Patent Publication Number: US-2011061795-A1

Title: Method for producing a stopper

Description:
FIELD OF THE INVENTION 
     The present invention relates to a method for producing a stopper for closing a container, in particular for closing a medicament container. 
     BACKGROUND 
     Stoppers of various forms and of various materials are used for sealing and closing containers that are used in particular for storing medicaments. Generally, such stoppers consist of natural or synthetic rubber or of rubber-elastic or pure thermoplastics. These materials are subsumed hereafter by the term “elastomeric materials”. 
     The elastic properties of such stoppers of elastomeric materials are particularly advantageous in the case of medicament bottles, syringe cylinders or other containers, often consisting of glass, since on the one hand they allow compensation for the tolerance of such bottle openings or syringe cylinders and on the other hand it is also possible to pierce the stopper by means of a cannula and in this way remove the container content or fill the container. The stoppers ensure good, dependable sealing of the container over a relatively long period of time. 
     The generally liquid or powdered pharmaceutical preparations that are to be stored in medicament bottles, syringe cylinders or similar containers impose very different requirements on the stopper material to be used. For example, the chemical and/or biological compatibility required by the bottle content. Furthermore, in the case of bottle contents that are sensitive to oxygen or moisture, the gas or water vapor permeability of the closure stopper is important. Furthermore, the stopper material must not cause any alteration of the therapeutic value of the container content, for example by giving off substances from the content that are harmful or alter a pharmaceutical preparation or by taking up constituents of the pharmaceutical preparation. 
     The problems set out above also apply equally to plungers of syringe cylinders, syringe ampoules and/or two-chamber syringe ampoules. 
     EP 0 148 426 discloses pharmaceutical stoppers for closing or subdividing a container that both ensure good sealing and reliably avoid interaction between the stopper material and the container content. The stoppers according to EP 0 148 426 substantially consist of rubber and have a region which faces the container content in the position for use and is enclosed by an inert film in the form of a cap. In a non-coated region adjacent to the inert film, the stopper neck lies directly against the wall of the container opening. In the case of such a stopper, in practice the container content only comes into contact with the inert film, while the uncoated region of the stopper neck with its rubber-elastic material provides a good seal against the inner wall of the container. 
     EP 0 148 426 also discloses a method for producing the stoppers described above. In this method, a rubber film—onto which, for example, a fluorinated polymer film has previously been laminated—is introduced as an initially planar composite into a molding tool and deformed there by means of pressure and heat—for example in a thermoforming process—into the form intended for the inner stopper part. The polymer film thereby bonds firmly with the rubber film and the latter is at least partially vulcanized. In the second working step, the inner stopper parts are removed from the molding tool and punched out. Subsequently, the outer parts of the stopper are placed with the inner parts of the stopper into a second molding tool and molded there, fully vulcanized together and bonded to one another. The finished stoppers are obtained by renewed punching out. 
     The above method for producing stoppers has the disadvantage that it is relatively complex and comprises many working steps. It is therefore an object of the present invention to provide a more efficient method for producing stoppers. 
     BRIEF SUMMARY OF THE INVENTION 
     The object is achieved by the method according to claim  1 . Other embodiments are claimed in the dependent claims. 
     The method according to various embodiments of the invention serves for producing a one-piece stopper with a carrier body of an elastomeric material and an inert layer, which stopper is intended for closing a container with an opening, in particular with a substantially circular opening. The carrier body of the stopper has a disk-shaped outer portion and a spigot-like inner portion, which is firmly connected to the outer portion, protrudes from the outer portion and has a free end remote from the outer portion. Preferably, the outer portion and the inner portion have a common center axis. The outer portion is intended for resting on the outer side of the container, and the inner portion is intended for being inserted with the free end in front into the opening of the container and protruding into the interior of the container. The surface of the inner portion is at least partially coated with an inert layer, so that contact of the carrier body with the content of the container can be at least almost completely avoided. 
     By analogy with the method according to EP 0 148 426, the production method may comprises the following steps:
     (a) placing a sheet of the elastomeric material and an inert film into a molding tool,   (b) molding the inner portion under the effect of heat, so that the inert film forms the inert layer and coats the free end of the inner portion and an adjacent region, the elastomeric material being at least partially vulcanized and inseparably bonded to the inert film, and a skin being formed,   (c) removing the skin from the molding tool,   (d) punching out the inner portion from the skin, and   (e) attaching the outer portion in a further molding tool.   

