Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
  • A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
  • A61K38/179—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • 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
  • 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
• • 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
  • A61M5/28—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle
• • 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
• • 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
  • A61M5/3129—Syringe barrels
• • 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
  • A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
  • A61M5/31501—Means for blocking or restricting the movement of the rod or piston
  • A61M5/31505—Integral with the syringe barrel, i.e. connected to the barrel so as to make up a single complete piece or unit
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • 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
  • A61M2005/3103—Leak prevention means for distal end of syringes, i.e. syringe end for mounting a needle
  • A61M2005/3104—Caps for syringes without needle
• • 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
  • A61M5/3129—Syringe barrels
  • A61M2005/3131—Syringe barrels specially adapted for improving sealing or sliding
• • 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
  • A61M5/3129—Syringe barrels
  • A61M5/3137—Specially designed finger grip means, e.g. for easy manipulation of the syringe rod
  • A61M2005/3139—Finger grips not integrally formed with the syringe barrel, e.g. using adapter with finger grips
• • 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
  • A61M5/31501—Means for blocking or restricting the movement of the rod or piston
  • A61M2005/31508—Means for blocking or restricting the movement of the rod or piston provided on the piston-rod
• • 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
  • A61M2210/00—Anatomical parts of the body
  • A61M2210/06—Head
  • A61M2210/0612—Eyes
• • 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
  • A61M5/31511—Piston or piston-rod constructions, e.g. connection of piston with piston-rod
  • A61M5/31513—Piston constructions to improve sealing or sliding

