US20170333641A1 - Syringe and method of preparing syringe - Google Patents

Syringe and method of preparing syringe Download PDF

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Publication number
US20170333641A1
US20170333641A1 US15/523,048 US201515523048A US2017333641A1 US 20170333641 A1 US20170333641 A1 US 20170333641A1 US 201515523048 A US201515523048 A US 201515523048A US 2017333641 A1 US2017333641 A1 US 2017333641A1
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US
United States
Prior art keywords
needle
syringe
water vapour
syringe according
rigid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US15/523,048
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English (en)
Inventor
Frank BAMBERG
Heather L. FLORES
Robert Müller
Elisabeth SCHAIBLE
Edward SCHWARB
Lionel Vedrine
Kewei Yang
Mathieu RIGOLLET
Pierre Goldbach
Baboo Dushyantsingh GOORDYAL
Ivy LIN
Florian WILDENHAHN
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Hoffmann La Roche Inc
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Hoffmann La Roche Inc
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Publication date
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Priority to US15/523,048 priority Critical patent/US20170333641A1/en
Assigned to HOFFMANN-LA ROCHE INC. reassignment HOFFMANN-LA ROCHE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: F. HOFFMANN-LA ROCHE AG
Assigned to F. HOFFMANN-LA ROCHE AG reassignment F. HOFFMANN-LA ROCHE AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SCHAIBLE, Elisabeth, SCHWARB, Edward, GOLDBACH, PIERRE, MUELLER, ROBERT, BAMBERG, Frank, GOORDYAL, BABOO DUSHYANTSING, RIGOLLET, Mathieu, WILDENHAHN, FLORIAN, YANG, KEWEI
Publication of US20170333641A1 publication Critical patent/US20170333641A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/3202—Devices for protection of the needle before use, e.g. caps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/002—Packages specially adapted therefor, e.g. for syringes or needles, kits for diabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/329—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles characterised by features of the needle shaft
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
    • B65B3/003—Filling medical containers such as ampoules, vials, syringes or the like
    • B65B3/006—Related operations, e.g. scoring ampoules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B7/00—Closing containers or receptacles after filling
    • B65B7/16—Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0216—Materials providing elastic properties, e.g. for facilitating deformation and avoid breaking
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0238—General characteristics of the apparatus characterised by a particular materials the material being a coating or protective layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M2207/00—Methods of manufacture, assembly or production
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes

Definitions

  • the present invention relates to a syringe according to the preamble of independent claim 1 and more particularly to a method of preparing an according syringe.
  • a syringe having a longitudinal body with an interior in which a pharmaceutical substance is arranged, a needle connected to one longitudinal end of the body and an elastomeric needle cap encasing the needle can be used for providing and applying the pharmaceutical substance to a patient.
  • staked-in needle pre-fillable syringes consist of a syringe body, a staked-in needle and a rigid needle shield (RNS).
  • the RNS is the closure of the needle which aims for preventing accidental stick injuries, leaking of pharmaceutical substance and entry of contaminations.
  • RNS have an inner elastomeric part which is adjacent to and incorporates the needle and an outer solid part which can be made of a thermoset plastic material or the like.
  • the syringe is typically pre-sterilized such that it is ready-to-fill before filling the pharmaceutical substance.
  • the sterilization process is normally done by ethylene oxide gas or other ways of sterilization.
  • Ethylene oxide sterilization requires gas permeability of the rigid needle shield in order to sterilize the needle surface. Therefore, the rigid needle shield often possesses significant gas permeability for other gases including water vapour.
  • the pharmaceutical substance is provided into an interior of the syringe body and the proximal opening of the syringe body is closed by an elastomeric plunger.
  • the invention is a syringe that has a longitudinal body with an interior in which a, typically liquid, pharmaceutical substance is arranged, a needle connected to one longitudinal end of the body and a rigid needle shield encasing the needle.
  • the rigid needle shield is water vapour tight.
  • rigid needle shield or RNS as used herein can relate to a closure which covers the needle. It prevents accidental needle stick injuries and serves as a closure which prevents leaking of the drug product solution and entry of microbiological or other contaminations.
  • water vapour tight as used herein can relate to no or a comparably low permeability for water vapour.
  • Comparably low permeability in this context can relate to a permeability of 1.2 gram per squared meter and day
  • the syringe body can be made from any inert material having suitable properties with respect to rigidity and usability.
