WO2019117267A1 - Medical glass container and method for manufacturing same - Google Patents

Abstract

The present disclosure provides a medical glass container and a method for manufacturing same, wherein: the medical glass container is heat resistant, has a large contact angle with aqueous content, is highly transparent, and has excellent lubricating properties (sliding properties); peeling of a silica component (a SiO2 component) of glass, which is a base material of the container, does not easily occur; aggregation (adsorption) of protein, which is an effective component of a medicine, does not easily occur; and peeling of a thin film is suppressed. The medical glass container according to the present disclosure is characterized in that a thin film is formed on at least a portion of an inner wall of the glass container, wherein the film is a diamond-like carbon film that does not contain silicon.

Description

Glass container for medical use and method of manufacturing the same

The present disclosure relates to medical glass containers, and more particularly to glass containers for storing and storing pharmaceuticals for medical purposes. Medical glass containers include, for example, vials, syringes, syringes with needles and cartridge type syringes.

There is a disclosure of a medical glass container containing silicon, oxygen, carbon, hydrogen and fluorine on the inner surface of the container, and having an anti-stick coating formed by a plasma-enhanced chemical vapor deposition process (see, for example, Patent Document 1). Patent Document 1 discloses that this anti-sticking coating is amorphous and transparent, meets medical requirements, and has a water contact angle of 80 ° or more.

There is a disclosure of a technology for applying a lubricious coating material to a container using PECVD (plasma enhanced chemical vapor deposition) (see, for example, Patent Document 2). The coating contains silicon, oxygen, carbon and hydrogen and is described to be a low friction coating for plastic syringes.

Although the techniques disclosed in Patent Documents 1 and 2 both cover the container with a silicon oxide-based thin film, there is a disclosure that the silicon oxide-based thin film has insufficient suppression of protein adsorption ( See, for example, Non-Patent Document 1.).

JP 2000-350770 A JP, 2015-180780, A

The technique disclosed in Patent Document 1 is easy to remove residual chemicals because the container has water repellency. However, the anti-stick coating is a coating containing silicon, and in view of Non-Patent Document 1, a glass container formed with a coating having a composition different from this coating, that is, the spread of biopharmaceuticals containing bioderived materials in recent years. At the same time, a glass container having a coating mainly composed of carbon and hydrogen close to a biological component is particularly desired.

In the technique disclosed in Patent Document 2, the coating material containing silicon is formed for the purpose of improving the lubricity, and since the target is a plastic syringe, it is preferable to use a glass syringe. I can not say. That is, the purpose is only to reduce the pushing force of the rubber gasket-equipped plunger in the plastic syringe to the same level as that of the glass syringe. With the widespread use of prefilled syringes in recent years, gaskets having high sealing performance and no leak over a long period of time are required, and it is also required in glass syringes to lower the plunger push-out force.

Therefore, the object of the present disclosure is to remove the silica component (SiO ₂ component) of the glass that is the base material of the container, because the contact angle with the aqueous contents is large, the transparency is high, the lubricity (slidability) is excellent. It is hard to form, there is little elution of glass-derived components (silicon, boron, sodium, potassium, aluminum) into the contents, aggregation (adsorption) of the protein which is the active ingredient of pharmaceuticals is hard to occur, and it is heat resistant. It is an object of the present invention to provide a medical glass container which realizes that peeling of a film is suppressed, in particular, a medical glass container in which at least a part of the surface of the container is coated with a silicon-free diamond-like carbon film and a manufacturing method thereof. .

As a result of intensive investigations, the present inventors have found that coating the silicon-free diamond-like carbon film on at least a portion of the surface, such as the inner surface of a glass container, solves the above-mentioned problems. Completed the invention. That is, the medical glass container according to the present invention is characterized in that, in the medical glass container having a film formed on at least a part of the inner wall of the glass container, the film is a silicon-free diamond-like carbon film. Do.

The medical glass container according to the present invention includes a form in which the film is a silicon-free and fluorine-containing diamond-like carbon film or a silicon-free and fluorine-free diamond-like carbon film.

In the medical glass container according to the present invention, it is preferable to have an intermediate layer containing silicon between the glass surface of the inner wall of the glass container and the film. By providing the intermediate layer containing silicon, the adhesion of the film is improved, and the transparency and heat resistance are improved.

In the medical glass container according to the present invention, it is preferable that at least a part of the glass surface of the inner wall of the glass container is subjected to a hydrophilization treatment. When the glass surface of the inner wall of the glass container is subjected to a hydrophilization treatment, the adhesion of the film is improved.

The medical glass container according to the present invention includes a form in which the glass forming the glass container is borosilicate glass, aluminosilicate glass or soda lime glass.

The medical glass container according to the present invention includes a form in which the glass container is a vial, a syringe, a syringe with a needle and a cartridge type syringe.

In the medical glass container according to the present invention, the glass container is a vial, and further comprises a rubber stopper, and at least a part of the inner surface of the rubber stopper is coated with a diamond-like carbon film or a fluorine resin film Is preferred. The contents contained in the container can be brought into contact with only the diamond-like carbon film, or only the two, such as the diamond-like carbon film and the fluorocarbon resin film, without touching the glass or rubber, and the stability of the contents Improve.

In the medical glass container according to the present invention, the glass container is a syringe, and further includes a plunger to which a gasket is attached, and at least a part of the surface of the gasket is coated with a diamond-like carbon film Is preferred. It can be moved smoothly when pushing the plunger.

In the medical glass container according to the present invention, the glass container is a syringe, and further, a plunger is provided with a gasket, and at least a surface of the gasket in contact with the inner surface of the syringe is fluorinated. It is preferable to adhere a resin film. The plunger can be moved more smoothly when pushed in.

In the medical glass container according to the present invention, the film is preferably a silicon-free and fluorine-containing diamond-like carbon film, and the transmittance of the glass container at 450 nm is 90% or more. The contents can be clearly viewed.

A method of manufacturing a medical glass container according to the present invention is a method of manufacturing a medical glass container in which a film is formed on at least a part of the inner wall of the glass container, wherein the glass contains a hydrocarbon gas containing no silicon as a constituent element. And forming a silicon-free diamond-like carbon film as the film by plasmatization in a storage space of the container.

