Smooth film laminated elastomeric article

Abstract

To provide excellent elastomer articles.SOLUTION: An elastomeric article for sealing a container, the elastomeric article comprises an elastomeric body having an outer side wall surface and an outer top surface, and a first fluoropolymer film layer. The first fluoropolymer film layer has an inner surface and an outer surface, where the inner surface of the first fluoropolymer film layer is laminated across a whole body of the outer side wall surface and the top surface of the elastomeric body, the outer top surface of the first fluoropolymer film layer has a drug contact surface configured to come into contact with a drug contained in the container, and the outer side wall surface has a sealing surface configured to come into contact with an inner surface of the container. The outer surface of the first fluoropolymer film layer is substantially free of striations.SELECTED DRAWING: Figure 1

Description

Identification of related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 599,259, filed December 15, 2017, entitled "Elastomeric Articles Having Smooth Film Laminates," the entire contents of which are incorporated herein by reference. [Technical Field]

[0002] FIELD OF THE DISCLOSURE The present disclosure relates generally to elastomeric articles, and more particularly to elastomeric stoppers and pistons. [Background technology]

[0003] To protect sensitive pharmaceutical products from leachable or migratory substances emanating from pharmaceutical product containers equipped with elastomeric seals or other closures, e.g., stoppers or pistons, it is known to improve product performance by applying a film laminate on the drug-contacting surface (i.e., between the drug and the elastomer) of the elastomeric seal or closure. This is an important risk mitigation measure to avoid and reduce unwanted leachable and migratory substances from the elastomer. For example, many typical plastic or glass syringe assemblies include elastomeric pistons, with or without a coating. In coated pistons, the distal surface, commonly referred to as the drug-contacting surface, is typically coated with an inert film to inhibit drug interaction with the elastomeric material of the piston. However, the entire surface of the piston, more specifically, the surrounding tubular surface, is typically uncoated. That is, in a typical elastomeric piston, the cylindrical sidewall, including the sealing ribs, is left bare elastomer to provide adequate sealing. This is also generally true for coated vial stoppers. That is, the drug-contacting surface is coated with an inert film, while the bottom surface and outer sidewall of the flange that contacts the vial are left uncoated to provide a more effective sealing. As used herein, sealing surface refers to the peripheral sidewall of a piston or stopper, with or without sealing ribs.

[0004] One consequence of bare elastomer contact with a glass barrel is that frictional forces prevent smooth and easy operation of the syringe. As a result, syringe barrels are typically treated with silicone oil to "bake" the silicone onto the syringe barrel to reduce static frictional forces, called sliding yield forces, and kinetic frictional forces, called sliding balance forces or extrusion forces.

[0005] However, silicone oils are known to interact with some biological agents. Silicone oils have also been known to separate from the barrel and become injected into the patient's body along with medications. Furthermore, lasers are often used during surgery in or around the eye, and silicone oils are known to outgas under the high temperatures generated during laser surgery, so the use of silicone oils in ophthalmic applications is generally discouraged by regulatory guidance.

[0006] Therefore, what is desired is an elastomer that does not interact with or causes minimal leachables and migration with the medication. A container system that is not a source of silicone oil is also desirable.

[0007] Another drawback associated with producing both stoppers and pistons with a partial film laminate is the additional manufacturing steps required compared to those for making unlaminated or fully laminated stoppers and pistons: the elastomeric article is subjected to a so-called "two-step" process in which the piston tip (distal end) or stopper base, i.e., the end that contacts the pharmaceutical product, is first partially treated with a film separately from the corresponding piston base or stopper flange, and then the piston tip and piston base or stopper base and stopper flange are bonded together and further treated overall in a subsequent step.

[0008] However, typical stoppers and pistons generally do not have a film laminated over their entire outer surface. This is because even a small defect in the laminate film layer can compromise container integrity (CCI) by allowing gas or fluid to penetrate through the seal between the laminate film layer and the container (i.e., syringe, cartridge, or vial). In particular, scratches or small defects that create an unbroken path across the sealing surface, i.e., the interface between the inert film-laminated elastomeric film side and the container (syringe, cartridge, or vial) that prevents leakage of the medication outside the container, can significantly compromise CCI. For example, in a piston used in a syringe, an axial scratch perpendicular to the sealing rib and parallel to the longitudinal axis of the syringe creates a path that compromises CCI (see FIG. 4A). Scratches on the periphery of the piston parallel to the sealing rib can also compromise the CCI (although such scratches do not necessarily cause CCI failure, such as leakage of medication) (FIG. 4B). Also, a sufficiently high overall surface roughness (Ra) generally still allows permeation of the medication or gas through random paths due to the roughness, thus compromising the CCI.

[0009] In systems that use silicone, the silicone itself is known to mitigate problems related to CCI, but in silicone-free drug encapsulation systems, there is no silicone present to mitigate problems related to CCI.

[0010] It would therefore be desirable to provide a film silicone-free pharmaceutical encapsulation system in which the entire closure (i.e., piston or stopper) is laminated with a film, maintaining a sufficiently high CCI at the interface between the sealing surface of the closure and the container substrate. Another advantage of covering all or most of the piston or stopper with an inert film is that it protects the elastomer from unintentional exposure to chemicals, including solvents used in the manufacturing process, such as dimethyl sulfoxide (DMSO). DMSO is known to cause rubber to swell, which can increase some dimensions of the stopper or piston beyond reasonable tolerances.

[0011] Thus, a piston or stopper with adequate sealing properties that can be fabricated in a single curing process or step by applying a film laminate thereto is also desirable.Furthermore, it is desirable to provide a film laminated piston or stopper configured for use in a silicone-free glass syringe, fabricated in a two-step process, and coated with silicone oil, or using a syringe or cartridge barrel that is coated with silicone oil or is silicone-based, and that has sealing and friction characteristics similar to those of a typical piston. Summary of the Invention

[0012] One aspect of the present disclosure relates to a method of making at least one elastomeric article, comprising placing an assembly of an uncured elastomeric sheet, a first film completely covering the elastomeric sheet, and a second film covering the first film into a mold such that the second film contacts and is disposed between the first film and an interior surface of the mold, and curing the assembly in the mold such that the first film is laminated onto the elastomeric sheet to form the at least one elastomeric article.

