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    • 专利摘要:
    "Packaging System for Oxygen Sensitive Drugs". The present invention relates to pharmaceutical packaging systems that prevent the oxidative degradation of oxygen-sensitive drugs, wherein such systems include a main packaging container (3) with an oxygen permeable component, a secondary packaging (1) with a very low oxygen permeability, and an oxygen absorber (2).
    公开号:BR112015022171A2
    申请号:R112015022171-8
    申请日:2014-03-12
    公开日:2021-05-25
    发明作者:Thomas DEVOUASSOUX；Eric FORAT；James Kenneth PROCTOR
    申请人:Fresenius Kabi Deutschland Gmbh；
    IPC主号:
    专利说明:

    [001] [001] This patent application claims the benefit of U.S. Patent Application no. Serial 61/785,158, filed March 14, 2013, which is incorporated by reference herein in its entirety. BACKGROUND OF THE INVENTION
    [002] [002] The sensitivity to oxygen in drugs and their formulations is a major problem in pharmaceutical development. Often, the oxygen-sensitive drug or formulation requires additional excipients, packaging and/or manufacturing steps to enhance stability and prevent degradation. Chemical approaches such as controlling the pH, adding an antioxidant, and controlling the components are normally considered primarily as means to enhance the stability of oxygen-sensitive solutions. A downside of chemical approaches is the added complexity of the formulation and the additional research needed for the identity, compatibility and toxicity of appropriate excipients. The gasification of nitrogen of a solution and the coating with nitrogen of a container during and/or after filling a drug are also commonly used in the pharmaceutical industry. However, the efficiency of this process is limited and leads to a residual oxygen level of a small percentage. With this standard manufacturing and filling process, the shelf life of oxygen-sensitive products is generally reduced to typically about six months compared to drugs that are not oxygen-sensitive. SUMMARY OF THE INVENTION
    [003] [003] A pharmaceutical packaging system for an injectable oxygen-sensitive drug is provided herein. In one aspect, the pharmaceutical packaging system comprises a main packaging container comprising an oxygen sensitive drug, wherein the main packaging container has an oxygen permeable component, and wherein the main packaging container is packaged. under inert conditions, a hermetically sealed secondary packaging that envelops the main packaging container, where the secondary packaging has a very low permeability to oxygen, and an oxygen absorber, where the oxygen absorber removes the oxygen present. at the time of packaging assembly at a rate of up to 60%, up to 70%, up to 80%, up to 90% or up to 100% per day in the secondary packaging and up to 60%, up to 70%, up to 80%, up to 90 % or up to 100% per month in the main packaging container.
    [004] [004] In some embodiments of the pharmaceutical packaging system, the main packaging container is a syringe, cartridge, vial or drug storage container. In certain cases, the main packaging container is a syringe. In some embodiments, the main packaging container is plastic or glass. In certain cases, the main packaging container is glass. In some embodiments, the oxygen permeable component is an oxygen permeable cap. In some types, the oxygen permeable component is rubber or plastic. In some embodiments, the oxygen permeable component is a rubber cap.
    [005] [005] In some embodiments of the pharmaceutical packaging system, the secondary packaging is a bag or a blister pack. In some modalities, the secondary packaging with-
    [006] [006] In some modalities of the pharmaceutical packaging system, the oxygen absorber is placed inside the secondary packaging. In certain cases, the oxygen absorber is a sachet, bag, canister, carpule bottle, label, sticker, strip, plate, cartridge, or container. In some embodiments, the oxygen absorber is incorporated into the secondary packaging material. In some embodiments, the oxygen scavenger is a coating or layer that coats the secondary package. In some embodiments, the oxygen absorber is selected from the group consisting of reduced iron compounds, catechol, ascorbic acid and its analogues, metal ligands, unsaturated hydrocarbons, and polyamides. In certain cases, the oxygen absorber is a reduced iron compound.
    [007] [007] In some modalities of the pharmaceutical packaging system, the oxygen absorber reduces the oxygen level from the time of packaging assembly to about zero percent in about one to seven days, or one to three days in the secondary packaging and about one to six months, or one to three months in the main packaging container. In some embodiments, the oxygen absorber reduces the oxygen level from the time of package assembly to about zero percent in about a day in the secondary package and in about a month in the main package container. In some embodiments, oxygen levels in primary and secondary packaging remain at about zero percent after the initial reduction in primary and secondary packaging for at least one year. In some embodiments, oxygen levels in primary and secondary packaging remain at about zero percent after the initial reduction in primary and secondary packaging for at least three years.
    [008] [008] In some modalities of the pharmaceutical packaging system, the oxygen-sensitive drug is selected from the group consisting of morphine, hydromorphone, promethazine, dopamine, epinephrine, norepinephrine, esterified estrogen, ephedrine, pseudoephedrine, acetaminophen, ibuprofen , damofloxacin, erythromycin, penicillin, cyclosporine, methyldopate, cetirizine, diltiazem, verapamil, mexiletine, chlorothiazide, carbamazepine, selegiline, oxybutynin, vitamin A, vitamin B, vitamin C, L-cysteine and L-tryptophan. In certain cases, the oxygen-sensitive drug is morphine. In certain cases, the oxygen-sensitive drug is hydromorphone. In certain cases, the oxygen-sensitive drug is promethazine.
    [009] [009] In another aspect, the pharmaceutical packaging system comprises a main packaging container comprising an oxygen sensitive drug, in which the main packaging container has an oxygen permeable component and in which the main packaging container is packaged under inert conditions, a hermetically sealed secondary packaging that encloses the main packaging container, where the secondary packaging has a very low permeability to oxygen, and an ab-
    [0010] [0010] This document also provides a pharmaceutical packaging system for an injectable oxygen-sensitive drug, in which the packaging system comprises a syringe loaded under inert conditions with an injectable oxygen-sensitive drug, in that the syringe has an oxygen-permeable tip cap, a hermetically sealed blister pack housing the syringe, wherein the blister pack comprises a multi-layer bottom mesh and a multi-layer top mesh cap; and an oxygen scavenger, in which the oxygen scavenger reduces the level of oxygen present from the time of package assembly by about zero percent in about one to three days in the blister package and in about from one to three months on the syringe.
    [0011] [0011] In some embodiments, the syringe is plastic or glass. In some embodiments, the secondary packaging material is a thermoformed, cold-formed, aluminum-based or molded blister. In some embodiments, the multilayer bottom network comprises an ethylene/vinyl alcohol (EVOH) copolymer. And bad-
    [0012] [0012] In some embodiments, the oxygen absorber is placed inside the blister pack. In certain cases, the oxygen absorber is a canister. In some embodiments, the oxygen absorber has a capacity to absorb about 30 cubic centimeters of oxygen at 1 atm. In some embodiments, the oxygen absorber is iron-based. In some embodiments, the oxygen absorber reduces the oxygen level in the blister pack from the time of pack assembly by about zero percent in about a day. In some embodiments, the oxygen absorber reduces the oxygen level in the syringe from the time of package assembly by about zero percent in about a month. In some embodiments, the oxygen level remains at about zero percent in the syringe and blister pack for at least three years.
    [0013] [0013] In some modalities, the injectable oxygen-sensitive drug is morphine. In some modalities, the injectable oxygen-sensitive drug is hydromorphone. In some modalities, the injectable oxygen-sensitive drug is promethazine.
    [0014] [0014] In the present document a pharmaceutical packaging system for injectable morphine is also provided, wherein the packaging system comprises a syringe loaded under inert conditions with morphine, wherein the syringe has an oxygen-permeable tip cap, a packaging of hermetically sealed blister housing the syringe, wherein the blister package comprises a multi-layer bottom mesh and a multi-layer top mesh cap; and an oxygen absorber, in which the oxygen absorber reduces the oxygen level from the time of package assembly by about zero percent in about one to three days in the blister pack and in about one to three months in the syringe. MERGER AS REFERENCE
    [0015] [0015] All publications, patents, and patent applications mentioned in this specification are incorporated by reference in this document to the same extent that each individual publication, patent, or patent application has been specifically and individually indicated. to be incorporated by way of reference. BRIEF DESCRIPTION OF THE DRAWINGS
    [0016] [0016] The new features of the invention are presented with particularity in the appended claims. A better understanding of the characteristics and advantages of the present invention will be obtained by referring to the following detailed description which presents illustrative embodiments, in which the principles of the invention are used, and the accompanying drawings:
    [0017] [0017] Figure 1: Schematic diagram of modalities of the exemplifying packaging system with oxygen absorber in a sachet (a), in the lid (b), in a container (c) and positioned in the main packaging (d) .
    [0018] [0018] Figure 2: Schematic diagram illustrating a packaging system that has (1) an oxygen barrier secondary packaging, (2) an oxygen absorber, and (3) a main packaging (syringe) along with rates of oxygen transfer from various environments.
