WO2015027219A2 - Appareils et procédés destinés à la distribution d'une ou plusieurs substances à partir d'un contenant unique - Google Patents

Appareils et procédés destinés à la distribution d'une ou plusieurs substances à partir d'un contenant unique Download PDF

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Publication number
WO2015027219A2
WO2015027219A2 PCT/US2014/052400 US2014052400W WO2015027219A2 WO 2015027219 A2 WO2015027219 A2 WO 2015027219A2 US 2014052400 W US2014052400 W US 2014052400W WO 2015027219 A2 WO2015027219 A2 WO 2015027219A2
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WO
WIPO (PCT)
Prior art keywords
substance
container
pathway
port
needle
Prior art date
Application number
PCT/US2014/052400
Other languages
English (en)
Other versions
WO2015027219A3 (fr
Inventor
Richard Lewis BECKMAN
Douglas K. KOLLMORGEN
Keith WESTBY
Original Assignee
Ophthotech Corporation
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 Ophthotech Corporation filed Critical Ophthotech Corporation
Publication of WO2015027219A2 publication Critical patent/WO2015027219A2/fr
Publication of WO2015027219A3 publication Critical patent/WO2015027219A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0026—Sprayable compositions
    • 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
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/20—Gaseous substances, e.g. vapours
    • A61L2/206—Ethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/26—Accessories or devices or components used for biocidal treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
    • A61L2202/10—Apparatus features
    • A61L2202/12—Apparatus for isolating biocidal substances from the environment
    • A61L2202/121—Sealings, e.g. doors, covers, valves, sluices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • 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
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body

Definitions

  • Certain portions of the body are susceptible to complications associated with injections.
  • complications can result from infection, and can include, for example, endophthalmitis, spondylodiscitis, septic arthritis, epidural abscess, necrotizing fasciitis, osteomyelitis, gas gangrene, albicans arthritis, and/or the like.
  • the target tissue can be susceptible to perforation and tearing, and/or can have limited wound- healing ability.
  • the tympanic membrane of the ear can be particularly susceptible to complications arising from injection.
  • injections into portions of the eye, such as the sclera can be more likely to result in microbial growth and/or tissue trauma than injection into other portions of the body such as skin and muscle tissue.
  • intravitreal administration of medicaments raises even further complications: excess fluid in the eye can result in an undesirable elevation of intraocular pressures.
  • the embodiments described herein relate to medicament delivery apparatus and methods. More particularly, the embodiments described herein relate to medicament delivery apparatus and methods useful for delivering one or more medications in a single operation.
  • an apparatus comprises a housing having a coupling portion and an access portion.
  • the access portion defines a guide opening.
  • the coupling portion is configured to be removably coupled to a syringe (e.g., a prefilled or prefillable syringe) such that the guide opening is aligned with an exit lumen defined by a tip of the syringe.
  • the apparatus also comprises a septum coupled to the housing.
  • the septum includes a first seal portion and a second seal portion.
  • the first seal portion is substantially planar, and is configured to define a substantially fluid-tight seal with a distal-end surface of the tip of the syringe.
  • the second seal portion is configured to define a substantially fluid- tight seal with a sidewall of the tip.
  • an apparatus comprises a housing including a coupling portion and an access portion.
  • the access portion defines a guide opening.
  • the coupling portion is configured to be removably coupled to a syringe such that the guide opening is aligned with an exit lumen defined by a tip of the syringe.
  • the housing defines one or more sterilization openings.
  • the apparatus further comprises a septum coupled to the housing.
  • the septum includes a seal portion configured to define a substantially fluid-tight seal with a distal-end surface of the tip of the syringe.
  • the apparatus further comprises a cover removably coupled to the access portion of the housing about the guide opening. The cover and the housing define a seal that is resistant to particulate penetration.
  • a method comprises inserting a first needle of a first container into a guide opening defined by a cap such that the first needle is substantially aligned with an exit lumen defined by a tip of a second container.
  • the cap is removably coupled to the second container.
  • the first container contains a first substance
  • the second container contains a second substance.
  • the method further comprises piercing a septum portion of the cap with the first needle such that a distal end portion of the first needle is placed in fluid communication with the exit lumen.
  • the method also comprises conveying the first substance from the first container into the second container via the first needle. The cap is removed from the second container.
  • an apparatus comprises an elastomeric member including a contact surface, a sealing surface and a retention portion.
  • the elastomeric member is configured to be disposed within a syringe (e.g., a prefifled or prefil!ab!e syringe) such that the retention portion and a. sidewall of the syringe define a substantially fluid-tight seal.
  • the apparatus also comprises a retainer configured to engage a portion of the syringe and the retention portion of the elastomeric member to maintain the elastomeric member in a first position within the syringe.
  • the contact surface of the elastomeric member is outside of the syringe when the elastomeric member is in the first position.
  • the elastomeric member is movable from the first position to a second position when the retainer is spaced apart from the retention portion of the elastomeric member.
  • a method comprises inserting a first needle of a first container into a retention portion of an elastomeric member disposed in a first position within a second container such that the first needle is placed in fluid communication with the second container.
  • a contact surface of the elastomeric member is outside of the second container when the elastomeric member is in the first position.
  • the first container contains a first substance and the second container contains a second substance.
  • the method also comprises conveying the first substance from the first container into the second container via the first needle.
  • the method further comprises moving the elastomeric member from the first position to a second position within the second container.
  • the contact surface is inside the second container when the elastomeric member is in the second position.
  • the method additionally comprises conveying, in a single operation, the first substance and the second substance from the second container via a second needle.
  • an apparatus comprises an elastomeric member including a contact surface, a sealing surface and a retention portion.
  • the elastomeric member is configured to be disposed within a syringe such that the sealing surface and a. sidewall of the syringe define a substantially fluid-tight seal.
  • the apparatus further comprises a retainer configured to engage a portion of the syringe and the retention portion of the elastomeric member to maintain the elastomeric member in a. first position within the syringe.
  • the contact surface of the elastomeric member is outside of the syringe when the elastomeric member is in the first position.
  • the elastomeric member is movable from the first position to a second position when the retainer is spaced apart from the retention portion of the elastomeric member.
  • an apparatus comprises an elastomeric member including a transfer portion and a sealing surface.
  • the elastomeric member is configured to be disposed within a medicament container such that the sealing surface and a sidewall of the medicament container define a substantially fluid-tight seal.
  • the transfer portion is configured to be moved between a first configuration and a second configuration.
  • the transfer portion is configured to be pierced by a needle to facilitate transfer of a substance into the medicament container when the transfer portion is in the first configuration.
  • the transfer portion is configured to receive a piston rod to move the elastomeric member between a first position and a second position within the medicament container.
  • the transfer portion is configured to receive the piston rod when the transfer member is in the second configuration.
  • a method of preparing one or more substances for delivery comprises coupling a first container to a first port of an adapter.
  • the first container contains a first substance including a platelet-derived growth factor (PGDF) antagonist.
  • the method further comprises coupling a second container to a second port of the adapter. At least a portion of the first substance is transferred from the first container to a pathway defined by the adapter, the pathway in fluid communication with the first port and the second port.
  • the method further comprises transferring the portion of the first substance from the pathway to one of the first container or the second container.
  • PGDF platelet-derived growth factor
  • an apparatus comprises a housing including a first port configured to be coupled to a first container containing a first substance, a second port configured to be coupled a second container containing a second substance, and a third port configured to be coupled to a needle.
  • the housing defines a first flow pathway, a second flow pathway and a third flow pathway.
  • the first flow pathway is in fluid communication with the first port
  • the second flow pathway is in fluid communication with the second port
  • the third flow pathway is in fluid communication with the third port.
  • the apparatus further includes a valve configured to selectively place the first pathway in fluid communication with one of the second pathway or the third pathway, the valve configured to selectively place the second pathway in fluid communication with one of the first pathway or the third pathway.
  • a method comprises coupling, to a first port of a housing of an apparatus, a first container containing a first substance, and coupling, to a second port of the housing, a second container.
  • a first pathway of the housing is selectively placed in fluid communication with a second pathway of the housing.
  • the first pathway is in fluid communication with the first port, and the second pathway is in fluid communication with the second port.
  • the method further comprises transferring at least a portion of the first substance to the second container via the first pathway and the second pathway.
  • a kit comprises a first container containing a first substance, the first substance including a platelet-derived growth factor (PGDF) antagonist.
  • the kit further comprises a second container containing a second substance, the second substance including a vascular endothelial growt factor (VEGF) antagonist.
  • the kit further comprises a mixing apparatus configured to couple to the first container and the second container to permit mixing of the first substance and the second substance.
  • PGDF platelet-derived growth factor
  • VEGF vascular endothelial growt factor
  • FIG, 1 is a cross-sectional schematic view of a cap assembly, according to an embodiment.
  • FIG. 2A is front view of a medicament container assembly, according to an embodiment.
  • FIG. 2B is a cross-sectional view of the container assembly shown in FIG. 2A taken along line X-X,
  • FIG. 2C is a top view of a medicament container assembly, according to an embodiment.
  • FIG. 3 is a flow chart of a method of conveying at least one medicament, according to an embodiment.
  • FIG. 4 is a cross-section schematic of a portion of a medicament delivery device, according to an embodiment.
  • FIG. 5 is a flow chart of a method of conveying at least one medicament, according to an embodiment.
  • FIGS. 6A-6C are schematic illustrations of the method of FIG. 5.
  • FIG, 7 is a schematic illustration of a medicament deliver ⁇ ? device, according to an embodiment.
  • FIGS. 8A-8E are schematic illustrations of a medicament delivery device in various stage of operation, according to an embodiment.
  • FIG. 9 is a schematic illustration of an assembly for mixing two or more substances using a mixing adapter, according to an embodiment.
  • FIG. 10 is a flow chart of a method of mixing two or more substances for delivery, according to an embodiment.
  • FIGS. 11 A-11B are schematic illustrations of a mixing apparatus during use, according to an embodiment.
  • FIG. 12 is a flo chart of another method of mixing two or more substances for delivery, according to an embodiment.
  • the embodiments described herein are useful for storing or administering to a mammal one or more, in some embodiments two or more, in some embodiments three or more, active agents.
  • the mammal is diagnosed with a disease or disorder, or diagnosed to be at risk of developing a disease or disorder, e.g., due to a genetic predisposition to develop the disease or disorder or due to the occurrence of an event, such as a surgery, associated with the disease or disorder.
  • the disease or disorder is an ophthalmological disease or disorder, including but not limited to those described herein.
  • the active agent is a pharmaceutically active agent, e.g., a drug, such as but not limited to a.
  • the one or more, or two or more, or three or more, active agents may be present in a composition, e.g., a pharmaceutical composition.
  • each active agent is present in a separate pharmaceutical composition.
  • at least one active agent is present in a separate pharmaceutical composition.
  • an active agent, a substance, and/or a mixture as disclosed herein includes a pharmaceutical composition.
  • the pharmaceutical composition comprises a pharmaceutically active agent and a pharmaceutically acceptable carrier or vehicle.
  • delivery of the active agent, the substance, the mixture and/or the pharmaceutical composition includes administration to a mammal, e.g., a human.
  • the administration is intravitreal
  • the kit further can further includes instructions for use with a mixing apparatus and/or a mixing adapter of the invention.
  • an apparatus comprises a housing and a septum.
  • the housing includes a coupling portion and an access portion.
  • the coupling portion is configured to be removably coupled to a medicament container, such as, for example, a prefilled or prefillable syringe.
  • the access portion defines a guide opening that is aligned with an exit lumen defined by a tip of the medicament container.
  • a sidewall of the access portion defining the guide opening is tapered.
  • the septum is coupled to the housing and can define a substantially fluid-tight seal with a distal- end surface of the tip.
  • the apparatus further comprises a cover removably coupled to the access portion of the housing, such that the cover and the housing define a seal that is resistant to particulate penetration.
  • the term "particulate" can refer to any undesirable entity including biological agents such as a virus and bacterium, chemical contaminant, dust, and/or the like.
  • the cover is a flexible layer formulated to allow a sterilant gas, such as, for example, ethylene oxide or water in the form of steam, to pass therethrough.
  • the septum includes a first seal portion and a second seal portion.
  • the first seal portion is substantially planar and configured to define a substantially fluid-tight seal with a distal-end surface of the tip of the medicament container.
  • the first seal portion includes a target portion aligned with the guide opening.
  • the second seal portion is configured to define a substantially fluid-tight seal with a sidewall of the tip. In this manner, the contents of the medicament container can be sealed therein when the housing (and therefore the septum) is coupled to the medicament container.
  • the housing defines at least one sterilization opening. In some embodiments, the housing defines a plurality of sterilization openings.
  • an apparatus comprises a housing and a septum.
  • the housing has a coupling portion and an access portion.
  • the access portion defines a guide opening.
  • the coupling portion is configured to be removably coupled to a syringe (e.g., a prefixed or prefillable syringe) such that the guide opening is aligned with an exit lumen defined by a tip of the syringe.
  • the housing also defines a plurality of sterilization openings through which a sterilant gas, such as, for example, ethylene oxide, can be conveyed.
  • the septum is coupled to the housing and includes a seal portion configured to define a substantially fluid-tight seal with a distal-end surface of the tip of the syringe.
  • the apparatus also comprises a cover removably coupled to the access portion of the housing about the guide opening, the cover and the housing defining a seal that is resistant to particulate penetration.
  • the cover is constructed from a material formulated to allow a sterilant gas to pass therethrough.
  • yet another apparatus comprises an eiastomeric member including a contact surface, a sealing surface and a retention portion.
  • the eiastomeric member is configured to be disposed within a prefilled or prefillable syringe such that the sealing portion and a sidewall of the syringe define a substantially fluid-tight seal
  • the apparatus also comprises a retainer configured to engage a portion of the syringe and the retention portion of the elastoineric member to maintain the plunger in a first position within the syringe.
  • the contact surface of the eiastomeric member is outside of the syringe when the elastomenc member is in the first position.
  • the elastomenc member is movable from the first position to a second position when the retainer is spaced apart, from the retention portion of the elastomenc member.
  • the contact portion of the elastomeric member is configured to receive a rod or other substantially rigid member configured to transmit a force to the elastomeric member to move the elastomeric member within the prefilled or prefillabie syringe.
  • the contact portion can define a recess or opening within which a rod can be disposed.
  • the contact surface includes a sterile target portion
  • the retainer includes a cover portion that is configured to cover the sterile target portion when the retainer in contact with the prefilled or prefillabie syringe and the retention portion of the elastomeric member.
  • the retainer includes a frangible portion that is configured to deform when the retainer is removed from the syringe and the retention portion of the elastomeric member. In this manner, the sterile target portion can be exposed to allow entry of one or needles without the need for additional sterilization at the point of delivery (e.g. via wiping with isopropyl alcohol or the like).
  • the cover and/or the frangible portion are constructed from a material that allows a sterilant gas to pass therethrough.
  • an apparatus comprises an elastomeric member.
  • the elastomeric member includes a transfer portion and a sealing surface, and is configured to be disposed within a medicament container (e.g., a prefilled or prefillabie syringe) such that the sealing surface and a sidewall of the medicament container define a substantially fluid-tight seal.
  • the transfer portion is configured to be moved between a first configuration and a second configuration.
  • the transfer portion is configured to be pierceable by one or more lancets and/or needles to facilitate transfer of one or more substances into and/or out of the medicament container when the transfer portion is in the first configuration.
  • the transfer portion is configured to receive a piston rod to move the elastomeric member between a first position and a second position within the medicament container.
  • the transfer portion is configured to receive the piston rod when the transfer member is in the second configuration.
  • a method of intra itreal injection comprises inserting a first needle of a first container into a guide opening defined by a cap such that, the first needle is substantially aligned with an exit lumen defined by a tip of a second container, where the cap is removably coupled to the second container.
