Smooth Film Laminated Elastomeric Articles

Abstract

A method for preparing at least one elastic article is provided. The method comprises placing an assembly of an uncured elastic sheet into a mold, with a first film completely covering the elastic sheet and a second film covering the first film, such that the second film contacts the first film and an inner surface of the mold and is positioned between the first film and the inner surface of the mold. The method further comprises curing the assembly in the mold, laminating the first film to the elastic sheet, thereby forming the at least one elastic article.

Description

[0001] This application is a divisional application, and its parent application is an invention patent application with the invention name "Smooth Film Laminated Elastomer Product", its application number is 201880081073.4 and the application date is December 17, 2018.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Patent Application No. 62 / 599,259, filed on December 15, 2017, entitled “Smooth Film Laminated Elastic Article,” the entire contents of which are incorporated herein by reference. Technical Field

[0004] The present invention relates generally to elastomeric articles and, more particularly, to elastomeric stoppers and pistons. Background Art

[0005] To protect sensitive drug products from extractable and leachable substances from drug product containers, drug product containers include elastomeric seals or other closures, such as stoppers or pistons. Including a film laminate on the elastomeric seal or closure on the drug-contacting surface (e.g., between the drug and the elastomer) is well known to improve product performance and is an important risk mitigation strategy for preventing or reducing unwanted extractables and leachables from the elastomer. For example, many conventional plastic or glass syringe assemblies feature coated or uncoated elastomeric pistons. With coated pistons, the distal surface, typically the drug-contacting surface, is typically coated with an inert film to minimize drug interaction with the piston's elastomeric material. However, the entire piston surface, and more specifically the outer tubular surface, is typically uncoated. That is, to provide an adequate seal, the cylindrical sidewall of conventional elastomeric pistons, including the sealing rib, is left bare elastomer. This is also typical of coated stoppers. That is, the drug-contacting surface is coated with an inert film, while the bottom flange and outer sidewall, which contact the vial, remain uncoated to provide a better seal. As used herein, the sealing surface refers to the surrounding side wall of the piston or stopper with or without sealing ribs.

[0006] One consequence of having a bare elastomer in contact with the glass barrel is that friction prevents a smooth and easy injection operation. Therefore, traditionally, syringe barrels are treated with silicone oil or "baked" with silicone to reduce static friction, which is called break-away force, and to reduce dynamic friction, which is called sliding or extrusion force.

[0007] However, silicone oil is known to interact with some biologic drugs. Silicone oil can also be separated from the cartridge and injected into the patient along with the medication. Furthermore, regulatory guidance generally advises against the use of silicone oil in ophthalmic applications, as lasers are frequently used for procedures in or around the eye, and silicone oil is known to outgas at high temperatures, which occur during laser surgery.

[0008] Therefore, there is a need for an elastomer that does not interact with the drug or produces minimal extractables and leachables. There is also a need for a container system that does not contain silicone oil.

[0009] Another disadvantage associated with the production of partially film-laminated stoppers and pistons is the need for additional manufacturing steps compared to the production processes for non-laminated or fully laminated stoppers and pistons. Specifically, the elastomeric article undergoes a so-called "two-step" process in which the tip (distal end) of the piston or the bottom of the stopper, the end in contact with the drug product, is first partially cured with the film separated from the respective piston base or stopper flange, and then the tip of the piston and the piston base, or the bottom of the stopper and the stopper flange, are joined and then fully cured in a subsequent step.

[0010] However, conventional stoppers and pistons typically do not include a film laminated across their entire outer surface. This is because even small defects in the laminated film layer may allow the permeation of gas or liquid through the seal between the laminated film layer and the container (i.e., syringe, cartridge or vial), potentially compromising container closure integrity (CCI). In particular, scratches or small defects that result in a continuous path on the sealing surface, i.e., the interface between the film side of the inert film laminated elastomer and the container (syringe, cartridge or vial) that prevents drug from escaping the container, can seriously compromise CCI. For example, on a piston used in a syringe, an axial scratch perpendicular to the sealing rib of the syringe and parallel to the axial direction of the syringe creates a path that compromises CCI (see Figure 4A Scratches around the piston circumference parallel to the sealing rib may also compromise the CCI (although such scratches may not necessarily lead to CCI failure, such as drug leakage). Figure 4B ). In addition, a sufficiently high overall surface roughness (Ra) will typically allow drug product or gas to penetrate through random paths through the surface roughness, thereby compromising CCI.

[0011] In systems using silicone, silicone itself has been shown to reduce CCI issues. However, in silicone-free drug-controlled systems, there is no silicone to reduce CCI issues.

[0012] Therefore, there is a need for a silicone-free drug control system in which the closure (i.e., piston or stopper) is entirely film-laminated and in which the CCI of the sealing surface interface between the closure and the container substrate is maintained at a sufficiently high level. Another benefit of coating the piston or stopper with an inert film, in whole or in large part, is that it can be used to protect the elastomer from accidental 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 cause certain dimensions of the stopper or piston to increase beyond the appropriate tolerances.

[0013] Therefore, there remains a need for a piston or stopper having adequate sealing properties that is entirely film laminated so that it can be prepared using a single curing process or step. Furthermore, there remains a need for a film laminated piston or stopper configured for use in silicone-free glass syringes that exhibits similar sealing and frictional properties to pistons prepared using conventional two-step processes and silicone oil coatings, or for use in syringes or cartridges coated with silicone oil or silicone-based drugs. Summary of the Invention

[0014] One embodiment of the present invention relates to a method for preparing at least one elastic article, comprising the steps of placing an assembly of uncured elastic sheets into a mold, with a first film completely covering the elastic sheets and a second film covering the first film, such that the second film is in contact with the first film and the inner surface of the mold and is positioned between the first film and the inner surface of the mold; and curing the assembly in the mold such that the first film is laminated to the elastic sheets, thereby forming the at least one elastic article.