    [0019] [0019] Figure 3: Drawing of an exemplary syringe and a secondary packaging modality where the secondary packaging includes a first compartment for receiving a syringe barrel and a second compartment for receiving a plunger rod separate and detached from the syringe barrel.
    [0020] [0020] Figure 4: Oxygen levels in bag environments for storage settings A, C, D and O stored at
    [0021] [0021] Figure 5: Oxygen levels in syringe drums for packaging settings A, C, and D stored at 25°C/60% RH.
    [0022] [0022] Figure 6: Comparison of oxygen levels in syringe barrels versus pouch environments for packaging configuration A stored at 25°C/60% RH.
    [0023] [0023] Figure 7: Oxygen levels in bag environments for packaging settings E, E bis, F and G stored at 25°C/60% RH.
    [0024] [0024] Figure 8: Oxygen levels in bag environments for packaging settings E, E bis, F and G stored at 25°C/60% RH for the first 8 days.
    [0025] [0025] Figure 9: Oxygen levels in syringe drums for packaging settings E, F, and G stored at 25°C/60% RH.
    [0026] [0026] Figure 10: Oxygen levels in defective bag environments of configurations E and G stored at 25°C/60% RH.
    [0027] [0027] Figure 11: Oxygen levels in bubble environments for packaging settings 1(◆), 2(■) and 3(▲) stored at 25°C/60% RH.
    [0028] [0028] Figure 12: Oxygen levels in syringe environments for packaging settings 1(◆), 2(■) and 3(▲) stored at 25°C/60% RH.
    [0029] [0029] Figure 13: Oxygen levels in a syringe of various filling and conditioning conditions over the course of one year.
    [0030] Figure 14: Pseudomorphine content of the 2 mg/ml morphine formulation of Example 5 stored at 40°C/75% RH.
    [0031] [0031] Figure 15: Pseudomorphine content of 2 mg/ml morphine formulations in the standard packaging (◆) and in the bar-
    [0032] [0032] Figure 16: Unknown impurity content of hydromorphone formulations of 1 mg/ml (top) or 10 mg/ml (bottom) in standard packaging (◆) and oxygen barrier packaging (■) stored under conditions of accelerated storage (40°C/75% RH).
    [0033] [0033] Figure 17: Premethazine sulfoxide content of 25 mg/ml promethazine formulations in standard packaging (◆) and oxygen barrier packaging (■) stored under ambient conditions (top) (25° 60% C/RH) or accelerated storage conditions (base) (40°C/75% RH). DETAILED DESCRIPTION OF THE INVENTION
    [0034] [0034] In the present document pharmaceutical packaging systems are provided for pre-filled liquid medicine containers which have an oxygen permeable component. The packaging systems described herein are useful for enhancing stability and preventing oxidative degradation of oxygen-sensitive drugs in liquid form, thereby allowing for extended product life and prolonged drug potency or efficiency.
    [0035] [0035] "Oxygen sensitive" or "oxygen sensitive" refers to the ability of a substance to react with oxygen under conditions at ambient temperature (eg 5°C to about 40°C). The chemical reaction may involve the addition of an oxygen atom to the substance, the removal of a hydrogen from the substance, or the loss or removal of one or more electrons from a molecular entity, with or without concomitant loss or removal of protons or protons.
    [0036] [0036] In one aspect, the pharmaceutical packaging systems herein comprise a drug container as a main package that has oxygen permeability and houses a drug sensitive to liquid oxygen; a secondary package that envelops the main package and has a very low oxygen permeability, and an oxygen absorber that is placed inside or incorporated in the secondary package. Figure 1 illustrates different configurations of pharmaceutical packaging system modalities with an oxygen absorber (2) as a sachet (Figure 1a) placed inside the secondary packaging (1) and under the main syringe packaging (3), in the cap 4 (Figure 1b) of the secondary package (1) and as a canister (Figure 1c) placed next to the main syringe package. Another modality where the oxygen absorber is placed directly in the main syringe package is also illustrated (Figure 1d). In this case, the oxygen absorber can be glued or bonded directly to the surface of the main package or even integrated into the thickness of the main package. Additional configurations are within the scope of pharmaceutical packaging systems herein.
    [0037] [0037] A feature of the pharmaceutical packaging systems in this document is that the configuration allows the absorption and removal of oxygen in all components of the system. As the examples show, the oxygen absorber quickly removes oxygen from the secondary packaging. However, surprisingly, the oxygen absorber also removes oxygen from the main packaging container and liquid as will be shown in Example 3. Figure 2 shows the removal of oxygen from an exemplary pharmaceutical packaging system. In this case, the oxygen absorber (2) is placed inside the pharmaceutical packaging system. Therefore, it removes oxygen within the initial air volume present in the secondary packaging (1) at a transfer rate.
    [0038] [0038] Essentially, the oxygen absorber in the pharmaceutical packaging system in this document leads to the absorption and removal of oxygen in the secondary packaging, in the main package and in the drug inside the main package. The oxygen absorber also removes low oxygen ingress through the secondary packaging over time. In this configuration, the residual amount of oxygen that is present within the primary and secondary packaging due to the pharmaceutical manufacturing process, as well as the oxygen that enters the packaging system from external environments over time, it is reduced and even eliminated.
    [0039] [0039] Another feature of the pharmaceutical packaging systems described in this document is that the pharmaceutical packaging system maintains a zero % oxygen level after removal of the initial oxygen in the main packaging container and in the secondary packaging by an extended period of time. As a result, the pharmaceutical packaging systems described in this document offer increases in the shelf life of oxygen-sensitive drugs after conventional packaging and method.
    [0040] [0040] The main packaging container of the pharmaceutical packaging systems described in this document houses or contains the oxygen-sensitive drug in liquid form. Various types of containers are suitable for containing oxygen-sensitive drugs. Examples of such containers include, without limitation, vials, syringes, ampoules, containers, cartridges, a carpule vial, and bags or pouches iv In some embodiments, the primary packaging container of the pharmaceutical packaging systems described herein is selected of a vial, syringe, ampoule, canister, cartridge, a carpule vial and a bag.
    [0041] [0041] Vials for the containment of oxygen-sensitive drugs generally have open mouths that are normally closed with an elastomer closure through which a hollow needle can be passed and through which liquid can be introduced or removed. of the bottle. Vials are typically made of type I glass or can be made of plastic such as PET. Suitable elastomers for such closures include, for example, vulcanized elastomers and thermoplastic elastomers of styrenic block copolymers, but also vulcanized natural rubber, acrylate-butadiene rubber, cis-polybutadiene, chlorine or bromobutyl rubber, elas- chlorinated polyethylene polymers, polyalkylene oxide polymers, ethylene vinyl acetate, fluorosilicone rubbers, hexafluoropropylene-vinylidene fluoride-tetrafluoroethylene terpolymers, butyl rubbers, polyisobutene, polyisoprene synthetic rubber, silicone rubbers, styrene-butadiene rubbers , tetrafluoroethylene-propylene copolymers, thermoplastic copolyesters, thermoplastic elastomers, or the like or a combination thereof.
    [0042] [0042] Syringes generally comprise a cylindrical barrel, often made of glass, but more recently made of plastic materials, eg cyclic olefin polymers or acrylonitrile butadiene styrene (ABS), polycarbonate (PC), polyoxymethylene (POM), polystyrene (PS), polybutylene terephthalate (PBT), polypropylene (PP), polyethylene (PE), polyamide (PA), thermoplastic elastomer (TPE) and combinations thereof. The barrels of such syringes are operated with an elastomer plunger that can be forced along the barrel to eject the liquid contents through a nozzle. Suitable elastomers for such plungers can be based on the same thermoplastic elastomers as mentioned above for vial closures. Ampoules are a type of sealed vial that are usually opened by tearing off the neck or the top of the ampoule. Cartridges and carpule vials are specialized containers that are inserted into a drug delivery device (eg, syringe or autoinjector). Finally, intravenous bags and pouches are typically used for infusion therapy or multiple dose administration.
    [0043] [0043] For more rigid main packaging containers, glass is an appropriate material because it provides several benefits. Glass is generally considered to be non-permeable to moisture and oxygen permeation. An alternative group of materials, cyclic olefin polymers, polypropylene or polyethylene terephthalate, is suitable for containers because it typically has fewer breakage problems compared to glass and still exhibits good transparency. Such materials include cyclic olefin copolymers such as TopasTM polymer (Topas Advanced Polymers gmbH) and cyclic olefin homopolymers such as Crystal ZenitTM polymer (Daikyo). For flexible main packaging containers such as bags, suitable materials include those that have oxygen barrier properties.
    [0044] [0044] With respect to light-sensitive drugs, the main packaging container must have light barrier properties that can be obtained with a colorant to produce the colored main packaging container (e.g., amber, dark blue) or opaque. A main package made of transparent materials may also be suitable as long as it is placed in secondary or tertiary packaging materials that are opaque to light.
