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WO2023153535A1 - Seringue contenant une formulation ophtalmique - Google Patents

Seringue contenant une formulation ophtalmique Download PDF

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Publication number
WO2023153535A1
WO2023153535A1 PCT/KR2022/002006 KR2022002006W WO2023153535A1 WO 2023153535 A1 WO2023153535 A1 WO 2023153535A1 KR 2022002006 W KR2022002006 W KR 2022002006W WO 2023153535 A1 WO2023153535 A1 WO 2023153535A1
Authority
WO
WIPO (PCT)
Prior art keywords
syringe
stopper
plunger
ophthalmic
insertion fixing
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.)
Ceased
Application number
PCT/KR2022/002006
Other languages
English (en)
Korean (ko)
Inventor
하병집
유창훈
최경원
이상욱
김동규
정재인
김선진
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sam Chun Dang Pharm Co Ltd
Original Assignee
Sam Chun Dang Pharm Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sam Chun Dang Pharm Co Ltd filed Critical Sam Chun Dang Pharm Co Ltd
Priority to PCT/KR2022/002006 priority Critical patent/WO2023153535A1/fr
Publication of WO2023153535A1 publication Critical patent/WO2023153535A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • 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
    • A61M5/315—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to a syringe containing an ophthalmic dosage form, and more particularly, to a pre-filled syringe filled with an ophthalmic dosage form containing aflibercept as an active ingredient.
  • VEGF vascular endothelial growth factor
  • VEGF is known to activate VEGF receptors (VEGFR-1, VEGFR-2, VEGFR-3), which are membrane-spanning tyrosine kinase receptors.
  • VEGFR-1 and VEGFR-2 have seven Ig-like sequences, a single transmembrane region, and a consensus tyrosine kinase region in their extracellular region for VEGF binding. This property is used as a sequence for a VEGF antagonist (anti-VEGF agent), and ophthalmic treatment
  • Aflibercept combines the second binding domain of VEGFR-1 and the third binding domain of VEGFR-2 with the Fc region of human IgG1. It is a soluble decoy receptor of about 115 kDa (including glycosylation).
  • Aflibercept is a recombinant fusion protein composed of VEGF binding sites derived from the extracellular domains of human vascular endothelial growth factor (VEGF) receptors 1 and 2 fused to the Fc part of human IgG1 immunoglobulin. am. Aflibercept has been approved in the US and Europe for the treatment of wet macular degeneration under the trade name Eylea TM . Abnormal angiogenesis in the mechanism through VEGF is an ophthalmic disease such as wet age-related macular degeneration, diabetic macular edema, and macular edema in retinal vein edema. It is known to be related to occlusion).
  • VEGF vascular endothelial growth factor
  • Protein-containing pharmaceutical compositions undergo physicochemical denaturation under less than optimal conditions.
  • factors such as protein concentration, type of buffer, type and concentration of stabilizer, type and concentration of organic co-solvent, concentration of salt, pH, temperature, contact with air, etc. affect protein oxidation and deamidation. It has significant effects on deamidation, isomerization, and polymerization.
  • denaturation may reduce physiological activity by generating protein aggregation, fragments, and isomers.
  • protein aggregation is a major intrinsic factor in forming insoluble particulates, and may cause side effects such as an immune response.
  • the standard for insoluble particulates must be maintained more strictly.
  • ophthalmic formulations containing aflibercept, a recombinant fusion protein composed of a VEGF binding site have been actively developed, but conventional formulations have a problem in that the stabilizing effect of aflibercept is reduced under harsh conditions.
  • sterilization can present difficulties not necessarily associated with larger syringes. Changes in pressure inside or outside the syringe can cause parts of the syringe to move unpredictably, which can change sealing properties and potentially harm sterilization. In addition, incorrect handling, including assembly of syringes, can jeopardize product sterilization.
  • a fusion protein such as aflibercept is not only stable for a long time under storage conditions, but also has improved stability even under harsh conditions, and a liquid formulation that can safely deliver the formulation to the eye, and is a commercially available ophthalmic syringe
  • the present invention has been completed by developing a syringe that has more improved properties and allows the drug to stably exist during the storage period.
  • the present invention provides a syringe filled with an ophthalmic formulation containing aflibercept as an active ingredient and containing a predetermined amount of silicone oil on the inner circumferential surface of the body.
  • an object of the present invention is a body 2 provided with an outlet 12 at an outlet end 14;
  • the plunger 4 includes a plunger rod 26 extending in the longitudinal direction, a flange portion 22 located at an end 24 adjacent to the stopper 10 on the plunger rod 26, and the flange portion. It includes a spherical or screw-shaped insertion fixing part 23 protruding from (22) toward the stopper 10,
  • the stopper 10 is provided with an insertion fixing groove 62 into which the insertion fixing part 23 is inserted and fixed.
  • the body 2 includes a body portion 3, and silicone oil is applied to a region 3c of an inner circumferential surface of the body portion 3,
  • the ophthalmic formulation comprises, in an aqueous medium, (a) a therapeutically effective amount of aflibercept; (b) stabilizers; (c) surfactants; And (d) an ionic isotonizing agent; to provide a syringe that includes, and has a pH of 5.2 to 6.2.
  • another object of the present invention is a container body 71 provided with a receiving part 72 molded to accommodate the syringe 1 containing the ophthalmic formulation; a fixing part 75 protruding to fix a part of the syringe accommodated in the accommodating part 72; It is to provide a syringe blister pack (7) including a sealing portion (73) to which a sealing film (74) can be attached.