  • the method optionally comprises removing, before the inserting, a cover to expose the guide opening.
  • the first container can contain a first substance, while the second container can contain a second substance.
  • the first substance and the second substance can be any suitable substances that are conveyable via a needle, such as a fluid, which can encompass a liquid, and which can particularly encompass an aqueous composition comprising a pharmaceutically active agent.
  • the first substance and the second substance are independently a vascular endothelial growth factor (VEGF) antagonist, a platelet-derived growth factor (PGDF) antagonist, or an anti-C5 agent.
  • one of the first substance and the second substance includes a vascular endothelial growth factor (VEGF) antagonist
  • the other of the first substance and the second substance includes a platelet-derived growth factor (PGDF) antagonist.
  • the first substance and the second substance are independently two or more of a vascular endothelial growth factor (VEGF) antagonist, a platelet-derived growth factor (PGDF) antagonist, or an anti-C5 agent.
  • VEGF vascular endothelial growth factor
  • PGDF platelet-derived growth factor
  • one of the first substance and the second substance includes a vascular endothelial growth tactor (VEGF) antagonist as well as a platelet-derived growth tactor (PGDF) antagonist
  • the other of the first substance and the second substance includes an anti-C5 agent.
  • one of the first substance and the second substance includes a vascular endothelial growth tactor (VEGF) antagonist as well as an anti-C5 agent, and the other of the first substance and the second substance includes a platelet-derived growth factor (PGDF) antagonist.
  • VEGF vascular endothelial growth tactor
  • PGDF platelet-derived growth factor
  • one of the first substance and the second substance includes a platelet-derived growth factor (PGDF) antagonist as well as an anti-C5 agent
  • the other of the first substance and the second substance includes a vascular endothelial growt factor (VEGF) antagonist as well as an anti-C5 agent.
  • one of the first substance and the second substance includes a platelet-derived growth factor (PGDF) antagonist as well as a vascular endothelial growth factor (VEGF) antagonist, and the other of the first substance and the second substance includes a platelet-derived growth factor (PGDF) antagonist as well as an anti-C5 agent.
  • one of the first substance and the second substance includes a platelet-derived growth factor (PGDF) antagonist, a vascular endothelial growth factor (VEGF) antagonist, as well as an anii-C5 agent, and the other of the first substance and the second substance includes an anii-C5 agent.
  • the method further comprises piercing a septum portion of the cap with the first needle such that a distal end portion of the first needle is placed in fluid communication with the exit lumen.
  • the method also comprises conveying the first substance from the first container into the second container via the first needle. In this manner, the second container includes both the first substance and the second substance.
  • conveying the first substance includes conveying a predetermined amount of the first substance.
  • the predetermined amount can be based on at least one of the following: an amount of the second substance in the second container; a volume of the exit lumen of the first container; a volume of the exit lumen of the second container; a volume of the first needle: a volume of the second needle and/or any other non- conveyable amount of the second substance that is contained within the second container.
  • the predetermined amount is from about 50 microliters to about 75 microliters.
  • the cap is removable from the second container.
  • the method further comprises coupling a second needle to the tip of the second container and conveying, in a single operation, the first substance and the second substance from the second container via a second needle.
  • the first substance and the second substance can be conveyed, for example, into the eye, for example, into the vitreous of the eye.
  • another method of intravitreai injection comprises inserting a first needle of a first container into a guide opening defined by a cap such that the first needle is substantially aligned with an exit lumen defined by a tip of a second container, where the cap is removably coupled to the second container.
  • the method optionally comprises removing, before the inserting, a cover to expose the guide opening.
  • the first container can contain a first substance, while the second container can contain a second substance.
  • the method further comprises piercing a septum portion of the cap with the first needle such that a distal end portion of the first needle is placed in fluid communication with the exit lumen.
  • the method also comprises conveying the first substance from the first container into the second container via the first needle.
  • the second container includes both the first substance and the second substance.
  • the method additionally includes inserting a third needle of a third container into the guide opening defined by the cap such that the third needle is substantially aligned with the exit lumen defined by the tip of the second container.
  • the method optionally comprises removing, before the inserting, the cover to expose the guide opening.
  • the third container can contain a third substance, while the second container now contains the first substance and the second substance.
  • the method further comprises piercing the same septum portion of the cap as was pierced with the first needle, or piercing another septum portion of the cap, such that a distai end portion of the third needle is placed in fluid communication with the exit lumen.
  • the method also comprises conveying the third substance from the third container into the second container via the third needle. In this manner, the second container includes the first substance, the second substance, and the third substance.
  • the first substance, the second substance, and the third substance can be any- suitable substances that are conveyable via a needle, such as a fluid, which can encompass a liquid, and which can particularly encompass an aqueous composition comprising a pharmaceutically active agent.
  • the first substance, the second substance, and the third substance are independently a vascular endothelial growth factor (VEGF) antagonist, a platelet-derived growth factor (PGDF) antagonist, or an anti-C5 agent.
  • VEGF vascular endothelial growth factor
  • PGDF platelet-derived growth factor
  • one of the first substance, the second substance, and the third substance includes a vascular endothelial growth factor (VEGF) antagonist, another of the first substance, the second substance, and the third substance includes a platelet-derived growth factor (PGDF) antagonist, and yet another of the first substance, the second substance, and the third substance includes an anii-C5 agent.
  • VEGF vascular endothelial growth factor
  • PGDF platelet-derived growth factor
  • conveying the third substance includes conveying a predetermined amount of the first substance.
  • the predetermined amount can be based on at least one of the following: an amount of the second substance in the second container; a volume of the exit lumen of the third container; a volume of the exit lumen of the second container; a volume of the third needle: a volume of the second needle and/or any other non- conveyabfc amount of the second substance that is contained within the second container.
  • the predetermined amount is from about 50 microliters to about 75 microliters.
  • the method further comprises coupling a second needle to the tip of the second container and conveying, in a single operation, the first substance, the second substance, and the third substance from the second container via a second needle.
  • the first substance, the second substance, and the third substance can be conveyed, for example, into the eye, for example, into the vitreous of the eye.
  • another method comprises inserting a first needle of a first container into septum portion of an elastomeric member disposed in a. first position within a second container such that the first needle is placed in fluid communication with the second container.
  • the first container contains a first substance
  • the second container contains a second substance.
  • the second container can be, for example a prefilled syringe containing the second substance.
  • the first substance and the second substance are independently a vascular endothelial growth factor (VEGF) antagonist, a platelet-derived growth factor (PGDF) antagonist, or an ant.i-C5 agent.
  • one of the first substance and the second substance comprises a vascular endothelial growth factor (VEGF) antagonist and the other of the first substance and the second substance comprises a platelet- derived growth factor (PGDF) antagonist.
  • VEGF vascular endothelial growth factor
  • PGDF platelet-derived growth factor
  • the inserting comprises inserting the first needle via a contact surface of the elastomeric member.
  • the contact surface of the elastomeric member can be outside of the second container when the elastomeric member is in the first position. In this manner, the contact surface is accessible to allow sterilization thereof and/or access by the first needle.
  • the method further comprises sterilizing the contact surface before the inserting.
  • the method further comprises removing, before the inserting, a cover to expose the contact surface, which has been pre- sterilized.
  • the inserting includes inserting the first needle via a guide opening defined by the contact surface.
  • the method also comprises conveying the first substance from the first container into the second container via the first needle.
  • the second container contains both the first substance and the second substance.
  • the elastomeric member is movable from the first position to a second position within the second container.
  • the contact surface is inside the second container when the elastomeric member is in the second position.
  • the method also comprises conveying, in a single operation, the first substance and the second substance from the second container via a second needle.
  • another method comprises inserting a first needle of a first container into septum portion of an elastomeric member disposed in a first position within a second container such that the first needle is placed in fluid communication with the second container.
  • the first container contains a first substance
  • the second container contains a second substance.
  • the second container can be, for example a prefilied syringe containing the second substance.
  • the inserting comprises inserting the first needle via a contact surface of the elastomeric member.
  • the contact surface of the elastomeric member can be outside of the second container when the elastomeric member is in the first position. In this manner, the contact surface is accessible to allow sterilization thereof and'Or access by the first needle.
  • the method further comprises sterilizing the contact surface before the inserting.
  • the method further comprises removing, before the inserting, a cover to expose the contact surface, which has been pre- sterilized.
  • the inserting includes inserting the first needle via a guide opening defined by the contact surface.
  • the method also comprises conveying the first substance from the first container into the second container via the first needle. In this manner, the second container contains both the first substance and the second substance.
  • the method further comprises inserting a third needle of a third container into the septum portion of the elastomeric member disposed in the first position within the second container such that the third needle is placed in fluid communication with the second container.
  • the third container contains a third substance.
  • the inserting the third needle comprises inserting the needle via the contact surface of the elastomeric member. In some embodiments, the method further comprises sterilizing and/or resterilizing the contact surface before the inserting the third needle. In other embodiments, the method further comprises removing, before the inserting, the cover to expose the contact surface. In some embodiments, the inserting the third needle includes inserting the third needle via the same guide opening used for inserting the first needle, or another guide opening defined by the contact surface. [1062] The method also comprises conveying the third substance from the third container into the second container via the third needle. In this manner, the second container contains the first substance, the second substance, and the third substance.
  • the elastomeric member is movable from the first position to a second position within the second container.
  • the contact surface is inside the second container when the elastomeric member is in the second position.
  • the method also comprises conveying, in a single operation, the first substance, the second substance, and the third substance from the second container via a second needle,
  • the first substance, the second substance, and the third substance can be any suitable substances thai are conveyabie via a needle, such as a fluid, which can encompass a liquid, and which can particularly encompass an aqueous composition comprising a pharmaceutically active agent.
  • the first substance, the second substance, and the third substance are independently a vascular endothelial growth factor (VEGF) antagonist, a platelet-derived growth factor (PGDF) antagonist, or an anti-C5 agent.
  • VEGF vascular endothelial growth factor
  • PGDF platelet-derived growth factor
  • one of the first substance, the second substance, and the third substance includes a vascular endothelial growth factor (VEGF) antagonist, another of the first substance, the second substance, and the third substance includes a platelet-derived growth factor (PGDF) antagonist, and yet another of the first substance, the second substance, and the third substance includes an anti-C5 agent.
  • VEGF vascular endothelial growth factor
  • PGDF platelet-derived growth factor
  • a method of preparing one or more substances for delivery comprises coupling a. first container to a first port of an adapter.
  • the first container contains a first substance including a platelet-derived growth factor (PGDF) antagonist.
  • the method further comprises coupling a second container to a second port of the adapter. At feast a portion of the first substance is transferred from the first container to a pathway defined by the adapter, the pathway in fluid communication with the first port and the second port.
  • the method further comprises transferring the portion of the first substance from the pathway to one of the first container or the second container.
  • PGDF platelet-derived growth factor
  • an apparatus comprises a housing including a first port configured to be coupled to a first container containing a first substance, a second port configured to be coupled a second container containing a second substance, and a third port configured to be coupled to a needle.
  • the housing defines a first flow pathway, a second flow pathway and a. third flow pathway.
  • the first flow pathway is in fluid communication with the first port
  • the second flo pathway is in fluid communication with the second port
  • the third flow pathway is in fluid communication with the third port.
  • the apparatus further includes a valve configured to selectively place the first pathway in fluid communication with one of the second pathway or the third pathway, the valve configured to selectively place the second pathway in fluid communication with one of the first pathway or the third pathway.
  • a method comprises coupling, to a first port of a housing of an apparatus, a first container containing a first substance, and coupling, to a second port of the housing, a second container, A first pathway of the housing is selectively placed in fluid communication with a second pathway of the housing. The first pathway is in fluid communication with the first port, and the second pathway is in fluid communication with the second port. The method further comprises transferring at least a portion of the first substance to the second container via. the first pathway and the second pathway.
  • a kit comprises a first container containing a first substance, the first substance including a platelet-derived growth factor (PGDF) antagonist.
  • the kit further comprises a second container containing a second substance, the second substance including a vascular endothelial growth factor (VEGF) antagonist.
  • the kit further comprises a mixing apparatus configured to couple to the first container and the second container to permit mixing of the first substance and the second substance
  • amino acid refers to natural or unnatural or synthetic amino acids, including glycine and both the D and L optical isomers, amino acid analogs and peptidomimetics.
  • angiogenesis refers to formation of new blood vessels in normal or in abnormal tissue or positions.
  • antagonist refers to an agent that inhibits, either partially or fully, the activity or production of a target molecule.
  • the term “antagonist,” as applied selectively herein, means an agent capable of decreasing levels of gene expression, mRNA levels, protein levels or protein activity of the target molecule.
  • Illustrative forms of antagonists include, for example, proteins, polypeptides, peptides (such as cyclic peptides), antibodies or antibody fragments, peptide mimetics, nucleic acid molecules, antisense molecules, ribozymes, aptamers, RNAi molecules, and small organic molecules.
  • Illustrative non-limiting mechanisms of antagonist inhibition include repression of one or both of iigand synthesis and stability (e.g., using, antisense, ribozymes or RNAi compositions targeting the Iigand gene/nucleic acid ), blocking of binding of the Iigand to its cognate receptor (e.g., using anti-ligand aptamers, antibodies, anti-receptor antibodies, or a soluble, decoy cognate receptor or fragment thereof!, repression of one or both of receptor synthesis and stability (e.g., using antisense, ribozymes or RNAi compositions targeting the iigand receptor gene/nucleic acid), blocking of the binding of the receptor to its cognate response element (e.g., using anti-receptor antibodies) and blocking of the activation of the receptor by its cognate Iigand (e.g., using receptor tyrosine kinase inhibitors).
  • the antagonist may directly or indirectly inhibit the target molecule.
  • an “antibody” includes whole antibodies and any antigen binding fragment or a single chain thereof.
  • the term “antibody” includes any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule having biological activity of binding to the antigen. Examples of such may comprise a complementarity determining region (CDR) of a heavy or light chain or a Iigand binding portion thereof, a. heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework (FR) region, or any portion thereof, or at least one portion of a binding protein.
  • CDR complementarity determining region
  • Antibodies include monoclonal antibodies and polyclonal antibodies,
  • antibody fragment includes a portion of an antibody that is an antigen binding fragment or single chains thereof.
  • An antibody fragment can be a synthetically or genetically engineered polypeptide.
  • binding fragments encompassed within the term "antigen-binding portion" of an antibody include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, L and CHI domains, (ii) a F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fd fragment consisting of the VH and Cm domains, (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al, (1989) Nature 341 544-546), which consists of a V H domain, and (vi) an isolated complementarity determining region (CDR).
  • CDR complementarity determining region
  • the two domains of the Fv fragment, VL and V H are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv), see e.g.. Bird et al. (1988) Science 242 423-426, and Huston et al. (1988) Proc Natl Acad Sci USA 85 5879-5883), Such single chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" of an antibody. These antibody fragments are obtained using conventional techniques known to those in the art, and the fragments can be screened for utility in the same manner as whole antibodies.
  • aptamer refers to a peptide or nucleic acid thai has an inhibitory effect on a target. Inhibition of the target by the aptamer can occur by binding of the target, by catalytically altering the target, by reacting with the target in a way which modifies the target or the functional activity of the target, by ionicaily or covalently attaching to the target as in a suicide inhibitor or by facilitating the reaction between the target and another molecule.
  • Aptamers can be peptides, ribonucleotides, deoxyribonucleotides, other nucleic acids or a mixture of the different types of nucleic acids.
  • Aptamers can comprise one or more modified amino acid, bases, sugars, polyethylene glycol spacers or phosphate backbone units as described in further detail herein.
  • Aptamers can be pegylated or unpegyiated.
  • one or more polyethylene glycol chains can be linked to the 5' end of a nucleic acid aptamer via a linker.
