US20050113763A1 - System for filling and assembling pharmaceutical delivery devices - Google Patents

System for filling and assembling pharmaceutical delivery devices Download PDF

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Publication number
US20050113763A1
US20050113763A1 US10/951,039 US95103904A US2005113763A1 US 20050113763 A1 US20050113763 A1 US 20050113763A1 US 95103904 A US95103904 A US 95103904A US 2005113763 A1 US2005113763 A1 US 2005113763A1
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Prior art keywords
piston
assembly
filling
capping
pharmaceutical
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US10/951,039
Inventor
David Reynolds
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Duoject Medical Systems Inc
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Duoject Medical Systems Inc
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Priority to US10/951,039 priority Critical patent/US20050113763A1/en
Assigned to DUOJECT MEDICAL SYSTEMS INC. reassignment DUOJECT MEDICAL SYSTEMS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: REYNOLDS, DAVID L.
Publication of US20050113763A1 publication Critical patent/US20050113763A1/en
Abandoned legal-status Critical Current

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14Details; Accessories therefor
    • A61J1/20Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2089Containers or vials which are to be joined to each other in order to mix their contents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/06Ampoules or carpules
    • A61J1/062Carpules
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/02Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
    • A61L2/04Heat
    • A61L2/06Hot gas
    • A61L2/07Steam
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/20Gaseous substances, e.g. vapours
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/20Gaseous substances, e.g. vapours
    • A61L2/206Ethylene oxide
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B65CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65BMACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B3/00Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
    • B65B3/003Filling medical containers such as ampoules, vials, syringes or the like
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B65CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65BMACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B7/00Closing containers or receptacles after filling
    • B65B7/16Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons
    • B65B7/28Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons by applying separate preformed closures, e.g. lids, covers
    • B65B7/2821Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons by applying separate preformed closures, e.g. lids, covers applying plugs or threadless stoppers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14Details; Accessories therefor
    • A61J1/20Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2003Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
    • A61J1/2006Piercing means
    • A61J1/201Piercing means having one piercing end
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14Details; Accessories therefor
    • A61J1/20Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2003Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
    • A61J1/2006Piercing means
    • A61J1/2013Piercing means having two piercing ends
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178Syringes
    • A61M5/31Details
    • A61M5/315Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
    • A61M5/31501Means for blocking or restricting the movement of the rod or piston
    • A61M5/31505Integral with the syringe barrel, i.e. connected to the barrel so as to make up a single complete piece or unit
    • A61M2005/31506Integral with the syringe barrel, i.e. connected to the barrel so as to make up a single complete piece or unit formed as a single piece, e.g. moulded
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2207/00Methods of manufacture, assembly or production
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2209/00Ancillary equipment
    • A61M2209/04Tools for specific apparatus
    • A61M2209/045Tools for specific apparatus for filling, e.g. for filling reservoirs
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T29/00Metal working
    • Y10T29/49Method of mechanical manufacture
    • Y10T29/49826Assembling or joining
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T29/00Metal working
    • Y10T29/53Means to assemble or disassemble
    • Y10T29/53313Means to interrelatedly feed plural work parts from plural sources without manual intervention
    • Y10T29/53322Means to assemble container
    • Y10T29/53339Hypodermic syringe

Definitions

  • This invention relates to the production of prefilled syringes for use in medical or veterinary treatment.
  • Prefilled disposable syringes have gained wide acceptance as a preferred dosage form for administration of medicaments, primarily for reasons of safety and convenience. Most importantly, prefilled syringes minimize handling of a medicament prior to administration, thereby reducing the chance of dosage errors or contamination of the medicament.
  • prefilled disposable syringes Many different types have been developed. Most known prefilled syringes include an elongate syringe “cartridge” or “barrel” comprising a cylindrical glass or plastic container into which the medicament or a component thereof is prefilled. In some types of prefilled syringes, the barrel forms the body of a syringe, having a mouth which permits attachment to an injection needle, and a movable bottom comprising an elastomeric piston which is acted upon by a plunger to administer the medicament.
  • the pharmaceutical vial is a standardized container which is widely used in the pharmaceutical industry, most pharmaceutical companies have existing vial filling equipment.
  • the equipment need only be modified by the addition of a station for insertion of the rubber piston into the body of the barrel. Therefore, the invention described in that prior patent eliminates the need for specialized filling equipment, thereby reducing cost.
  • the present invention provides for an assembly for filling and capping a barrel of a pre-filled syringe comprising:
  • the stabilization member comprises a sleeve, the sleeve has a top end and a base end, and the rimmed end of the body is positioned within the sleeve proximate the base end of the sleeve.
  • the base end of the sleeve has a radially projecting flange.
  • the flange has a substantially flat outwardly facing wall that is substantially vertical when the assembly is standing longitudinally upright.
  • the stabilization member further comprises a stabilization cap having a hollow portion with an upper end and a lower end, the lower end having a finger flange that extends radially outwardly therefrom, the hollow portion is sized to closely fit within the body, and the finger flange is sized to fit within the base end of the sleeve.
  • the piston comprises a material that is impermeable to liquid and sufficiently permeable to a sterilizing gas to permit sterilization of the seal between the inner surface of the body and the side surface of the piston upon exposure to a sterilizing gas.
  • the piston comprises neoprene.
  • the piston comprises a material that is substantially resistant to the effects of at least one standard cycle of gamma radiation.
  • the piston comprises bromo-butyl rubber.
  • the syringe body comprises cerium oxide in an amount sufficient to prevent discoloration of the body upon exposure to at least one standard cycle of gamma radiation.
  • the syringe body comprises about 1 wt % cerium oxide based on the total weight of the syringe body.
  • the present invention provides a method for producing a barrel for a pre-filled syringe, comprising:
  • the syringe body provided in step (a) is pre-sterilized
  • the piston provided in step (b) is pre-sterilized
  • the stabilization member provided in step (c) is pre-sterilized and steps (a)-(d) are performed in an aseptic environment.
  • the method further comprises, subsequent to step (d), the step of (e) overwrapping the assembly with an overwrap material in an aseptic environment to maintain sterility.
  • the method further comprises, subsequent to step (e), the steps of:
  • the at least one pharmaceutical component is in the form of a solid when filled into the body.
  • the at least one pharmaceutical component is in the form of a liquid when filled into the body.
  • the method further comprises, subsequent to step (g) and prior to step (h), the step of lyophilizing the at least one pharmaceutical.
  • the method further comprises, prior to step (b), the step of selecting a material for the piston that is impermeable to liquid but sufficiently permeable to a sterilizing gas to permit sterilization of the seal between the inner surface and the body and the side surface of the piston upon exposure to a sterilizing gas.
  • the method further comprises, subsequent to step (d), the step of (e) overwrapping the assembly with an overwrap material.
  • the method further comprises, subsequent to step (e), the step of (f) sterilizing the barrel with a sterilizing gas.
  • the method further comprises, prior to step (b), the step of selecting a material for the piston that is sufficiently resistant to at least one cycle of gamma radiation.
  • the method further comprises, prior to step (a), the step of selecting a material for the syringe body material that comprises cerium oxide in an amount sufficient to prevent discoloration of the body upon exposure to at least one cycle of gamma radiation.
  • the method further comprises, subsequent to step (d), the step of (e) overwrapping the assembly with an overwrap material.
  • the method further comprises, subsequent to step (e), the step of (f) sterilizing the barrel with at least one cycle of gamma radiation.
  • the present invention provides a method for producing a pre-filled syringe barrel, comprising:
  • the method further comprises, prior to step (b), the step of maintaining the assembly in an aseptic environment until it is ready to be filled through the neck end of the body with the at least one pharmaceutical component.
  • steps (b) and (c) are performed in an aseptic environment.
  • FIG. 1 schematically illustrates a method for preparing a prefilled syringe barrel according to a first preferred embodiment of the present invention
  • FIG. 2 illustrates the lower portion of the syringe barrel of FIG. 1 prior to insertion of the piston into the body
  • FIG. 3 illustrates the lower portion of the syringe barrel of FIG. 1 after insertion of the piston into the body
  • FIG. 4 schematically illustrates a variant of the method shown in FIG. 1 in which the syringe barrels are packaged in trays for sterilization;
  • FIG. 5 schematically illustrates a variant of the method shown in FIG. 1 in which the body is filled with a powder
  • FIG. 6 schematically illustrates a variant of the method shown in FIG. 1 in which the body is filled with a freeze-dried medicament
  • FIG. 7 illustrates combination of the syringe barrel of the first preferred embodiment with other components to form a delivery device for a two component medicament
  • FIG. 8 schematically illustrates a method for preparing a prefilled syringe barrel according to a second preferred embodiment of the present invention
  • FIG. 9 schematically illustrates a variant of the second preferred embodiment in which a plurality of piston supports and sleeves are secured to a handling tray;
  • FIG. 10 schematically illustrates another variant of the second preferred embodiment in which a plurality of piston supports are secured to a handling tray;
  • FIG. 11 illustrates a variant of the syringe barrel according to the second preferred embodiment of the present invention.
  • FIG. 12 illustrates a further variant of the syringe barrel according to the second preferred embodiment of the present invention.
  • FIG. 13 illustrates a further variant of the syringe barrel according to the second preferred embodiment of the present invention.
  • FIG. 14 illustrates a variant of the syringe barrel according to the first preferred embodiment of the present invention.
  • FIG. 15 illustrates a variant of the syringe barrel according to the first or second preferred embodiment of the present invention.
  • FIG. 1 illustrates a preferred sequence of steps to be followed during preparation of a prefilled syringe barrel 10 for use in a two component delivery device.
  • the illustrations of the syringe barrel shown in FIG. 1 are somewhat schematic. Details of the lower portions of the syringe barrel 10 are more clearly shown in FIGS. 2 and 3 .
  • the barrel 10 comprises a body 12 preferably made of glass and having a generally cylindrical side wall 14 with an inner surface 16 and an outer surface 18 .
  • the body 12 has a relatively narrow neck 20 with a neck flange 21 surrounding an open mouth 22 , and at the other end the body 12 has an open rimmed end 24 .
  • the lower end of the body 12 is referred to herein as the “rimmed end”, it is to be appreciated that the body 12 may or may not have a perceptible inwardly or outwardly extending rim or flange at its lower edge.
  • the body 12 illustrated in FIG. 1 has a height to base ratio of approximately 4.5:1. It will be appreciated that the present invention can be utilized with barrels of various dimensions, including barrels having greater height to base ratios than that shown in FIG. 1 , and barrels having lower height to base ratios, such as the vial-shaped barrels previously described which generally have height to base ratios not exceeding 2.5:1.
  • Barrel 10 further comprises a generally cylindrical elastomeric piston 26 having an upper surface 28 which forms the bottom wall of the barrel 10 in its assembled state, and an opposed lower surface 30 with an internally threaded bore (not shown).
  • Piston 26 also has a side surface 32 connecting the upper and lower surfaces 28 and 30 , the side surface 32 being adapted to form a hermetic seal with the inner surface 16 of body 12 , and preferably being provided with one or more ribs 34 to improve the seal with the body 12 .
  • Piston 26 is preferably made from an elastomeric material such as rubber.
  • the open mouth 22 of body 12 is sealed in a conventional manner by an elastomeric closure 36 with an overlying metal cap 38 crimped over the neck flange 21 .
  • Barrel 10 is also provided with an activation cap 40 at its rimmed end 24 , the cap 40 performing a number of functions which are described below.
  • activation cap 40 comprises a generally cylindrical sleeve 42 having a base end 44 and a top end 46 , the rimmed end 24 of body 12 being received inside the top end 46 of sleeve 42 in a close fit with the rimmed end 24 being located intermediate the top end 46 and the base end 44 of the sleeve 42 (best seen in FIG. 2 ).
  • the sleeve 42 has an inwardly projecting portion 48 extending radially inwardly from the inner wall of the sleeve 42 .
  • the inwardly projecting portion 48 shown in FIG. 1 comprises a detent of sufficient shape and size to retain the rimmed end 24 of the syringe body 12 intermediate the top end 46 and the base end 44 of the sleeve 42 in the absence of a force which pushes the rimmed end 24 of the body 12 and the base end 44 of the sleeve 42 toward one another, but which permits the rimmed end 24 to be pushed toward the base end 44 in response to a predetermined force, such as a downward force applied to the body 12 when the barrel 10 is standing upright on the base end 44 of the sleeve 42 .
  • a predetermined force such as a downward force applied to the body 12 when the barrel 10 is standing upright on the base end 44 of the sleeve 42 .