  • Another object of the present invention is to provide a method for filling the syringe with an ophthalmic formulation.
  • the present invention body (2) provided with an outlet (12) at the outlet end (14);
  • the plunger 4 includes a plunger rod 41 extending in the longitudinal direction, a flange portion 22 positioned at an end 24 adjacent to the stopper 10 on the plunger rod 26, and the flange portion. It includes a spherical or screw-shaped insertion fixing part 23 protruding from (22) toward the stopper 10,
  • the stopper 10 is provided with an insertion fixing groove 62 into which the insertion fixing part 23 is inserted and fixed.
  • the body 2 includes a body portion 3, and silicone oil is applied to a region 3c of an inner circumferential surface of the body portion 3,
  • the ophthalmic formulation comprises (a) a therapeutically effective amount of 10 to 100 mg/ml of aflibercept; (b) 2 to 10 w/v % of a stabilizer; (c) 0.01 to 0.1 w/v% of a surfactant; and (d) 5 to 100 mM of an ionic tonicity agent; It provides a syringe that includes, and has a pH of 5.2 to 6.2.
  • the syringe of the present invention is for use in administering an ophthalmic formulation to a patient with an ophthalmic disease, which includes age-related macular degeneration (AMD), visual impairment due to diabetic macular edema (DME), and retinal vein occlusion (branching). visual impairment due to secondary macular edema of RVO or central RVO), diabetic retinopathy in patients with diabetic macular edema, or visual impairment due to choroidal neovascularization (CNV) secondary to pathologic myopia.
  • AMD age-related macular degeneration
  • DME diabetic macular edema
  • CNV choroidal neovascularization
  • the syringe of the present invention includes a body 2 provided with an outlet 12 at an outlet end 14; a plunger (4) located inside the body (2); and a front surface 16 located at the front of the plunger 4 inside the body 2 and forming a variable volume chamber 18 with the body 2 to move the plunger 4 and a stopper 10 for discharging the ophthalmic formulation 20 filled in the variable volume chamber 18 by the outlet 12, and the plunger 4 includes a plunger rod extending in the longitudinal direction ( 41), a flange portion 22 located at the end 24 adjacent to the stopper 10 in the plunger rod 41, and a spherical or protruding from the flange portion 22 toward the stopper 10 It includes an insertion fixing part 23 in the form of a screw, and may be provided with an insertion fixing groove 62 into which the insertion fixing part 23 is pressed into the stopper 10 or inserted and fixed by screwing.
  • (2) includes the body portion 3 and includes a silicone film 29 formed by applying silicone oil to the region 3c of the
  • the screw shape means a screw shape in which the surface partially protrudes, and specifically, it may mean that the screw thread includes a screw coupling protrusion forming a spiral shape.
  • the screw thread includes a screw coupling protrusion forming a spiral shape.
  • it may mean the same shape as the insertion fixing part 63a including a screw protrusion in the right picture of FIG. 7 .
  • the insertion fixing groove 62 of the stopper 10 may have a screw hole 63 to be screwed so that the screw-shaped insertion fixing part 23 and the stopper 10 can be coupled by screwing.
  • the threaded hole 63 screwed serves as a female screw.
  • the screw-type insertion fixing part 23 is represented by an insertion fixing part 63a including a screw-engineering protrusion.
  • the spherical shape means that it does not have a protruding surface such as a screw coupling protrusion unlike the screw shape and has a smooth shape
  • the bore of the insertion fixing groove 62 (64) may have a lower end (64a) having a similar or identical size and shape and an upper end (65a) having a similar or identical size and shape to the inner fixing groove (65).
  • the plunger and the stopper are coupled by coupling the insertion fixing part 23 to the insertion fixing groove 62 of the stopper 10 by press-fitting or screwing, so that the plunger and the stopper is integrated so that the stopper is retractable and does not distort in an unpredictable way, does not compromise the sealing and/or sterilization of the final product, and provides stable storage and proper delivery of the ophthalmic formulation without leaking or contamination of the ophthalmic formulation.
  • the body 2 may be a substantially cylindrical shell or may include a substantially cylindrical bore having a non-circular external shape.
  • the outlet end 14 of the body 2 includes an outlet 12 through which the ophthalmic formulation 20 stored in the variable volume chamber 18 can be released when the volume of the variable volume chamber 18 is reduced.
  • the outlet 12 may include a protrusion from the outlet end 14 through which a channel having a smaller diameter than the diameter of the variable volume chamber 18 extends.
  • the outlet 12 may be configured to connect to a needle or other accessory, such as a sealing device, for example by a luer lock type connection, which seals the variable volume chamber but can be manipulated or removed to close the variable chamber.
  • the body 2 extends along a first axis A from the outlet end 14 to the rear portion 25 .
  • the body 2 includes a body portion 3, and the body portion 3 may include a region 3a of an outer circumferential surface of the body portion and a thick body portion 3b.
  • the wall thickness of the thick body portion 3b may be 1.0 to 2.0 mm, preferably 1.2 to 1.8 mm, more preferably 1.45 to 1.65 mm, and most preferably 1.525 ⁇ 0.1 mm.
  • the effect of sterilizing the outer surface of the syringe body with gas can be minimized. Moreover, it has sufficient advantages in that it minimizes denaturation reactions such as oxidation of the active ingredients in the chemical solution filled in the syringe body and can easily mold it.
  • the length of the body 2 may be 55 to 75 mm, preferably 60 to 70 mm, more preferably 62 to 66 mm, and most preferably 64.4 ⁇ 0.2 mm.