[0013] Another aspect of the present disclosure relates to an elastomeric article for sealing a container, comprising an elastomeric body having an outer sidewall surface and an outer top surface, and a first fluoropolymer film layer having an inner surface and an outer surface. The inner surface of the first fluoropolymer film layer is laminated over the entire outer sidewall and top surfaces of the elastomeric body. The outer top surface of the first fluoropolymer film layer has a medication-contacting surface configured to contact a medication contained in the container, and the outer sidewall surface has a sealing surface configured to contact the inner surface of the container.

[0014] Another aspect of the present disclosure relates to a drug injection device, comprising a silicone-free barrel and an elastomeric piston having a laminate film layer in contact with the silicone-free barrel. The interface between the laminate film layer and the silicone-free barrel is approximately 6×10 -6 It has a seal that can withstand gas leakage of less than atm·cc / sec.

[0015] Another aspect of the present disclosure relates to a method of making an elastomeric article, including placing an uncured elastomeric sheet and a first film completely covering the elastomeric sheet into a mold, curing the elastomeric sheet together with the first film in the mold into at least one elastomeric article, removing the elastomeric article from the mold, and removing the first film from the at least one elastomeric article. [Brief explanation of the drawings]

[0016] The following detailed description of certain aspects of the present disclosure can be better understood when read in conjunction with the accompanying drawings, it being understood, however, that the present disclosure is not limited to the precise arrangements and instrumentalities shown.

[0017] [Figure 1] FIG. 1 illustrates a one-step method for producing an elastomeric article according to one embodiment of the present disclosure. [Figure 2] FIG. 2 illustrates the first step of a two-step method for making an elastomeric article according to one embodiment of the present disclosure. [Figure 3] FIG. 3 illustrates the second step of a two-step method for making an elastomeric article according to one embodiment of the present disclosure. [Figure 4A] FIG. 4A shows a prior art piston with axial scratches perpendicular to the sealing rib and parallel to the axis of rotational symmetry, creating a path that can compromise the CCI. [Figure 4B] FIG. 4B shows a prior art piston with scratches on the periphery of the piston parallel to the sealing rib, which can compromise the CCI. [Figure 5A] FIG. 5A is a scanning electron microscope (SEM) image (150x magnification) of the drug contact surface of an elastomeric piston made by a method according to an embodiment of the present disclosure. [Figure 5B] FIG. 5B is an SEM image (magnification 150) of the peripheral side of an elastomeric piston made by a method according to an embodiment of the present disclosure, more specifically, the sealing rib. [Figure 5C] FIG. 5C is a scanning electron microscope (SEM) image (150x magnification) of the drug contact surface of an elastomeric piston made by a method according to an embodiment of the present disclosure. [Figure 5D] FIG. 5D is an SEM image (150x magnification) of the peripheral side of an elastomeric piston made by a method according to an embodiment of the present disclosure, more specifically the sealing rib. [Figure 6A] FIG. 6A is an SEM image (150x magnification) of the drug-contacting surface of an elastomeric piston made by a method that does not employ a release film layer. [Figure 6B] FIG. 6B is an SEM image (150x magnification) of the peripheral side of an elastomeric piston, more specifically the sealing rib, made by a method that does not employ a release film layer. [Figure 6C] FIG. 6C is an SEM image (150x magnification) of the drug-contacting surface of an elastomeric piston made by a method that does not employ a release film layer. [Figure 6D]FIG. 6D is an SEM image (150x magnification) of the peripheral side of an elastomeric piston, more specifically the sealing rib, made by a method that does not employ a release film layer. [Figure 7] FIG. 7 is a graphical plot of various surface roughness parameters for samples of elastomeric articles and comparative articles produced by a method according to one embodiment of the present disclosure. [Figure 8] FIG. 8 is a graphical plot of various surface roughness parameters for samples of an elastomeric article produced by a method according to an embodiment of the present disclosure and a comparative article, with a 2 μm Gaussian filter applied. [Figure 9] FIG. 9 is a graphical plot of various surface roughness parameters for samples of elastomeric articles produced by a method according to an embodiment of the present disclosure and comparative articles, with a 0.08 μm Gaussian filter applied. [Figure 10] FIG. 10 is a graphical plot of various profile roughness parameters for samples of elastomeric articles and comparative articles produced by a method according to one embodiment of the present disclosure. [Figure 11] FIG. 11 graphically illustrates single contact profile measurements highlighting the difference in surface roughness between an elastomeric article made according to one embodiment of the present disclosure and a typical elastomeric article. [Figure 12] FIG. 12 graphically illustrates the measurements of FIG. [Figure 13] FIG. 13 shows an optical microscope image of an elastomeric piston according to one embodiment of the present disclosure, which has an improved surface finish compared to that provided by a typical process that does not include a release film layer. [Figure 14] FIG. 14 shows CCI in cyclic olefin polymer containers, more specifically, containers formed from polymers produced and / or sold under the Crystal Zenith® trademark and supplied by Daikyo Seiko Co., Ltd. (hereinafter referred to as "Crystal Zenith® polymer"), using helium leak tests for Inventive Sample C and Comparative Sample 4. [Figure 15] FIG. 15 shows the CCI in Crystal Zenith® polymer, silicone-free glass, and baked silicone glass by helium leak testing for invention sample C. [Figure 16] FIG. 16 shows the CCI in siliconized glass and baked silicone glass for Inventive Sample D and Comparative Sample 5 using helium leak tests. [Figure 17] FIG. 17 shows the force performance of inventive sample C. [Figure 18] FIG. 18 shows the force performance of inventive sample C. [Figure 19A] FIG. 19A shows an adaptive optics image of the surface of Comparative Sample 1. [Figure 19B] FIG. 19B shows the surface undulations and roughness profile of Comparative Sample 1. [Figure 20A] FIG. 20A shows an adaptive optics image (intensity used to indicate depth and height) of the surface of Comparative Sample 2. [Figure 20B] FIG. 20B shows the surface undulations and roughness profile of Comparative Sample 2. [Figure 21A] FIG. 21A shows an adaptive optics image of the surface of Comparative Sample 3. [Figure 21B] FIG. 21B shows the surface undulations and roughness profile of Comparative Sample 3. [Figure 22A] FIG. 22A shows an adaptive optics image of the surface of Inventive Sample 1. [Figure 22B] FIG. 22B shows the surface undulations and roughness profile of Inventive Sample 1. [Figure 23A] FIG. 23A shows an adaptive optics image of the surface of Inventive Sample 2. [Figure 23B] FIG. 23B shows the surface undulations and roughness profile of Inventive Sample 2. DETAILED DESCRIPTION OF THE INVENTION