[0015] Another embodiment of the present invention relates to an elastic article for sealing a container, comprising: an elastic body having an outer surface and an outer crown 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 to the entirety of the outer surface and the outer crown surface of the elastic body. The outer crown surface of the first fluoropolymer film layer comprises a drug contact surface configured to contact a drug contained in the container, and the outer surface comprises a sealing surface configured to contact the inner surface of the container.

[0016] Another embodiment of the present invention relates to a device for injecting a drug. The device comprises a silicone-free barrel and an elastic piston, wherein the elastic piston has a laminated film layer and contacts the silicone-free barrel. The interface between the laminated film layer and the silicone-free barrel has a gas leakage resistance of less than 6×10 -6 atm*cc / sec sealed structure.

[0017] Another embodiment of the present invention relates to a method for preparing an elastic article, comprising the following steps: placing an uncured elastic sheet and a first film of the elastic sheet into a mold; curing the elastic sheet and the first film in the mold into at least one elastic article; removing the elastic article from the mold; and removing the first film from the at least one elastic article. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The following description of specific embodiments of the present invention will be better understood in conjunction with the accompanying drawings. However, it should be understood that the present invention is not limited to the precise arrangements and apparatus shown. In the accompanying drawings:

[0019] Figure 1 Describe a one-step method for preparing an elastic article according to an embodiment of the present invention;

[0020] Figure 2 The first step of a two-step method for preparing an elastic article according to an embodiment of the present invention is described;

[0021] Figure 3 Describe the second step of the two-step method for preparing an elastic article according to an embodiment of the present invention;

[0022] Figure 4A It shows that the piston in the prior art has an axial scratch perpendicular to the sealing rib and parallel to the axis of rotational symmetry, thereby forming a path that harms CCI;

[0023] Figure 4B It shows that the piston in the prior art has scratches on the piston circumference parallel to the sealing rib, which may endanger the CCI;

[0024] Figure 5A and Figure 5C This is a scanning electron microscope (SEM) image (150 times magnification) of the drug contact surface of the elastic piston produced according to the method of an embodiment of the present invention;

[0025] Figure 5B and Figure 5D The figure is a SEM image (150 times magnified) of the surrounding side surface of the elastic piston produced according to the method of an embodiment of the present invention, more specifically of the sealing rib;

[0026] Figure 6A and Figure 6C This is an SEM image (150 times magnification) of the drug contact surface of the elastic piston produced without using the peeling film method;

[0027] Figure 6B and Figure 6D This is an SEM image (150 times magnification) of the surrounding side surface of the elastic piston produced by the method without using the peeling film layer, more specifically the sealing rib;

[0028] Figure 7 A graph showing roughness parameters of various regions of samples of elastic products prepared according to the method of an embodiment of the present invention and comparative products;

[0029] Figure 8 A graph showing roughness parameters of various regions drawn using a 2 μm Gaussian filter for samples of elastic products and comparative products prepared according to the method of an embodiment of the present invention;

[0030] Figure 9 A graph showing roughness parameters of various regions drawn using a 0.08 μm Gaussian filter for samples of elastic products and comparative products prepared according to the method of an embodiment of the present invention;

[0031] Figure 10 A graph showing roughness parameters of various regions of samples of elastic products prepared according to the method of an embodiment of the present invention and comparative products;

[0032] Figure 11 Graphically depicting single contact profilometry measurements to highlight the differences in surface roughness between elastic articles produced by the invention and conventional elastic articles;

[0033] Figure 12 Graphical description Figure 11 The measured value of

[0034] Figure 13 An optical microscope image showing an elastic piston according to the present invention having an improved surface finish compared to an image of an elastic piston prepared by a conventional process not involving a stripping film layer;

[0035] Figure 14 The cyclic olefin polymer container CCI used in the invention sample C and the comparative sample 4 is shown, especially the polymer is made of the trademark Crystal and derived from a polymer manufactured and sold by Daikyo Seiko, Co., Ltd. (hereinafter referred to as "Crystal Containers formed of polymers ("polymers"), using helium leak testing;

[0036] Figure 15 Shows the Crystal applied to the invention sample C CCI in polymers, silicone-free glass, and baked-on silicone glass using a helium leak test.

[0037] Figure 16 Shows CCI in siliconized glass and baked silicone glass applied to Inventive Sample D and Comparative Sample 5, using a helium leak test;

[0038] Figure 17 and Figure 18The mechanical properties of the inventive sample C are given;

[0039] Figure 19A Describes the surface enhancement optical image of comparative sample 1;

[0040] Figure 19B Describe the surface waviness and roughness profile of comparative sample 1;

[0041] Figure 20A Describes the surface enhancement optical image of comparative sample 2 (used to show depth and height intensity);

[0042] Figure 20B Describe the surface waviness and roughness profile of comparative sample 2;

[0043] Figure 21A Describes the surface enhancement optical image of comparative sample 3;

[0044] Figure 21B Describe the surface waviness and roughness profile of comparative sample 3;

[0045] Figure 22A Describe the surface enhanced optical image of the inventive sample 1;

[0046] Figure 22B Describe the surface waviness and roughness profile of Inventive Sample 1;

[0047] Figure 23A Describe the surface enhanced optical image of Inventive Sample 2; and

[0048] Figure 23B Describe the surface waviness and roughness profile of Inventive Sample 2. DETAILED DESCRIPTION

[0049] See also Figure 1 Here, a method for making an elastic article, such as a piston 11, is shown using a first mold 14, an elastomeric sheet 44, a first film 16, and more specifically, an inert film layer or sleeve layer 16, and a second film 46, and more specifically, a release film layer 46, in a one-step molding process, and 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 cavity 17a. The open cavity 17a is preferably an open heated mold cavity. In a preferred embodiment, the first mold 14 includes a plurality of upper mold halves 15 and lower mold halves 17 arranged in an array.