     The method according to various embodiments of the invention is characterized in that, to attach the outer portion,
     (e1) the inner portion is placed into a cavity of an injection mold in such a way that a molding-on end opposite from the free end is exposed in the cavity,   (e2) the outer portion is molded by means of injection molding onto the molding-on end of the inner portion, whereby the stopper is given its final form, and   (e3) the fully vulcanized or at least partially cured stopper is removed from the injection mold.   

     The method according to various embodiments of the invention allows the attachment of the outer portion to the inner portion to be significantly simplified: while in the case of the method according to EP 0 148 426, two further molding working steps—thermoforming and punching out—are necessary, in the case of the method according to the invention the outer portion is completely molded and bonded to the inner portion in a single injection-molding operation. It has consequently been possible to reduce the number of working steps and make the production method shorter, less complex and more efficient. 
     This sheet of elastomeric material that is placed in the molding tool in step (a) is not completely vulcanized, i.e. it is partially vulcanized or unvulcanized. The sheet is preferably unvulcanized. 
     In a preferred embodiment, the carrier body of the stopper is produced from a natural or synthetic rubber material. The use of a rubber material for the carrier body ensures an optimum sealing function of the stopper. Bromobutyl rubber, nitrile rubber (NBR) or ethylene-propylene-diene rubber (EPDM), in particular bromobutyl rubber, is preferably used as the elastomeric material. These materials are particularly suitable since they are gas-impermeable and chemically relatively inert. 
     In a preferred embodiment, a fluorinated polymer film is used as the inert film. Fluorinated polymer films are chemically very inert and resistant and can therefore prevent an interaction between the container content and the stopper material. This avoids impairment of the container content, which is of great importance particularly in the case of pharmaceutical preparations. Fluorinated polymer films of polytetrafluoroethylene (Teflon®, PTFE), tetrafluoroethylene perfluoropropylene copolymer (FEP), perfluoroalkoxy copolymer (PFA), ethylene tetrafluoroethylene copolymer (ETFE), polyvinylidene fluoride (PVDF) or polyvinyl fluoride (PVF), are preferably used, in particular a Teflon film. 
     In a preferred embodiment, the inner portion is molded in step (b) at a temperature of 120° C. to 250° C., preferably at a temperature of 150° C. to 200° C., in particular at approximately 180° C. Heat is preferably transferred through the molding tool. Preferably, in step (b), a pressure is additionally exerted on the sheet of elastomeric material and the inert film. 
     In a preferred embodiment, in step (b), the inert layer is molded in such a way that it completely coats the outer surface of the inner portion that protrudes from the outer portion of the finished spigot. In this way, the entire portion that is introduced into the opening of the container is therefore coated with the inert layer on the finished spigot and the container content does not come into any contact with the material of the carrier body. In this manner, impairment of the container content by the stopper can be completely avoided. 
     In a preferred embodiment, in step (b), a depression is formed on an end face lying at the free end of the inner portion. This reduces the thickness of the stopper in the region of the depression, so that it can be pierced more easily with a cannula. Moreover, such a depression at the free end of the inner portion allows the formation of an elastic sealing lip, which additionally improves the sealing function of the stopper. 
     In a preferred embodiment, in step (b), a peripheral annular groove is formed in an extreme end face lying at the molding-on end of the inner portion and is open toward the end face. This annular groove has the effect of increasing the size of the contact area between the inner portion and the outer portion and thereby improving the bonding of the outer portion to the extreme end face of the inner portion. 
     In a preferred embodiment, in step (e1), the inner portion is placed in the cavity of the injection mold in such a way that a region adjacent to the molding-on end is exposed. This arrangement in the cavity has the effect that, during the injection molding, not only the molding-on end of the inner portion is molded on axially but also the exposed, circumferential region adjacent thereto is molded on in the radial direction. This in turn has the effect of increasing the size of the contact area between the inner portion and the outer portion and improving the bonding of the outer portion to the inner portion. 
     In a preferred embodiment, in step (e1), the inner portion is placed in the cavity of the injection mold in such a way that only that region at the molding-on end of the inner portion that is not coated with the inert layer, i.e. that region that is free from the inert layer, is exposed. In this manner, the contact area between the two parts of the carrier body belonging to the inner portion and the outer portion is maximized and at the same time the carrier body itself is prevented from coming into contact with the container content during use. 