  • a detent includes any inward projection of the sleeve 42 which is effective to retain the rimmed ends 24 of the body 12 , including a continuous circumferential lip or one or more protrusions, as shown in FIGS. 1 to 3 , on the inner surface of the sleeve 42 .
  • the activation cap 40 further comprises piston support means 50 including a piston support surface 52 on which the piston 26 is supported such that its upper surface 28 is spaced from the rimmed end 24 of the body 12 (shown in FIG. 2 ), thereby providing a gap 54 between the piston 26 and the body 12 which permits exposure of substantially the entire piston 26 and body 12 to a sterilizing gas as discussed below in greater detail. Furthermore, the piston 26 is supported such that it is substantially concentric with the rimmed end 24 of the body 12 , ready for insertion into the rimmed end 24 of the body 12 .
  • the piston support means 50 is in contact with the sleeve 42 and is integrally formed therewith, both being components of the activation cap 40 .
  • the piston support surface 52 is positioned radially inwardly of the inner surface of the sleeve 42 .
  • the piston support surface 52 is spaced inwardly from the inner surface of the sleeve 42 by a distance which is substantially equal to the thickness of the body side wall, thereby forming an annular recess 56 between the piston support surface 52 and the inner surface of the sleeve 42 .
  • the annular recess 56 has a bottom wall 58 connecting the piston support means 50 and the sleeve 42 and located intermediate the piston support surface 52 and the lower surface of the base end 44 of the sleeve 42 , such that when a predetermined force is applied to push the rimmed end 24 of the body 12 into the annular recess 56 until the rimmed end 24 engages the bottom wall 58 , the piston 26 becomes fully inserted in the body 24 with its side surface 32 forming a hermetic seal with the inner surface 16 of the body 12 .
  • the piston support surface 52 is annular with a central aperture 64 , and engages an outer edge of the lower surface 30 of the piston 26 .
  • the piston is preferably provided with a threaded bore (not shown) open to its lower surface 30 which is adapted for connection to the threaded end of a plunger.
  • the system of the invention is adapted to improve the stability of conventional, elongate syringe barrels, thereby permitting them to be conveyed standing upright through standard equipment for filling and capping pharmaceutical vials.
  • This object is partly attained by provision of the sleeve 42 , which may lower the centre of gravity of the barrel 10 somewhat, thereby improving its stability. Stability can be further enhanced by increasing the thickness of the sleeve 42 throughout part or all of its height.
  • the sleeve 42 may preferably be provided with an outwardly projecting flange 66 at its base end 44 .
  • the flange 66 has a diameter and a height so as to prevent interference such as would cause tipping when the barrel 10 is conveyed standing upright on the base end 44 through standard equipment for filling and capping pharmaceutical vials.
  • interference typically comprises a phenomenon known as “shingling”, in which the flange or one barrel rides up over the flange of another barrel, resulting in tipping.
  • Shingling can be prevented as shown in the preferred embodiment of FIG. 1 , in which the flange 66 has a substantially flat radially outwardly facing wall 68 and is of sufficient height that the flanges 66 of adjacent barrels 10 will not ride up over one another.
  • FIG. 1 illustrates the steps involved in assembling and filling a barrel 10 with a liquid component of a medicament, which may comprise an active ingredient or a diluent to be combined with an active ingredient prior to administration.
  • the first step of the method comprises the formation of a first assembly 70 by inserting the piston 26 inside the sleeve 42 of activation cap 40 such that the lower surface 30 of piston 26 is supported by the piston support surface 52 .
  • a second assembly 72 (shown in FIG. 1 c ) is formed by inserting the rimmed end 24 of body 12 into the top end 46 of sleeve 42 to a sufficient depth that the body 12 is stably supported in the sleeve 42 , and so that the rimmed end 24 is located intermediate the top end 46 and the base end 44 of the sleeve and gap 54 being formed between the upper surface 28 of piston 26 and the rimmed end 24 of the body 12 , thereby permitting sterilization of the body 12 , piston 26 and activation cap 40 by a sterilizing gas.
  • a close-up cross-sectional view of the lower portion of second assembly 72 is shown in FIG. 2 .
  • FIG. 4 schematically illustrates a variant of the method in which the sterilization is performed while a plurality of assemblies 72 are packaged in trays 73 and covered with a plastic overwrap 75 so as to maintain sterility and keep them in place.
  • a preferred plastic overwrap is sold under the trade-mark TYVEKTM, which maintains sterility while allowing penetration of sterilizing gases such as ethylene oxide.
  • a force is applied to the second assembly 72 to cause relative movement of the body 12 toward the base end 44 of the sleeve 42 , thereby causing insertion of the piston 26 into the body 12 such that the side surface 32 of the piston 26 forms a hermetic seal with the inner surface 16 of the body 12 and seals the rimmed end 24 .
  • the body 12 is pushed downward into sleeve 42 in the direction shown by the arrow in FIG. 1 e . This step may be performed while the assemblies 72 are packaged in trays 73 and covered with the overwrap 75 .
  • the overwrap 75 may preferably be removed from the sterile assemblies 72 (preferably in a sterile environment) prior to pushing the body 12 into sleeve 42 , and the assemblies 72 may preferably also be removed from the tray 73 prior to performing this step.
  • the sterile tray of assemblies may be shipped to a location for filling, stored for future filling, or immediately filled with a pharmaceutical component. In the first two situations, preferably the tray 73 and assemblies 72 are maintained in the overwrap 75 until they are to be filled, thus maintaining them in a sterile environment.
  • the body 12 With the piston 26 fully inserted in the body 12 as shown in FIG. 1 e , and shown in greater detail in FIG. 3 , the body 12 is now ready to be filled with a medicament, or a component thereof.
  • the medicament is a liquid which is filled into the open mouth 22 of the body 12 .
  • the body 12 is filled on standard equipment for filling and capping pharmaceutical vials, and is conveyed through at least part of said equipment freestanding on the base end 44 of sleeve 42 .
  • the filled body 12 is illustrated in FIG. 1 f.
  • the mouth 22 of the body 12 is then sealed in a conventional manner by application of an elastomeric closure 36 as shown in FIG. 1 g , followed by application of a metal cap 38 over the closure 36 as shown in FIG. 1 h , the cap 38 preferably being crimped over the neck flange 21 of the body 12 .
  • This is also the most common method for sealing standard pharmaceutical vials and is therefore easily performed on standard equipment for filling and capping pharmaceutical vials.
  • the next step in the method is illustrated in FIG. 1 i and comprises an optional terminal sterilization step, in which the sealed barrel 10 is subjected to sterilization, for example by exposure to high temperatures in an autoclave.
  • This step is also part of the normal vial filling process and is performed on standard equipment for filling and capping pharmaceutical vials.
  • the barrel 10 of the first preferred embodiment comprises an activation cap 40 and is therefore specifically directed to delivery devices for two component pharmaceuticals.
  • a liquid medicament, or a liquid component of a medicament is contained in the barrel 10 .
  • the first preferred embodiment is also adaptable to the situation where the barrel 10 contains a solid medicament or a solid component of a medicament, which is to be combined with a liquid, such as a diluent, prior to administration.
  • FIG. 5 A first preferred method for filling barrel 10 with a solid medicament is illustrated in FIG. 5 .
  • the steps followed in FIG. 5 are preferably the same as those described above with reference to FIG. 1 , with the exception of step 5 f , in which a powdered substance is filled into body 12 through the mouth 22 . Powder filling is also performed on standard equipment for filling and capping pharmaceutical vials.
  • FIG. 6 A second preferred method for filling barrel 10 with a solid medicament is illustrated in FIG. 6 .
  • FIGS. 6 a to 6 e show preparation of the second assembly 72 , followed by sterilization and seating of the piston 26 in the barrel body 10 . These steps are identical to the steps followed in FIGS. 1 a to 1 e , discussed above.
  • the body 12 is filled in FIG. 6 f with a liquid composition containing a medicament or a component thereof. This step is identical to that shown in FIG. 1 f .
  • a lyophilization stopper 74 comprising a vented elastomeric closure, is partially inserted into the neck 20 of body 12 such that a vent space 76 is formed.
  • the liquid contents of the body 12 are then lyophilized as shown in FIG. 6 g such that only a solid remains in the body 12 .
  • the stopper 74 is then completely inserted into neck 20 to close vent space 76 and seal the body, and a metal cap 38 is applied as in FIG. 1 h .
  • the sealed barrel may be subjected to terminal sterilization.
  • the steps shown in FIGS. 6 f to 6 i are performed on standard equipment for filling, lyophilizing and capping pharmaceutical vials.
  • the barrel 10 is capable of use in a two component delivery device, such as preferred delivery device 78 shown in FIG. 7 b .
  • a pre-assembly 80 of the type illustrated in FIG. 7 a comprising a standard pharmaceutical vial 82 having a sealed neck 84 , a vial coupling 86 with a vial socket 88 into which the neck 84 of vial 82 is received, and a syringe socket 90 with a finger flange 91 into which the barrel 10 is received.
  • the pre-assembly further comprises a rear needle 93 and a forward needle 94 housed in a luer lock assembly 96 which is secured to both the vial coupling 86 and the syringe socket 90 .
  • the delivery device 78 is assembled as in FIG. 7 b with the finger flange 92 engaging the top end 46 of activation cap 40 , the ends of needles 93 and 94 do not penetrate the elastomeric closures of either the vial 82 or the barrel 10 .
  • the device 78 is activated by pushing the syringe socket 90 and the activation cap 40 together such that the sleeve 42 of cap 40 is received inside syringe socket 90 .
  • the socket 90 and cap 40 are pushed together until the finger flange 92 engages the flange 66 of activation cap 40 , at which point the ends of needles 93 and 94 penetrate the closures of the barrel 10 and the vial 82 respectively, allowing mixing of the respective contents of the vial 82 and barrel 10 , in this example by attaching plunger 98 to the piston 26 and aspirating the liquid contents of the vial 82 into the barrel 10 .
  • the vial coupling 86 is then unthreaded from the luer 96 , also removing the forward needle 94 .
  • An injection needle (not shown) is then threaded onto the exposed luer 96 to provide a complete prefilled disposable syringe (not shown).
  • pre-assembly 80 and the method for combining barrel 10 and pre-assembly 80 are described in greater detail in above-mentioned U.S. Pat. No. 6,149,623, which is incorporated herein by reference in its entirety. It will be appreciated that the activation cap 40 described herein functions in a manner similar to the driver described in the above-mentioned U.S. patent and identified by reference numeral 21 in FIGS. 17 and 18 thereof.
  • the vial 82 of pre-assembly 80 may comprise either a solid or liquid.
  • the medicament is formed by pushing the liquid contents of barrel 10 into the vial 82 , mixing the solid and liquid ingredients, followed by aspirating the medicament suspension or solution into the barrel 10 prior to removal of the vial coupling 86 .
  • FIG. 8 A second preferred embodiment of the present invention is now described below with reference to FIG. 8 , comprising preparation of a barrel 110 for use in the preparation of a prefilled disposable syringe for administration of a single component medicament.
  • a barrel similar to barrel 110 is shown in FIG. 13 of U.S. Pat. No. 5,137,511, issued on Aug. 11, 1992, and is incorporated herein by reference in its entirety.
  • Barrel 110 comprises a body 112 preferably made of glass and having a generally cylindrical side wall 114 with an inner surface 116 and an outer surface 118 . At one end, the body 112 has a relatively narrow neck 120 with a neck flange 121 surrounding an open mouth 122 , and at the other end the body 112 has an open rimmed end 124 . Preferably, the rimmed end 124 is provided with an inwardly extending projection 125 which has a function to be described below.
  • the dimensions of body 112 are similar to those of body 12 described above, although it will be appreciated that the dimensions of body 112 can be varied as discussed above in the context of the first preferred embodiment.
  • Barrel 110 further comprises a generally cylindrical elastomeric piston 126 having an upper surface 128 which forms the bottom wall of barrel 110 in its assembled state, and an opposed lower surface 130 .
  • Piston 126 also has a side surface 132 connecting the upper and lower surfaces 128 and 130 , the side surface 132 being adapted to form a hermetic seal with the inner surface 116 of body 112 , and preferably being provided with one or more ribs 134 to improve the seal with the body 112 .
  • Piston 126 is preferably made from an elastomeric material such as rubber.
  • the lower surface of piston 126 comprises an extension 139 for attachment to a plunger as described in greater detail in above-mentioned European Patent No. 298,585.
  • the open mouth 122 of body 112 is sealed in a conventional manner by an elastomeric closure 136 with an overlying metal cap 138 crimped over the neck flange 121 .
  • the barrel 110 further comprises a stabilization cap 140 which has a number of functions.