  • compositions can comprise an active agent and a carrier, inert or active.
  • the compositions are useful for diagnostic or therapeutic use in vitro, in vivo or ex vivo.
  • the compositions are sterile, substantially free of endotoxins or nontoxic to recipients at the dosage or concentration employed.
  • a composition comprises an active agent and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the term "effective amount" when used in connection with an active agent refers to an amount of the active agent, e.g., a PDGF antagonist, a VEGF antagonist or an anti-C5 agent, alone or in combination with another active agent, that is useful to treat or prevent an ophthalmological disease or disorder.
  • the "effective amount” can vary depending upon the mode of administration, specific locus of the ophthalmological disease or disorder, the age, body weight, and general health of the subject.
  • the effective amount of two or more active agents is the combined amount of the active agents that is useful for treating or preventing an ophthalmological disease or disorder, even if the amount of one of the agents, in the absence of one or more of the other agents, is ineffective to treat or prevent the ophthalmological disease or disorder.
  • the term "excipient” refers to a typically inert substance that is commonly used as a diluent, vehicle, preservative, binder, or stabilizing agent for active agents and includes, but is not limited to, proteins (e.g., serum albumin, etc.), amino acids (e.g., aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, alanine, etc.), fatty acids and phospholipids (e.g., alkyl sulfonates, caprylate, etc.), surfactants (e.g., SDS, polysorbate, nonionic surfactant, etc.), saccharides (e.g., sucrose, maltose, trehalose, etc.) and polyols (e.g., mannitol, sorbitol, etc.).
  • proteins e.g., serum albumin, etc.
  • amino acids e.g., aspartic acid, gluta
  • the excipient(s) imparts a beneficial physical property to the composition, such as increased protein, polynucleotide, aptamer or small molecule stability, increased protein, polynucleotide aptamer or small molecule solubility, or decreased viscosity.
  • the compositions comprise a plurality of active agents, and the excipient(s) help stabilize the active agents.
  • mammal includes human and non-human mammals, such as, e.g., a human, mouse, rat, rabbit, monkey, cow, hog, sheep, horse, dog, and cat.
  • neovascularization refers to new blood vessel formation in abnormal tissue or in abnormal positions.
  • nucleic acid refers to a polynucleotide such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA).
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • analogs of RNA or DNA made from nucleotide analogs, and, as applicable to the embodiment being described, single (sense or antisense) and double-stranded polynucleotides, expressed sequence tags (ESTs), chromosomes, cDNAs, mRNAs, and rRNAs.
  • ESTs expressed sequence tags
  • Nucleic acids include modified forms of nucleic acids that deviate structurally from naturally occurring nucleic acid structures based on the standard building blocks (adenosine, cytidine, guanosine, thymidine and uridine). Modifications may be to the backbone, sugar or nucleobase and can be naturally occurring or artificially introduced. For example, nucleic acids may be modified within their backbone. Illustrative modifications are disclosed herein. Nucleic acids can include nucleic acid aptamers and aptmers. [1081] In some embodiments, Antagonist A or another pharmaceutically acceptable salt thereof exists in a modified form.
  • Antagonist A is that which comprises a nucleotide in a modified form as described herein, where the nucleotide is present in an unmodified form in Antagonist A.
  • Antagonist A is intended to encompass pharmaceutically acceptable salts (defined below) thereof.
  • ocular neovascular disorder refers to an ocular disorder characterized by neovascularization. Certain cancers are ocular neovascular disorders. In one embodiment, the ocular neovascular disorder is a disorder other than cancer. Examples of ocular neovascular disorders other than cancer include diabetic retinopathy and age-related macular degeneration.
  • ophthalmological disease includes diseases of the eye and diseases of the ocular adnexa.
  • ophthalmological diseases include age-related macular degeneration (e.g., nonneovascular, also known as “dry”, and neovascular, also known as “wet” or “exudative,' ' ' macular degeneration), a condition associated with choroidal neovascularization (e.g., a degenerative, inflammatory, traumatic or idiopathic condition, or a.
  • age-related macular degeneration e.g., nonneovascular, also known as “dry”
  • neovascular also known as “wet” or "exudative,' ' ' macular degeneration
  • choroidal neovascularization e.g., a degenerative, inflammatory, traumatic or idiopathic condition, or a.
  • heredodegerative disorder e.g., vitelliform macular dystrophy, fundus fiavimaculatus and optic nerve head drusen, myopic degeneration, angioid streaks, ocular histoplasmosis syndrome, multifocal choroiditis, serpimnous choroiditis, toxoplasmosis, toxocariasis, rubella, Vogt-Koyanagi- Harada syndrome, Behcet syndrome, sympathetic ophthalmia, choroidal rupture or a traumatic condition caused by intense photocoagulation), proliferative vitreoretinopathy (PVR), glaucoma (e.g., open angle glaucoma, primary open angle glaucoma, secondary open angle glaucoma, closed angle glaucoma, glaucoma that is associated with diabetes, glaucoma that is associated with diabetic retinopathy, angle closure glaucoma, narrow angle glaucoma or acute glaucom
  • venous occlusive disease e.g., a retinal vein occlusion, branch retinal vein occlusion or central retinal vein occlusion
  • arterial occlusive disease e.g., branch retinal artery occlusion (BRAO), central retinal artery occlusion or ocular ischemic syndrome
  • BRAO branch retinal artery occlusion
  • CSC central retinal artery occlusion or ocular ischemic syndrome
  • CSC central serous chorioretinopathy
  • CME cystoid macular edema
  • retinal telangiectasia e.g., characterized by dilation and tortuosity of retinal vessels and formation of multiple aneurysms, idiopathic JXT, Leber's miliary aneurysms, or Coats' disease
  • arterial macroaneurysm e.g., characterized by dilation and tortuosity of retinal vessels and formation of multiple
  • SS hemoglobinopathy and SC hemoglobinopathy non-sickling hemoglobinopathy (e.g., AC hemoglobinopathy and AS hemoglobinopathy), hyperviscosity syndrome (e.g., leukemia, Waldenstrom macroglobulinemia, multiple myeloma, polycythemia or myeloproliferative disorder), an inflammatory disease with possible ischemia (e.g., retinal vasculitis associated with systemic disease, retinal vasculitis associated with an infectious agent, uveitis or birdshot retinopathy;
  • systemic diseases include systemic lupus erythematosus, Behcet's disease, inflammatory bowel disease, sarcoidosis, multiple sclerosis, Wegener's granulomatosis and polyarteritis nodosa;
  • infectious agents include a bacterial agent that is the causative agent for syphilis, tuberculosis, Lyme disease or cat-scratch disease, a virus such as
  • Examples of a. "pharmaceutically acceptable salt” include sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, lsomcotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toiuenesuifonaie, camphorsulfonate, pamoate, phenylacetate, trifluoroacetate, aery late, chiorobenzoate, dimtrobenzoate, hydroxybenzoate, methoxybenz
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium, hydroxides of alkaline earth metal such as calcium and magnesium, hydroxides of other metals, such as aluminum and zinc, ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or tri- alkylamines, dicyclohexylamine, tributyiamine, pyridine, N-methyl, N-ethylamine, diethyl amine, triethyl amine, mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-buty
  • protein and "polypeptide” are used interchangeably and in their broadest sense refer to a compound of two or more subunit amino acids, amino acid analogs or peptidomimetics.
  • the subunits may be linked by peptide bonds.
  • the subunit may be linked by other bonds, e.g., ester, ether, etc. No limitation is placed on the maximum number of amino acids which may comprise a. protein's or peptide's sequence, X
  • proximal and distal refer to direction closer to and away from, respectively , an operator of the medical device.
  • distal-end the end of any apparatus described herein contacting the patient's body
  • distal-end the end of any apparatus described herein contacting the patient's body
  • prefilled syringe refers to a syringe assembly that is received by a practitioner and/or an end user already having been at least partially filled with one or more medicaments and/or substances, such a those described herein. Thus, a prefilled syringe need not be fully filled with the medicament(s), and may contain cadspace therein. Prefilled syringes typically include a syringe body within which one or more medicaments are contained.
  • the distal end portion of a prefilled syringe cars include a staked needle (i.e., a needle that is permanently coupled to the syringe body during manufacture), the end of which is disposed within a needle cover to maintain the sterility of the needle prior to use.
  • a prefilled syringe can include a Luer fitting, or are otherwise adapted such that the distal end portion of the syringe body can be coupled to a needle.
  • the proximal end portion of the syringe body of a is
  • prefilled syringe can include a plunger and/or stopper that defines a portion of the container closure, and that can be moved within the syringe body to inject the medicament through the needle.
  • the proximal end portion can also include a flange to allow the user to grasp the syringe body and manually apply a force to a piston to move the plunger, thereby causing injection of the medicament(s),
  • prefilled syringes Although described herein with respect to prefilled syringes, aspects of the disclosure are extendible to any suitable medicament containers including, but not limited to, vials, cartridges, bottles, bags, tubes, and/or the like. Moreover, although some embodiments are described herein as being applicable to prefilled syringe (i.e., a medicament container that includes some amount of one or more substances), any of the embodiments described here can be applied and/or used in conjunction with any suitable medicament container, whether containing a substance or empty.
  • an apparatus can include a "prefillable syringe,” which refers to the syringe body or container of thai is included in a prefilled syringe, but that does not contain a medicament or substance.
  • a prefillable syringe refers to the syringe body or container of thai is included in a prefilled syringe, but that does not contain a medicament or substance.
  • empty as used herein in connection with a container does not necessarily imply that the container is devoid of matter and/or is under a vacuum, but merely means that the container does not include a substance, active agent and/or a pharmaceutically acceptable salt as defined herein.
  • an "empty" container can contain a gas.
  • sterilization results in at least about 99% destruction or elimination of pathogens, at least about 95% destruction or elimination of pathogens, at least about 90%, at feast about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, at least about 10%, at least about 1%, at least about 0.1%, and all values in between.
  • pathogen can refer to a bacterium, a virus, and/or any other undesirable biological entity.
  • fluid-tight is understood to encompass hermetic sealing (i.e., a seal that is gas-impervious) as well as a seal that is liquid-impervious.
  • the term “substantially” when used in connection with "fluid-tight,” “gas-impervious,” and/or “liquid-impervious” is intended to convey that, while total fluid imperviousness is desirable, some minimal leakage due to manufacturing tolerances, or other practical considerations (such as, for example, the pressure applied to the seal and/or within the fluid), can occur even in a “substantially fluid- tight" seal.
  • a "substantially fluid-tight" includes a seal that prevents the passage of a fluid (including gases, liquids and/or slurries ) therethrough when the seal is maintained at a constant position and at pressures of less than about 5 psig, less than about 10 psig, less than about 20 psig, less than about 30 psig, less than about 50 psig, less than about 75 psig, less than about 100 psig and all values in between. Any residual fluid layer that may be present on a portion of a wall of a container after component defining a "substantially-fluid tight" seal are moved past the portion of the wall are not considered as leakage.
  • FIG. 1 is a cross section view of an apparatus 1000 such as a cap assembly, according to some embodiments.
  • the apparatus 1000 comprises a housing 1010 and a septum 1030.
  • the housing 1010 has a coupling portion 1010A and an access portion 1010B.
  • the housing 1010 can be formed of any suitable biocompatible material, such as a hard plastic.
  • the housing 1010 or any of the housing described herein can be constructed from moldable plastic materials such as, for example, a polymeric plastic including, but not limited to, polyethylene, polypropylene, polycarbonate, polytetrafluoroethylene (PTFE), a phenol formaldehyde resin (e.g., Bakelite), and/or the like.
  • a polymeric plastic including, but not limited to, polyethylene, polypropylene, polycarbonate, polytetrafluoroethylene (PTFE), a phenol formaldehyde resin (e.g., Bakelite), and/or the like.
  • PTFE polytetrafluor
  • a proximal end of the coupling portion 1010A is configured to be removably- coupled to the distal-end of a prefilied or prefillabie syringe 1 100
  • the syringe 1 100 can either include one or more substances of the types shown and described herein (e.g., one or more medicaments, such as a vascular endothelial growth factor (VEGF) antagonist, a platelet-derived growth factor (PGDF) antagonist and/or an anti-C5 agent), and can thus be a prefilied syringe, or can be devoid of any such substance! ' s), and can thus be a prefillabie syringe.
  • VEGF vascular endothelial growth factor
  • PGDF platelet-derived growth factor
  • an anti-C5 agent an anti-C5 agent
  • the coupling portion 1010A can threadedly engage a collar portion 1200 (e.g., a Luer Lock collar) at the distal-end of the syringe 1 100.
  • a collar portion 1200 e.g., a Luer Lock collar
  • the cap assembly 1000 can provide a fluid-tight seal at a distal tip 1 120 of the syringe.
  • the cap assembly 1000 can be coupled to the syringe 1 100 to provide a distal-end container closure for the syringe.
  • any suitable mechanism for removably coupling the housing 1010 to the syringe 1100 can be employed.
  • a coupling portion can include a protrusion that matingly engages a recess and/or opening of a syringe to define an interference (or "snap") fit.
  • a coupling portion can define a recess and/or opening that receives a locking member of a syringe that maintains the cap assembly in a constant position relative to the syringe.
  • the access portion 1010B defines, at a distal-end of the housing 1010, a guide opening 1040 that, during use, is aligned with an exit lumen 1130 of the syringe 1 100.
  • the guide opening 1040 is aligned with and/or is coaxial to a centerline or longitudinal axis AX defined by the exit lumen 1 130. In this manner, and as is described in more detail herein, a user can locate the point of insertion for a piercing needle or lancet (not shown in FIG. 1) to inject a substance into the syringe 1 100.
  • the sidewalls defining the guide opening 1040 can contact and/or guide the needle to maintain the needle in a substantially aligned orientation when the needle is disposed through the septum 1030 and/or within the exit lumen 1 130. Said another way, the sidewalls defining the guide opening 1040 can maintain the needle such that a longitudinal axis with the needle is coaxial with or within a desired angular offset from (e.g., by a maximum of five degrees, 10 degrees, 15 degrees, 20 degrees or 30 degrees) the longitudinal axis AX.
  • the sidewalls defining the guide opening 1040 can be tapered. In this manner, the guide opening 1040 is readily discernible to the naked eye, yet aligns suitably with the relatively small exit lumen 1130. It is hence understood that the guide opening may be formed in any suitable shape that permits such benefits including, but not limited to, an inverted pyramid, an inverted cone, an inverted frustum, and/or the like.
  • the guide opening 1040 is reusable for multiple piercings such as when, for example, multiple injections are sequentially employed to deliver one or more substances to the syringe 1 100.
  • more than one guide opening can be formed on the access portion 1010B.
  • each guide opening can be used once, and the number of guide openings provided is formulation specific.
  • each opening is uniquely color coded and/or labeled.
  • aspects of the disclosure can guide a user (e.g., a caregiver) to generate accurate formulations within the syringe 1 100
  • a formulation that requires three substances i.e., a first substance, a second substance, and a third substance
  • a formulation that requires three substances can be achieved by providing a second substance within the syringe, by injecting the first substance into the syringe via a first guide opening of two guide openings provided on the apparatus, and by injecting the third substance into the syringe via a second guide opening of the two guide openings.
  • aspects of the disclosure prevent the use of incomplete formulations, the inadvertent injection of one substance twice over into the syringe along with non-injection of the other substance, and/or the like.
  • the septum 1030 can be coupled to the housing 1010 as illustrated in FIG. 1.
  • the septum 1030 can be constructed from rubber or other suitable material formulated to be pierceable by a needle or lancet, including (but not limited to) silicone and'Or butyl rubber, or a polymeric plastic such as polyethylene, polypropylene, polycarbonate, PTFE, a phenol formaldehyde resin (e.g. Bakelite), and/or the like.
