copolymer syringes. Moreover, the said container can be surface-treated and used according to the objectives, such as improving slidability, airtightness, and stability. Examples of such surface treatment include fluorination treatment and silicone treatment.

Thus, the liquid pharmaceutical composition of the present invention is obtained.

In the liquid pharmaceutical composition of the present invention, the formation of related substances is suppressed even after long-term storage. In the present specification, the related substance is a substance generated by impurities or decomposition in pemetrexed, and the content of the related substance can be measured according to the method described in the examples described later.

In addition, the liquid pharmaceutical composition of the present invention is preferably stored under storage conditions generally used in pharmaceutical products. The storage temperature is preferably 40 ° C. or lower, more preferably 25 ° C. or lower, and further preferably 10 ° C. or lower. The lower limit is not particularly set, but 2 ° C. or higher is preferable.

The method of using the liquid pharmaceutical composition of the present invention is not particularly limited as long as the composition can be transferred into the circulating blood. For example, it can be administered intravenously, intramuscularly, subcutaneously, intradermally, etc., and can be suitably used for the treatment of malignant pleural mesothelioma, non-small cell lung cancer and the like.

The dosage of the liquid pharmaceutical composition of the present invention is appropriately set depending on the administration method, the purpose of use and the age, weight and symptom of the patient to whom the composition is administered, and is not constant. For example, in the case of a human adult, it is preferable to administer the liquid pharmaceutical composition of the present invention in such an amount that the amount of pemetrexed is preferably 500 mg / m ² or less per body surface area per day. Administration may be performed within a desired dose range in a single day or divided into several times, and the method may be either instantaneous administration or continuous administration. The administration period is also arbitrary.

In the present specification, the subject of administration of the liquid pharmaceutical composition of the present invention is preferably a human who needs treatment for malignant pleural mesothelioma and non-small cell lung cancer, but domestic animals such as cattle, horses, goats, etc. It may be a pet animal such as a dog, cat or rabbit, or a laboratory animal such as a mouse, rat, guinea pig or monkey.

The present invention also includes administering a therapeutically effective amount of the liquid pharmaceutical composition of the present invention to an individual in need of treatment for malignant pleural mesothelioma, non-small cell lung cancer, or malignant pleural mesothelioma or non-small Methods of treating cell lung cancer are provided. The individual who needs to treat malignant pleural mesothelioma and non-small cell lung cancer is the same as the administration subject of the liquid pharmaceutical composition of the present invention described above.

Further, in the present specification, the therapeutically effective amount refers to malignant pleural mesothelioma or non-small cell lung cancer when the liquid pharmaceutical composition of the present invention is administered to the above-mentioned individual as compared to an individual not administered. The amount to reduce. The specific effective amount is appropriately set according to the administration form, administration method, purpose of use, individual age, weight, symptoms, etc., and is not constant.

Hereinafter, the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples. In this embodiment, the room temperature is 25 ° C.

[Measurement of related substances]
The amount of related substances is measured by high performance liquid chromatography (HPLC) performed under the following conditions.
<HPLC conditions>
Detector: UV absorptiometer (measurement wavelength 250 nm)
Mobile phase A: pH 3.5 ammonium formate solution / acetonitrile mixture (19/1)
Mobile phase B: ammonium formate solution of pH 3.5 / acetonitrile mixture (7/3)
Gradient condition:
Time (min) after injection Mobile phase A (vol%) Mobile phase B (vol%)
0-3 100 0
3 to 45 100 → 0 0 → 100
45-46 0 → 100 100 → 0
46-55 100 0
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm is packed with 3.5 μm of octylsilylated silica gel.

Example 1 and Comparative Examples 1 to 4
First, 14 L of Preparation Solution 1 was prepared according to the formulation in Table 1.

4 mL of the above-prepared solution 1 was enclosed in a glass vial coated with fluoride and used as Comparative Example 1. In addition, L-cysteine hydrochloride hydrate and sodium edetate hydrate shown in Table 2 were added to Preparation Solution 1, adjusted to 8.5 with a pH regulator, and sealed in a fluoride-coated glass vial. Comparative Examples 2 to 4 and Example 1 were used. In Example 1, the ratio of the amount as L-cysteine to the amount as EDTA-Na (L-cysteine / EDTA-Na) was 1.36 / 1.70 (= 0.80).

<Total amount of related substances>
After the vials of Comparative Examples 1 to 4 and Example 1 were stored under conditions of 5 ° C. × 12 days and 60 ° C. × 12 days, the total amount of related substances was measured. The results are shown in Table 3. Storage at 5 ° C for 12 days corresponds to the initial value of room temperature storage in terms of calorie, and storage at 60 ° C for 12 days corresponds to 20 months of storage at room temperature.

From Table 3, in Comparative Examples 1 to 4, the concentration of related substances after storage at 60 ° C. × 12 days is more than twice the concentration of related substances after storage at 5 ° C. × 12 days. On the other hand, in Example 1, the concentration of the related substance after storage at 60 ° C. × 12 days is about 1.4 times the concentration of the related substance after storage at 5 ° C. × 12 days. It can be seen that the increase is suppressed.

<Color test>
After the vials of Comparative Examples 1 to 4 and Example 1 were stored under the conditions of 5 ° C. × 12 days and 60 ° C. × 12 days, the presence or absence of coloring was visually confirmed, and when colorless, “-”, colored yellow The case was evaluated as “+”. The results are shown in Table 4.