[0050] The elastomeric sheet 44 is preferably formed from one or more elastomeric materials in a partially cured stage. In a preferred embodiment, the elastomeric material is a thermosetting elastomer or a thermoplastic elastomer (TPE). The elastomeric material used for the elastic closure member can be, for example, a synthetic or natural rubber, such as butyl rubber, isoprene rubber, butadiene rubber, halogenated butyl rubber (such as bromobutyl rubber), EPDM rubber, silicone rubber, and combinations thereof. Preferably, the elastomeric material is butyl or halogenated butyl elastomer.

[0051] Inert film layer 16 is preferably formed by polymer, more specifically has the highly inert polymer of good barrier property and lubricity.More preferably, film 16 is preferably olefin polymer, and can comprise cycloolefin polymer.More preferably, inert film layer 16 is formed by fluoropolymer, as tetrafluoroethylene or ethylene tetrafluoroethylene.Some non-limiting polymer examples that can be used to form inert film layer 16 include tetrafluoroethylene, polytetrafluoroethylene (PTFE), ethylene tetrafluoroethylene (ETFE), fluorinated ethylene propylene (FEP), polyvinylidene fluoride (PVF), polyvinylidene fluoride (PVDF), polychlorotrifluoroethylene (PCTFE), perfluoroalkoxy alkane (PFA), ethylene chlorotrifluoroethylene (ECTFE), perfluoroelastomer (FFPM), fluoroelastomer polymer (FPM), polyethylene (PE), cycloolefin polymer (COP), cycloolefin copolymer (COC) and polypropylene (PP). The inert film layer 16 preferably has a thickness of from 0.5 μm to 300 μm, more preferably from 10 μm to 150 μm, and most preferably from 25 μm to 100 μm.

[0052] A wider array of polymers are suitable for forming release film layer 46 due to different chemical requirements. That is, all of the typical polymers identified above as materials for inert film layer 16 can also be used to form release film layer 46. In addition, high-temperature resistant polymers, such as polyimide or silicone, are also suitable for forming release film layer 46. Similar to inert film layer 16, release film layer 46 preferably has a thickness of from 0.5 μm to 300 μm, more preferably from 10 μm to 150 μm, and most preferably from 25 μm to 100 μm.

[0053] The elastomer sheet 44 has a first surface 44a and an opposing second surface 44b. The inert film layer 16 has a first surface 16a and an opposing second surface 16b. The release film layer 46 has a first surface 46a and an opposing second surface 46b. The first surface 16a of the inert film layer 16 can be surface modified / treated so that it has a lower water contact angle and a higher surface energy than the unmodified second surface 16b. Preferably, the first surface 16a of the inert film layer 16 is etched, and more preferably plasma etched. The surface modification / treatment of the first surface 16a of the inert film layer 16 enables it to be strongly bonded to the elastomer sheet 44 after compression molding. Because the second surface 16b of the inert film layer 16 is not modified, it has a larger water contact angle and a lower surface energy, making it easier to separate from the untreated surface of another film (such as the release film layer 46).

[0054] The elastomeric sheet 44, the inert film layer 16, and the release film layer 46 can be securely connected to one another or independently of one another in sequence and loosely stacked upon one another when introduced into the first mold 14. More specifically, to be placed in the mold 14, the release film layer 46 is positioned so that its second surface 46b contacts the inner surface 19 of the open cavity 17a of the lower mold half 17; the inert film layer 16 is positioned so that its second surface 16b contacts the first surface 46a of the release film layer 46 and is more preferably completely covered by the first surface 46a of the release film layer 46; and the elastomeric sheet 44 is positioned so that its first surface 44a contacts the protrusion 15a of the upper mold half 15 and its second surface 44b contacts the first surface 16a of the inert film layer 16, and more preferably, its second surface 44b is completely covered by the first surface 16a of the inert film layer 16. The two halves of the mold 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 forces the layered arrangement of the elastomeric sheet 44, the inert film layer 16, and the release film layer 46 into the open cavity 17a, thereby compressing and molding the arrangement of the elastomeric sheet 44, the inert film layer 16, and the release film layer 46 in each open cavity 17a in a single compression molding step.

[0055] This compression molding step is performed at a temperature of 120°C to 310°C and a pressure of approximately 40 to 350 kg / cm 2 More preferably, the single compression molding step is carried out at a temperature of about 120°C to 220°C and a pressure of about 40 to 70 kg / cm 2 Most preferably, the single compression molding step is performed at a temperature of about 140°C to 220°C and a pressure of about 40 to 70 kg / cm 2The pressure is maintained for about 2 minutes to 15 minutes.

[0056] In a preferred embodiment, the compression molding step is performed at a temperature of 160°C to 165°C and a pressure of 50 kg / cm 2 , which lasts about 15 minutes.

[0057] In another preferred embodiment, the compression molding step is carried out at a temperature of 160°C to 175°C and a pressure of 40 to 70 kg / cm 2 , which lasts about 8 minutes.

