JP2009248983A - Medicine tablet - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To solve a problem that a glass-made ampoule container is easily broken, and must be handled with care, and causes troubles such as scattering of glass pieces derived from the cutting of the glass-made ampoule container over a face of a person engaged in medicinal preparation, and mixing of glass pieces in medicine, and any plastic container not causing such troubles is oxygen-permeable, and allows oxygen outside the container to be permeable, and edaravone in a solvate is decomposed thereby. <P>SOLUTION: In the medicinal preparation 1, the solvate containing pyrazolone derivative or its physiologically acceptable salt as an active ingredient is stored in an oxygen permeable container 3, and the oxygen permeable container 3 is stored in a container with oxygen barrier property. A means 5 for removing oxygen is provided in a space between the oxygen permeable container and the container with oxygen barrier property. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

The present invention relates to a pharmaceutical preparation comprising a solvate containing a pyrazolone derivative or a physiologically acceptable salt thereof as an active ingredient in an oxygen permeable container, and further containing the oxygen permeable container in an oxygen barrier container. The invention relates to a pharmaceutical preparation comprising a means for removing oxygen in a gap between the oxygen permeable container and the oxygen barrier container.

  Conventionally, regarding a pyrazolone derivative or a physiologically acceptable salt thereof, a brain function normalizing agent (Patent Document 1), a lipid peroxide production inhibitor (Patent Document 2), and the like are known for pharmaceutical use. A pharmaceutical preparation containing 3-methyl-1-phenyl-2-pyrazolin-5-one (generic name: edaravone), which is one of pyrazolone derivatives, as an active ingredient is a nerve agent associated with an acute phase of cerebral infarction as an effect and effect. It is marketed with improvement of symptoms, daily life movement disorder, and functional disorder (Non-patent Document 1).

  The edaravone is a compound that becomes an anion under physiological conditions, has a property of donating an electron to capture a hydroxy radical, and is very easily oxidized. Therefore, conventional pharmaceutical preparations containing edaravone as an active ingredient prevent the degradation of edaravone by including an antioxidant as an additive. Examples of the antioxidant include sodium sulfite, sodium hydrogen sulfite, and sodium pyrosulfate, which are compounds that generate sulfite ions (Patent Documents 3 to 6). And normally, the said pharmaceutical formulation has prevented decomposition | disassembly of edaravone by accommodating the solvate which uses edaravone as an active ingredient in a glass ampoule container.

Japanese Patent Publication No. 5-31523 Japanese Patent Publication No. 5-35128 Japanese Examined Patent Publication No. 7-121861 JP 2008-1605 A JP 2008-1606 A JP 2008-1607 A "Radicut (registered trademark) Note 30 mg" package insert for ethical drugs, revised in October 2007 (13th edition)

  The glass ampoule container is suitable for preventing the decomposition of edaravone, which is a very easily oxidized compound, because it hardly transmits oxygen outside the container. However, glass ampoule containers are easily damaged and require care in handling, as well as inconveniences such as scattering of glass fragments originating from the cutting of glass ampoule containers to the preparer's face and glass fragments entering the drug. Produce.

  Moreover, since the plastic container which does not produce such an inconvenience is oxygen permeable, it permeate | transmits oxygen outside a container, Therefore The edaravone in the said solvate may be decomposed | disassembled.

  The present inventors have completed the present invention in which a solvate containing a pyrazolone derivative or a physiologically acceptable salt thereof as an active ingredient can be contained in an oxygen permeable container.

  That is, the present invention relates to a pharmaceutical comprising a solvate containing a pyrazolone derivative or a physiologically acceptable salt thereof as an active ingredient in an oxygen permeable container, and further containing the oxygen permeable container in an oxygen barrier container. The present invention relates to a pharmaceutical preparation comprising a means for removing oxygen in a gap between the oxygen permeable container and the oxygen barrier container.

According to the present invention, even when a solvate containing a pyrazolone derivative or a physiologically acceptable salt thereof is contained in an oxygen permeable container such as a plastic container, the quality of the solvate is stabilized. Therefore, it is possible to provide a pharmaceutical preparation suitable for long-term storage of the drug solution.
Furthermore, according to the present invention, the solvate contained in the pyrazolone derivative or physiologically acceptable salt thereof does not contain, for example, an antioxidant such as sulfite, bisulfite and pyrosulfite. Even if it is a case, the stability of the quality of the said solvate is maintained, and the pharmaceutical formulation suitable for the long-term preservation | save of the said chemical | medical solution can be provided.