    [0045] [0045] In one embodiment of the pharmaceutical packaging systems described herein, the main packaging container is a syringe. Syringes, and in particular hypodermic syringes, are useful in the medical field for delivering fluids, including medications. A conventional syringe typically includes a syringe barrel with an opening at one end and a plunger mechanism disposed through the opposite end. Syringes in the pharmaceutical packaging systems described in this document contain the liquid drug to be applied and are stored over time once filled. They are denoted as a "pre-filled" syringe. One advantage of the pre-filled syringe is that the drug is loaded at an appropriate dose and can be applied to a patient quickly compared to conventional methods of filling the syringe with liquid drug in a vial prior to administration, thereby saving time , maintaining a consistent dosage and volumes for the application and ending with the problems of contamination and degradation of multi-dose drug vials. Exemplary syringes for use in the pharmaceutical packaging systems described herein include those described in U.S. Patents no. 6,196,998; 6,200,627; 6,217,550; 6,743,216;
    [0046] [0046] In the pharmaceutical packaging systems described herein, the main packaging container also has an oxygen permeable component. "Oxygen Permeable" as used herein refers to materials that permit the passage of oxygen through the material. Certain rubbers, plastics and papers have oxygen permeable properties and can be molded into plugs, plugs, seals, membranes and
    [0046] [0046] other components that may be structural or protective. When an oxygen-permeable component separates two environments of different oxygen levels, the oxygen-permeable component allows the passage of oxygen from the higher oxygen level environment to the lower oxygen level environment. Over time, the two environments balance with respect to oxygen levels. Typically, these materials are also permeable to other gases. In this way, the oxygen permeable component allows for sterilization processes such as through gas (eg ethylene oxide) or steam sterilization. For example, a syringe main packaging container may have a tip cap that is permeable to gas or oxygen that allows for sterilization of the interior of the syringe and, if the syringe is filled, also the drug itself. Therefore, in some embodiments, the main packaging container is a syringe that has an oxygen-permeable tip cap which can be a single-material tip cap or a two-material tip cap. In an exemplary embodiment, the oxygen permeable syringe tip cap includes a rubber portion. Exemplary end caps include those described in U.S. Patents Nos.
    [0047] [0047] The secondary packaging component of the pharmaceutical packaging systems described herein envelops or surrounds the main packaging container containing the liquid drug. In the embodiments herein, after placing the main packaging container in the secondary packaging, the secondary packaging is sealed to prevent any contamination as well as the ingress of oxygen. To prevent further ingress of oxygen into the secondary packaging, the secondary packaging is composed of an oxygen barrier material that has a very low permeability to oxygen molecules. The secondary packaging may be any type of packaging suitable for the main packaging container, where the types include, without limitation.
    [0048] [0048] Oxygen barrier materials for secondary packaging have a very low permeability to oxygen molecules (eg ~1 or less cm3 O2/m2 per day, atm). Non-limiting examples of suitable oxygen barrier materials for secondary packaging include ethylene/vinyl alcohol (EVOH), polyvinyl alcohol (PVOH), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), vinylidene chloride/methyl acrylate copolymer, polyamide and polyester. Thin sheet metal (eg aluminum) or SiOx compounds can be used to impart very low oxygen permeability in the secondary packaging. Metallized films can include an ion bombardment coating or other application of a layer of metal such as aluminum to a polymeric substrate such as high density polyethylene (HDPE), low density polyethylene (LDPE), a copolymer. of ethylene/vinyl alcohol (EVOH), polypropylene (PP), polyethylene terephthalate (PET) including amorphous forms (APET) and modified forms with glycol (PET-G), polyethylene naphthalate (PEN ), an ethylene/acrylic acid copolymer (EAA), and a polyamide (PA). Alternative-
    [0049] [0049] The modalities of the oxygen barrier materials can be present in the form of multilayer films. Multilayer films (e.g., 2, 3, 4, 5, or 6 layer films) may comprise one or more of the previously described oxygen barrier material(s), and may include additional layers of non-barrier materials such as PET, polyethylene (PE) and/or coated paper (eg clay, wax, plastic or the like) or uncoated. Suitable multilayer films include, but are not limited to, PVC/EVOH, PET/EVOH, PET/EVOH/PE, PET/EVOH/PET, PE/EVOH/PE, PVC/PCTFE/EVOH, Paper/Aluminium (Alu)/PE, PET/Alu/PE, Paper/PE/Thin Sheet/PE, Paper/PET/Alu, Paper Coated with Clay/PE/Thin Sheet/LDPE, Paper/LDPE/Thin Sheet/ EEA, and its related films. The layers can be joined together through the use of adhesives, eg a polyolefin blend (poly(α-olefin blend), or polyamide resins. In some embodiments, the secondary packaging comprises a bar material - oxygen resistance as a multilayer film. In certain cases the multilayer film is PVC/EVOH, PET/EVOH, PET/EVOH/PE, PET/EVOH/PET, PE/EVOH/PE, PVC/PCTFE /EVOH, Paper/Aluminium (Alu)/PE, PET/Alu/PE, Paper/PE/Thin Sheet/PE, Paper/PET/Alu, Clay Coated Paper/PE/Thin Sheet/LDPE or Paper/LDPE/Sheet thin/EEA.
    [0050] [0050] Multilayer films are made by any known method, including conventional extrusion, coextrusion and/or lamination processes. Likewise, conventional manufacturing processes can be used to produce a bag, pouch, box, bag, blister, canister, canister or other container from the oxygen barrier materials for packaging. secondary as well as to provide a hermetic seal. Hermetic sealing is of importance in the pharmaceutical packaging systems described in this document to keep the oxygen level low. Of course, when the secondary package is improperly sealed or is leaking, the oxygen level can rapidly increase to 21% after the oxygen scavenger is at its maximum capacity, as shown in Example 4. Optionally, in some embodiments, the seal hermetic takes place under an inert environment (eg, nitrogen blanket) to reduce initial oxygen levels in the secondary packaging air volume.
    [0051] [0051] In some embodiments, the secondary packaging is a blister pack. Blister packaging is known in the packaging industry and commonly used to package pharmaceutical compounds and medical devices such as solid dosage forms (tablets, capsules, etc.), transdermal patches, syringes, and so on. The term "bubble" refers to a bottom mesh substrate that is rigid and has one or more recesses that conform and can be trapped in the place where the contents are being wrapped (in this case the main packaging container). The recesses can be formed by a deformation process such as an aluminum-based cold forming process or by means of injection molding. For the pharmaceutical packaging systems described in this document where the secondary packaging is a blister pack, the lower mesh substrate comprises an oxygen barrier material (eg, multilayer film with an EVOH layer) . Depending on the materials used and the nature of the drugs stored inside the main package, the lower mesh substrate can be transparent or opaque with the use of dyes.
    [0052] [0052] Another component of blister packaging is a top mesh laminate ("lid") which is laminated to the blister by means of heat sealing. The top mesh lid is normally flexible and can be peeled off from the blister to allow access to the conditioned contents. For modalities where the secondary packaging is a blister pack, the mesh top cap also comprises an oxygen barrier material such as thin sheet metal (eg aluminium). In certain cases, the top mesh cover comprises a multilayer film having an aluminum layer and one or more additional layers. Additional layers include coated or uncoated paper, PE and/or PET layers. In certain cases, the top mesh cover comprises a film comprising the paper, aluminum and PET layers. The upper mesh cap also comprises a laminate to seal the blister. The laminate is applied to the lid by co-methods.
    [0053] [0053] In an exemplary embodiment, the secondary packaging comprises a blister package that has a thermoformed transparent wrap made of a multi-layer plastic film that includes EVOH (bottom mesh) and a heat-sealed lid material multi-layer plastic paper that includes a layer of aluminum (top mesh).