Definitions

• the present invention relates to a syringe, particularly to a small volume syringe such as a syringe suitable for ophthalmic injections.
• medicaments are delivered to a patient in a syringe from which the user can dispense the medicament. If medicament is delivered to a patient in a syringe it is often to enable the patient, or a caregiver, to inject the medicament. It is important for patient safety and medicament integrity that the syringe and the contents of that syringe are sufficiently sterile to avoid infection, or other, risks for patients. Sterilisation can be achieved by terminal sterilisation in which the assembled product, typically already in its associated packaging, is sterilised using heat or a sterilising gas.
• syringes for example those for injections into the eye in which it is intended that about 0.1ml or less of liquid is to be injected the sterilisation can pose difficulties that are not necessarily associated with larger syringes. Changes in pressure, internal or external to the syringe, can cause parts of the syringe to move unpredictably, which may alter sealing characteristics and potentially compromise sterility. Incorrect handling of the syringe can also pose risks to product sterility.
• certain therapeutics such as biologic molecules are particularly sensitive to sterilisation, be it cold gas sterilisation, thermal sterilisation, or irradiation.
• a careful balancing act is required to ensure that while a suitable level of sterilisation is carried out, the syringe remains suitably sealed, such that the therapeutic is not compromised.
• the syringe must also remain easy to use, in that the force required to depress the plunger to administer the medicament must not be too high. There is therefore a need for a new syringe construct which provides a robust seal for its content, but which maintains ease of use.
• the present invention provides a pre-filied syringe, the syringe comprising a body, a stopper and a plunger, the body comprising an outlet at an outlet end and the stopper being arranged within the body such that a front surface of the stopper and the body define a variable volume chamber from which a fluid can be expelled though the outlet, the plunger comprising a plunger contact surface at a first end and a rod extending between the plunger contact surface and a rear portion, the plunger contact surface arranged to contact the stopper, such that the plunger can be used to force the stopper towards the outlet end of the body, reducing the volume of the variable volume chamber, characterised in that the fluid comprises an ophthalmic solution.
• the ophthalmic solution comprises a VEGF-antagonist.
• the syringe is suitable for ophthalmic injections, more particularly intravitreal injections, and as such has a suitably small volume.
• the syringe may also be silicone oil free, or substantially silicone oil free, or may comprise a low level of silicone oil as lubricant. In one embodiment, despite the low silicone oil level, the stopper break loose and slide force is less than 20N.
• the syringe meets US Pharmacopeia standard 789 (USP789).
• the body of the syringe may be a substantially cylindrical shell, or may include a substantially cylindrical bore with a non circular outer shape.
• the outlet end of the body includes an outlet through which a fluid housed within the variable volume chamber can be expelled as the volume of said chamber is reduced.
• the outlet may comprise a projection from the outlet end through which extends a channel having a smaller diameter than that of the variable volume chamber.
• the outlet may be adapted, for example via a luer lock type connection, for connection to a needle or other accessory such as a sealing device which is able to seal the variable volume chamber, but can be operated, or removed, to unseal the variable volume chamber and allow connection of the syringe to another accessory, such as a needle. Such a connection may be made directly between the syringe and accessory, or via the sealing device.
• the body extends along a first axis from the outlet end to a rear end.
• the body may be made from a plastic material (e.g. a cyclic olefin polymer) or from glass and may include indicia on a surface thereof to act as an injection guide.
• the body may comprise a priming mark. This allows the physician to align a pre-determined part of the stopper (such as the tip of the front surface or one of the circumferential ribs, discussed later) or plunger with the mark, thus expelling excess ophthalmic solution and any air bubbles from the syringe.
• the priming process ensures that an exact, pre-determined dosage is administered to the patient.
• the stopper may be made from rubber, silicone or other suitable resiliently deformable material.
• the stopper may be substantially cylindrical and the stopper may include one or more circumferential ribs around an outer surface of the stopper, the stopper and ribs being dimensioned such that the ribs form a substantially fluid tight seal with an internal surface of the syringe body.
• the front surface of the stopper may be any suitable shape, for example substantially planar, substantially conical or of a domed shape.
• the rear surface of the stopper may include a substantially central recess. Such a central recess could be used to connect a plunger to the stopper using a snap fit feature or thread connection in a known manner.