  • the septum 1030 can be resealed after piercing, and'Or can be formulated to have sufficient elasticity to reseai after piercing.
  • the septum 1030 can be usable for multiple piercing, such as when, for example, two or more substances are sequentially delivered via the exit lumen 1130.
  • the septum 1030 is selectively or nonselectively porous to permit diffusion of a sterilization gas such as ethylene oxide or water in the form of steam into the exit lumen 1 130 and/or adjacent the tip 1 120 of the syringe 1 100.
  • a sterilization gas such as ethylene oxide or water in the form of steam
  • the syringe 1 100 can be sterilized using a. gas sterilization technique that can penetrate the septum 1030, but that will not react with any substanee(s) disposed in the syringe 1100. This arrangement allows the syringe 1 100 to be sterilized after the cap assembly 1000 has been coupled to the syringe 1 100.
  • the septum 1030 includes a first seal portion 1030A and a second seal portion 1030B.
  • the first seal portion 1030A is configured to define a substantially fluid-tight seal with a distal-end surface 1 140 of the tip 1120 of the syringe 1100.
  • the first seal portion 1030A is substantially planar.
  • the first seal portion 1030A has a flatness of less than about 500 microns, less than about 200 microns, less than about 100 microns, less than about 50 microns, less than about 20 microns and all values in between, when in an unloaded state.
  • a distal surface of the first seal portion 1030A can include a stress concentration raiser, and/'or any other suitable target portion aligned with the exit lumen 1 130 and the guide opening 1040 (i.e., laterally along the axis AX) that further aids to guide a. piercing needle into the exit lumen 1130 via the guide opening 1040.
  • multiple guide openings 1040 are formed as described earlier, and corresponding multiple target portions are formed on the first seal portion 103QA .
  • each target portion is uniquely colored and/or labeled to guide a. user in generating accurate formulations.
  • the second seal portion 1030B can be configured to define a substantially fluid-tight seal with a sidewali 1150 of the tip 1 120 in any suitable manner including, but not limited to, a pressure fit, an adhesive fit, and so on.
  • FIGS. 2A-2B illustrate a medicament container assembly 2000, according to an embodiment.
  • the medicament container assembly comprises a cap assembly 2006 and a syringe 2100.
  • the syringe 2100 can be, for example, a prefilled or prefillable syringe of a type described herein.
  • the syringe 2100 can either include one or more substances of the types shown and described herein (e.g., one or more medicaments, such as a vascular endothelial growth factor (VEGF) antagonist, a platelet-derived growth factor (PGDF) antagonist, and/or an anti-C5 agent), and can thus be a prefilled syringe, or can be devoid of any such substance, and can thus be a prefillable syringe.
  • VEGF vascular endothelial growth factor
  • PGDF platelet-derived growth factor
  • anti-C5 agent an anti-C5 agent
  • the coupling portion 2010A can be configured to engage a Luer Lock collar 2200 at the distal-end of the syringe 2100 to provide a. sealing fit between the cap assembly 2006 and a distal tip 2120 of the syringe.
  • the housing 2010 can be formed of any suitable biocompatible material, such as a hard plastic.
  • the housing 2010 or any of the housing described herein can be constructed from a. moldable plastic material such as, for example, a. polymeric plastic including, but not limited to, polyethylene, polypropylene, polycarbonate, PTFE, a phenol formaldehyde resin (e.g. Bakelite), and/or the like.
  • the housing 2010 is constructed from a different material than the septum 2030.
  • the access portion 201 OB defines a tapered guide opening 2040 that, during use, is aligned with an exit lumen 2130 of the syringe 2100.
  • the exit lumen 2130 defined by the sidewall 2160, can have any size and'Or length suitable for injection of a desired quantity of a substance into a desired target location.
  • the exit lumen 2130 can have a diameter and length suitable for intravitreal injection.
  • the exit lumen 2130 and the sidewall 2160 can define an outer diameter from about 0,01025 inches to about 0.01625 inches.
  • the exit lumen 2130 can define an inner diameter from about 0.00525 inches to about 0.00825 inches.
  • the sidewall 2160 can have a wall thickness from about 0.0025 inches to about 0.004 inches.
  • the guide opening 2040 can have an inner diameter that is equal to or smaller than the inner diameter of the exit lumen 2130.
  • the guide opening 2040 can have an inner diameter from about 0.01025 inches to about 0,01625 inches.
  • the exit lumen 2130 can have a length from about 0.5 inches to about 0.675 inches,
  • the guide opening 2040 can have a shape, size, position and/or orientation configured to facilitate alignment of a piercing needle with the exit lumen 2130.
  • a piercing needle can be inserted into the exit lumen 2130 via the guide opening 2040 in a manner that reduces the likelihood of contact between the needle and the sidewall 2160.
  • the guide opening 2040 is distinguishable (e.g. visually and'Or photometrically) from the remainder of the access portion 2010B, such as by having a different color associated therewith.
  • multiple guide openings are formed, and each guide opening can be uniquely colored and/or labeled to better guide users for generating formulations.
  • the septum 2030 includes a first seal portion 2030A and a second seal portion 2030B.
  • the first seal portion 2030A defines a substantially fluid-tight, substantially planar seal with a distal-end surface 2140 of the tip 2120 of the syringe 2100.
  • the planar seal allows use of standard needles (that are appropriate sized for entering the exit lumen 2130) for piercing the septum 2030, and places no design constraints on the proximal end of the syringe 2100.
  • multiple guide openings are formed, and portions of the first seal portion 2030A that align with each guide opening can be uniquely colored and/or labeled to better guide users for generating formulations.
  • the second seal portion 2030B disposed between the coupling portion 201 OA and a tapered sidewall 2150 of the tip 2120, can define a substantially fluid-tight tapered seal with a tapered sidewall 2150 of the tip 2.120 via an interference fit.
  • the first seal portion 2030A and/or the second seal portion 2030B can be constructed from a compressible material that can elastically deform, e.g., when the housing 2010 is tightened, to establish the fluid-tight planar seal and/or the pressure fit.
  • the second seal portion 2030B is constructed from a different material than the first seal portion 2030A.
  • the first seal portion 2030A and the second seal portion 2030B to be monolithically constructed, or to be modularly constructed of similar (or dissimilar) materials and assembled thereafter.
  • the apparatus 2006 can also comprise a cover 2300 removably coupled to the access portion 2010B of the housing 2010.
  • the cover 2300 can be suitably shaped and sized to cover at least the guide opening 2040 and/or the exit lumen 2130.
  • the cover 2300 is removable by peeling the cover away from the access portion 2010B of the housing 2010,
  • the cover 2300 can be constructed from a flexible material and can include one or more portions that are coupled to the access portion of the housing via an adhesive, chemical bond, mechanical bond or the like.
  • the cover can be "peeled” or pulled from the housing to expose the access portion 2010B and/or the guide opening 2040,
  • the cover 2300 is partially or completely transparent to the naked eye, so that the guide opening 2040 or multiple guide openings (not shown), which can itself be colored and/or otherwise distinguishable, is discernible through the cover.
  • the cover is color coded in portions that align with one or more guide openings (not shown).
  • the cover 2300 is formed from a suitable material that resists or substantially prevents microbial penetration therethrough, and thus can maintain sterility of the access portion 2010B and/or the guide opening 2040.
  • the cover 2300 can further be constructed of a suitable porous material that selectively or nonseiectively permits or inhibits diffusion of a sterilization gas such as ethylene oxide, water in the form of steam, or any other sterilization agents, therethrough.
  • a sterilization gas such as ethylene oxide, water in the form of steam, or any other sterilization agents, therethrough.
  • the cover 2300 is formed of polyethylene, and/or any other suitable poly olefin material such as polypropylene, polycarbonate, PTFE, a phenol formaldehyde resin (e.g. Bakelite), and/or the like.
  • the cover 2300 can be configured to allow sterilization of the access portion 2010B when the cover 2300 is disposed over the access portion 201 OB and/or the guide opening 2040.
  • the combination of the cover 2300 and the housing 2010 defines a seal that is resistant to particulate penetration, and obviates the need to disinfect the cover, e.g., wipe the cover with a disinfecting agent such as isopropyl alcohol (IP A) prior to use.
  • IP A isopropyl alcohol
  • no cover may be present.
  • a cap assembly such as the cap assembly 2006, can comprise a housing constructed from a hard plastic material. Such materials, however, can impede the flow of a sterilant gas and/or other sterilizing agents. Accordingly, in some embodiments a housing can define one or more sterilization openings having a size and/or configuration to allow a sterilant gas therethrough. In this manner, the housing can define a sterilization gas pathway other than and/or in addition to the guide opening.
  • FIG, 2C shows a top view of a housing 2010' disposed on and/or coupled to a syringe 2100'. The housing 2010' has formed thereon a plurality of sterilization openings 2050' about the guide opening 2040'.
  • the sterilization openings 2050' include and/or contain a porous material that is contiguous with an exit lumen of the syringe 2100'.
  • the sterilization openings 2050' are through- holes that allow access to the septum (not shown in FIG. 2C) therebelow. Any suitable number, shape, layout of the sterilization openings 2050' can be employed.
  • the use of sterilization openings 2050' hence allows for rapid, consistent, and reliable sterilization of the exit lumen and/or the interior of the syringe 2100' while maintaining the structural integrity provided by the relatively harder, impervious construction of the cap assembly.
  • the presence of sterilization openings 2050' also provides multiple pathways for a. sterilant gas (as opposed to a singular pathway, such as via the guide opening 2040') thereby increasing the efficiency with which the syringe can be sterilized,
  • FIG. 3 illustrates a method 3000 of conveying at least one substance, according to some embodiments. Although described herein with respect to the embodiments of FIGS. 1, 2A-2B for ease of explanation, it will be understood that the method 3000 is generally applicable to other apparatus designs having the elements described herein, as well.
  • a first needle e.g. a piercing needle
  • a guide opening e.g., the guide opening 1040
  • a cap e.g. the housing 1010
  • the first needle is substantially aligned with an exit iumen (e.g. exit lumen 1 130) defined by a tip (e.g. the syringe tip 1 120) of a second container (e.g. the syringe 1100).
  • sidewalk defining the guide opening can maintain the first needle such that a longitudinal axis of the first needle is coaxial with or within a desired angular offset from (e.g., by a maximum of about five degrees, about 10 degrees, about 15 degrees, about 20 degrees or about 30 degrees) a longitudinal axis (e.g. the longitudinal axis AX) of the second container.
  • the cap can be removably coupled to the second container that can contain a second substance, where the first container can contain a first substance.
  • inserting the first needle into the guide opening can encompass any approach that results in disposing the first needle within the guide opening, including moving the first container towards the first needle while maintaining the first needle in a fixed position, aligning the first needle with the exit lumen and the guide opening, and so on.
  • the exit lumen and a sidewall can define an outer diameter from about 0,01025 inches to about 0.01625 inches.
  • the exit lumen can define an inner diameter from about 0.00525 inches to about 0.00825 inches.
  • the guide opening can have an inner diameter that is equal to or smaller than the inner diameter of the exit lumen.
  • the exit lumen can have a length from about 0.5 inches to about 0.675 inches.
  • a cover (e.g. the cover 2300) is removed from the cap to expose the guide opening prior to inserting the first needle.
  • the cover can be porous to sterilization gases, the need for sterilization of the guide opening and/or the portion of the cap defining the guide opening, e.g., via a sterilizing wipe, is obviated. Further, the risk of exposure during injection of sensitive sites, such as the eye, to alcohol is greatly reduced or eliminated by including a removable cover. Further, this arrangement reduces the possibility of particulate contamination, e.g. from the use of a wipe.
  • a septum portion (e.g. the septum 1030) of the cap is pierceabie with the first needle such that a distal end portion of the first needle is placed in fluid communication with the exit lumen of the second container.
  • the exit lumen can have a diameter and/or length suitable for intravitreal injection.
  • the guide opening can have a shape, size, position and/or orientation configured to facilitate alignment of the first needle with the exit lumen.
  • the first needle can pierce the guide opening and be placed in fluid communication with the exit lumen, in a manner that reduces the likelihood of contact between the first needle and a sidewall of the exit lumen, thereby reducing the risk of damaging the second container and/or the piercing needle.
  • the first substance is conveyed, pumped, injected, and/or otherwise transferred from the first container into the second container via the first needle.
  • a predetermined amount of the first substance is conveyed into the second container via the first needle.
  • the predetermined amount can be based on at least one of the following: an amount of the second substance in the second container, a volume of the exit lumen of the first container, a volume of the exit lumen of the second container, a volume of the first needle and/or a volume of the second needle, in some embodiments, the predetermined amount is from about 50 microliters to about 75 microliters.
  • a second needle can be coupled to the tip of the second container.
  • the second needle can be coupled to the second container via any suitable mechanism.
  • the second needle can be coupled to the second container via a Luer Lock collar and/or fitting of the syringe. In this manner, the opportunity for contamination is reduced since one needle is coupled to the second container prior to injection into the target tissue.
  • the second needle is suitable for intravitreai injection.
  • the first substance and the second substance are conveyed, pumped, injected, and/or otherwise transferred from the second container via the second needle.
  • the second needle can be used once (since the first needle is used to deliver the second substance into the second container).
  • the second needle which can be used to inject the first substance and the second substance into a target, e.g. a tissue, and is not dulled, contaminated and/or othenvise compromised by being used in the preparatory operations of transferring substances into the second container.
  • first substance, the second substance, the third substance, etc. can be administered at substantially the same time from a single container using a single needle, thereby mitigating the contamination and/or infection risks associated with multiple injections during the same treatment session.
  • a first substance, a second substance, and optionally a third substance are conveyed to the eye of a subject.
  • the first substance, the second substance, and optionally the third substance are conveyed into any suitable target tissue of a subject, in yet other embodiments, the first substance, the second substance, and optionally the third substance are conveyed to a third container.
  • FIG. 4 illustrates a portion of an apparatus 4000 such as a substance delivery device, according to an embodiment.
  • the device 4000 comprises a syringe 4400, an elastomeric member 4010 and a retainer 4100.
  • the elastomeric member includes a contact surface 401 OA, a sealing surface 4010B, and a retention portion 4010C.
  • the elastomeric member 4010 is configured to be disposed within a proximal end of a prefilled or prefillable syringe 4400 as illustrated.
  • the syringe 4400 can either include one or more substances of the types shown and described herein (e.g., one or more medicaments, such as a vascular endothelial growth factor (VEGF) antagonist, a platelet-derived growth factor (PGDF) antagonist, and/or an anti-C5 agent), and can thus be a prefilled syringe or can be devoid of any such substance, andean thus be a prefillable syringe.
  • the sealing surface 4010B and a sidewall 4410 of the syringe can define a substantially fluid tight seal.
  • the contact surface 4010A can include one or more sterile target portions (not shown) for receiving one or more piercing needles.
  • the retainer 4100 can engage a portion 4420 on the syringe 4400 as well as at least the retention portion 40 IOC of the elastomeric member 4010 to maintain the elastomeric member 4010 in a first position within the syringe, as illustrated in FIG.
  • the portion 4420 of the syringe 4400 is a portion of a finger flange integrally formed with the syringe 4400, In other embodiments, the portion 4420 can be detachabiy formed on the syringe 4400, and/or be any suitable structure that permits the retainer to maintain the elastomeric member 4010 in the first position, such as, for example, a ring structure associated with the retainer 4100 for snapping onto the syringe 4400. In the illustrated configuration, the contact surface 4010A of the elastomeric member 4010 is outside of the syringe 4400 when the elastomeric member is in the first position.