In the method for producing a medical glass container according to the present invention, the hydrocarbon-based gas not containing silicon is modified with a first hydrocarbon-based gas not containing fluorine and silicon as constituent elements, and is constituted A mixed gas with a second hydrocarbon gas that does not contain silicon as an element,
It is preferable that the film is a silicon-free and fluorine-containing diamond-like carbon film. By using the above mixed gas, it becomes easy to set the fluorine content in the film to a desired ratio.

In the method for producing a medical glass container according to the present invention, the hydrocarbon-based gas containing no silicon is a first hydrocarbon-based gas containing neither fluorine nor silicon as a constituent element, and the film contains no silicon. A fluorine-free diamond-like carbon film is preferred. A silicon-free and fluorine-free diamond-like carbon film can be easily formed.

In the method of manufacturing a medical glass container according to the present invention, the first hydrocarbon-based gas is preferably acetylene and / or methane. By using the above-mentioned source gas as the first hydrocarbon gas, it is possible to obtain a diamond-like carbon film which is less in coloration and high in heat resistance.

In the method for manufacturing a medical glass container according to the present invention, it is preferable that the gas volume ratio of the mixed gas satisfy the range of the number 1. The content of fluorine in the film is within a predetermined range, for example, 8 to 50 atomic% (atomic percentage), and an excellent water repellent effect is obtained.
(1)
(Second hydrocarbon gas): (first hydrocarbon gas) = 7: 3 to 9: 1

In the method for manufacturing a medical glass container according to the present invention, it is preferable to plasmatize the silicon-free hydrocarbon gas by high frequency output or microwave output. With such a configuration, the source gas can be easily plasmatized to form a high-density film on the inner surface of the container.

In the method for manufacturing a medical glass container according to the present invention, before forming the silicon-free diamond-like carbon film as the film, a gas containing silicon is plasmatized in the storage space of the glass container to form the glass It is preferable to include the step of forming an intermediate layer on the glass surface of the inner wall of the container. By providing the intermediate layer containing silicon, the adhesion of the film is improved.

In the method of manufacturing a medical glass container according to the present invention, before forming the film and / or the intermediate layer, a fluorine gas-modified hydrocarbon gas or oxygen gas is added to at least the inner surface of the medical glass container. It is preferable to include a hydrophilization treatment step of contacting a part to form a plasma. When the glass surface of the inner wall of the glass container is subjected to a hydrophilization treatment, the adhesion of the film is improved, and the transparency and heat resistance are improved.

According to the present disclosure, the contact angle with the aqueous content is large, the transparency is high, the lubricity (slidability) is excellent, and peeling of the silica component of the glass that is the substrate of the container does not easily occur. , Elution of glass-derived components (silicon, boron, sodium, potassium, aluminum) into contents is low, aggregation (adsorption) of protein that is the active ingredient of pharmaceuticals is difficult to occur, heat resistance is provided, and The medical glass container which realized that exfoliation was realized can be provided, and the medical glass container which covered the silicon-free diamond-like carbon film especially to at least one copy of the surface of a container, and its manufacturing method can be provided.

It is a sectional view when a medical glass container concerning this embodiment is a vial. It is a sectional view when a medical glass container concerning this embodiment is a syringe barrel. It is the schematic of the high frequency-type inner surface film-forming apparatus for vials. It is the schematic of the microwave type | formula inner surface film-forming apparatus for vials. It is the schematic of the high-frequency-type inner surface film-forming apparatus for syringe barrels. It is the schematic of the microwave type inner surface film-forming apparatus for syringe barrels.

Hereinafter, the present invention will be described in detail by way of embodiments, but the present invention is not interpreted as being limited to these descriptions. The embodiment may be variously modified as long as the effects of the present invention are exhibited.

The medical glass container according to the present embodiment is a medical glass container in which a film is formed on at least a part of the inner wall of the glass container, wherein the film is a silicon-free diamond-like carbon film.
(Glass container)

Medical glass containers include forms that are vials, syringes, syringes with needles and cartridge type syringes. The syringe includes a syringe with a needle and a cartridge type syringe. The glass forming the glass container is borosilicate glass, aluminosilicate glass or soda lime glass.

As shown in FIG. 1, when the medical glass container 1 is in the form of a vial, the film 3 is preferably formed 15% or more in area ratio of the inner wall 2a of the vial 2, 30% or more It is more preferable that it is formed, and it is more preferable that 80% or more is formed. As for the film | membrane 3, it is preferable that the bottom part of the accommodation space of a vial is formed in the whole surface. Furthermore, in the container height direction h, it is more preferable that the container inner wall surface below the center be formed on the entire surface. Furthermore, it is particularly preferable that the film 3 be formed on the entire surface of the inner wall 2a of the glass container (vial 2). Peeling (delamination) of the silica component (SiO ₂ component) of the glass which is the base material of the vial 2 becomes difficult to occur due to the presence of the film 3. In particular, when the vial is made of borosilicate glass, peeling of silica is likely to occur, and this peeling can be suppressed.

Further, in the medical glass container 1 according to the present embodiment, the glass container is the vial 2 and the rubber stopper 4 is further provided, and at least a part of the inner surface of the rubber stopper 4 is the diamond-like carbon film 6 or the fluorine resin It is preferable that the film is coated. The rubber stopper 4 is molded of a thermoplastic elastomer, butyl rubber (isobutyl isoprene rubber), silicone rubber or the like. The chemical contained in the vial 2 can be brought into contact with only the diamond-like carbon film, or only the two, such as the diamond-like carbon film and the fluorocarbon resin film, without touching the glass or rubber, and the contents are stabilized. Improves the quality.

As shown in FIG. 2, when the medical glass container 20 is in the form of a syringe, the film 22 is at least a sliding contact between the glass container (syringe 21) and the gasket 24 attached to the plunger 23. Preferably, it is formed on the surface which can be contacted. The presence of the coating 22 improves the lubricity, that is, the slidability of the plunger 23 and allows the plunger 23 to be moved smoothly when pushed in. Furthermore, it is further preferable that the film 22 be formed on the entire surface of the inner wall 21 a of the injection cylinder 21. In addition to the improvement of the slidability, the film 22 prevents the contact between the drug liquid which is the contents and the glass which is the constituent material of the injection cylinder 21 and the high water repellency of the film 22 makes the residual liquid Less.