• the stopper may be substantially rotationally symmetric about an axis through the stopper.
• the plunger comprises a plunger contact surface and extending from that a rod extends from the plunger contact surface to a rear portion.
• the rear portion may include a user contact portion adapted to be contacted by a user during an injection event.
• the user contact portion may comprise a substantially disc shaped portion, the radius of the disc extending substantially perpendicular to the axis along which the rod extends.
• the user contact portion could be any suitable shape,
• the axis along which the rod extends may be the first axis, or may be substantially parallel with the first axis.
• the syringe may include a backstop arranged at a rear portion of the body.
• the backstop may be removable from the syringe. If the syringe body includes tenninal flanges at the end opposite the outlet end the backstop may be configured to substantially sandwich tenninal flanges of the body as this prevent movement of the backstop in a direction parallel to the first axis.
• the rod may comprise at least one rod shoulder directed away from the outlet end and the backstop may include a backstop shoulder directed towards the outlet end to cooperate with the rod shoulder to substantially prevent movement of the rod away from the outlet end when the backstop shoulder and rod shoulder are in contact. Restriction of the movement of the rod away from the outlet end can help to maintain sterility during terminal sterilisation operations, or other operations in which the pressure within the variable volume chamber or outside the chamber may change. During such operations any gas trapped within the variable volume chamber, or bubbles that may form in a liquid therein, may change in volume and thereby cause the stopper to move. Movement of the stopper away from the outlet could result in the breaching of a sterility zone created by the stopper.
• sterility zone as used herein is used to refer to the area within the syringe that is sealed by the stopper from access from either end of the syringe. This may be the area between a seal of the stopper, for example a circumferential rib, closest to the outlet and a seal of the stopper, for example a circumferential rib, furthest from the outlet. The distance between these two seals defines the sterility zone of the stopper since the stopper is installed into the syringe barrel in a sterile environment.
• the stopper may comprise at a front circumferential rib and a rear circumferential rib and those ribs may be separated in a direction along the first axis by at least 3mm, by at least 3.5 mm, by at least 3.75mm or by 4mm or more.
• One or more additional ribs (for example 2, 3, 4 or 5 additional ribs, or between 1 -10, 2-8, 3-6 or 4-5 additional ribs) may be arranged between the front and rear ribs. In one embodiment there are a total of three circumferential ribs.
• a stopper with such an enhanced sterility zone can also provide protection for the injectable medicament during a terminal sterilisation process. More ribs on the stopper, or a greater distance between the front and rear ribs can reduce the potential exposure of the medicament to the sterilising agent. However, increasing the number of ribs can increase the friction between the stopper and syringe body, reducing ease of use. While this may be overcome by increasing the siliconisation of the syringe, such an increase in silicone oil levels is particularly undesirable for syringes for ophthalmic use.
• the rod shoulder may be arranged within the external diameter of the rod, or may be arranged outside the external diameter of the rod. By providing a shoulder that extends beyond the external diameter of the rod, but still fits within the body, the shoulder can help to stabilise the movement of the rod within the body by reducing movement of the rod perpendicular to the first axis.
• the rod shoulder may comprise any suitable shoulder forming elements on the rod, but in one embodiment the rod shoulder comprises a substantially disc shaped portion on the rod.
• variable volume chamber when arranged with the plunger contact surface in contact with the stopper and the variable volume chamber is at its intended maximum volume there is a clearance of no more than about 2mm between the rod shoulder and backstop shoulder. In some embodiments there is a clearance of less than about 1.5 mm and in some less than about 1mm. This distance is selected to substantially limit or prevent excessive rearward (away from the outlet end) movement of the stopper.
• the variable volume chamber has an internal diameter greater than 5mm or 6mm, or less than 3mm or 4mm. The internal diameter may be between 3mm and 6mm, or between 4mm and 5mm.
• the syringe is dimensioned so as to have a nominal maximum fill volume of between about 0.1ml and about 1.5ml. In certain embodiments the nominal maximum fill volume is between about 0.5ml and about 1 ml. In certain embodiments the nominal maximum fill volume is about 0.5ml or about lml, or about 1.5ml.
• the length of the body of the syringe may be less than 70mm, less than 60mm or less than 50mm. In one embodiment the length of the syringe body is between 45mm and 50mm. In one embodiment, the syringe is filled with between about 0.01ml and about 1.5ml (for example between about 0.05ml and about lml, between about 0.1ml and about 0.5ml, between about 0.15ml and about 0.175ml) of a VEGF antagonist solution. In one embodiment, the syringe is filled with 0.165ml of a VEGF antagonist solution.