  • the contact surface 401 OA By maintaining the contact surface 401 OA in a position outside of the syringe 4400, the contact surface 401 OA can be accessed by a needle or a sterilization wipe, as described herein. Similarly stated, when the elastomeric member 4000 is in the first position, the contact surface 401 OA is accessible to any of the substance transfer operations described herein (e.g., being wiped and/or sterilized by an IP A wipe, being pierced by a transfer needle, or the like). In other embodiments, however, the contact surface 401 OA can lie within the syringe 4400, such as when the syringe is less than 100% full (e.g., is empty), for example.
  • the elastomeric member 4010 is movable from the first position to a second position when the retainer 4100 is spaced apart and/or otherwise disengaged from the retention portion 40 IOC of the elastomeric member. In this manner, after one or more medicaments or other substances are transferred into the syringe via the elastomeric member 4000, the elastomeric member 4010 can be moved within the syringe to prepare the substance and/or medicament for injection into the target, e.g., a tissue.
  • the contact surface 401 OA is configured to receive and/or be coupled to a push rod. In this manner, the push rod (not shown in FIG.
  • 4) can be used to move the elastomeric member 4010 from the first position to the second position and back, and further, to move the elastomeric member 4010 within the syringe to inject the medicament(s) and/or substanee(s).
  • the contact surface 4010A can include a sterile target portion as described above, and the retainer 4100 can include a cover portion formed thereon and/or attached thereto, similar to the cover portion 2300.
  • a cover can be configured to cover a sterile target portion when the retainer is in contact with the syringe 4400 and the retention portion 40 IOC of the elastomeric member 4010.
  • the need for a pre-transfer sterilization procedure is ob viated.
  • At least a portion of the retainer 4100 is frangible.
  • the retainer can include a frangible portion configured to deform when the retainer is removed from the retention portion 40 IOC of the elastomeric member 4010.
  • at least a portion of the retainer 4100 is reversibly deformabie so that it can be snapped on/off the syringe 4400.
  • FIG. 5 illustrates a method 5000 of conveying at least one substance, and is explained in a non-limiting manner using the apparatus of FIGS. 6A-6C, which show a medicament deliver ⁇ ? device according to an embodiment.
  • FIG. 6A illustrates the apparatus 6010 in use at the proximal end of the syringe 6400, where the syringe 6400 is prefilled with a second substance 6460.
  • a first needle 7100 of a first container can be inserted into the elastomeric member 6010 via the contact surface 601 OA.
  • the elastomeric member 6010 can be disposed in a first position (as shown in FIG. 6B) within a second container (the syringe 6400) such that the contact surface 601 OA of the elastomeric member 6010 is outside of the second container 6400.
  • the first needle 7100 can be placed in fluid communication with the second container 6400.
  • the contact surface 601 OA is sterilized before inserting the first needle 7100. Such sterilization can be performed by a medical practitioner and/or the end user, for example, by wiping the contact surface 601 OA with 1PA,
  • the contact surface 601 OA can be provided to a medical practitioner and/or the end user in a pre-sterilized condition.
  • the contact surface 60I0A can have a cover formed thereon, as described with respect to the embodiment of FIGS. 2A-2B, and which maintains the sterility of the contact surface 6010A. The cover can be removed to expose the contact surface prior to inserting the first needle 7100.
  • the contact surface 601 OA has a guide opening (similar to the guide openings 1040 and 2040) formed thereon, and the first needle 7100 is insertabie via the guide opening.
  • the first container (not shown in FIGS. 6A-6C) can contain a first substance 6480, while the second container 6400 can contain the second substance 6460.
  • the first substance and the second substance are independently one or more of a vascular endothelial growth factor (VEGF) antagonist, a platelet-derived growth factor (PGDF) antagonist, and/or an anti-C5 agent.
  • VEGF vascular endothelial growth factor
  • PGDF platelet-derived growth factor
  • the first substance at least includes a PGDF antagonist.
  • the second substance at least includes a VEGF antagonist.
  • the first substance 6480 can be conveyed from the first container into the second container 6400 via the first needle 7100 (see FIG. 6B).
  • the elastomeric member 6010 is moved from the first position to a second position within the second container 6400, such that the contact surface 601 OA is inside the second container 6400.
  • the elastomeric member 6010 can be moved to the second position in any suitable manner.
  • FIG. 6C illustrates a push rod 7200 being employed for this purpose, though other embodiments (e.g. using a pump) are within the scope of this disclosure.
  • the first substance 6460 and the second substance 6480 which are both present in the second container 6400 (see FIG. 6C) are conveyed from the second container via a second needle (not shown).
  • the first substance and the second substance are conveyed to a biological injection site, such as the eye of a subject.
  • the first substance and the second substance are conveyed to a third container, such as a vial, which can be sterile.
  • the retainer 4100 in the embodiment of FIG. 4 can keep the elastomeric member 4010 (and any plunger/stopper mechanism associated therewith) proud of the portion 4420 of the syringe 4400.
  • the retainer 4100 is frangible, which deters its reuse.
  • the retainer 4100 is deformable, which allows reuse after sterilization, auioelaving, and/or the like.
  • any needle assembly can be used at the distal-end of the syringe 4400, 6400 for delivering one or more substances from the second container.
  • a syringe having a fixed, non-removable needle i.e., a "staked needle”
  • FIG. 7 illustrates a syringe 7400 having a nonremovable needle 7420 formed thereon (a "staked needle").
  • An elastomeric member 7010 is disposed in a first position (not shown) at the distal end of the syringe 7400 to make possible injecting one or more substances into the syringe, consistent with the embodiments described herein (e.g. see FIG.
  • a standard push rod / plunger 8200 can then be used to move the elastomeric member 7010 to the second position (see FIG. 7) for delivery via the needle 7420, although other mechanisms can be employed as well.
  • FIGS. 8A-8E illustrate a substance delivery device 8000, according to another embodiment.
  • the device 8000 comprises an elastomeric member 8010 that is configured to be disposed within a proximal end of a prefilled or prefillable syringe 8400 containing a substance 8460 as illustrated (see e.g., FIG. 8C).
  • the syringe 8400 can either include one or more substances of the types shown and described herein (e.g., one or more medicaments, such as a vascular endothelial growth factor (VEGF) antagonist, a platelet-derived growth factor (PGDF) antagonist, and/or an anti-C5 agent), and can thus be a prefilled syringe or can be devoid of any such substance(s), and can thus be a prefillable syringe.
  • VEGF vascular endothelial growth factor
  • PGDF platelet-derived growth factor
  • anti-C5 agent an anti-C5 agent
  • the elastomeric member 8010 includes a contact surface 801 OA and a sealing surface 8010B.
  • the sealing surface 8010B and a sidewall 8410 of the syringe 8400 can define a substantially fluid-tight seal
  • the contact surface 8010A is configured to receive a needle to transfer one or more substances into the syringe 8400.
  • the contact surface 801 OA includes a septum portion to allow transfer of one or more substances therethrough via a needle.
  • the contact surface 801 OA can include a sterile target portion (not shown) for receiving a piercing needle.
  • the eiastomeric member 8010 can include a cover formed thereon and/or attached thereto, similar to the cover portion 2300. Such a cover can be configured to cover a sterile target portion through which a needle is disposed. In such embodiments, the need for a pre-transfer sterilization procedure (e.g., via a wipe at the point of use) is obviated.
  • the elastomeric member 8010 can be moved between a first configuration (see FIG. 8A) and a second configuration (see FIG. 8B) by application of a deforming force on the contact surface 801 OA, such as by the push rod 9200, for example (see FIG. 8E).
  • a deforming force on the contact surface 801 OA such as by the push rod 9200, for example (see FIG. 8E).
  • the contact surface 801 OA and the sealing surface 8010B are concave in shape when viewed from a distal end of the syringe 8400 (i.e.
  • each of the contact surface 801 OA and the sealing surface 8010B can take a different form when in the second configuration.
  • the contact surface 801 OA can be flat when in the first configuration and the contact surface 801 OA' can be convex when in the second configuration.
  • the contact surface 801 OA of the eiastomeric member 8010 is disposed within the syringe 8400.
  • the proximal end of the syringe 8400 can maintain an unobtrusive profile, yet the contact surface 8010A can be accessed by a needle assembly, as described herein.
  • a cover portion similar to the cover 2300 of FIG. 2B can be formed over the proximal end of the syringe 8400, the elastomeric member 8010 and/or the contact surface 8010A.
  • the contact surface 801 OA can protrude partly or wholly outside the syringe 8400 when the elastomeric member 8010 is in the first configuration, and in the first position within the syringe 8400.
  • the contact surface 8010A can be more readily accessible for procedures such as being wiped and/or sterilized by an IP A wipe, being pierced by one or more transfer needles, and/or the like,
  • the apparatus 8000 is illustrated as comprising a syringe 8400 with a fixed, impenetrable needle assembly 8490, though other forms of the needle assembly, such as a needle coupled to a Luer Lock collar of the syringe 8400, are within the scope of this disclosure.
  • aspects of the elastomeric member 8010 hence provide a point of access for injecting one or more substance(s) into the syringe 8400 from the proximal end of the syringe when the distal needle limits such access to the interior of the syringe.
  • one or more substances 8480 can be transferred into the syringe 8400 via the elastomeric member 8010 using a needle assembly 9100.
  • the elastomeric member 8010 can be maintained in the first configuration when pierced by the needle assembly 9100.
  • the material of the elastomeric member 8010 can provide sufficient resilience to the forces imposed on the elastomeric member during piercing by the needle assembly 9100 to limit deformation of the elastomeric member to the extent necessary to reach the second configuration.
  • the elastomeric member 8010 can be maintained in its first configuration after the transfer of the one or more substances 8480 therethrough, thus allowing for additional substances to be transferred into the syringe 8400 via multiple needles and/or piercing operations,
  • the elastomeric member 8010 undergoes deformation from the first configuration to a different configuration upon piercing and/or during transfer of the substance 8480.
  • the elastomeric member 8010 is configured to irreversibly move from the first configuration to the second configuration as a result of the piercing and/or transferring of the substance 8480. In this manner the elastomeric member can limit the transfer of additional substances and/or can limit additional piercing operations by limiting access to the contact portion 801 OA.
  • the elastomeric member 8010 can be moved within the syringe 8400 to inject the substances 8460, 8480. As described above, the elastomeric member 8010 can first be moved to a second position within the syringe 8400 to purge the air present therein and/or otherwise prepare the substances 8460, 8480 for injection prior to further moving the elastomeric member 8010 to cause injection. To facilitate such movement, the contact surface 801 OA is configured to receive and/or be coupled to a push rod 9200. In this manner, the push rod 92.00 can be used to deform and/or otherwise transform the elastomeric member 8010 from the first configuration to the second configuration.
  • the push rod 9200 cars also be configured to grip and move the elastomeric member 8010 from the first position illustrated in FIG. 8C to the second position illustrated in FIG. 8E and back, and thereby inject the medicaments and/or substances 8460, 8480.
  • the push rod 9200 can have a corrugated design that engages corrugated walls or deformable straight walls of the elastomeric member 8010 in a locking manner to permit movement of the elastomeric members between any number of positions using the push rod.
  • the shape of the contact surface 8010A in the second configuration corresponds substantially to a surface of the push rod 9200 that engages the contact surface 801 OA.
  • one or more portions of the contact surface 801 OA is geometrically congruent to one or more portions of a surface of the pushrod 9200.
  • the push rod 9200 can be disengaged from the elastomeric member 8010, and the elastomeric member can attain a third configuration different from the second configuration if the deforming force (e.g., as applied by the push rod 9200) is removed.
  • the third configuration is substantially similar to the first configuration.
  • methods can include mixing of a first substance and a second substance to prepare a mixture for deliver ⁇ '.
  • a mixing assembly 9000 includes a mixing adapter 9100.
  • the mixing adapter 9100 can be employed to prepare a mixture of the first substance and the second substance as described herein.
  • the mixing adapter 9100 includes a first port 9224A configured to be coupled to a first container 9200A containing the first substance 921 OA, and includes a second port 9224B configured to be coupled to a second container 9200B containing the first substance 9210B.
  • the mixing adapter 9100 can further include a third port (not shown) configured to be coupled to a third container (not shown) that can receive a mixture of the first substance from the mixing adapter.
  • a third port configured to be coupled to a third container (not shown) that can receive a mixture of the first substance from the mixing adapter.
  • at least one of the first port 9224A, the second port 9224B, or the third port can be formed as a tapered female connector, such as a Luer Lock connector.
  • at least one of the first port 9224A, the second port 9224B, or the third port can include a membrane portion (not shown) that is pierceabie by a needle during use.
  • the membrane portion can be formed in a manner substantially similar to the housing 2010 or the housing 2010'.
  • the mixing adapter 9100 can include a female-to-female tapered connector. Said another way, in some embodiments, the first port 9224A and/or the second port 9224B can be formed as female tapered connectors. In some embodiments, the mixing adapter 9100 can define a pathway 91 18 that is in fluid communication with the first port 9224A and the second port 9224B. In some embodiments, the pathway 91 18 is in fluid communication with a third port as described above,
  • the mixing adapter 9100 can include a valve (not shown) in the pathway 9118 such that it controls fluid communication between any of the ports, i.e., the first port 9224A and the second port 9224B, the second port 9224B and the third port (not shown), or the first port 9224A and the third port (not shown).
  • a substance e.g., a fluid
  • the valve can be configured to prevent and/or otherwise control flow to the first port 9224A and the second port 9224B.
  • more than one valve can be included within the pathway 91 18.
  • Such valves can include any suitable mechanism for performing the functions described herein, such as, for example a check valve, a ball valve, or the like
  • the mixing adapter 9100 can be configured for a variety of operations involving the first substance 921 OA and the second substance 9210B including, but not limited to, receiving and transferring the first substance 9210A, receiving and transferring the second substance 921 OA, receiving and/or mixing portions of the first substance 9210A and the second substance 9210B to yield a mixture, transferring the mixture back to the first container 9200A for further mixing with a remainder of the first substance 921 OA therein, transferring the mixture back to the second container for further mixing with a remainder of the second substance 921 OB therein, transferring the first substance 92I0A to a third container (not shown), transferring the second substance 921 OA to the third container, transferring the mixture to the third container, and/or the like, and combinations thereof.
  • each of the first container 9200A, the second container 9200B, and the optional third container can include male tapered connectors.
  • each of the first container 9200A, the second container 9200B, and the optional third container (not shown) can be independently formed as in a. manner as substantially disclosed herein for FIGS. 1-2, 4, 6-8.
  • FIG. 9 illustrates the containers 9200A, 9200B as including elasiomeric members 9214 A, 92I4B, respectively, which can be similar to the elasiomeric member 4010 and/or the elastomeric member 8010.
  • FIG. 9 also illustrates plungers 9218A, 9218B that can be similar to the plunger 8020, or any suitable plungers capable of moving the elasiomeric members 9214A, 9214B, respectively.
  • FIG, 10 illustrates a method 10000 of preparing one or more substances for delivery, according to an embodiment.
  • the method 10000 can be performed using any suitable device and/or assembly.
  • the method 10000 includes coupling a first container (e.g., the container 9200A) to a first port (e.g., the port 9224A) of an adapter (e.g., the adapter 9100), the first container containing a first substance.
  • the first substance can include a platelet-derived growth factor (PGDF) antagonist.
  • coupling the first container can include piercing a membrane portion of the first port.
  • the piercing can be include piercing a septum or other membrane portion, such as that described above with respect to the septum 2030.
  • the method 10000 further includes, at 10200, coupling a second container (e.g., the container 9200B) to a second port (e.g., the port 9224B) of the adapter.
  • the second container contains a second substance including a vascular endothelial growt factor VEGF) antagonist.
  • at least one of the first port or the second port includes a female tapered portion.
  • coupling the second container includes piercing a membrane portion of the second port.
  • the piercing can be include piercing a septum or other membrane portion, such as that described above with respect to the septum 2030.
  • the method 10000 further includes, at 10300, transferring at least a portion of the first substance from the first container to a pathway (e.g., the pathway 91 1 8) defined by the adapter.