  • the length of the variable volume chamber 18 may be 45 to 60 mm, preferably 50 to 58 mm, more preferably 52 to 56 mm, and most preferably 53.85 ⁇ 0.2 mm.
  • the body 2 may be made from a plastic material or from glass or from any other suitable material and may include an indicator on its surface which serves as an injection guide.
  • the plastic material may be, for example, a cycloolefin polymer (COP) or a cycloolefin copolymer (COC).
  • COP material is used.
  • the stopper 10 may have a stopper body 58 made of rubber, silicone or other suitable elastic and deformable material. According to one embodiment of the present invention, chlorinated butyl rubber was used.
  • the stopper 10 provides a sealing function by forming a seal at the rear of the variable volume chamber 18 that does not leak the ophthalmic formulation 20 filled in the variable volume chamber 18 .
  • the stopper 10 may be substantially cylindrical, the stopper may include one or more ribs 50, 51 around the outer surface of the stopper, and the stopper 10 and the ribs 50, 51 may be ribs. It can contact the inner surface of the syringe body to form a substantially leaktight seal.
  • the front surface 16 of the stopper may have any suitable shape and may be flat or conical, preferably conical.
  • the stopper 10 may include an insertion fixing groove 62, and the insert fixing groove 62 may have any shape as long as it does not harm the sealing function of the stopper.
  • the insertion locking groove 62 may be cylindrical, or the insertion locking groove 62 may include a bore 64 having a first diameter, the bore 64 extending from the rear surface 60 inside the stopper to a length It leads to an internal fixing groove 65 having a second diameter running in a direction, the second diameter being larger than the first diameter and may be conical.
  • the insertion fixing groove 62 may have a screw hole 63 to be screwed.
  • the threaded hole 63 screwed here serves as a female screw.
  • the stopper and the plunger may be coupled.
  • the insertion fixing part 23 includes a spherical shape or a screw shape, and may be specifically a screw (or screw) shape or a spherical shape.
  • the spherical insertion fixing part 23 can be strongly fixed to the stopper by the spherical protrusion of the insertion fixing part 23 while being inserted into the insertion fixing groove 62 of the stopper having elasticity by press-fitting (FIG.
  • the insertion fixing portion 63a including a screw-type screw protrusion can be strongly fixed to the stopper while being inserted in a screw-type manner with the screw hole 63 serving as a female screw (FIG. 7).
  • removing material from the central portion of the stopper reduces the weight of the stopper and reduces the amount of material required to manufacture the stopper, while reducing the insertion fixture (23) of the plunger. ) can be inserted into the insertion fixing groove 62 of the stopper and coupled.
  • the plunger 4 includes a flange portion 22 and includes a plunger rod 41 extending from the flange portion 22 to the rear portion 25 .
  • the rear portion 25 may include a disk-shaped flange 42 that is a user-contacting portion adapted to be in contact with the user while the formulation filled in the syringe is being injected.
  • the disk-shaped flange 42 may include a disk-shaped portion, and the radius of the disk extends perpendicular to the axis along which the rod extends, but the user contact portion may have various other suitable shapes other than the disk shape.
  • An axis along which the plunger rod 41 extends may be the first axis A, and may be substantially parallel to the first axis.
  • the flange portion 22 is located at an end adjacent to the stopper 10 and may have a structure capable of coupling with the stopper 10 .
  • a spherical or screw-type insertion fixing part 23 protruding from the central portion of the flange portion 22 toward the stopper, the insertion fixing part 23 is pressed into the insertion fixing groove 62 of the stopper.
  • the plunger 4 and the stopper 10 are coupled by being inserted by a fitting action, or the insertion fixing part 23 is coupled and inserted into the screw hole 63 of the insertion fixing groove 62 of the stopper in a screwing manner.
  • the plunger 4 and the stopper 10 may be coupled, and the coupled form is as shown in FIGS. 7 and 8 (right side of FIGS.
  • the flange portion 22 may have a circular shape with an outer diameter smaller than the inner diameter of the body 2 .
  • the diameter of the flange portion 22 may be the same as the diameter of the rear surface 60 of the stopper in contact with the flange portion 22 .
  • the flange portion 22 may be rotationally symmetrical to the rear surface 60 of the stopper.
  • the plunger rod 41 may have a circular, H-shaped or cross-shaped cross section.
  • the H-shaped cross section may be formed from the plunger rib 43 around the plunger rod 41 as shown in FIG. 6 .
  • the plunger rib 43 may extend substantially parallel to the axis along which the plunger rod 41 extends, and the H-shaped cross section may provide rigidity to the plunger rod 41 without increasing manufacturing complexity.
  • the plunger rod 41 may be made of plastic such as cycloolefin polymer (COP) and cycloolefin copolymer (COC), preferably made of cycloolefin polymer (COP).
  • COP cycloolefin polymer
  • COC cycloolefin copolymer
  • the plunger rod 41 may be substantially rigid under expected conditions of use.
  • the syringe may include a finger grip portion 6 arranged at the rear portion 25 of the body.
  • the finger grip portion 6 may be removable from the syringe. If the body 2 of the syringe includes a distal flange 28 at the end opposite the outlet end 14, the finger grip portion 6 is such that the distal flange 28 of the body is sandwiched with the sandwich portion 30. It can be configured to be, which can prevent the movement of the finger grip portion 6 in a direction parallel to the first axis (A).
  • the finger grip portion 6 may be attached to the body 2 by coupling to the distal flange 28 of the body 2, wherein at least a portion of the distal flange 28 of the body 2 is substantially sandwiched. It may include a sandwich portion 30 adapted to be possible (FIG. 10).