    [0054] [0054] In a further embodiment, a secondary packaging container suitable for the pharmaceutical packaging systems described herein is provided which includes a first compartment for receiving a syringe barrel and a second compartment for receiving a separate piston rod and detached from the barrel of the syringe. With the syringe barrel received in the first compartment and the plunger rod received within the second compartment, the plunger rod sealing member seals the syringe barrel and the plunger rod within the secondary package. This configuration of the secondary packaging container allows for reduced storage space for the syringe. In this way, with the removal of the plunger rod and syringe barrel from the secondary packaging, the plunger rod can be quickly and easily attached to the syringe barrel via a plug for the application of a drug formulation contained within the syringe. An exemplary syringe and secondary packaging configuration is shown in Figure 3. Figure 3 shows a syringe barrel (30) containing a drug formulation with a sealing cap (20) and a flange
    [0055] [0055] In the pharmaceutical packaging systems described herein, oxygen absorbers absorb and remove oxygen from all system components. Oxygen absorbers are available in any size or shape, including sachet, bag, capsule, label, strip, plate, canister, cartridge, liner, adhesive, etc., which are placed inside a secondary packaging as well as a part of the secondary packaging itself, but can also be integrated into the main packaging. In some embodiments, the oxygen absorber is in the form of a sachet. In other embodiments, the oxygen absorber is in the form of a canister. In some other embodiments, the oxygen absorber is in the form of a tag. In still other embodiments, the oxygen absorbers are in the form of a strip. In other embodiments, the oxygen absorbent is a label or adhesive that adheres to the secondary package or main package. In still other mo-
    [0056] Suitable materials for oxygen absorbers include metal-based substances that remove oxygen by reacting with it through chemical bonding, generally forming a metal oxide component. Metal-based substances include elemental iron as well as iron oxide, iron hydroxide, iron carbide, and others. Other metals for use as oxygen scavengers include nickel, tin, copper and zinc. Metal-based oxygen scavengers are typically in the form of a powder to increase surface area. Dust formation of metal-based oxygen absorbers is by any known method including, but not limited to, atomization, grinding, spraying and electrolysis. Additional materials for oxygen scavengers include low molecular weight organic compounds such as ascorbic acid, sodium ascorbate, catechol and phenol, activated carbon, and polymeric materials that incorporate a resin and a catalyst . In some embodiments of the pharmaceutical packaging system, the oxygen absorber is a metal-based oxygen absorber. In certain cases of the pharmaceutical packaging system, the oxygen absorber is an iron-based oxygen absorber. In other cases of the pharmaceutical packaging system, the oxygen absorber is an iron-based oxygen absorber in the form of a canister. OXYGEN ABSORBENTS AND SECONDARY PACKAGING
    [0057] [0057] A feature of the oxygen absorber in pharmaceutical packaging systems in this document is the rapid absorption of oxygen present in the secondary packaging.
    [0058] [0058] In additional embodiments, the oxygen absorber reduces about 2 to about 10 cubic centimeters of oxygen per day, atm; about 3 to about 8 cubic centimeters of oxygen per day, atm; or about 4 to 6 cubic centimeters of oxygen per day, atm, in the secondary packaging. In certain cases, the oxygen absorber reduces about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 cubic centimeters of oxygen per day, atm, on secondary packaging. In some cases, the oxygen absorber reduces about 4 cubic centimeters of oxygen per day, atm. In other cases, the oxygen absorber reduces about 6 cubic centimeters of oxygen per day, atm. In additional cases, the oxygen absorber reduces about 8 cubic centimeters of oxygen per day, atm.
    [0059] [0059] Another characteristic of the oxygen absorber is that it maintains an oxygen level of zero % after removal of the initial oxygen in the secondary packaging for an extended period of time. In some embodiments, the oxygen absorber maintains the oxygen level at zero % in the secondary packaging for the life of the drug. In some embodiments, the oxygen absorber maintains the oxygen level at zero % in the secondary packaging for at least about 12 months, at least about 15 months, at least about 18 months, at least about 24 months, at least - in about 30 months, at least about 36 months, at least about 48 months, or at least about 60 months. In certain cases, the oxygen absorber maintains the oxygen level at zero % in the secondary packaging for at least 12 months. In certain cases
    [0060] [0060] An advantageous characteristic of the oxygen absorber in pharmaceutical packaging systems in this document is the absorbance and removal of oxygen present in the main packaging and in the liquid drug itself. Surprisingly, it was found that the oxygen absorber in exemplary packaging systems also removed residual oxygen in the main package and liquid over time to an oxygen level of zero%. Liquids degassed by bubbling nitrogen still contain a residual oxygen level of about 1%, or about 400 parts per billion (PPB) of oxygen, or a partial pressure of about 7.6 mm of Hg. As will be illustrated and described later in the description referring to Example 3 and Figure 9, the oxygen absorber in exemplary pharmaceutical packaging systems reduced the level of residual oxygen (about 1%) in the main packaging and the liquid inside it to zero % in one to three months. Thus, in some embodiments, the oxygen absorber reduces oxygen to zero % in the main package in about three months, in about two months, or in about a month after assembly of the initial main package under inert conditions. In some embodiments, the oxygen absorber reduces oxygen in the main package by about 35%, by about 50%, by about 60%, by about 65%, by about 70%, by about 75 %, in about 80%, in about 85%, in about 90%, or in about 95% of the residual oxygen per month after assembly of the initial main package under inert conditions. In certain cases, the oxygen absorber
    [0061] [0061] In other embodiments, the oxygen absorber reduces oxygen in the main package by about 150 ppb oxygen, about 200 ppb oxygen, about 250 ppb oxygen, about 300 ppb oxygen, about 350 ppb oxygen or about 400 ppb of oxygen in the liquid contained in the main package per month after assembly of the initial main package under inert conditions. In certain cases, the oxygen absorber reduces the oxygen in the liquid contained in the main package by about 200 ppb of oxygen per month. In other cases, the oxygen absorber reduces the oxygen in the liquid contained in the main package by about 300 ppb of oxygen per month. In other cases, the oxygen absorber reduces the oxygen in the liquid contained in the main package by about 400 ppb of oxygen per month. In other embodiments, the oxygen absorber reduces the oxygen in the liquid contained in the main package by about 150 ppb to about 300 ppb oxygen, about 250 ppb to about 350 ppb oxygen, or about 300 ppb to about 400 ppb oxygen per month after assembly of the initial main package under inert conditions.
    [0062] [0062] In additional embodiments, the oxygen absorber reduces the partial pressure of oxygen in the main package by about 2.5 mm of Hg, by about 3.0 mm of Hg, by about 3.5 mm of Hg, in about 4.0 mm of Hg, in about 4.5 mm of Hg, in about
    [0063] [0063] The oxygen absorber, in some modalities, also maintains the oxygen level at zero % after removing the initial oxygen in the main package for an extended period of time. In some embodiments, the oxygen absorber maintains the oxygen level at zero % in the main package for the life of the drug. In some embodiments, the oxygen absorber maintains the oxygen level at zero % in the main package for at least about 12 months, at least about 15 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 48 months, or at least about 60 months. In certain cases, the oxygen absorber maintains the oxygen level at zero % in the main package for at least 12 months. In certain cases, the ab-
    [0064] [0064] An interesting property of the pharmaceutical packaging systems in this document is that, after the removal of oxygen in the main and secondary packaging by the oxygen absorber, the air pressure in the environment of the secondary packaging is lower than atmospheric pressure in such a way that there is a vacuum effect. OXYGEN ABSORBENT CAPACITIES
    [0065] [0065] The capacity to absorb oxygen for the oxygen absorbers of the pharmaceutical packaging systems described in this document encompasses sufficient capacities to reduce the initial oxygen levels of the main and secondary packaging to an oxygen level of zero % to a rate as described in the preceding embodiments and maintaining the oxygen level at zero % for a period of time as described in the preceding embodiments. The capacity of the oxygen absorber can be optimized according to the materials used in the secondary packaging, the surface area of the secondary packaging, and the amount of starting oxygen in the primary and secondary packaging. For example, the oxygen-absorbing capacity of the absorbent is decreased when the secondary packaging has very low oxygen permeability, whereas the oxygen-absorbing capacity of the absorbent is increased when the secondary packaging is made of a material that is more permeable to oxygen. This is illustrated in more detail in Example 3 and Figure 7. It is also within the scope of the modalities of the pharmaceutical packaging systems described in this document that the oxygen absorption capacity is greater than that required for the total amount of oxygen for the lifetime of the pharmaceutical packaging system, that is, the overflow capacity. The extra capacity can allow for a larger buffer in the manipulation process for assembling the pharmaceutical packaging system.
    [0066] [0066] Exemplary oxygen absorber capacities, in some embodiments, range from about 10 cubic centimeters (cm3, atm) to about 50 cubic centimeters of oxygen absorbance capacity of about 15 cubic centimeters at about 40 cubic centimeters of oxygen absorbing capacity, or at about 20 to about 30 cubic centimeters of oxygen absorbing capacity. In some embodiments, the oxygen absorption capacity of the oxygen absorber in the pharmaceutical packaging system is about 10 cubic centimeters, about 15 cubic centimeters, about 20 cubic centimeters, about cubic centimeters, about 30 cubic centimeters, about 35 cubic centimeters, about 40 cubic centimeters, about 45 cubic centimeters, or about 50 cubic centimeters of oxygen absorbing capacity. In certain cases, the oxygen absorption capacity of the oxygen absorber in the pharmaceutical packaging system is about 15 cubic centimeters. In certain cases, the oxygen absorption capacity of the oxygen absorber in the pharmaceutical packaging system is about 30 cubic centimeters. PACKAGING ASSEMBLY
    [0067] [0067] In preparing the pharmaceutical packaging systems described in this document, the package, in some embodiments, is assembled in an environment that contains an inert gas, that is, under inert packaging conditions, to reduce the concentration of initial oxygen in the main and/or secondary packaging. Under inert packaging conditions that include the use of purging or capping a main and/or secondary packaging container with an inert gas, as well as degassing a drug formulation by an inert gas. The use of an inert gas (eg, nitrogen, argon, CO2, helium and others) limits the drug formulation to exposure to oxygen. In some embodiments, the liquid drug formulation is also sprayed or bubbled by the inert gas to remove oxygen in the liquid. The solutions are then loaded and sealed in main containers and, in some arrangements, in secondary packaging under an inert gas.
