JP2002177364A - Drug container - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a prefilled syringe reduced in the adsorption of a drug. SOLUTION: A drug container has a Parylene layer and is characterized in that a ratio (b/a)×100 (keeping ratio) of the substantial amount (a) of the drug in a drug liquid at a point of time when the drug liquid is charged and the substantial amount (b) of the drug in the drug liquid preserved for six months at 40 deg.C in such a state that the drug liquid is charged to be hermetically closed by a lid material is not less than 90%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicine container. More specifically, the present invention relates to a transparent plastic medicine container having a parylene layer formed on at least a part of the surface thereof in contact with a medicine.

[0002]

2. Description of the Related Art Conventionally, glass vials have been used for medicine containers. However, glass bottles were damaged by the accident of dropping during transportation or handling, and were heavy, giving physical and mental burdens to carriers and medical staff. As a solution to this problem, there is plasticization of the container. At present, a substantial portion of infusion-related drugs has been converted from a glass container to a plastic container. On the other hand, in recent years, a syringe or syringe is filled with a medicinal solution or injection solution, and the other is transported and stored in a state in which one is sealed with a gasket. A so-called pre-filled syringe that can be administered by attaching an administration device, pushing in a gasket and sliding in the syringe to allow a drug solution or an injection solution to flow out, has begun to be used. Prefilled syringes are extremely simple to operate, can be administered accurately without misuse because the drug solution and dose are already set, and do not need to adjust the drug even in an emergency, eliminating the need for bacteria. It has many advantages, such as being able to avoid infection. In recent medical sites, it has been desired to convert various drugs into prefilled from the viewpoints of treatment efficiency, medical malpractice, and prevention of bacterial contamination. However, prefilled syringes are required to have high airtightness during transportation and storage, and at the same time, it is necessary to slide a sealed portion during administration of a drug solution, and contradictory functions such as airtightness and low slidability are required. .

[0003] The most problematic point in making the medicine container plastic is that the medicine is adsorbed on the container and the potency is reduced. Many liposoluble drugs such as nitroglycerin, cyclosporine, and benzodiazepines have already been reported to reduce their content in various drug containers and infusion sets. (Journal of Pharmaceutical Science 71, 55-59 1982, American Journal of Hospital Pharmacy
41, 142-144 1984, American Journal of
Hospital Pharmacy 43, 94-97 1984, American Journal of Hospital Pharmacy 4
0, 417-423 1983, Hospital Pharmacy, 2, 1996 167-1996). In particular, isosorbyl nitrate (ISDN) injection and nitroglycerin (GTN) injection are used for severe angina, myocardial infarction, acute heart failure,
It is a drug used for intraoperative and postoperative management during cardiac surgery, and precise control of the dose is required. In recent years, these injections have been increasingly used as undiluted solutions using precision automatic infusion devices because patients who have strong congestive symptoms do not want to increase the amount of water taken. For these reasons, there is a need for a drug container that does not cause a decrease in the drug content (so-called titer reduction) in the container. In addition, a prefilled syringe has high airtightness during transportation and storage and a gasket during actual use. Parts are required to have low slidability. Glass drugs or glass prefilled syringes are still used for drugs that are prone to drug absorption due to this problem of drug absorption, which places a great physical and mental burden on the above-mentioned doctors, nurses, and carriers. is the current situation.

[0004]

DISCLOSURE OF THE INVENTION The present invention has a problem in that the workability of various drug storage containers such as glass vials and prefilled syringes used for the conventionally used drugs having a high drug adsorption property is poor. There are those that try to overcome (easy to break, heavy) by using plastic. That is, by coating parylene on at least a part of a part of a medicine container made of a specific plastic material and a medicine container made of an elastic lid material, which comes in contact with the medicine, the potency or the potency of the medicine during transportation, storage, etc. An object of the present invention is to provide a plastic medicine container in which a decrease in the amount of a substantially effective medicine is suppressed. A further object of the present invention is to provide a syringe container having a low drug-adsorbing property, which has not been practically used. The technique using parylene for the medicine container is disclosed in Japanese Patent Publication No. 3-58742, but here, the elastic lid member is coated with parylene so that calcium ions and aluminum ions from the lid member can be removed. It discloses only preventing elution of metal ions, and does not disclose any technique for preventing drug adsorption.