[0018] 1, a method of manufacturing an elastomeric article, such as a piston 11, is shown using a first mold 14, an elastomeric sheet 44, a first film 16, more specifically an inert film layer or barrier layer 16, and a second film 46, more specifically a release film layer 46, in a one-step molding process, more specifically a one-step compression molding process. The first mold 14 includes an upper mold half 15 having a protrusion 15a and a lower mold half 17 having an open recess 17a. The open recess 17a is preferably an open heated mold recess. In a preferred embodiment, the first mold 14 includes a plurality of upper and lower mold halves 15, 17 aligned in a row.

[0019] The elastomeric sheet 44 is preferably made from one or more elastomeric materials in a partially cured stage. In a preferred embodiment, the elastomeric material is a thermoset elastomer or a thermoplastic elastomer (TPE). The elastomeric material used in the elastomeric closure may be a synthetic or natural rubber, such as, for example, butyl rubber, isoprene rubber, butadiene rubber, halogenated butyl rubber (e.g., bromobutyl rubber), ethylene propylene terpolymer, silicone rubber, or a combination thereof. Preferably, the elastomeric material is a butyl or halobutyl elastomer.

[0020] The inert film layer 16 is preferably made of a polymer, more specifically, a polymer that has barrier properties, lubricity, and high inertness. The film 16 is preferably an olefin polymer, and may contain a cyclic olefin polymer. More specifically, the inert film layer 16 is made of a fluoropolymer such as tetrafluoroethylene or ethylenetetrafluoroethylene. Some non-limiting examples of polymers that can be used to form the inert film layer 16 include tetrafluoroethylene, polytetrafluoroethylene (PTFE), ethylene tetrafluoroethylene (ETFE), fluorinated ethylene propylene (FEP), polyvinylidene fluoride (PVF), polyvinylidene difluoride (PVDF), polychlorotrifluoroethylene (PCTFE), perfluoroalkoxyalkane (PFA), ethylene chlorotrifluoroethylene (ECTFE), perfluoroelastomer (FFPM), fluoroelastomer polymer (FPM), polyethylene (PE), cyclic olefin polymer (COP), cyclic olefin copolymer (COC), and polypropylene (PP). The inert film layer 16 preferably has a thickness of 0.5 μm to 300 μm, more preferably 10 μm to 150 μm, and most preferably 25 μm to 100 μm.

[0021] Due to differing chemical requirements, an even wider variety of polymers are suitable for use in forming the release film layer 46. That is, all of the exemplary polymers listed above as materials for the inert film layer 16 can also be used to form the release film layer 46. Additionally, high-temperature compatible polymers such as polyimides or silicones are also suitable for use in forming the release film layer 46. Like the inert film layer 16, the release film layer 46 preferably has a thickness of 0.5 μm to 300 μm, more preferably 10 μm to 150 μm, and most preferably 25 μm to 100 μm.

[0022] The elastomeric sheet 44 has a first surface 44a and an opposite second surface 44b. The inert film layer 16 has a first surface 16a and an opposite second surface 16b. The release film layer 46 has a first surface 46a and an opposite second surface 46b. The first surface 16a of the inert film layer 16 can be surface-modified or surface-treated to have a smaller water contact angle and a higher surface energy than the unmodified second surface 16b. The first surface 16a of the inert film layer 16 is preferably etched, more preferably plasma etched. The surface modification / treatment of the first surface 16a of the inert film layer 16 can allow for strong bonding to the elastomeric sheet 44 after compression molding. Because the second surface 16b of the inert film layer 16 is unmodified, it has a larger water contact angle and a lower surface energy, which allows it to more easily detach from the untreated side of other films, such as the release film layer 46.

[0023] The elastomeric sheet 44, the inert film layer 16, and the release film layer 46 may be firmly bonded to one another, or may be independent of one another and loosely stacked on top of one another in that order when placed in the first mold 14. More specifically, for placement in the mold 14, the release film layer 46 is configured so that the second surface 46b contacts the inner surface 19 of the open recess 17a of the lower mold half 17, the inert film layer 16 is configured so that the second surface 16b of the inert film layer 16 contacts the first surface 46a of the release film layer 46, and more preferably is entirely covered by the first surface 46a of the release film layer 46, and the elastomeric sheet 44 is positioned so that the first surface 44a contacts the protrusion 15a of the upper mold half 15 and the second surface 44b of the elastomeric sheet 44 contacts the first surface 16a of the inert film layer 16, and more preferably is entirely covered by the first surface 16a of the inert film layer 16. The two mold halves 15, 17 are then brought into contact with each other so that each protrusion 15a contacts the first surface 44a of the elastomeric sheet 44 and presses the layered arrangement of the elastomeric sheet 44, inert film layer 16 and release film layer 46 into the open recesses 17a, compressing and molding the elastomeric sheet 44, inert film layer 16 and release film layer 46 in this arrangement within each open recess 17a in a single compression molding step.