  • it can be made of or comprise glass.
  • it can be made of or comprise plastics.
  • the problem of needle clogging in pre-filled syringes can be solved or prevented by a modification of the rigid needle shield.
  • the term “clogging” can refer to needle clogging being a blockage of the needle preventing or substantially reducing ejection of the pharmaceutical substance out of the syringe.
  • the pre-filled syringe according to the invention allows for proper administration of pharmaceuticals, particularly by subcutaneous, intramuscular, ocular, intradermal or intravitreal injection.
  • a needle neighbouring part of the rigid needle shield being adjacent to the needle has a low leaching capacity, particularly a low Zinc (Zn) leaching capacity.
  • the pharmaceutical solution in the needle can also solidify by interaction with leachable material from the material of the rigid needle shield. More specifically, Zinc ions which can leach from the part of the rigid needle shield neighbouring the needle, which conventionally is an elastomer part, can interact with the pharmaceutical substance or components thereof such as proteins. Such leachable or Zinc ion induced interaction can lead to a comparably strong increase of the viscosity of the pharmaceutical substance which can induce or produce clogging in the needle.
  • the term “low leaching capacity” or “low Zinc leaching capacity” can relate to a material or part leaching to an extent that the viscosity of the pharmaceutical substance is not or substantially not affected. More particular, a material can have such low Zinc leaching capacity if it has a maximum release of 5 ⁇ g Zinc ions per day and needle neighbouring part after incubation for 1 day at 25° C.
  • Such water vapour tight rigid needle shield having reduced water vapour permeability also has a reduced leaching, in particular of Zinc ions.
  • the preferred improved rigid needle shield therefore possesses the combined properties of reduced permeability for water vapour and the reduced leaching of material or components, specifically Zinc ions.
  • the rigid needle shield comprises a water vapour tight coat.
  • a vapour tight coat can be arranged as an outer shell of the rigid needle shield. It allows for adapting a common syringe in order to implement a syringe in according with the invention having a reduced tendency of needle clogging. In particular, this allows for efficiently preparing syringes essentially in accordance with known systems and to add the coat as vapour barrier separately.
  • the coat comprises wax that can be selected from organic wax. Adding wax to the needle cap allows for efficiently providing the water vapour barrier to the rigid needle shield. It also allows for adapting conventionally prepared syringes in order to provide it with increased properties regarding the prevention of needle clogging. Materials other than wax are similarly possible for being applied to conventionally prepared syringes.
  • the coat additionally or alternatively comprises a water vapour tight pouch filled with an aqueous fluid.
  • the pouch can be made of aluminium.
  • the aqueous fluid can particularly be water or a water like solution.
  • a suitable matrix such as a cotton ball can be arranged for gathering or holding the aqueous solution.
  • the rigid needle shield preferably comprises a needle neighbouring part being adjacent to the needle which is made of a water vapour tight material.
  • a rigid needle shield allows for an efficient one step provision of the water vapour barrier to the needle.
  • the water vapour tight material preferably is ethylene propylene diene methylene based thermoplastic elastomer.
  • ethylene propylene diene methylene based thermoplastic elastomer ethylene propylene diene methylene based thermoplastic elastomer.
  • Such a material allows for providing a vapour tight barrier which on one hand is not water permeably enough for allowing significant needle clogging and on the other hand is gas permeable enough for still allowing conventional sterilization of the needle such as, e.g., by ethylene oxide gas sterilization. It also allows an efficient manufacture or preparation of the syringe.
  • the water vapour tight material preferably is styrene-butadiene rubber compound free from 2 mercaptobenzothiazole.
  • a vapour tight barrier which on one hand is not water permeably enough for allowing significant needle clogging and on the other hand is gas permeable enough for still allowing conventional sterilization of the needle such as, e.g., by ethylene oxide gas sterilization.
  • it allows an efficient manufacture or preparation of the syringe.
  • the interior of the body is sealed at a side opposite to the needle by a plunger.
  • the plunger can be made of or comprise an elastic material or an elastic plastic material such as fluoro resin laminated butyl rubber.
  • a plunger allows for safely sealing the interior of the body. Further, it can be easily pushed into the proximal opening of the needle body which allows for an efficient preparation of the syringe. Still further, it can be further pushed by an activation rod into the direction of the needle in order to provide the pharmaceutical substance out of the needle.