[0058] During the compression molding process step, the elastic sheet 44 is vulcanized under heat and pressure and is non-detachably connected to the inert film layer 16. More specifically, the elastic sheet 44 forms the body 21 of the piston 11, and the inert film layer 16 becomes the laminated film 23 that is non-detachably formed on the surface, and more preferably forms the side surface and crown surface of the body 21. The process is carried out below the melting temperature of both the inert film layer 16 and the release film layer 46 so that the films do not fuse together. Therefore, the release film layer 46, on the other hand, is removably added to the laminated film layer 23. If the film does not melt, the layers can be separated. Different films can be used as release layers than the film layers on the elastic article (different chemical composition and / or higher melting point). For example, in many composite materials, polyamide films that melt above 340°C are used as release layers.

[0059] After curing or vulcanization, the piston 11 is removed from the first mold 14, and the release film 46 is then peeled off the piston 11. The release film 46 is not adhered to the inert film 16, and therefore, it can be mechanically separated from the individual pistons as a continuous piece or cut portion of the inert film 16, for example, using pulling, blowing with a liquid, or grinding peeling techniques.

[0060] During the molding process, before curing the assembly of the elastic sheet 44, the inert film layer 16, and the release film layer 46, the inert film layer 16 has a surface roughness characterized by a first peak density. After curing and removing the release film layer 46, the inert film layer 16, and particularly the laminating film layer 23, the surface roughness is characterized by a second peak density, and the second peak density increases relative to the first peak density. Preferably, after the curing process and removal of the release film layer 46, the peak density of the inert film layer 16 increases by at least 3%, and more preferably, by at least 25%. More specifically, after the curing process and removal of the release film layer 46, the peak density of the inert film layer 16 preferably increases by 3% to 165%, and more preferably, by 25% to 35%.

[0061] Although the discussion is about the process of producing the piston 11, those skilled in the art will readily understand that the same process can be used to produce other elastic articles, such as stoppers or other closures.

[0062] See also Figure 2 and 3 , shows a method for preparing an elastic article, such as a piston 12, according to another embodiment of the present invention. Figure 2 The process utilizes a second mold 24 that is sized and shaped to form a molded portion of the elastic article, serving as the piston crown 12a. Thus, the mold 24 serves as the initial mold for the manufacturing process. Figure 3 The process uses a mold 14 (ie, Figure 1 The mold shown is sized and shaped to form the entire elastic article (e.g., piston 12). Figure 2 and Figure 3 A two-step molding process according to an embodiment of the present invention is described together, particularly a two-step compression molding process.

[0063] See also Figure 2 , the mold 24 used in the first step of the two-step molding process includes an upper mold 15 with an open cavity 25a and a lower mold 27 with an open cavity 27a. The open cavities 25a, 27a are preferably open heated mold cavities. In a preferred embodiment, the first step mold 24 includes a plurality of upper and lower molds 15, 27 arranged in an array. As in the one-step molding process, the elastomer sheet 44, the inert film layer 16, and the release film layer 46 can be firmly connected to each other or independent of each other in sequence and are loosely stacked on each other when introduced into the second mold 24. The arrangement of the elastomer sheet 44, the inert film layer 16, and the release film layer 46 is the same as above. Figure 1 Same as described.

[0064] Figure 2 The process conditions of the molding steps shown are Figure 1 The one-step process conditions are the same as Figure 1 As in the one-step process, the elastic sheet 44 is vulcanized under the influence of heat and pressure and is non-detachably bonded to the inert film layer 16, so that the vulcanized elastic material forms the body 31 of the piston crown 12a and the inert film layer 16 becomes the laminated film layer 33 that is non-detachably formed on the surface of the piston crown 12a (i.e., the laminated piston crown 12a). On the other hand, the release film layer 46 is removably bonded to the laminated film layer 33.

[0065] After vulcanization, the laminated piston crown 12a is removed from the mold 24, and the release film layer 46 is retained intact on the laminated piston crown 12a. Next, the assembly of the laminated piston crown 12a and the release film layer 46 is trimmed and placed into the mold 14, as shown in FIG. Figure 3 As shown, the release film layer 46 is brought into contact with the inner surface 19 of the open cavity 17a of the lower mold half 17, and the release film layer 46 is sandwiched between the laminated piston crown 12a and the open cavity 17a. Figure 2 and 3In the two-step process, mold 14 is the second step mold.

[0066] Next, the second elastomeric sheet 44 is placed in the first mold 14, and more specifically on the open cavity 17a of the lower mold half 17. The two mold halves 15, 17 are then brought into contact with each other, causing each protrusion 15a to contact the first surface 44a of the second elastomeric sheet 44 and forcing the material of the second elastomeric sheet 44 into the open cavity 17a and into contact with the laminated piston crown 12a, thereby compressing and molding the arrangement of the second elastomeric sheet 44 and the laminated piston crown 12a in each open cavity 17a during the compression molding step. The vulcanization process is as described above. Figure 1 Correspondingly, to produce a piston 12 having a removable release film layer 46, the release film layer 46 is used to mask the crown portion 12a during subsequent operations (e.g., operations to produce a piston that has silicone oil only on the exposed elastomer side and not on the laminated crown portion 12a).

[0067] During the molding process, before curing the assembly of the elastic sheet 44, the inert film layer 16, and the release film layer 46, the inert film layer 16 has a surface roughness characterized by a first peak density. After curing and removing the release film layer 46, the inert film layer 16, and in particular the laminating film layer 33, has a surface roughness characterized by a second peak density. The second peak density increases relative to the first peak density. Preferably, after the curing process and removing the release film layer 46, the peak density of the inert film layer 16 increases by at least 3%, more preferably by at least 25%. More specifically, after the curing process and removing the release film layer 46, the peak density of the inert film layer 16 preferably increases by 3% to 165%, more preferably by 25% to 35%.