  • stabilization cap 140 functions as a piston support means, having a cylindrical portion 142 with an upper end 144 and a lower end 146 , the upper end having a piston support surface 148 .
  • the outer diameter of the cylindrical portion 142 is such that the cylindrical portion 142 can be received inside the body 112 .
  • the stabilization cap 140 also has a radially projecting flange 150 at its lower end which functions as a finger flange during use of the syringe.
  • cylindrical portion 142 of cap 140 has a radially inwardly recessed band 152 which is adapted to form a snap fit with the inwardly projecting portion 125 of the body side wall 114 , thereby preventing removal of piston 126 from the body.
  • FIG. 8 illustrates the steps involved in assembling and filling a barrel 110 with a liquid component of a medicament.
  • the first step illustrated in FIG. 8 a , comprises placement of the piston 126 on top of the piston support surface 148 of the stabilization cap 140 , such that the extension 139 of piston 126 is received inside the cylindrical portion 142 , which is of sufficient height that the extension 139 does not contact the surface on which the stabilization cap 140 is supported.
  • the next step comprises placement of a cylindrical sleeve 154 over the piston 126 and cap 140 as illustrated in FIG. 8 b .
  • the cylindrical sleeve 154 performs a function similar to that of sleeve 42 of activation cap 40 described above, namely to add stability to the barrel 110 and to support the body 112 in spaced relation to the piston 126 during initial assembly of the barrel 110 .
  • the cylindrical sleeve 154 does not form part of the barrel 110 , but rather is removed after filling and capping of the barrel 110 on standard equipment for filling and capping pharmaceutical vials.
  • the cylindrical sleeve 154 can further enhance stability of the barrel 110 by being increased in thickness, by providing a flange similar to flange 66 of cap 40 and/or by forming the sleeve 154 from a relatively dense material, such as stainless steel. Since the sleeve 154 is removed from the barrel, preferably for re-use, forming the sleeve from a relatively thick and/or dense material does not add to the weight or cost of the barrel.
  • the sleeve with a partial recess 156 in its lower surface 158 to fit over the flange of the stabilization cap 140 , thereby substantially centering the piston 126 within the sleeve 154 and preventing relative movement between the sleeve 154 and the cap 140 .
  • the body 112 is inserted into the top end of the sleeve 154 to form a second assembly 162 , with the body 112 being inserted into the sleeve 154 to a sufficient depth that the body 112 is stably supported therein and so that the rimmed end 124 of the body 112 is supported intermediate the top end of sleeve 154 and the flange 150 of the stabilization cap 140 .
  • the inner surface of the sleeve 154 is provided with a detent 164 which prevents premature insertion of the piston 126 into the body 112 , as discussed in detail with reference to the first preferred embodiment.
  • the next step of the method comprises sterilization of the second assembly 162 by a sterilizing gas.
  • a plurality of assemblies 162 may preferably be packaged in trays with a plastic overwrap prior to sterilization.
  • the piston 126 is inserted into the body 112 by pushing the body 112 downward relative to sleeve 154 in the direction of the arrow shown in FIG. 8 e until the inward projection 125 of body 112 snaps into the recess 152 of the stabilization cap.
  • FIGS. 8 e to 8 i The steps followed for filling, capping and terminal sterilization of the sealed body 112 are shown in FIGS. 8 e to 8 i and are identical to the corresponding steps followed in FIGS. 1 e to 1 i . As with the first preferred embodiment, these steps are performed on standard equipment for filling and capping pharmaceutical vials, with the sealed body 112 and the associated sleeve 154 being conveyed through at least a portion of this equipment while freestanding upright on the finger flange 150 .
  • the barrel 110 can be combined with a needle (not shown) and a plunger (not shown) to form a prefilled disposable syringe, as described in above-mentioned U.S. Pat. No. 5,137,511.
  • FIGS. 9 and 10 illustrate variants of the second preferred embodiment of the invention in which components of the system are attached to trays.
  • prefilled syringe barrels 168 are produced by combining a body 12 or 112 with a piston 126 having an extension 139 .
  • the barrels 168 include neither an activation cap 40 or a stabilization cap 140 and are therefore similar to pharmaceutical vials, although they may preferably have a greater height to base ratio than standard pharmaceutical vials.
  • a handling tray 170 is provided on which are arranged a plurality of support assemblies 172 , each of which comprises a generally cylindrical sleeve 174 having a base end 175 and a top end 177 , and piston support means 176 integrally formed with the sleeve 174 and having an annular piston support surface 178 adapted to support piston 126 by engaging the lower surface 130 thereof.
  • a plan view of tray 170 with support assemblies 172 is shown in FIG. 9 d .
  • piston support surface 178 is spaced from the inner surface of sleeve by a distance substantially equal to a thickness of the wall of the body 12 or 112 to form an annular gap 180 into which the rimmed end of the body 12 or 112 is received during insertion of the piston 126 into the body 12 or 112 .
  • each sleeve 174 is preferably provided with a detent (not shown) as described above in the context of sleeve 42 and 154 .
  • the pistons 126 are then inserted into the bodies 12 or 112 by pushing the bodies 12 or 112 downward such that the rimmed ends thereof are pushed down into the gaps 180 ( FIGS. 9 c and 9 e ), as described above in connection with the first preferred embodiment illustrated in FIG. 1 .
  • the trays 170 and the barrels 168 are conveyed through equipment adapted for filling syringe barrels packaged in trays. After filling, the barrels 168 are sealed and capped as described above, preferably while standing on the trays 170 . The filled and capped barrels 168 may then be removed from trays 170 prior to shipment, with the trays being reused. Alternatively, the tray 170 and barrels 168 may be shipped as a unit to their final destination.
  • FIG. 10 illustrates a variant of the method of FIG. 9 , in which trays 182 are provided with piston support means 184 attached thereto.
  • a plan view of the tray is shown in FIG. 10 a .
  • pistons 139 are placed on the support means.
  • the bodies 12 or 112 are inserted into an assembly 186 comprising a plurality of sleeves 188 joined together, the inner surface of each sleeve 188 having a detent (not shown) to support the rimmed end of the body 12 or 112 as shown in FIG. 10 d .
  • FIG. 10 illustrates a variant of the method of FIG. 9 , in which trays 182 are provided with piston support means 184 attached thereto.
  • a plan view of the tray is shown in FIG. 10 a .
  • pistons 139 are placed on the support means.
  • the bodies 12 or 112 are inserted into an assembly 186 comprising a plurality of sleeves 188 joined together, the inner surface of each sleeve 188 having a detent
  • the assembly 186 is placed over the tray 182 so that a piston support means 184 and an associated piston is inserted into each sleeve 188 as shown in FIG. 10 e .
  • the pistons 126 are inserted into bodies 12 or 112 as shown in FIG. 10 e , thereby providing a tray of sterilized barrels shown in FIG. 10 f , ready for filling and capping as described above with reference to FIG. 9 .
  • FIG. 11 illustrates a variant of the second preferred embodiment in which a syringe barrel 192 is produced by combining a body 12 or 112 with a piston 26 having an internally threaded bore.
  • the variant of FIG. 11 does not include an activation cap 40 or a stabilization cap 140 .
  • the barrel 192 is stabilized on standard equipment for filling and capping vials by a stabilization means 194 comprising a sleeve 196 and an integrally formed piston support means 198 comprising an annular piston support surface 200 and having a raised central portion 201 to be received in the bore of the piston 26 , thereby centering the piston inside the sleeve 196 .
  • the sleeve 196 is provided with a plurality of axially extending, circumferentially spaced support ribs 195 , best seen in FIG. 11 d , which is a cross-sectional plan view showing the stabilization means 194 in isolation, the cross-section being taken in a plane perpendicular to the axis of sleeve 196 and between the detents 202 and the piston support means 198 .
  • each rib 195 is provided with a detent 202 on its inner surface for supporting the body 12 or 112 above the upper surface 28 of the piston.
  • the piston 26 is first inserted into the stabilization means as shown in FIG. 11 a .
  • the body 12 or 112 is inserted into the sleeve 196 as shown in FIG. 11 b until the rimmed end engages the detents 202 on ribs 195 as shown in FIG. 11 c .
  • stabilization means 194 is shown in cross-section in FIGS. 11 a to 11 c , with the other components being shown in elevation. The remaining steps are analogous to those shown in FIG. 8 , with the exception that, after the barrel 192 is filled and capped, it is pulled out of engagement with the stabilization means 194 .
  • FIG. 12 also illustrates a variant of the second preferred embodiment, and is similar to the variant of FIG. 11 , with the exception that it is adapted for forming a syringe barrel comprising a body 12 or 112 and a piston 126 having an extension 139 .
  • the embodiment of FIG. 12 utilizes a stabilization means 190 comprising a sleeve 191 and a piston support means 193 , the sleeve 191 having a plurality of axially extending ribs 197 , each of which is provided with a detent 199 .
  • FIG. 12 a illustrates the subassembly of the piston 126 and the stabilization means 190 prior to insertion of body 12 or 112 .
  • FIG. 12 b illustrates body 12 or 112 having been inserted into sleeve 191 and being supported by detent 189 , such that a gap exists between the rimmed end of the body 12 and the upper surface of piston 126 .
  • FIGS. 12 a and 12 b only the stabilization means 190 is shown in cross section, with the other components being shown in elevation.
  • FIG. 12 c is a cross-sectional plan view showing the stabilization means in isolation, in a plane which is perpendicular to the axis of sleeve 191 , and which is between the detents 199 and piston support means 193 .
  • FIG. 13 illustrates yet another variant of the second preferred embodiment, which is similar to that illustrated in FIG. 8 except that piston 126 is replaced by piston 26 having an internal bore, and sleeve 154 is replaced by sleeve 203 , having axially extending ribs 205 , each of which is provided with a detent 207 . As shown in FIG. 13 b , ribs 205 terminate immediately below detent 207 .
  • FIG. 13 a illustrates piston 26 being placed on stabilization cap 204 , comprising a cylindrical portion 206 with a flange 208 at the base end thereof, the flange 208 serving as a finger flange.
  • Stabilization cap 204 also comprises a recessed band 210 adapted to snap into engagement with the inwardly projecting portion 125 at the rimmed end 124 of body 112 .
  • FIG. 13 b illustrates the placement of the cylindrical sleeve 203 over the piston 26 and the stabilization means 204 to form the assembly 212 shown in FIG. 13 c .
  • FIG. 13 c also shows insertion of the insertion of body 112 into sleeve 203 to form the assembly 213 shown in FIG. 13 d , which is ready for sterilization and further processing according to the method described in connection with FIG. 8 .
  • FIGS. 13 a to 13 d illustrate the sleeve 203 in cross section and the other components in elevation.
  • FIG. 13 a is a cross-sectional plan view showing the sleeve 203 in isolation, taken in a plane extending through ribs 205 and perpendicular to the axis of sleeve 203 .
  • FIG. 14 illustrates a variant of the first preferred embodiment of the present invention, identical to that shown in FIGS. 1 to 3 except that body 214 replaces syringe body 12 .
  • Body 214 has a rimmed edge 216 with slight outward projection 218 and a slight inward projection 220 .
  • FIG. 14 a is analogous to FIG. 2 and illustrates an assembly comprising the body 214 , piston 26 and activation cap 40 prior to insertion of piston 26 into body 214 .
  • FIG. 14 b is analogous to FIG. 3 and illustrates the assembly of FIG. 14 a after the body 214 has been pushed down into activation cap 40 , and piston 26 is inserted into body 214 .
  • FIG. 15 illustrates a variant that may be implemented with either the first or second preferred embodiments of the invention, but for convenience will be described having reference to the first preferred embodiment shown in FIG. 1 .
  • the variant shown in FIG. 15 includes an upper cylindrical sleeve 250 .
  • the upper cylindrical sleeve 250 has an upper end 252 , a lower end 254 , and inner surface 256 and an outer surface 258 .
  • the interior diameter of the upper sleeve 250 is such as to closely, but not tightly, surround the body of the syringe barrel.
  • the outer diameter of the upper sleeve 250 is approximately the same as the outer diameter of the sleeve 42 .
  • the upper sleeve may have an outer collar 260 , having an inner surface 262 and an outer surface 264 , the collar 260 surrounding at least a portion of the upper sleeve 250 .
  • the inner surface 262 of the collar 260 preferably has a greater diameter than the outer surface 258 of the upper sleeve 250 thereby creating an annular gap 266 between the upper sleeve 250 and the collar 260 .
  • the collar 260 has an open bottom end 268 towards the lower end 254 of the sleeve 250 , and a closed end 270 towards the upper end 252 where the collar 260 has the same outer diameter as the flange 66 of the base end 44 of the sleeve 42 .