    [0068] [0068] The pharmaceutical packaging systems described in this document can remove oxygen from a main packaging container that is packaged under ambient conditions (where the oxygen concentration is about 21%) as shown in the Example 5 and Figure 12. However, the removal of oxygen from a 21% level is slow as shown in the example and therefore the main package in ambient conditions is not recommended as a large amount of oxygen residual can cause degradation before its slow removal. OXYGEN SENSITIVE DRUGS
    [0069] [0069] As used herein, the term "drug" refers to a pharmaceutically active ingredient(s) and any liquid pharmaceutical composition containing the pharmaceutically active ingredient(s) ). Liquid pharmaceutical compositions include forms such as solutions, suspensions, emulsions and the like. These liquid pharmaceutical compositions can be administered orally or via injection.
    [0070] [0070] Any drug that is sensitive to oxygen, that is, can degrade as a result of exposure to oxygen, is suitable for incorporation into the described pharmaceutical packaging systems.
    [0071] [0071] The oxygen-sensitive drugs in the pharmaceutical packaging systems described herein are stable under various storage conditions including ambient, intermediate, and accelerated conditions. Stability as used herein refers to a formulation that meets all stability criteria over its particular shelf life as defined in the USP monograph or drug product equivalent (for drug substance testing in particular) and the current stability criteria of ICH Q3B guidance for impurities. All critical quality attributes must remain within your acceptance range for the lifetime of the formulation. As an example, for a morphine formulation to be stable, the drug substance test, ie,
    [0072] [0072] In some embodiments, an oxygen-sensitive drug, when stored in the pharmaceutical packaging systems described herein, is stable at ambient conditions (eg, 25°C/60% RH) for at least 12 months es, at least 15 months, at least 18 months, or at least 24 months. In certain cases, an oxygen-sensitive drug, when stored in the pharmaceutical packaging systems described in this document, is stable under ambient conditions for at least 24 months. In other embodiments, an oxygen-sensitive drug, when stored in the pharmaceutical packaging systems described herein, is stable under intermediate conditions (eg, 30°C/65% RH) for at least 6 months, at least 6 months. at least 8 months, at least 10 months, or at least 12 months. In certain cases, an oxygen-sensitive drug, when stored in the pharmaceutical packaging systems described in this document, is stable under intermediate conditions for at least 12 months. In additional modalities, an oxygen-sensitive drug, when stored in the pharmaceutical packaging systems described in this document, is stable under accelerated conditions (eg, 40°C/RH and 75%) for at least 4 months, at least 5 months, or at least 6 months. In certain cases, an oxygen-sensitive drug, when stored in the pharmaceutical packaging systems described herein, is stable under accelerated conditions for at least 6 months.
    [0073] [0073] The pharmaceutical packaging systems described in this document are also suitable for liquid pharmaceutical compositions that comprise an oxygen sensitive excipient. Degradation of oxygen sensitive excipients in a pharmaceutical composition can lead to a variety of effects ranging from composition discoloration, reduced composition performance or efficiency, and/or detrimental reactivity with the active pharmaceutical ingredient. Non-exclusive examples of oxygen-sensitive excipients that benefit from the pharmaceutical packaging systems described herein include polyethylene oxide (PEO) or polyethylene glycol (PEG) and polyoxyethylene alkyl ethers. KITS AND MANUFACTURING ITEMS
    [0074] [0074] For the pharmaceutical packaging systems described in this document, kits and articles of manufacture are also described. Such kits comprise each of the assembled components of the pharmaceutical packaging system and may optionally comprise an outer packaging that surrounds the secondary packaging. A kit can also join multiple pharmaceutical packaging systems for a particular drug to allow for multi-dose (for example, a one-week kit of a drug dosed daily). Multiple pharmaceutical packaging systems in a kit can also contain different drugs for purposes such as drug combinations or rotations.
    [0075] [0075] A kit may comprise one or more additional components such as additional devices, desirable from a commercial and user point of view for pharmaceutical packaging systems. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; adaptors, waste receptacles and/or labels that list the contents and/or instructions for use, and packaging inserts with instructions for use associated with the pharmaceutical packaging system. A set of instructions will also typically be included.
    [0076] [0076] A tag may be placed on or associated with the secondary packaging. A label can be in a secondary packaging when letters, numbers or other characters that form the label are affixed, molded or engraved on the container itself; a label may be associated with a secondary package when it is present within a receptacle or carrier that also contains the main packaging container, for example, as a package insert. A tag can be used to indicate that the content is to be used for a specific therapeutic application. The label may also indicate instructions for using the content, such as in the methods described in this document.
    [0077] [0077] Exemplary secondary packaging was developed and analyzed with respect to oxygen levels in Examples 2 to 4 below. The different configurations allowed the comparison of the performance of the materials with respect to the oxygen barrier properties; the behavior and performance of the oxygen absorber; and the kinetics and impact on the amount of oxygen inside the syringe. In addition, two systems were tested for oxygen removal in the secondary packaging: nitrogen purge before sealing the packaging or with the use of an oxygen absorber.
    [0078] [0078] Main packaging container: De-aerated water was loaded into 1.25 ml glass syringes (HipakTM, Becton
    [0079] [0079] Secondary packaging: Materials for the secondary packaging have included an APET pad that is without specific gas barrier properties; and multilayer films that included an EVOH layer as a gas barrier. Selected oxygen absorbers included an absorbent in a sachet, the absorbent in a tag, and the absorbent embedded in the mesh film. The eight different tested configurations are described in the following table: Configuration Lower net Upper net Oxygen removal A APET Paper/Alu 25 µm/PE N2 C purge PET/EVOH/PE PET/Alu 8 µm/PE N2 D PVC purge /PCTFE/EVOH oPA/Alu 45 µm/PVC N2 purge E-absorbent sachet APET Paper/Alu 205 µm/30 cc O2 PE E-bis APET absorber sachet Paper/Alu 20 µm/30 cc O2 PE Sachet of absorber F PET/EVOH/PE PET/Alu 8 µm/PE from 30 cc O2 By top mesh of G PET/EVOH/PE Sealed Air OS 12 cc O PET/EVOH/PET Paper/Alu 20 µm/PE Purging of N2
    [0080] [0080] APET: Amorphous polyethylene terephthalate
    [0081] [0081] PET: Polyethylene terephthalate
    [0082] [0082] EVOH: Ethylene Vinyl Alcohol
    [0083] [0083] PE: Polyethylene
    [0084] [0084] PVC: Polyvinyl chloride
    [0085] [0085] PCTFE: Polychlorotrifluoroethylene
    [0086] [0086] Alu: Aluminum
    [0087] [0087] Sealed Air OS: Oxygen scrubber film delivered by Sealed Air Company
    [0088] [0088] The pouches were prepared with the two films (lower mesh and upper mesh) that enclosed the syringes and were subsequently sealed. Four configurations were prepared with nitrogen purge (configurations A, C, D and O). The sealing of these bags was performed in a glove box with a manual sealing clamp. Prior to sealing, an OxyDot® oxygen sensor was stuck inside the pouch. The other configurations contained one type of oxygen absorber (Configurations E, E bis, F and G). These were sealed from ambient air with an O2 level of around 21%. The dimensions of the bag were approximately 130 mm x 90 mm and had a volume, with the syringe inside, of approximately 30 to 35 ml.
    [0089] [0089] Analytical Equipment: The equipment used to measure the oxygen levels inside the bags and syringes included an oxygen analyzer that measured the oxygen level by reading through the OxyDot® visual indicator (OxySense analyzer) and ABL5 blood gas analyzer (Radiometer) which measured the oxygen level in the syringe water.
    [0090] [0090] Storage: In Examples 2 to 4 below, the syringes in the secondary packaging were placed in a climatic chamber at 25°C/60% relative humidity (RH). Example 2: Oxygen Levels in Nitrogen Purged Package OXYGEN IN BAG ENVIRONMENTS
    [0091] [0091] The table below shows the oxygen levels for Settings A, C, D and O. % Oxygen in Setup Config./Days 0 14 30 60 90 '20 150 180 210 360 A 0.06 0 .44 0.93 1.83 2.62 3.34 3.98 4.6 5.18 7.91 C 0.16 0.22 0.33 0.48 0.65 0.8 0.97 1, 14 1.24 1.91 D 0.27 0.33 0.47 0.53 0.57 0.55 0.6 0.65 0.65 0.79 O 0.83 0.96 1.09 1, 19 1.25 1.4 1.45
    [0092] [0092] Figure 4 is a graphical representation of the table above and describes the ingress of oxygen into the nitrogen purged bags (Settings A, C, D and O). Configurations A, C, D and O were all prepared with an aluminum foil top mesh. Due to the fact that the aluminum foil has very strong oxygen barrier properties, the impact of the upper web on oxygen ingress is negligible. In this way, the graph essentially allows for a direct comparison between the properties of the lower network barrier.