[0068] It will be appreciated that the first stage mold 24 can be sized and shaped to form different portions of different elastomeric articles (e.g., the body of a stopper) rather than the piston crown 12a, and that the second stage mold 14 can be sized and shaped to form different elastomeric articles rather than the piston.

[0069] An elastomeric article, such as a piston or stopper, is formed using a two-step process to produce an article having a drug-interfacing portion covered with an inert membrane 16, with the remainder of the elastomeric article surface uncovered (ie, bare elastomer).

[0070] The elastic articles 11, 12 produced according to the present invention are smooth film laminated elastic articles. In one embodiment, the resulting elastic articles 11, 12 are silicone-free elastic articles. A release film layer 46 is sandwiched between the elastic sheet 44 covered with the inert film layer 16 and the mold cavity surface 19 to protect the smooth film laminate (i.e., piston 11) from damage during the manufacturing process, such as damage that may occur when the laminated films 23, 33 slide across the mold surface 19 during the forming and / or demolding steps. The release film layer 46 also protects the laminated films 23, 33 from developing any texture imparted by the mold surface 19 (i.e., a mechanical analogy of a low-pass filter). The use of the release film layer 46 also protects the laminated films 23, 33 from any material contamination that may be imparted by the mold surface 19, such as processing aids used in the forming process, adhered elastomers, or any other environmental contaminants. The use of the release film layer 46 creates a unique surface morphology due to the intimate contact and subsequent separation of the surface-to-surface interface of the laminated films 23, 33 and the release film layer 46.

[0071] Furthermore, the use of the release film layer 46 provides a mirror finish to the outer surfaces of the laminate film layers 23, 33. Thus, the elastic article prepared according to the present invention has an outer surface, more specifically, an outer sealing surface, which is composed of a laminate film having a mirror finish or a laminate film having a substantially streak-free or substantially smooth finish. Figure 13 Comparing the texture of a plunger having a laminated film according to the present invention with the texture of a conventional laminated plunger shows that the plunger according to the present invention has a smooth or mirror-like outer surface (left) compared to a conventional film laminated plunger having a rough, textured and non-mirror-like outer surface (right).

[0072] Specific embodiments of the present invention will now be described by way of the following non-limiting examples and experiments.

[0073] Examples 1-4

[0074] The following Examples 1-4 use four PTFE-laminated elastic pistons (i.e., a laminated PTFE film layer covers the body of the piston and thereby forms the outer side surface and crown surface of the piston) and are based on the relative Figure 1 The process described above produces a release film layer with ETFE. For comparison purposes, four elastic pistons (hereinafter referred to as Comparative Examples 1-4) were produced according to the same process, except that no release film layer was used. All of them had a PTFE barrier layer. The piston crowns of Examples 1-4 (eg Figure 5A and 5C As shown) and around the sealing surface, and more specifically the basic sealing rib (as Figure 5B and 5D) has an extremely smooth laminated film surface with no clear texture, mark, or stripe on the surface. In contrast, the laminated film surface of any of the piston crowns of Comparative Examples 1-4 (as shown) Figure 6A and 6C As shown) and around the sealing surface, and more specifically the basic sealing rib (as Figure 6B and 6D ) has significant surface features in the form of broken rings, scratches and striations of arbitrary depth and length, indentations of arbitrary size and depth, flat areas, broken shallow grooves, and the like.

[0075] Test 1

[0076] According to the above correspondence Figure 1 The process described herein produces a 5-mL elastomeric piston having a laminated PTFE barrier layer, and a release film layer formed from ETFE having a thickness of 2 mil (~50 microns) (the analysis was performed on different areas of the first rib of the piston (i.e., the rib closest to the drug contact surface) to illustrate surface variations, and the analysis was performed with reference to Inventive Samples A and B in Table 1 (Inventive Samples A and B). For comparison, a bare elastomeric piston was produced using the same process parameters as those used to produce Inventive Samples A and B, but without using a laminated film layer or a release film layer (see Comparative Sample 1 in Table 1) (Comparative Sample 1); an elastomeric piston having a laminated PTFE barrier film was produced using the same process parameters as those used to produce Inventive Samples A and B, except that a release film layer was not used (see Comparative Sample 2 in Table 1) (Comparative Sample 2); and a PTFE film before molding was provided (see Comparative Sample 3 in Table 1) (Reference Document 3).

[0077] The surface texture of each piston and membrane was measured using a Keyence 3D laser scanning confocal microscope. To measure the areal roughness parameters, the results were evaluated using the ISO 25178 surface texture standard under three different methods: first, without using a filter, as shown in Ex. A-1 to A-5; second, using a 2 μm Gaussian filter to eliminate the high-frequency components of the measurement and separate the ripples from the roughness according to JIS B 0632:2001 (ISO 11562:1996) and ISO 16610-21:2011, as shown in Ex. B-1 to B-5; and third, using a 0.08 μm Gaussian filter to eliminate the high-frequency components of the measurement and separate the ripples from the roughness according to JIS B 0632:2001 (ISO 11562:1996) and ISO 16610-21:2011, as shown in Ex. C-1 to C-5, to measure the areal roughness parameters of each piston and membrane. The areal roughness parameters are summarized in Table 1 and plotted in detail in Figure 7-9, where the y-axis is parallel to the longitudinal axis of the piston, so that the drug contacting surface of the piston is positioned near the top of each figure.