In the present embodiment, the syringe 21 may be a prefilled syringe in addition to a normal syringe. Further, the shape of the tip of the injection cylinder is not particularly limited, and can take various shapes such as lure slip type, luer lock type, luer metal type, catheter tip type, enema type and the like.

As shown in FIG. 2, in the medical glass container according to the present embodiment, the medical glass container 20 is an injection cylinder, and further includes a plunger 23 to which a gasket 24 is attached. Preferably, at least a portion of the diamond-like carbon film 25 is coated. The diamond-like carbon film 25 is preferably formed on a portion of the surface of the gasket 24 in contact with the inner surface 21 a of the injection cylinder 21. The diamond-like carbon film 25 formed on the surface of the gasket 24 and the inner surface of the glass container 20 (the surface of the film 22) come in contact with each other and move the plunger 23 more smoothly when pushed in. it can. Furthermore, the diamond-like carbon film 25 is preferably formed on a portion of the surface of the gasket 24 in contact with the drug. In addition to the improvement of the slidability of the plunger 23, the contact between the gasket 24 and the drug can be prevented. More preferably, the diamond-like carbon film 25 is formed on both the surface of the gasket 24 in contact with the inner surface of the syringe and in contact with the drug. The gasket 24 is molded of thermoplastic elastomer (such as butyl rubber and isoprene rubber), plastic (such as polypropylene and polystyrene), or the like.

Instead of the diamond-like carbon film 25 formed on the surface of the gasket 24 shown in FIG. 2, a fluorine resin film 26 may be disposed. That is, in the medical glass container according to the present embodiment, the medical glass container 20 is an injection cylinder, and further, the plunger 23 to which the gasket 24 is attached is provided. It is preferable that the fluorocarbon resin film 26 be adhered to the surface in contact with the inner surface of the glass container 20 (the surface of the film 22). When the plunger 23 is pushed in, it can be moved more smoothly. The fluorine resin film is made of polytetrafluoroethylene, tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer, tetrafluoroethylene / hexafluoropropylene copolymer, tetrafluoroethylene / ethylene copolymer, polyvinylidene fluoride, polychlorotriol. It can be formed of one or more fluoroplastics such as fluoroethylene and chlorotrifluoroethylene-ethylene copolymer.
(Coating)

The films 3 and 22 are silicon-free diamond-like carbon films. Here, diamond-like carbon is also referred to as a diamond-like carbon film, a DLC film, or an amorphous carbon film, and is a hydrogenated amorphous carbon film containing at least a carbon atom and a hydrogen atom. The film thickness of each of the films 3 and 22 is preferably 1 to 70 nm, and more preferably 2 to 10 nm. If the film thickness is less than 1 nm, it may be difficult to form a film uniformly without defects, and if it exceeds 70 nm, peeling may occur or coloring may exceed the allowable range.

Here, the films 3 and 22 which are silicon-free diamond-like carbon films are silicon-free and fluorine-containing diamond-like carbon films (hereinafter sometimes referred to as "F-DLC films"), Or the form which is a silicon-free and fluorine-free diamond-like carbon film (Hereafter, it may only be described as a "DLC film") is included. The fluorine-containing diamond-like carbon film is also referred to as a fluorinated amorphous carbon film.

When the films 3 and 22 are silicon-free and fluorine-free diamond-like carbon films, the water repellency, heat resistance, and protein non-adsorbability are excellent.

When the films 3 and 22 are silicon-free and fluorine-containing diamond-like carbon films, the properties of transparency, water repellency, protein non-adsorption and heat resistance are excellent. The fluorine content in the coatings 3 and 22 is preferably 10 to 50 atomic% in the outermost surface of the coating. If the fluorine content is less than 10 atomic percent, the meaning of containing fluorine is reduced, and for example, water repellency and transparency may be reduced. If the fluorine content exceeds 50 atomic%, the heat resistance may be reduced. The fluorine content in the coatings 3 and 22 is preferably in the range of 0 to 20 atomic% at the innermost surface of the coatings in order to maintain adhesion. For this reason, it is preferable to set it as the gradient composition to which fluorine content increases toward the outermost surface from the inner surface of a film.

In this embodiment, it is preferable to have an intermediate layer containing silicon between the glass surface of the inner wall of the glass container 2, 21 and the film. By providing the intermediate layer containing silicon, the adhesion of the film is improved. Specifically, (1) a mode in which an intermediate layer containing silicon is formed on the glass surface of the inner wall of the glass container 2, 21 and a silicon-free and fluorine-free diamond-like carbon film is further formed thereon And (2) there is a form in which an intermediate layer containing silicon is formed on the glass surface of the inner wall of the glass container 2, 21 and a silicon-free and fluorine-containing diamond-like carbon film is formed thereon.

An embodiment will be described in which an intermediate layer containing silicon is formed on the glass surface of the inner wall of the glass container 2, 21 and a silicon-free and fluorine-free diamond-like carbon film is further formed thereon. The intermediate layer containing silicon is, for example, a silicon oxide film, and the silicon oxide film preferably contains silicon, oxygen, carbon and hydrogen, and the film thickness is preferably 3 to 50 nm. The thickness of the silicon oxide film is more preferably 5 to 20 nm. If the thickness of the silicon oxide film is less than 3 nm, the significance of providing the intermediate layer may be reduced, and the adhesion of the film provided on the intermediate layer may be reduced. When the film thickness of the silicon oxide film exceeds 50 nm, it may take time to generate a crack due to internal stress and to form a film. In addition, the silicon-free and fluorine-free diamond-like carbon film provided on the intermediate layer has a density of 1.6 to 2.4 g / cm ³ and a hydrogen content of 8 to 40 atomic%. And, the thickness is preferably 1 to 70 nm. Here, the density is more preferably 1.8 to 2.2 g / cm ³ , the hydrogen content is more preferably 10 to 30 atomic%, and the thickness is more preferably 2 to 10 nm. If the density is less than 1.6 g / cm ³ , the heat resistance may be lowered, and if the density is more than 2.4 g / cm ³ , a crack may be generated or coloring may be intense. If the hydrogen content is less than 8 atomic%, the density may be high, cracks may occur, or coloring may be severe, and if the hydrogen content exceeds 40 atomic%, the density may be reduced, and the heat resistance may be reduced. There is. When the thickness is less than 1 nm, uniform film formation can not be performed, which may cause defects in the film, and when the thickness exceeds 70 nm, the transparency may be reduced.