    [0093] [0093] At the start of the study (day = 0) oxygen levels at all settings were about 0%, with the exception of Setting O with less than 1%. Configuration A, which comprised the APET film without oxygen barrier properties, allowed the constant ingress of oxygen. At the end of the study (day = 360), the Setting A oxygen level was about 8%. The other Configurations C, D and O showed good oxygen permeation barrier properties. However, these settings still allowed oxygen ingress to some extent as oxygen levels within the pockets increased by the study endpoint (eg, 2% for C, 1% for D). OXYGEN IN SYRINGE ENVIRONMENTS
    [0094] [0094] Figure 5 shows the oxygen levels in the filled syringes of Configurations A, C and D. The syringes filled with degassed water had about 1% residual oxygen at t0. According to Figure 5, the oxygen levels of all syringes are close to zero % oxygen after 1 month. It is contemplated that, since Configurations A, C, and D bag environments had lower levels of oxygen than their syringes (see Figure 4), the reduced level of oxygen outside the syringe promotes residual oxygen egress inside the syringe as facilitated by the permeability of the tip cap in accordance with Fick's law.
    [0095] [0095] However, a hysteresis phenomenon (delay effect) was observed between the oxygen level in the bag environment and the oxygen level inside the syringe barrel. This is highlighted by the observation that, after one year, syringes in Configurations C and D (placed in the regular EVOH film) remained at zero % oxygen levels while oxygen levels increased slightly in the respective bags ( 2% for C, 1% for D). This effect was most prominent in Setting A, where the syringe in A (placed on the regular APET film) remained at zero % oxygen for more than six months, after which the oxygen level then began to rise around the seventh month. month to 2% at the end of the study. On the other hand, the oxygen level in the pouch environment of Configuration A continuously increased to 8% by the end of the study. Figure 6 shows this phenomenon of hysteresis of oxygen levels between the bag and syringe for Configuration A only.
    [0096] [0096] It is contemplated that the phenomenon of hysteresis can be attributed to the oxygen sensor (OxyDot®) which has the intrinsic oxygen absorption capacity as part of its detection capacity. Example 3: Oxygen Levels in Oxygen Absorbent Packaging OXYGEN IN BAG ENVIRONMENTS
    [0097] [0097] Configurations E, E bis, F and G were examined with respect to oxygen levels within the bag and syringe environments. The study allowed the comparison with different materials for the types of secondary packaging and oxygen absorber. Figure 7 shows the oxygen levels in the bag environment in 360-day storage at 25°C/60% RH. As described in Example 1, Configurations E, E bis, F and G were sealed in ambient air environment at 21% oxygen. Offsets in t0 are attributed to the time between sealing the bag and measuring the oxygen level. After 2 to 3 days, the bag environment of all settings (E bis, E, F and G) was at zero % oxygen. This indicates that the oxygen absorber rapidly absorbs the initial oxygen content within the bag. Figure 8 shows the rapid absorption in more detail on an 8-day range plot. After 1 year, it was observed that Settings E and F are still at zero % oxygen in the bag environment (Figure 7). For E bis, the oxygen level started to increase after 6 months to a level of about 5% at the 1 year endpoint. Bag G comprised an oxygen-absorbing top mesh film with a capacity of about 12 cubic centimeters of O2. However, the oxygen level in the bag environment in Configuration G started to increase after one month and the oxygen level was around 2% within the first 6 months, indicating that the oxygen absorption capacity is not sufficient.
    [0098] [0098] With respect to Configurations E and F, the results indicate that a ratio between the barrier property of the film (oxygen transfer rate) and the oxygen absorption capacity can be manipulated to obtain a environment with zero oxygen at the end of the study. Thus, the secondary packaging with a poor barrier (APET) and a large O2 absorption capacity (30 cubic centimeters), that is, the Configuration E, and the secondary packaging, with a good barrier (EVOH) and a small O2 absorption capacity (15 cubic centimeters) can provide the same result (zero % oxygen level in the bag).
    [0099] [0099] The E bis Configuration has the same materials as the secondary packaging, but with a lower O2 absorption capacity (15 cubic centimeters versus 30 cubic centimeters for E). The results in Figure 7 indicate that the total O2 absorption capacity was consumed within 6 months due to the poor barrier properties of the APET film. The oxygen input is then equivalent to Setting A, ie 5% oxygen input within 6 months. The results also showed that Configuration G with the oxygen absorber embedded in the polymer base film had the slowest oxygen removal (3 days to zero % oxygen). Finally, the results showed that the oxygen absorption kinetics are very fast and can remove the total amount of oxygen in the bag (about 6 to 7 cubic centimeters of O2) in about 2 to 3 days.
    [00100] [00100] It was also unexpectedly observed that the secondary package air pressure in some of the configurations reached a pressure lower than atmospheric and created a vacuum-like effect. OXYGEN IN SYRINGE ENVIRONMENTS
    [00101] [00101] Figure 9 shows the oxygen levels of syringe environments in Settings E, F and G. Syringes filled with degassed water had about 1% residual oxygen at t0. After 1 month, oxygen levels in the Configurations E, F, and G syringes were at zero % oxygen. The results suggest that the system tends to balance the oxygen level outside (zero %) and inside the syringe. However, it is interesting to note that the oxygen level in syringe G remains close to zero % oxygen despite the slight increase in bag oxygen (4% oxygen) after one year. Example 4: Sealing Effects of Secondary Packaging Settings and Oxygen Levels
    [00102] [00102] Figure 10 illustrates a number of pouches of Configurations E and G with defective sealing. As described previously, all bags with oxygen absorbers were sealed at a 21% oxygen level. The results in Figure 10 show that most of these samples reached zero % oxygen and returned to 21% at different time points depending on the leakage rate of each sample or the breakage of the sealing cable after some time. Despite the excessive size of the oxygen absorber (30 cc capacity in E compared to 7 cc of pure oxygen in the bag volume), the oxygen level in the bag can be raised back to 21% very quickly if the bag is full. leaking. The large number of defective E-configuration pouches suggests that some materials have better sealing properties than others and are a consideration for secondary packaging. Example 5: Oxygen Levels of Filled Syringes at Ambient Conditions (~21% O2) in Blister Packaging with Oxygen Absorbents
    [00103] [00103] This study evaluated the oxygen level and extraction kinetics of a loaded syringe under ambient conditions (the O2 concentration is ~ 21%). Three different bubble configurations (n = 10, per configuration) containing oxygen absorbers in a volume of about 32 cubic centimeters were prepared with the following materials at ambient conditions (~21% O2): Configuration Absorber Lower mesh Upper mesh Oxygen 1 (◆) PET/EVOH/PE 500 µm Paper/Alu 9 µm/PE 30 cc sachet 2 (■) PET/EVOH/PET 457 µm Paper/PET/Alu 20 µm 30 cc canister 3 (▲) PET/EVOH/LDPE 457 µm Paper/Alu 9 µm/PE 30 cc canister
    [00104] [00104] 1.25 ml glass syringes (HipakTM, Becton Dickinson & Co.) with oxygen-permeable tip caps were filled with purified (degassed) water and subsequently placed in one of the above blister packs. Thus, the water contained 8 ppm of the initial oxygen levels (equilibrium with air at 21% oxygen.
    [00105] [00105] For all three settings, the oxygen level is zero in the blister pack after one day and remains at zero until the end of the study (360 days) (Figure 11). This indicates that the oxygen uptake kinetics have a much faster rate than the oxygen permeation flow through the bubble. In Figure 11, the oxygen concentration at T0 (time zero) should be 21%, but the time delay between sample manufacture and measurement (a few hours span) is sufficient to obtain low concentrations at the first point of measurement. OXYGEN IN SYRINGE ENVIRONMENTS
    [00106] [00106] For a syringe loaded under ambient conditions (21% oxygen) and placed in the blister pack with oxygen absorber, the oxygen level in the syringe decreases to 5% within six months, and less than 2% within about one year for all three bubble configurations (Figure 12). The trendline in Figure 12 appears to follow an exponential curve.