• a syringe is filled with more than the desired dose to be administered to the patient, to take into account wastage due to "dead space" within the syringe and needle. There may also be a certain amount of wastage when the syringe is primed by the physician, so that it is ready to inject the patient.
• the syringe is filled with a dosage volume (i.e. the volume of medicament intended for delivery to the patent) of between about 0.01ml and about 1.5ml (e.g. between about 0,05ml and about lml, between about 0.1ml and about 0.5ml) of a VEGF antagonist solution.
• the dosage volume is between about 0.03ml and about 0.05ml.
• the dosage volume is 0.05ml or 0.03ml (0.5mg or 0.3mg) of a l Omg/ml injectable medicament solution; for Eylea, the dosage volume is 0.05ml of a 40mg/ml injectable medicament solution.
• bevacizumab is used off-label in such ophthalmic indications at a concentration of 25mg/ml; typically at a dosage volume of 0.05ml (1.25mg).
• the extractable volume from the syringe (that is the amount of product obtainable from the syringe following filling, taking into account loss due to dead space in the syringe and needle) is about 0.09ml.
• the length of the syringe body is between about 45mm and about 50mm, the internal diameter is between about 4mm and about 5mm, the fill volume is between about 0.12 and about 0.3ml and the dosage volume is between about 0.03ml and about 0.05ml.
• the outlet may be reversibly sealed to maintain sterility of the medicament. This sealing may be achieved through the use of a sealing device as is known in the art.
• a sealing device for example the OVSTM system which is available from Vetter Pharma International GmbH. It is typical to siliconise the syringe in order to allow ease of use, i.e. to apply silicone oil to the inside of the barrel, which decreases the force required to move the stopper.
• a syringe according to the invention comprises less than about 800 ⁇ g (i.e.
• the syringe comprises a low level of silicone oil, this may be more than about 1 , more than about 3 ⁇ g, more than about 5 g, more than about 7 ⁇ g or more than about 10 ⁇ g silicone oil in the barrel.
• the syringe may comprise about ⁇ g-about 500 ⁇ g, about 3 ⁇ g-about 200 g, about 5 ⁇ g-about 100 ⁇ g or about K ⁇ ug-about 50 ⁇ g silicone oil in the barrel.
• Methods for measuring the amount of silicone oil in such a syringe barrel include, for example, differential weighing methods and quantitation by infrared-spectroscopy of the oil diluted in a suitable solvent.
• Various types of silicone oil are available, but typically either DC360 (Dow Corning ® ; with a viscosity of 1 OOOcP) or DC365 emulsion (Dow Corning ® ; DC360 oil with a viscosity of 350cP) are used for syringe siliconisation.
• the pre-filled syringe of the invention comprises DC 365 emulsion.
• the glide/slide force for the stopper within the pre-filled syringe is less than about UN or less than 9N, less than 7N, less than 5N or between about 3N to 5N.
• the break loose force is less than about 1 IN or less than 9N, less than 7N, less than 5N or between about 2N to 5N. Note that such measurements are for a filled syringe, rather than an empty syringe.
• the forces are typically measured at a stopper travelling speed of 190mm/rnin. In one embodiment, the forces are measured with a 30G x 0.5 inch needle attached to the syringe.
• the syringe has a nominal maximal fill volume of between about 0.5ml and l ml, contains less than about 100 ⁇ g silicone oil and has a break loose force between about 2N to 5N.
• the syringe barrel has an internal coating of silicone oil that has an average thickness of about 450nm or less (i.e. 400nm or less, 350nm or less, 300nm or less, 200nm or less, lOOnm or less, 50nm or less, 20nm or less).
• Methods to measure the thickness of silicone oil in a syringe are known in the art and include the rap.
• ID Layer Explorer® Application which can also be used to measure the mass of silicone oil inside a syringe barrel.
• the syringe is silicone oil free, or substantially silicone oil free.
• Such low silicone oil levels can be achieved by using uncoated syringe barrels and/or by avoiding the use of silicone oil as a lubricant for product contacting machine parts, or pumps in the syringe assembly and fill line.
• a further way to reduce silicone oil and inorganic silica levels in a pre- filled syringe is to avoid the use of silicone tubing in filling lines, for example between storage tanks and pumps.
• the ophthalmic solution comprises no more than 2 particles >50 ⁇ in diameter per ml. In one embodiment, the ophthalmic solution comprises no more than 5 particles >25 ⁇ in diameter per ml. In one embodiment, the ophthalmic solution comprises no more than 50 particles >10 ⁇ in diameter per ml. In one embodiment, the ophthalmic solution comprises no more than 2 particles >50 ⁇ in diameter per ml, no more than 5 particles >25pm in diameter per ml and no more than 50 particles >10 ⁇ in diameter per ml.
• a syringe according to the invention meets USP789 (United States Pharmacopoeia: Particulate Matter in Ophthalmic Solutions).
• the syringe has low levels of silicone oil sufficient for the syringe to meet USP789.
• VEGF is a well-characterised signal protein which stimulates angiogenesis.
• Two antibody VEGF antagonists have been approved for human use, namely ranibizumab (Lucentis®) and bev acizumab (Avastin®) .