  • the upper sleeve 250 may be removed before packaging and shipment, and reused.
  • the upper sleeve 250 may be removed by blasting air into the annular gap 266 , causing the upper sleeve to blow off the top of the barrel.
  • the inclusion of the upper sleeve may increase the stability of the barrels as they travel through a filling line, since the upper collar 260 and the flange 66 are preferably of the same diameter. Thus, if adjacent barrels traveling through the filling line contact one another, they will do so at the flange 66 near the base of the barrel, and also at the collars 260 . This will increase the stability of the barrels as they travel through the filling line.
  • activation caps, stabilization caps, sleeves and handling trays described above will preferably be made from materials which are substantially unaffected by the conditions employed during sterilization. As sterilization is usually performed at elevated temperature, it is preferred that these components be made of heat-resistant materials. It is preferred that these components be formed from plastics, more preferably heat-resistant plastics.
  • syringe bodies and pistons which are siliconized. Siliconization is preferably performed during manufacture of the syringe body and the piston.
  • the present invention provides an assembly for filling and capping a barrel 10 of a pre-filled syringe.
  • the assembly generally has a syringe body 12 , a piston 26 , and a stabilization member.
  • the stabilization member is positioned proximate the rimmed end of the body to provide additional mass thereto in an amount sufficient to permit the barrel 10 to be conveyed freestanding in a longitudinally upright position on the stabilization member through an apparatus for filling and capping pharmaceutical vials.
  • the stabilization member acts to lower the center of gravity of the barrel 10 while the barrel 10 is in a longitudinally upright position (see FIGS. 1 e , 4 f , 5 e 6 e , 8 e , and 9 e ).
  • the stabilization member is sleeve 42 .
  • the stabilization member includes sleeve 154 and stabilization cap 140 .
  • the stabilization member is sleeve 174 .
  • the stabilization member is sleeve 196 .
  • the stabilization member is sleeve 191 .
  • the stabilization member includes sleeve 203 and stabilization cap 204 .
  • the following description is a variant on the method steps for assembling and filling a barrel with at least one pharmaceutical component in accordance with either the first or the second preferred embodiments of the invention.
  • the method variant will be described having reference to FIG. 1 .
  • the syringe body 12 , piston 26 , and sleeve 42 can be pre-sterilized in any method known in the art.
  • the pre-sterilized syringe body 12 , the pre-sterilized piston 26 , and the pre-sterilized sleeve 42 can be assembled in an aseptic environment to form the assembly shown in FIG. 1 e . While in this position, the piston 26 is located within the body 12 so that a liquid impermeable seal is formed between the inner surface 16 of the body 12 and the side surface 34 of the piston 26 .
  • the assembly shown in FIG. 1 e is packaged in a plastic overwrap sold under the trade-mark TYVEKTM while still in the aseptic environment.
  • the assembly is maintained in the sterile packaging until it is ready to be filled.
  • the subsequent steps for filling and capping can be identical to the corresponding steps previously described depending on the state of the at least one pharmaceutical component to be filled (e.g., FIGS. 1 f to 1 i or FIGS. 8 f to 8 j for filling an assembly with at least one liquid pharmaceutical component, FIGS. 5 f to 5 i for filling an assembly with at least one solid pharmaceutical, FIGS. 6 f to 6 j for filling an assembly with at least one liquid pharmaceutical followed by lyophilization such that only a solid remains).
  • the following description is a variant on the method steps for assembling and filling a barrel with at least one pharmaceutical component in accordance with either the first or the second preferred embodiments of the invention.
  • the method variant will be described having reference to FIG. 1 .
  • the syringe body 12 , piston 26 , and sleeve 42 can be assembled in a relatively clean room to form the assembly shown in FIG. 1 e . While in this position, the piston is located within the body 12 so that a liquid impermeable seal is formed between the inner surface 16 of the body 12 and the side surface 34 of the piston 26 .
  • the material for the piston 26 is selected to be liquid impermeable and sufficiently permeable to a sterilizing gas to permit sterilization of the seal between the inner surface 16 of the body 12 and the side surface 34 of the piston 26 upon exposure to a sterilizing gas.
  • the material for the piston 26 can be selected from any material that is known in the art to be liquid impermeable and permeable to a sterilizing gas.
  • elastomer formulations comprising neoprene (e.g., elastomer formulation FM-27 which is commercially available from Helvoet Pharma).
  • elastomer formulation FM-27 which is commercially available from Helvoet Pharma.
  • the assembly shown in FIG. 1 e is packaged in a plastic overwrap sold under the trade-mark TYVEKTM.
  • the wrapped assembly can then be sterilized by exposure to a sterilizing gas such as ethylene oxide.
  • the assembly is maintained in the sterile packaging until it is ready to be filled. It is understood that the subsequent steps for filling and capping can be identical to the corresponding steps previously described depending on the state of the at least one pharmaceutical component to be filled.
  • the following description is a variant on the method steps for assembling and filling a barrel with at least one pharmaceutical component in accordance with either the first or the second preferred embodiments of the invention.
  • the method variant will be described having reference to FIG. 1 .
  • the syringe body 12 , piston 26 , and sleeve 42 can be assembled in a relatively clean room to form the assembly shown in FIG. 1 e . While in this position, the piston is located within the body 12 so that a liquid impermeable seal is formed between the inner surface 16 of the body 12 and the side surface 34 of the piston 24 .
  • the syringe body 12 is selected from a material that comprises cerium oxide in an amount sufficient to prevent discoloration of the body upon exposure to at least one standard cycle of gamma radiation (e.g., 25 kilogray).
  • the syringe body 12 comprises about 1 wt % cerium oxide based on the total weight of the syringe body 12 .
  • the material for the piston 26 is selected to be substantially resistant to the effects of at least one standard cycle of gamma radiation (e.g., 25 kilogray) to the extent that the function of the piston 26 is not impaired.
  • the material for the piston 26 can be selected from any material that is known in the art to be resistant to the effects of at least one standard cycle of gamma radiation. Examples of such materials include, but are not limited to, elastic formulations comprising bromobutyl rubber (e.g., elastomer fomulation FM-457 which is commercially available from Helvoet Pharma).
  • the assembly shown in FIG. 1 e is packaged in a plastic overwrap sold under the trade-mark TYVEKTM.
  • the wrapped assembly can then be sterilized by exposure to at least one standard cycle of gamma radiation (e.g., 25 kilogray).
  • at least one standard cycle of gamma radiation e.g. 25 kilogray
  • the assembly is maintained in the sterile packaging until it is ready to be filled. It is understood that the subsequent steps for filling and capping can be identical to the corresponding steps previously described depending on the state of the at least one pharmaceutical component to be filled.

Abstract

The present invention provides for an assembly for filling and capping a barrel of a pre-filled syringe. The assembly includes a syringe body having a neck end, a rimmed end, and a side wall extending between the neck end and rimmed end. The body has an outer surface and an inner surface. The assembly includes a piston having an upper surface, a lower surface, and a side surface extending between the upper and lower surfaces. The inner surface of the body and the side surface of the piston is in contact to form a liquid impermeable seal. The assembly further includes a stabilization member that at least partially surrounds and contacts the outer surface of the body. The stabilization member is positioned proximate the rimmed end of the body to provide additional mass thereto in an amount sufficient to permit the assembly to be conveyed freestanding in a longitudinally upright position on the stabilization member through an apparatus for filling and capping pharmaceutical vials. Methods for producing a pre-filled syringe barrel are also provided.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation-in-part of co-pending patent application Ser. No. 09/993,299, filed on Nov. 23, 2001.
  • FIELD OF THE INVENTION
  • This invention relates to the production of prefilled syringes for use in medical or veterinary treatment.
  • BACKGROUND OF THE INVENTION
  • Prefilled disposable syringes have gained wide acceptance as a preferred dosage form for administration of medicaments, primarily for reasons of safety and convenience. Most importantly, prefilled syringes minimize handling of a medicament prior to administration, thereby reducing the chance of dosage errors or contamination of the medicament.
  • Many different types of prefilled disposable syringes have been developed. Most known prefilled syringes include an elongate syringe “cartridge” or “barrel” comprising a cylindrical glass or plastic container into which the medicament or a component thereof is prefilled. In some types of prefilled syringes, the barrel forms the body of a syringe, having a mouth which permits attachment to an injection needle, and a movable bottom comprising an elastomeric piston which is acted upon by a plunger to administer the medicament.
  • One common problem with prefilled disposable syringes is that a dedicated filling and capping line is usually required to fill the medicament into the syringe barrel. This problem has previously been addressed by the invention described in European Patent No. 298,585, which describes a system for producing prefilled syringe barrels on ordinary equipment for filling and capping pharmaceutical vials. That patent describes a system whereby the syringe barrel is made shorter and wider than a conventional barrel, so that it has the shape of a standard pharmaceutical vial, and is then filled and capped on standard machinery for filling and capping vials, through which the barrels are conveyed while standing on their bases. Since the pharmaceutical vial is a standardized container which is widely used in the pharmaceutical industry, most pharmaceutical companies have existing vial filling equipment. The equipment need only be modified by the addition of a station for insertion of the rubber piston into the body of the barrel. Therefore, the invention described in that prior patent eliminates the need for specialized filling equipment, thereby reducing cost.
  • Despite the improvements described in the applicant's above-mentioned European patent, the further disadvantage exists that the relatively squat vial-shaped barrels cannot be used in all types of delivery systems. Some delivery systems, such as syringe pumps and two component systems, may require the use of conventional, elongate barrels which cannot be filled on standard vial-filling equipment. Therefore, it would be advantageous to provide a system which allows the preparation of conventional, elongate prefilled syringe barrels on standard equipment for filling and capping pharmaceutical vials.
  • SUMMARY OF THE INVENTION
  • The one aspect, the present invention provides for an assembly for filling and capping a barrel of a pre-filled syringe comprising:
      • a) a syringe body having a neck end, a rimmed end, and a side wall extending between the neck end and rimmed end, the body having an outer surface and an inner surface;
      • b) a piston having an upper surface, a lower surface, and a side surface extending between the upper and lower surfaces, the inner surface of the body and the side surface of the piston in contact to form a liquid impermeable seal; and
      • c) a stabilization member that at least partially surrounds and contacts the outer surface of the body, the stabilization member is positioned proximate the rimmed end of the body to provide additional mass thereto in an amount sufficient to permit the assembly to be conveyed freestanding in a longitudinally upright position on the stabilization member through an apparatus for filling and capping pharmaceutical vials.
  • In a further aspect, the stabilization member comprises a sleeve, the sleeve has a top end and a base end, and the rimmed end of the body is positioned within the sleeve proximate the base end of the sleeve.
  • In still a further aspect, the base end of the sleeve has a radially projecting flange.
  • In yet a further aspect, the flange has a substantially flat outwardly facing wall that is substantially vertical when the assembly is standing longitudinally upright.
  • In still a further aspect, the stabilization member further comprises a stabilization cap having a hollow portion with an upper end and a lower end, the lower end having a finger flange that extends radially outwardly therefrom, the hollow portion is sized to closely fit within the body, and the finger flange is sized to fit within the base end of the sleeve.
  • In yet a further aspect, the piston comprises a material that is impermeable to liquid and sufficiently permeable to a sterilizing gas to permit sterilization of the seal between the inner surface of the body and the side surface of the piston upon exposure to a sterilizing gas.
  • In still a further aspect, the piston comprises neoprene.
  • In yet a further aspect, the piston comprises a material that is substantially resistant to the effects of at least one standard cycle of gamma radiation.
  • In still a further aspect, the piston comprises bromo-butyl rubber.
  • In yet a further aspect, the syringe body comprises cerium oxide in an amount sufficient to prevent discoloration of the body upon exposure to at least one standard cycle of gamma radiation.
  • In still a further aspect, the syringe body comprises about 1 wt % cerium oxide based on the total weight of the syringe body.
  • In a second aspect, the present invention provides a method for producing a barrel for a pre-filled syringe, comprising:
      • a) providing a syringe body having a neck end, a rimmed end, and a side wall extending between the neck end and rimmed end, the body having an outer surface and an inner surface;
      • b) providing a piston having an upper surface, a lower surface, and a side surface extending between the upper and lower surfaces;
      • c) providing a stabilization member; and
      • d) forming an assembly comprising the syringe body, the piston, and the stabilization member such that: (i) the inner surface of the body contacts at least a portion of the side surface of the piston to form a liquid impermeable seal; (ii) the stabilization member at least partially surrounds and contacts the outer surface of the body; and (iii) the stabilization member is positioned proximate the rimmed end of the body to provide additional mass thereto in an amount sufficient to permit the assembly to be conveyed freestanding in a longitudinally upright position on the stabilization member through an apparatus for filling and capping pharmaceutical vials.