  • the pathway is in fluid communication with the first port and the second port.
  • the portion of the first substance is transferred from the pathway to one of the first container or the second container.
  • the method 10000 can further include transferring at least a. portion of the second substance to the pathway to produce a mixture of the first substance in the pathway and the second substance in the pathway. In some embodiments, the method 10000 can further include transferring at least a portion of the mixture to one of the first container or the second container.
  • VEGF vascular endothelial growth factor
  • the transferring the portion of the mixture can include transferring the portion of the mixture to the first container. This results in the mixing of the portion of the mixture with a remainder portion of the first substance in the first container. In some embodiments, transferring the portion of the mixture can include transferring the portion of the mixture to the second container. This results in the mixing of the portion of the mixture with a remainder portion of the second substance in the second container.
  • the transferring can be performed a predetermined number of times to facilitate such mixing. For example, in some embodiments, the transferring can be performed five times, ten times or more.
  • the method 10000 can further include coupling a. third container to a third port of the adapter, where the pathway is in fluid communication with the third port. In such embodiments, the method 10000 can further include transferring at least a portion of the mixture to the third container.
  • the method includes transerring a portion of the second substance from the second container into the pathway to produce a mixture of the first substance and the second substace.
  • the volume of the mixture can be any suitable volume, such as about 10 microliters, about 30 microliters, about 40 microliters, about 45 microliters, about 50 microliters, about 55 microliters, about 60 microliters, about 70 microliters, about 75 microliters, about 80 microliters, about 90 microliters, about 100 microliters, about 200 microliters, about 500 microliters, about 1 milliliter, about 2 milliliters, about 3 milliliters, about 4 milliliters, about 5 milliliters, and all values and ranges in between.
  • the volume of the mixture is from about 50 microliters to about 75 microliters.
  • aspects of the assembly 9000 and/or the method 10000 are hence beneficial for mixing two or more substances, such as active agents, that need to be mixed and/or otherwise combined prior to delivery and/or storage.
  • a high degree of mixing can be achieved via repeated transfer of portions of the first substance, the second substance, and the mixture between the first container 9200A, the second container 9200B, and the pathway 9118 of the adapter 9100 by repeated and alternating actuation of the plungers 9218A, 9218B by a user.
  • Additional substances can be mixed via the 9000 and/or the method 10000 such as by, for example, mixing the first substance and the second substance, transferring the mixture to the first container, replacing the second container with a third container including a third substance, and mixing the mixture of the first substance and the second substance in the first container with the third substance in the third container.
  • Thorough mixing can also permit accurate dosing of each of the substances being mixed, since there is little to no dead volume in the assembly 9000.
  • the assembly 9000 and/or method 10000 can be particularly applicable for mixing when one of the substances is sensitive to agitation.
  • a non-limiting example is Fovista®, an anti-PDGF agent that can undergo pegylation with conventional mixing techniques.
  • FIGS. 11A-11B show a schematic illustration of a mixing apparatus 11000 according to an embodiment, in a first configuration and a second configuration.
  • the apparatus 1 1000 includes a housing 1 1 100 that includes a first port 1 1104A.
  • the first port 11104A is configured to be coupled to a first container 1 1200A.
  • the first container 1 1200A contains a first substance.
  • the first port 1 1104 A includes a piercing needle 1 1 124A configured to pierce a membrane 1 1 128A of the first container 1 1200A to establish fluid communication between the first pathway 11 1 12A and the first container 11200A.
  • the housing 11 100 further includes a second port 11 104B configured to be coupled a second container 11200B containing a second substance.
  • the second port 1 1 104B includes a piercing needle ⁇ ⁇ 124B configured to pierce a membrane 11 128B of the second container 11200B to establish fluid communication between the second pathway 11 1 12B and the second container 1 1200B.
  • first container 1 1200A and/or the second container 1 1200B can include a septum and/or housing (similar to the housing 2010 or the housing 2010'), which provides a piercable membrane or substance.
  • the housing 1 1000 can accommodate a vial or ampule with a crimp seal (i.e., a piercable membrane).
  • a crimp seal i.e., a piercable membrane.
  • the first port 1 1104A and/or the second port 1 1 104B eed not include a piericing needle.
  • the first substance and the second substance are independently a vascular endothelial growth factor (VEGF) antagonist, a platelet-derived growth factor (PGDF) antagonist, or an anti-C5 agent.
  • VEGF vascular endothelial growth factor
  • PGDF platelet-derived growth factor
  • VEGF vascular endothelial growth factor
  • the housing 11 100 further includes a third port 1 1 108 configured to be coupled to a needle, such as a staked needle of a syringe (not shown). As shown, the housing 1 1 100 defines a first flow pathway 1 1 1 12 A, a second flow pathway 1 11 12B, and a third flow pathway 1 11 16. In some embodiments, the first flow pathway 11 112 A is in fluid communication with the first port 1 1104A, the second flow pathway 1 1 1 12 B is in fluid communication with the second port 1 1 104B and the third flow pathway 1 11 16 is in fluid communication with the third port 11 108.
  • the apparatus 11000 further includes a valve 1 1 120 that is configured to selectively place the first pathway 1 11 12A in fluid communication with one of the second pathway ⁇ ⁇ 12 ⁇ or the third pathway 11 116.
  • the valve 1 1 120 is configured to selectively place the second pathway 1 1 112B in fluid communication with one of the first pathway 11 112 A or the third pathway 1 1 1 16. In this manner, mixing and delivery of the first substance and the second substance can be controlled.
  • the apparatus 1 1000 further includes a first plunger 1 1136A and a second plunger 1 1 136B.
  • the first plunger 1 1136A is configured to engage the first container 1 1200A, and is configured to convey the first substance from the first container 1 1200A into the first pathway 1 1104 A when the first plunger is actuated.
  • the second plunger 1 1136B is configured to convey the second substance from the second container 1 1200B into the second pathway 1 1 104B when the second plunger is actuated.
  • FIG. 11 A illustrates the first container 11200A as including an elastomeric member 1 1132A, which can be similar to the elastomeric member 4010 and/or the elastomeric member 8010.
  • FIG. 11 A illustrates the first container 11200A as including an elastomeric member 1 1132A, which can be similar to the elastomeric member 4010 and/or the elastomeric member 8010.
  • FIG. 1 1A also illustrates a plunger 1 1 136A that can be similar to the plunger 8020, or any suitable plungers capable of moving the elastomeric member 1 1132A.
  • a plunger ⁇ 136 ⁇ is illustrated as capable of moving an elastomeric member (not visible) within the second container 11200B.
  • the apparatus 11000 is shown and described as including the first plunger 1 1136A and the second plunger 1 1 136B, in other embodimens, the apparatus need not include any plungers.
  • the apparatus 1 1000 can include any suitable mechanism for actuating the first container 11200A and/or the second container 11200B.
  • Containers 1 1200A, 1 1200B can be coupled to the housing 1 1100 by insertion in the direction AA, BB, respectively such that, for example, membrane portions formed on the containers are pierced by needles of the housing.
  • the first container 11200 A is in fluid communication with the first pathway 1 H I2A
  • the second container is in fluid communication with the second pathway 111 12B.
  • the valve 1 1 120 can moved to selectively place the first pathway 11 1 12A and the second pathway 1 11 12B in fluid communication, while preventing access to the third pathway 1 1 16
  • portions of the first substance, the second substance, and a mixture thereof can be repeatedly transferred between the first container 1 1200A, the first pathway 11 112A, the second pathway 1 1112B, and the second container 1 1200B, as indicated by the birectional flow CC.
  • the mixture can be transferred to the first container 1 1200A, to the second container 1 1200B, or both (or neither).
  • valve 1 1120 When the mixture or a path thereof resides in the first container 1 1200A, the valve 1 1120 can then be configured to selectively place the first pathway 1 1 1 12A in fluid communication with the third pathway 1 1 1 16, and the mixture can be transferred from the first container to the third pathway and out of port 1 1108 in the direction DD, When the mixture or a path thereof resides in the second container 1 1200B, the valve 1 1120 can then be configured to selectively place the second pathway 1 1 1 12B in fluid communication with the third pathway 1 1 16, and the mixture can be transferred from the second container to the third pathway and out of port 11 108 in the direction DD.
  • FIG. 12 illustrates a method 12000, according to some embodiments.
  • the method 12000 can be generally directed to preparing one or more substances for delivery, mixing two or more substances using an apparatus and/or adapter with three or more ports, and/or the like.
  • the method 12000 can be performed using any suitable mechanism or assembly.
  • the method 12000 includes, at 12100, coupling, to a first port (e.g., the port 1 1104A) of a housing (e.g., the housing 1 1 100) of an apparatus (e.g., the apparatus 1 1000), a first container (e.g., the first container 11200A) containing a first substance.
  • a first port e.g., the port 1 1104A
  • a housing e.g., the housing 1 1 100
  • an apparatus e.g., the apparatus 1 1000
  • a first container e.g., the first container 11200A
  • coupling the first container includes piercing a membrane (e.g., the membrane 11 128A) of the first container with a piercing needle (e.g., the piercing needle 1 1 124A) of the first port to establish fluid communication between the first pathway and the first container.
  • a membrane e.g., the membrane 11 128A
  • a piercing needle e.g., the piercing needle 1 1 124A
  • the method 12000 further includes, at 12200, coupling, to a second port (e.g., the port 1 1 104B) of the housing, a second container (e.g., the second container I I200B).
  • the second container contains a second substance.
  • the first substance and the second substance are independently a. vascular endothelial growth factor (VEGF) antagonist, a platelet-derived growth factor (PGDF) antagonist, or an anti-C5 agent.
  • one of the first substance and the second substance includes a platelet-derived growth factor (PGDF) antagonist
  • the other of the first substance and the second substance includes a vascular endothelial growth factor (VEGF) antagonist.
  • the method 12000 further includes, at 12300, selectively placing a first pathway (e.g., the first pathway 1 1 I I2A) of the housing in fluid communication with a second pathway (e.g., the first pathway 111 12B) of the housing.
  • the first pathway is in fluid communication with the first port
  • the second pathway is in fluid communication with the second port.
  • the method 12000 further includes, at 12400, transferring at least a portion of the first substance to the second container via the first pathway and the second pathway.
  • the transferring at operation 12400 includes producing a mixture of the portion of the first substance and the second substance in the second container.
  • the method 12000 further includes transferring the mixture to a third pathway (e.g., the third pathway 11 116) of the housing, where the third pathway in fluid communication with a third port (e.g., the third port 1 1108).
  • the method 12000 further includes, prior to the transferring the mixture to the third pathway, selectively placing at least one of the first pathway in fluid communication with the third pathway, or the second pathway in fluid communication with the third pathway.
  • the method 12000 further includes coupling the third port of the housing to a needle, and dispensing the mixture via the third port.
  • transferring the mixture to the third pathway can include conveying a portion of the mixture to the first container, to the first pathway, or both.
  • the method 12000 can further include selectively placing the first pathway in fluid communication with the third pathway.
  • the method 12000 can further include conveying the portion of the mixture to the third pathway, and selectively placing the second pathway in fluid communication with the third pathway.
  • the method 12000 can further include conveying a remainder portion of the mixture to the third pathway.
  • transferring the mixture to the third pathway can include conveying a portion of the mixture to the first container, to the first pathway, or both.
  • the method 12000 can further include selectively placing the first pathway in fluid communication with the third pathway, and conveying the mixture to the third pathway.
  • transferring the mixture to the third pathway can include conveying a portion of the mixture to the first container, to the first pathway, or both.
  • the method 12000 can further include selectively placing the first pathway in fluid communication with the third pathway, and conveying the mixture to the third pathway.
  • transferring the mixture to the third pathway can include selectively placing the second pathway in fluid communication with the third pathway, and conveying the mixture to the third pathway.
  • coupling the first container at 12100 includes piercing a membrane (e.g., the membrane 1 1128A) of the first container with a piercing needle (e.g., the piercing needle 1 1 124A) of the first port to establish fluid communication between the first pathway and the first container.
  • coupling the second container at 12200 includes piercing a membrane (e.g., the membrane 1 1 128B) of the second container with a piercing needle (e.g., the piercing needle 1 1124B) of the second port to establish fluid communication between the second pathway and the second container.
  • kits can include a first container containing a first substance including a platelet-derived growth factor (PGDF) antagonist.
  • the kit can further include a second container containing a second substance including a vascular endothelial growth factor (VEGF) antagonist.
  • the kit can further include a mixing apparatus configured to couple to the first container and the second container to permit mixing of the first substance and the second substance.
  • PGDF platelet-derived growth factor
  • VEGF vascular endothelial growth factor
  • the mixing apparatus is substantially similar to the adapter 9100, and is usable in a manner as substantially described by the method 10000.
  • the mixing apparatus includes a housing including a. first port configured to be coupled to the first container containing a first substance.
  • the housing further includes a second port configured to be coupled the second container containing a second substance.
  • the housing further includes a third port configured to be coupled to a needle.
  • the housing defines a first flow pathway, a second flow pathway and a third flow pathway. The first flow pathway is in fluid communication with the first port, the second flow pathway is in fluid communication with the second port and the third flow pathway is in fluid communication with the third port.
  • the mixing apparatus further includes a first plunger configured to engage the first container.
  • the first plunger is further configured to convey the first substance from the first container into the first pathway when the first plunger is actuated.
  • the mixing apparatus further includes a second plunger configured to engage the second container.
  • the second plunger is further configured to convey the second substance from the second container into the second pathway when the second plunger is actuated.
  • the mixing apparatus is substantially similar to the apparatus 1 1000, and is usable in a manner as substantially described by the method 12000.
  • the mixing apparatus includes a first port configured to couple the first container, and a second port configured to couple the second container.
  • the mixing apparatus further includes a pathway in fluid communication with the first port and the second port. The pathway receives the first substance from the first container via the first port.
  • the pathway further receives the second substance from the second container via the second port to generate a mixture including the first substance and the second substance.
  • the mixing apparatus further includes a third port in fluid communication with the pathway, the third port configured to convey the mixture.
  • the mixing apparatus further includes one or more of the following: a female tapered portion (e.g., a female Luer Lock) formed on the first port; a female tapered portion (e.g., a female Luer Lock) formed on the second port; a pierceable membrane portion formed on the first port; and a pierceable membrane portion formed on the second port.
  • a female tapered portion e.g., a female Luer Lock
  • a female tapered portion e.g., a female Luer Lock
  • a pierceable membrane portion formed on the first port
  • a pierceable membrane portion formed on the second port e.g., a pierceable membrane portion formed on the second port.
  • the method 3000 is described as comprising both an inserting operation (at 3100) and a piercing operation (at 3200), in some embodiments, a method can comprise both inserting and piercing in substantially the same operation.
  • the methods and apparatus are also useful for conveying one or more medicaments to any suitable target location.
  • the target location is an ear of a subject, an artery or vein of a subject, a muscle of a. subject, an organ of a subject, and/or the like.
  • the target location is a container such as a vial, a syringe, a cartridge, an infusion bag, and/or the like.
  • a septum can have a sealing portion characterized by any suitable geometry.
  • a septum can comprise a sealing portion configured to seal a distal-end surface of a syringe having any suitable geometry, but that is devoid of a tip or protrusion that is disposed into to an exit lumen of the syringe.
  • a septum can comprise a sealing portion having a curved surface.
  • a diameter of a guide opening can be less than or equal to a diameter of an exit lumen of a syringe. In other embodiments, a guide opening can have a diameter that is about 75 percent or less of a diameter of an exit lumen of a syringe.
  • the containers, delivery devices and/or methods disclosed herein can contain any suitable amount of any substance(s).
  • a syringe as shown herein can be a single-dose device containing an amount of from about 50 microliters to about 75 microliters of a pharmaceutical composition comprising one or more active agents.