  • butyl rubber plungers do not significantly leach Zinc which can be additionally beneficial.
  • the needle is integral with the syringe body.
  • syringes are also referred to as staked-in needle syringes. They can comparably efficiently be manufactured. Also, they can be comparably easy to handle, e.g. in auto-injection, since it is not required to mount the needle before application.
  • the pharmaceutical substance is a biopharmaceutical substance.
  • biopharmaceutical substance can relate to any biologic therapeutic formulation in a liquid from.
  • Many biopharmaceutical substances comprise comparably large molecules and have a comparably high tendency for clogging such that providing a vapour tight barrier and/or a reduced capacity for leaching, particularly Zinc leaching, to a rigid needle shield of respective syringe can be particularly useful.
  • the biopharmaceutical substance preferably comprises a protein.
  • the protein can, e.g., be a monoclonal antibody or the like.
  • such substances can have an even higher tendency for clogging such that, again, providing a vapour tight barrier and/or a reduced capacity for leaching, particularly Zinc leaching, to a needle of respective syringe can be particularly useful.
  • the substance preferably comprises the protein at a concentration in a range of about 50 mg/ml to about 250 mg/ml or to about 300 mg/ml.
  • the abbreviation “mg” relates to milligram and the abbreviation “ml” to millilitre.
  • Another aspect of the present invention relates to a method of preparing a syringe having a longitudinal body with an interior and a needle connected to one longitudinal end of the body.
  • the method comprises the steps of: filling a pharmaceutical substance inside the interior of the body of the syringe; sealing the interior of the body of the syringe by pushing a plunger through an opening embodied at a longitudinal end of the body opposite to the needle; and encasing the needle with a water vapour tight rigid needle shield.
  • encasing the needle with the rigid needle shield comprises covering a needle cap with a water vapour tight coat.
  • a coat can be wax or a pouch filled with a liquid as described hereinbefore.
  • Embodiment 1 is a syringe having a longitudinal body with an interior in which a pharmaceutical substance is arranged, a needle connected to one longitudinal end of the body and a rigid needle shield encasing the needle, wherein a needle neighbouring part of the rigid needle shield being adjacent to the needle has a low leaching capacity such as a low Zinc leaching capacity.
  • the pharmaceutical solution in the needle can also solidify by interaction with leachable material from the rigid needle shield.
  • Such Zinc ion or leachable material induced interaction can lead to a comparably strong increase of the viscosity of the pharmaceutical substance which can induce clogging of the needle. Therefore, providing the needle neighbouring part of the rigid needle shield in a material that does leach, particularly leach Zinc, to no substantial extent or that has the low leaching or Zinc leaching capacity can prevent such increase of the viscosity regardless if the rigid needle shield is water vapour tight or not.
  • the term “low leaching capacity” or “low Zinc leaching capacity” can relate to a material or part leaching material or components such as Zinc to an extent that the viscosity of the pharmaceutical substance is not or substantially not affected. More particular, a material can have such low Zinc leaching capacity if it has a maximum release of 5 ⁇ g Zinc ions per day and needle neighbouring part after incubation for 1 day at 25° C. in 1 mL of a 20 mM histidine-HCl, 100 mM arginine-HCl, 30 mM L-methione, 0.02% polysorbate 80, pH 6.0 ⁇ 0.5 aqueous solution. Thereby, the needle neighbouring part of the rigid needle shield is cut into 4 equal sized pieces.
  • Embodiment 2 is the syringe of embodiment 1, wherein the rigid needle shield is water vapour tight.
  • the rigid needle shield is water vapour tight.
  • Embodiment 3 is a syringe according to embodiment 1 or 2, wherein the rigid needle shield comprises a water vapour tight coat.
  • Embodiment 4 is a syringe according to embodiments 3, wherein the coat comprises wax, particularly organic wax.
  • Embodiment 5 is a syringe according to embodiment 3 or 4, wherein the coat comprises a water vapour tight pouch filled with an aqueous fluid.
  • Embodiment 6 is a syringe according to embodiment 1 or 2, wherein the rigid needle shield comprises a needle neighbouring part being adjacent to the needle which is made of a water vapour tight material.
  • Embodiment 7 is a syringe according to embodiment 6, wherein the water vapour tight material is ethylene propylene diene methylene based thermoplastic elastomer.