  • the finger grip portion 6 is perpendicular to the first axis A and includes two finger protrusions 40 extending in opposite directions away from the body 2 to facilitate the use and handling of the syringe 1 can do.
  • the syringe may be sterilized using terminal sterilization methods, which may utilize known methods such as ethylene oxide or steam hydrogen peroxide sterilization methods.
  • Such a sterilization process has a problem in that the air bubbles generated in the filling process expand under reduced pressure accompanying the sterilization process, resulting in a change in the volume of the syringe.
  • the combination of the stopper and the plunger according to the present invention has the advantage of being able to more accurately control the volume change at the intended position, thereby preventing problems such as unexpected sterilization breakage.
  • Including one or more circumferential ribs 50, 51 on the stopper 10 can change the force required to move the stopper from a rest position and can change the sealing properties of the stopper.
  • the stopper may serve to protect the injectable medicament (ophthalmic formulation) during the terminal sterilization process. Since some medicines, such as biopharmaceuticals, can be damaged by exposure to a sterilizing agent such as ethylene oxide, the rib of the stopper can reduce this exposure and protect the medicine filled in the syringe. By adjusting the number of the ribs and the distance between the ribs, exposure and damage caused by the sterilant may be reduced.
  • the sealing part 8 is composed of an upper part 81 and a lower part 82, the lower part may have a smaller diameter than the diameter of the upper part, and the lower part 82 has a central recessed part 83, which is an empty space.
  • the outlet 12 provided at the outlet end 14 of the body 2 may be inserted into the recessed portion 83, and the distal end of the outlet contacts the protruding portion 84 to seal the formulation 20 filled in the syringe. ) can be prevented from leaking out from the outlet 12.
  • the lower end 83 is a portion that can be coupled to the body 2 and includes a screw shape, so that it can be sealed by screwing. Accordingly, a portion of the body 2 coupled to the lower end may also include a screw shape.
  • the upper end 81 of the sealing part 8 is a part that the user contacts to release the sealing by coupling the lower end and the body, and may have a repeatedly protruding shape at regular intervals to prevent slipping (Fig. 9).
  • the syringe is suitable for ophthalmic injection and thus has a suitably small volume.
  • the syringe may be adapted for ophthalmic injection.
  • the syringe may include silicone oil, and specifically, may include a silicone film 29 formed by applying silicone oil to the region 3c of the inner circumferential surface of the body portion, which is the inner wall of the body.
  • the stopper of the present invention may contain silicone oil.
  • including silicone oil may mean that the surface of the stopper is coated with silicone oil.
  • the silicon film is about 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.2 mg, 1.4 mg, and 1.5 mg of silicon with respect to the area 3c of the inner circumferential surface of the body. may have been applied. More specifically, the silicone oil may be applied at approximately 0.3 to 1.5 mg, 0.4 to 1.4 mg, more preferably 0.5 to 1.3 mg, and still more preferably 0.6 to 1.2 mg. .
  • the drug solution is minimized from being denatured by contact with the area 3c of the inner circumferential surface of the body or affecting the efficacy of the drug, while suppressing glare in the area of the inner circumferential surface of the body, while providing sufficient sliding properties. It is possible to smoothly move the stopper by giving.
  • the syringe of the present invention is an ophthalmic syringe wherein the variable volume chamber 18 is filled with an injectable ophthalmic dosage form and the outlet can be reversibly sealed.
  • variable volume chamber of the syringe may be filled with any suitable injectable liquid or medicament, for example, it may be filled with an injectable medicament.
  • the variable volume chamber has an inside diameter greater than 5 mm or 6 mm and less than 3 mm or 4 mm.
  • the inner diameter may be between 3 mm and 6 mm, or between 4 mm and 5 mm.
  • the volume of the liquid formulation that can be filled in the variable volume chamber is about 0.05 ml to about 1 ml, preferably about 0.1 ml to about 0.5 ml, more preferably 0.14 ml to 0.3 ml, most preferably 0.15 ml. to 0.2 ml.
  • the volume actually administered to the patient is 0.01 ml to 1 ml, preferably 0.02 to 0.5 ml, more preferably 0.025 to 0.3 ml, even more preferably 0.03 ml to 0.1 ml.
  • FIGS. 1 to 3 The syringe of the present invention is shown in FIGS. 1 to 3, the plunger is shown in FIGS. 4 to 6, the stopper is shown in FIGS. 7 and 8, the sealing part is shown in FIG. 9, and the finger grip part is shown in FIG. 10.
  • the present invention provides a blister pack containing a pre-filled syringe.
  • the container body 71 equipped with a housing portion 72 shaped to accommodate a pre-filled syringe; a fixing part 75 protruding inward to fix a part of the syringe accommodated in the accommodating part 72; and a sealing portion 73 to which a sealing film 74 can be attached.
  • the pre-filled syringe may include a body, a stopper, and a plunger, and may include a liquid medicine in a volume chamber formed by the body and the stopper.
  • the body may include an outlet capable of discharging the filled medicament, the plunger may be in contact with or coupled to the stopper in the form of a long rod, and the discharge of the medicament capable of pushing the filled medicament into the outlet may be performed. It may be due to the movement of the plunger to which the stopper is contacted or coupled.
  • Syringes are not limited thereto and may include all types of syringes commonly used in the field.
  • the drug may include an ophthalmic formulation, more preferably may include a VEGF-antagonist liquid formulation, and more preferably may include an afliberceptor liquid formulation, but the scope of the drug is not limited thereto, and may include a wide range of general liquid formulations that can be administered by syringe.