     In a further preferred embodiment, a negative pressure is produced in the injection mold before the molding on of the outer portion. The negative pressure has the effect that as much air as possible is removed from the cavity of the injection mold before the injection molding and the injection-molding operation is made easier. For this purpose, the injection mold is preferably evacuated by means of an external device via a negative pressure channel, which is connected to the cavity. In order that the air can be expelled up until immediately before the injection-molding operation, the injection mold preferably has a closing valve, which is brought into the closed position by the molding material itself and prevents the molding material from penetrating into the negative pressure channel during the injection-molding operation. The production of a negative pressure in the injection mold also serves the purpose of avoiding the inclusion of air bubbles in the molded-on outer portion and thus improving the quality of the product. 
     In a preferred embodiment, in step (e2), an injection pressure of 800 to 1400 bar, preferably of 1000 to 1200 bar, in particular of approximately 1100 bar, is used for the molding on of the outer portion. 
    
    
     
       BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS 
       The present invention is further illustrated on the basis of the schematic sectional representations shown in the following drawing, in which: 
         FIG. 1  shows a molding tool in the open position; 
         FIG. 2  shows the placement of a sheet of elastomeric material and an inert film in the molding tool; 
         FIG. 3  shows the molding of the inner portion from the elastomeric material and the inert film in the molding tool; 
         FIG. 4  shows the removal of the skin from the molding tool; 
         FIG. 5  shows the placement of the skin in a punching tool; 
         FIG. 6  shows the closing of the punching tool; 
         FIG. 7  shows the punching out of the inner portion; 
         FIG. 8  shows the injection mold in the open position; 
         FIG. 9  shows the placement of the inner portion in a cavity of the injection mold; 
         FIG. 10  shows the molding on of the outer portion; 
         FIG. 11  shows a stopper produced by the method according to the invention; 
         FIG. 12  shows a container with a stopper produced with the aid of the method according to the invention. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       FIG. 1  schematically shows a section through a molding tool  10  in the open position, which can be used in the method according to the invention for the production of a stopper  12  (cf.  FIG. 11 ). The molding tool  10  has a first mold plate  14  and, arranged parallel thereto, a second mold plate  16 . The two mold plates  14  and  16  are movable with respect to one another, normal in relation to the planes of the plates. The first mold plate  14  has first mold impressions  20  on its side  18  facing the second mold plate  16 . The second mold plate  16  has second mold impressions  24  on its side  22  facing the first mold plate  14 . The individual first mold impressions  20  are arranged in such a way that they can interact with the second mold impressions  24  when the molding tool  10  is being used. In particular, a first mold impression  20  is respectively assigned to a second mold impression  24  and they are arranged one above the other in the direction normal to the planes of the plates. 
     The section represented in  FIG. 2  schematically shows the first step (a) of the method according to the invention, according to which a sheet  26  of an elastomeric material and an inert film  28  are placed in the molding tool  10 . In this case, the elastomeric sheet  26  and the inert film  28  are arranged parallel to one another between the two mold plates  14  and  16 . The elastomeric sheet  26  and the inert film  28  may be bonded to one another before placement, for example by the inert film  28  being laminated onto the sheet  26  of the elastomeric material. Alternatively, however, it is also possible for the sheet  26  and the inert film  28  to be placed in the molding tool  10  separately. In step (a), the elastomeric sheet  26  is arranged between the first mold plate  14  and the inert film  28 , and the inert film  28  is arranged between the second mold plate  16  and the elastomeric sheet  26 . 
     In  FIG. 3 , the molding of an inner portion  30  (cf.  FIG. 11 ) according to step (b) of the method according to the invention is schematically represented. For this purpose, the molding tool  10  is closed around the sheet  26  of elastomeric material and the inert film  28 , in that the first and second mold plates  14 ,  16  are moved with respect to one another, so that the elastomeric sheet  26  and the inert film  28  are together pressed into the mold impressions  20  and  24 . Under the effect of heat, a skin  32  with a number of spigot-like inner portions  30  is thus formed, the elastomeric material being at least partially vulcanized and bonded to the inert film  28 . The inert film  28  thereby forms an inert layer  34  (cf.  FIG. 11 ), which coats the inner portions on the side facing the second mold plate  16 . 