An embodiment will be described in which an intermediate layer containing silicon is formed on the glass surface of the inner wall of the glass container 2, 21 and a silicon-free and fluorine-containing diamond-like carbon film is further formed thereon. The intermediate layer containing silicon is, for example, a silicon oxide film, and the silicon oxide film contains silicon, oxygen, carbon and hydrogen, may contain fluorine, and preferably has a film thickness of 3 to 50 nm. The thickness of the silicon oxide film is more preferably 5 to 20 nm. If the thickness of the silicon oxide film is less than 3 nm, the significance of providing the intermediate layer becomes thin, and the adhesion of the film provided on the intermediate layer may be reduced. When the film thickness of the silicon oxide film exceeds 50 nm, it may take time to generate a crack due to internal stress and to form a film. The silicon-free and fluorine-containing diamond-like carbon film provided on the intermediate layer has a density of 1.6 to 2.4 g / cm ³ and a hydrogen content of 8 to 40 atomic%, It is preferable that the average fluorine content in the film is 10 to 20 atomic percent, the fluorine content on the outermost surface is 8 to 50 atomic percent, and the thickness is 1 to 70 nm. Here, the density is more preferably 1.8 to 2.2 g / cm ³ , the hydrogen content is more preferably 10 to 30 atomic%, and the fluorine content on the outermost surface is 10 to 40 atomic% Is more preferable, and the thickness is more preferably 2 to 10 nm. If the density is less than 1.6 g / cm ³ , the heat resistance may be reduced. If the hydrogen content is less than 8 atomic%, the density may increase, cracks may occur, or the coloration may be severe. If the hydrogen content exceeds 40 atomic%, the density may decrease, and the heat resistance may decrease. There is. If the fluorine content is less than 8 atomic%, the significance of containing the fluorine decreases, for example, the water repellency and transparency may decrease, and if the fluorine content exceeds 50 atomic%, the heat resistance decreases. There is a fear. If the thickness is less than 1 nm, the uniformity of the film formation may be degraded. If the thickness exceeds 70 nm, peeling may occur or coloring may exceed the allowable range.

An intermediate layer and a silicon-free, fluorine-containing diamond-like carbon film having a graded composition in the form of forming an intermediate layer containing silicon and further forming a silicon-free and fluorine-containing diamond-like carbon film thereon It may be a substantially single layer gradient composition film. That is, the films 3 and 22 are (1) the outermost surface is the surface of silicon-free and fluorine-containing diamond-like carbon, and the surface in contact with the inner surface of the container is the surface of silicon oxide or the surface of silicon oxide containing fluorine And (2) the gradient composition film has a density of 1.6 to 2.4 g / cm ³ , preferably 1.8 to 2.2 g / cm ³ from the outermost surface to a thickness of 1 nm, and a thickness from the outermost surface Hydrogen content up to 1 nm is 8 to 40 atomic percent, preferably 10 to 30 atomic percent, and fluorine content is 8 to 50 atomic percent, preferably 10 to 40 atomic percent, from the outermost surface to a thickness of 1 nm (3) The surface of silicon oxide in contact with the inner surface of the container contains silicon, oxygen, carbon, hydrogen and may contain fluorine. (4) The composition changes in an inclined manner in the thickness direction of the film from the surface in contact with the inner surface of the container to the outermost surface, and the thickness of the films 3 and 22 which are gradient composition films is 1 to 70 nm, preferably 5 to 20 nm . If the density in (2) is less than 1.6 g / cm ³ , the heat resistance may be lowered, and if the density exceeds 2.4 g / cm ³ , a crack may occur or the coloration may be intense. . If the hydrogen content is less than 8 atomic%, the density may be reduced and the heat resistance may be reduced. If the hydrogen content is more than 40 atomic%, the density may be increased to cause cracking or intense coloration. There is a fear. If the fluorine content is less than 8 atomic percent, the significance of containing the fluorine decreases, for example, the water repellency and transparency decrease, but if the fluorine content exceeds 50 atomic percent, the heat resistance decreases. There is a risk of If the thickness in (4) is less than 1 nm, the uniformity of film formation may be lowered, and if the thickness exceeds 70 nm, peeling may occur or coloring may exceed the allowable range.

In the embodiment, in the medical glass container according to the embodiment, it is preferable that at least a part of the glass surface of the inner wall of the glass container 2 or 21 is hydrophilized in the form in which the intermediate layer is provided. When the glass surface of the inner wall of the glass container 2 or 21 is subjected to a hydrophilization treatment, the adhesion of the film including the intermediate film is improved. The hydrophilization treatment includes, for example, a form in which a carbonyl group or a carboxyl group is added to the glass surface, and a form in which an OH group is added or bonded. When the glass container for medical use 1, 20 is used, it is preferable that a layer containing a carbonyl group having a thickness of 0.5 to 10 nm is formed at the interface between the intermediate layer and the inner surface of the container. More preferably, a layer containing a carbonyl group is formed. In the hydrophilized form, the intermediate layer containing silicon is, for example, a silicon oxide film, and the silicon oxide film contains silicon, oxygen, carbon, hydrogen, may contain fluorine, and has a film thickness Is preferably 3 to 50 nm. The thickness of the silicon oxide film is more preferably 5 to 20 nm. If the thickness of the silicon oxide film is less than 3 nm, the significance of providing the intermediate layer may be reduced, and the adhesion of the film provided on the intermediate layer may be reduced. When the film thickness of the silicon oxide film exceeds 50 nm, it may take time to generate a crack due to internal stress and to form a film.