  • the fill volume can be such that the ratio of the delivery volume to the fill volume is any suitable value (e.g., about 0.4, about 0.6 or the like).
  • any of the embodiments described here can be applied and/or used in conjunction with any suitable medicament container, whether containing a substance or empty.
  • an elastomeric member such as the elastomeric member 8010 can be configured to be disposed within a pre- fiilable syringe.
  • the elastomeric member 8010 (or any of the other elastomeric member described herein) can be configured to be included with a medicament container that does not contain any substance.
  • FIG, 9 illustrates the mixing adapter 9100 as a two-port adapter, in some embodiments described above, a third port can also be present.
  • Any of the ports can include a membrane portion formed in a manner substantially similar to the housing 2010 or the housing 2010'.
  • any suitable port(s) can be configured for injecting one or more substances, or a mixture thereof, into the pathway 9100, and any suitable port(s) can be configured for receiving the one or more substances, or a mixture thereof, into a container, syringe, etc. coupled to the port(s). Fluid communication between the various ports can be controlled by a valve,
  • FIGS, 1 1A, 1 I B illustrate the mixing apparatus 11000 as having ports 11 104A, 1 1104B configured to accepting filled containers 11200A, 11200B, respectively
  • any of the ports ⁇ 104 ⁇ , ⁇ 104 ⁇ , and 11 108 can be configured for injecting one or more substances, or a mixture thereof, into the pathways of the housing 11 100.
  • any of the ports I I 104A, 1 1104B, and I I 108 can be configured for receiving the one or more substances, or a mixture thereof, into a container, syringe, etc. coupled to the port(s).
  • the second container 1 1200B can be an empty container (e.g., an empty staked needle syringe or an empty Luer syringe), and a substance-containing syringe can be coupled to the third port 11 108, such as via. a membrane portion formed on the third port.
  • the substance can be drawn into the first container 1 1200A, and then transferred to the second container 1 1200B (e.g. by manipulating the valve 11 120, etc.).
  • the first container 1 1200A can contain a first substance and the second container 1 1200B can be an empty container.
  • a second substance-containing syringe can be coupled to the third port 1 1108, such as via a membrane portion formed on the third port.
  • the second substance and the first substance can be mixed between the first container 11200A, the first pathway 11 112A, the third pathway 111 16, and the second substance-containing syringe can be coupled to the third port 1 1 108. The mixture can then be transferred to the second container 1 1200B.
  • both the first container 11200A and the second containter 1 1200B can be empty, and a substance-containing syringe can be coupled to the third port 11 108.
  • the substance can be drawn into both the first container 1 1200A, and the second container 1 1200B.
  • a method of treating a patient suffering from an ophthalmological disease includes administering one or more substances, or a mixture thereof, to the patient using at least one of the apparatus according to FIGS. 1 , 2, 4, 6-9, or 1 1 as described above, or the kit as described above.
  • each of the one or more substances is independently selected from a VEGF antagonist, a PGDF antagonist, and an anti-C5 agent.
  • any suitable volume including the one or more substances, or a mixture thereof can be mixed and/or administered via the apparatus(es) and method(s) disclosed herein.
  • the volume of the mixture can be about 10 microliters, about 30 microliters, about 40 microliters, about 45 microliters, about 50 microliters, about 55 microliters, about 60 microliters, about 70 microliters, about 75 microliters, about 80 microliters, about 90 microliters, about 100 microliters, about 200 microliters, about 500 microliters, about 1 milliliter, about 2 milliliters, about 3 milliliters, about 4 milliliters, about 5 milliliters, and all values and ranges in between.
  • the volume of the mixture is from about 50 microliters to about 75 microliters.
  • any of the devices, containers and/or methods shown and described herein can comprise and/or be used in conjunction with any suitable substance or substances.
  • suitable substance or substances can include those disclosed in U.S. Provisional Application No. 61/845,936, filed July 12, 2013, the disclosure of which is incorporated herein in its entirety, which describes combinations of medicaments for treating ophthalmic disorders
  • the first substance and/or the second substance and/or the third substance, etc. as described in conjunction with the methods and devices disclosed herein comprises any suitable active agent, such as a. platelet-derived growth factor (PGDF) antagonist of the types shown and described herein.
  • PGDF platelet-derived growth factor
  • the first substance and/or the second substance and/or the third substance, etc., as described in conjunction with the methods and devices disclosed herein comprises a vascular endothelial growth factor (VEGF) antagonist of the types shown and described herein.
  • VEGF vascular endothelial growth factor
  • the first substance and/or the second substance and/or the third substance, etc. as described in connection with, the methods and devices disclosed herein comprises an anti-C5 agent, such as those shown and described herein.
  • two of the active agents are selected from a PDGF antagonist, a VEGF antagonist and an anti-C5 agent.
  • two of the active agents are a PDGF antagonist and a VEGF antagonist.
  • two of the active agents are a PDGF antagonist and an anti-C5 agent.
  • two of the active agents are a VEGF antagonist and an anti-C5 agent.
  • one of the active agents is a PDGF antagonist and one of the active agents is a. VEGF antagonist.
  • one of the active agents is a PDGF antagonist and one of the active agents is an anti-C5 agent.
  • one of the active agents is a VEGF antagonist and one of the active agents is an anti- C5 agent.
  • the PDGF antagonist is an aptamer, optionally a pegylated aptamer.
  • the VEGF antagonist is an antibody or fragment thereof, or a fusion protein.
  • the anti-C5 agent is an aptamer, optionally a pegylated aptamer.
  • the PDGF antagonist is an antagonist of PDGF-B, such as Antagonist A or a modified version thereof.
  • the VEGF antagonist is bevacizumab, ranibizumab, ailibercept, or pegaptanib sodium.
  • the PDGF antagonist is Antagonist A, and the VEGF antagonist is bevacizumab; the PDGF antagonist is Antagonist A, and the VEGF antagonist is ranibizumab; the PDGF antagonist is Antagonist A, and the VEGF antagonist is ailibercept; or the PDGF antagonist is Antagonist A, and the VEGF antagonist is pegaptanib sodium.
  • Antagonist A is present in a composition comprising 30.0 mg of Antagonist A, 0.3 mg of monobasic sodium phosphate monohydrate, 2.1 mg of dibasic sodium phosphate heptahydrate and 9.0 mg of sodium chloride per 1 mL.
  • hydrochloric acid and/or sodium hydroxide are added as needed to adjust the pH of the composition.
  • the pH is about pH 5.5 to about pH 7.5 or about pH 6.0.
  • Antagonist A is present in a composition compriing 3% (w/v) of Antagonist A, 0.03% (w/v) of monobasic sodium phosphate monohydrate, 0.2% (w/v) of dibasic sodium phosphate heptahydrate, 0.9% (w/v) of sodium chloride and 95.9% (w/v) of water.
  • hydrochloric acid and/or sodium hydroxide are added as needed to adjust the pH of the composition.
  • the pH is about pH 5.5 to about pH 7.5 or about pH 6.0.
  • the anti-C5 agent is ARC 1905.
  • the PDGF antagonist is Antagonist A
  • the anti- C5 agent is ARC 1905.
  • the VEGF antagonist is bevacizumab, ranibizumab, ailibercept, or pegaptanib sodium
  • the anti-C5 agent is ARC 1905.
  • the dazzling-C5 agent is ARC 1905, and the VEGF antagonist is bevacizumab
  • the anti-C5 agent is ARC-1905
  • the VEGF antagonist is ranibizumab
  • the anti-C5 agent is ARC ! 905, and the VEGF antagonist is aflibercept
  • the anti-C5 agent is ARC 1905
  • the VEGF antagonist is pegaptanib sodium.
  • an active agent is a PDGF antagonist.
  • PDGF antagonist refers to an agent that reduces, or inhibits, either partially or fully, the activity or production of a PDGF.
  • the PDGF antagonist inhibits one or more of PDGF -A, PDGF-B, PDGF--C and PDGF-D.
  • the PDGF antagonist inhibits one or more of PDGF-A, PDGF-B, and PDGF-C.
  • the PDGF antagonist inhibits a dimerized form of PDGF, such as PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD.
  • the PDGF antagonist inhibits PDGF- BB. In other embodiments, the PDGF antagonist inhibits PDGF-AB.
  • a PDGF antagonist can directly or indirectly reduce or inhibit the activity or production of a specific PDGF such as PDGF-B.
  • PDGF antagonists consistent with the above definition of "antagonist,” include agents that act on a PDGF ligand or its cognate receptor so as to reduce or inhibit a PDGF-associated receptor signal.
  • PDGF antagonists include antisense molecules, ribozymes or RNAi that target a PDGF nucleic acid; anti-PDGF aptamers, anti-PDGF antibodies to PDGF itself or its receptor, or soluble PDGF receptor decoys that prevent binding of a PDGF to its cognate receptor; antisense molecules, ribozymes or RNAi that target a cognate PDGF receptor (PDGFR) nucleic acid; anti-PDGFR aptamers or anti-PDGFR antibodies that bind to a cognate PDGFR receptor; and PDGFR tyrosine kinase inhibitors.
  • PDGFR tyrosine kinase inhibitors.
  • PDGF refers to a platelet-derived growth factor that regulates cell growth or division.
  • the term “PDGF” includes the various subtypes of PDGF including PDGF-B (see Figure 1 (A) and (B) of US Patent Application Publication No. 20120100136, which is incorporated by reference in its entirety), PDGF-A (see Figure 1(C) and (D) of US Patent Application Publication No. US20120100136), PDGF-C (see Figure 1(E) and (F) of US Patent Application Publication No. 20120100136), PDGF-D, variants 1 and 2 (see Figure 1(G), (H), (I) and (J) of US Patent Application Publication No.
  • Platelet derived growth factors includes homo- or heterodimers of A-chain (PDGF-A) and B-chain (PDGF-B) that exert their action via binding to and dimerization of two related receptor tyrosine kinase platelet-derived growth factor cell surface receptors (i.e. , PDGFRs), PDGFR-ct (see Figure 3 (C) and (D) of US Patent Application Publication No. 20120100136) and PDGFR- ⁇ (see Figure 3 (A) and (B) of US Patent Application Publication No. 20120100136).
  • PDGFRs two related receptor tyrosine kinase platelet-derived growth factor cell surface receptors
  • PDGF-C and PDGF-D two additional protease-activated ligands for the PDGFR complexes, have been identified (Li et al, (2000) Nat. Ceil. Biol. 2: 302-9; Bergsten et al, (2001 ) Nat. Cell. Biol. 3 : 512-6; and Uutele et al, (2001 ) Circulation 103 : 2242-47).
  • PDGFR- ⁇ / ⁇ binds PDGF-AA, PDGF-BB, PDGF-AB, and PDGF-CC; PDGFR- ⁇ / ⁇ binds PDGF-BB and PDGF-DD; whereas PDGFR- ⁇ / ⁇ binds PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD (Betsholtz et al, (2001) BioEssays 23 : 494-507).
  • the term "PDGF” also refers to those members of the class of growth factors that induce DNA synthesis and mitogenesis through the binding and activation of a PDGFR on a.
  • PDGFs can effect, for example: directed cell migration (chemotaxis) and cell activation; phospholipase activation; increased phosphatidylinositol turnover and prostaglandin metabolism; stimulation of both collagen and coflagenase synthesis by responsive ceils; alteration of cellular metabolic activities, including matrix synthesis, cytokine production, and lipoprotein uptake; induction, indirectly, of a proliferative response in cells lacking PDGF receptors; and potent vasoconstrictor activity.
  • the term "PDGF” can be used to refer to a "PDGF" polypeptide, a "PDGF” encoding gene or nucleic acid, or a dimerized form thereof.
  • the PDGF antagonist is ARC 127, Antagonist A, Antagonist B, Antagonist C, Antagonist D, 1B3 antibody, CDP860, IMC-3G3, imatinib, 162.62 antibody, 163.31 antibody, 169.14 antibody, 169.31 antibody, aRl antibody, 2A1E2 antibody, M4TS.1 1 antibody, M4TS.22 antibody, A10, brefeldin A, sunitinib, Hyb 120.1.2, 1.2 antibody, Hyb 121.6.1.1.1 antibody, Hyb 127.5.7.3.1 antibody, Hyb 127.8.2.2.2 antibody, Hyb 1.6.1 antibody, Hyb 1.1 1.1 antibody, Hyb 1 .17.1 antibody, Hyb 1 .18.1 antibody, Hyb 1.19.1 antibody, Hyb 1.23.1 antibody, Hyb 1.24 antibody, Hyb 1.25 antibody, Hyb 1.29 antibody, Hyb 1 .33 antibody, Hyb 1.38 antibody, Hyb 1.39 antibody, Hyb 1.40 antibody, Hy
  • the PDGF antagonist is a PDGF Trap.
  • the PDGF Trap comprises the extracellular domain of a PDGFR fused to an Fc portion of an immunoglobulin.
  • the PDGF Trap is a chimera consisting of the extracellular domain of PDGFRa fused to human XgG Fc5 (Pennock and Kazlauskas (2012) Mol. Cell. Biol. 2012, 32(10): 1955-3966).
  • the PDGF antagonist comprises an extracellular domain of a PDGF receptor and a immunoglobulin constant region.
  • the PDGF antagonist is a "PDGF-Trap.”
  • the PDGF-Trap comprises an extracellular domain of human PDGFR and human Fc5, such as described in Lei et al., (2009) IOVS, 50(7):3394-3403 and Mol. Cell. Biol. (2012), which is incorporated by reference in its entirety.
  • the PDGF -Trap is from Regeneron Pharmaceuticals, Inc. (Tanytown, NY), such as described in Lu et al., (2008) Am. J. Obstet. Gynecol. ! 98(4):477.el -477.e!Q, which is incorporated by reference in its entirety.
  • the PDGF antagonist is ARC! 27.
  • ARC 127 is a PEGylated, anti-PDGF aptamer having the sequence CAGGCUACGN CGTAGAGCAU CANTGATCCU GT (see Examples 3 and 6 of US Patent Application Publication No.
  • the PEG group of ARC 127 is straight or branched, and has a molecular weight of about 10 kD to about 80 kD, e.g., about 10 kD, about 20 kD, about 30 kD, about 40 kD, about 50 kD, about 60 kD, about 70 kD or about 80 kD.
  • the PDGF antagonist a compound of Formula A (disclosed in U.S. Patent Application Publication No. 20120100136), wherein w is an integer from 2 to 12.
  • the PDGF antagonist is Antagonist A (disclosed in U.S. Patent Application Publication No. 20120100136), or a modified version thereof, or a pharmaceutically acceptable salt thereof.
  • the chemical name of Antagonist A is [(monomethoxy 20K polyethylene glycol carbamoyl-N2 ⁇ ) (monomefhoxy 20K polyethylene glycol carbamoyl-N6-)]-lysine-amido-6-hexandiiyl-( 1-5')- 2 -deoxycytidylyl -(3'-5')-2'- deoxyadeny]yl-(3'-5')-2'-deoxyguanylyl-(3'-5')- 2'-deoxyguanylyl-(3'-5')-2 , -deoxycytidylyl- (3 , -5')-2'-deoxy-2 , -fluorouridylyl- (3 , -5 , )-2 ,
  • an active agent a VEGF antagonist.
  • VEGF antagonist refers to an agent that reduces, or inhibits, either partially or fully, the activity or production of a VEGF.
  • a VEGF antagonist can directly or indirectly reduce or inhibit the activity or production of a specific VEGF such as VEGF 155-
  • VEGF antagonists consistent with the above definition of "antagonist,” include agents that act on either a VEGF ligand or its cognate receptor so as to reduce or inhibit a VEGF-associated receptor signal.