  • Embodiment 8 is a syringe according to embodiments 6, wherein the water vapour tight material is styrene-butadiene rubber compound free from 2 mercaptobenzothiazole.
  • Embodiment 9 is a syringe according to any one of the preceding embodiments 1 to 8, wherein the interior of the body is sealed at a side opposite to the needle by a plunger.
  • Embodiment 10 is a syringe according to any one of the preceding embodiments 1 to 9, wherein the needle is integral with the body.
  • Embodiment 11 is a syringe according to any one of the preceding embodiments 1 to 10, wherein the pharmaceutical substance is a biopharmaceutical substance.
  • Embodiment 12 is a syringe according to embodiment 11, wherein the biopharmaceutical substance comprises a protein.
  • Embodiment 13 is a syringe according to embodiment 12, wherein the substance comprises the protein at a concentration in a range of about 50 mg/ml to about 250 mg/ml.
  • Embodiment 14 is a syringe according to embodiment 12 or 13, wherein the protein is a monoclonal antibody.
  • FIG. 1 shows a view on a first embodiment of a needle according to the invention having a rigid needle shield with a water vapour tight elastomeric needle neighbouring part;
  • FIG. 2 shows view on a second embodiment of a needle according to the invention having a rigid needle shield with a wax coat
  • FIG. 3 shows a view on a third embodiment of a needle according to the invention having a rigid needle shield with a pouch filled with an aqueous solution as coat;
  • FIG. 4 shows a graphical view representing viscosity vs. incubation temperature and time of plural examples of syringes according to the invention.
  • the exemplary term “below” can encompass both positions and orientations of above and below.
  • the device may be otherwise oriented (rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein interpreted accordingly.
  • descriptions of movement along and around various axes includes various special device positions and orientations.
  • FIG. 1 shows a staked-in needle (SIN) pre-filled syringe (PFS) 1 as a first embodiment of a syringe according to the invention.
  • the SIN-PFS 1 has a longitudinal hollow glass body 2 which, at its one end along its longitudinal axis 6 , passes over into a needle via a neck 5 .
  • the body 2 has an opening.
  • the border of the opening is embodied as finger flange 21 .
  • the interior 22 of the body 2 is delimited in a direction along the axis 6 opposite to the needle by a butyl rubber plunger 4 .
  • the plunger 4 seals the interior 22 of the body 2 .
  • a liquid biopharmaceutical substance is arranged which comprises proteins at a concentration in a range between 50 mg/ml and 250 mg/ml.
  • the needle of the SIN-PFS 1 is protected by a rigid needle shield 3 comprising an elastomeric needle cover 31 as needle neighbouring part and a thermoset cap 32 .
  • the rigid needle shield 3 extends from the tip of the needle to the neck 5 .
  • the needle cover 31 is made from either ethylene propylene diene methylene based thermoplastic elastomer or from styrene-butadiene rubber compound free from 2 mercaptobenzothiazole. It directly encases the needle of the SIN-PFS 1 .
  • the cap 32 of the rigid needle shield 3 is comparably solid and resistant to mechanical stress. It encases the needle cover 31 wherein it has plural axial slits widening in a distal direction. Through the slits of the cap 32 the needle cover 31 is accessible. In particular, through the slits of the cap 32 the needle can be sterilized in a common fashion, e.g. by ethylene oxide gas sterilization or the like. Thus, the material of the needle cover 31 is permeable with respect to an appropriate sterilization and in the mean time water vapour tight in the sense of the invention. Furthermore, the material of the needle cover 31 has a low Zinc leaching capacity.
  • FIG. 2 another staked-in needle pre-filled syringe 18 as a second embodiment of a syringe according to the invention is shown.
  • the SIN-PFS 18 has a body 28 , a neck 58 , a plunger 48 , a needle and a longitudinal axis 68 witch are identically embodied as the same parts of the SIN-PFS 1 shown in FIG. 1 .
  • the body 28 comprises an identical opening with a finger flange 218 and an identical interior 228 between the plunger 48 and the needle which is filled with a liquid biopharmaceutical substance.
  • the SIN-PFS 18 further has a rigid needle shield 38 protecting the needle of the SIN-PFS 18 .
  • the rigid needle shield 38 comprises an elastomeric needle cover 318 as needle neighbouring part, a thermoset cap 328 and a coat 338 .