• the non-antibody VEGF antagonist is an immunoadhesin.
• aflibercept Esylea®
• VEGF-trap VEGF-trap
• Aflibercept is the preferred non-antibody VEGF antagonist for use with the invention.
• Aflibercept is a recombinant human soluble VEGF receptor fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgGl.
• Each monomer can have the following amino acid sequence (SEQ ID NO: 1):
• CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFIJWYVDGVEVHNAKTKPREEQYNST YRWSVLTVLHQD LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPE NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG and disulfide bridges can be formed between residues 30-79, 124-185, 246-306 and 352-410 within each monomer, and between residues 21 1 -211 and 214-214 between the monomers.
• VEGF antagonist immunoadhesin currently in pre-clinical development is a recombinant human soluble VEGF receptor fusion protein similar to VEGF-trap containing extracellular ligand-binding domains 3 and 4 from VEGFR2/KDR, and domain 2 from VEGFRl Flt-1 ; these domains are fused to a human IgG Fc protein fragment (Li et al, 2011 Molecular Vision 17:797-803).
• This antagonist binds to isoforms VEGF-A, VEGF-B and VEGF- ('.
• the molecule is prepared using two different production processes resulting in different glycosylation patterns on the final proteins.
• the two glyeoforms are referred to as KH902 (conbercept) and KH906.
• the fusion protein can have the following amino acid sequence (SEQ ID NO:2): MVSYWOTGVLLCALLSCLLLTGSSSGGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNI VTL KFPLDT LIPDGKRIIWDSRKGFI ISNATYKEIGLLTCEATVNGHLYKTWYLTHRQTNTIIDWLSPSHGIELSVGEK LVLNCTARTELNVGIDFNWEYPSSKHQHK LVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSG LMTKKNS FVRVHEKPFVAFGSGMESLVEA VGERVRLPAKYLGYPPPEIKWY NGIPLESNHTIKAGHVL TIMEVSERDTGNYTVILTNPIS EKQSHWSLWYVPPGPGDKTHTCPLCPAPELLGGPSVFLFPP PKDT LMI SRTPEVTCV
• This fusion protein and related molecules are further characterized in EP 1767546.
• Other non-antibody VEGF antagonists include antibody mimetics (e.g. Affibody® molecules, affilins, affitins, anticalins, avimers, Kunitz domain peptides, and monobodies) with VEGF antagonist activity.
• ankyrin repeat domain that binds VEGF-A and prevents it from binding to VEGFR-2.
• the ankyrin binding domain may have the following amino acid sequence (SEQ ID NO: 3):
• Recombinant binding proteins comprising an ankyrin repeat domain that binds VEGF-A and prevents it from binding to VEGFR-2 are described in more detail in WO2010/060748 and WO2011/135067.
• Non-antibody VEGF antagonist activity are the 40 kD pegylated anticalin PRS-050 and the monobody angiocept (CT-322).
• CT-322 monobody angiocept
• the afore-mentioned non-antibody VEGF antagonist may be modified to further improve their pharmacokinetic properties or bioavailability.
• a non-antibody VEGF antagonist may be chemically modified (e.g., pegylated) to extend its in vivo half-life. Alternatively or in addition, it may be modified by glycosylation or the addition of further glycosylation sites not present in the protein sequence of the natural protein from which the VEGF antagonist was derived.
• Variants of the above-specified VEGF antagonists that have improved characteristics for the desired application may be produced by the addition or deletion of amino acids.
• these amino acid sequence variants will have an amino acid sequence having at least 60% amino acid sequence identity with the amino acid sequences of SEQ ID NO; 1 , SEQ ID NO: 2 or SEQ ID NO: 3, preferably at least 80%, more preferably at least 85%, more preferably at least 90%, and most preferably at least 95%, including for example, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%o, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 100%.
• Identity or homology with respect to this sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical with SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity.
• Sequence identity can be determined by standard methods that are commonly used to compare the similarity in position of the amino acids of two polypeptides. Using a computer program such as BLAST or FASTA, two polypeptides are aligned for optimal matching of their respective amino acids (either along the full length of one or both sequences or along a predetermined portion of one or both sequences). The programs provide a default opening penalty and a default gap penalty, and a scoring matrix such as PAM 250 [a standard scoring matrix; see Dayhoff et al., in Atlas of Protein Sequence and Structure, vol. 5, supp. 3 (1978)] can be used in conjunction with the computer program.
• PAM 250 a standard scoring matrix; see Dayhoff et al., in Atlas of Protein Sequence and Structure, vol. 5, supp. 3 (1978)
• the percent identity can then be calculated as: the total number of identical matches multiplied by 100 and then divided by the sum of the length of the longer sequence within the matched span and the number of gaps introduced into the longer sequences in order to align the two sequences.
• the non-antibody VEGF antagonist of the invention binds to VEGF via one or more protein domain(s) that are not derived from the antigen-binding domain of an antibody.
• the non- antibody VEGF antagonist of the invention are preferably proteinaceous, but may include modifications that are non-protei nac ecus (e.g., pegylation, glycosylation).