  • VEGF antagonists include antisense molecules, ribozymes or RNAi that target a VEGF nucleic acid; anti-VEGF aptamers, anti-VEGF antibodies to VEGF itself or its receptor, or soluble VEGF receptor decoys that prevent binding of a VEGF to its cognate receptor; antisense molecules, ribozymes, or RNAi that target a cognate VEGF receptor (VEGFR) nucleic acid; anti-VEGFR aptamers or anti-VEGFR antibodies that bind to a cognate VEGFR receptor; and VEGFR tyrosine kinase inhibitors.
  • VEGFR VEGFR tyrosine kinase inhibitors.
  • inhibitory antibodies directed against VEGF are known in the art, e.g., those described in U.S. Patent Nos. 6,524,583, 6,451 ,764 (VRP antibodies), 6,448,077, 6,416,758, 6,403,088 (to VEGF-C), 6,383,484 (to VEGF-D), 6,342,221 (anti-VEGF antibodies), 6,342,219 6,33 1 ,301 (VEGF-B antibodies), and 5,730,977, and PCX publications W096/30046, WO 97/44453 , and WO 98/4533 1 , the contents of which are incorporated by reference in their entirety.
  • VEGF refers to a vascular endothelial growth factor that induces angiogenesis or an angiogenic process.
  • VEGF includes the various subtypes of VEGF (also known as vascular permeability factor (VPF) and VEGF-A) (see Figure 2(A) and (B) of US Patent Application Publication No. 20120100136) that arise by, e.g., alternative splicing of the VEGF-A/VPF gene including VEGF121, VEGF j 65 and VEGF 18 .
  • VEGF includes VEGF -related angiogenic factors such as PIGF (placenta growth factor), VEGF-B, VEGF-C, VEGF-D and VEGF-E, which act through a cognate VEFG receptor (i.e., VEGFR) to induce angiogenesis or an angiogenic process.
  • VEGF includes any member of the class of growth factors that binds to a VEGF receptor such as VEGFR- 1 (Flt-1) (see Figure 4(A) and (B) of US Patent Application Publication No. 20120100136), VEGFR-2 (KDR/Flk- 1) (see Figure 4(C) and (D) of US Patent Application Publication No.
  • VEGF can be used to refer to a "VEGF” polypeptide or a "VEGF” encoding gene or nucleic acid.
  • the VEGF antagonist is a VEGF-A antagonist.
  • the VEGF antagonist is a peptide, e.g., a peptide comprising three or more amino acid residues.
  • the VEGF antagonist is a bicyclic peptide.
  • the VEGF antagonist inhibits one or more of VEGFA, VEGFB, VEGFC or VEGFD.
  • the VEGF antagonist is ranibizumab, bevacizumab, aflibercept, KH902 VEGF receptor-Fc fusion protein, 2C3 antibody, ORA102, pegaptanib, bevasiranib, SIR A-027, decursin, decursinol, picropodophyllin, guggulsterone, PLG101, eicosanoid LXA4, PTK787, pazopanib, axitinib, CDDO-Me, CDDO-Imm, shikonin, beta- hydroxyisovalerylshikonin, or ganglioside GM3, DC .101 antibody, Mab25 antibody, Mab73 antibody, 4A5 antibody, 4E10 antibody, 5F .12 antibody, VA01 antibody, BL2 antibody, VEGF-related protein, sFLTOl, sFLT02, Peptide B3, TG100801, sorafenib, simitn
  • the VEGF antagonist is the antibody ranibizumab or a pharmaceutically acceptable salt thereof (see U.S. Pat. No. 7,060,269 ( Figure 1) for the heavy chain and light chain variable region sequences, which is hereby incorporated by reference in its entirety).
  • Ranibizumab is commercially available under the trademark Lucentis (Genentech USA, Inc., a member of the Roche Group).
  • the VEGF antagonist is the antibody bevacizumab or a pharmaceutically acceptable salt thereof (see U.S. Pat. No. 6,054,297 ( Figure 1 ) for the heavy chain and light chain variable region sequences, which is hereby incorporated by reference in its entirety).
  • Bevacizumab is commercially available under the trademark Avastin (Genentech USA, Inc., a member of the Roche Group).
  • the VEGF antagonist is aflibercept or a pharmaceutically acceptable salt thereof (Do et al. (2009) Br J Ophthalmol. 93 : 144-9, which is hereby- incorporated by reference in its entirety).
  • Aflibercept is commercially available under the trademark Eylea (Regeneron Pharmaceuticals, Inc.).
  • the VEGF antagonist is KH902 or a pharmaceutically acceptable salt thereof (Zhang et al. (2008) Mol Vis. 14:37-49, which is hereby incorporated by reference in its entirety).
  • the VEGF antagonist is the antibody 2C3 or a pharmaceutically acceptable salt thereof (U.S. Pat. No. 6,342,221 (Column 8, lines 48-67, Column 9, lines 1-21), which is hereby incorporated by reference in its entirety).
  • the VEGF antagonist is ORA 102 or a pharmaceutically acceptable salt thereof (Ora Bio, Ltd).
  • the VEGF antagonist is pegaptanib or a pharmaceutically acceptable salt thereof, such as pegaptanib sodium (U.S. Pat, No. 6,051,698 ( Figure 1), which is hereby incorporated by reference in its entirety).
  • a composition comprising pegaptanib is commercially available under the trademark Macugen (Valeant Ophthalmics, a division of Valeant Pharmaceuticals North America LLC).
  • the VEGF antagonist includes antibody mimetics (e.g., Affibody® molecules, affilins, affitins, anticalins, avimers, unitz domain peptides, and monobodies) with VEGF antagonist activity.
  • antibody mimetics e.g., Affibody® molecules, affilins, affitins, anticalins, avimers, unitz domain peptides, and monobodies
  • MP0112 also known as AGN 150998 (DARPin®).
  • the ankyrin binding domain may have an amino acid sequence of SEQ ID NO: 97.
  • the VEGF antagonist is E8BA1008 or a pharmaceutically acceptable salt thereof (see U.S. Patent No. 8,349,322).
  • the active agent is an anti-C5 agent.
  • the anti-C5 agent modulates a function of a C5 complement protein or a variant thereof.
  • the anti-C5 agent inhibits a function of C5 complement protein or a variant thereof, in some embodiments in vivo, in some embodiments in vivo in humans.
  • the function modulated, in some embodiments inhibited, by the anti-C5 agent is C5 complement protein cleavage.
  • An anti-C5 agent can directly or indirectly reduce or inhibit the activity or production of a C5 complement protein or variant thereof.
  • An anti-C5 agent can reduce or inhibit the conversion of C5 complement protein into its component polypeptides C5a and C5b.
  • Anti-C5 agents can also refer to agents that reduce or inhibit the activity or production of C5a and/or C5b.
  • anti-C5 agents include antisense molecules, ribozymes or R Ai that target a C5 nucleic acid; anti-C5 aptamers including anti-C5a and anti-C5b aptamers, anti-C5 antibodies directed against C5, C5a, or C5b, or soluble C5 receptor decoys that prevent binding of a C5 complement protein or variant or fragment thereof (e.g. C5a or C5b) to a binding partner or receptor.
  • a C5 complement protein or variant or fragment thereof e.g. C5a or C5b
  • a C5 complement protein variant as used herein encompasses variants thai perform essentially the same function as a C5 complement protein function.
  • a C5 complement protein variant in some embodiments comprises substantially the same structure and in some embodiments comprises at least 80% sequence identity, in some embodiments at least 90% sequence identity, and in some embodiments at least 95% sequence identity to the amino acid sequence of the C5 complement protein comprising the amino acid sequence below (cited in Haviland et al. (1991) J Immunol.
  • eoi a 1® is yds 3 ⁇ 4vy ervfqf Isks
  • the anti-C5 agent is selected from a nucleic acid molecule, an aptamer, an antisense molecule, an RNAi molecule, a protein, a peptide, a cyclic peptide, an antibody or antibody fragment, a sugar, a polymer, or a. small molecule.
  • the anti-C5 agent is an anti-C5 agent described in PCT Patent Application Publication No. WO 2007/103549.
  • the anti-C5 agent is an anti-C5 aptamer.
  • Apiamers are nucleic acid molecules having specific binding affinity to molecules through interactions other than classic Watson-Crick base pairing.
  • Apiamers like peptides generated by phage display or monoclonal antibodies ("mAbs"), are capable of specifically binding to selected targets and modulating the target's activity, e.g., through binding aptamers may block their target's ability to function.
  • the C5 specific apiamers can be about 15 to about 60 nucleotides in length and bind specifically to complement protein C5 and functionally modulate, e.g., block, the activity of complement protein C5 in in vivo and/or cell-based assays.
  • the aptamers may be unpegyiated or pegylated.
  • the aptamers may contain one or more 2' sugar modifications, such as 2'-0- alkyl (e.g., 2'-0- methyl or 2'-0-methoxyethyl) or 2'-fTuoro modifications.
  • Illustrative C5 specific aptamers include the aptamers disclosed in PCT Publication No, WO 2007/103549, which is incorporated by reference in its entirety.
  • the C5 specific aptamer is an aptamer according to ARC 186 or an aptamer comprising a nucleotide sequence according to ARC 186 conjugated to a PEG moiety.
  • this ARC! 86 aptamer/PEG conjugate comprises substantially the same binding affinity for C5 complement protein as an aptamer consisting of the nucleotide sequence according to ARC 186, but lacking the PEG moiety.
  • substantially the same binding affinity as used herein means no more than about a 2 to ten fold difference, in some embodiments no more than a 2 to five fold difference in dissociation constants as measured by dot blot analysis.
  • the dissociation constants are measured by competition dot blot analysis.
  • the polyethylene glycol moiety has a molecular weight greater than 10 kDa, particularly a molecular weight of 20 kDa, more particularly 30 kDa and more particularly 40 kDa,
  • the PEG moiety is conjugated to the 5' end of ARC 186.
  • the PEG conjugated to the 5' end of ARC 186 is a 40 kDa PEG.
  • the 40 kDa PEG is a branched PEG.
  • the branched 40 kDa PEG is l,3-bis(rnPEG- [20 kDa])-propyl-2-(4'-butamide). In other embodiments the branched 40 kDa PEG is 2,3- bis(mPEG-[20 kDa])-propyl- 1 -carbamoyl .
  • the anti-C5 agent is an antagonist antibody directed against complement protein C5.
  • the C5 antagonist antibodies tightly bind C5 and prevent its activation and cleavage.
  • the antagonist antibodies include monoclonal inhibitory antibodies.
  • Monoclonal antibodies, or fragments thereof, encompass ail immunoglobulin classes such as IgM, IgG, IgD, IgE, IgA, or their subclasses, such as the IgG subclasses or mixtures thereof.
  • IgG and its subclasses are useful, such as IgGl, IgG2, IgG2a, IgG2b, IgG3 or IgGM.
  • the IgG subtypes IgGl kappa and IgG2b/kappa are included as useful embodiments.
  • Fragments which may be mentioned are all tnincaied or modified antibody fragments with one or two antigen-complementary binding sites which show high binding and neutralizing activity toward mammalian C5, such as parts of antibodies having a binding site which corresponds to the antibody and is formed by light and heavy chains, such as Fv, Fab or F(ab')2 fragments, or single-stranded fragments.
  • Tnincaied double-stranded fragments such as Fv, Fab or F(ab')2 are particularly useful These fragments can be obtained, for example, by enzymatic means by eliminating the Fc part of the antibody with enzymes such as papain or pepsin, by chemical oxidation or by genetic manipulation of the antibody genes. It is also possible and advantageous to use genetically manipulated, non-truncated fragments.
  • Ecuiizumab also known as SoiirisTM, Alexion, Cheshire, CT
  • Pexelizumab Alexion, Cheshire, CT
  • the anti-C5 agent is an antisense oligonucleotide or ribozyme targeted to C5 that effects C5 inhibition by inhibiting protein translation from the messenger KNA or by targeting degradation of the corresponding C5 rnR A.
  • the anti-C5 agent is an anti-C5 RNA interference (RNAi) construct
  • R Ai is a process of sequence-specific post-transcriptional gene repression that cars occur in eukaryotie cells. In general, this process involves degradation of an mRNA of a particular sequence induced by double-stranded RNA (dsRNA) that is homologous to that sequence.
  • RNAi may be effected by introduction or expression of relatively short homologous dsRNAs.
  • Certain double stranded oligonucleotides used to effect RNAi against C5 complement protein are less than 30 base pairs in length and may comprise about 25, 24, 23, 22, 21, 20, 19, 18 or about 17 base pairs of ribonucleic acid and comprise a sequence with substantial sequence identity to the mRNA sequence of complement C5 protein, particularly human complement CS protein.
  • the dsRNA oligonucleotides may include 3 ' overhang ends.
  • Non-limiting exemplary 2-nucleotide 3' overhangs may be composed of ribonucleotide residues of any type and may even be composed of 2'-deoxyfhymidine resides, which lowers the cost of RNA synthesis and may enhance nuclease resistance of siRNAs in the cell culture medium and within transfected cells (see Elbashi et al, (2001 ) Nature, 411 : 494-8).
  • the anti-C5 agent is a protein or polypeptide.
  • the anti-C5 agent is an anti-C5 protein or polypeptide agent described in U.S. Patent Nos. 5,212,071 ; 5,252,216; 5,256,642; 5,456,909; 5,472,939; 5,840,858; 5,856,297; 5,858,969; 5,981,481 ; 6,057, 131 ; 6,169,068 or 6,316,604, each of which is herein incorporated by reference in its entirety,

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Abstract

Cette invention concerne un appareil comprenant un boîtier présentant une partie d'accouplement et une partie d'accès. Ladite partie d'accès définit une ouverture de guidage. La partie d'accouplement est conçue de manière à être accouplée de manière amovible à une seringue (par exemple, une seringue pré-remplie ou apte à être pré-remplie) de telle façon que l'ouverture de guidage est alignée avec un canal de sortie défini par une pointe de la seringue. Ledit appareil comprend en outre une cloison accouplée au boîtier. Ladite cloison comprend une première partie de joint et une seconde partie de joint. Ladite première partie de joint est sensiblement plane et elle est conçue pour définir un joint sensiblement étanche aux fluides avec une surface d'extrémité distale de la pointe de la seringue. Ladite seconde partie de joint est conçue pour définir un joint sensiblement étanche aux fluides avec une paroi latérale de la pointe.
PCT/US2014/052400 2013-08-23 2014-08-22 Appareils et procédés destinés à la distribution d'une ou plusieurs substances à partir d'un contenant unique WO2015027219A2 (fr)

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CN106824886A (zh) * 2015-10-05 2017-06-13 德克萨斯医药集团控股有限公司 设备端口清洁器
TWI732800B (zh) * 2015-11-25 2021-07-11 美商拜耳保健公司 注射器填充適配器及流體傳輸組件

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DE29915878U1 (de) * 1999-09-09 2000-10-26 Disetronic Licensing Ag Vorrichtung zur Umfüllung von Arzneimitteln und Kanülenanordnung
US6585691B1 (en) * 2001-05-11 2003-07-01 Jonathan J. Vitello Tamper evident end cap assembly for a loaded syringe and process
US20060167435A1 (en) * 2003-02-18 2006-07-27 Adamis Anthony P Transscleral drug delivery device and related methods
US7632244B2 (en) * 2006-08-10 2009-12-15 Comar, Inc. Tamper evident tip cap assembly
US8353869B2 (en) * 2010-11-02 2013-01-15 Baxa Corporation Anti-tampering apparatus and method for drug delivery devices

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Publication number Priority date Publication date Assignee Title
CN106824886A (zh) * 2015-10-05 2017-06-13 德克萨斯医药集团控股有限公司 设备端口清洁器
TWI732800B (zh) * 2015-11-25 2021-07-11 美商拜耳保健公司 注射器填充適配器及流體傳輸組件

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