[0005]

This and other objects are achieved by the present invention which is defined below as (1) to (12). (1) A medicine container having a container made of a synthetic resin for containing a liquid containing a pharmacologically effective substance, and a lid material for closing an opening of the container, the surface of the medicine container being in contact with the liquid. At least a portion is covered with a parylene layer, and the container has a structure in which the lid and the lid material come into contact with each other through the parylene layer. (A) and the substantial amount of the substance (b) in the liquid when the liquid is filled in the container and the container is stored at 40 ° C. for 6 months with the container closed. A medicine container having a ratio (b / a) × 100 (retention rate) of 90% or more. (2) The parylene layer described in (1), wherein the parylene layer covers all of the surface formed by the lid material, and the storage in (b) is performed in a state where the liquid is in contact with the lid material. Medicine storage container. (3) The above (1), wherein the parylene layer has a thickness of 1 to 30 μm.
(4) The parylene layer according to (1) to (3), wherein the parylene layer is made of parylene N represented by the following chemical formula 1.
The drug storage container according to any one of the above.

[0006]

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(5) The medicine container according to any one of (1) to (4), wherein the lid member is an elastic body made of rubber or elastomer. (6) The medicine container according to any one of (1) to (5), wherein the container is made of an optically transparent plastic. (7) The medicine container according to any one of (1) to (6) above, wherein the container is made of a transparent polyolefin having a melting point of 120 ° C. or higher or a glass transition point. (8) The medicine container according to any one of (1) to (7), wherein the container is made of polypropylene, poly (4-methylpentene-1), cyclic polyolefin, or polyethylene naphthalate. (9) The container according to any one of (1) to (8) above, wherein the container contains a liquid containing a pharmacologically effective substance, and has a container-side parylene layer at a portion where the liquid contacts. Medicine storage container. (10) The drug container according to any one of (1) to (9), wherein the pharmacologically effective substance is any one of the group consisting of nitroglycerin, isosorbide dinitrate, and nicardipine hydrochloride.

(11) A medicine container having a synthetic resin container for containing a liquid containing a pharmacologically effective substance, and a lid member for closing an opening of the container, the medicine container being in contact with the liquid. At least a part of the surface to be covered is covered with a parylene layer, and the container has a structure in which the lid material comes into contact with the parylene layer via the parylene layer, and the container is filled with a 0.5 mg / mL nitroglycerin aqueous solution. The substantial amount of nitroglycerin in the aqueous solution at the time (a) and the amount of the nitroglycerin in the aqueous solution when the container was stored at 40 ° C. for 6 months with the aqueous solution filled in the container and sealed with a lid. A drug container wherein the ratio (b / a) × 100 (retention rate) to the substantial amount of nitroglycerin (b) is 90% or more. (12) The container is a cylindrical body having a front end that can be opened and a rear end having an opening, and the lid is a gasket that slidably closes the inside of the cylindrical body. The medicine container according to any one of the above (1) to (11), wherein the container is a syringe.