The diamond-like carbon film 6 formed on the surface of the rubber plug 4 and the diamond-like carbon film 25 formed on the surface of the gasket 24 preferably contain 30 to 45 atomic% of hydrogen and 0 to 20 atomic% of fluorine The film thickness is preferably 1 to 70 nm, and more preferably 5 to 20 nm.

The fluorine resin film which coats the surface of the rubber stopper 4 is polytetrafluoroethylene, tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer, tetrafluoroethylene / hexafluoropropylene copolymer, tetrafluoroethylene / ethylene copolymer, It can be formed of one or more fluoroplastics such as polyvinylidene fluoride, polychlorotrifluoroethylene and chlorotrifluoroethylene-ethylene copolymer.

The medical glass container 1, 20 preferably has translucency, and specifically, the transmittance at a wavelength of 590 to 610 nm or 290 to 450 nm is preferably 45% or more, and is 60% or more. Is more preferred. The evaluation method of the transparency test conforms to "Japanese Pharmacopoeia (17th revision) 7. Container and packaging material test method 7.01 Test method for glass container for injection (5) Light shielding test of colored container".
(Manufacturing equipment for medical glass containers)

Next, a manufacturing apparatus will be described before describing a method for manufacturing a medical glass container. FIG. 3 shows a schematic view of a high frequency inner surface film forming apparatus for a vial. The high-frequency internal surface film-forming apparatus 100 for vials shown in FIG. 3 has source gas input systems 31, 32, 33. Each raw material gas input system has a stop valve 34 and a gas flow meter 35, and is connected to one mixed gas piping 36. Although FIG. 3 shows a mode in which there are three source gas input systems, more may be provided. The pipe 36 is connected to a conductive pipe 43 a which doubles as an internal electrode disposed in the vacuum chamber 38 and a gas introduction pipe. The vacuum chamber 38 is grounded and a vacuum gauge 37 is connected. In the vacuum chamber 38, the vial 2, an external electrode 45 disposed to surround the side and bottom of the vial 2, a dielectric member 46 disposed to surround the external electrode 45, and a dielectric An outer case 48 made of a conductive material is disposed to surround the body member 46 and stabilize the plasma formation of the source gas. The vacuum chamber 38 is connected to the exhaust pipe 49. Further, the external electrode 45 is connected to the auto matching device 40 so as not to conduct to the vacuum chamber 38. The auto matching device 40 is connected to a high frequency power supply 41. The frequency of the high frequency is, for example, 1 to 100 MHz, preferably 13.56 MHz. The raw material gas blown out from the conductive pipe 43a flows through the inside of the vial 2 and is then discharged from the tip end of the vial 2. After passing through the space 48a provided on the upper side in the outer case 48, the vacuum chamber 38 To reach the interior space of Thereafter, it is exhausted by the exhaust pipe 49.

FIG. 4 shows a schematic view of a microwave type inner film forming apparatus for vials. The microwave type internal film forming apparatus 200 for vials shown in FIG. 4 has source gas input systems 31, 32, 33. Each raw material gas input system has a stop valve 34 and a gas flow meter 35, and is connected to one mixed gas piping 36. Although FIG. 4 shows a mode in which there are three source gas input systems, more may be provided. The pipe 36 is connected to a gas introduction pipe 43 b disposed in the microwave shield 39. A vacuum gauge 37 is connected to the pipe 36. In the microwave shield 39, the vial 2 and a dielectric member 46 for fixing the mouth of the vial 2 so as not to leak the gas, and a pedestal 52 made of a dielectric for mounting the vial 2 A vacuum chamber 51 and an exhaust pipe 50 connected to the vacuum chamber 51 are disposed. The mouth of the vial 2 is connected to the space in the vacuum chamber 51, and when the vacuum chamber 51 is evacuated, the internal space of the vial 2 is also evacuated. In addition, a microwave oscillator 42 for outputting microwaves is provided inside the microwave shield 39. The frequency of the microwave is, for example, 0.9 to 45 GHz, preferably 2.45 GHz. The raw material gas blown out from the tip end of the gas introduction pipe 43 b flows through the inside of the vial 2 and is then discharged from the port, passes through the vacuum chamber 51, and is exhausted by the exhaust pipe 49.

FIG. 5 is a schematic view of a high-frequency inner surface film forming apparatus for a syringe barrel. The high frequency internal surface film-forming apparatus 300 for syringe barrels shown in FIG. 5 has source gas input systems 31, 32, 33. Each raw material gas input system has a stop valve 34 and a gas flow meter 35, and is connected to one mixed gas piping 36. Although FIG. 5 shows a mode in which there are three source gas input systems, more may be provided. The pipe 36 is connected to a gas introduction pipe 43 c disposed in the vacuum chamber 38. The vacuum chamber 38 is grounded and a vacuum gauge 37 is connected. In the vacuum chamber 38, the injection cylinder 21, an external electrode 45 disposed to surround the injection cylinder 21, a dielectric member 46 disposed to surround the external electrode 45, and a dielectric member 46 are provided. An outer case 48 made of a conductive material is disposed so as to surround and stabilize the plasma formation of the source gas. The vacuum chamber 38 is connected to the exhaust pipe 49. Further, the external electrode 45 is connected to the auto matching device 40 so as not to conduct to the vacuum chamber 38. The auto matching device 40 is connected to a high frequency power supply 41. The frequency of the high frequency is, for example, 1 to 100 MHz, preferably 13.56 MHz. The distal end portion of the gas introduction pipe 43 c is connected to a connecting portion which is the distal end portion of the injection cylinder 21. The raw material gas is fed from the tip end of the gas introduction tube 43c to the coupling portion which is the tip portion of the injection cylinder 21 and flows from the inside of the injection cylinder 21 and then discharged from the opening on the flange side of the injection cylinder 21 After passing through the space 48 a provided on the upper side of the outer case 48, the inner space of the vacuum chamber 38 is reached. Thereafter, it is exhausted by the exhaust pipe 49.

