JP2003342165A - Pharmaceutical preparation having improved stability - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To improve the stability of a pharmaceutical preparation filled in a container sealed with a rubber plug. <P>SOLUTION: The pharmaceutical preparation is stably stored in a container sealed with a rubber plug having no polymer film on the surface and essentially free from carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine by immersion test and evaporation test. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug product filled with a drug in a container closed by a rubber stopper. The formulations of the present invention can improve the stability of the encapsulated drug.

[0002]

2. Description of the Related Art In general, preparations have a temperature, humidity,
It is known that physicochemical changes occur due to light or vibration during transportation. The change is the change in appearance,
It is confirmed by a decrease in the content of active ingredients and an increase in impurities. There are many types of drug storage containers that are sealed with stoppers, such as automatic bottles, tube bottles, syringes, capsules, and vials, depending on the purpose. Further, the materials thereof are various such as glass, plastic, and metal, and a stability test is carried out for each drug to be used to determine a material which does not deteriorate the quality of the drug. As the material of the plug body, there are rubber, glass, metal, ceramics, cork and the like, but rubber is widely used in terms of adhesion, lightness, damage resistance, cost and the like.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to improve the stability of a drug in a drug product comprising a container filled with a drug and sealed with a rubber stopper.

[0004]

[MEANS FOR SOLVING THE PROBLEMS] A rubber stopper is superior to a stopper made of glass or the like in many points in terms of adhesion to a container, lightness, breakage resistance and the like. However, the present inventors have found that when a drug is filled in a container closed with a rubber stopper, the storage stability and heat stability of the drug may not be sufficiently satisfied in some cases.

That is, in the rubber stopper used to seal the drug storage container, the vulcanization accelerator contained therein, the sulfur or amine compound contained in the plasticizer, etc. elute into the drug, The present inventors have found that it may interact with a drug, affect the stability of the drug, or cause generation of fine particles.

Therefore, the present inventor diligently studied the properties of the rubber stopper in order to improve the stability of the drug. As a result, surprisingly, in water and volatilization tests, drug stability was achieved by filling the drug in a container sealed by a rubber stopper with virtually no detectable carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine. It has been found that it is possible to significantly improve the sex.

Therefore, it is considered possible to suppress the outflow of sulfur and amine compounds by coating the surface of the rubber plug with a polymer film. Examples of the polymer film include polyfluorinated ethylene resins such as tetrafluoroethylene and tetraethylene fluoroethylene-ethylene copolymer resin, and examples of the coated portion include at least the portion exposed to the drug as the coated portion. To be However, in this method, when the adhesion of the polymer film to the surface of the rubber stopper is insufficient, or when a high frequency of friction between the rubber stopper and the container occurs, a part of the polymer film on the coated surface may not be removed. It may be peeled off, and it is considered that a sufficient effect of preventing eluates cannot be obtained. Further, it is conceivable that the fitting property with the container is deteriorated as compared with the rubber stopper not covered with the polymer film. Further, there are drawbacks such as a complicated manufacturing process of the rubber stopper and an increase in cost. Therefore, it is preferable not to use the polymer film.

[0008] That is, the present invention is a drug product in which a drug is filled in a container sealed with a rubber stopper, wherein the rubber stopper does not have a polymer film on the surface, and is subjected to an underwater test and a volatility test. , A drug stopper characterized in that carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine are substantially undetectable. As the drug to be filled in the present invention, a protein or peptide, particularly calcitonin, more preferably an aqueous solution thereof is used. In addition, as the container, automatic bottle, tube bottle, syringe,
A capsule or the like is used. The invention further relates to methods of improving drug stability by reducing contact of the drug with at least any of carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine. Also,
The present invention, a rubber stopper having no polymer film on the surface,
It relates to a method for inspecting a rubber stopper, which comprises confirming that carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine are not substantially detected in an underwater test and a volatilization test.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, substantially no carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine are detected in an underwater test. When the extracted liquid was analyzed by a gas chromatograph mass spectrometer (GC / MS), carbon disulfide, piperidine, dibutylamine and
It means that N-acetylpiperidine is not detected. Also, if carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine were not substantially detected in the volatilization test, the rubber stopper was heated at 200 ° C and the volatilized components were cooled at -80 ° C and collected. Means that carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine are not detected when is analyzed by a gas chromatograph mass spectrometer (GC / MS).

