JP2012001493A - Ritodrine hydrochloride injection formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a ritodrine hydrochloride injection formulation containing ritodrine hydrochloride having a specific concentration and a sulfite having a specific concentration, controlled to a specific pH and effective for suppressing formation of a threo-isomer and a sulfite adduct.SOLUTION: There is provided a ritodrine hydrochloride injectable formulation prepared by filling a plastic container with an injection liquid containing 5-15 mg/mL of ritodrine hydrochloride and 0.3-0.7 mg/mL of a sulfite and having a pH of 4.7-5.5, and sealing the container together with a deoxidation agent in a poorly oxygen-permeating packaging material.

Description

The present invention relates to a liquid drug in which ritodrine hydrochloride is dissolved.

Ritodrine hydrochloride is a pharmaceutical used as a treatment for imminent abortion / premature labor, and is administered by intravenous infusion in the form of diluted glucose or maltose injection.
In general, ritodrine hydrochloride injection solution is difficult to store at room temperature because oxidative degradation products and isomerized products (threo form) are generated by heat. Therefore, commercially available ritodrine hydrochloride injection is a glass ampoule filling preparation that requires refrigerated storage at 5 ° C. or less, and sulfites are blended as an antioxidant.
However, when sulfites are added, instead of inhibiting the formation of oxidative degradation products, the sulfido adduct of ritodrine hydrochloride (S1: threo-1- (4-hydroxyphenyl) -2- [2- (4-hydroxyphenyl) ) Ethylamino] -1-propanesulfonic acid, S2: erythro-1- (4-hydroxyphenyl) -2- [2- (4-hydroxyphenyl) ethylamino] -1-propanesulfonic acid) There's a problem. In particular, it has been reported that when high-pressure steam sterilization is performed during the production process, the production of threo bodies and sulfite adducts increases (Non-patent Document 1).
In this way, ritodrine hydrochloride has no problem if stored refrigerated, but threo and sulfite adducts are generated due to the effect of heat, so it is very easy to perform heat sterilization or change to room temperature storage. Have difficulty.

Rindolph Intravenous Infusion 50mg Purity Test

The ritodrine hydrochloride injection solution was a glass ampoule-filled preparation that required refrigerated storage at 5 ° C. or lower in order to suppress the formation of related substances as described above. In order to provide this injection solution more safely in the medical field, a prefilled syringe preparation filled in a syringe, particularly a plastic syringe, is required instead of a glass ampule. However, when prefilled syringes are used, the shape is different from that of conventional ampules and vials, so storage in a refrigerator that is generally laid out suitable for storage of ampules and vials becomes complicated, so there is no such limitation. In the medical field, it is desired to provide a plastic prefilled syringe preparation that can be stored at room temperature.
In order to preserve at room temperature, it is important to suppress the formation of a threo form. For this reason, if an excessive amount of sulfite is added as a stabilizer, a large amount of sulfidoline adduct of ritodrine hydrochloride is produced. Accordingly, an object of the present invention is to provide a safe ritodrine hydrochloride injection preparation that can be stored at room temperature for a long period of time by suppressing the formation of a threo form as well as the formation of a sulfite adduct.

  In view of the above-mentioned problems, as a result of intensive research on an injection solution containing ritodrine hydrochloride and containing sulfites, it was found that the above problem can be solved by setting the blending amount of sulfites to a specific range, The present invention has been reached.

The above problems are solved by the present invention described below.

(1) A ritodrine hydrochloride injection preparation containing 5-15 mg / mL ritodrine hydrochloride and 0.3-0.7 mg / mL sulfites and having a pH of 4.7-5.5.

(2) The ritodrine hydrochloride injection preparation according to (1) filled in a plastic container.

(3) The ritodrine hydrochloride injection preparation according to (2), wherein the plastic container is a syringe.

(4) The ritodrine hydrochloride injection preparation according to (2) or (3), which is enclosed in a poorly oxygen permeable packaging material together with an oxygen scavenger.

(5) The ritodrine hydrochloride injection preparation according to (4), wherein the oxygen poorly permeable packaging material has light shielding properties.

(6) The ritodrine hydrochloride injection preparation according to any one of (1) to (5), which has been subjected to high-pressure steam sterilization.

  The present invention is a ritodrine hydrochloride injection preparation in which an aqueous ritodrine hydrochloride solution contains a specific concentration of sulfite and is adjusted to a specific pH, and the production of threo form and sulfite adduct is suppressed. Further, since the container is made of plastic, there is no fear of breakage, and there is no possibility of glass flakes being mixed into the injection solution. In addition, since the container is a syringe or other syringe, it can be easily and reliably mixed in a diluted solution such as glucose injection solution or maltose injection solution in a short time. Is to provide.