In the present invention, the quantitative determination of the substantial amount of the substance or nitroglycerin in a liquid containing a pharmacologically effective substance or an aqueous nitroglycerin solution filled in a container is performed by liquid chromatography. A chart area of the substance in the liquid or the aqueous solution at the time of filling the liquid or the aqueous solution into the container,
The area ratio between the chart area of the substance in the liquid or the aqueous solution at the time when the container was stored at 40 ° C. for 6 months in a state sealed with a lid material was determined, and the amount of the substance or the amount of nitroglycerin (%) was determined. did. The concentration of nitroglycerin in the aqueous nitroglycerin solution was 0.5 mg / mL, and as nitroglycerin, Nippon Kayaku Co., Ltd., Millisrol Injection was used.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the drug container of the present invention is limited to a prefilled syringe having the most complicated shape as a container, and will be described in detail with reference to the schematic diagram shown below.
The present invention is not limited to this, and includes a medicine container having a lid made of various elastic bodies found in an infusion bag or the like, such as a vial with a rubber stopper. FIGS. 1 and 2 show cross-sectional views of a syringe, but this is merely an example of a syringe shape, and the syringe container of the present invention is not limited to this. In this figure, a cylinder 2 corresponds to a container for storing a liquid containing a pharmaceutically effective substance in the present invention, and a gasket 4 corresponds to a lid used together with the container. Syringe 1 is cylinder 2 and plunger 3 and gasket located at the tip of this
4, a space 22 for storing a chemical solution is formed inside the cylinder 2 and an opening 21 is formed at the tip of the space 22 for sucking and discharging the chemical solution. 1 and 2, the gasket 4 is composed of a main body 41 and a parylene layer 42 present on the surface thereof. In the case of a pre-filled syringe, the seal member 5 that separates the space 22 from the outside is fixed to the opening 21 in a state where it can be easily peeled off. The same material as the cylinder 2 described later can be used for the sealing material 5.

The cylinder 2 is formed of a cylindrical body having an opening 21 for sucking and discharging a liquid such as a drug solution or blood formed at a distal end thereof, and a flange 23 formed around the opening on the base end side. Have been. The cylinder 2 is formed of a synthetic resin such as a polyolefin-based synthetic resin and a polyester-based synthetic resin. Of these, polypropylene, poly
Optically transparent materials having a glass transition point or melting point of 110 ° C. or more, such as (4-methylpentene-1), polyolefins such as cyclic polyolefins, and polyesters such as polyethylene terephthalate, polyethylene naphthalate and amorphous polyarylate. It is preferable to be formed.
In particular, polypropylene, poly (4-methylpentene-1),
Cyclic polyolefin and polyethylene naphthalate are desirable in terms of transparency, steam sterilization, and drug non-adsorption. These materials can be used not only for the cylinder but also for the container containing the pharmaceutically effective substance constituting the present invention. When the medicine container has a bag shape, an elastomer such as PP or PE can be used in addition to the above materials. In the case where all surfaces of the container that come into contact with the drug are coated with parylene, various synthetic resin materials can be used in addition to the above-mentioned resins.

The plunger 3 is formed of polypropylene or the like, and has a means for detachably fixing the gasket 4 at its tip. Further, the plunger 3 moves in the proximal direction together with the gasket 4 so that
It plays a role of discharging the drug solution or blood stored in the space 22 by sucking the drug solution or blood into the space or moving in the distal direction. The gasket 4 is detachably fixed to the tip of the plunger 3 by means such as fitting, and includes a main body 41 and a parylene layer formed on the surface thereof. This gasket is made of styrene-based elastomer, hydrogenated styrene-based elastomer, polyolefin such as polyethylene, polypropylene, polybutene, α-olefin copolymer, liquid paraffin, oil such as process oil, powder such as talc, cast, mica, etc. What mixed body minerals is mentioned. In addition, polyvinyl chloride elastomer,
Olefin-based elastomer, polyester-based elastomer, polyamide-based elastomer, polyurethane-based elastomer, natural rubber, isoprene rubber, butyl rubber, chloroprene rubber, nitrile-butadiene rubber, styrene-
Various rubber materials such as butadiene rubber and silicone rubber (especially those subjected to a flowing treatment), and mixtures thereof, and the like are listed as constituent materials. Above all, styrene-based elastomers, butyl rubber, silicone rubber, and the like are desirable from the viewpoint of elastic properties, steam sterilization resistance, and the like. These materials are not limited to gaskets and can be used in common for the lid material constituting the present invention.