       FIG. 4  schematically shows a section through the molding tool  10 , at the time when the skin  32  is removed from it. For this purpose, the molding tool  10  is in turn brought into an open position, so that the skin  32  can be detached from the mold impressions  20  and  24 . The spigot-like inner portions  30 , which are part of the skin  32 , each have on the side of the skin that is facing the second mold plate  16  a free end  36  with a depression  38 , which is formed in the end face  40  lying at the free end  36 . The inner portions  30  also each have a molding-on end  42 , which lies opposite from the free end  36 . In the extreme end face lying at the molding-on end  42  of the inner portion  30  there is also formed a peripheral annular groove  44 , which is open toward the end face. 
     In step (d) of the method according to the invention, the inner portions  30  are then punched out from the skin  32 . This operation is schematically shown in the sectional representation in  FIGS. 5 to 7 : the skin  32  (or part thereof) is placed in a punching tool  46  ( FIG. 5 ), the punching tool  46  is closed ( FIG. 6 ) and the inner portion  30  is punched out ( FIG. 7 ). 
     The punching tool  46  has a first punching plate  48  with a first clearance  50  and, arranged parallel to the first punching plate  48 , a second punching plate  52  with a second clearance  54 , the two punching plates  48  and  52  being movable normal to the plane of the plates. The two circular-cylindrical clearances  50  and  54  run normal to the plane of the plate, have the same diameter d 1  and are arranged in such a way that they form a continuous hollow space when the punching mold  46  is closed. The second punching plate  52  has a supporting surface  56  on its side facing the first punching plate  48 . The skin  32  is placed on the supporting surface  56  in such a way that the inner portion  30  protrudes with the free end  36  in front into the second clearance  54 . The spigot-shaped region protruding from the skin  32  into the second clearance  54  is substantially circular-cylindrical, has a center axis A and preferably has at least approximately the same diameter d 1  as the two clearances  50  and  54 . 
     The punching tool  46  has, furthermore, a circular-cylindrical punching ram  58 , which is movable along the center axis A normal to the planes of the plates. The punching ram  58  is arranged in the first clearance  50  before the actual punching operation and has a diameter that is somewhat smaller in comparison with d 1 , for example 0.01 to 0.03 mm smaller. Before the punching out, the skin  32  is clamped in between the two punching plates  48  and  52  and thus fixed. For the punching out, the punching ram  58  is forced through the first clearance  50  into the second clearance  54  and thereby severs the skin  32  along the outer circumference of the inner portion  30 . 
       FIGS. 8 to 10  show a schematic section through an injection mold  60 , which can be used in the case of the method according to the invention for molding on an outer portion  62  (cf.  FIG. 11 ).  FIG. 8  shows the injection mold  60  in the open position,  FIG. 9  shows the placement of the inner portion  30  in the injection mold  60 , and  FIG. 10  shows the actual molding on of the outer portion  62 . 
     The injection mold  60  has a first outer plate  64 , a first inner plate  66 , a second inner plate  68  and a second outer plate  70 , which are all arranged parallel to one another and are movable normal to the planes of the plates. The two inner plates  66  and  68  are arranged between the outer plates  64  and  70 . In the open position shown in  FIG. 8 , the first outer plate  64  and the first inner plate  66  are firmly connected to one another, and remain so during the entire method. In the open position shown in  FIG. 8 , the first inner plate  66  is at a distance from the second inner plate  68 . The first inner plate  66  and the first outer plate  64  are stationarily connected to the injection mold  60 . 
     The second inner plate  68  and the second outer plate  70  may, however, be moved in relation to one another and likewise moved away from the first inner plate  66  and the first outer plate  64 , in particular during the demolding operation. During the injection molding operation, the second inner plate  68  and the second outer plate  70  are pressed against one another and the injection mold  60  is closed. 
     Running through the first outer plate  64  and the two inner plates  66  and  68  is a feed channel  72  for feeding in the molding material, which is made up of the three feed channel portions  74 ,  76  and  78  respectively arranged in one of the three plates  64 ,  66  and  68 . Running at right angles to the feed channel  72 , between the second inner plate  68  and the second outer plate  70 , is at least one, preferably flat-form, runner  80 , through which the molding material can be passed to the cavities of the injection mold  60 . 