FIG. 1 is a cross-sectional view of an embodiment of the medical container of the present invention.

  The ritodrine hydrochloride injection preparation of the present invention comprises a plastic container filled with a ritodrine hydrochloride injection solution prepared by adjusting an aqueous solution containing a specific concentration of ritodrine hydrochloride and a specific concentration of sulfite to a specific pH, and oxygenated together with an oxygen scavenger. It is a stable injectable preparation that is sealed in a poorly permeable packaging material and suppresses the formation of threo and sulfite adducts.

  The concentration of ritodrine hydrochloride in the injection solution is 5 to 15 mg / mL, and the concentration of sulfites is 0.3 to 0.7 mg / mL. As the sulfites, for example, alkali metal sulfites such as sodium hydrogen sulfite, sodium pyrosulfite and sodium sulfite are preferably used. An isotonic agent such as sodium chloride, glucose, maltose, mannitol, sorbitol, mannose, sodium citrate, sodium acetate, sodium dihydrogen phosphate, or sodium lactate can be appropriately added to the injection solution. In addition, this injection is composed of acetic acid, glacial acetic acid, hydrochloric acid, citric acid, lactic acid, sulfuric acid, succinic acid, L-aspartic acid, L-glutamic acid, benzoic acid, phosphoric acid, malic acid, ascorbic acid, gluconic acid, or nicotine. Acidic substances such as sodium hydroxide, sodium acetate, sodium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium lactate, dipotassium phosphate, trisodium phosphate, disodium hydrogen phosphate, or ammonium acetate Etc. can be added.

  For the plastic container of the present invention, a material having low water vapor permeability is desirable. From these viewpoints, polypropylene, polyethylene, polystyrene, polyamide, poly (4-methylpentene-1), acrylic resin, acrylonitrile-butadiene-styrene copolymer, polyethylene terephthalate, polyethylene naphthalate, cyclic olefin polymer, cyclic olefin copolymer, etc. It is preferably formed of an optically transparent material such as a cyclic polyolefin, a polyolefin such as amorphous polyarylate, or a polyester. Cyclic polyolefin, polypropylene, and polyethylene are particularly desirable.

  The container can be in the form of a plastic ampoule, plastic vial, etc., but is preferably in the form of a syringe. The syringe has an injection needle attached to the tip, or an outer cylinder having an attachment part for the injection needle, is in close contact with the inner surface of the outer cylinder, seals the rear end opening side of the outer cylinder inner space, and The thing of the syringe form comprised with the slidable gasket and the plunger attached to this gasket rear end is preferable. In this case, the injection solution is sealed in the internal space. As the gasket, any material having the above-described functions may be used. Examples of the forming material include synthetic rubbers such as butyl rubber and isoprene rubber, and elastomer compositions mainly composed of styrene elastomers and olefin elastomers. In addition, as a syringe, it is possible to employ various known syringe shapes such as a syringe shape configured to discharge from a syringe needle to which an injection solution filled by pressing the container itself from the outside is attached. it can.

The packaging material used in the present invention has poor oxygen permeability. The material forming the packaging material has no oxygen permeability or is extremely low, for example, aluminum foil, aluminum vapor deposition film, aluminum oxide vapor deposition film, silicon oxide vapor deposition film, polyvinyl alcohol, ethylene vinyl alcohol. Examples thereof include a laminate film having a copolymer, polyethylene terephthalate, polyethylene naphthalate, polyvinylidene chloride, etc. as a gas barrier layer. When it is necessary to visually recognize the inside from the outside of the packaging material when it is used as a package, aluminum oxide vapor-deposited film, silicon oxide vapor-deposited film, polyvinyl alcohol, ethylene vinyl alcohol copolymer, polyethylene terephthalate, polyethylene naphthalate, polyvinylidene chloride It is preferable to employ a highly transparent gas barrier layer such as, etc., but if necessary, an aluminum foil, an aluminum vapor-deposited film or the like may be employed to form a light-shielding packaging material.

  As the oxygen scavenger, those containing iron compounds such as iron hydroxide, iron oxide and iron carbide as active ingredients can be used. Examples of the commercially available products include AGELESS (registered trademark: manufactured by Mitsubishi Gas Chemical Co., Inc.), Modulan (manufactured by Nippon Kayaku Co., Ltd.), Secur (registered trademark: manufactured by Nippon Soda Co., Ltd.), and the like.

