JP2008101007A - Injection containing pyrimidine antimetabolite - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for stabilizing a 5-fluorouracil-containing injection against an appearance change whereby the injection can be stably preserved without being colored even when stored for a long term at room temperature or when sterilized by heating. <P>SOLUTION: This method is a method for stabilizing a 5-fluorouracil-containing injection comprising adding (especially in 0.01-10 wt.%) trishydroxymethylaminomethane to the 5-fluorouracil-containing injection and filling the resultant injection into a plastic container. It is desirable that the injection further contains an isotonicifier (especially, sodium chloride or glucose). The plastic container is desirably a container made from polystyrene, polyamide, polycarbonate, polymethylpentene, polyester, polypropylene, or a resin comprising a cycloolefin compound or a bridged polycyclic hydrocarbon compound as a polymer-forming component. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an injection solution containing a pyrimidine antimetabolite.

Many injection solutions encapsulated in ampoules are commercially available as injection solutions containing pyrimidine antimetabolites, but when injecting drug solutions, ampule cut work, suction of drug solution into syringes, etc. are necessary There may be problems such as mixing of glass pieces into the drug solution during ampoule cutting or contamination of the drug solution from the outside. In addition, vial preparations are mainly used overseas, but the preparations have a property of yellowing during heat sterilization and storage at room temperature, and a means for preventing this yellowing is desired in preparations. In Patent Document 1, an antioxidant such as metabisulfite and bisulfite is blended in an amount of about 0.05 to 2 mol ions per mol of 1- (2-tetrahydrofuryl) -5-fluorouracil, and has a pH of about 9 to 11 In Patent Document 2, the metal salt of formaldehyde sulfoxylic acid is added in an amount of 0.005 to 5 w / v% with respect to the solution of 1- (2-tetrahydrofuryl) -5-fluorouracil. And a method for preventing coloration is disclosed.
However, in the method of Patent Document 1, bronchospasm, anaphylactic shock, etc. may be caused by the use of an antioxidant. In the method of Patent Document 2, a metal salt of formaldehyde sulfoxylic acid is not recognized as a pharmaceutical additive. However, considering the effect on the living body, it is difficult to say that this is a preferable method from the viewpoint of safety.
Therefore, there is a demand for the development of an injectable solution containing a stable pyrimidine antimetabolite that is highly safe and does not color the pyrimidine antimetabolite even when stored at room temperature.
Japanese Patent Laid-Open No. 52-130906 JP 52-102415 A

  An object of the present invention is to provide an injection solution containing a pyrimidine antimetabolite that can be stably stored without being colored even when stored for a long time under room temperature conditions or during heat sterilization.

  An injection solution containing a pyrimidine antimetabolite in a plastic container is provided. The injection solution disclosed in the present invention does not affect the active ingredient, the added ingredient does not affect the safety, the adjustment process is simple, and the pyrimidine antimetabolite is stable even when stored at room temperature. This is an injection solution containing a pyrimidine antimetabolite.

  As a result of diligent research, the present inventors have obtained an injection solution that does not color even when stored at room temperature and at the time of heat sterilization, if a solution containing a pyrimidine antimetabolite is enclosed in a plastic container, and a preparation process Has been found to be simple, and the present invention has been completed.

  The present invention relates to an injection solution containing a pyrimidine antimetabolite in a plastic container. It is more preferable that the injection solution contains a pH adjuster or an isotonic agent.

  The present invention also relates to a method for stabilizing a solution, characterized in that a solution containing a pyrimidine antimetabolite is present in a plastic container.

The pyrimidine antimetabolite used in the injection solution of the present invention is not particularly limited, and specific examples include 5-fluorouracil, 1- (2-tetrahydrofuryl) -5-fluorouracil, 2′-deoxy-5-fluoro. Uridine, 4-amino-1-arabinofuranosyl-2-oxo-1,2-dihydropyrimidine, 5-fluoro-N-hexyl-1,2,3,4-tetrahydro-2,4-dioxo-1- Examples include pyrimidinecarboxamide, 5′-deoxy-5-fluorouridine, N4-behenoyl-1-β-D-arabinofuranosylcytosine and the like.
Particularly preferred as a pyrimidine antimetabolite are 5-fluorouracil and 1- (2-tetrahydrofuryl) -5-fluorouracil.