[0024] The compression molding process is carried out at temperatures between 120°C and 310°C and pressures between about 40 and 350 kg / cm 2 More specifically, the single compression molding step is carried out at a temperature of 120°C to 220°C and a pressure of about 40 to 70 kg / cm for a duration of a few seconds to 30 minutes. 2 Most preferably, the single compression molding step is carried out at a temperature of about 140°C to 220°C and a pressure of about 40 to 70 kg / cm for a duration of about 30 seconds to 30 minutes. 2 for a duration of about 2 to 15 minutes.

[0025] In a preferred embodiment, the compression molding step is carried out at a temperature of 160°C to 165°C and 50 kg / cm 2 The pressure is then increased to 1000 psi for a duration of approximately 15 minutes.

[0026] In another preferred embodiment, the compression molding step is carried out at a temperature of 160°C to 175°C and a pressure of about 40 to 70 kg / cm 2 The pressure is 0.01 psi and the duration is approximately 8 minutes.

[0027] During the compression molding process, the elastomeric sheet 44 is vulcanized under the influence of heat and pressure, becoming inseparably bonded to the inert film layer 16. More specifically, the elastomeric sheet 44 forms the body 21 of the piston 11, and the inert film layer 16 becomes the inseparably laminated film 23 formed on the entire surface, more specifically, the sidewall and top surfaces of the body 21. This process is performed below the melting temperature of both the inert film layer 16 and the release film layer 46 to prevent the films from fusing together. Thus, the release film layer 46, on the other hand, becomes detachably bonded to the laminated film layer 23. If the films do not melt, the layers can be separated. A different film (dissimilar in chemistry and / or higher in melting point) can be used for the release layer than the film layer on the elastomeric article. For example, polyamide films, which melt at temperatures above 340°C, are used as release layers in many composite materials.

[0028] After curing or vulcanization, the piston 11 is removed from the first mold 14, after which the release film layer 46 is peeled from the piston 11. The release film layer 46 does not adhere to the inert film layer 16 and can be mechanically separated from the inert film layer 16, either as a continuous sheet or as segments from the individual pistons 11, for example, by squeezing and pulling, spraying with a fluid, or abrasion, among other techniques.

[0029] Prior to curing the assembly of elastomeric sheet 44, inert film layer 16, and release film layer 46 in the molding process, inert film layer 16 has a surface roughness characterized by a first peak density. After the curing process and removal of release film layer 46, inert film layer 16, more specifically, laminate film layer 23, has a surface roughness characterized by a second peak density, which is increased relative to the first peak density. The peak density of inert film layer 16 is preferably increased by at least 3%, more preferably by at least 25%, after the curing process and removal of release film layer 46. More specifically, the peak density of inert film layer 16 is preferably increased by 3% to 165%, more preferably by 25% to 35%, after the curing process and removal of release film layer 46.

[0030] Although the process has been described in terms of making piston 11, those skilled in the art will appreciate that the same process can be used to make other elastomeric articles, such as stoppers or other closures.

[0031] Referring to Figures 2 and 3, a method for manufacturing an elastomeric article, such as piston 12, according to another embodiment of the present disclosure is shown. The process of Figure 2 employs a second mold 24 sized and shaped to form a molded portion of the elastomeric article as piston top 12a. Mold 24 thus serves as the first mold in the manufacturing process. The process of Figure 3 uses mold 14 (i.e., the mold shown in Figure 1) sized and shaped to form the entire elastomeric article (e.g., piston 12). Figures 2 and 3 together illustrate a two-step molding process, more specifically, a two-step compression molding process, according to one embodiment of the present disclosure.

[0032] Referring to FIG. 2, the mold 24 used in the first step of the two-step molding process includes an upper mold half 25 having an open recess 25a and a lower mold half 27 having an open recess 27a. The open recesses 25a, 27a are preferably open, heated mold recesses. In a preferred embodiment, the first-step mold 24 includes a plurality of upper and lower mold halves 25, 27 arranged in a line. As in the one-step molding process, the elastomeric sheet 44, inert film layer 16, and release film layer 46 may be firmly bonded to one another, or they may be independent and loosely stacked on top of one another in that order when placed in the second mold 24. The arrangement of the elastomeric sheet 44, inert film layer 16, and release film layer 46 is similar to that described above with reference to FIG. 1.

[0033] The process conditions for the molding process shown in Figure 2 are similar to those described above for the one-step process of Figure 1. As in the one-step process of Figure 1, the elastomeric sheet 44 is vulcanized under the influence of heat and pressure, and is inseparably bonded to the inert film layer 16 such that the vulcanized elastomeric material forms the body 31 of the piston top 12a and the inert film layer 16 becomes a laminate film layer 33 inseparably formed on the surface of the piston top 12a (i.e., laminated piston top 12a). The release film layer 46, on the other hand, is detachably bonded to the laminate film layer 33.

[0034] After vulcanization, the laminated piston top 12a is removed from mold 24 with the release film layer 46 still on the laminated piston top 12a. The assembly of laminated piston top 12a and release film layer 46 is then cut away and placed into mold 14 such that the release film layer 46 contacts the inner surface 19 of the open recess 17a of lower mold half 17, sandwiching the release film layer 46 between the laminated piston top 12a and the open recess 17a, as shown in Figure 3. Thus, in the two-step process of Figures 2 and 3, mold 14 is the second-step mold.

[0035] Next, a second elastomeric sheet 44 is placed across the open recess 17a of the first mold 14, more specifically, the lower mold half 17. The two mold halves 15, 17 are then brought into contact with each other so that each projection 15a contacts the first surface 44a of the second elastomeric sheet 44, forcing the material of the second elastomeric sheet 44 into the open recess 17a and into contact with the laminated piston top 12a, compressing and molding the second elastomeric sheet 44 and laminated piston top 12a in this arrangement within their respective open recesses 17a in a compression molding process. Vulcanization proceeds as described above with respect to FIG. 1 to produce a piston 12 having a removable release film layer 46 for masking the top 12a in a subsequent operation (e.g., to produce a piston having silicone oil only on the exposed elastomeric side, and not on the laminated top 12a).