  As shown in FIG. 1, the pharmaceutical preparation 1 of the present invention contains an oxygen permeable container 3 containing a solvate 2 containing a pyrazolone derivative or a physiologically acceptable salt thereof, and an oxygen permeable container 3. The oxygen barrier container 4 and the gap 9 between the oxygen permeable container 3 and the oxygen barrier container 4 are provided with means 5 for removing oxygen.

  The pharmaceutical preparation 1 in the present invention contains a pyrazolone derivative or a physiologically acceptable salt thereof as an active ingredient. The pyrazolone derivative is a compound represented by the following (Chemical Formula 1) and includes even related substances.

In Chemical Formula ₁ , R ₁ includes, for example, a hydrogen atom, an aryloxy group, an aryl mercapto group, an alkyl group having 1 to 5 carbon atoms, and a hydrogen atom is particularly desirable. Examples of R ₂ include a hydrogen atom, an aryl group, and an alkyl group having 1 to 5 carbon atoms, and a methyl group is particularly desirable. Examples of R ₃ include a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group, and an aryl group. Is desirable. As the pyrazolone derivative of the present invention, 3-methyl-1-phenyl-2-pyrazolin-5-one (generic name: edaravone) is particularly preferable.

  Edaravone is a white to slightly yellowish white crystal or crystalline powder, and is particularly used as an active ingredient of Radicut (registered trademark) Note. Since edaravone is neutral to basic and easily ionized, it is desirable that edaravone be stored in a weakly acidic state. The weak acidity is preferably in the range of pH 2.5 to 6.5, more preferably in the range of pH 3.0 to 4.5, but the range is not particularly limited.

  Examples of physiologically acceptable salts include salts with mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, salts with organic acids such as acetic acid, oxalic acid, citric acid, malic acid and fumaric acid, sodium and potassium. Examples thereof include salts with alkali metals such as magnesium, and salts with alkaline earth metals such as magnesium and calcium, but the type is not particularly limited.

  The solvate 2 is a solution in which solute molecules or ions and solvent molecules are stabilized by interaction in the solution. The pyrazolone derivative of the present invention or a physiologically acceptable salt thereof is contained in the solvate 2, and the concentration of the pyrazolone derivative or the physiologically acceptable salt thereof is 0.05. It is desirable to contain ˜7 mg / mL. More preferably, the weight / volume concentration of the pyrazolone derivative or physiologically acceptable salt thereof is preferably 0.3 to 3 mg / mL.

The oxygen permeable container 3 is a container that can accommodate the solvate 2 and is a container in which the inside and the outside of the container easily transmit oxygen. Examples of the material of the oxygen permeable container 3 include polyolefin resins such as polypropylene (PP), polyethylene (PE) and polymethylpentene (TPX), polyvinyl resins such as polyvinyl chloride (PVC), and cyclic olefin copolymers ( COC) and cyclic olefin-based resins such as cyclic olefin homopolymer (COP), and the like, or a single layer composed of a combination of these, or a multilayer material thereof, in particular, from the viewpoint of a material with little interaction with active ingredients, etc. Cyclic olefin resins are desirable. Applications of the oxygen permeable container 3 include prefilled syringes, plastic ampules, plastic bottles, plastic bags, and the like, but the applications are not particularly limited. The oxygen permeability in the present invention is, for example, an oxygen permeability measured by JIS standard (1987 edition) K7126 “Plastic film and sheet gas permeability test method” of 20 cm ³ / m ² · 24 hrs · atm or more. It points to something.

  When using a prefilled syringe, a plastic bottle, a plastic bag, or the like in the oxygen permeable container 3, a member such as rubber may be used. Examples of the member used for the oxygen permeable container 3 include chlorinated butyl rubber, normal butyl rubber, butadiene rubber, isoprene rubber, silicone rubber, and elastomer. The member used for the oxygen permeable container 3 is, for example, ethylene / tetrafluoro from the viewpoint of suppressing the permeation of oxygen and preventing the interaction with the active ingredient pyrazolone derivative or a physiologically acceptable salt thereof. It is desirable that some or all of them be laminated with ethylene, polytetrafluoroethylene, tetrafluoroethylene / hexafluoropropylene copolymer or the like.