  • In a further aspect, the syringe body provided in step (a) is pre-sterilized, the piston provided in step (b) is pre-sterilized, and the stabilization member provided in step (c) is pre-sterilized and steps (a)-(d) are performed in an aseptic environment.
  • In still a further aspect, the method further comprises, subsequent to step (d), the step of (e) overwrapping the assembly with an overwrap material in an aseptic environment to maintain sterility.
  • In yet a further aspect, the method further comprises, subsequent to step (e), the steps of:
      • f) removing the overwrap;
      • g) filling the body with at least one pharmaceutical component through the neck end using the apparatus for filling and capping pharmaceutical vials; and
      • h) capping the neck end of the body using the apparatus for filling and capping pharmaceutical vials.
  • In still a further aspect, the at least one pharmaceutical component is in the form of a solid when filled into the body.
  • In yet a further aspect, the at least one pharmaceutical component is in the form of a liquid when filled into the body.
  • In still a further aspect, the method further comprises, subsequent to step (g) and prior to step (h), the step of lyophilizing the at least one pharmaceutical.
  • In yet a further aspect, the method further comprises, prior to step (b), the step of selecting a material for the piston that is impermeable to liquid but sufficiently permeable to a sterilizing gas to permit sterilization of the seal between the inner surface and the body and the side surface of the piston upon exposure to a sterilizing gas.
  • In still a further aspect, the method further comprises, subsequent to step (d), the step of (e) overwrapping the assembly with an overwrap material.
  • In yet a further aspect, the method further comprises, subsequent to step (e), the step of (f) sterilizing the barrel with a sterilizing gas.
  • In still a further aspect, the method further comprises, prior to step (b), the step of selecting a material for the piston that is sufficiently resistant to at least one cycle of gamma radiation.
  • In yet a further aspect, the method further comprises, prior to step (a), the step of selecting a material for the syringe body material that comprises cerium oxide in an amount sufficient to prevent discoloration of the body upon exposure to at least one cycle of gamma radiation.
  • In still a further aspect, the method further comprises, subsequent to step (d), the step of (e) overwrapping the assembly with an overwrap material.
  • In yet a further aspect, the method further comprises, subsequent to step (e), the step of (f) sterilizing the barrel with at least one cycle of gamma radiation.
  • In a third aspect, the present invention provides a method for producing a pre-filled syringe barrel, comprising:
      • a) providing a sterile assembly comprising a syringe body having a neck end, a rimmed end, a side wall extending between the neck end and the rimmed end, an outer surface and an inner surface, a piston having an upper surface, a lower surface, and a side surface extending between the upper and lower surfaces and a stabilization member, the sterile assembly formed such that: (i) the inner surface of the body contacts at least a portion of the side surface of the piston to form a liquid impermeable seal; (ii) the stabilization member is at least partially surrounds and contacts the outer surface of the body; and (iii) the stabilization member is positioned proximate the rimmed end of the body to provide additional mass thereto in an amount sufficient to permit the assembly to be conveyed freestanding in a longitudinally upright position on the stabilization member through an apparatus for filling and capping pharmaceutical vials;
      • b) filling the body with at least one pharmaceutical component through the neck end using the apparatus for filling and capping pharmaceutical vials; and
      • c) capping the neck end of the body using the apparatus for filling and capping pharmaceutical vials.
  • In a further aspect, the method further comprises, prior to step (b), the step of maintaining the assembly in an aseptic environment until it is ready to be filled through the neck end of the body with the at least one pharmaceutical component.
  • In still a further aspect, steps (b) and (c) are performed in an aseptic environment.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • The invention will now be described, by way of example only, by reference to the accompanying drawings in which:
  • FIG. 1 schematically illustrates a method for preparing a prefilled syringe barrel according to a first preferred embodiment of the present invention;
  • FIG. 2 illustrates the lower portion of the syringe barrel of FIG. 1 prior to insertion of the piston into the body;
  • FIG. 3 illustrates the lower portion of the syringe barrel of FIG. 1 after insertion of the piston into the body;
  • FIG. 4 schematically illustrates a variant of the method shown in FIG. 1 in which the syringe barrels are packaged in trays for sterilization;
  • FIG. 5 schematically illustrates a variant of the method shown in FIG. 1 in which the body is filled with a powder;
  • FIG. 6 schematically illustrates a variant of the method shown in FIG. 1 in which the body is filled with a freeze-dried medicament;
  • FIG. 7 illustrates combination of the syringe barrel of the first preferred embodiment with other components to form a delivery device for a two component medicament;
  • FIG. 8 schematically illustrates a method for preparing a prefilled syringe barrel according to a second preferred embodiment of the present invention;
  • FIG. 9 schematically illustrates a variant of the second preferred embodiment in which a plurality of piston supports and sleeves are secured to a handling tray;
  • FIG. 10 schematically illustrates another variant of the second preferred embodiment in which a plurality of piston supports are secured to a handling tray;
  • FIG. 11 illustrates a variant of the syringe barrel according to the second preferred embodiment of the present invention;
  • FIG. 12 illustrates a further variant of the syringe barrel according to the second preferred embodiment of the present invention;
  • FIG. 13 illustrates a further variant of the syringe barrel according to the second preferred embodiment of the present invention;
  • FIG. 14 illustrates a variant of the syringe barrel according to the first preferred embodiment of the present invention; and
  • FIG. 15 illustrates a variant of the syringe barrel according to the first or second preferred embodiment of the present invention.
  • DETAILED DESCRIPTION OF THE INVENTION
  • A first preferred embodiment of the invention will now be discussed below in the context of a syringe barrel which is intended for use in a delivery device for a two component medicament. Such a delivery device is described in U.S. Pat. No. 6,149,623, issued on Nov. 21, 2000 which is incorporated herein by reference in its entirety.
  • FIG. 1 illustrates a preferred sequence of steps to be followed during preparation of a prefilled syringe barrel 10 for use in a two component delivery device. The illustrations of the syringe barrel shown in FIG. 1 are somewhat schematic. Details of the lower portions of the syringe barrel 10 are more clearly shown in FIGS. 2 and 3.
  • The barrel 10 comprises a body 12 preferably made of glass and having a generally cylindrical side wall 14 with an inner surface 16 and an outer surface 18. At one end, the body 12 has a relatively narrow neck 20 with a neck flange 21 surrounding an open mouth 22, and at the other end the body 12 has an open rimmed end 24. Although the lower end of the body 12 is referred to herein as the “rimmed end”, it is to be appreciated that the body 12 may or may not have a perceptible inwardly or outwardly extending rim or flange at its lower edge.
  • The body 12 illustrated in FIG. 1 has a height to base ratio of approximately 4.5:1. It will be appreciated that the present invention can be utilized with barrels of various dimensions, including barrels having greater height to base ratios than that shown in FIG. 1, and barrels having lower height to base ratios, such as the vial-shaped barrels previously described which generally have height to base ratios not exceeding 2.5:1.
  • Barrel 10 further comprises a generally cylindrical elastomeric piston 26 having an upper surface 28 which forms the bottom wall of the barrel 10 in its assembled state, and an opposed lower surface 30 with an internally threaded bore (not shown). Piston 26 also has a side surface 32 connecting the upper and lower surfaces 28 and 30, the side surface 32 being adapted to form a hermetic seal with the inner surface 16 of body 12, and preferably being provided with one or more ribs 34 to improve the seal with the body 12. Piston 26 is preferably made from an elastomeric material such as rubber.
  • The open mouth 22 of body 12 is sealed in a conventional manner by an elastomeric closure 36 with an overlying metal cap 38 crimped over the neck flange 21.
  • Barrel 10 is also provided with an activation cap 40 at its rimmed end 24, the cap 40 performing a number of functions which are described below. As best seen in FIGS. 2 and 3, activation cap 40 comprises a generally cylindrical sleeve 42 having a base end 44 and a top end 46, the rimmed end 24 of body 12 being received inside the top end 46 of sleeve 42 in a close fit with the rimmed end 24 being located intermediate the top end 46 and the base end 44 of the sleeve 42 (best seen in FIG. 2).
  • Preferably, the sleeve 42 has an inwardly projecting portion 48 extending radially inwardly from the inner wall of the sleeve 42. The inwardly projecting portion 48 shown in FIG. 1 comprises a detent of sufficient shape and size to retain the rimmed end 24 of the syringe body 12 intermediate the top end 46 and the base end 44 of the sleeve 42 in the absence of a force which pushes the rimmed end 24 of the body 12 and the base end 44 of the sleeve 42 toward one another, but which permits the rimmed end 24 to be pushed toward the base end 44 in response to a predetermined force, such as a downward force applied to the body 12 when the barrel 10 is standing upright on the base end 44 of the sleeve 42. As defined herein, a detent includes any inward projection of the sleeve 42 which is effective to retain the rimmed ends 24 of the body 12, including a continuous circumferential lip or one or more protrusions, as shown in FIGS. 1 to 3, on the inner surface of the sleeve 42.
  • The activation cap 40 further comprises piston support means 50 including a piston support surface 52 on which the piston 26 is supported such that its upper surface 28 is spaced from the rimmed end 24 of the body 12 (shown in FIG. 2), thereby providing a gap 54 between the piston 26 and the body 12 which permits exposure of substantially the entire piston 26 and body 12 to a sterilizing gas as discussed below in greater detail. Furthermore, the piston 26 is supported such that it is substantially concentric with the rimmed end 24 of the body 12, ready for insertion into the rimmed end 24 of the body 12.
  • In the preferred embodiment of FIG. 1, the piston support means 50 is in contact with the sleeve 42 and is integrally formed therewith, both being components of the activation cap 40. As best seen in FIGS. 1 and 2, the piston support surface 52 is positioned radially inwardly of the inner surface of the sleeve 42. Preferably, the piston support surface 52 is spaced inwardly from the inner surface of the sleeve 42 by a distance which is substantially equal to the thickness of the body side wall, thereby forming an annular recess 56 between the piston support surface 52 and the inner surface of the sleeve 42. The annular recess 56 has a bottom wall 58 connecting the piston support means 50 and the sleeve 42 and located intermediate the piston support surface 52 and the lower surface of the base end 44 of the sleeve 42, such that when a predetermined force is applied to push the rimmed end 24 of the body 12 into the annular recess 56 until the rimmed end 24 engages the bottom wall 58, the piston 26 becomes fully inserted in the body 24 with its side surface 32 forming a hermetic seal with the inner surface 16 of the body 12.
  • In order to permit engagement of piston 26 by a plunger, the piston support surface 52 is annular with a central aperture 64, and engages an outer edge of the lower surface 30 of the piston 26. In the embodiment illustrated in FIGS. 1 to 3, the piston is preferably provided with a threaded bore (not shown) open to its lower surface 30 which is adapted for connection to the threaded end of a plunger.
  • As discussed above, the system of the invention is adapted to improve the stability of conventional, elongate syringe barrels, thereby permitting them to be conveyed standing upright through standard equipment for filling and capping pharmaceutical vials. This object is partly attained by provision of the sleeve 42, which may lower the centre of gravity of the barrel 10 somewhat, thereby improving its stability. Stability can be further enhanced by increasing the thickness of the sleeve 42 throughout part or all of its height. For example, as shown in FIG. 1, the sleeve 42 may preferably be provided with an outwardly projecting flange 66 at its base end 44. The flange 66 has a diameter and a height so as to prevent interference such as would cause tipping when the barrel 10 is conveyed standing upright on the base end 44 through standard equipment for filling and capping pharmaceutical vials. Such interference typically comprises a phenomenon known as “shingling”, in which the flange or one barrel rides up over the flange of another barrel, resulting in tipping.
  • Shingling can be prevented as shown in the preferred embodiment of FIG. 1, in which the flange 66 has a substantially flat radially outwardly facing wall 68 and is of sufficient height that the flanges 66 of adjacent barrels 10 will not ride up over one another.
  • FIG. 1 illustrates the steps involved in assembling and filling a barrel 10 with a liquid component of a medicament, which may comprise an active ingredient or a diluent to be combined with an active ingredient prior to administration.
  • The first step of the method, illustrated in FIG. 1 a, comprises the formation of a first assembly 70 by inserting the piston 26 inside the sleeve 42 of activation cap 40 such that the lower surface 30 of piston 26 is supported by the piston support surface 52.