[0036] Prior to curing the assembly of elastomeric sheet 44, inert film layer 16, and release film layer 46 in the molding process, inert film layer 16 has a surface roughness characterized by a first peak density. After the curing process and removal of release film layer 46, inert film layer 16, and more specifically, laminated film layer 33, has a surface roughness characterized by a second peak density. The second peak density is increased relative to the first peak density. Preferably, the peak density of inert film layer 16 is increased by at least 3%, more preferably by at least 25%, after the curing process and removal of release film layer 46. More specifically, the peak density of inert film layer 16 is increased by 3% to 165%, more preferably by 25% to 35%, after the curing process and removal of release film layer 46.

[0037] It will be appreciated that the first step mold 24 may be sized and shaped to form a different portion of a different elastomeric article (e.g., the body of a stopper) instead of the piston top 12a, and the second step mold 14 may be sized and shaped to form a different elastomeric article instead of the piston.

[0038] An elastomeric article, such as a piston or stopper, is molded in a two-step process to produce an article having a drug interface coated with an inert film 16 and the remaining surface of the elastomeric article uncovered (i.e., bare elastomer).

[0039] The resulting elastomeric articles 11, 12 produced by a method according to one embodiment of the present disclosure are smooth film laminated elastomeric articles. In one embodiment, the resulting elastomeric articles 11, 12 are silicone-free. The release film layer 46 sandwiched between the elastomeric sheet 44 coated with the inert film layer 16 and the mold cavity surface 19 protects the smooth film laminated article (i.e., the piston 11) from damage during the manufacturing process, such as damage that may occur to the laminate film 23, 33 from sliding over the mold surface 19 during the molding and / or demolding steps. The release film layer 46 also protects the laminate film 23, 33 from any surface texture that may be imparted by the mold surface 19 (i.e., a mechanical analogy to a low-pass filter). The use of the release film layer 46 also protects the laminate films 23, 33 from any material contamination that may be encountered by the mold surface 19, such as processing aids used in the molding process, adhesive elastomers, or any other environmental contaminants. The use of the release film layer 46 creates a unique surface morphology as a result of the intimate face-to-face interfacial contact between the laminate films 23, 33 and the release film layer 46 and their subsequent separation.

[0040] Additionally, the use of release film layer 46 imparts a mirror-like finish to the outer surfaces of laminate film layers 23, 33. Thus, an elastomeric article made according to one embodiment of the present disclosure has an outer surface, more specifically, an outer sealing surface formed by a laminate film having a mirror-like finish or that is substantially scratch-free or substantially smooth. Figure 13 compares the surface profile of a plunger having a laminate film according to one embodiment of the present disclosure to that of a typical laminated plunger, showing that the plunger according to this embodiment has a smooth or mirror-like outer surface (left-hand side) compared to a plunger having a typical film laminate (right-hand side) that has a rough outer surface and is scratched and not mirror-like.

[0041] Certain embodiments according to the present disclosure are described by way of the following non-limiting examples and experiments.

[0042] Examples 1 to 4 The following Examples 1-4 employ four elastomeric pistons fabricated by the process described above with reference to FIG. 1 using a PTFE laminate (i.e., a laminated PTFE film layer covering the piston body and thereby forming the piston's exterior sidewall and top surfaces) and an ETFE release film layer. For comparison purposes, four elastomeric pistons (hereinafter referred to as "Comparative Examples 1-4") were fabricated using the same process, each with a PTFE barrier layer, except that no release film layer was used. The piston top and peripheral sealing surfaces of Examples 1-4 (shown in FIGS. 5A and 5C), and more specifically, the first sealing rib (shown in FIGS. 5B and 5D), have extremely smooth laminated film surfaces without any obvious surface features, marks, or striations. In contrast, the sealing surfaces of the piston top and periphery (shown in Figures 6A and 6C) of each of Comparative Examples 1 to 4, more specifically the laminate film surface of the first sealing rib (shown in Figures 6B and 6D), have distinctive features on the surface in the form of broken circles of any depth and length, diagonal lines and striations, holes of any size and depth, flat areas, broken shallow grooves, etc.

[0043] (Test 1) Five-mL elastomeric pistons with a laminated PTFE barrier layer were fabricated using the process described above with respect to FIG. 1, with a release film layer formed from ETFE having a thickness of 2 mil (∼50 μm). (The analysis was performed on different areas of the first rib of the piston (i.e., the rib closest to the drug-contacting surface) to show variations across the surface, and are therefore referred to as Inventive Samples A and B in Table 1.) For comparison purposes, a bare elastomeric piston was fabricated (referred to as Comparative Sample 1 in Table 1) using the same process parameters used to fabricate Inventive Samples A and B, but without a laminate or release film layer. An elastomeric piston with a laminated PTFE barrier film was fabricated (referred to as Comparative Sample 2 in Table 1) using the same process parameters used to fabricate Inventive Samples A and B, but without a release film layer. Additionally, a pre-formed PTFE film was provided (referred to as Comparative Sample 3 in Table 1).

[0044] The surface topography of each piston and film was measured using a Keyence 3D laser scanning confocal microscope. To determine area roughness parameters, the measurements were evaluated using three different methods according to ISO 25178, Surface Texture Standard. To determine the surface roughness parameters for each piston and film, the first method, as reflected by Examples A-1 through A-5, did not apply a filter; the second method, as reflected by Examples B-1 through B-5, applied a 2 μm Gaussian filter to remove high-frequency components of the measurements and separate waviness from roughness, in accordance with JIS B0632:2001 (ISO 11562:1996) and ISO 16610-21:2011; and the third method, as reflected by Examples C-1 through C-5, applied a 0.08 μm Gaussian filter to remove high-frequency components of the measurements and separate waviness from roughness, in accordance with JIS B0632:2001 (ISO 11562:1996) and ISO 16610-21:2011. The surface roughness parameters are summarized in Table 1 and plotted in Figures 7 through 9. In Figures 7 to 9, the y-axis is parallel to the longitudinal axis of the piston, so that the drug-contacting surface of the piston is located near the top of each graph.