  • the prefilled syringe contains a drug in the form of a fluid, it is necessary to prevent the plunger from retracting or advancing in the longitudinal direction of the syringe during transport, movement or sterilization.
  • the prefilled syringe is fixed and stored, and the space in which the syringe can be accommodated is designed according to the length of the syringe, so that the plunger does not retreat or advance even during the sterilization process under reduced pressure, and the plunger does not advance, and plays a role in preventing breakage.
  • a blister pack for packaging prefilled syringes that can be used has been implemented.
  • the present invention is a container body 71 provided with a receiving portion 72 molded to accommodate the syringe 1 containing the ophthalmic dosage form; a fixing part 75 protruding inward to fix a part of the syringe accommodated in the accommodating part 72; and a sealing portion 73 to which a sealing film 74 can be attached.
  • Syringe 1 containing the ophthalmic dosage form is as described above.
  • a syringe filled with an ophthalmic formulation may be packaged in a blister pack 7 .
  • the blaster pack 7 includes a container body 71 having an accommodating part 72 molded so that the syringe can be fixed and accommodated inside the container body 71, and a seal adhered to the sealing part 73.
  • a film 74 is included.
  • the sealing part 73 is a surface to which one surface of the sealing film 74 can be attached and may include an adhesive. It can be sealed by bonding the sealing part 73 and the sealing film 74, and the sealing can be peeled off.
  • the container body 71 includes the fixing part 75, the fixing part 75 includes a first fixing part 75a and a second fixing part 75b, and is formed to accommodate a syringe. It has an accommodating part 72 including a space, and the accommodating part 72 is separated by the fixing part 75 to form a first accommodating part 72a, a second accommodating part 72b, and a third accommodating part. (72c) is formed, and an upper portion of the syringe including the sealing portion 8 of the syringe is stored in the first accommodating portion 72a, and the finger grip portion 6 and the plunger of the syringe are stored in the accommodating portion 72c The rear part of 4) can be accommodated.
  • the container body 71 includes a fixing part 75 that serves to fix the syringe and is molded to fit the diameter of the syringe so that a part of the stored syringe can be fitted and fixed.
  • the fixing part 75 includes a first fixing part 75a and a second fixing part 75b.
  • the syringe is accommodated in the storage unit, and a part of the body 2 is fitted and fixed by the fixing unit 75.
  • the fixing part 75 protrudes toward the inside of the container body so that a part of the body 2 of the syringe can be fixed in a tightening manner by the fixing part 75, and the fixing part 75 acts as a buffer to It is also possible to prevent damage to the syringe stored in the blister pack from external shock or fall.
  • the plunger 4 of the syringe stored inside the container body 71
  • the distance between the disc-shaped flange 42, which is the rear part, and the wall of the third accommodating part 72c facing the disc-shaped flange 42 is 2 mm, 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm, 0.05 mm, 0.01 mm or less, preferably a disk-shaped flange 42 and a third receiving portion facing the disk-shaped flange 42 ( The walls of 72c) may be in contact with each other. Accordingly, the syringe is prevented from moving in the longitudinal direction or the plunger is retracted and moved in the longitudinal direction of the second shaft (B).
  • the container body 71 constituting the blister pack 7 of the present invention is a plastic film or sheet having a degree of hardness that does not collapse in shape in order to fix and hold the accommodated syringe, and the syringe stored in the container body 71 It is preferable to have transparency to the extent that (1) can be confirmed from the outside.
  • the plastic film may be, for example, a plastic film or sheet including polyvinyl chloride (PVC), polyethylene terephthalate (PET), polypropylene (PP), polystyrene, polyethylene, polyester, polypropylene, and the like, preferably may be polyethylene terephthalate (PET).
  • the sealing film 74 is adhered to the sealing portion 73 to the extent that it can be peeled off from the sealing portion 73 included in the container body 71, such as paper, aluminum film, plastic film, plastic sheet, or plastic nonwoven fabric. may be used, and preferably may be a high-density polyethylene (HDPE) film. In one embodiment of the present invention, TYVEK ® 1073B product was used as the sealing film 74 .
  • HDPE high-density polyethylene
  • the stored syringe is accommodated in the form of floating in the air, so that it can prevent damage due to impact such as vibration during fall and transportation, and the storage unit 72 is the syringe in the direction of the second axis (B). It is designed to fit the length of the syringe and limits the movement of the syringe in the direction of the second axis (B)
  • the blister pack can be sterilized using steam hydrogen peroxide or ethylene oxide gas inside the blister pack.
  • the blister pack of the present invention has the advantage of being able to prevent the stopper from retracting while expanding under reduced pressure conditions accompanying a hydrogen peroxide sterilization process or an ethylene oxide gas sterilization process.
  • a blister pack of the syringe of the present invention may be shown as in FIG. 11 .
  • the stopper of the present invention can be aseptically installed by an automatic filling machine after the ophthalmic formulation is filled in the variable volume chamber.
  • the method of filling the ophthalmic dosage form in the syringe of the present invention comprises: 1) preparing the ophthalmic dosage form of claim 1; 2) bactericidal filtering the prepared ophthalmic formulation; 3) aseptically filling the sterile-filtered formulation into a variable volume chamber of a syringe using a pump of an automatic filling machine; 4) Aseptically mounting the stopper by an automatic filling machine; and 5) coupling the stopper with the plunger.
  • the ophthalmic formulation of the present invention can be filled into the variable volume chamber of a syringe.
  • the ophthalmic formulation according to the present invention has a formulation most suitable for use in the above-mentioned syringe conditions.