Examples of the plastic container include containers made of a resin having a polymer component of polystyrene, polyamide, polycarbonate, polymethylpentene, polyester, polypropylene, a cyclic olefin compound, or a crosslinked polycyclic hydrocarbon compound.
Preferable as the plastic container is a container made of a resin having polystyrene or polypropylene as a polymer component.

Examples of the pH adjuster include aqueous ammonia, sodium acetate, potassium hydroxide, sodium hydroxide, meglumine, sodium bicarbonate, sodium carbonate, trishydroxymethylaminomethane, and the isotonic agent includes, for example, sodium chloride. , Calcium chloride, potassium chloride, magnesium chloride, fructose, sodium citrate, glucose, D-mannitol and the like.
Sodium hydroxide and trishydroxymethylaminomethane are preferable as the pH adjusting agent, and sodium chloride and glucose are preferable as the isotonic agent.

  Examples of the solution containing a pyrimidine antimetabolite include an aqueous solution containing a pyrimidine antimetabolite.

  INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide an injection solution that is stably retained without being colored by decomposition of a pyrimidine antimetabolite even when stored at room temperature for a long period.

  An injection solution containing a pyrimidine antimetabolite in a plastic container is prepared by dispensing a solution containing a pyrimidine antimetabolite and, if necessary, a pH adjuster or an isotonic agent into a plastic container after aseptic filtration using a membrane filter or the like. It can be obtained by pouring and sealing with a rubber stopper, an aluminum cap or the like, or filling into an integrally molded plastic bottle using a blow fill seal system (Blow / Fill / Seal System).

  When the plastic container is, for example, a plastic syringe (syringe) and an injection solution (so-called prefilled syringe preparation) in which a solution containing a pyrimidine antimetabolite is filled in advance (so-called prefilled syringe preparation), a needle or cannula for mounting It is possible to produce a kit by sealing the tip with a rubber or plastic part and sealing the plunger rod with a rubber or plastic gasket or plunger rod. That is, when a solution containing a pyrimidine antimetabolite is filled from the tip for attaching an injection needle or cannula, the tip is then sealed with a rubber or plastic part, and the plunger rod is When a solution containing a pyrimidine antimetabolite is filled, it can be prepared as a kit by sealing with the plunger rod.

  The solution may appropriately contain components that can be used for injections, such as buffers, solubilizers, preservatives, and the like, if desired. Examples of the buffer include potassium dihydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium citrate, and so on. Ethanol, ethylenediamine, capric acid, L-glutamic acid, L-lysine, calcium oxide, magnesium oxide, sorbitan sesquioleate, D-sorbitol, nicotinamide, propylene glycol, polysorbate 80, lauromacrogol (9E.O.), etc. Examples of the preservative include phenol, sodium edetate, benzalkonium chloride, citric acid, chlorocresol, chlorobutanol, sodium salicylate, ethyl paraoxybenzoate, butyl paraoxybenzoate, and the like.

  The content of the pyrimidine antimetabolite in the injection solution is appropriately determined according to various properties of each drug. In the case of an injection solution, it is generally in the range of 1 to 10% by weight, preferably 2 to 5% by weight. The content of the pH adjusting agent is preferably 0.01 to 10% by weight, and the content of the tonicity agent is preferably 0.01 to 10% by weight. Moreover, as pH of the solution containing a pH adjuster, 7-10 are preferable.

  When the injection solution of the present invention is used, injection is performed by removing the tip-sealing part, attaching an injection needle, a cannula, etc. to the tip, and operating the plunger rod.

When the preparation of the present invention is used as, for example, an antitumor agent, the dose and frequency of administration vary depending on factors such as the patient's age, weight, and symptoms, but are usually 0.01 to 20 mg / kg once a day (single (Multiple administration or daily administration) or intermittent administration such as 1 to 5 times a week or once every 3 weeks is suitable.
Next, the stability of the injection solution of the present invention is shown by test examples.