  • In the second step illustrated in FIG. 1 b, a second assembly 72 (shown in FIG. 1 c) is formed by inserting the rimmed end 24 of body 12 into the top end 46 of sleeve 42 to a sufficient depth that the body 12 is stably supported in the sleeve 42, and so that the rimmed end 24 is located intermediate the top end 46 and the base end 44 of the sleeve and gap 54 being formed between the upper surface 28 of piston 26 and the rimmed end 24 of the body 12, thereby permitting sterilization of the body 12, piston 26 and activation cap 40 by a sterilizing gas. A close-up cross-sectional view of the lower portion of second assembly 72 is shown in FIG. 2.
  • The next step in the method, schematically illustrated in FIG. 1 d comprises sterilization of the second assembly 72 by a sterilizing gas such as steam or ethylene oxide. FIG. 4 schematically illustrates a variant of the method in which the sterilization is performed while a plurality of assemblies 72 are packaged in trays 73 and covered with a plastic overwrap 75 so as to maintain sterility and keep them in place. A preferred plastic overwrap is sold under the trade-mark TYVEK™, which maintains sterility while allowing penetration of sterilizing gases such as ethylene oxide.
  • After sterilization, a force is applied to the second assembly 72 to cause relative movement of the body 12 toward the base end 44 of the sleeve 42, thereby causing insertion of the piston 26 into the body 12 such that the side surface 32 of the piston 26 forms a hermetic seal with the inner surface 16 of the body 12 and seals the rimmed end 24. Preferably, the body 12 is pushed downward into sleeve 42 in the direction shown by the arrow in FIG. 1 e. This step may be performed while the assemblies 72 are packaged in trays 73 and covered with the overwrap 75. Alternatively, the overwrap 75 may preferably be removed from the sterile assemblies 72 (preferably in a sterile environment) prior to pushing the body 12 into sleeve 42, and the assemblies 72 may preferably also be removed from the tray 73 prior to performing this step. The sterile tray of assemblies may be shipped to a location for filling, stored for future filling, or immediately filled with a pharmaceutical component. In the first two situations, preferably the tray 73 and assemblies 72 are maintained in the overwrap 75 until they are to be filled, thus maintaining them in a sterile environment.
  • With the piston 26 fully inserted in the body 12 as shown in FIG. 1 e, and shown in greater detail in FIG. 3, the body 12 is now ready to be filled with a medicament, or a component thereof. In this embodiment, the medicament is a liquid which is filled into the open mouth 22 of the body 12. As discussed above, the body 12 is filled on standard equipment for filling and capping pharmaceutical vials, and is conveyed through at least part of said equipment freestanding on the base end 44 of sleeve 42. The filled body 12 is illustrated in FIG. 1 f.
  • The mouth 22 of the body 12 is then sealed in a conventional manner by application of an elastomeric closure 36 as shown in FIG. 1 g, followed by application of a metal cap 38 over the closure 36 as shown in FIG. 1 h, the cap 38 preferably being crimped over the neck flange 21 of the body 12. This is also the most common method for sealing standard pharmaceutical vials and is therefore easily performed on standard equipment for filling and capping pharmaceutical vials.
  • The next step in the method is illustrated in FIG. 1 i and comprises an optional terminal sterilization step, in which the sealed barrel 10 is subjected to sterilization, for example by exposure to high temperatures in an autoclave. This step is also part of the normal vial filling process and is performed on standard equipment for filling and capping pharmaceutical vials.
  • As mentioned above, the barrel 10 of the first preferred embodiment comprises an activation cap 40 and is therefore specifically directed to delivery devices for two component pharmaceuticals. In the example described above, a liquid medicament, or a liquid component of a medicament, is contained in the barrel 10. However, the first preferred embodiment is also adaptable to the situation where the barrel 10 contains a solid medicament or a solid component of a medicament, which is to be combined with a liquid, such as a diluent, prior to administration.
  • A first preferred method for filling barrel 10 with a solid medicament is illustrated in FIG. 5. The steps followed in FIG. 5 are preferably the same as those described above with reference to FIG. 1, with the exception of step 5 f, in which a powdered substance is filled into body 12 through the mouth 22. Powder filling is also performed on standard equipment for filling and capping pharmaceutical vials.
  • A second preferred method for filling barrel 10 with a solid medicament is illustrated in FIG. 6. FIGS. 6 a to 6 e show preparation of the second assembly 72, followed by sterilization and seating of the piston 26 in the barrel body 10. These steps are identical to the steps followed in FIGS. 1 a to 1 e, discussed above. Next, the body 12 is filled in FIG. 6 f with a liquid composition containing a medicament or a component thereof. This step is identical to that shown in FIG. 1 f. Next, a lyophilization stopper 74, comprising a vented elastomeric closure, is partially inserted into the neck 20 of body 12 such that a vent space 76 is formed. The liquid contents of the body 12 are then lyophilized as shown in FIG. 6 g such that only a solid remains in the body 12. The stopper 74 is then completely inserted into neck 20 to close vent space 76 and seal the body, and a metal cap 38 is applied as in FIG. 1 h. Although not shown in FIG. 6, the sealed barrel may be subjected to terminal sterilization. The steps shown in FIGS. 6 f to 6 i are performed on standard equipment for filling, lyophilizing and capping pharmaceutical vials.
  • As mentioned above, the barrel 10 according to the first preferred embodiment is capable of use in a two component delivery device, such as preferred delivery device 78 shown in FIG. 7 b. In order to assemble delivery device 78, the barrel 10 is combined with a pre-assembly 80 of the type illustrated in FIG. 7 a, comprising a standard pharmaceutical vial 82 having a sealed neck 84, a vial coupling 86 with a vial socket 88 into which the neck 84 of vial 82 is received, and a syringe socket 90 with a finger flange 91 into which the barrel 10 is received.
  • The pre-assembly further comprises a rear needle 93 and a forward needle 94 housed in a luer lock assembly 96 which is secured to both the vial coupling 86 and the syringe socket 90. When the delivery device 78 is assembled as in FIG. 7 b with the finger flange 92 engaging the top end 46 of activation cap 40, the ends of needles 93 and 94 do not penetrate the elastomeric closures of either the vial 82 or the barrel 10. The device 78 is activated by pushing the syringe socket 90 and the activation cap 40 together such that the sleeve 42 of cap 40 is received inside syringe socket 90. The socket 90 and cap 40 are pushed together until the finger flange 92 engages the flange 66 of activation cap 40, at which point the ends of needles 93 and 94 penetrate the closures of the barrel 10 and the vial 82 respectively, allowing mixing of the respective contents of the vial 82 and barrel 10, in this example by attaching plunger 98 to the piston 26 and aspirating the liquid contents of the vial 82 into the barrel 10. The vial coupling 86 is then unthreaded from the luer 96, also removing the forward needle 94. An injection needle (not shown) is then threaded onto the exposed luer 96 to provide a complete prefilled disposable syringe (not shown). The components of pre-assembly 80, and the method for combining barrel 10 and pre-assembly 80 are described in greater detail in above-mentioned U.S. Pat. No. 6,149,623, which is incorporated herein by reference in its entirety. It will be appreciated that the activation cap 40 described herein functions in a manner similar to the driver described in the above-mentioned U.S. patent and identified by reference numeral 21 in FIGS. 17 and 18 thereof.
  • Where the barrel 10 contains a liquid medicament or a component thereof, the vial 82 of pre-assembly 80 may comprise either a solid or liquid. Where the vial 82 contains a solid, the medicament is formed by pushing the liquid contents of barrel 10 into the vial 82, mixing the solid and liquid ingredients, followed by aspirating the medicament suspension or solution into the barrel 10 prior to removal of the vial coupling 86.
  • A second preferred embodiment of the present invention is now described below with reference to FIG. 8, comprising preparation of a barrel 110 for use in the preparation of a prefilled disposable syringe for administration of a single component medicament. A barrel similar to barrel 110 is shown in FIG. 13 of U.S. Pat. No. 5,137,511, issued on Aug. 11, 1992, and is incorporated herein by reference in its entirety.
  • Barrel 110 comprises a body 112 preferably made of glass and having a generally cylindrical side wall 114 with an inner surface 116 and an outer surface 118. At one end, the body 112 has a relatively narrow neck 120 with a neck flange 121 surrounding an open mouth 122, and at the other end the body 112 has an open rimmed end 124. Preferably, the rimmed end 124 is provided with an inwardly extending projection 125 which has a function to be described below. The dimensions of body 112 are similar to those of body 12 described above, although it will be appreciated that the dimensions of body 112 can be varied as discussed above in the context of the first preferred embodiment.
  • Barrel 110 further comprises a generally cylindrical elastomeric piston 126 having an upper surface 128 which forms the bottom wall of barrel 110 in its assembled state, and an opposed lower surface 130. Piston 126 also has a side surface 132 connecting the upper and lower surfaces 128 and 130, the side surface 132 being adapted to form a hermetic seal with the inner surface 116 of body 112, and preferably being provided with one or more ribs 134 to improve the seal with the body 112. Piston 126 is preferably made from an elastomeric material such as rubber. The lower surface of piston 126 comprises an extension 139 for attachment to a plunger as described in greater detail in above-mentioned European Patent No. 298,585.
  • The open mouth 122 of body 112 is sealed in a conventional manner by an elastomeric closure 136 with an overlying metal cap 138 crimped over the neck flange 121.
  • The barrel 110 further comprises a stabilization cap 140 which has a number of functions. Firstly, stabilization cap 140 functions as a piston support means, having a cylindrical portion 142 with an upper end 144 and a lower end 146, the upper end having a piston support surface 148. The outer diameter of the cylindrical portion 142 is such that the cylindrical portion 142 can be received inside the body 112. The stabilization cap 140 also has a radially projecting flange 150 at its lower end which functions as a finger flange during use of the syringe. Furthermore, the cylindrical portion 142 of cap 140 has a radially inwardly recessed band 152 which is adapted to form a snap fit with the inwardly projecting portion 125 of the body side wall 114, thereby preventing removal of piston 126 from the body.
  • FIG. 8 illustrates the steps involved in assembling and filling a barrel 110 with a liquid component of a medicament. The first step, illustrated in FIG. 8 a, comprises placement of the piston 126 on top of the piston support surface 148 of the stabilization cap 140, such that the extension 139 of piston 126 is received inside the cylindrical portion 142, which is of sufficient height that the extension 139 does not contact the surface on which the stabilization cap 140 is supported.
  • The next step comprises placement of a cylindrical sleeve 154 over the piston 126 and cap 140 as illustrated in FIG. 8 b. The cylindrical sleeve 154 performs a function similar to that of sleeve 42 of activation cap 40 described above, namely to add stability to the barrel 110 and to support the body 112 in spaced relation to the piston 126 during initial assembly of the barrel 110. In contrast to sleeve 42 of cap 40, the cylindrical sleeve 154 does not form part of the barrel 110, but rather is removed after filling and capping of the barrel 110 on standard equipment for filling and capping pharmaceutical vials. As with sleeve 42, the cylindrical sleeve 154 can further enhance stability of the barrel 110 by being increased in thickness, by providing a flange similar to flange 66 of cap 40 and/or by forming the sleeve 154 from a relatively dense material, such as stainless steel. Since the sleeve 154 is removed from the barrel, preferably for re-use, forming the sleeve from a relatively thick and/or dense material does not add to the weight or cost of the barrel.
  • As shown in FIG. 8, it may be preferred to form the sleeve with a partial recess 156 in its lower surface 158 to fit over the flange of the stabilization cap 140, thereby substantially centering the piston 126 within the sleeve 154 and preventing relative movement between the sleeve 154 and the cap 140.
  • After combining the piston 126, stabilization cap 140 and sleeve 154 to form a first assembly 160 as shown in FIG. 8 c, the body 112 is inserted into the top end of the sleeve 154 to form a second assembly 162, with the body 112 being inserted into the sleeve 154 to a sufficient depth that the body 112 is stably supported therein and so that the rimmed end 124 of the body 112 is supported intermediate the top end of sleeve 154 and the flange 150 of the stabilization cap 140.
  • Preferably, the inner surface of the sleeve 154 is provided with a detent 164 which prevents premature insertion of the piston 126 into the body 112, as discussed in detail with reference to the first preferred embodiment.
  • The next step of the method, illustrated in FIG. 8 d, comprises sterilization of the second assembly 162 by a sterilizing gas. As in the first preferred embodiment, a plurality of assemblies 162 may preferably be packaged in trays with a plastic overwrap prior to sterilization. After sterilization, the piston 126 is inserted into the body 112 by pushing the body 112 downward relative to sleeve 154 in the direction of the arrow shown in FIG. 8 e until the inward projection 125 of body 112 snaps into the recess 152 of the stabilization cap.