  • the ophthalmic dosage form according to the present invention maintains the efficacy of the drug even when stored for a long time (in particular, minimizes adsorption or decomposition of active ingredients on the inner wall surface) and secures excellent stability in the syringe. It can exhibit excellent properties when provided with.
  • the ophthalmic formulation comprises, in an aqueous medium, (a) a therapeutically effective amount of aflibercept; (b) stabilizers; (c) surfactants; and (d) an ionic tonicity agent; and may have a pH of 5.2 to 6.2.
  • the ophthalmic formulation comprises (a) a therapeutically effective amount of 10 to 100 mg/ml of aflibercept; (b) 2 to 10 w/v % of a stabilizer; (c) 0.01 to 0.1 w/v% of a surfactant; and (d) 5 to 100 mM of an ionic tonicity agent; Including, it may have a pH of 5.2 to 6.2.
  • aflibercept is a VEGF-specific fusion protein in which VEGF binding sites derived from the extracellular domains of human VEGF receptor 1 and VEGF receptor 2 and the Fc region of human IgG1 are fused.
  • the VEGF-specific fusion protein is a region that essentially includes immunoglobulin-like (Ig) domain 2 of human VEGF receptor 1 (Flt1) and Ig domain 3 of human VEGF receptor 2 (Flt1 or Flt4) and human IgG1
  • Ig immunoglobulin-like domain 2 of human VEGF receptor 1
  • Flt1 or Flt4 human IgG1
  • It is a fusion protein in which the Fc region of is fused, and may be aflibercept having the amino acid sequence of SEQ ID NO: 1 below.
  • amino acid sequence of aflibercept (SEQ ID NO: 1) is as follows:
  • Such aflibercepts may be recombinantly or synthetically produced.
  • excellent stability or “remains stable” may mean that the structure and / or physical, chemical, and / or biological properties of the protein in the composition are maintained during storage (eg, storage low rates of protein duplexes, multimers, polymer formation, low rates of protein aggregation, low rates of protein fragmentation, degradation, and/or low rates of denaturation, etc.).
  • a variety of analytical techniques for measuring the stability of proteins are well known in the art. Proteins show little or no change in aggregation, precipitation and/or denaturation when observed by visual inspection of color and/or clarity, or when measured by UV light scattering (measuring visible aggregates) or size exclusion chromatography (SEC).
  • a formulation can be said to "retain its physical stability” if it does not change at all.
  • the ophthalmic formulation of the present invention may contain aflibercept in an amount of 10 to 100 mg/ml as a therapeutically effective amount, preferably 10 to 50 mg/ml, and more preferably 20 to 50 mg/ml. can do.
  • the ophthalmic formulation may further include a 5 to 20 mM buffer solution, and the concentration of the buffer solution may be preferably 7 to 15 mM, more preferably 8 to 12 mM.
  • a "buffered solution” refers to a buffered solution that resists changes in pH by the action of its acid-base conjugate components.
  • the buffer solution may be an acetate buffer solution, and preferably may include a sodium acetate buffer solution.
  • the aqueous medium includes, without limitation, an aqueous medium capable of providing a buffer solution together with an acetate salt buffer, and includes, for example, distilled water for injection, sterile purified water, and the like.
  • the stabilizer may include sucrose, trehalose, mannitol, glucose, and the like, preferably sucrose.
  • the concentration of the stabilizer may be 2 to 12 w/v%, preferably 3 to 10 w/v%, and more preferably 5 to 8 w/v%.
  • the surfactant may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, etc., and polysorbate 20 may be preferably used.
  • the formulation may include a surfactant at a concentration of 0.01 to 0.1 w/v%, preferably 0.01 to 0.08 w/v%, and more preferably 0.01 to 0.05 w/v%.
  • the ionic tonicity agent is sodium chloride
  • the formulation of the present invention contains 5 to 100 mM, preferably 10 to 50 mM, more preferably 10 to 40 mM of sodium chloride, which is an ionic tonicity agent. concentration can be included.
  • the formulation provided herein may be isotonic with a living body.
  • the formulation may have an osmotic pressure of about 200 mOsm/kg to about 400 mOsm/kg, for example, about 250 mOsm/kg to about 300 mOsm/kg, but the scope of the present invention is not limited thereto, and the osmotic pressure can be controlled by a stabilizer.
  • ophthalmic use according to the present invention (a) about 40 mg/ml of aflibercept in a therapeutically effective amount; (b) about 10 mM sodium acetate buffer; (c) about 6.5 w/v% sucrose; (d) 0.03 w/v% polysorbate 20; and (e) about 15 mM of an ionic tonicity agent of sodium chloride; It may include, and may be 5.4 to 6.0. Specifically, it may be about pH 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 or 6.0.
  • the ophthalmic formulation may be provided in the form of a prefilled syringe.
  • the ophthalmic formulation according to the present invention has excellent self-stability and exhibits an excellent effect of inhibiting formation of aggregates (duplexes, multimers, etc.) and fragments.
  • the invention also provides a kit comprising one or more of the prefilled syringes of the invention.
  • the kit includes a blister pack.
  • the kit may additionally include a needle if the prefilled syringe does not include a stacked-in needle. Kits may further include instructions for use.
  • the syringe containing the ophthalmic dosage form of the present invention has excellent storability and can maintain the efficacy of the drug even when stored for a long period of time. Since the structure of the syringe is also stable, the formulation can be safely delivered to the eye without leakage, and the formulation can be stably present in the syringe during the storage period of the formulation.
  • FIG. 1 is a side view of the syringe of the present invention.
  • FIGS. 2 and 3 are cross-sectional views of the syringe of the present invention.