The form of the drug storage container used in the present invention includes automatic bottles, tube bottles, syringes, capsules, vials and the like. In the present invention, the rubber stopper is an automatic bottle,
In tube bottles, syringes, capsules, vials, etc., it includes all means for preventing drug outflow by rubber. For example, in a vial, a part for sealing the drug outlet of a vial, in a syringe, a piston part, a drug releasing part, etc. Means are included to prevent the outflow of drug from the. There is no particular limitation on the portion sealed by the rubber stopper and the number thereof. As the containers such as these automatic bottles, tube bottles, syringes, capsules, and vials, containers or individual parts that have been sterilized by dry heat sterilization, steam sterilization, gas sterilization, radiation sterilization, etc. can be used as necessary. These sterilization treatments may be carried out after the medicine is filled, as long as there is no safety problem or influence on the medicine.

The material other than the rubber stopper is, for example, glass or polypropylene, polyethylene, cyclic polyolefin, a copolymer of cyclic polyolefin and α-olefin, polyethylene terephthalate, polystyrene,
Plastics such as ABS resin, polyester, polyvinyl chloride, nylon, polytetrafluoroethylene, polymethylpentene, hexafluororesin, polymethylmethacrylate, polycarbonate, metals such as stainless steel, gold, aluminum, aluminum alloys, titanium , Ceramics, composite materials such as carbon composite materials, quartz, etc., but are not limited thereto.

The composition of the rubber plug used in the present invention is a cross-linkable rubber such as butyl rubber, chlorinated butyl rubber or brominated butyl rubber, and the thermoplastic elastomer is, for example, a styrene-conjugated diene block copolymer, or a combination thereof. Examples thereof include hydrogenated block copolymers, epoxidized and carboxylated block copolymers, and hydroxyl group-containing ones. Note that the rubber and the elastomer may be composed of one kind or a mixture of two or more kinds, and a material that does not substantially elute in water and carbon disulfide, piperidine, and butylamine are not substantially detected as volatile components. If so, it is not particularly limited.

[0013] Substantially no elution in the water test is defined as above, but to confirm that it is not substantially detected, 5 g of the molded rubber stopper is dissolved in 50 ml of water.
The liquid extracted at 21 ° C for 60 minutes is analyzed by a gas chromatograph mass spectrometer (GC / MS) to determine whether carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine are detected. You can The measurement conditions of GC / MS are as follows, for example.

[0014] GC / MS measurement conditions   Model Hewlett-Packard Company HP-5973 type   Column PTA-5 (length 30m, inner diameter 0.25mm, film thickness 0.5μm)   Initial temperature 40 ° C (hold for 2 minutes)   Temperature rising rate 5 ℃ per minute (up to 180 ℃)   Inlet temperature 240 ℃   Carrier gas helium   Ionization method EI   Ionization voltage 70 eV   Measured mass number m / z = 30 to 550

Further, it is defined as described above that carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine are not substantially detected in the volatilization test.
To confirm that these components were virtually undetectable, heat 50-150 mg of the rubber stopper at 200 ° C to evaporate the volatilized components around the chamber filled with glass wool at -80 ° C.
It can be carried out by analyzing whether or not it is cooled and collected in a gas chromatograph mass spectrometer (GC / MS) to determine whether carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine are detected. .

[0016] GC / MS measurement conditions   Model Shimadzu GCMS-QP5000 type   Column CBP1-M25-025 (length 30m, inner diameter 0.25mm, film thickness 0.5 μm)   Initial temperature 40 ° C (hold for 3 minutes)   Temperature rising rate 10 ℃ per minute (up to 300 ℃)   Inlet temperature 300 ℃   Carrier gas helium   Ionization method EI   Ionization voltage 1.5KV   Measured mass number m / z = 20 to 600

The rubber plug having the above properties and having no polymer film layer on its surface is the rubber plug used in the present invention.

The agents to be filled and stored in the present invention include proteins, peptides such as insulin, secretin, oxytocin, growth hormone, angiotensin,
Bradykinin, β-endorphin, substance
P, glucagon, dynorphin, somatostatin, thyroid stimulating hormone (TSH), enkephalin, neurotensin, interferon, interleukin, G-CS
F, glutathione peroxidase, superoxide dismutase (SOD), soluble thrombomodulin, calcitonin, elcatonin, PTH (parathyroid hormone), erythropoietin, etc. and one or more amino acids substituted while retaining their activities And analogs thereof, their derivatives or salts.