  • the needle cover 318 is made from a conventional material such as, e.g., polyisoprene. It directly encases the needle of the SIN-PFS 18 .
  • the cap 328 is identically embodied as the cap 32 of the rigid needle shield 3 of the SIN-PFS 1 of FIG. 1 . It is covered by the coat 338 made of an organic wax which is arranged on the cap 328 , the neck 58 and a section of the body 28 . Thus, the rigid needle shield 38 extends from the tip of the needle to the body 28 .
  • the SIN-PFS 18 For preparing the SIN-PFS 18 , it can be obtained in a pre-arranged manner. I.e., the interior 228 of the body 28 of the SIN-PFS 18 is filled with the biopharmaceutical substance and sealed by pushing the plunger 48 through the opening of the body 228 , and the needle is encased with the conventional needle cover 318 and needle cap 328 . Then the obtained SIN-PFS 18 can be dipped needle down into liquid organic wax up to the section of the body 228 . After a short time the SIN-PFS 18 is removed from the liquid wax and the layer adhering on the SIN-PFS 18 is building the coat 338 after cooling and thereby curing.
  • FIG. 3 shows a further other staked-in needle pre-filled syringe 19 as a third embodiment of a syringe according to the invention.
  • the SIN-PFS 19 has a body 29 , a neck 59 , a plunger 49 , a needle and a longitudinal axis 69 witch are identically embodied as the same parts of the SIN-PFS 1 shown in FIG. 1 .
  • the body 29 comprises an identical opening with a finger flange 219 and an identical interior 229 between the plunger 49 and the needle which is filled with a liquid biopharmaceutical substance.
  • the SIN-PFS 19 further has a rigid needle shield 39 protecting the needle of the SIN-PFS 19 .
  • the rigid needle shield 39 comprises an elastomeric needle cover 319 as needle neighbouring part, a thermoset cap 329 and a pouch 339 as coat.
  • the needle cover 319 is made from a conventional material such as, e.g., polyisoprene. It directly encases the needle of the SIN-PFS 19 .
  • the cap 329 is identically embodied as the cap 32 of the rigid needle shield 3 of the SIN-PFS 1 of FIG. 1 .
  • the SIN-PFS 19 For preparing the SIN-PFS 19 , it can be obtained in a pre-arranged manner as described above in connection with the preparation of the SIN-PFS 18 of FIG. 2 . Then the obtained SIN-PFS 19 can be wrapped in the pouch 339 and the aqueous solution can be provided into the inside of the pouch 339 via the inlet 349 . For obtaining or gathering the aqueous solution a matrix such as a cotton ball can be provided inside the pouch 339 . Thereby, the pouch 339 together with the aqueous solution forms the coat.
  • Example 1 is a prior art syringe as reference.
  • the reference syringe is a staked-in needle pre-filled glass syringe with a rigid needle shield having an inner core made from polyisoprene elastomer (formulation 4800, Stelmi) and an outer thermoset cover.
  • the interior of the reference syringe is filled with a concentrated Tocilizumab (available from or provided by F. Hoffmann La Roche A G, INN) formulation as biopharmaceutical substance using a tray filler (Inova V122) with a target extractable volume of 0.959 mL.
  • Tocilizumab available from or provided by F. Hoffmann La Roche A G, INN
  • an initial Tocilizumab formulation (180 mg/ml Tocilizumab, 20 mM L-histidine-HCL, 30 mM L-methionine, 100 mM L-arginine-HCL, 0.02% polysorbate 80, pH 6.0) is concentrated to a Tocilizumab concentration of 189 mg/mL Tocilizumab using tangential flow filtration process with a semipermeable membrane with 30 kD molecular weight cut-off.
  • the concentrated Tocilizumab solution is sterile filtered through 0.22 ⁇ m polyvinylidene difluoride (PVDF) filter membrane.
  • PVDF polyvinylidene difluoride
  • Example 2 is a staked-in needle pre-filled glass syringe with a rigid needle shield having an inner core made from polyisoprene elastomer (formulation 4800, Stelmi) and an outer thermoset cover.
  • the interior of the syringe is filled with the same concentrated Tocilizumab formulation as mentioned above using a tray filler (Inova V122) with a target extractable volume of 0.959 mL.
  • the syringe is co-packed in a water vapour tight aluminium pouch filled with an aqueous solution as water vapour tight coat.
