WO2014052792A1 - Revêtement de polymère halogéné ou de parylène - Google Patents

Revêtement de polymère halogéné ou de parylène Download PDF

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Publication number
WO2014052792A1
WO2014052792A1 PCT/US2013/062247 US2013062247W WO2014052792A1 WO 2014052792 A1 WO2014052792 A1 WO 2014052792A1 US 2013062247 W US2013062247 W US 2013062247W WO 2014052792 A1 WO2014052792 A1 WO 2014052792A1
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WO
WIPO (PCT)
Prior art keywords
injection
drug comprises
drug
sliding surface
alternatively
Prior art date
Application number
PCT/US2013/062247
Other languages
English (en)
Inventor
Paul R. Resnick
Thomas E. Fisk
Christopher Weikart
Original Assignee
Sio2 Medical Products, Inc.
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 Sio2 Medical Products, Inc. filed Critical Sio2 Medical Products, Inc.
Publication of WO2014052792A1 publication Critical patent/WO2014052792A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
    • A61M5/31511—Piston or piston-rod constructions, e.g. connection of piston with piston-rod
    • A61M5/31513—Piston constructions to improve sealing or sliding
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/06—Ampoules or carpules
    • C—CHEMISTRY; METALLURGY
    • C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
    • C23C16/04—Coating on selected surface areas, e.g. using masks
    • C23C16/045—Coating cavities or hollow spaces, e.g. interior of tubes; Infiltration of porous substrates
    • C—CHEMISTRY; METALLURGY
    • C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
    • C23C16/22—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the deposition of inorganic material, other than metallic material
    • C23C16/30—Deposition of compounds, mixtures or solid solutions, e.g. borides, carbides, nitrides
    • C23C16/40—Oxides
    • C23C16/401—Oxides containing silicon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/3129—Syringe barrels
    • A61M2005/3131—Syringe barrels specially adapted for improving sealing or sliding
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2207/00—Methods of manufacture, assembly or production
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2207/00—Methods of manufacture, assembly or production
    • A61M2207/10—Device therefor

Definitions

  • the present invention relates to the technical field of syringes, cartridges, vials, or similar containers and other pharmaceutical packages for storing, dispensing, or other contact with fluids.
  • suitable fluids include foods or biologically active compounds or body fluids, for example injectable pharmaceuticals or blood.
  • the present invention also relates to a pharmaceutical package or other vessel and to a method for coating an inner or interior surface of a pharmaceutical package or other vessel.
  • the present invention also relates more generally to medical devices, including devices other than packages or vessels, for example catheters.
  • the present disclosure also relates to improved methods for processing pharmaceutical packages or other vessels, for example multiple identical pharmaceutical packages or other vessels used for pharmaceutical preparation storage and delivery, venipuncture and other medical sample collection, and other purposes.
  • Such pharmaceutical packages or other vessels are used in large numbers for these purposes, and must be relatively economical to manufacture and yet highly reliable in storage and use.
  • a prefilled syringe is capped at the distal end, as with a cap, and is closed at the proximal end by its drawn stopper, O-ring, plunger tip or piston.
  • the prefilled syringe can be wrapped in a sterile package before use.
  • the packaging and shield are removed, optionally a hypodermic needle or another delivery conduit is attached to the distal end of the barrel, the delivery conduit or syringe is moved to a use position (such as by inserting the hypodermic needle into a patient's blood vessel or into apparatus to be rinsed with the contents of the syringe), and the stopper, O-ring, plunger tip or piston is advanced in the barrel to inject the contents of the barrel.
  • a desirable shelf life is at least one year, preferably at least two years.
  • Prefilled syringes, cartridges, or similar articles are commonly prepared and sold so the syringe does not need to be filled before use, and can be disposed of after use.
  • the syringe can be prefilled with saline solution, a dye for injection, or a pharmaceutically active preparation, for some examples.
  • the stopper, O-ring, plunger tip or piston, or other interior structure which slides down the barrel to dispense fluid will be resting or parked in a fixed position in the barrel. It is well known that a parked stopper, O-ring, plunger tip or piston, or other interior structure will tend to adhere to the barrel over time.
  • the syringe, cartridge, or other article is lubricated, commonly with silicone oil, to reduce the friction encountered when advancing the stopper, O-ring, plunger tip or piston, or other interior structure down the barrel.