  • 4 and 5 are views showing the plunger of the present invention.
  • FIG. 6 is a view showing a cross section of a plunger rod.
  • FIG. 7 and 8 are views showing a cross section of the stopper and a cross section in which the plunger and the stopper are coupled.
  • FIG. 10 is a view showing a finger grip part.
  • FIG. 11 is a view showing the front and side views of a blister pack in which a syringe is stored.
  • Example 1 Preparation of an ophthalmic formulation
  • Ophthalmic formulations were prepared according to the ingredients and contents in Table 1 below.
  • the pH of the formulation was adjusted to 5.2 to 6.2 by changing the sodium-acetate ratio of the sodium acetate buffer, and in the case of polysorbate 20, it was added to a content of 0.03% at the end, and as shown in Table 1 below, about 40 mg / A liquid formulation containing ml of aflibercept was prepared.
  • division ingredient content active ingredient aflibercept 40 mg/ml
  • Acetate buffer solution sodium acetate 10 mM stabilizer sucrose 6.5%
  • Surfactants polysorbate 20 0.03%
  • Ionic tonicity agent sodium chloride 15 mM menstruum water balance
  • Example 2 Preparation of syringe formulation filled with ophthalmic dosage form
  • the ophthalmic formulation prepared in Example 1 was sterile filtered using a disposable 0.22 ⁇ m polyethersulfone membrane. Thereafter, it was aseptically filled with a capacity of about 0.17 ml into the variable volume chamber of the syringe according to the present invention using a pump of an automatic filling machine.
  • the above-mentioned syringe used a 1 ml syringe barrel treated with 0.9 ⁇ 0.5 mg of silicone oil in COP material.
  • the wall thickness of the thick body part (3b) of the syringe used was 1.5 ⁇ 0.2 mm, the length of the body was 64.4 ⁇ 2.0 mm, and the length of the variable volume chamber was 54.85 ⁇ 2.0 mm.
  • the insertion fixing part including the screw-type screw protrusion is inserted into the screw hole 63 serving as a female screw and the screwing method, and the stopper and the insertion fixing part are combined so as to be strongly fixed to the stopper. Chlorinated butyl rubber was used as the stopper, and a screw hole was used for the screw connection method.
  • a syringe filled with the ophthalmic formulation of Example 1 (specifically, a formulation having a pH of 5.5 was used) by aseptically mounting a stopper by an automatic filling machine after filling, coupling the stopper and plunger, and mounting a finger grip portion.
  • a formulation was prepared.
  • Example 3 Stability analysis of the syringe formulation of the present invention under refrigerated storage conditions and accelerated storage conditions
  • Example 2 Stability of the syringe formulation prepared in Example 2 (specifically, a formulation having a pH of 5.5 was used) under refrigerated storage conditions (5 ⁇ 3 ° C) and accelerated storage conditions (25 ⁇ 2 ° C / 60 ⁇ 5% RH) To this end, analysis of insoluble particles in each condition, analysis of binding ability to VEGF, evaluation of fragment/dimer/multimer formation, asparagine deamidation analysis, electrophoresis analysis, and biological activity analysis were performed. Here's how.
  • rhVEGF 200 ng/mL of rhVEGF was coated on a plate and then incubated at 4° C. for 18 to 20 hours. After blocking for 1 hour, 1000, 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39, 0.08 ng/mL of standard solution (Eylea) and sample solution were loaded, and at room temperature at 200 rpm for 1 hour reacted 1/10,000 diluted detection antibody (Goat anti-Human IgG Fc Cross Adsorbed Secondary Antibody, HRP conjugate) and TMB substrate solution were sequentially treated and reacted for 1 hour and 30 minutes.
  • standard solution Eylea
  • HRP conjugate Goat anti-Human IgG Fc Cross Adsorbed Secondary Antibody, HRP conjugate
  • Size exclusion chromatography is used to determine the presence and content of various impurities, such as fragments of protein material or higher molecular weight dimers and multimers that may be produced during stability testing.
  • the peak area % of the main peak (monomer) and the peak area % of the measured impurity were obtained, and the analysis conditions of the size exclusion HPLC were as follows:
  • Protein denaturation was performed by performing asparagine deamidation analysis, that is, isoaspartate quantitative analysis for asparagine deamidation, on samples for stability testing stored under refrigerated conditions (2-8°C) and accelerated conditions (25°C). was evaluated. Asparagine deamidation assay was performed using the ISOQUANT Isoasparatate Detection Kit (Promega, Cat. # MA1010) according to the manufacturer's instructions, and the results are summarized in Tables 2 and 3.
  • Biological activity of the ophthalmic formulation included in the syringe of the present invention was evaluated under refrigerated storage conditions and accelerated conditions.
  • umbilical vein endothelial cells (HUVEC, Human Umbilical Vein Endothelial Cell) are treated with Vascular Endothelial Growth Factor (VEGF), the cells proliferate. At this time, an in vitro test was performed to evaluate the degree of cell proliferation inhibition caused by treatment with aflibercept.
  • VEC Human Umbilical Vein Endothelial Cell
  • VEGF Vascular Endothelial Growth Factor
  • rhVEGF165 Promokine, Cat. # C-64420
  • aflibercept was set to have a concentration gradient of 2.4 to 2500 ng/ml, followed by 3 hours at 37°C
  • Cells were treated using a neutralized sample in a humidified 5% CO 2 incubator and cultured for 3 days.
  • alamarBlue Invitrogen Cat. # DAL 1025
  • 590 nm fluorescence was measured to measure the concentration of the drug required for half (50%) inhibition (IC 50 ), and the results are shown in Table 2 and summarized in Table 3.