Test Example: Appearance Stability Comparison Test The liquid preparation of the present invention obtained in Examples 1 to 3 described later and the liquid preparation obtained in Comparative Examples 1 to 4 are stored for 3 months under the conditions of 40 ° C. and 75% relative humidity. Then, the absorbance (Abs) at 430 nm was measured using an absorptiometer (layer length 10 mm, reference: distilled water).
The results are shown in Table 1.

As is apparent from Table 1, coloring was remarkably observed in the liquid preparation obtained in the comparative example, whereas almost no coloring was observed in the liquid preparation of the present invention, and the liquid preparation of the present invention or the solution of the present invention was not observed. It was confirmed that the appearance stability was excellent.
Examples of the present invention and comparative examples are shown below.

  An aqueous solution (5 ml) containing 5-fluorouracil (250 mg) and trishydroxymethylaminomethane (423.5 mg) was prepared, and after sterile filtration, it was aseptically filled into a polystyrene Spitz tube (Falcon, 2054) and sealed tightly, and the solution was Obtained.

  A liquid agent was obtained in the same manner as in Example 1 except that a polypropylene spitz tube (Falcon, 2063) was used instead of the polystyrene spitz tube.

Ftorafur ^TM Notes [1- (2-tetrahydrofuryl) -5-fluorouracil 400 mg / 10 ml ampoule, Taiho Pharmaceutical Co.] and polystyrene Spitz tube (Falcon, 2054) and aseptically filled into and sealed A solution was obtained.

Comparative Example 1
An aqueous solution (5 ml) containing 5-fluorouracil (250 mg) and trishydroxymethylaminomethane (423.5 mg) was prepared. After aseptic filtration, it was aseptically filled into a glass vial [Daiwa Special Glass Co., Ltd.], with a rubber stopper and aluminum The solution was obtained by sealing with a cap.

Comparative Example 2
A brown glass vial [manufactured by Daiwa Specialty Glass Co., Ltd.] was used instead of the glass vial, and a liquid was obtained in the same manner as in Comparative Example 1.

Comparative Example 3
Ftorafur ^TM Notes [1- (2-tetrahydrofuryl) -5-fluorouracil 400 mg / 10 ml ampoule, Taiho Pharmaceutical Co.] and aseptically filled into glass vials [Yamato Special Glass Co., Ltd.], Rubber The solution was obtained by sealing with a stopper and an aluminum cap.

Comparative Example 4
A brown glass vial [manufactured by Daiwa Specialty Glass Co., Ltd.] was used instead of the glass vial, and a liquid was obtained in the same manner as in Comparative Example 3.

Claims (9)

  A method for stabilizing the appearance of a 5-fluorouracil-containing solution during long-term storage, which comprises adding trishydroxymethylaminomethane to a solution containing 5-fluorouracil and filling the solution in a plastic container.   2. The stabilization method according to claim 1, wherein trishydroxymethylaminomethane is contained in an amount of 0.01 to 10% by weight in a solution containing 5-fluorouracil.   3. The stabilization method according to claim 1, wherein a solution containing 5-fluorouracil further contains an isotonic agent.   4. The stabilization method according to claim 3, wherein the tonicity agent is sodium chloride or glucose.   The stabilization method according to claim 3 or 4, wherein the isotonizing agent is contained in a solution containing 5-fluorouracil in an amount of 0.01 to 10% by weight.   6. The plastic container is a container made of a resin having a polymer component of polystyrene, polyamide, polycarbonate, polymethylpentene, polyester, polypropylene, a cyclic olefin compound or a crosslinked polycyclic hydrocarbon compound. The stabilization method described in 1.   The stabilization method according to any one of claims 1 to 6, wherein the plastic container is a plastic bottle integrally formed using a blow fill seal system (Blow / Fill / Seal System).   The stabilization method according to any one of claims 1 to 6, wherein the plastic container is a plastic syringe.   The plastic container is a plastic syringe, the tip for mounting the injection needle or cannula of the plastic syringe is sealed with a rubber or plastic part, and the plunger rod part of the plastic syringe is made of rubber or plastic 7. The stabilization method according to claim 1, which is sealed with a gasket or a plunger rod.