• the syringe of the invention may be used to treat an ocular disease, including but not limited to choroidal neovascularisation, age-related macular degeneration (both wet and dry forms), macular edema secondary to retinal vein occlusion (RVO) including both branch RVO (bRVO) and central RVO (cRVO), choroidal neovascularisation secondary to pathologic myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and proliferative retinopathy.
• an ocular disease including but not limited to choroidal neovascularisation, age-related macular degeneration (both wet and dry forms), macular edema secondary to retinal vein occlusion (RVO) including both branch RVO (bRVO) and central RVO (cRVO), choroidal neovascularisation secondary to pathologic myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and proliferative reti
• the invention provides a method of treating a patient suffering from of an ocular disease selected from choroidal neovascularisation, wet age-related macular degeneration, macular edema secondary to retinal vein occlusion (RVO) including both branch RVO (bRVO) and central RVO (cRVO), choroidal neovascularisation secondary to pathologic myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and proliferative retinopathy, comprising the step of administering an ophthalmic solution to the patient using a pre-filled syringe of the invention.
• This method preferably further comprises an initial priming step in which the physician depresses the plunger of the pre-iilled syringe to align the pre-determined part of the stopper with the priming mark.
• the invention provides a method of treating an ocular disease selected from choroidal neovascularisation, wet age-related macular degeneration, macular edema secondary to retinal vein occlusion (RVO) including both branch RVO (bRVO) and central RVO (cRVO), choroidal neovascularisation secondary to pathologic myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and proliferative retinopathy, comprising administering a non- antibody VEGF antagonist with a pre-filled syringe of the invention, wherein the patient has previously received treatment with an antibody VEGF antagonist.
• Kits selected from choroidal neovascularisation, wet age-related macular degeneration, macular edema secondary to retinal vein occlusion (RVO) including both branch RVO (bRVO) and central RVO (cRVO), choroidal neovascularisation secondary to pathologic myopia (PM), diabetic macular edema
• kits comprising the pre-filled syringes of the invention.
• a kit comprises a pre-filled syringe of the invention in a blister pack.
• the blister pack may itself be sterile on the inside, in one embodiment, syringes according to the invention may be placed inside such blister packs prior to undergoing sterilisation, for example terminal sterilisation.
• Such a kit may further comprise a needle for administration of the VEGF antagonist. If the VEGF antagonist is to be administered intravitreally, it is typical to use a 30-gauge x 1 ⁇ 2 inch needle, though 31 -gauge and 32-gauge needles may be used. For intravitreal administration, 3 -gauge or 34-gauge needles could alternatively be used.
• kits may further comprise instructions for use.
• the invention provides a carton containing a pre-filled syringe according to the invention contained within a blister pack, a needle and optionally instructions for administration.
• a terminal sterilisation process may be used to sterilise the syringe and such a process may use a known process such as an ethylene oxide (EtO) or a hydrogen peroxide (H 2 O 2 ) sterilisation process.
• EtO ethylene oxide
• H 2 O 2 hydrogen peroxide
• Needles to be used with the syringe may be sterilised by the same method, as may kits according to the invention.
• a syringe according to the invention may have a shelf life of up to 6 months, 9 months, 12 months, 15 months, 18 months, 24 months or longer. In one embodiment, less than one syringe in a million has detectable microbial presence on the outside of the syringe after 18 months of storage.
• the pre-filled syringe has been sterilised using EtO with a Sterility Assurance Level of at least 10 "6 .
• the pre- filled syringe has been sterilised using hydrogen peroxide with a Sterility Assurance Level of at least 10 "6 .
• significant amo unts refers to an amount of gas that would cause unacceptable modification of the ophthalmic solution within the variable volume chamber.
• the sterilisation process causes ⁇ 10% (preferably ⁇ 5%, ⁇ 3%, ⁇ 1 %) alkylation of the VEGF antagonist.
• the pre-filled syringe has been sterilised using EtO, but the outer surface of the syringe has ⁇ lppm, preferably ⁇ 0.2ppm EtO residue. In one embodiment, the pre-filled syringe has been sterilised using hydrogen peroxide, but the outer surface of the syringe has ⁇ l pm, preferably ⁇ 0.2ppm hydrogen peroxide residue. In another embodiment, the pre-filled syringe has been sterilised using EtO, and the total EtO residue found on the outside of the syringe and inside of the blister pack is ⁇ 0.1mg. In another embodiment, the pre-filled syringe has been sterilised using hydrogen peroxide, and the total hydrogen peroxide residue found on the outside of the syringe and inside of the blister pack is ⁇ 0.1 mg.
• composition comprising X may consist exclusively of X or may include something additional e.g. X + Y.
• references to a percentage sequence identity between two amino acid sequences means that, when aligned, that percentage of amino acids are the same in comparing the two sequences.