Although not shown here, a syringe in which a plunger and a gasket are integrally formed is connected to a two-part syringe.
It is called a syringe, but in this case, the tip side of the plunger,
That is, it goes without saying that a portion that comes into contact with a liquid such as a drug solution or blood and a portion that comes into contact with the cylinder are combined to form a gasket. In the case of such a two-part syringe, the parylene layer 42 may be applied to the entire plunger, or may be applied so as to include a portion in contact with a liquid such as a drug solution or blood and a portion in contact with the cylinder.

Next, parylene used in the present invention will be described. Parylene referred to in the present invention refers to parylene having no substituent on the benzene ring represented by the following chemical formula 1 (hereinafter referred to as parylene N) and various functional groups introduced into the benzene ring, and methylene group adjacent to the benzene ring. These include those in which hydrogen has been substituted, such as parylene C (chemical formula 2) having chlorine introduced on the benzene ring, parylene M (chemical formula 3) having a methyl group introduced, and fluorine introduced into a methylene group. And parylene F (chemical formula 4). Considering recent environmental issues, it is desirable to use parylene N or parylene M that does not contain a halogen element.
Furthermore, when these parylenes are used in prefilled syringes, by coating them on the gasket surface,
Although the sliding resistance of the gasket decreases, Parylene N has the lowest value as shown in the experimental examples. Therefore, considering these facts, in the present invention, it is most preferable to use Parylene N when the container is used as a syringe.

[0015]

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[0016]

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[0017]

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[0018]

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In the present invention, in a container for accommodating a pharmaceutically effective substance, and in a structure used with the container, at least a part of the surface that comes into contact with the pharmaceutically effective substance is covered with parylene. Any material may be used as long as the container and the lid material are in contact with each other via parylene. Therefore, in the present invention, each of the parylene layers represented by the above-mentioned chemical formulas 1 to 4 is coated in multiple layers, or a copolymer prepared from diparaxylylene monomer corresponding to each of the parylenes shown by the above-mentioned chemical formulas 1 to 4 The effects of the present invention are exhibited even when they are combined. The parylene coating method of the present invention comprises three steps as shown in FIG. Step (A) where sublimation of diparaxylylene as a raw material solid dimer occurs, Step (B) where diradical paraxylylene occurs due to thermal decomposition of the dimer, and poly (polymerization) by polymerization of radical monomers on the surface of containers and lids This is a step (C) in which a paraxylylene (parylene) layer is formed. The processing conditions in each of the steps A to C are shown in Table 1 below.

[0020]

[Table 1]

The obtained parylene layer is excellent in heat resistance, chemical resistance and gas shielding properties, and is formed by a gas phase polymerization method, so that even a member having a complicated shape can be coated. . Further, since the treatment is performed at room temperature in the step C, the treatment can be performed even on a material having low heat resistance. Therefore, it is possible to coat a container or a lid having a complicated shape as in the present invention. The thickness of the parylene coating layer used in the present invention can be controlled by the temperature, pressure, and coating time shown in Table 1. In the present invention, the thickness of the coat layer in which the effect is remarkably exhibited is usually 1 μm to 30 μm. , More preferably 2 μm
２０20 μm. If it is less than 1 μm, the suppression of drug adsorption is not sufficient, and if it is more than 30 μm, a problem such as peeling of the parylene coat layer occurs.

Next, drug adsorption will be described. As described above, it has been reported that many drugs such as nitroglycerin, cyclosporine, and benzodiazepines cause a decrease in the content in various drug containers and infusion sets, and the interaction between the injection solution and the medical device is a problem. (Journal of Pharmaceutical Sciences 71, 55-59 1982, American Journal of Hospital Pharmacy 41, 142-144 1984, American Journal of Hospital Pharmacy 43, 94-97 1984, American Journal of Pharmacy
Hospital Pharmacy 40, 417-423 1983, Hospital Pharmacy, 2, 1996 167-1996). This reduction in content is also an issue for prefilled syringes, and has high airtightness during transportation and storage and low sliding properties during actual use, as well as a reduction in content in pharmaceutical containers (so-called titer reduction).
Is required not to occur. As shown in Table 2, parylene has high resistance to various solvents and high crystallinity, and thus it is presumed that the adsorption of various drugs to the surface of the pharmaceutical container is small.