  • a parked stopper, O-ring, plunger tip or piston, or other interior structure of such an article often will push the lubricant aside and provide a thinner lubricant layer, possibly substantially eliminating the lubricant layer, where the stopper, O-ring, plunger tip or piston, or other interior structure is parked.
  • the lubrication may be inadequate and the breakout force, the same concept sometimes referred to as the break loose force (the force required to start the parked stopper, O-ring, plunger tip or piston, or other interior structure moving) may be very high.
  • the break loose force of a syringe also commonly continues to increase over time, and if it increases too much it can limit the shelf life of the syringe, cartridge, or similar article.
  • Polymeric materials as lubricants in medical devices include low molecular weight silicones (e.g. polydimethylsiloxanes (PDMS)) and polyperfluorocarbons (e.g. polytetrafluoroethylene (PTFE)).
  • PDMS polydimethylsiloxanes
  • PTFE polytetrafluoroethylene
  • the elastomeric rubber plunger tip is an area of concern for extractable solutes, potentially interfering with the therapeutic function of the drug.
  • Thick (greater than 50 microns) PTFE molded laminates rubber elastomer overmolded from PTFE resin preforms
  • linear PTFE coatings either molded from preformed linear PTFE over molding, or from linear PTFE CVD coatings
  • the PTFE/rubber elastomer laminate can realize an overall increase in stiffness behavior, resulting in poorer container closure integrity (CCI) of the syringe system.
  • CCI integrity is a critical function in syringe systems.
  • An aspect of the invention is a container, for example a syringe, cartridge, vial or similar article.
  • the container includes a barrel or other vessel and a stopper, O-ring, plunger tip or piston.
  • the barrel or other vessel includes a lumen defined at least in part by a internal wall of the barrel or other vessel.
  • the barrel includes a substrate defining at least a portion of the lumen and an internal sliding surface on the vessel substrate adjacent to the lumen.
  • the stopper, O-ring, plunger tip or piston is located within the lumen and has an external sliding surface slidable in the lumen at least substantially in contact with the internal sliding surface.
  • the internal wall, the internal sliding surface, the external sliding surface, or both are made at least in part of a parylene or halogenated polymer, for example a fluorinated polymer in any embodiment, which can be in the form of a coating or a bulk material.
  • a fluorinated polymer, fluoropolymer, and fluorocarbon polymer are different terms for the same type of material.
  • One non- limiting example of such a fluorinated polymer, fluoropolymer, or fluorocarbon polymer is polytetrafluoroparaxylylene.
  • Another non-limiting example of such a fluorinated polymer, fluoropolymer, or fluorocarbon polymer is polytetrafluoroethylene.
  • Another aspect of the invention is a method of making the syringe, cartridge, or similar article. This can be done by depositing the parylene or halogenated polymer directly or with intervening layers to define the external sliding surface, the internal internal sliding surface, or both.
  • Two non-limiting examples of suitable equipment for deposition of the parylene or halogenated polymer are hot filamenthot filament chemical vapor deposition and pyrolysis chemical vapor deposition.
  • thin (less than 10 microns) parylene polymer coatings can function both as effective lubricants and barriers to solute extraction from the elastomeric plunger tips with minimal changes in CCI.
  • the Invention optionally can provide in a single coating, both good lubricity and low extractables, defined as
  • PDMS polydimethylsiloxane
  • FIG. 1 shows a side elevation view of a prefilled syringe made according to one embodiment of the invention.
  • FIG. 2 is a longitudinal section of the prefilled syringe of FIG. 1 .
  • FIG. 3 is a schematic longitudinal section of a plasma enhanced chemical vapor deposition coating station for coating the interior of a syringe barrel, showing a syringe barrel positioned to be coated.
  • FIG. 4 is a schematic view of the coating station of FIG. 3, showing more details of the precursor supply apparatus.
  • FIG. 5 which is modified from a Figure in US Publ. Appl. 2012/0003497, is a schematic view of a hot filament chemical vapor deposition machine.
  • Fig. 6 shows three log-log plots of plunger breakloose force versus parking time, showing short-term test results of HWCVD working examples and extrapolated two-year results.
  • Fig. 7 shows three log-log plots of plunger breakloose force versus parking time, showing short-term test results of the Parylene working examples, extrapolated to provide two-year results.