[0045] Additionally, the profile roughness parameters for each sample were collected using a Mitutoyo SurfTest surface profilometer with a low-force probe and are summarized in Table 2 and plotted in the graph in Figure 10. In Figure 10, the y-axis is parallel to the longitudinal axis of the piston, so that the drug-contacting surface of the piston is located near the top of the graph. Optical images showing the surface topography of each sample obtained from a 3D laser scanning confocal microscope are shown in Figures 19A, 20A, 21A, 22A, and 23A, and the surface topography of each sample is shown in Figures 19B, 20B, 21B, 22B, and 23B. [Table 1] [Table 2]

[0046] Referring to Table 1, the measured and / or calculated parameters include the arithmetic mean height (Sa), maximum height (Sz), surface aspect ratio (Str), arithmetic mean peak curvature (Spc), developed interfacial area ratio (Sdr), kurtosis (Sku), auto-correction length (Sal), and peak density (Spd). The arithmetic mean height is the absolute mean height relative to the mean height along the sample length (i.e., relative, not absolute). Peak density is the number of peaks per unit area. For optical measurements, the minimum detectable peak is a function of the wavelength of the light source. While data filtering is commonly used to remove noise, filtering can also be used to effectively define what qualifies as a peak.

[0047] As will be understood by those skilled in the art, both arithmetic mean height and peak density are parameters used to characterize surface roughness, and these parameters are not necessarily related or correlated to one another. For example, when an elastomeric article coated with an inert film is molded (without a release layer), the inert film conforms to the surface of the mold, exhibiting the surface profile of the mold and, therefore, theoretically, the roughness of the mold. Thus, the peak density and arithmetic mean height of the inert film are directly related to the peak density and arithmetic mean height of the mold. Subsequent surface treatments to the elastomeric article, such as burnishing, can reduce the height of some of the peaks, effectively reducing the arithmetic mean height. However, the peak density does not necessarily change as a result of these subsequent surface treatments. Thus, the arithmetic mean height and peak density cannot be considered parameters that can be correlated to one another.

[0048] Referring to Table 2, the parameters measured and / or calculated include the arithmetic mean height (Ra), maximum height (Rz), average width of the profile elements (RSm), kurtosis (Rku), peaks per length (Pc / cm), and arithmetic mean wavelength (Rλa). The parameters shown in Table 1 represent measurements taken over an area, while the parameters shown in Table 2 represent measurements taken along a sample line. The measurement results indicate that the inert film of Comparative Sample 2 would have exhibited the surface profile and roughness of the mold during curing and vulcanization. The arithmetic mean height (Sa) of the inert films of Inventive Samples A and B was significantly better than the arithmetic mean height (Sa) of the bare elastomer of Comparative Sample 1. Furthermore, as seen in Table 1, the peak density (Spd) of Inventive Samples A and B increased compared to that of the inert film before molding (i.e., Comparative Sample 3). This is because the outer surface of the release film conformed to the inner surface of the mold, while the inert films of Inventive Samples A and B exhibited the surface profile and roughness of the release film. It is therefore apparent that the release film layer can be used to deliberately manipulate the surface topography of the inert film layer as a result of the release film layer and the inert film layer mechanically interacting with each other during the molding process.

[0049] Furthermore, during the molding process, the inert film layer 16 and the release film layer 46 are stretched by approximately 400% as they are forced into the mold. Stretching the release film layer has two effects. First, the Poisson's ratio proportionally reduces surface features, effectively reducing the arithmetic mean height. Second, micro-tear-like features form, effectively creating new peaks and valleys. Furthermore, removing the release film layer 46 from the inert film layer 16 may also create additional peaks. For example, the adhesive contact area between the inert film layer 16 and the release film layer 46 may be localized, so that when the release film layer 46 is peeled away, the surface of the inert film may be stretched at that contact area until the adhesive bond is broken. Stretching the inert film 16 leaves residual deformation peaks on its surface.

[0050] In other words, the inventors have discovered that the release film layer 46 not only protects the laminate film 23, 33 from damage, but actually improves the surface profile of the film. More specifically, the surface roughness of the inert film 16, characterized by its peak density (when no filter is applied), is increased by 3.8% to 28.7% by a molding process according to an embodiment of the present disclosure when forming the laminate film 23, 33. The surface roughness of the inert film 16, characterized by its peak density (when a 2.0 micron Gaussian filter is applied), is increased by 105.5% to 162.5% by a molding process according to an embodiment of the present disclosure when forming the laminate film 23, 33. The surface roughness of the inert film 16, characterized by its peak density (when a 0.08 micron Gaussian filter is applied), is increased by 4.9% to 34.2% by a molding process according to an embodiment of the present disclosure when forming the laminate film 23, 33.

[0051] Additionally, in one embodiment, the sealing surfaces configured to contact the container or syringe along their respective boundaries circumscribing the elastomeric article have a porosity of 50,000 peaks / mm when a 2.0 micron Gaussian filter is applied. 2 Peak densities greater than 300,000 peaks / mm when a 0.08 micron Gaussian filter is applied 2 and preferably the sealing surface has a surface roughness characterized by a peak density of greater than 100,000 peaks / mm when a 2.0 micron Gaussian filter is applied. 2 Peak densities greater than 500,000 peaks / mm when a 0.08 micron Gaussian filter is applied 2 and more preferably the sealing surface has a surface roughness characterized by a peak density of greater than 150,000 peaks / mm when a 2.0 micron Gaussian filter is applied. 2 Peak densities greater than 600,000 peaks / mm when a 0.08 micron Gaussian filter is applied 2 and most preferably the sealing surface has a surface roughness characterized by a peak density of greater than 200,000 peaks / mm when a 2.0 micron Gaussian filter is applied. 2 Peak densities greater than 700,000 peaks / mm when a 0.08 micron Gaussian filter is applied 2 The surface roughness is characterized by a peak density greater than that of the surface roughness of the SiO2 film.