• This alignment and the percent homology or sequence identity can be determined using software programs known in the art. for example those described in section 7.7.18 of Current Protocols in Molecular Biology (F.M. Ausubel et al , eds., 1987) Supplement 30.
• a preferred alignment is determined by the Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 2, BLOSUM matrix of 62.
• the Smith- Waterman homology search algorithm is disclosed in Smith & Waterman (1981) Adv. Appl. Math. 2: 482-489
• Figure 1 shows a side view of a syringe
• Figure 2 shows a cross section of a top down view of a syringe
• Figure 3 shows a view of a plunger
• Figure 4 shows a cross section though a plunger
• Figure 5 shows a stopper MODES FOR CARRYING OUT THE INVENTION
• Figure 1 shows a view from a side of a syringe 1 comprising a body 2, plunger 4, backstop 6 and a sealing device 8.
• FIG 2 shows a cross section through the syringe 1 of Figure 1 from above.
• the syringe 1 is suitable for use in an ophthalmic injection.
• the syringe 1 comprises a body 2, a stopper 10 and a plunger 4.
• the syringe 1 extends along a first axis A.
• the body 2 comprises an outlet 12 at an outlet end 14 and the stopper 10 is arranged within the body 2 such that a front surface 16 of the stopper 10 and the body 2 define a variable volume chamber 18.
• the variable volume chamber 18 contains an injectable medicament 20 comprising an ophthalmic solution comprising a VEGF antagonist such as ranibizumab.
• the injectable fluid 20 can be expelled though the outlet 12 by movement of the stopper 10 towards the outlet end 14 thereby reducing the volume of the variable volume chamber 18.
• the plunger 4 comprises a plunger contact surface 22 at a first end 24 and a rod 26 extending between the plunger contact surface 22 and a rear portion 25.
• the plunger contact surface 22 is arranged to contact the stopper 10, such that the plunger 4 can be used to move the stopper 10 towards the outlet end 14 of the body 2. Such movement reduces the volume of the variable volume chamber 18 and causes fluid therein to be expelled though the outlet.
• the backstop 6 is attached to the body 2 by coupling to a terminal flange 28 of the body 2.
• the backstop 6 includes sandwich portion 30 which is adapted to substantially sandwich at least some of the terminal flange 28 of the body 2.
• the backstop 6 is adapted to be coupled to the body 2 from the side by leaving one side of the backstop 6 open so that the backstop 6 can be fitted to the syringe 2.
• the body 2 defines a substantially cylindrical bore 36 which has a bore radius.
• the rod 26 comprises a rod shoulder 32 directed away from the outlet end 14.
• the rod shoulder 32 extends from to a rod shoulder radius from the first axis A which is such that it is slightly less than the bore radius so that the shoulder fits within the bore 36.
• the backstop 6 includes a backstop shoulder 34 directed towards the outlet end 14.
• the shoulders 32, 34 arc configured to cooperate to substantially prevent movement of the rod 26 away from the outlet end 14 when the backstop shoulder 34 and rod shoulder 32 are in contact.
• the backstop shoulder 34 extends from outside the bore radius to a radius less than the rod shoulder radius so that the rod shoulder 32 cannot pass the backstop shoulder 34 by moving along the first axis A.
• the rod shoulder 32 is substantially disc, or ring, shaped and the backstop shoulder 34 includes an arc around a rear end 38 of the body 2.
• the backstop 6 also includes two linger projections 40 which extend in opposite directions away from the body 2 substantially perpendicular to the first axis A to facilitate manual handling of the syringe 1 during use.
• the syringe comprises a 0.5ml body 2 filled with between about 0.1 and 0.3 ml of an injectable medicament 20 comprising a lOmg ml injectable solution comprising ranibizumab.
• the syringe body 2 has an internal diameter of about between about 4.5mm and 4.8mm, a length of between about 45mm and 50mm.
• Figure 3 shows a perspective view of the plunger 4 of Figure 1 showing the plunger contact surface 22 at the first end 24 of the plunger 4.
• the rod 26 extends from the first end 24 to the rear portion 25.
• the rear portion 25 includes a disc shaped flange 42 to facilitate user handling of the device.
• the flange 42 provides a larger surface area for contact by the user than a bare end of the rod 26.
• Figure 4 shows a cross section though a syringe body 2 and rod 26.
• the rod 26 includes four longitudinal ribs 44 and the angle between the ribs is 90°.
• Figure 5 shows a detailed view of a stopper 10 showing a conical shaped front surface 16 and three circumferential ribs 52,54,56 around a substantially cylindrical body 58.
• the axial gap between the first rib 52 and the last rib 56 is about 3mm.
• the rear surface 60 of the stopper 10 includes a substantially central recess 62.
• the central recess 62 includes an initial bore 64 having a first diameter.
• 0.5ml syringes siliconised with ⁇ 100 ⁇ ig silicone oil, filled with Lucentis, comprising one of two different stopper designs were tested for maximal and average break out and slide force. Prior to testing, 30G x 0.5" needles were attached to the syringes. The testing was carried out at a stopper speed of 190mm/min over a travel length of 10.9mm. Stopper design 2 had a 45% increase in the distance between the front circumferential rib and rear circumferential rib. Stopper design 1 Stopper design 2