  When encapsulating the solvate 2 in the oxygen permeable container 3, it is desirable to exhaust the oxygen in the solvate 2 or the oxygen permeable container 3 by bubbling the solvate 2 with an inert gas. . Examples of the inert gas include nitrogen gas and helium gas, but nitrogen gas is desirable from the viewpoint of being inexpensive (hereinafter bubbling the solvate 2 with nitrogen gas is abbreviated as nitrogen purge). ). Since the oxygen concentration in the oxygen permeable container 3 can be reduced by evacuating the oxygen in the solvate 2 or the oxygen permeable container 3, the pharmaceutical preparation is a pyrazolone derivative or a physiologically acceptable salt thereof. It is possible to prevent the decomposition of edaravone and the like. The oxygen concentration is preferably 6 ppm to 0.001 ppm, and more preferably 4 ppm to 0.01 ppm. In addition, when the solvate 2 is sealed in a glass ampoule container and a glass vial container having an oxygen barrier property, the solvate 2 or the glass product is made by bubbling the solvate 2 with an inert gas. Oxygen inside the ampoule container and the glass vial container can be exhausted, and the effect is the same as in the case of the oxygen permeable container 3 described above.

  The oxygen barrier container 4 contains the oxygen permeable container 3 and is a container in which the inside and the outside of the container do not easily transmit oxygen. Examples of the material of the oxygen barrier container 4 include polyethylene terephthalate, ethylene vinyl alcohol copolymer, polyvinylidene chloride, polyacrylonitrile, polyvinyl alcohol, polyamide, polyester, nylon, and a single layer or a combination of these materials. Among them, polyethylene terephthalate is desirable particularly from the viewpoint that the material is inexpensive. The oxygen barrier container 4 may be any film or sheet of various materials generally used for medical purposes. For example, an alumina vapor-deposited film (GX film, manufactured by Toppan Printing Co., Ltd.) and a silica vapor-deposited film (Tech barrier ( Registered trademark) and Mitsubishi Plastics Co., Ltd.). Furthermore, as a method for accommodating the oxygen permeable container 3 in the oxygen barrier container 4, from the viewpoint of reducing the oxygen concentration in the gap 9 between the oxygen permeable container 3 and the oxygen barrier container 4, nitrogen gas, helium gas, etc. It is possible to use a means such as packaging, vacuum packaging, shrink packaging, etc.

  The means 5 for removing oxygen is a means for making the atmosphere of the gap 9 between the oxygen permeable container 3 and the oxygen barrier container 4 free from oxygen. The means 5 for removing oxygen includes, for example, installing an oxygen absorbent (deoxygenating agent) in the gap 9 between the oxygen permeable container 3 and the oxygen barrier container 4, and setting the oxygen permeable container 3 to oxygen. Substitution with inert gas such as nitrogen gas or helium gas in the barrier container 4 and packaging, vacuum packaging, shrink packaging, etc. are mentioned, but the packaging operation in the oxygen barrier container 4 is simple. In view of the above, it is desirable to install the oxygen absorbent.

  Examples of the oxygen absorbent include those that absorb oxygen and generate carbon dioxide, those that absorb oxygen and generate ethanol, and those that absorb oxygen and do not generate gas. As the oxygen absorber in the foregoing, among the pyrazolone derivatives or physiologically acceptable salts thereof, oxygen is absorbed particularly from the viewpoint of stability when edaravone is weakly acidic, or from the viewpoint that this pharmaceutical preparation is an injection. At the same time, those that do not generate ethanol are desirable. That is, as the oxygen absorbent of the present invention, those that absorb oxygen and generate carbon dioxide, and those that only absorb oxygen and do not generate gas are desirable. In short, as the oxygen absorbent of the present invention, iron-based self-reactive and organic self-reactive deoxygenating agents are desirable. Known oxygen absorbers include, for example, AGELESS (registered trademark) SA type, ZP type, GL type, GT type (manufactured by Mitsubishi Gas Chemical Co., Ltd.), Tamotsu (registered trademark) VX type, D type (Oe Chemical Co., Ltd.) Company-made), Sansocut (registered trademark) FW type, GD type (manufactured by Oe Chemical Co., Ltd.), and the like.