  • The steps followed for filling, capping and terminal sterilization of the sealed body 112 are shown in FIGS. 8 e to 8 i and are identical to the corresponding steps followed in FIGS. 1 e to 1 i. As with the first preferred embodiment, these steps are performed on standard equipment for filling and capping pharmaceutical vials, with the sealed body 112 and the associated sleeve 154 being conveyed through at least a portion of this equipment while freestanding upright on the finger flange 150.
  • After removal of the sleeve 154, the barrel 110 can be combined with a needle (not shown) and a plunger (not shown) to form a prefilled disposable syringe, as described in above-mentioned U.S. Pat. No. 5,137,511.
  • FIGS. 9 and 10 illustrate variants of the second preferred embodiment of the invention in which components of the system are attached to trays. In the variant shown in FIG. 9, prefilled syringe barrels 168 are produced by combining a body 12 or 112 with a piston 126 having an extension 139. The barrels 168 include neither an activation cap 40 or a stabilization cap 140 and are therefore similar to pharmaceutical vials, although they may preferably have a greater height to base ratio than standard pharmaceutical vials.
  • In the variant shown in FIG. 9, a handling tray 170 is provided on which are arranged a plurality of support assemblies 172, each of which comprises a generally cylindrical sleeve 174 having a base end 175 and a top end 177, and piston support means 176 integrally formed with the sleeve 174 and having an annular piston support surface 178 adapted to support piston 126 by engaging the lower surface 130 thereof. A plan view of tray 170 with support assemblies 172 is shown in FIG. 9 d. As in the first embodiment shown in FIGS. 1 to 3, piston support surface 178 is spaced from the inner surface of sleeve by a distance substantially equal to a thickness of the wall of the body 12 or 112 to form an annular gap 180 into which the rimmed end of the body 12 or 112 is received during insertion of the piston 126 into the body 12 or 112.
  • In order to assemble syringe barrels 168, the pistons 126 are first inserted into the support assemblies 172 as shown in FIG. 9 a and supported on the piston support means 176. Next, the bodies 12 or 112 are inserted into the sleeves 174 as shown in FIG. 9 b and supported therein with their rimmed ends spaced above the upper surfaces 128 of the pistons 126. In order to support the bodies 12 or 112 in the position shown in FIG. 9 c, the inner surface of each sleeve 174 is preferably provided with a detent (not shown) as described above in the context of sleeve 42 and 154. After sterilization, the pistons 126 are then inserted into the bodies 12 or 112 by pushing the bodies 12 or 112 downward such that the rimmed ends thereof are pushed down into the gaps 180 (FIGS. 9 c and 9 e), as described above in connection with the first preferred embodiment illustrated in FIG. 1.
  • After insertion of the pistons 126, the trays 170 and the barrels 168 are conveyed through equipment adapted for filling syringe barrels packaged in trays. After filling, the barrels 168 are sealed and capped as described above, preferably while standing on the trays 170. The filled and capped barrels 168 may then be removed from trays 170 prior to shipment, with the trays being reused. Alternatively, the tray 170 and barrels 168 may be shipped as a unit to their final destination.
  • FIG. 10 illustrates a variant of the method of FIG. 9, in which trays 182 are provided with piston support means 184 attached thereto. A plan view of the tray is shown in FIG. 10 a. As shown in FIGS. 10 b and 10 c, pistons 139 are placed on the support means. The bodies 12 or 112 are inserted into an assembly 186 comprising a plurality of sleeves 188 joined together, the inner surface of each sleeve 188 having a detent (not shown) to support the rimmed end of the body 12 or 112 as shown in FIG. 10 d. After insertion of bodies 12 or 112 into sleeves 188 as shown in FIG. 10 d, the assembly 186 is placed over the tray 182 so that a piston support means 184 and an associated piston is inserted into each sleeve 188 as shown in FIG. 10 e. After sterilization, the pistons 126 are inserted into bodies 12 or 112 as shown in FIG. 10 e, thereby providing a tray of sterilized barrels shown in FIG. 10 f, ready for filling and capping as described above with reference to FIG. 9.
  • FIG. 11 illustrates a variant of the second preferred embodiment in which a syringe barrel 192 is produced by combining a body 12 or 112 with a piston 26 having an internally threaded bore. As in the variant shown in FIGS. 9 and 10, the variant of FIG. 11 does not include an activation cap 40 or a stabilization cap 140. In the variant of FIG. 11, the barrel 192 is stabilized on standard equipment for filling and capping vials by a stabilization means 194 comprising a sleeve 196 and an integrally formed piston support means 198 comprising an annular piston support surface 200 and having a raised central portion 201 to be received in the bore of the piston 26, thereby centering the piston inside the sleeve 196. The sleeve 196 is provided with a plurality of axially extending, circumferentially spaced support ribs 195, best seen in FIG. 11 d, which is a cross-sectional plan view showing the stabilization means 194 in isolation, the cross-section being taken in a plane perpendicular to the axis of sleeve 196 and between the detents 202 and the piston support means 198. As shown in FIG. 11 a, each rib 195 is provided with a detent 202 on its inner surface for supporting the body 12 or 112 above the upper surface 28 of the piston.
  • To produce a prefilled syringe barrel 192, the piston 26 is first inserted into the stabilization means as shown in FIG. 11 a. Next, the body 12 or 112 is inserted into the sleeve 196 as shown in FIG. 11 b until the rimmed end engages the detents 202 on ribs 195 as shown in FIG. 11 c. It is to be noted that only stabilization means 194 is shown in cross-section in FIGS. 11 a to 11 c, with the other components being shown in elevation. The remaining steps are analogous to those shown in FIG. 8, with the exception that, after the barrel 192 is filled and capped, it is pulled out of engagement with the stabilization means 194.
  • FIG. 12 also illustrates a variant of the second preferred embodiment, and is similar to the variant of FIG. 11, with the exception that it is adapted for forming a syringe barrel comprising a body 12 or 112 and a piston 126 having an extension 139. As in FIG. 11, the embodiment of FIG. 12 utilizes a stabilization means 190 comprising a sleeve 191 and a piston support means 193, the sleeve 191 having a plurality of axially extending ribs 197, each of which is provided with a detent 199. FIG. 12 a illustrates the subassembly of the piston 126 and the stabilization means 190 prior to insertion of body 12 or 112. FIG. 12 b illustrates body 12 or 112 having been inserted into sleeve 191 and being supported by detent 189, such that a gap exists between the rimmed end of the body 12 and the upper surface of piston 126. In FIGS. 12 a and 12 b, only the stabilization means 190 is shown in cross section, with the other components being shown in elevation. FIG. 12 c is a cross-sectional plan view showing the stabilization means in isolation, in a plane which is perpendicular to the axis of sleeve 191, and which is between the detents 199 and piston support means 193.
  • FIG. 13 illustrates yet another variant of the second preferred embodiment, which is similar to that illustrated in FIG. 8 except that piston 126 is replaced by piston 26 having an internal bore, and sleeve 154 is replaced by sleeve 203, having axially extending ribs 205, each of which is provided with a detent 207. As shown in FIG. 13 b, ribs 205 terminate immediately below detent 207. FIG. 13 a illustrates piston 26 being placed on stabilization cap 204, comprising a cylindrical portion 206 with a flange 208 at the base end thereof, the flange 208 serving as a finger flange. Stabilization cap 204 also comprises a recessed band 210 adapted to snap into engagement with the inwardly projecting portion 125 at the rimmed end 124 of body 112. FIG. 13 b illustrates the placement of the cylindrical sleeve 203 over the piston 26 and the stabilization means 204 to form the assembly 212 shown in FIG. 13 c. FIG. 13 c also shows insertion of the insertion of body 112 into sleeve 203 to form the assembly 213 shown in FIG. 13 d, which is ready for sterilization and further processing according to the method described in connection with FIG. 8. FIGS. 13 a to 13 d illustrate the sleeve 203 in cross section and the other components in elevation. FIG. 13 a is a cross-sectional plan view showing the sleeve 203 in isolation, taken in a plane extending through ribs 205 and perpendicular to the axis of sleeve 203.
  • FIG. 14 illustrates a variant of the first preferred embodiment of the present invention, identical to that shown in FIGS. 1 to 3 except that body 214 replaces syringe body 12. Body 214 has a rimmed edge 216 with slight outward projection 218 and a slight inward projection 220. FIG. 14 a is analogous to FIG. 2 and illustrates an assembly comprising the body 214, piston 26 and activation cap 40 prior to insertion of piston 26 into body 214. FIG. 14 b is analogous to FIG. 3 and illustrates the assembly of FIG. 14 a after the body 214 has been pushed down into activation cap 40, and piston 26 is inserted into body 214.
  • FIG. 15 illustrates a variant that may be implemented with either the first or second preferred embodiments of the invention, but for convenience will be described having reference to the first preferred embodiment shown in FIG. 1. In addition to the body, piston, sleeve, and other components previously described in reference to FIG. 1, the variant shown in FIG. 15 includes an upper cylindrical sleeve 250. The upper cylindrical sleeve 250 has an upper end 252, a lower end 254, and inner surface 256 and an outer surface 258. The interior diameter of the upper sleeve 250 is such as to closely, but not tightly, surround the body of the syringe barrel. Preferably, the outer diameter of the upper sleeve 250 is approximately the same as the outer diameter of the sleeve 42. The upper sleeve may have an outer collar 260, having an inner surface 262 and an outer surface 264, the collar 260 surrounding at least a portion of the upper sleeve 250. The inner surface 262 of the collar 260 preferably has a greater diameter than the outer surface 258 of the upper sleeve 250 thereby creating an annular gap 266 between the upper sleeve 250 and the collar 260. Preferably the collar 260 has an open bottom end 268 towards the lower end 254 of the sleeve 250, and a closed end 270 towards the upper end 252 where the collar 260 has the same outer diameter as the flange 66 of the base end 44 of the sleeve 42. After the barrel is filled with a pharmaceutical component, the upper sleeve 250 may be removed before packaging and shipment, and reused. For example, the upper sleeve 250 may be removed by blasting air into the annular gap 266, causing the upper sleeve to blow off the top of the barrel.
  • The inclusion of the upper sleeve may increase the stability of the barrels as they travel through a filling line, since the upper collar 260 and the flange 66 are preferably of the same diameter. Thus, if adjacent barrels traveling through the filling line contact one another, they will do so at the flange 66 near the base of the barrel, and also at the collars 260. This will increase the stability of the barrels as they travel through the filling line.
  • It will be appreciated that the activation caps, stabilization caps, sleeves and handling trays described above will preferably be made from materials which are substantially unaffected by the conditions employed during sterilization. As sterilization is usually performed at elevated temperature, it is preferred that these components be made of heat-resistant materials. It is preferred that these components be formed from plastics, more preferably heat-resistant plastics.
  • Furthermore, it may be preferred in some embodiments of the present invention to utilize syringe bodies and pistons which are siliconized. Siliconization is preferably performed during manufacture of the syringe body and the piston.
  • In one aspect, the present invention provides an assembly for filling and capping a barrel 10 of a pre-filled syringe. The assembly generally has a syringe body 12, a piston 26, and a stabilization member. The stabilization member is positioned proximate the rimmed end of the body to provide additional mass thereto in an amount sufficient to permit the barrel 10 to be conveyed freestanding in a longitudinally upright position on the stabilization member through an apparatus for filling and capping pharmaceutical vials. In essence, the stabilization member acts to lower the center of gravity of the barrel 10 while the barrel 10 is in a longitudinally upright position (see FIGS. 1 e, 4 f, 5 e 6 e, 8 e, and 9 e). This permits the stable conveyance of the assembly through an apparatus for filling and capping pharmaceutical vials. In the embodiment illustrated in FIGS. 1-7, the stabilization member is sleeve 42. In the embodiment illustrated in FIG. 8, the stabilization member includes sleeve 154 and stabilization cap 140. In the embodiment illustrated in FIG. 9, the stabilization member is sleeve 174. In the embodiment illustrated in FIG. 11, the stabilization member is sleeve 196. In the embodiment illustrated in FIG. 12, the stabilization member is sleeve 191. In the embodiment illustrated in FIG. 13, the stabilization member includes sleeve 203 and stabilization cap 204.
  • The following description is a variant on the method steps for assembling and filling a barrel with at least one pharmaceutical component in accordance with either the first or the second preferred embodiments of the invention. For convenience, the method variant will be described having reference to FIG. 1.