[0078] Meanwhile, the profile roughness parameters of each sample were collected by a Mitutoyo Surftext profilometer using a low-force probe and are summarized in Table 2 and plotted in Figure 10 , where the y-axis is parallel to the longitudinal axis of the piston, positioning the drug contacting surface of the piston near the top of each figure. Figure 19A , 20A, 21A, 22A and 23A, provide optical images showing the surface morphology of each sample under a 3D laser scanning confocal microscope, and Figure 19B , 20B, 21B, 22B and 23B provide the surface morphology of each sample.

[0079] Table 1

[0080]

[0081]

[0082] -The results are under 50X objective lens.

[0083] Table 2

[0084] sample Ra(μm) Rz(μm) RSm(μm) RKU Pc / cm Rλa(μm) Invention Sample A 0.195011 1.626049 10.28698 5.18205 986.5094 2.363367 Invention Sample B 0.123327 2.244208 22.96563 26.7377 481.2344 2.973297 Comparative Sample 1 0.473978 3.134142 39.95096 3.350478 282.9486 13.34772 Comparative Sample 2 0.113927 0.568438 44.82615 2.058096 262.8811 9.818667 Comparative Sample 3 0.025882 0.14815 37.9068 2.304411 272.3878 9.535636

[0085] Referring to Table 1, the parameters measured and / or calculated include the arithmetic mean height (Sa), maximum height (Sz), texture aspect ratio (Str), arithmetic mean peak curvature (Spc), developed interface area ratio (Sdr), kurtosis (Sku), self-correction length (Sal) and peak density (Spd). The arithmetic mean height is the average height of the absolute value relative to the average height of the sampling length (not the absolute value). 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. Filtering data is usually used to remove noise, but can also be used to effectively define peaks.

[0086] As will be appreciated by those skilled in the art, although both arithmetic mean height and peak density are parameters used to characterize surface roughness, these parameters are not necessarily interrelated or correlated. For example, when an elastic article covered with an inert film is molded (without a release layer), the inert film conforms to the mold surface, assumes the mold surface contour, and theoretically assumes the mold roughness. Therefore, 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 treatment of the elastic article, such as polishing, can reduce the height of certain peaks and effectively reduce the arithmetic mean height. However, the peak density does not necessarily change as a result of these subsequent surface treatments. Therefore, the arithmetic mean height and peak density cannot be considered as parameters that can be correlated.

[0087] Referring to Table 2, the measured and / or calculated parameters include the arithmetic mean height (Ra), maximum height (Rz), mean width of profile elements (RSm), kurtosis (Rku), peak length (Pc / cm), and arithmetic mean wavelength (Rλa). The parameters shown in Table 2 represent measurements taken along a sampling line, while the parameters shown in Table 1 represent measurements taken within a region. The measurement results indicate that the inert film of Comparative Sample 2 may have taken on the surface profile and roughness of the mold during the curing or vulcanization process. The average arithmetic height (Sa) of the inert films of Inventive Samples A and B is significantly better than that of the bare elastomer of Comparative Sample 1. Furthermore, Table 1 shows that the peak density (Spd) of Inventive Samples A and B increases compared to the inert film before molding (i.e., Comparative Sample 3). This is because the outer surface of the release film is aligned with the inner surface of the mold, while the inert films of Inventive Samples A and B take on the surface profile and roughness of the release film. This demonstrates that due to the mechanical interaction between the release film layer and the inert film layer during the molding process, the release film layer can be used to manipulate the surface texture of the inert film layer.

[0088] Furthermore, during the molding process, the inert film layer 16 and the release film layer 46 are stretched by approximately 400% as they are pressed into the mold. Stretching the release film layer has two effects. First, surface features may effectively decrease due to the Poisson's ratio, thereby proportionally reducing the average arithmetic height. Second, features similar to microcracks may form, effectively creating new peaks and valleys. Furthermore, removing the release film layer 46 from the inert film layer 16 may create additional peaks. For example, as the release film layer 46 is peeled away until the bond breaks, the localized adhesive contact area between the inert film layer 16 and the release film layer 46 can cause the inert film surface to stretch in the contact area. The stretching of the inert film 16 causes the residual deformation to produce peaks on its surface.

[0089] That is, the inventors surprisingly discovered that the release film layer 46 not only protects the laminated films 23 and 33 from damage, but actually improves the surface texture of the films. More specifically, the molding process of the present invention increases the surface roughness of the inert film 16 by 3.8% to 28.7% when forming the laminated films 23 and 33, as measured by peak density (without a filter). The molding process of the present invention also increases the surface roughness of the inert film 16 by 105.5% to 162.5% when forming the laminated films 23 and 33, as measured by peak density (when using a 2.0 micron Gaussian filter). The molding process of the present invention also increases the surface roughness of the inert film 16 by 4.9% to 34.2% when forming the laminated films 23 and 33, as measured by peak density (when using a 0.08 micron Gaussian filter).

[0090] At the same time, in one embodiment, the sealing surface is configured to contact the container or syringe with a common perimeter that constrains the at least one elastic article, and the sealing surface has a surface roughness characterized by a peak density that is greater than 50,000 peaks / square millimeter when a 2.0 micron Gaussian filter is applied, or greater than 300,000 peaks / square millimeter when a 0.08 micron Gaussian filter is applied; preferably, the sealing surface has a surface roughness characterized by a peak density that is greater than 100,000 peaks / square millimeter when a 2.0 micron Gaussian filter is applied, or greater than 100,000 peaks / square millimeter when a 0.08 micron Gaussian filter is applied. density greater than 500,000 peaks / mm²; more preferably, the sealing surface has a surface roughness characterized by a peak density greater than 150,000 peaks / mm² when a 2.0 micron Gaussian filter is applied, or greater than 600,000 peaks / mm² when a 0.08 micron Gaussian filter is applied; most preferably, the sealing surface has a surface roughness characterized by a peak density greater than 200,000 peaks / mm² when a 2.0 micron Gaussian filter is applied, or greater than 700,000 peaks / mm² when a 0.08 micron Gaussian filter is applied.