FIG. 6 shows a schematic view of a microwave type inner surface film forming apparatus for a syringe. The microwave type inner surface film-forming apparatus 400 for syringe barrels shown in FIG. 6 has source gas input systems 31, 32, 33. Each raw material gas input system has a stop valve 34 and a gas flow meter 35, and is connected to one mixed gas piping 36. Although FIG. 6 shows a mode in which there are three source gas input systems, more may be provided. The pipe 36 is connected to a gas introduction pipe 43 b disposed in the microwave shield 39. A vacuum gauge 37 is connected to the pipe 36. Further, in the microwave shield 39, the injection cylinder 21, a dielectric member 46 for fixing a connecting portion (opening) of the tip end portion of the injection cylinder 21, and a dielectric for mounting the flange side of the injection cylinder 21 The pedestal 52 and the exhaust pipe 50 connected to the opening on the flange side of the injection cylinder 21 are disposed. The joint (opening) of the tip end portion of the injection cylinder 21 and the tip end of the gas introduction pipe 43b are connected so as not to leak. An opening on the flange side of the injection cylinder 21 is connected to the exhaust pipe 50. In addition, a microwave oscillator 42 for outputting microwaves is provided inside the microwave shield 39. The frequency of the microwave is, for example, 0.9 to 45 GHz, preferably 2.45 GHz. The raw material gas introduced from the tip end of the gas introduction pipe 43 b flows through the inside of the injection cylinder 21 and is then discharged from the opening on the flange side and exhausted by the exhaust pipe 49.
(Method of manufacturing glass container for medical use)

The manufacturing method of the medical glass container which concerns on this embodiment is a manufacturing method of the medical glass container 1, 20 in which the film 3 is formed in at least one part of the inner wall of the medical glass container, and does not contain silicon as a constituent element. And forming a silicon-free diamond-like carbon film as the film 3 by plasmatizing the hydrocarbon-based gas in the storage space of the glass container, specifically, the vial 2 or the injection cylinder 21.

Here, the hydrocarbon-based gas which does not contain silicon is a first hydrocarbon-based gas which does not contain fluorine and silicon as constituent elements (hereinafter sometimes referred to as "first hydrocarbon-based gas") and fluorine. And a second hydrocarbon gas containing no silicon as a constituent element (hereinafter sometimes referred to as “second hydrocarbon gas”).

Examples of the first hydrocarbon gas include acetylene, methane, ethylene and propane, with acetylene and methane being preferred.

Examples of the second hydrocarbon gas include ethane hexafluoride, C ₆ F ₁₀ (CF ₃ ) ₂ , and C ₆ F ₆ , with ethane hexafluoride being preferable.

In order to plasmify the hydrocarbon-based gas not containing silicon, for example, high frequency or microwave is applied to plasmify using the film forming apparatus shown in FIGS.

In this embodiment, the hydrocarbon-based gas containing no silicon is modified with a first hydrocarbon-based gas containing neither fluorine nor silicon as a constituent element, and a second one containing no silicon as a constituent element. It is preferable that it is a mixed gas with a hydrocarbon-based gas, and the film is a silicon-free and fluorine-containing diamond-like carbon film. By using the above mixed gas, it becomes easy to set the fluorine content in the film to a desired ratio. It is preferable that the gas volume ratio of the mixed gas satisfy the range of Equation 1. The content of fluorine in the film is within a predetermined range, for example, 8 to 50 atomic% (atomic percentage), and an excellent water repellent effect is obtained.
(1)
(Second hydrocarbon gas): (first hydrocarbon gas) = 7: 3 to 9: 1

In the present embodiment, the hydrocarbon-based gas containing no silicon is the first hydrocarbon-based gas containing neither fluorine nor silicon as a constituent element, and the film is a silicon-free / fluorine-free diamond-like carbon film Is preferred. A silicon-free and fluorine-free diamond-like carbon film can be easily formed.

In this embodiment, before forming a silicon-free diamond-like carbon film as a film, a gas containing silicon is plasmatized in the storage space of the vial 2 or the syringe 21 to make the vial 2 or the syringe 21 It is preferable to include the step of forming an intermediate layer on the glass surface of the inner wall. By providing the intermediate layer containing silicon, the adhesion of the film is improved, the uniformity of the film is improved, the inner surface temperature at the time of the hydrophilization treatment is increased, and the density of the film is improved.
As a gas containing silicon, for example, trimethylsilane (TrMS), hexamethyldisiloxane (HMDSO), tetramethyl orthosilicate (Si (OCH ₃ ) ₄ ), tetraethoxysilane (Si (OC ₂ H ₅ ) ₄ ) and the like And oxygen gas.

In the present embodiment, when the film is formed, the mixing ratio of the gas containing silicon to the hydrocarbon-based gas not containing silicon is set to 100: 0 at the beginning of film formation, and the mixing ratio is increased as the film formation time progresses. It may be changed to 0: 100 at the end of film formation. At this time, the film becomes a gradient composition film.

In the present embodiment, before forming the film and / or the intermediate layer, the fluorine-modified hydrocarbon gas or oxygen gas is brought into contact with at least a part of the inner surface of the vial 2 or the syringe 21 to perform plasma. It is preferable to include a hydrophilization treatment step of forming Since the glass surface of the inner wall of the vial 2 or the injection cylinder 21 is hydrophilized, the adhesion of the film is improved, the uniformity of the film is improved, and the inner surface temperature at the time of the hydrophilization treatment is high. And the density of the film is improved. As a fluorine gas modified hydrocarbon gas, for example, there are ethane hexafluoride, C ₆ F ₁₀ (CF ₃ ) ₂ and C ₆ F ₆ , and ethane hexafluoride is preferable.

Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not construed as being limited to the examples.

The conditions for forming a film on a flat plate are as follows.
Equipment: Parallel plate type low pressure plasma CVD equipment High frequency output: 200 W, 13.56 MHz
Initial decompression: 0.02 torr
Deposition pressure: 0.1 torr
Deposition time: As shown in the table below: Mixed gas: As shown in the table below. However, the ratio indicates the volumetric flow rate mixing ratio.
Pretreatment: None or O ₂ plasma treatment 5 min or C ₂ F ₆ plasma treatment 5 min
Base material: Borosilicate glass substrate (length 20 mm x width 20 mm x thickness 0.1 mm) (in the table, it is described as glass) or Si substrate (length 20 mm x width 20 mm x thickness 0.38 mm) (in the table, it is described as Si) Do.)