These may be solid (eg powdery) or liquid (eg aqueous solution, suspension). When the drug is an aqueous solution containing elcatonin as an active ingredient, it is not particularly limited as long as it contains an effective amount of elcatonin, but for example, an aqueous solution in which an appropriate pH is ensured is preferable. As a solvent for ensuring an appropriate pH, a known buffer solution, for example, a citrate buffer solution or an acetate buffer solution can be used. The pH is preferably 5 to 7, and more preferably 5 to 6. The concentration of these is preferably, for example, 0.05 mmol or more, and more preferably 0.1 mmol or more. Although the upper limit of the concentration is not particularly limited, it is usually 20 millimoles or less, preferably 1 millimoles or less.

Specifically, it contains one or more compounds selected from the group consisting of acetic acid, lactic acid, monocarboxylic acids such as L-histidine and / or water-soluble salts thereof, and the concentration thereof is 0.05 to 20. Solvent adjusted to a millimolar concentration, a pH of 5.0 to 6.5 and an ionic strength of μ = 0.01 to 0.5 (JP-A-2-
174726), polycarboxylic acids such as succinic acid, tartaric acid and citric acid, and / or one or more compounds selected from the group consisting of water-soluble salts thereof.
A solvent having a concentration of 0.05 to 20 mmol, a pH of 5.0 to 6.5 and an ionic strength of μ = 0.01 to 0.5 can be used. If necessary, sodium hydroxide, hydrochloric acid or the like can be used to adjust the pH. In addition, additives can be added if necessary. The concentration of elcatonin used may be, for example, 10 to 80 units / mL.

The present invention also provides for stability of a drug by reducing substantial elution in water and reducing contact of the drug with any of carbon disulfide, piperidine, dibutylamine or N-acetylpiperidine. On how to improve. This is compared with the case of using a rubber stopper in which carbon disulfide, piperidine, dibutylamine, and N-acetylpiperidine are substantially detected in an underwater test and a volatilization test, as in Comparative Examples 1 to 3 described below, In the underwater test and volatilization test as in Examples 1 and 2, a significant stabilizing effect was observed by using a rubber stopper in which carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine were not substantially detected. It can be confirmed that this is an effective method. Further, the present invention, a rubber stopper having no polymer film on the surface, in water test and volatilization test, to confirm that carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine are not substantially detected. To a method for inspecting a rubber stopper made of By inspecting the rubber stopper according to the method of the present invention, by using this inspected rubber stopper, the drug whose rubber stopper is filled in the formulation,
In particular, it is possible to prevent interaction with proteins or peptides, stably hold the drug, and prevent the generation of fine particles.

[0022]

The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited thereto.

[0023]

Example 1 0.1 mM sodium acetate buffer (pH
Elcatonin is dissolved in 5.5) to obtain a 40 unit / mL concentration elcatonin aqueous solution composition. Next, after aseptic filtration of this elcatonin aqueous solution composition, a glass 10 mL capacity vial bottle (manufactured by Murase Glass Co., Ltd.) whose inner surface was dealkalized was dispensed into dry-heat sterilized 5.0 mL each, After sealing with a rubber stopper, it was wound with an aluminum cap to obtain a vial preparation. The rubber stopper was previously subjected to the underwater test and the volatilization test by the above method. Then, in the underwater test and the volatilization test of the rubber stopper, a rubber stopper in which carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine are not detected (Oats Tire F10-65 (material F-100
A)) was used.

[0024]

Example 2 0.1 mM sodium acetate buffer (pH 5.
Elcatonin is dissolved in 5) to obtain an elcatonin aqueous solution composition having a concentration of 20 units / mL. Next, a glass syringe with a volume of 1 mL whose inner surface was dealkalized, was attached to the tip of a dry heat sterilized one, and 1.0 mL each of the sterile-filtered elcatonin aqueous solution composition was dispensed, then sealed with a piston and prefilled. A syringe formulation was obtained. The rubber stopper was previously subjected to the underwater test and the volatilization test by the above method. In the water test and the volatilization test of the sealing plug and the piston, those in which carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine were not detected were used.