[0091] The elastomeric articles produced according to the present invention have very low, directionally independent surface roughness, forming an optimal interface with the container or syringe, thereby resulting in improved CCI. The elastomeric articles of the present invention are suitable for use in silicone-free systems, i.e., without silicone oil, to help alleviate CCI issues.

[0092] At the same time, figuratively, in the surface profile diagram, there are obvious differences between the elastic articles of the present invention produced with the release film layer, the release film and the traditional elastomer articles, such as Figure 11 As shown, although the average figures for the piston faces are presented in the graph ( Figure 12 ) does not show any significant difference. The curvature of the trace comes from the curvature of the lower surface of the elastomer article. The results of the quantitative measurements are summarized in Figure 12 middle.

[0093] In a qualitative visual evaluation, the differences in surface finish discussed above were evident. Figure 13 The images in FIG. 1 show an elastomeric piston according to the present invention having an improved surface finish (labeled "smooth") that appears glossy compared to a piston produced using a conventional process that does not involve a release film layer and results in a frosted surface (labeled "rough"). The improved surface finish is uniformly applied to the sidewall and crown surfaces, whereas the conventionally produced part has a more variable texture with a noticeably rough surface.

[0094] Test 2

[0095] Except for the inventive samples A and B and comparative samples 1-3, the Figure 1 The process described above provides a batch of 1-mL long elastic pistons with laminated PTFE barrier films covering the outer surface and the crown surface, and the release film layer formed by ETFE has a thickness of 2 mil (~50 μm) (various tests were conducted using this type of piston, and the various tests were conducted according to the following method). Figure 14 , 15, 17 and 18 as Invention Sample C) (Invention Sample C); and a batch of 1-mL long elastic pistons with laminated ETFE barrier film covering the outer surface and crown surface produced according to the same process parameters as used to produce Invention Sample C (see Figure 16 For comparison, a batch of 1-mL long elastomeric pistons (see Invention Sample D) were produced according to the same process parameters as used to produce Invention Sample C (i.e., with a laminated PTFE barrier film), but without the use of a release film layer. Figure 14 and a batch of 1-mL long elastic pistons produced according to the same process parameters as used to produce Inventive Sample D (i.e., with a laminated ETFE film), but without the release film layer (see Figure 16 Comparative sample 5) (Comparative sample 5).

[0096] Figure 14 Crystal PTFE laminated pistons produced with (Inventive Sample C) or without (Comparative Sample 4) release liner are shown using helium leak testing. CCI in polymers. Figure 14 resemblance, Figure 15 Crystal PTFE laminated piston with release liner (Inventive Sample C) produced using helium leak testing Polymer, silica-free glass, and baked silica glass CCI. In addition, Figure 16 The CCI of silicate glass and baked silicate glass produced using helium leak testing for ETFE-laminated pistons with (Inventive Sample D) and without (Comparative Sample 5) a release liner is shown. Helium leak rate is an industry standard used to quantify the quality of a seal, using helium as an inert tracer gas. While the same improved surface finish can be imparted to a bare rubber part by omitting a film layer, the CCI is unaffected by variations in surface roughness, likely because its viscoelastic flow under pressure fills surface imperfections. When the finished part is laminated with a polymer film, the film cannot flow, and any surface imperfection (on either sealing surface) creates a leak path. Figure 14-16This demonstrates that the final roughness of the sealing surface is critical to performance, whereas the initial roughness of the membrane does not necessarily correlate with functional performance in all cases. The sterility threshold of 6 x 10 atm*cc / sec, from Kirsch et al.'s article "Pharmaceutical Container / Closure Integrity," is consistent with USP 1207. Although PTFE and ETFE were the laminated pistons produced for these experiments, those of ordinary skill will readily recognize that other laminate materials using release liners will improve the sealing performance of rubber elastomers.

[0097] Figure 17 and Figure 18 The performance of PTFE laminated pistons produced using release liners is shown. Specifically, Figure 17 Shown is the Instron BLE method at 304.8 mm / min under dry conditions, in Crystal Break-loose force and average tensile force of Invention Sample C on polymer, silicone-free glass, and baked silicone glass. Figure 18 Shown using the Instron BLE method at 304.8 mm / min under dry and wet conditions, at Crystal Figure 2 shows the break-away force of Sample C on polymer, non-silicone glass, and baked silicone glass (note that Sample C on baked silicone glass was not tested under wet conditions). Along with significantly improved sealing performance, the PTFE-laminated pistons produced with release liners exhibited break-away and average tensile force characteristics similar to those of commercial pistons that require the use of silicone oil (although commercial pistons using silicone oil were not tested in this experiment). The improved force performance is due to the entire piston contact surface (i.e., lateral and crown surfaces) being coated with a smooth, inert film, rather than just the drug interface surface (if any), as is typical for pistons used with silicone oil. While this experiment characterized the force performance of PTFE-laminated pistons, those skilled in the art will recognize that ETFE and other laminated pistons produced with release liners in various barrel configurations can also exhibit improved force performance.

[0098] The method can also be used to make elastic articles that do not contain any laminating film layers (ie, the bare elastomer is protected during the molding process by a release film layer 46). Other surface modifications may include chemical functionalization, which requires coating of a smooth substrate.

[0099] Good control of surface roughness enables the total contact area to be tuned, thereby improving other functional properties (i.e., breakaway and squeeze force). Similarly, this may enable geometries that were previously unattainable with previous products.