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Engineering & Computer Science (AREA)
• Heart & Thoracic Surgery (AREA)
• Vascular Medicine (AREA)
• Biomedical Technology (AREA)
• Hematology (AREA)
• Anesthesiology (AREA)
• Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Ophthalmology & Optometry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Dermatology (AREA)
• Immunology (AREA)
• Zoology (AREA)
• Cell Biology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Gastroenterology & Hepatology (AREA)
• Diabetes (AREA)
• Cardiology (AREA)
• Urology & Nephrology (AREA)
• Infusion, Injection, And Reservoir Apparatuses (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Medical Preparation Storing Or Oral Administration Devices (AREA)
• Materials For Medical Uses (AREA)
• Peptides Or Proteins (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (37)

Applications Claiming Priority (22)

Related Child Applications (3)

Publications (1)

Family

ID=48051683

Family Applications (1)

Country Status (39)

Cited By (32)

Families Citing this family (53)

Citations (4)

Family Cites Families (82)

• 2012
  • 2012-07-03 JO JOP/2020/0175A patent/JOP20200175A1/ar unknown
• 2013
  • 2013-01-23 DE DE201320000688 patent/DE202013000688U1/de not_active Expired - Lifetime
  • 2013-01-24 JO JOP/2013/0026A patent/JO3655B1/ar active
  • 2013-01-25 KR KR1020237000676A patent/KR20230013282A/ko not_active Ceased
  • 2013-01-25 EA EA201590139A patent/EA031583B1/ru not_active IP Right Cessation
  • 2013-01-25 CN CN201380035900.3A patent/CN104427972A/zh active Pending
  • 2013-01-25 AR ARP130100235 patent/AR090059A1/es not_active Application Discontinuation
  • 2013-01-25 DK DK20159408.2T patent/DK3685826T3/da active
  • 2013-01-25 SI SI201331357T patent/SI2869813T1/sl unknown
  • 2013-01-25 PL PL19210117T patent/PL3656373T3/pl unknown
  • 2013-01-25 HR HRP20220535TT patent/HRP20220535T1/hr unknown
  • 2013-01-25 ES ES19210117T patent/ES2912848T3/es active Active
  • 2013-01-25 LT LTEP19210117.8T patent/LT3656373T/lt unknown
  • 2013-01-25 WO PCT/EP2013/051491 patent/WO2014005728A1/en not_active Ceased
  • 2013-01-25 EP EP18162017.0A patent/EP3381444B1/en active Active
  • 2013-01-25 CN CN201910358417.8A patent/CN110115657A/zh active Pending
  • 2013-01-25 US US13/750,352 patent/US9220631B2/en active Active
  • 2013-01-25 BR BR122020020290-4A patent/BR122020020290B1/pt active IP Right Grant
  • 2013-01-25 HU HUE18162017A patent/HUE055227T2/hu unknown
  • 2013-01-25 KR KR1020217041316A patent/KR102395557B1/ko active Active
  • 2013-01-25 LT LTEP13701276.1T patent/LT2869813T/lt unknown
  • 2013-01-25 HR HRP20190300TT patent/HRP20190300T1/hr unknown
  • 2013-01-25 KR KR1020227031067A patent/KR102487296B1/ko active Active
  • 2013-01-25 PL PL20159408T patent/PL3685826T3/pl unknown
  • 2013-01-25 CA CA2803566A patent/CA2803566A1/en not_active Abandoned
  • 2013-01-25 KR KR1020147036866A patent/KR102092427B1/ko active Active
  • 2013-01-25 EP EP20159408.2A patent/EP3685826B1/en active Active
  • 2013-01-25 CH CH00298/13A patent/CH706741B1/de unknown
  • 2013-01-25 ES ES20159408T patent/ES2906812T3/es active Active
  • 2013-01-25 KR KR1020217028012A patent/KR102341670B1/ko active Active
  • 2013-01-25 SG SG11201408261UA patent/SG11201408261UA/en unknown
  • 2013-01-25 SI SI201331917T patent/SI3381444T1/sl unknown
  • 2013-01-25 EP EP13701276.1A patent/EP2869813B1/en not_active Revoked
  • 2013-01-25 FR FR1350671A patent/FR2983077B1/fr not_active Revoked
  • 2013-01-25 PE PE2014002573A patent/PE20150196A1/es not_active Application Discontinuation
  • 2013-01-25 PL PL13701276T patent/PL2869813T3/pl unknown
  • 2013-01-25 DK DK13701276.1T patent/DK2869813T3/en active
  • 2013-01-25 CN CN202110166906.0A patent/CN112972828A/zh active Pending
  • 2013-01-25 EP EP19210117.8A patent/EP3656373B1/en active Active
  • 2013-01-25 PT PT13701276T patent/PT2869813T/pt unknown
  • 2013-01-25 MA MA37740A patent/MA37740B2/fr unknown
  • 2013-01-25 ES ES18162017T patent/ES2882254T3/es active Active
  • 2013-01-25 MX MX2014015743A patent/MX358323B/es active IP Right Grant
  • 2013-01-25 DK DK18162017.0T patent/DK3381444T3/da active
  • 2013-01-25 BR BR112014032990-7A patent/BR112014032990B1/pt active IP Right Grant
  • 2013-01-25 MY MYPI2014003426A patent/MY164536A/en unknown
  • 2013-01-25 HU HUE20159408A patent/HUE057746T2/hu unknown
  • 2013-01-25 HU HUE13701276A patent/HUE042652T2/hu unknown
  • 2013-01-25 LT LTEP20159408.2T patent/LT3685826T/lt unknown
  • 2013-01-25 SI SI201331979T patent/SI3656373T1/sl unknown
  • 2013-01-25 CN CN202010134846.XA patent/CN111249062A/zh active Pending
  • 2013-01-25 EP EP18202752.4A patent/EP3470058A1/en active Pending
  • 2013-01-25 AU AU2013201624A patent/AU2013201624A1/en not_active Abandoned
  • 2013-01-25 HR HRP20220083TT patent/HRP20220083T1/hr unknown
  • 2013-01-25 DK DK19210117.8T patent/DK3656373T3/da active
  • 2013-01-25 ES ES13701276T patent/ES2712152T3/es active Active
  • 2013-01-25 NZ NZ702980A patent/NZ702980A/en unknown
  • 2013-01-25 PL PL18162017T patent/PL3381444T3/pl unknown
  • 2013-01-25 JP JP2013012497A patent/JP5744927B2/ja active Active
  • 2013-01-25 SI SI201331963T patent/SI3685826T1/sl unknown
  • 2013-01-25 KR KR1020227014971A patent/KR102443606B1/ko active Active
  • 2013-01-25 KR KR1020207006794A patent/KR102299177B1/ko active Active
  • 2013-01-25 LT LTEP18162017.0T patent/LT3381444T/lt unknown
  • 2013-01-25 TW TW102103005A patent/TWI632920B/zh active
  • 2013-12-25 JP JP2013266737A patent/JP6313038B2/ja active Active
• 2014
  • 2014-12-11 PH PH12014502785A patent/PH12014502785B1/en unknown
  • 2014-12-11 ZA ZA2014/09411A patent/ZA201409411B/en unknown
  • 2014-12-12 TN TN2014000517A patent/TN2014000517A1/fr unknown
  • 2014-12-15 IL IL236296A patent/IL236296B/en active IP Right Grant
  • 2014-12-18 CO CO14278405A patent/CO7151483A2/es unknown
  • 2014-12-29 GT GT201400300A patent/GT201400300A/es unknown
  • 2014-12-31 CL CL2014003619A patent/CL2014003619A1/es unknown
• 2015
  • 2015-02-03 EC ECIEPI20154005A patent/ECSP15004005A/es unknown
• 2019
  • 2019-02-21 CY CY20191100225T patent/CY1121497T1/el unknown
• 2020
  • 2020-02-26 IL IL272915A patent/IL272915B/en active IP Right Grant
• 2021
  • 2021-07-27 HR HRP20211216TT patent/HRP20211216T1/hr unknown
  • 2021-08-12 CY CY20211100725T patent/CY1124431T1/el unknown

Patent Citations (4)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events