  • the aluminium foil pouch is made of adhesive laminate of 12 ⁇ m printable polyester, 20 ⁇ m white polyethylene, 9 ⁇ m aluminium foil and 65 ⁇ m CleanPeelTM peelable polyethylene sealant layer (240 ⁇ 240 mm), with a WVTR of less than 0.01 g/(m2 ⁇ day) (at 38° C./90% rh). PFS were put in aluminium foil pouch together with a 5 ⁇ 5 cm cotton tissue adsorbing 5 mL pure water, followed by heat sealing (170-200° C.) of the aluminium pouch.
  • Example 3 is a staked-in needle pre-filled glass syringe with a rigid needle shield having an inner core made from ethylene propylene diene methylene (EPDM) based thermoplastic elastomer (formulation 8550, Stelmi) as vapour tight needle neighbouring part and an outer thermoset cover.
  • EPDM ethylene propylene diene methylene
  • formulation 8550, Stelmi thermoplastic elastomer
  • the interior of the syringe is filled with the same concentrated Tocilizumab formulation as mentioned above using a tray filler (Inova V122) with a target extractable volume of 0.959 mL.
  • Example 4 is a staked-in needle pre-filled glass syringe with a rigid needle shield having an inner core made from styrene-butadiene rubber compound free from 2-mercaptobenzothiazole (MBT) (formulation FM30, Datwyler) as vapour tight needle neighbouring part and an outer thermoset cover.
  • MBT 2-mercaptobenzothiazole
  • the interior of the syringe is filled with the same concentrated Tocilizumab formulation as mentioned above using a tray filler (Inova V122) with a target extractable volume of 0.959 mL.
  • Example 5 is a staked-in needle pre-filled glass syringe with a rigid needle shield having an inner core made from polyisoprene elastomer (formulation 4800, Stelmi) and an outer thermoset cover.
  • the interior of the syringe is filled with the same concentrated Tocilizumab formulation as mentioned above using a tray filler (Inova V122) with a target extractable volume of 0.959 mL.
  • the thermoset cover of the rigid needle shield is coated with a water vapour tight material such as wax after filling of the drug product solution.
  • the rigid needle shield (RNS) inner rubber material or needle neighbouring part of respective RNS variants are cut into four pieces and incubated with 1 mL Tocilizumab solution (180 mg/mL, 20 mM L-histidine-HCL, 30 mM L-methionine, 100 mM L-arginine-HCL, 0.02% polysorbate 80, pH 6.0) in a sealed glass vial at 5° C., 25° C. and 40° C., respectively. After 4 weeks, 8 weeks and 13 weeks incubation, samples are analysed with respect to dynamic viscosity.
  • Tocilizumab solution 180 mg/mL, 20 mM L-histidine-HCL, 30 mM L-methionine, 100 mM L-arginine-HCL, 0.02% polysorbate 80, pH 6.0
  • Example 1 shows a clogging rate set to 100%.
  • Example 2 demonstrates that appropriate packaging prevents needle clogging completely after one month storage at 40° C./25% rh.
  • Example 3 demonstrates that an alternative RNS variant with smaller water vapour transmission rate and improved material compatibility reduces needle clogging significantly compared to Example 1.
  • Example 4 does not decrease clogging rate in comparison to Example 1, although the compatibility with the Tocilizumab (INN) formulation is demonstrated in the RNS incubation study.
  • Example 5 is expected to show similar results as Example 2.
  • the disclosure also covers all further features shown in the Figs. individually although they may not have been described in the afore or following description. Also, single alternatives of the embodiments described in the figures and the description and single alternatives of features thereof can be disclaimed from the subject matter of the invention or from disclosed subject matter.
  • the disclosure comprises subject matter consisting of the features defined in the claims or the exemplary embodiments as well as subject matter comprising said features.

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CN115607771A (zh) 2023-01-17
RU2708974C2 (ru) 2019-12-12
JP2017538463A (ja) 2017-12-28
RU2017118396A (ru) 2018-12-04
CA2963325A1 (en) 2016-05-06
EP3212252A1 (en) 2017-09-06
RU2017118396A3 (zh) 2019-05-29
US20220203041A1 (en) 2022-06-30
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MX2017005512A (es) 2018-08-16
US11771843B2 (en) 2023-10-03

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