[0100] The product can also be produced by designing new molds. Other possible production methods include, but are not limited to, polished molds, molds without sharp features (to avoid film damage), PTFE (or other polymer) coated molds, alternative mold materials (i.e., polymers or ceramics), and alternative release techniques. However, because the release film layer protects the inert film layer from the mold surface features, the present invention is applicable to rough molds and can potentially extend the life of any mold—ultimately reducing costs.

[0101] The present invention is applicable to any type of seal that contains or contacts an injectable drug. This includes, but is not limited to, pistons, stoppers, and liner seals. A significant need for this invention is silicone-free sealing systems for injectable drugs, as CCI is crucial for maintaining these systems. This invention is particularly suitable for sensitive biopharmaceuticals and intraocular drug delivery. It can also be applied to reduce the manufacturing cost of any elastomer used to seal injectable drugs that exhibits good barrier properties.

[0102] The technology of the present invention can be used to produce fully or partially film laminated pistons, stoppers, etc., and / or silicone-free closure systems with barrier properties. Preferably, the technology of the present invention is used to produce fully film laminated pistons, stoppers, etc., and / or silicone-free closure systems with barrier properties.

[0103] Certain terms are used in the following description for convenience only and are not limiting. Terms such as "proximal," "distal," "upward," "downward," "bottom," and "top" designate directions of reference in the drawings. "Inward" and "outward" refer to directions toward and away from, respectively, the geometric center of the device, and designated parts of the device according to the present invention. Unless otherwise specified herein, the terms "a," "an," and "the" are not limited to one element, but should be construed to mean "at least one." The terminology includes the above-mentioned words, derivatives thereof, and words of similar import.

[0104] Those skilled in the art will appreciate that changes may be made to the above embodiments without departing from the broad inventive concept thereof. It should therefore be understood that the present invention is not limited to the particular embodiments disclosed, but is intended to cover modifications within the spirit and scope of the present invention.

Claims

1. An elastic article for sealing a container, comprising: an elastic body having an outer surface and an outer crown surface; a fluoropolymer film layer having an inner surface and an outer surface, the inner surface of the fluoropolymer film layer being laminated to and covering the entirety of the outer surface and the outer crown surface, the outer surface of the fluoropolymer film layer comprising: (i) a drug contact surface located on the outer crown surface and configured to contact a drug contained in the container; (ii) a sealing surface located on the outer surface and configured to contact the inner surface of the container; and a release film layer removably attached to an outer surface of the fluoropolymer film layer; Wherein, the outer surface of the fluoropolymer film layer is substantially free of striations, and removal of the release film layer increases the peak density of the sealing surface.

2. The elastic article of claim 1 , wherein after removing the release film layer, the peak density is greater than 50,000 peaks / mm2 when a 2.0 micron Gaussian filter is applied, or greater than 300,000 peaks / mm2 when a 0.08 micron Gaussian filter is applied.

3. The elastic article of claim 1 , wherein after removal of the release film layer, the peak density is greater than 100,000 peaks / mm² when a 2.0 micron Gaussian filter is applied, or greater than 500,000 peaks / mm² when a 0.08 micron Gaussian filter is applied.

4. The elastic article of claim 1 , wherein after removal of the release film layer, the peak density is greater than 150,000 peaks / mm2 when a 2.0 micron Gaussian filter is applied, or greater than 600,000 peaks / mm2 when a 0.08 micron Gaussian filter is applied.

5. The elastic article of claim 1 , wherein after removal of the release film layer, the peak density is greater than 200,000 peaks / mm2 when a 2.0 micron Gaussian filter is applied, or greater than 700,000 peaks / mm2 when a 0.08 micron Gaussian filter is applied. The elastic article according to claim 1 , wherein the elastic article is a piston or a bottle stopper.

7. The elastic article of claim 1 wherein the outer surface of the fluoropolymer film layer has a glossy finish.

8. An injection device comprising: cylinder; and The elastic article according to claim 1, wherein the release film layer of the elastic article has been removed; The tube is free of silicone, the fluoropolymer film layer is in contact with the tube, and the interface between the fluoropolymer film layer and the tube has an air leakage resistance of less than 6×10 -6 atm*cc / sec sealed structure.

9. The injection device of claim 8, wherein actuation of the elastic article within the barrel applies a sliding force on the barrel of less than 15N, 10N, 7.5N or 5N.

10. The injection device of claim 8, wherein the barrel is composed of glass or a polymer.

11. The injection device of claim 8, wherein after removing the release film layer, the peak density is greater than 50,000 peaks / mm² when a 2.0 micron Gaussian filter is applied, or greater than 300,000 peaks / mm² when a 0.08 micron Gaussian filter is applied.

12. The injection device of claim 8, wherein after removing the release film layer, the peak density is greater than 100,000 peaks / mm² when a 2.0 micron Gaussian filter is applied, or greater than 500,000 peaks / mm² when a 0.08 micron Gaussian filter is applied.

13. The injection device of claim 8, wherein after removing the release film layer, the peak density is greater than 150,000 peaks / mm2 when a 2.0 micron Gaussian filter is applied, or greater than 600,000 peaks / mm2 when a 0.08 micron Gaussian filter is applied.

14. The injection device of claim 8, wherein after removing the release film layer, the peak density is greater than 200,000 peaks / mm2 when a 2.0 micron Gaussian filter is applied, or greater than 700,000 peaks / mm2 when a 0.08 micron Gaussian filter is applied.

15. The injection device of claim 8, wherein an outer surface of the fluoropolymer film layer has a glossy finish.

Images