  • FIG. 8 shows a diagrammatic cross-section of a vial 170 which is an embodiment of the preassembly 12.
  • Fig. 9 is a diagrammatic wall cross section of a barrel 14, which alternatively can be a vial wall or other substrate in any embodiment, in which the fluorinated polymer optionally can comprise a composite of polytetrafluoroethylene 34 and a fluorine substituted derivative of poly(paraxylylene) 31 .
  • Fig. 10 is a view similar to Fig. 9 in which the fluorinated polymer optionally can comprise a composite of a first layer 31 of one fluorinated polymer, for example a fluorine substituted derivative of poly(paraxylylene), and a second layer of another fluorinated polymer, for example polytetrafluoroethylene, optionally comprising linear polytetrafluoroethylene.
  • Fig. 1 1 is a view similar to Fig. 9 providing three coating layers: a barrier coating or layer 30, a protective coating or layer 31 , and a separate lubricity coating or layer.
  • FIG. 12 is a schematic view of a chemical vapor deposition apparatus useful, for example, for depositing a coating of a fluorinated polymer, for example polytetrafluoroethylene.
  • Fig. 13 is a bar plot showing vacuum decay test results according to the work in Example 20.
  • Fig. 14 is a log-log plot of F m results versus park time for Example P19.
  • Fig. 15 is a log-log plot of F, results versus park time for Working Example A.
  • Precursor vaporvapor source 588 Organosilicon liquid reservoir
  • RF is radio frequency
  • an "organosilicon precursor” is a compound having at least one of the linkages:
  • a volatile organosilicon precursor defined as such a precursor that can be supplied as a vapor in a PECVD apparatus, is an optional organosilicon precursor.
  • the organosilicon precursor is selected from the group consisting of a linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, an alkyl trimethoxysilane, a linear silazane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, and a combination of any two or more of these precursors.
  • the feed amounts of PECVD precursors, gaseous reactant or process gases, and carrier or diluent gas are sometimes expressed in "standard volumes" in the specification and claims.
  • the standard volume of a charge or other fixed amount of gas is the volume the fixed amount of the gas would occupy at a standard temperature and pressure (without regard to the actual temperature and pressure of delivery).
  • Standard volumes can be measured using different units of volume, and still be within the scope of the present disclosure and claims.
  • the same fixed amount of gas could be expressed as the number of standard cubic centimeters, the number of standard cubic meters, or the number of standard cubic feet. Standard volumes can also be defined using different standard temperatures and pressures, and still be within the scope of the present disclosure and claims.
  • the standard temperature might be 0°C and the standard pressure might be 760 Torr (as is conventional), or the standard temperature might be 20 °C and the standard pressure might be 1 Torr. But whatever standard is used in a given case, when comparing relative amounts of two or more different gases without specifying particular parameters, the same units of volume, standard temperature, and standard pressure are to be used relative to each gas, unless otherwise indicated.
  • the corresponding feed rates of PECVD precursors, gaseous reactant or process gases, and carrier or diluent gas are expressed in standard volumes per unit of time in the specification.
  • the flow rates are expressed as standard cubic centimeters per minute, abbreviated as seem.
  • other units of time can be used, such as seconds or hours, but consistent parameters are to be used when comparing the flow rates of two or more gases, unless otherwise indicated.
  • a "vessel" in the context of the present invention can be any type of vessel with at least one opening and a wall defining an inner or interior surface.
  • the substrate can be the inside wall of a vessel having a lumen. Though the invention is not necessarily limited to pharmaceutical packages or other vessels of a particular volume, pharmaceutical packages or other vessels are contemplated in which the lumen has a void volume of from 0.5 to 50 ml_, optionally from 1 to 10 ml_, optionally from 0.5 to 5 ml_, optionally from 1 to 3 ml_.
  • the substrate surface can be part or all of the inner or interior surfaceinner or interior surface of a vessel having at least one opening and an inner or interior surfaceinner or interior surface.
  • a vessel in the context of the present invention has one or more openings.
  • One or two openings like the openings of a sample tube (one opening) or a syringe barrel (two openings) are preferred. If the vessel has two openings, they can be of same or different size. If there is more than one opening, one opening can be used for the gas inlet for a PECVD coating method according to the present invention, while the other openings are either capped or open.