The evaluation was as follows.
Film thickness: Step thickness meter (DEKTAK XT, made by BRUKER)
Contact angle: A contact angle measuring device (DM300, manufactured by KYOWA), pure water was used as an alternative to the water-based content to be brought into contact. It was based on JIS R3257 "Wettability test method of substrate glass surface". The aqueous content is a liquid medicine.
Adhesion: cross-cut test, JIS K 5600-5-6 (1999)

The conditions when forming a film on the inner surface of a container are as follows.
Device: Low-pressure plasma CVD device shown in FIG. 3 or 5 High frequency output: 100 W, 13.56 MHz
Initial pressure reduction: 0.02 torr
Deposition pressure: 2 torr
Deposition time: As shown in the table below: Mixed gas: As shown in the table below. However, the ratio indicates the volumetric flow rate mixing ratio.
Pretreatment: None, O ₂ plasma treatment 5 min or C ₂ F ₆ plasma treatment 5 min
Base material: borosilicate glass vial (outside diameter 16 mm, inside diameter 14 mm x height 35 mm x volume 2 ml) (In the table, it is referred to as a bottle. In addition, it may be called "vial") or a syringe (outside) Diameter 12.3 mm, inner diameter 10.6 mm x length 60 mm x volume 2 ml) (In the table, it is described as a syringe.)

Example A
An F-DLC film (hereinafter referred to as "F-DLC" in the table) was deposited as a film of the outermost layer. The middle layer was not provided. The results are shown in Tables 1, 2 and 3.

Example B
A DLC film (hereinafter referred to as "DLC" in the table) was formed as the outermost layer film. The middle layer was not provided. The results are shown in Table 4.

Example C
A DLC film was formed as a film of the outermost layer. The intermediate layer (SiO: CH) containing silicon was formed into a film as an intermediate layer. The results are shown in Table 5.

Example D
A DLC film or F-DLC film was formed as a film of the outermost layer. In Examples D-4 to 6, an intermediate layer (SiO: CH) containing silicon was formed as the intermediate layer. The results are shown in Table 6.

Example E
A DLC film or an F-DLC film was formed as the film of the outermost layer to obtain Example E-1 and Example E-2. Comparative Example E-1 was a glass substrate without the film of the outermost layer.
Transmittance
The measurement was carried out according to "JP 17 7.01 Glass container test method for injection (5) Light shielding property test of colored container". Specifically, it was carried out as follows. The absorbance at 290-810 nm was measured with an ultraviolet / visible spectrophotometer (ASUV 6300 PC, manufactured by As One).
The measurement results of the contact angle and the transmittance are shown in Table 7 and Table 8. In Tables 7 and 8, the transmissions at 290 nm, 450 nm, 590 nm and 610 nm were compared.

Example F
DLC film equivalent to Example E-1 or F-DLC film equivalent to Example E-2 as the outermost layer film (medical glass container for vial (vial bottle: 23 mm outer diameter, 21 mm inner diameter x height 35 mm x capacity) 5 ml, hereinafter referred to as “vial 2”) to form a membrane as Example F-1 and Example F-2. Comparative Example F-1 was a medical glass container (vial 2) having no film on the outermost layer.
[Remaining liquid of water]
Measurement of the amount of residual liquid of water was performed as follows. Weigh the vial 2, rubber stopper and aluminum cap (mass 1). Next, the vial 2 is filled with about 50% of the full volume of ultrapure water, capped with a rubber stopper and an aluminum cap, and weighed (mass 2). Then, the syringe is pierced with a rubber stopper, sucked while turning the vial upside down, and weighed (mass 3). Each mass was measured using an electronic balance (MSA224S100DI, manufactured by Sartorius). The mass of water was determined by subtracting mass 1 from mass 3.
[Serum albumin adsorption amount]
First, the coated vial 2 is washed with ultrapure water and dried at room temperature. Next, transfer 1 mL of a 10 ug / mL solution of BSA (bovine serum albumin) to each of the dried vials 2 and move the vial 2 so that the whole is touched and allowed to stand for 10 minutes. Next, 10 ug of the BSA solution in each vial 2 is measured, the fluorescence at 470/570 nm is measured, and the adsorption amount is calculated from the calibration curve. For measurement of fluorescence, a plate reader (EnSpire, manufactured by PerkinElmer) was used.
Tables 9 and 10 show the measurement results of the amount of residual liquid water and the amount of adsorbed serum albumin.

Example G
A DLC film equivalent to that of Example E-1 was formed as the outermost layer film on the inner wall of a medical glass container (vial 2) to obtain Example G-1. In Comparative Example G, a medical glass container (vial 2) without the film of the outermost layer was used.
[Dissolution amount after steam sterilization treatment]
The measurement was carried out according to "EP 8.4 3.2.1 Glass containers for pharmaceutical use test A. hydrolytic resistance of the inner surfaces of glass containers (surface test)". Specifically, it was carried out as follows. . Each vial 2 is filled with a full volume of 90% of each solution to obtain an extract after high-pressure steam sterilization treated at 121 ° C. for 1 h. Next, the metal ion concentration of the extract is measured with an ICP emission analyzer (OPTIMA 8300, manufactured by PerkinElmer).
[Number of insoluble fine particles contained per 1 mL after steam sterilization]
The measurement was carried out according to "JP 17 6.07 Insoluble fine particle test method for injection 1. Method 1 light shielding particle measurement method". Specifically, it was carried out as follows. Each vial 2 is filled with a full volume of 90% of each solution to obtain an extract after high-pressure steam sterilization treated at 121 ° C. for 1 h. Next, the number of insoluble fine particles is measured for the above extract with a fine particle counter in liquid (KL-04, manufactured by Rion).
Tables 11 and 12 show the elution amount after the steam sterilization treatment and the measurement results of the number of insoluble fine particles contained per 1 mL after the steam sterilization treatment.