In the present invention, since a plastic container is used, sulfites are consumed by oxygen permeating through the plastic during storage, and the effect of suppressing the production of related substances by sulfites may be impaired. For this reason, by actively utilizing the oxygen permeability of the container and sealing the plastic container filled with ritodrine hydrochloride injection solution with oxygen scavenger with oxygen poorly permeable packaging material, long-term storage stability even at room temperature Is possible. In order to prevent oxidation due to oxygen present in the injection solution or in the space in the container, it is desirable to replace the gas in the container space and the chemical with an inert gas such as nitrogen. For example, it is carried out by bubbling the injection solution with nitrogen and filling the container under a nitrogen atmosphere.

The present invention will be described in detail below, but the present invention is not limited to the following examples.

(Preparation Example 1)
In 450 mL of water for injection, 5.0 g of ritodrine hydrochloride and 1.45 g of sodium chloride were added, and 0, 0.05, 0.15, 0.25, 0.35, and 0.50 g of sodium pyrosulfite were added and dissolved by stirring. After ritodrine hydrochloride and sodium chloride were completely dissolved, 2.175 g of glacial acetic acid was added, and sodium hydroxide was added to adjust to pH 5.25. Water for injection was added to make the total volume 500 mL, and ritodrine hydrochloride injection solution (10 mg / mL) was prepared. This solution is aseptically filtered through a 0.2 μm cellulose acetate filter, and then dissolved oxygen is replaced with nitrogen by nitrogen bubbling, and then 5 mL is filled into a 5 mL polypropylene syringe outer cylinder with the tip nozzle portion sealed as a container. After replacing the space with nitrogen, insert a gasket made of a styrene elastomer composition from the back end opening of the syringe used as a filling port for the injection solution, and plugging with the gasket so that the space becomes as small as possible, A prefilled syringe filled with ritodrine hydrochloride injection was prepared.

Subsequently, the prefilled syringe filled with the ritodrine hydrochloride injection solution was sterilized by high-pressure steam at 115 ° C. for 15 minutes, and an oxygen barrier comprising a laminate film having a gas barrier layer made of an aluminum vapor deposition film together with an oxygen scavenger (trade name: Ageless, manufactured by Mitsubishi Gas Chemical Co., Ltd.). The permeable packaging material was hermetically packaged by heat-sealing the opening to obtain a prefilled syringe package filled with ritodrine hydrochloride injection solution.

(Test Example 1)
Each of the ritodrine hydrochloride injection-filled prefilled syringe packages obtained in Preparation Example 1 was stored at 40 ° C., and the ritodrine hydrochloride content, threo form and sulfite adduct content after 3 months were measured by HPLC, The results are shown in Table 1 (in the table, the value is an average value of n = 3, and the unit is%).

In the measurement, the JP ritodrine hydrochloride purity test was applied mutatis mutandis and the test was carried out by the internal standard method. The content of ritodrine hydrochloride was calculated as the ritodrine hydrochloride content from the peak area of ritodrine with respect to the peak area of the internal standard substance in the sample solution, with the peak area of the internal standard substance in the standard solution being 100. The content of threo form and sulfite adduct was calculated as the ratio of the peak area of threo form and sulfite adduct to the peak area of ritodrine in the sample solution.

  As a result of the measurement, the content of the preparation of Test Example 1 was not significantly decreased over 3 months under storage conditions. However, when sodium pyrosulfite was 0.1 mg / mL or less, an increase in threo form was observed after 3 months, and in the range of 0.3 to 0.7 mg / mL, the production of threo form was suppressed. In addition, the sulfite adduct tends to increase with the amount of sodium pyrosulfite, and a remarkable increase was observed at 1.0 mg / mL or more.

(Preparation Example 2)
In 450 mL of water for injection, 5.0 g of ritodrine hydrochloride and 1.45 g of sodium chloride were added, and 0.15 g of sodium pyrosulfite was added and dissolved by stirring. After ritodrine hydrochloride and sodium chloride were completely dissolved, the pH was adjusted to 5.50, 4.70, 4.00, and 3.00 by adding 2.175 g of glacial acetic acid and glacial acetic acid or sodium hydroxide. Water for injection was added to make the total volume 500 mL, and ritodrine hydrochloride injection solution (10 mg / mL) was prepared. This solution is aseptically filtered through a 0.2 μm cellulose acetate filter, and then dissolved oxygen is replaced with nitrogen by nitrogen bubbling, and then 5 mL is filled into a 5 mL polypropylene syringe outer cylinder with the tip nozzle portion sealed as a container. After replacing the space with nitrogen, insert a gasket made of a styrene elastomer composition from the back end opening of the syringe used as a filling port for the injection solution, and plugging with the gasket so that the space becomes as small as possible, A prefilled syringe filled with ritodrine hydrochloride injection was prepared.