[0023]

[Table 2]

The syringe used in the present invention is a general syringe used for administering a drug to a patient, collecting blood from the patient, mixing a drug solution, a micro syringe used for administering insulin, or used for dental treatment. Examples of such syringes include dental syringes that involve an operation of pressing a plunger and sliding an airtight holding section, and a prefilled syringe that performs a long-term indirect liquid injection in a state in which a syringe is pre-filled with a drug solution can be preferably used. In the case of a prefilled syringe, a chemical solution is stored in the cylinder as needed. The type of drug in the drug solution is not particularly limited. For example, antibiotics, vitamins (multivitamins), various amino acids, antithrombotics such as heparin, insulin, antitumor agents, analgesics, inotropic agents, intravenous injection Anesthetics, antiparkinson agents, ulcer treatment agents, corticosteroids, arrhythmia agents, correction electrolytes, antiviral agents, immunostimulants, etc., may be used, but lipophilic drugs which are particularly problematic in drug adsorption Demonstrate that ability.

[0025]

EXAMPLES The present invention will be specifically described below with reference to experimental examples and examples.・ Slidability (Experimental Examples 1 to 6, Comparative Examples 1 and 2) In order to examine the possibility of using a syringe gasket, a styrene-based elastomer was selected as a gasket base material, and polypropylene and a cyclic polyolefin were selected as a cylinder base material. The evaluation was performed using a sheet sample.
Styrene-based elastomer (JSR manufactured by Nippon Synthetic Rubber Co., Ltd.)
TR) was coated on a sheet of 10 mm × 10 mm × 1 mm with parylene under the conditions shown in Table 1. The parylene thickness of the obtained sample was measured with an electron microscope (scanning electron microscope JSM-5300 manufactured by JEOL Datum Co., Ltd.).
The coefficient of friction was measured to evaluate the lubricity of the obtained sample. The friction coefficient was calculated from the frictional resistance generated between the sample and the surface of another material using a surface property measuring device (Tribogear TYPE 14S / 14DR manufactured by Shinto Kagaku Co., Ltd.). Specifically, a parylene film-forming sample was fixed to a movable table of a measuring instrument, and 10 g of each sheet made of polypropylene (Chisso Polypro, manufactured by Chisso Corporation) or cyclic polyolefin (Apel, Mitsui Chemicals, Inc.) was placed thereon. The sample was brought into contact with a vertical load, and the value was measured when the sample was moved at a speed of 100 mm / min at room temperature. Table 3 shows the results.

[0026]

[Table 3]

From Table 3, it can be seen that the styrene-based elastomer coated with parylene of 1 μm or more shows that polypropylene, polyethylene and cyclic polyolefin are all
Good slidability was exhibited.

Drug Adsorption (Examples 1-8) As a typical example of drug adsorption experiments, nitroglycerin (Nippon Kayaku Co., Ltd., Millisrol) having a problem of adsorption and diffusion to a container was compared and studied. 5 mL of 0.5 mg / mL nitroglycerin aqueous solution was dispensed into a 20 mL polypropylene (Chisso Corporation, Chisso Polypro) or cyclic polyolefin cylinder, sealed with a parylene-coated gasket (Asahi Rubber), and then autoclaved. It was sterilized, stored in an oven at 40 ° C. for 6 months, and subjected to an adsorption test in an accelerated system. For the determination of nitroglycerin, high performance liquid chromatography Shimadzu LC-9A (manufactured by Shimadzu Corporation) was used for liquid chromatography, and Inters was used for the column.
til ODS (0.46mmφ × 250mm, GL Sciences)
Was carried out by using an ultraviolet absorption spectrophotometer (at 220 nm) as a detector and water / methanol (2: 3) as a mobile phase. The nitroglycerin amount (%) was defined as the chart area of nitroglycerin in the unopened glass ampule and the area ratio with each sample. Table 4 shows the results.

Comparative Example 1-5 A gasket without coating was subjected to a nitroglycerin adsorption experiment in the form of a syringe in the same manner as in Example 1. Table 4 shows the results.