As shown in Table 7 and Table 8, according to comparison between Example E-1 and Example E-2 and Comparative Example E-1, by forming a diamond-like carbon film on the glass substrate, contact with the aqueous contents You can make the corners larger. Further, according to the comparison between Example E-1 and Example E-2, the transmittance of the glass substrate can be improved by containing a high content of fluorine in the diamond-like carbon film.

As shown in Tables 9 and 10, a diamond-like carbon film was formed on the inner wall of a glass container for medical use (vial) from comparison of Example F-1 and Example F-2 with Comparative Example F-1. The amount remaining in the container can be reduced, and protein aggregation (adsorption) can be less likely to occur. Further, from the comparison between Example F-1 and Example F-2, it is possible to minimize the remaining amount in the container by making the diamond-like carbon film contain a high content of fluorine.

As shown in Tables 11 and 12, by forming a diamond-like carbon film corresponding to Example E-1 on the inner wall of a medical glass container (vial), an aqueous content of metal ions (Si ions, Na ions) It is possible to reduce the amount of elution into insoluble particles and the amount of insoluble fine particles, and to improve the stability of the aqueous content.

1, 20 Glass containers for medical use 2 Glass containers (vials for film formation)
2a inner wall of vial h container height direction 3, 22 film 4 rubber plug 6, 25 diamond-like carbon film 21 glass container (injection cylinder to be formed into a film)
21a Injection cylinder inner wall 23 Plunger 24 Gasket 24a Gasket surface 26 Fluororesin film 31, 32, 33 Raw material gas input system 34 Stop valve 35 Gas flow meter 36 Piping 37 Vacuum gauge 38 Vacuum chamber 39 Microwave shield 40 Automatic matching device 41 high frequency power source 42 microwave oscillator 43a conductive pipe 43b gas introduction pipe 43c gas introduction pipe 45 external electrode 46 dielectric member 48 external case 48a space 49 exhaust piping 50 exhaust piping 51 vacuum chamber 52 pedestal 100 vial high frequency Inner surface film forming apparatus 200 microwave internal surface film forming apparatus 300 for vials high frequency internal surface film forming apparatus 400 for injection cylinder microwave internal surface film forming apparatus for injection cylinder

Claims (18)

1. In a medical glass container in which a film is formed on at least a part of the inner wall of the glass container,
   The medical glass container characterized in that the film is a silicon-free diamond-like carbon film.
2. The medical glass container according to claim 1, wherein the film is a silicon-free and fluorine-containing diamond-like carbon film, or a silicon-free and fluorine-free diamond-like carbon film. .
3. The medical glass container according to claim 1 or 2, further comprising an intermediate layer containing silicon between the glass surface of the inner wall of the glass container and the film.
4. The medical glass container according to any one of claims 1 to 3, wherein at least a part of the glass surface of the inner wall of the glass container is subjected to a hydrophilization treatment.
5. The medical glass container according to any one of claims 1 to 4, wherein the glass forming the glass container is borosilicate glass, aluminosilicate glass or soda lime glass.
6. The medical glass container according to any one of claims 1 to 5, wherein the glass container is a vial, a syringe, a syringe with a needle and a cartridge type syringe.
7. The glass container according to claim 6, wherein the glass container is a vial and further comprises a rubber stopper, and at least a part of the inner surface of the rubber stopper is coated with a diamond-like carbon film or a fluorine resin film. Medical glass container.
8. 7. The apparatus according to claim 6, wherein the glass container is a syringe, and further comprising a plunger attached with a gasket, wherein at least a part of the surface of the gasket is coated with a diamond-like carbon film. Medical glass container.
9. The glass container is a syringe, and further, a plunger is attached to the gasket, and a fluorocarbon resin film is adhered to a surface of the gasket that contacts at least the inner surface of the syringe. The medical glass container according to claim 6.
10. The medical glass container according to claim 2, wherein the film is a silicon-free and fluorine-containing diamond-like carbon film, and the transmittance at 450 nm of the glass container is 90% or more.
11. In a method of manufacturing a medical glass container, wherein a film is formed on at least a part of the inner wall of the glass container,
    Forming a silicon-free diamond-like carbon film as the film by plasmatizing a hydrocarbon-based gas not containing silicon as a constituent element in the storage space of the glass container;
    A method of manufacturing a medical glass container, comprising:
12. The hydrocarbon-based gas not containing silicon is modified with a first hydrocarbon-based gas containing neither fluorine nor silicon as a constituent element, and a second hydrocarbon-based gas not containing silicon as a constituent element. Mixed gas with
    The method for producing a medical glass container according to claim 11, wherein the film is a silicon-free and fluorine-containing diamond-like carbon film.
13. The hydrocarbon-based gas which does not contain silicon is a first hydrocarbon-based gas which does not contain fluorine and silicon as constituent elements,
    The method for producing a medical glass container according to claim 11, wherein the film is a silicon-free and fluorine-free diamond-like carbon film.
14. The method for manufacturing a medical glass container according to claim 12 or 13, wherein the first hydrocarbon gas is acetylene and / or methane.
15. The method for producing a medical glass container according to claim 12, wherein a gas volume ratio of the mixed gas satisfies a range of Equation 1.
    (1)
    (Second hydrocarbon gas): (first hydrocarbon gas) = 7: 3 to 9: 1
16. The method for producing a medical glass container according to any one of claims 11 to 15, wherein the silicon-free hydrocarbon-based gas is plasmatized by high frequency output or microwave output.
17. Before forming the silicon-free diamond-like carbon film as the film,
    Forming an intermediate layer on the glass surface of the inner wall of the glass container by plasmatizing a gas containing silicon in the storage space of the glass container;
    The method for producing a medical glass container according to any one of claims 11 to 16, comprising
18. Before forming the film and / or the intermediate layer,
    A hydrophilization treatment step of forming a plasma by bringing a fluorine-modified hydrocarbon gas or oxygen gas into contact with at least a part of the inner surface of the medical glass container;
    The method for producing a medical glass container according to any one of claims 11 to 17, comprising:
    
    
    

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