[0052] Due to the extremely low, direction-independent surface roughness, an elastomeric article made according to an embodiment of the present disclosure forms an optimal interface with a container or syringe, thereby resulting in improved CCI. The elastomeric article according to an embodiment of the present disclosure is silicone-free, meaning it is applicable for use in systems that lack silicone oils to help mitigate CCI issues.

[0053] Furthermore, visually, there are clear differences in the surface profile plots between an elastomeric article according to an embodiment of the present disclosure made with a release film layer and a typical elastomeric article, as shown in Figure 11, even though the average numbers shown in the graph (Figure 12) for the piston face do not appear to be significantly different. The curvature of the imprint is dependent on the underlying curvature of the elastomeric article. A collection of quantitative measurements is summarized in Figure 12.

[0054] The differences in surface finish noted above are clearly visible in a quantitative visual evaluation. The image in Figure 13 compares an elastomeric piston according to one embodiment of the present disclosure with a glossy, enhanced surface finish (labeled "smooth") against a non-glossy-appearing piston (labeled "rough") prepared by a typical process that does not include a release film layer. The typically fabricated element has greater variability in surface topography across the visibly rough surface, while the enhanced surface finish is evenly applied across the sidewall and top surfaces.

[0055] (Test 2) In addition to Inventive Samples A and B, and Comparative Samples 1 to 3, a number of 1 mL long elastomeric pistons having a PTFE barrier film laminated to the entire outer sidewall and top surfaces were fabricated by the process described above with respect to FIG. 1 using a 2 mil (-50 μm) thick release film layer formed from ETFE (various tests were conducted with pistons of this type, shown as Inventive Sample C in FIGS. 14, 15, 17, and 18) (Inventive Sample C), and a number of 1 mL long elastomeric pistons having an ETFE barrier film laminated to the entire outer sidewall and top surfaces were fabricated by the same process parameters used to fabricate Inventive Sample C (shown as Inventive Sample D in FIG. 16) (Inventive Sample D). For comparison purposes, a number of 1 mL long elastomeric pistons were made using the same process parameters used to make Inventive Sample C (i.e., with a laminated PTFE barrier film) but without a release film layer (shown as Comparative Sample 4 in FIG. 14) (Comparative Sample 4), and a number of 1 mL long elastomeric pistons were made using the same process parameters used to make Inventive Sample D (i.e., with a laminated ETFE film) but without a release film layer (shown as Comparative Sample 5 in FIG. 16) (Comparative Sample 5).

[0056] Figure 14 shows the CCI in Crystal Zenith® polymer, as measured by helium leak testing, for pistons with a PTFE laminate made with (invention sample C) and without (comparative sample 4) a release liner. Similar to Figure 14, Figure 15 shows the CCI in Crystal Zenith® polymer, silicone-free glass, and baked silicone glass, as measured by helium leak testing, for pistons with a PTFE laminate made with a release liner (invention sample C). Additionally, Figure 16 shows the CCI in siliconized glass and baked silicone glass, as measured by helium leak testing, for pistons with an ETFE laminate made with (invention sample D) and without (comparative sample 5) a release liner. The helium leak rate is an industry standard used to qualify seal quality using helium as an inert tracer gas. The same improved surface finish can be applied to a bare rubber article by omitting one film layer, but the CCI is not affected by changes in surface roughness because the viscoelastic flow will fill surface imperfections under pressure. When a polymer film laminate is applied to the finished article, the film cannot flow, and any surface imperfections (on either sealing surface) will create a leak path. Figures 14 through 16 show that the final roughness of the sealing surface is important to performance, and the initial roughness of the film does not necessarily correlate to functional performance under all circumstances. A threshold of 6 x 10 indicates sterility. -6 The atm·cc / sec is derived from Kirsch et al. (titled "Pharmaceutical container / closure integrity") and is consistent with USP 1207. PTFE and ETFE were the laminate pistons fabricated for these tests, but one skilled in the art would recognize that other laminates can improve the sealing of rubber elastomers with release liners.

[0057] Figures 17 and 18 show the performance of PTFE-laminated pistons made with release liners. Specifically, Figure 17 shows the sliding yield force and average extension force for inventive Sample C in dry conditions using the Instron BLE method at 304.8 mm / min on Crystal Zenith® polymer, silicone-free glass, and baked silicone glass. Figure 18 shows the sliding yield force for Sample C in dry and wet conditions using the Instron BLE method at 304.8 mm / min on Crystal Zenith® polymer, silicone-free glass, and baked silicone glass (note that testing was not performed on Sample C in wet conditions on baked silicone glass). As well as the marked improvement in sealing properties, the PTFE-laminated pistons made with release liners have sliding yield force and average extension force characteristics similar to some commercially available pistons that require the use of silicone oil (however, commercially available pistons used with silicone oil were not tested in this experiment). The improved force performance is due to the entire contact surface of the piston (i.e., sidewall and top surfaces) being coated with a lubricating, inert film, rather than just the drug interface, as is (hypothetically) common for pistons intended for use with silicone oil. While this experiment characterized the force performance of a PTFE-laminated piston, one skilled in the art will recognize that ETFE and other laminated pistons made with release liners will also have improved force characteristics in a variety of barrel configurations.

[0058] This method can also be used to create elastomeric articles without any laminate film layer (i.e., bare elastomer protected by release film layer 46 during the molding process). Other modifications to the surface can include chemical functionalization, coatings, which require a smooth substrate.