From Table 4, Comparative Examples 1 and 2 colored yellow after storage at 60 ° C. for 12 days. Comparative Example 4 was colored deep yellow after storage at 60 ° C. for 12 days. On the other hand, Comparative Example 3 and Example 1 were hardly colored even after storage at 60 ° C. for 12 days.

Examples 2 to 10
A liquid composition was prepared in the same manner as in Example 1 using the raw materials shown in Table 5. The pH of the solution after preparation is as shown in Table 5. The obtained solution was sealed in a glass vial (manufactured by Fuji Glass Co., Ltd.) coated with a SiO ₂ glass thin film. For comparison, a solution of Comparative Example 2 was also prepared.

<Total amount of related substances>
The obtained sample was stored under conditions of 60 ° C. × 12 days and 60 ° C. × 21 days, and then the total amount of related substances was measured. The results are shown in Table 5. Storage at 60 ° C for 21 days corresponds to 36 months of storage at room temperature. The total amount of related substances in each sample immediately after preparation was also measured.

<Color test>
The obtained sample was stored under conditions of 5 ° C. × 21 days and 60 ° C. × 21 days, and was visually checked for coloration. When it was colorless, it was “−”, and when it was yellow, “+”. evaluated. The results are shown in Table 5.

From Table 5, as a result of experimenting with varying concentrations of L-cysteine and sodium edetate hydrate, the compositions of the examples were L-cysteine, L-cysteine hydrochloride hydrate, and sodium edetate hydrate. Even if the addition concentration of each was different, the inhibitory effect on the increase in the concentration of the related substances was recognized as compared with Comparative Example 2 not containing them.

Example 11
L-stein hydrochloride hydrate and sodium edetate hydrate in the amounts shown in Table 6 were dissolved in 30 mL of injection solution, and the pH was adjusted to 8.5 with a pH adjuster. Thereafter, the amount of pemetrexed disodium 2.5 hydrate shown in Table 6 was added to the resulting solution, the pH was adjusted to 8.5 again with a pH adjuster, and the volume was made up to 50 mL with water for injection. The prepared solution was sealed in a glass vial (Fuji Glass Co., Ltd.) coated with a SiO ₂ glass thin film.

Comparative Example 5
Prepared in the same manner as in Example 11 except that it did not contain sodium edetate hydrate.

<Color test>
The obtained sample was stored under the conditions of 60 ° C. × 13 days and 60 ° C. × 21 days, and then visually confirmed for coloration. When it was colorless, it was “−”, and when it was colored yellow, “+”. evaluated. The results are shown in Table 6.

From Table 6, Example 11 and Comparative Example 5 were colorless and clear even after storage at 60 ° C. for 21 days.

<Total amount of related substances>
The samples of Example 11 and Comparative Example 5 were stored under conditions of 5 ° C. × 13 days, 60 ° C. × 13 days, and 60 ° C. × 21 days, and then the total amount of related substances was measured. The results are shown in Table 7.

From Table 7, after storing at 60 ° C. for 21 days, the concentration of the related substance in Comparative Example 5 increased to about 1.4 times the impurity concentration in Example 11.

According to the present invention, it has been clarified to provide a pemetrexed solution composition that can be stored for a long period of time at room temperature, in which an increase in related substances is suppressed and further coloring is also suppressed.

The pemetrexed-containing liquid pharmaceutical composition of the present invention suppresses an increase in related substances even after long-term storage, and further suppresses coloration. For example, treatment of malignant pleural mesothelioma, non-small cell lung cancer, etc. For example, it is suitably used.

Claims (10)

(A) pemetrexed, a pharmaceutically acceptable salt thereof, or a solvate thereof, (B) cysteine, a pharmaceutically acceptable salt thereof, or a solvate thereof, and (C) a chelating agent. A liquid pharmaceutical composition. The composition according to claim 1, wherein the content of component (A) is 0.1 to 100 mg / mL as pemetrexed. The composition according to claim 1 or 2, wherein the content of component (B) is 0.05 to 100 parts by weight as cysteine with respect to 100 parts by weight of pemetrexed. The composition according to any one of claims 1 to 3, wherein the content of component (C) is 0.01 to 10 parts by weight with respect to 100 parts by weight of pemetrexed. The composition according to any one of claims 1 to 4, wherein component (B) comprises L-cysteine, a pharmaceutically acceptable salt thereof, or a solvate thereof. The composition according to any one of claims 1 to 5, wherein the component (C) comprises sodium edetate or a hydrate thereof. The composition according to any one of claims 1 to 6, wherein component (B) comprises L-cysteine hydrochloride or a hydrate thereof. A liquid containing (A) pemetrexed, a pharmaceutically acceptable salt thereof, or a solvate thereof, (B) cysteine, a pharmaceutically acceptable salt thereof, or a solvate thereof, and (C) a chelating agent. A method for treating malignant pleural mesothelioma or non-small cell lung cancer, comprising the step of administering a therapeutically effective amount thereof to an individual in need of treatment for malignant pleural mesothelioma or non-small cell lung cancer. (A) pemetrexed, a pharmaceutically acceptable salt thereof, or a solvate thereof, (B) cysteine, a pharmaceutically acceptable salt thereof, or for treating malignant pleural mesothelioma or non-small cell lung cancer, or A liquid pharmaceutical composition comprising these solvates and (C) a chelating agent. (A) pemetrexed, a pharmaceutically acceptable salt thereof, or a solvate thereof, (B) cysteine, a pharmaceutically acceptable salt thereof, or for treating malignant pleural mesothelioma or non-small cell lung cancer, or Use of a liquid pharmaceutical composition comprising the solvate and (C) a chelating agent.