     Inserted in the first inner plate  66  is an exchangeable first mold insert  82 , which has a first part-cavity  84 , which is open toward the second inner plate  68 . Inserted in the second inner plate  68  is an exchangeable second mold insert  86 , which has a second part-cavity  84 , which is open toward the first inner plate  66 . The first part-cavity  84  and the second part-cavity  96  are arranged along a center axis A running normal to the planes of the plates and, when the injection mold  60  is closed, form the cavity of the injection mold  60 . The first mold insert  82  is prestressed in the first inner plate  66  by disk springs  88 , which are inserted in a hollow space  90  in the first inner plate  66  and are arranged around a guiding cylinder  92  running along the center axis A. The first mold insert  82  lies against the first inner plate  66  by means of outer radial shoulders  93  and is kept in position by the spring force of the disk springs. In the open position shown in  FIG. 8 , the first mold insert  82  protrudes slightly from the first inner plate  66 . When the injection mold  60  is closed, the first mold insert  82  is pushed back, and consequently achieves a neat form-fitting connection. The second mold insert  86  is fixed in the second inner plate  68  by the second outer plate  70 . The second inner mold insert  86  also has injection channels  94 , which connect the runner  80  to the second part-cavity  96 . 
     Arranged in the second outer plate  70  is a negative pressure channel  98 , by means of which air is removed from the closed injection mold  60  before the molding material is introduced. This produces a negative pressure on the cavities of the closed injection mold  60 . The negative pressure channel  98  can be closed by means of a closing valve  100 , which is kept open by a spiral spring  102 . The closing valve  100  shown is brought into the closed position by means of back pressure by the molding material itself as soon as the latter is introduced into the mold, so that the molding material is prevented from penetrating into the negative pressure channel  98  during the injecting operation. 
     To mold on the outer portion  62  (cf.  FIG. 10 ), the punched-out inner portion  30  is placed in the first part-cavity  84  in such a way that the molding-on end  42  is exposed in the cavity and the region toward the free end  36  is completely enclosed by the first part-cavity  84  ( FIG. 9 ). Preferably, the inner portion  30  is placed in such a way that a cylindrical region adjacent to the molding-on end  42  is also exposed in the cavity, so that the inner portion  30  can be molded on not only axially from the molding-on end  42  but also radially in the exposed region. After the injection mold  60  is closed, the molding material is injected and passes through the feed channel  72  via the runner  80  and the injection channels  94  into the second part-cavity  96 , where the outer portion  62  is formed. During the injection, the closing valve  100  is closed. The stopper  12  (cf.  FIG. 11 ) is given its final form by this injection molding and can be removed from the injection mold  60  as soon as it is vulcanized or at least partially cured. In order to remove the stopper  12  from the injection mold  60 , first the second inner plate  68  and the second outer plate  70  are moved in relation to the first inner plate  66  and the first outer plate  64 . In this step, the inner portion  30  or the partially cured finished stopper  12  becomes detached from the first mold insert  82 . Subsequently, by means of a hydraulic or electric drive, the second inner plate  68  is separated from the second outer plate  70  or moved apart in relation thereto. This has the effect that the molding material that has remained in the runner  80  and the injection channels  94  is separated from the second outer plate  70 . The stopper  12  can then be separated from the molding material that has remained in the injection channels  94 . Subsequently, the remaining molding material is removed from the injection mold  60  together with the sprue remaining in the third feed channel portion  78 . 
       FIG. 11  schematically shows a section through a stopper  12 , which has been produced by means of the method according to the invention. The stopper  12  has a carrier body  104  and an inert layer  34 , which coats the carrier body  104  in the region of the inner portion  30 . The inner portion  30  of the stopper  12  has a free end  36 , which is remote from the outer portion  62  and in the extreme end of which a depression  38  has been introduced. Moreover, the inner portion  30  has a casing-like sealing surface  106 , which is adjacent to the outer portion  62  and is completely coated with the inert layer  34 . The disk-shaped outer portion  62  has a lateral surface  108  and, arranged normal thereto, an annular supporting surface  110 , which is adjacent to the inner portion  30 . On the side remote from the inner portion  30 , the outer portion  62  also has a recess  112 , which together with the depression  38  serves the purpose of making it easier for the stopper  12  to be pierced with a cannula. 
       FIG. 12  schematically shows a section through a stopper  12 , which has been fitted onto a container  114 . The container  114  has been filled with a content  116 , in particular a pharmaceutical composition, and is closed by the stopper  12 . The annular supporting surface  110  of the stopper  12  rests on the upper rim of the container  114 , while the casing-like sealing surface  106  of the stopper  12  lies against the inner side of the container wall and seals the container. The inert layer  34  completely coats that region of the stopper  12  that is arranged in the interior of the container  114  and thus prevents the content  116  of the container  114  from coming into contact with the material of the carrier body  104  of the stopper  12 .