  Furthermore, the present invention is also applied to the case where the solvate 2 contained in the pyrazolone derivative or a physiologically acceptable salt thereof does not contain an antioxidant as an additive. Examples of the antioxidant include sulfite, bisulfite, pyrosulfite and the like. More specifically, as the antioxidant, from the viewpoint of strong oxidation, for example, sodium sulfite, potassium sulfite, calcium sulfite, sodium hydrogen sulfite, potassium hydrogen sulfite, ammonium hydrogen sulfite, sodium pyrosulfite, potassium pyrosulfite, etc. Is mentioned. The present invention can be applied to inconvenient patients who develop allergic side effects by not containing a highly oxidizing antioxidant in the pharmaceutical preparation.

  Examples are shown below, but the present invention is not limited thereto.

[Example 1]
20 mL of a solvate containing edaravone as an active ingredient was filled in a plastic syringe (oxygen permeable container in the present invention). The solvate contains 30 mg of edaravone as an active ingredient in 20 mL, and 20 mg of sodium bisulfite, 10 mg of L-cysteine hydrochloride monohydrate, 135 mg of sodium chloride, sodium hydroxide and phosphoric acid as other additives. Appropriate amount is contained. And about the said plastic syringe and Ageless (registered trademark) ZP (Mitsubishi Gas Chemical Co., Ltd.), two alumina vapor deposition films (GX2 film, Toppan Printing Co., Ltd.) (oxygen barrier container in the present invention) The peripheral portions were sealed by heat sealing.

[Example 2]
20 mL of a solvate containing edaravone as an active ingredient was filled in a plastic syringe (oxygen permeable container in the present invention). The solvate contains 30 mg of edaravone as an active ingredient in 20 mL, no sodium bisulfite is added as an additive, L-cysteine hydrochloride monohydrate 10 mg, sodium chloride 135 mg, sodium hydroxide and It contains an appropriate amount of phosphoric acid. And about the said plastic syringe and Ageless (registered trademark) ZP (Mitsubishi Gas Chemical Co., Ltd.), two alumina vapor deposition films (GX2 film, Toppan Printing Co., Ltd.) (oxygen barrier container in the present invention) The peripheral portions were sealed by heat sealing.

[Comparative Example 1]
20 mL of a solvate containing edaravone as an active ingredient was filled in a plastic syringe (oxygen permeable container in the present invention). The solvate contains 30 mg of edaravone as an active ingredient in 20 mL, and 20 mg of sodium bisulfite, 10 mg of L-cysteine hydrochloride monohydrate, 135 mg of sodium chloride, sodium hydroxide and phosphoric acid as other additives. Appropriate amount is contained. And about the said plastic syringe, it enclosed by heat-sealing the peripheral parts of two alumina vapor deposition films (GX2 film, Toppan Printing Co., Ltd.) (oxygen barrier container in this invention).

[Comparative Example 2]
20 mL of a solvate containing edaravone as an active ingredient was filled in a plastic syringe (oxygen permeable container in the present invention). The solvate contains 30 mg of edaravone as an active ingredient in 20 mL, no sodium bisulfite is added as an additive, L-cysteine hydrochloride monohydrate 10 mg, sodium chloride 135 mg, and sodium hydroxide and It contains an appropriate amount of phosphoric acid. And about the said plastic syringe, it enclosed by heat-sealing the peripheral parts of two alumina vapor deposition films (GX2 film, Toppan Printing Co., Ltd.) (oxygen barrier container in this invention).

[Reference Example 1]
A glass vial was filled with 20 mL of a solvate containing edaravone as an active ingredient, purged with nitrogen, and a rubber stopper was attached to the inlet of the glass vial. The solvate contains 30 mg of edaravone as an active ingredient in 20 mL, and as other additives, sodium bisulfite 20 mg, L-cysteine hydrochloride monohydrate 10 mg, sodium chloride 135 mg, sodium hydroxide and phosphoric acid Is contained in an appropriate amount.