[0030]

[Table 4]

(Examples 11-14) The drug adsorption of nicardipine hydrochloride (verdipine injection, Yamanouchi Pharmaceutical Co., Ltd.) was examined in the same manner as in Example 1 and Comparative Example 1. Table 5 shows the results.

[0032]

[Table 5]

(Examples 14-16, Comparative Example 8-9) The drug adsorption of isosorbide dinitrate (Nitrole Injection, Eisai Co., Ltd.) was compared and studied in the same manner as in Example 1 and Comparative Example 1.
Table 6 shows the results.

[0034]

[Table 6]

[0035]

According to the present invention, there is provided a container which is practically free from a decrease in drug potency or a substantially effective drug amount during transportation and storage. Furthermore, when a syringe-type drug storage container is used, a gasket having a parylene layer provides a prefilled syringe made of plastic with low drug adsorption.

[Brief description of the drawings]

FIG. 1 is a cross-sectional view showing one embodiment of a medicine container according to the present invention.

FIG. 2 is a sectional view showing another embodiment of the medicine container of the present invention.

FIG. 3 is a view showing a parylene coating process of the present invention.

Claims (12)

[Claims] Claims: 1. A medicine container having a synthetic resin container for containing a liquid containing a pharmacologically effective substance, and a lid material for closing an opening of the container, the medicine container being in contact with the liquid. At least a part of the surface is covered with a parylene layer, and the container has a structure in which the lid material comes into contact with the parylene layer via the parylene layer. Substantial substance amount (a) and substantial substance amount in liquid when the liquid is filled in the container and the container is stored at 40 ° C. for 6 months in a state of being sealed with a lid material (b) Ratio (b / a) x 100
(Maintenance rate) is 90% or more. 2. The method according to claim 1, wherein the parylene layer covers all of the surface formed by the lid material, and the storage in the step (b) is performed in a state where the liquid is in contact with the lid material. The medicine storage container according to the above. 3. The medicine container according to claim 1, wherein the parylene layer has a thickness of 1 to 30 μm. 4. The medicine container according to claim 1, wherein the parylene layer is made of parylene N represented by the following chemical formula 1. Embedded image 5. The medicine container according to claim 1, wherein said lid member is an elastic body made of rubber or elastomer. 6. The medicine container according to claim 1, wherein the container is made of an optically transparent plastic. 7. The drug container according to claim 1, wherein the container is made of a transparent polyolefin having a melting point or a glass transition point of 120 ° C. or higher. 8. The drug container according to claim 1, wherein the container is made of polypropylene, poly (4-methylpentene-1), cyclic polyolefin, or polyethylene naphthalate. 9. The container according to claim 1, wherein said container has a container-side parylene layer at a portion where said liquid contacts a liquid containing a pharmacologically effective substance. Drug storage container. 10. The drug container according to claim 1, wherein the pharmacologically effective substance is any one of the group consisting of nitroglycerin, isosorbide dinitrate, and nicardipine hydrochloride. 11. A medicine container having a synthetic resin container for containing a liquid containing a pharmacologically effective substance, and a lid member for closing an opening of the container, wherein the container is in contact with the liquid. At least a part of the surface is covered with a parylene layer,
And a structure in which the container and the lid material come into contact with each other via the parylene layer, and a substantial amount of nitroglycerin (a) in the aqueous solution at the time of filling the aqueous solution with 0.5 mg / mL nitroglycerin (a ) And the substantial amount of nitroglycerin (b) in the aqueous solution when the container is stored at 40 ° C. for 6 months in a state where the aqueous solution is filled in the container and sealed with a lid. /
a) A medicine storage container characterized in that x100 (retention rate) is 90% or more. 12. A gasket, wherein the container is a cylindrical body having a front end sealed to be openable and having an opening at a rear end, and the lid member is slidably closed in the cylindrical body. The medicine container according to any one of claims 1 to 11, wherein the medicine container has a syringe shape.