  Subsequently, the prefilled syringe filled with the ritodrine hydrochloride injection solution was sterilized by high-pressure steam at 115 ° C. for 15 minutes, and an oxygen barrier comprising a laminate film having a gas barrier layer made of an aluminum vapor deposition film together with an oxygen scavenger (trade name: Ageless, manufactured by Mitsubishi Gas Chemical Co., Ltd.). The permeable packaging material was hermetically packaged by heat-sealing the opening to obtain a prefilled syringe package filled with ritodrine hydrochloride injection solution.

(Test Example 2)
Each of the ritodrine hydrochloride injection-filled prefilled syringe packages obtained in Preparation Example 2 was stored at 40 ° C., and the ritodrine hydrochloride content, threo form and sulfite adduct content after 3 months were measured by HPLC, The results are shown in Table 2 (in the table, the value is an average value of n = 3, and the unit is%).

  As a result of the measurement, almost no reduction in the content of ritodrine hydrochloride was observed in the preparation of Test Example 2 over 3 months under storage conditions. However, at pH 4.00 or less, an increase in threo form was observed after 3 months.

(Preparation Example 3)
In 450 mL of water for injection, 2.5 and 7.5 g of ritodrine hydrochloride and 1.45 g of sodium chloride were added, and 0.15 g of sodium pyrosulfite was added and dissolved by stirring. After ritodrine hydrochloride and sodium chloride were completely dissolved, 2.175 g of glacial acetic acid was added, and sodium hydroxide was added to adjust to pH 5.25. Water for injection was added to make the total volume 500 mL, and ritodrine hydrochloride injection solution (5 mg / mL, 15 mg / mL) was prepared. This solution is aseptically filtered through a 0.2 μm cellulose acetate filter, and then dissolved oxygen is replaced with nitrogen by nitrogen bubbling, and then 5 mL is filled into a 5 mL polypropylene syringe outer cylinder with the tip nozzle portion sealed as a container. After replacing the space with nitrogen, insert a gasket made of a styrene elastomer composition from the back end opening of the syringe used as a filling port for the injection solution, and plugging with the gasket so that the space becomes as small as possible, A prefilled syringe filled with ritodrine hydrochloride injection was prepared.

  Subsequently, the prefilled syringe filled with the ritodrine hydrochloride injection solution was sterilized by high-pressure steam at 115 ° C. for 15 minutes, and an oxygen barrier comprising a laminate film having a gas barrier layer made of an aluminum vapor deposition film together with an oxygen scavenger (trade name: Ageless, manufactured by Mitsubishi Gas Chemical Co., Ltd.). The permeable packaging material was hermetically packaged by heat-sealing the opening to obtain a prefilled syringe package filled with ritodrine hydrochloride injection solution.

(Test Example 3)
The ritodrine hydrochloride injection filled prefilled syringe package obtained as described above was stored at 40 ° C., and the ritodrine hydrochloride content, threo form and sulfite adduct content after 3 months were measured by HPLC. As in the case of sodium pyrosulfite 0.3 mg / mL in Example 1, no increase in the amount of threo compound and sulfite adduct was observed.

DESCRIPTION OF SYMBOLS 1 Prefilled syringe 2 Outer cylinder 21 Front end opening 22 Rear end opening 3 Gasket 4 Drug 5 Sealing member 6 Plunger

Claims (6)

  A ritodrine hydrochloride injection formulation containing 5-15 mg / mL ritodrine hydrochloride and 0.3-0.7 mg / mL sulfites and having a pH of 4.7-5.5.   The ritodrine hydrochloride injection preparation according to claim 1, which is filled in a plastic container.   The ritodrine hydrochloride injection preparation according to claim 2, wherein the plastic container is a syringe.   The ritodrine hydrochloride injection preparation according to claim 2 or 3, which is enclosed in a poorly oxygen permeable packaging material together with an oxygen scavenger.   The ritodrine hydrochloride injection solution preparation according to claim 4, wherein the oxygen poorly permeable packaging material has a light shielding property.   The ritodrine hydrochloride injection preparation according to any one of claims 1 to 5, which has been subjected to autoclaving.

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