    [00107] [00107] The study showed that the oxygen extraction flow within the syringe is a relatively slow process: it takes about six months to decrease levels to about 5% oxygen, and a year for oxygen levels of about of 2%. These slow kinetics indicate that syringes filled under ambient conditions will expose the contents of the syringes to about six months of exposure to oxygen, thus likely with an increased risk of oxidation/degradation. Although the packaging will eventually reduce the oxygen levels in the syringe to less than 2% in about a year, it is recommended to fill the syringe under inert conditions (ie nitrogen) to prevent the possibility of degradation. Example 6: Syringe Oxygen Levels in Various Filling and Conditioning Conditions
    [00108] [00108] Figure 13 summarizes oxygen levels in syringes of various filling and conditioning conditions over the course of one year. For a syringe loaded under inert conditions (degassed, purged with N2) with an O2 level of ~1% and placed in ambient air storage (no secondary packaging), oxygen levels eventually increased to 21% at about one year (▲). For a syringe loaded under inert conditions (degassed, purged with N2) with an O2 level of ~1% and placed in the oxygen barrier package with an absorbent, the oxygen levels decrease to zero in about a month and there they remain after about a year (◆). A syringe loaded under ambient conditions (~21% O2 level) and placed in the oxygen barrier package with an absorbent, oxygen levels decrease to about 1% after one year (■). Example 7: Accelerated Stability Studies of a Morphine Formulation in Main and Secondary Packages without Oxygen Absorbent
    [00109] [00109] 2 mg/ml and 10 mg/ml of morphine formulations were prepared according to the table below.
    [00110] [00110] Morphine formulations of 2 mg/ml and 10 mg/ml were evaluated under accelerated conditions ICH at 40°C/RH 75% for 6 months in a 1.25 ml glass syringe (HipakTm) with an oxygen permeable plug. The syringes containing the morphine formulations were placed in the secondary blister pack of PET material (polyethylene terephthalate) with a protective paper cap liner.
    [00111] [00111] The results of the stability test after 6 months of storage at 40°C/RH 75% revealed that the morphine content remained within specification parameters (NMT ± 10% change) for both concentrations. Assay values remained stable on the 2 mg/ml formulation, whereas assay values for morphine declined slightly on the 10 mg/ml formulation but remained within specification. Similarly, the level of total impurities steadily increased over time, but was below specification (NMT 1.5%) for both intensities. The pH values also remained stable for the 6-month storage period.
    [00112] [00112] With respect to individual impurities, pseudomorphine appeared after the storage period of 1 month and increased steadily over the storage period AM both 2 mg/ml and 10 mg/ml morphine formulations. At the end of 6 months of storage, this impurity exceeded the specification limit (NMT 0.2%). The following table describes the pseudomorphine concentration over time in the 2 mg/ml morphine formulation: 2 mg/ml Morphine in Oxygen Barrier Packaging - Pseudomorphine Content T0 T1 Month T2 Months T3 Months T6 Months Batch 1 0 0.05 0.05 0.1 0.21 Batch 2 0 0.05 0.06 0.11 0.23 Batch 3 0 0.06 0.06 0.11 0.24
    [00113] [00113] Figure 14 shows the presence of pseudomorphine over time in the 2 mg/ml formulation from three different groups. The increase in pseudomorphine was at a higher rate in the mg/ml formulation and reached the specification limit earlier (data not shown). Example 8: Accelerated Stability Studies of a Morphine Formulation in Primary and Secondary Packages with Oxygen Absorbent
    [00114] [00114] In order to improve the stability and shelf life of the morphine formulation of Example 7, a secondary package with an oxygen absorber was developed.
    [00115] [00115] The alternative blister package included a thermoformed transparent wrap made from a multi-layer plastic film including PET and EVOH (Ethylene Vinyl Alcohol) (bottom mesh), and a heat-sealed paper-made lid material, PET and aluminum foil (top mesh). The EVOH layer of the lower mesh has a very low permeability to oxygen molecules and the thin aluminum sheet is impermeable to any gas. Thus, this blister packaging restricts the re-entry of atmospheric oxygen into the secondary packaging. An oxygen absorber (30 cubic centimeters capacity) was placed inside the bubble. This absorbent included an iron powder formula loaded in a canister made of HDPE plastic and functioned to absorb all the oxygen present in the secondary packaging. The main packaging container, i.e. the syringe, containing the morphine formulation was then placed in this alternative blister package.
    [00116] [00116] Accelerated conditions of 40°C/RH 75% for 6 months were evaluated similarly to the preceding example. For both intensities, the morphine content remained stable over time and the results were compatible with the specification (90 to
    [00117] [00117] As shown above, the pseudomorphine content also remained far below the specification limit (NMT 0.2%). The data in the example showed that the stability results obtained in the groups conditioned with the secondary packaging system with an oxygen absorber show that the combination of the formulation with the buffer and chelation systems, the process of manufacture under nitrogen and the oxygen barrier packaging with an oxygen absorber ensure good preservation of the morphine formulation against oxidation reactions. COMPARISON OF MORPHINE FORMULATION IN PACKAGING BARRIER TO OXYGEN WITH STANDARD PACKAGING
    [00118] [00118] In another study, the stability of the 2 mg/ml morphine formulation was examined in the standard packaging (ie without the secondary oxygen barrier and/or oxygen absorbent packaging) and in the barrier packaging to oxygen (ie, with secondary oxygen barrier and oxygen absorber packaging) at ambient conditions (25°C/60% RH) and accelerated s (40°C/75% RH). The following tables show that, under ambient and accelerated conditions, the pseudomorphine content in morphine formulations with oxygen barrier packaging was low and lower than the specification limits, whereas morphine formulations with standard packaging had unacceptable levels (0.2% or greater) of pseudomorphine: 2 mg/ml Morphine in Oxygen Barrier Packaging - Pseudomorphine Content Storage at 25°C/RH 60% T3 T6 T9 T12 T18 T24 T0 Months Months Months Months Months Months Packaging 0 0.040 0.060 0.080 0.110 0.210 0.300 standard Barrier Packaging 0 0.020 0.024 0.030 0.033 N/A 0.032 to Oxygen 2 mg/ml Morphine in Oxygen Barrier Packaging - Pseudomorphine Content Storage at 40°C/RH of 75% T0 T1 Month T2 Months T3 Months T6 Months Packaging 0.010 0.050 0.090 0.100 0.200 standard Barrier Packaging 0.010 0.040 0.020 0.030 0.030 to Oxygen
    [00119] [00119] Figure 15 is a graphical representation of the results in the preceding tables. Figure 15 (top) shows storage of the 2 mg/ml (MPH) morphine formulation in standard and oxygen barrier packaging at ambient conditions (25°C / 60% RH) for 24 months. The graph shows that the 2 mg/ml morphine formulation in the standard packaging, when stored at ambient conditions, reached unacceptable levels of pseudomorphine impurity in about 18 months. Figure 15 (baseline) shows storage of the 2 mg/ml morphine formulation in standard and oxygen barrier packages under accelerated conditions (40°C/75% RH) for six months. At the end of the six-month period under accelerated conditions, morphine formulations in standard packaging reached the specification limit for pseudomorphine. Oxygen barrier package morphine formulations stored at ambient and accelerated conditions were stable and had pseudomorphine levels well below specification limits. Example 9: Comparison of Stability of the Morphine Formulation of Example 7 in Oxygen Barrier Packaging with Marketed Morphine Formulation Products of Equal Intensities
    [00120] Morphine formulations of 2 mg/ml, 5 mg/ml and 10 mg/ml were prepared according to Example 7 and loaded into a 1.25 ml glass syringe (HipakTm) with a stopper and placed in the secondary packaging system with an oxygen absorber as described in Example 8. Stability was compared to marketed morphine formulation products of equal strengths. Test conditions and results are summarized in the following table:
    [00121] [00121] As shown above, the morphine formulations of Example 7 in the secondary packaging system with an oxygen absorber had much better stability than marketed morphine products of comparable strengths even when marketed morphine products were stored in ambient conditions, whereas the morphine formulations of Example 7 were stored under accelerated conditions (40°C/75% RH). The stability test shows that all marketed morphine products were outside specification limits for either the total and/or a particular impurity, whereas the morphine formulations of Example 7 were completely within specification. The morphine product marketed at 2 mg/ml had a high level of total impurities (1.7%) and was out of specification (according to the ICH Q3B guideline) for two unknown impurities; other unknown impurities were found significantly in more than 0.1%. Morphine product marketed at mg/ml showed unacceptable pseudomorphine levels and unknown levels of impurity. Finally, the morphine product marketed at 10 mg/ml, analyzed at about half its shelf life, had a high total impurity level and up to 6 unknown impurities, 4 of which are very close to or could be rounded off. to 0.2%; this indicates that this product is unlikely to meet the stability acceptance criteria after two years. The results in this example demonstrate the increased purity and stability of the exemplary morphine formulations described herein with the oxygen absorber secondary packaging system. Example 10: Additional Stability Studies with Various Oxygen Sensitive Drugs in Standard and Oxygen Barrier Packaging
    [00122] [00122] Additional stability studies were performed for the hydromorphone and promethazine formulation similar to the morphine standard versus the oxygen barrier packaging study in Example 8. HYDROMORPHONE
    [00123] [00123] The stability of 1 mg/ml and 10 mg/ml hydromorphone formulations has been examined in the standard packaging (ie, no secondary oxygen barrier and/or oxygen absorbent packaging) and in the oxygen barrier packaging. oxygen (ie, with oxygen barrier and oxygen absorber secondary packaging) at ambient conditions (25°C/60% RH) for 24 months and accelerated (40°C/75% RH) for six months.