[0059] High control of surface roughness allows for tuning of total contact area, thereby improving other functional attributes (i.e., sliding yield strength and tensile strength), which in turn allows for product geometries that were not previously possible.

[0060] This product can be provided through new mold designs as well. Other possible manufacturing methods include, but are not limited to, polished molds, blunt molds (to prevent damage to the film), PTFE (or other polymer) coated molds, alternative mold materials (i.e., polymer or ceramic), and alternative mold release techniques. However, due to how the release film protects the inert film layer from mold surface features, the present disclosure is well suited to rough molds and can extend the product life of any mold, ultimately reducing costs.

[0061] The present disclosure is suitable for use in any type of seal used to contain or contact injectable medications, including, but not limited to, pistons, stoppers, and liner seals. The greatest need for the present disclosure is in silicone-free containment systems for injectable medications, where maintaining CCI is critical. The present disclosure is more suitable for sensitive biological agents and intraocularly administered medications. The present disclosure is also suitable for reducing the manufacturing costs of any elastomer for containing injectable medications with good barrier properties.

[0062] The disclosed technology can be used to manufacture fully or partially film-laminated pistons, stoppers, etc. and / or silicone-free barrier closure systems. Preferably, the disclosed technology is used to manufacture fully film-laminated pistons, stoppers, etc. and / or silicone-free barrier closure systems.

[0063] Certain terminology has been used in the foregoing description merely for convenience and without limitation. Words such as "proximal," "distal," "upper," "lower," "bottom," and "top" designate directions in the drawings to which reference is made. Words such as "inward" and "outward" designate directions toward or away from the geometric center of the device and its designated portion in accordance with the present disclosure, respectively. Unless otherwise stated herein, terms such as "a," "an," and "the" should not be read as being limited to one element, but rather as meaning "at least one." The terminology includes the words set forth above, as well as derivatives and words of similar import.

[0064] It will be understood by those skilled in the art that modifications may be made to the above-described embodiments without departing from the broadest technical concept of the present disclosure. Therefore, it is understood that the present disclosure is not limited to the particular embodiments disclosed, but is intended to include modifications within the spirit and scope of the present disclosure.

Claims

1. 1. An elastomeric article for sealing a container, comprising: an elastomeric body having an outer sidewall surface and an outer top surface; a polymer film layer having an inner surface and an outer surface, the inner surface of the polymer film layer being laminated to the outer sidewall surface and the outer top surface, the outer surface of the polymer film layer having a drug-contacting surface disposed on the outer top surface and configured to contact a drug contained in the container, and a sealing surface disposed on the outer sidewall surface and configured to contact the inner surface of the container; Equipped with the outer surface of the polymer film layer is scratch-free; The sealing surface has a peak density of 50,000 peaks / mm when a 2.0 μm Gaussian filter is applied. 2 or 300,000 peaks / mm when a 0.08 μm Gaussian filter is applied. 2 having a surface roughness characterized by a peak density greater than Elastomeric articles.

2. The surface roughness is 100,000 peaks / mm when a 2.0 μm Gaussian filter is applied. 2 or 500,000 peaks / mm when a 0.08 μm Gaussian filter is applied. 2 characterized by a peak density greater than The elastomeric article of claim 1 .

3. The surface roughness is 150,000 peaks / mm when a 2.0 μm Gaussian filter is applied. 2 or 600,000 peaks / mm when a 0.08 μm Gaussian filter is applied. 2 characterized by a peak density greater than The elastomeric article of claim 1 .

4. The surface roughness is 200,000 peaks / mm when a 2.0 μm Gaussian filter is applied. 2 or 700,000 peaks / mm when a 0.08 μm Gaussian filter is applied. 2 characterized by a peak density greater than The elastomeric article of claim 1 .

5. the elastomeric article is a piston or a vial stopper; The elastomeric article of claim 1 .

6. the outer surface of the polymer film layer has a mirror-like finish; The elastomeric article of claim 1 .

7. Barrel and The elastomeric article of claim 1. Equipped with the barrel is silicone-free, the polymer film layer is in contact with the barrel, At the interface between the polymer film layer and the barrel, -6 A seal is provided that can withstand gas leakage of less than atm·cc / sec. injection device.

8. Operation of the piston within the barrel generates a sliding force on the barrel of less than 15 N.

8. An injection device according to claim 7.

9. Actuation of the piston within the barrel generates a sliding force on the barrel of less than 10 N.

8. An injection device according to claim 7.

10. Actuation of the piston within the barrel generates a sliding force on the barrel of less than 7.5 N.

8. An injection device according to claim 7.

11. Operation of the piston within the barrel generates a sliding force on the barrel of less than 5 N.

8. The injection device of claim 7.

12. The barrel is made of glass or polymer.

8. An injection device according to claim 7.

13. The surface roughness of the sealing surface is 100,000 peaks / mm when a 2.0 μm Gaussian filter is applied. 2 or 500,000 peaks / mm when a 0.08 μm Gaussian filter is applied. 2 characterized by a peak density greater than 8. An injection device according to claim 7.

14. The surface roughness of the sealing surface is 150,000 peaks / mm when a 2.0 μm Gaussian filter is applied. 2 or 600,000 peaks / mm when a 0.08 μm Gaussian filter is applied. 2 characterized by a peak density greater than 8. An injection device according to claim 7.

15. The surface roughness of the sealing surface is 200,000 peaks / mm when a 2.0 μm Gaussian filter is applied. 2 or 700,000 peaks / mm when a 0.08 μm Gaussian filter is applied. 2 characterized by a peak density greater than 8. An injection device according to claim 7.

16. the outer surface of the polymer film layer has a mirror-like finish; 8. An injection device according to claim 7.

17. The inner surface of the polymer film layer is laminated over the outer sidewall surface and the outer top surface. The elastomeric article of claim 1 .

18. The polymer film layer is a fluoropolymer film layer. The elastomeric article of claim 1 .

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