  • The syringe body 12, piston 26, and sleeve 42 can be pre-sterilized in any method known in the art. The pre-sterilized syringe body 12, the pre-sterilized piston 26, and the pre-sterilized sleeve 42 can be assembled in an aseptic environment to form the assembly shown in FIG. 1 e. While in this position, the piston 26 is located within the body 12 so that a liquid impermeable seal is formed between the inner surface 16 of the body 12 and the side surface 34 of the piston 26. Preferably, the assembly shown in FIG. 1 e is packaged in a plastic overwrap sold under the trade-mark TYVEK™ while still in the aseptic environment. Preferably, the assembly is maintained in the sterile packaging until it is ready to be filled. It is understood that the subsequent steps for filling and capping can be identical to the corresponding steps previously described depending on the state of the at least one pharmaceutical component to be filled (e.g., FIGS. 1 f to 1 i or FIGS. 8 f to 8 j for filling an assembly with at least one liquid pharmaceutical component, FIGS. 5 f to 5 i for filling an assembly with at least one solid pharmaceutical, FIGS. 6 f to 6 j for filling an assembly with at least one liquid pharmaceutical followed by lyophilization such that only a solid remains).
  • The following description is a variant on the method steps for assembling and filling a barrel with at least one pharmaceutical component in accordance with either the first or the second preferred embodiments of the invention. For convenience, the method variant will be described having reference to FIG. 1.
  • The syringe body 12, piston 26, and sleeve 42 can be assembled in a relatively clean room to form the assembly shown in FIG. 1 e. While in this position, the piston is located within the body 12 so that a liquid impermeable seal is formed between the inner surface 16 of the body 12 and the side surface 34 of the piston 26. The material for the piston 26 is selected to be liquid impermeable and sufficiently permeable to a sterilizing gas to permit sterilization of the seal between the inner surface 16 of the body 12 and the side surface 34 of the piston 26 upon exposure to a sterilizing gas. The material for the piston 26 can be selected from any material that is known in the art to be liquid impermeable and permeable to a sterilizing gas. Examples of such materials include, but are not limited to, elastomer formulations comprising neoprene (e.g., elastomer formulation FM-27 which is commercially available from Helvoet Pharma). Preferably, the assembly shown in FIG. 1 e is packaged in a plastic overwrap sold under the trade-mark TYVEK™. The wrapped assembly can then be sterilized by exposure to a sterilizing gas such as ethylene oxide. Preferably, the assembly is maintained in the sterile packaging until it is ready to be filled. It is understood that the subsequent steps for filling and capping can be identical to the corresponding steps previously described depending on the state of the at least one pharmaceutical component to be filled.
  • The following description is a variant on the method steps for assembling and filling a barrel with at least one pharmaceutical component in accordance with either the first or the second preferred embodiments of the invention. For convenience, the method variant will be described having reference to FIG. 1.
  • The syringe body 12, piston 26, and sleeve 42 can be assembled in a relatively clean room to form the assembly shown in FIG. 1 e. While in this position, the piston is located within the body 12 so that a liquid impermeable seal is formed between the inner surface 16 of the body 12 and the side surface 34 of the piston 24. Preferably, the syringe body 12 is selected from a material that comprises cerium oxide in an amount sufficient to prevent discoloration of the body upon exposure to at least one standard cycle of gamma radiation (e.g., 25 kilogray). Preferably, the syringe body 12 comprises about 1 wt % cerium oxide based on the total weight of the syringe body 12. The material for the piston 26 is selected to be substantially resistant to the effects of at least one standard cycle of gamma radiation (e.g., 25 kilogray) to the extent that the function of the piston 26 is not impaired. The material for the piston 26 can be selected from any material that is known in the art to be resistant to the effects of at least one standard cycle of gamma radiation. Examples of such materials include, but are not limited to, elastic formulations comprising bromobutyl rubber (e.g., elastomer fomulation FM-457 which is commercially available from Helvoet Pharma). Preferably, the assembly shown in FIG. 1 e is packaged in a plastic overwrap sold under the trade-mark TYVEK™. The wrapped assembly can then be sterilized by exposure to at least one standard cycle of gamma radiation (e.g., 25 kilogray). Preferably, the assembly is maintained in the sterile packaging until it is ready to be filled. It is understood that the subsequent steps for filling and capping can be identical to the corresponding steps previously described depending on the state of the at least one pharmaceutical component to be filled.
  • Although the invention has been described with reference to certain preferred embodiments, it is not limited thereto. Rather, the invention includes all embodiments which may fall within the scope of the following claims.

Claims (39)

1. An assembly for filling and capping a barrel of a pre-filled syringe, the assembly comprising:
a) a syringe body having a neck end, a rimmed end, and a side wall extending between the neck end and rimmed end, the body having an outer surface and an inner surface;
b) a piston having an upper surface, a lower surface, and a side surface extending between the upper and lower surfaces, the inner surface of the body and the side surface of the piston in contact to form a liquid impermeable seal; and
c) a stabilization member that at least partially surrounds and contacts the outer surface of the body, the stabilization member is positioned proximate the rimmed end of the body to provide additional mass thereto in an amount sufficient to permit the assembly to be conveyed freestanding in a longitudinally upright position on the stabilization member through an apparatus for filling and capping pharmaceutical vials.
2. An assembly according to claim 1, wherein the stabilization member comprises a sleeve, the sleeve has a top end and a base end, and the rimmed end of the body is positioned within the sleeve proximate the base end of the sleeve.
3. An assembly according to claim 2, wherein the base end of the sleeve has a radially projecting flange.
4. An assembly according to claim 3, wherein the flange has a substantially flat outwardly facing wall that is substantially vertical when the assembly is standing longitudinally upright.
5. An assembly according to claim 2, wherein the stabilization member further comprises a stabilization cap having a hollow portion with an upper end and a lower end, the lower end having a finger flange that extends radially outwardly therefrom, the hollow portion is sized to closely fit within the body, and the finger flange is sized to fit within the base end of the sleeve.
6. An assembly according to claim 1, wherein the piston comprises a material that is impermeable to liquid and sufficiently permeable to a sterilizing gas to permit sterilization of the seal between the inner surface of the body and the side surface of the piston upon exposure to a sterilizing gas.
7. An assembly according to claim 1, wherein the piston comprises neoprene.
8. An assembly according to claim 1, wherein the piston comprises a material that is substantially resistant to the effects of at least one standard cycle of gamma radiation.
9. An assembly according to claim 1, wherein the piston comprises bromo-butyl rubber.
10. An assembly according to claim 9, wherein the syringe body comprises cerium oxide in an amount sufficient to prevent discoloration of the body upon exposure to at least one standard cycle of gamma radiation.
11. An assembly according to claim 9, wherein the syringe body comprises about 1 wt % cerium oxide based on the total weight of the syringe body.
12. A method for producing a barrel for a pre-filled syringe, comprising:
a) providing a syringe body having a neck end, a rimmed end, and a side wall extending between the neck end and rimmed end, the body having an outer surface and an inner surface;
b) providing a piston having an upper surface, a lower surface, and a side surface extending between the upper and lower surfaces;
c) providing a stabilization member; and
d) forming an assembly comprising the syringe body, the piston, and the stabilization member such that: (i) the inner surface of the body contacts at least a portion of the side surface of the piston to form a liquid impermeable seal; (ii) the stabilization member at least partially surrounds and contacts the outer surface of the body; and (iii) the stabilization member is positioned proximate the rimmed end of the body to provide additional mass thereto in an amount sufficient to permit the assembly to be conveyed freestanding in a longitudinally upright position on the stabilization member through an apparatus for filling and capping pharmaceutical vials.
13. A method according to claim 12, wherein the syringe body provided in step (a) is pre-sterilized, the piston provided in step (b) is pre-sterilized, and the stabilization member provided in step (c) is pre-sterilized and steps (a)-(d) are performed in an aseptic environment.
14. A method according to claim 13, further comprising, subsequent to step (d), the step of (e) overwrapping the assembly with an overwrap material in an aseptic environment to maintain sterility.
15. A method according to claim 14, further comprising, subsequent to step (e), the steps of:
f) removing the overwrap;
g) filling the body with at least one pharmaceutical component through the neck end using the apparatus for filling and capping pharmaceutical vials; and
h) capping the neck end of the body using the apparatus for filling and capping pharmaceutical vials.
16. A method according to claim 15, wherein the at least one pharmaceutical component is in the form of a solid when filled into the body.
17. A method according to claim 15, wherein the at least one pharmaceutical component is in the form of a liquid when filled into the body.
18. A method according to claim 17, further comprising, subsequent to step (g) and prior to step (h), the step of lyophilizing the at least one pharmaceutical.
19. A method according to claim 12, further comprising, prior to step (b), the step of selecting a material for the piston that is impermeable to liquid but sufficiently permeable to a sterilizing gas to permit sterilization of the seal between the inner surface and the body and the side surface of the piston upon exposure to a sterilizing gas.
20. A method according to claim 19, further comprising, subsequent to step (d), the step of (e) overwrapping the assembly with an overwrap material.
21. A method according to claim 20, further comprising, subsequent to step (e), the step of (f) sterilizing the barrel with a sterilizing gas.
22. A method according to claim 21, further comprising, subsequent to step (f), the steps of:
g) removing the overwrap;
h) filling the body with at least one pharmaceutical component through the neck end using the apparatus for filling and capping pharmaceutical vials; and
i) capping the neck end of the body using the apparatus for filling and capping pharmaceutical vials.
23. A method according to claim 22, wherein the at least one pharmaceutical component is in the form of a solid when filled into the body.
24. A method according to claim 22, wherein the at least one pharmaceutical component is in the form of a liquid when filled into the body.
25. A method according to claim 24, further comprising, subsequent to step (h) and prior to step (i), the step of lyophilizing the at least one pharmaceutical.
26. A method according to claim 12, further comprising, prior to step (b), the step of selecting a material for the piston that is sufficiently resistant to at least one cycle of gamma radiation.
27. A method according to claim 26, further comprising, prior to step (a), the step of selecting a material for the syringe body material that comprises cerium oxide in an amount sufficient to prevent discoloration of the body upon exposure to at least one cycle of gamma radiation.
28. A method according to claim 27, further comprising, subsequent to step (d), the step of (e) overwrapping the assembly with an overwrap material.
29. A method according to claim 28, further comprising, subsequent to step (e), the step of (f) sterilizing the barrel with at least one cycle of gamma radiation.
30. A method according to claim 29, further comprising, subsequent to both steps (f) the steps of:
g) removing the overwrap;
h) filling the body with at least one pharmaceutical component through the neck end using the apparatus for filling and capping pharmaceutical vials; and
i) capping the neck end of the body using the apparatus for filling and capping pharmaceutical vials.
31. A method according to claim 30, wherein the at least one pharmaceutical component is in the form of a solid when filled into the body.
32. A method according to claim 30, wherein the at least one pharmaceutical component is in the form of a liquid when filled into the body.
33. A method according to claim 32, further comprising, subsequent to step (h) and prior to step (i), the step of lyophilizing the at least one pharmaceutical.
34. A method for producing a pre-filled syringe barrel, comprising:
a) providing a sterile assembly comprising a syringe body having a neck end, a rimmed end, a side wall extending between the neck end and the rimmed end, an outer surface and an inner surface, a piston having an upper surface, a lower surface, and a side surface extending between the upper and lower surfaces and a stabilization member, the sterile assembly formed such that: (i) the inner surface of the body contacts at least a portion of the side surface of the piston to form a liquid impermeable seal; (ii) the stabilization member is at least partially surrounds and contacts the outer surface of the body; and (iii) the stabilization member is positioned proximate the rimmed end of the body to provide additional mass thereto in an amount sufficient to permit the assembly to be conveyed freestanding in a longitudinally upright position on the stabilization member through an apparatus for filling and capping pharmaceutical vials;
b) filling the body with at least one pharmaceutical component through the neck end using the apparatus for filling and capping pharmaceutical vials; and
c) capping the neck end of the body using the apparatus for filling and capping pharmaceutical vials.
35. A method according to claim 34, further comprising, prior to step (b), the step of maintaining the assembly in an aseptic environment until it is ready to be filled through the neck end of the body with the at least one pharmaceutical component.
36. A method according to claim 35, wherein steps (b) and (c) are performed in an aseptic environment.
37. A method according to claim 36, wherein the at least one pharmaceutical component is in the form of a solid when filled into the body.
38. A method according to claim 36, wherein the at least one pharmaceutical component is in the form of a liquid when filled into the body.
39. A method according to claim 38, further comprising, subsequent to step (b) and prior to step (c), the step of lyophilizing the at least one pharmaceutical.
US10/951,039 2001-11-23 2004-09-25 System for filling and assembling pharmaceutical delivery devices Abandoned US20050113763A1 (en)

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EP1455865B1 (en) 2009-01-14
AU2002342479A1 (en) 2003-06-10
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WO2003045477B1 (en) 2003-07-10
EP1455865A1 (en) 2004-09-15

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