    [00124] [00124] Under ambient conditions, no significant difference in impurity content was observed for hydromorphone formulations of 1 mg/ml in standard packaging or in oxygen barrier packaging. However, under accelerated conditions, both the 1 mg/ml and 10 mg/ml formulations exhibited an unknown impurity at RRT 0.72 that exceeded or approached the specification limits: 1 mg/ml Hydromorphone in Barrier Packaging to Oxygen - Pseudomorphine Content Storage at 40°C/RH 75% T0 T1 Month T2 Months T3 Months T6 Months Packaging 0 N/AN/A 0.090 0.240 standard Barrier Packaging 0 N/AN/A 0.080 0.070 to Oxygen 10 mg/ml of Hydromorphone in Oxygen Barrier Packaging - Pseudomorphine Content Storage at 40°C/RH 75% T0 T1 Month T2 Months T3 Months T6 Months Standard Packaging 0 N/AN/A 0.080 0.190 Packaging 0 N/ AN/A 0.040 0.030 Oxygen Barrier
    [00125] [00125] Figure 16 is a graphical representation of the results in the preceding table. Figure 16 (top) shows the storage of 1 mg/ml hydromorphone formulation (HYD) in both standard and oxygen barrier packages under accelerated conditions (40°C/75% RH) for six months. The graph shows that the 1 mg/ml hydromorphone formulation in the standard package had an unacceptable unknown impurity (RRT 0.72) at the end of the six month storage period. Figure 16 shows storage (base) of 10 mg/ml hydromorphone formulations in standard and oxygen barrier packages under accelerated conditions (40°C/75% RH) for six months. At the end of the six month period under accelerated conditions, the hydromorphone formulations in the standard package were very close to the specification limit for the unknown impurity (RRT 0.72). The 1 mg/ml and 10 mg/ml hydromorphone formulations in the oxygen barrier package were stable with stable impurity levels and below specification limits. PROMETAZINE
    [00126] [00126] The stability of 25 mg/ml promethazine formulations was examined in the standard packaging (ie without the secondary oxygen barrier and/or oxygen absorber packaging) and in the oxygen barrier packaging (ie, with secondary oxygen barrier and oxygen absorber packaging) in ambient conditions (25°C/60% RH) for 24 months and accelerated s (40°C/75% RJ+H) for six months.
    [00127] [00127] The following tables show that, under both ambient and accelerated conditions, the sulfoxide impurity content in the promethazine formulations with the oxygen barrier packaging were under the specification limits, whereas the Standard packaged promethazine formulations quickly showed unacceptable levels (0.2% or greater) of sulfoxide impurity:
    [00128] [00128] Graphical figure of the results in the preceding table. Figure 17 (top) shows a storage of the promethazine (PRZ) formulation of 25 mg/ml in standard and oxygen barrier packages at ambient conditions (25°C/60% RH) for twelve months. The graph shows that the promethazine formulation in the standard package had unacceptable levels of sulfoxide by the three-month test point that continued to increase through the end of the storage period. The promethazine formulation in the oxygen barrier packaging had sulfoxide impurity levels under specification limits. Figure 17 shows storage (base) of 25 mg/ml promethazine formulations in standard and oxygen barrier packages under accelerated conditions (40°C/75% RH) for six months. At the one-month test point, the promethazine formulations in the standard package have already exceeded the specification limit for sulfoxide. Promethazine formulations in oxygen barrier packaging were stable with stable sulfoxide impurity levels and below specification limits.
    [00129] [00129] Although preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be employed in the practice of the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of those claims and their equivalents are covered therein.
    权利要求:
    Claims (15)
    [1]
    1. Pharmaceutical packaging system for an injectable oxygen-sensitive drug, the packaging system characterized by comprising: (i) a syringe loaded under inert conditions with an injectable oxygen-sensitive drug, wherein the syringe has a tip cap permeable to oxygen, (ii) a hermetically sealed oxygen barrier blister package housing the syringe, wherein the blister package comprises a multilayer bottom network comprising an ethylene/vinyl alcohol (EVOH) copolymer and a cap. multilayer top web comprising a thin sheet of aluminum or EVOH; and (iii) an oxygen absorber, wherein the oxygen absorber reduces the level of oxygen present from the time of package assembly by about zero percent in about one to three days in the blister package and in about one to three months in the syringe.
    [2]
    2. Pharmaceutical packaging system, according to claim 1, characterized in that the syringe is made of plastic or glass.
    [3]
    3. Pharmaceutical packaging system, according to claim 1, characterized in that the blister packaging is a blister formed or cold molded based on aluminum.
    [4]
    4. Pharmaceutical packaging system, according to claim 1, characterized in that the oxygen absorber is placed inside the blister package.
    [5]
    5. Pharmaceutical packaging system, according to claim 1, characterized in that the oxygen absorber is a container.
    [6]
    6. Pharmaceutical packaging system, according to claim 1, characterized in that the oxygen absorber has a capacity to absorb 30 cm3 of oxygen at 1 atm.
    [7]
    7. Pharmaceutical packaging system, according to claim 1, characterized in that the oxygen absorber is iron-based.
    [8]
    8. Pharmaceutical packaging system, according to claim 1, characterized in that the oxygen absorber reduces the oxygen level in the blister package from the moment of assembly of the package by about zero percent in one day.
    [9]
    9. Pharmaceutical packaging system, according to claim 1, characterized in that the oxygen absorber reduces the oxygen level in the syringe from the moment of packaging assembly by about zero percent in one month.
    [10]
    10. Pharmaceutical packaging system, according to claim 1, characterized in that the blister packaging is a thermoformed blister.
    [11]
    11. Pharmaceutical packaging system, according to claim 1, characterized in that the oxygen absorber is selected from the group consisting of reduced iron compounds, catechol, ascorbic acid and the like, metallic binders, unsaturated hydrocarbons and polyamides.
    [12]
    12. Pharmaceutical packaging system, according to claim 1, characterized in that the injectable oxygen-sensitive drug is selected from the group consisting of morphine, hydromorphone, promethazine, dopamine, epinephrine, norepinephrine, esterified estrogen , ephedrine, pseudoephedrine, acetaminophen, ibuprofen, damofloxacin, erythromycin, penicillin, cyclosporine, methyldopate, cetirizine, diltiazem, verapamil, mexiletine, chlorothiazide, carbamazepine, se-
    legiline, oxybutynin, vitamin A, vitamin B, vitamin C, L-cysteine and L-tryptophan.
    [13]
    13. Pharmaceutical packaging system, according to claim 12, characterized in that the injectable oxygen-sensitive drug is morphine.
    [14]
    14. Pharmaceutical packaging system, according to claim 12, characterized in that the injectable oxygen-sensitive drug is hydromorphone.
    [15]
    15. Pharmaceutical packaging system, according to claim 12, characterized in that the injectable oxygen-sensitive drug is promethazine.
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    同族专利:
    公开号 | 公开日
    US20210130071A1|2021-05-06|
    US20190168943A1|2019-06-06|
    ES2695158T3|2019-01-02|
    EP2968729B1|2018-08-15|
    CN104528165B|2018-06-29|
    AU2014230836B2|2018-08-16|
    US10214338B2|2019-02-26|
    US20160100889A1|2016-04-14|
    CN204798475U|2015-11-25|
    WO2014140097A1|2014-09-18|
    HK1208015A1|2016-02-19|
    CA2902346A1|2014-09-18|
    PT2968729T|2018-11-06|
    CN104528165A|2015-04-22|
    JP2016512455A|2016-04-28|
    AU2014230836C1|2018-12-20|
    DK2968729T3|2018-12-03|
    US11214426B2|2022-01-04|
    US9248229B2|2016-02-02|
    US20140262883A1|2014-09-18|
    AU2018236914A1|2018-10-25|
    EP3424547A1|2019-01-09|
    US10781027B2|2020-09-22|
    US9545473B2|2017-01-17|
    EP2968729A1|2016-01-20|
    AU2014230836A1|2015-09-10|
    US20170088333A1|2017-03-30|
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    法律状态:
    2017-08-29| B25A| Requested transfer of rights approved|Owner name: FRESENIUS KABI DEUTSCHLAND GMBH (DE) |
    2018-11-13| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-02-18| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2020-07-21| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|
    2020-09-01| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    US201361785158P| true| 2013-03-14|2013-03-14|
    US61/785,158|2013-03-14|
    PCT/EP2014/054834|WO2014140097A1|2013-03-14|2014-03-12|Packaging system for oxygen-sensitive drugs|
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