[0025]

[Comparative Example 1] An elcatonin aqueous solution obtained in the same manner as in Example 1 was a dry-heat sterilized 5.0 mL mL glass-made 10 mL capacity vial bottle (made by Murase Glass Co., Ltd.) whose inner surface was dealkalized. Each of them was dispensed, sealed with a rubber stopper, and then tightly wound with an aluminum cap to obtain a vial preparation. The rubber stopper was previously subjected to an extraction test in water and a volatile component detection test by the above method. A rubber stopper was used in which carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine were detected in an underwater test and a volatilization test of the rubber stopper.

[0026]

[Comparative Example 2] An aqueous elcatonin solution obtained in the same manner as in Example 1 was a dry-heat sterilized glass syringe having a volume of 1 mL, the inner surface of which was dealkalized. After that, it was sealed with a piston to obtain a prefilled syringe preparation. The sealing plug and the piston were previously subjected to the extraction test in water and the volatile component detection test by the above-mentioned method. In the extraction test in water, piperidine, dibutylamine, and N-acetylpiperidine, which are components other than water, were detected, and in the detection test for volatile components, carbon disulfide, piperidine, and dibutylamine were detected. .

[0027]

[Test Example 1] The filling and storing container of the elcatonin aqueous solution of the present invention obtained in Examples 1 and 2 and the filling and storing container of the elcatonin aqueous solution obtained in Comparative Examples 1 to 3 were placed in a thermostat.
It was stored at 60 ° C for 8 days and at 40 ° C for 3 months, and its stability was measured by high performance liquid chromatography, and it remained when the amount of elcatonin in the elcatonin aqueous solution taken out from the storage container immediately after filling was 100%. I asked for the rate. The results are shown in Table 1 and Table 2.

[High-performance liquid chromatography measurement conditions] Column: ODS column 4.6 × 150 mm Detection: UV225 nm Mobile phase: CH ₃ CN-0.1% TFA (33:67)

[0029]

【table 1】

[0030]

[Table 2]

From the above results, carbon disulfide, piperidine, dibutylamine and N
In Comparative Examples 1 to 3 using rubber stoppers in which acetylpiperidine was detected, elcatonin was unstable to heat. On the other hand, in Examples 1 and 2, elcatonin was found to be stable.

[0032]

According to the present invention, since a rubber stopper which does not elute sulfur compounds and amine compounds into the drug is used, deactivation is suppressed during storage of the drug, and the activity is maintained and preferable properties are obtained. Can be provided.

Continued front page    (72) Inventor Hiroshi Kodaira             Otsuta 9-1 Kawaramachi, Izumiotsu City, Osaka Prefecture             Ear Co., Ltd. F term (reference) 4C076 AA12 DD41 FF63 FF66 GG50                 4C084 AA03 BA44 DB31 MA17 NA03                       ZA96 ZC21

Claims (8)

[Claims] 1. A formulation comprising a container filled with a drug and sealed with a rubber stopper, wherein the rubber stopper does not have a polymer film on the surface, and carbon disulfide is tested by an underwater test and a volatilization test. A preparation, which is a rubber stopper in which piperidine, dibutylamine and N-acetylpiperidine are not substantially detected. 2. The preparation according to claim 1, wherein the filled drug is a drug containing a protein or a peptide as an active ingredient. 3. The preparation according to claim 1 or 2, wherein the filled drug is a drug containing calcitonin as an active ingredient. 4. The preparation according to claim 3, wherein the drug containing calcitonin as an active ingredient is an aqueous solution of calcitonin. 5. The preparation according to any one of claims 1 to 4, wherein the container is selected from an automatic bottle, a tube bottle, a syringe, and a capsule. 6. A method of improving drug stability by reducing contact of the drug with at least any of carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine. 7. A rubber stopper having no polymer film on its surface is confirmed to be substantially free from the detection of carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine in an underwater test and a volatilization test. Inspection method for rubber stoppers. 8. A rubber stopper having no polymer film on its surface was confirmed to have substantially no carbon disulfide, piperidine, dibutylamine and N-acetylpiperidine detected in an underwater test and a volatilization test. A drug product made by sealing a container filled with a drug with a rubber stopper.