[Reference Example 2]
A glass vial was filled with 20 mL of a solvate containing edaravone as an active ingredient, purged with nitrogen, and a rubber stopper was plugged at the inlet of the glass vial. The solvate contains 30 mg of edaravone as an active ingredient in 20 mL, no sodium bisulfite is added as an additive, L-cysteine hydrochloride monohydrate 10 mg, sodium chloride 135 mg, sodium hydroxide and It contains an appropriate amount of phosphoric acid.

[Experiment 1]
As the plastic syringe, a barrel (syringe outer cylinder) and a plunger made of polypropylene (made by Nipro Pharma Corporation) and a top cap and a gasket made of chlorinated butyl rubber (made by Nipro Corporation) were used.

  As the glass vial, a white vial (manufactured by Maruemu Co., Ltd.), which is a borosilicate glass, was used as a material.

  The pharmaceutical preparations contained in these 6 groups of plastic syringes and glass vials were subjected to storage experiments for 20 days under accelerated conditions of 60 ° C. ± 2 ° C. and 75% RH ± 5% RH.

The concentration of edaravone related substances was measured by liquid chromatography.
Test conditions Detector: UV absorption photometer (measurement wavelength: 240 nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 15 cm was filled with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 40 degrees Mobile phase: Ammonia water was added to a water / methanol / acetic acid mixture (100/100/1) to adjust the pH to 5.5.
Flow rate: The edaravone retention time was adjusted to 4 minutes.
Injection volume: 20 μL

After collecting 1 mL of 20 mL of each solvate of Example 1, Example 2, Comparative Example 1, Comparative Example 2, Reference Example 1 and Reference Example 2, the mobile phase was further added to make 20 mL. Each sample solution was used. Then, 1 mL of 20 mL of the sample solution was collected, and then the mobile phase was added to make 100 mL, which was used as each standard solution. Using the sample solution and the standard solution, the test was performed by the liquid chromatograph method, the respective peak areas were measured by the automatic integration method, and the total amount of related substances (%) was determined by the following formula.
Total related substance amount (%) = (sum of peak areas other than edaravone in sample solution (total related substances) ÷ peak area of edaravone in standard solution) × 1

  FIG. 2 is a graph showing the experimental results of Experimental Example 1. The vertical axis represents the total amount of related substances (%), and the horizontal axis represents the storage period (days). In the figure, thin broken line a is Example 1, thick broken line b is Example 2, thin dotted line c is Comparative Example 1, thick dotted line d is Comparative Example 2, thin solid line e is Reference Example 1, and thick solid line f is Reference Example 2. The change of the total related substance amount (%) in each storage period is shown. As is clear from FIG. 2, Example 1 and Example 2 are different from Comparative Example 1 and Comparative Example 2 in terms of the total amount of related substances in Reference Example 1 and Reference Example 2 filled in the glass vial. Showed close quality. That is, it became clear that Example 1 and Example 2 can suppress deterioration in the quality of the drug compared to Comparative Example 1 and Comparative Example 2.

It is sectional drawing which shows the pharmaceutical formulation of preferable embodiment of this invention. It is a graph which shows the experimental result of Experimental example 1, and the vertical axis | shaft has shown the total amount of related substances (%), and the horizontal axis has shown the preservation | save period (day).

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Pharmaceutical preparation 2 Solvate 3 Oxygen permeable container 4 Oxygen barrier container 5 Means to remove oxygen 6 Top cap 7 Gasket 8 Plunger 9 Gap

Claims (5)

  A pharmaceutical preparation comprising a solvate containing a pyrazolone derivative or a physiologically acceptable salt thereof as an active ingredient in an oxygen permeable container, and further containing the oxygen permeable container in an oxygen barrier container, A pharmaceutical preparation comprising means for removing oxygen in a gap between the oxygen permeable container and the oxygen barrier container.   The pharmaceutical preparation according to claim 1, wherein the material of the oxygen permeable container is a polyolefin resin, a polyvinyl resin or a cyclic olefin resin.   The pharmaceutical preparation according to claim 1, wherein the oxygen permeable container is a prefilled syringe, a plastic ampule, a plastic bottle or a plastic bag.   The pharmaceutical preparation according to any one of claims 1 to 3, wherein the means for removing oxygen is an oxygen absorbent.   The pharmaceutical preparation according to claim 4, wherein the oxygen absorbent is an iron-based self-reactive or organic self-reactive oxygen absorber.

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