  • a vessel according to the present invention can be a sample tube, for example for collecting or storing biological fluids like blood or urine, a syringe (or a part thereof, for example a syringe barrel) for storing or delivering a biologically active compound or composition, for example a medicament or pharmaceutical composition, a vial for storing biological materials or biologically active compounds or compositions, a pipe, for example a catheter for transporting biological materials or biologically active compounds or compositions, or a cuvette for holding fluids, for example for holding biological materials or biologically active compounds or compositions.
  • a sample tube for example for collecting or storing biological fluids like blood or urine
  • a syringe or a part thereof, for example a syringe barrel
  • a biologically active compound or composition for example a medicament or pharmaceutical composition
  • a vial for storing biological materials or biologically active compounds or compositions
  • a pipe for example a catheter for transporting biological materials or biologically active compounds or compositions
  • a vessel can be of any shape, a vessel having a substantially cylindrical wall adjacent to at least one of its open ends being preferred.
  • the interior wall of the vessel is cylindrically shaped, like, for example in a sample tube or a syringe barrel. Sample tubes and syringes, cartridges, or similar articles or their parts (for example syringe barrels) are contemplated.
  • a "hydrophobic layer” in the context of the present invention means that the coating or layer lowers the wetting tension of a surface coated with the coating or layer, compared to the corresponding uncoated surface. Hydrophobicity is thus a function of both the uncoated substrate and the coating or layer. The same applies with appropriate alterations for other contexts wherein the term “hydrophobic” is used.
  • the term “hydrophilic” means the opposite, i.e. that the wetting tension is increased compared to reference sample.
  • the present hydrophobic layers are primarily defined by their hydrophobicity and the process conditions providing hydrophobicity
  • w, x, y, and z used throughout this specification should be understood as ratios or an empirical formula (for example for a coating or layer), rather than as a limit on the number or type of atoms in a molecule.
  • octamethylcyclotetrasiloxane which has the molecular composition Si 4 0 4 C 8 H 24
  • Si 4 0 4 C 8 H 24 can be described by the following empirical formula, arrived at by dividing each of w, x, y, and z in the molecular formula by 4, the largest common factor: Si-
  • the values of w, x, y, and z are also not limited to integers.
  • (acyclic) octamethyltrisiloxane molecular composition Si 3 02C 8 H2 4 , is reducible to Si1O0.67C2.67Hs.
  • SiO x CyH z is described as equivalent to SiO x C y , it is not necessary to show the presence of hydrogen in any proportion to show the presence of SiO x C y .
  • wetting tension is a specific measure for the hydrophobicity or hydrophilicity of a surface.
  • An optional wetting tension measurement method in the context of the present invention is ASTM D 2578 or a modification of the method described in ASTM D 2578. This method uses standard wetting tension solutions (called dyne solutions) to determine the solution that comes nearest to wetting a plastic film surface for exactly two seconds. This is the film's wetting tension.
  • the procedure utilized is varied herein from ASTM D 2578 in that the substrates are not flat plastic films, but are tubes made according to the Protocol for Forming PET Tube and (except for controls) coated according to the Protocol for coating Tube Interior with Hydrophobic Coating or Layer (see Example 9 of EP2251671 A2).
  • a "lubricity and/or protective coating or layer” is a coating or layer which has a lower frictional resistance than the uncoated surface, which is a lubricity layer, and/or protects an underlying surface or layer from a fluid composition contacting the layer, which is a protective coating or layer (as more extensively defined elsewhere in this specification). In other words, respecting a lubricity layer, it reduces the frictional resistance of the coated surface in comparison to a reference surface that is uncoated.
  • the present lubricity and/or protective coating or layers are primarily defined as lubricity layers by their lower frictional resistance than the uncoated surface and the process conditions providing lower frictional resistance than the uncoated surface, and optionally can have a composition according to the empirical composition Si w O x C y H z , (or its equivalent SiO x C y ) as defined herein. It generally has an atomic ratio Si w O x C y (or its equivalent SiO x C y ) wherein w is 1 , x is from about 0.5 to about 2.4, y is from about 0.6 to about 3.
  • the atomic ratios of Si, O, and C in the "lubricity and/or protective coating or layer" are, as several options:
  • the coating or layer may thus in one aspect have the formula Si w O x C y H z (or its equivalent SiOxCy), for example where w is 1 , x is from about 0.5 to about 2.4, y is from about 0.6 to about 3, and z is from about 2 to about 9.