  • the syringe formulation of the present invention was found to maintain the same physical properties as the initial state even under refrigerated storage conditions and storage conditions for up to 6 months, and there was no significant change in biological activity.
  • the syringe formulation of the present invention was confirmed to have physical properties almost similar to those of the initial period even when stored for a long time under accelerated storage conditions. Although the biological activity was lowered after storage for 6 months compared to the initial period, it was confirmed that the level met the standard for use as a pharmaceutical preparation.
  • the syringe containing the ophthalmic formulation of the present invention does not generate foreign substances even when stored for a long time under refrigerated storage and accelerated storage conditions, and has the advantage of maintaining excellent physical properties as an ophthalmic formulation as in the beginning.
  • the results were maintained without significant change in terms of physical properties such as protein content.
  • a syringe prepared by the method of Example 2 was prepared, and on the other hand, the other components of the syringe were similarly prepared by the method of Example 2, but there was no protrusion at the distal end of the plunger rod, so a syringe in which the stopper and the plunger were not coupled was separately After manufacturing, each of the two products was packaged in a Tyvek sealed blister form.
  • a syringe in a silicone oil-free condition in which silicone oil was not applied to the inner circumferential surface of the body was separately prepared and then packaged in a Tyvek sealed blister form.
  • the distance between the disc-shaped flange 42 and the wall of the third accommodating portion 72c facing the disc-shaped flange was minimized so that the entire syringe including the flange was fixed by the wall.
  • Stopper and plunger rod separate products 4.6 25 Stopper and plunger rod combined type (silicone oil free) product 2.8 0 Stopper and plunger rod combined type (silicone oil coating) product 1.7 0
  • the syringe coupled by the screw fastening method using the insertion fixing part 63a including the screw hole and the screw coupling protrusion minimizes shaking through the strong coupling between the stopper and the plunger, resulting in microbial contamination. showed the strength of minimizing
  • 3 body portion, 3a: area of the outer circumferential surface of the body portion
  • 3b thick body portion
  • 3c region of the inner circumferential surface of the body portion
  • variable volume chamber variable volume chamber
  • 20 ophthalmic formulation
  • insertion fixing portion including a screw coupling protrusion
  • 64 bore having a first diameter
  • 65 inner fixing groove having a second diameter
  • 64a lower end of the spherical insertion fixing part
  • 65a upper end of the spherical insertion fixing part
  • 72 storage unit
  • 72a first storage unit

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Abstract

L'invention concerne une seringue contenant une formulation ophtalmique. Une seringue contenant une formulation ophtalmique, selon la présente invention, présente d'excellentes propriétés de stockage, et peut ainsi conserver l'efficacité du médicament même dans le cas d'un stockage à long terme. La structure de la seringue est également stable, et permet ainsi une administration sûre à l'oeil sans fuite de la formulation, et permet à la formulation d'être stable dans la seringue pendant une période de stockage de ladite formulation.
PCT/KR2022/002006 2022-02-09 2022-02-09 Seringue contenant une formulation ophtalmique Ceased WO2023153535A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/KR2022/002006 WO2023153535A1 (fr) 2022-02-09 2022-02-09 Seringue contenant une formulation ophtalmique

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PCT/KR2022/002006 WO2023153535A1 (fr) 2022-02-09 2022-02-09 Seringue contenant une formulation ophtalmique

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024248292A1 (fr) * 2023-05-31 2024-12-05 Sam Chun Dang Pharm. Co., Ltd. Contenant pour l'emballage d'une seringue préremplie

Citations (5)

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Publication number Priority date Publication date Assignee Title
JP3404109B2 (ja) * 1994-02-24 2003-05-06 第一製薬株式会社 薬液充填済みプラスチック製シリンジ製剤の製造方法
KR100527151B1 (ko) * 1997-11-28 2005-11-09 세이가가쿠 고교 가부시키가이샤 의약 멸균 포장을 위한 멸균 방법 및 주사 팩
KR101406811B1 (ko) * 2006-06-16 2014-06-12 리제너론 파마슈티칼스 인코포레이티드 유리체내 투여에 적당한 ｖｅｇｆ 길항제 제형
KR20150021924A (ko) * 2012-06-01 2015-03-03 노파르티스 아게 시린지
KR20170030631A (ko) * 2014-07-18 2017-03-17 사노피 암을 앓고 있는 것으로 의심되는 환자를 아플리베르셉트로 치료한 결과를 예측하는 방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3404109B2 (ja) * 1994-02-24 2003-05-06 第一製薬株式会社 薬液充填済みプラスチック製シリンジ製剤の製造方法
KR100527151B1 (ko) * 1997-11-28 2005-11-09 세이가가쿠 고교 가부시키가이샤 의약 멸균 포장을 위한 멸균 방법 및 주사 팩
KR101406811B1 (ko) * 2006-06-16 2014-06-12 리제너론 파마슈티칼스 인코포레이티드 유리체내 투여에 적당한 ｖｅｇｆ 길항제 제형
KR20150021924A (ko) * 2012-06-01 2015-03-03 노파르티스 아게 시린지
KR20170030631A (ko) * 2014-07-18 2017-03-17 사노피 암을 앓고 있는 것으로 의심되는 환자를 아플리베르셉트로 치료한 결과를 예측하는 방법

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024248292A1 (fr) * 2023-05-31 2024-12-05 Sam Chun Dang Pharm. Co., Ltd. Contenant pour l'emballage d'une seringue préremplie

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