  • such coating or layer would hence contain 36% to 41 % carbon normalized to 100% carbon plus oxygen plus silicon.
  • Fritional resistance can be static frictional resistance and/or kinetic frictional resistance.
  • One of the optional embodiments of the present invention is a low friction syringe part, for example a syringe barrel having an internal wall made in least in part of a parylene or halogenated polymer, a stopper, O-ring, plunger tip or piston comprising a sliding surface made at least in part of a parylene or halogenated polymer, or both.
  • the relevant static frictional resistance in the context of the present invention is the breakout force as defined herein
  • the relevant kinetic frictional resistance in the context of the present invention is the stopper, O-ring, plunger tip or piston sliding force as defined herein.
  • the stopper, O-ring, plunger tip or piston sliding force as defined and determined herein is suitable to determine the presence or absence and the lubricity and/or protective characteristics of a lubricity and/or protective coating or layer in the context of the present invention whenever the coating or layer is applied to any syringe or syringe part, for example to the inner wall of a syringe barrel.
  • the breakout force is of particular relevance for evaluation of the coating or layer effect on a prefilled syringe, i.e.
  • a syringe which is filled after coating and can be stored for some time, for example several months or even years, with the stopper, O-ring, plunger tip or piston "parked,” before the stopper, O-ring, plunger tip or piston is moved again (has to be "broken out”).
  • stopper, O-ring, plunger tip or piston sliding force (synonym to “glide force,” “maintenance force”, or Fm, also used in this description) in the context of the present invention is the force required to maintain movement of a stopper, O-ring, plunger tip or piston in a syringe barrel, for example during aspiration or dispensing. It can advantageously be determined using the ISO 7886-1 :1993 test described herein and known in the art.
  • a synonym for "stopper, O-ring, plunger tip or piston sliding force” often used in the art is “stopper, O-ring, plunger tip or piston force” or “pushing force”.
  • the "stopper, O-ring, plunger tip or piston breakout force” (synonym to “breakout force”, “break loose force”, “initation force”, Fi, also used in this description) in the context of the present invention is the initial force required to move the stopper, O- ring, plunger tip or piston in a syringe, for example in a prefilled syringe.
  • Sliding force and breakout force are sometimes used herein to describe the forces required to advance a stopper or other closure into a pharmaceutical package or other vessel, such as a medical sample tube or a vial, to seat the stopper in a vessel to close the vessel. Its use is analogous to use in the context of a syringe and its stopper, O-ring, plunger tip or piston, and the measurement of these forces for a vessel and its closure are contemplated to be analogous to the measurement of these forces for a syringe, except that at least in most cases no liquid is ejected from a vessel when advancing the closure to a seated position.
  • an aspect of the invention in any embodiment is a pharmaceutical package illustrated in any of the Figures having:
  • a substrate 14 which can be a syringe barrel or other vessel 12 or a stopper
  • O-ring, plunger tip or piston is either made of thermoplastic material or glass; • optionally, an oxygen barrier coating or layer, which can be made of SiO x as defined in this specification or of other materials known to form a barrier coating or layer, typically provided adjacent to the substrate 14;
  • a protective coating or layer which can either be a fluorinated Parylene polymer or can be made of SiO x C y as defined in this specification and can function as a pH protective coating or layer, a solute barrier, or both; and
  • a lubricity coating or layer which can either be a fluorinated Parylene polymer or can be made of SiO x C y as defined in this specification and can function to improve lubricity,
  • the substrate and at least one of the parylene or halogenated polymer layers must be present.
  • Another aspect of the invention is a method in which a vapor-deposited coating or layer 30 is directly or indirectly applied to at least a portion of the internal sliding surface of the barrel or wall 14 of a container 12, alternatively referred to as a pre-assembly or capped container in the case of a syringe.
  • a capped container 12 can be a portion of a complete article adapted to dispense fluid, such as a syringe, a cartridge, a catheter, or other article.
  • the capped container 12 optionally can comprise a barrel or wall 14, a dispensing portion 20, and a shield 28.
  • the container 12 alternatively can be a complete article such as a vial having a wall 14.
  • the container or capped container 12 to be processed optionally has a single opening in any embodiment at the time of chemical vapor deposition or similar treatment, so it can be treated through one opening at a pressure different from ambient, without the need for a separate vacuum chamber.
  • the barrel or wall 14 has an internal sliding surface defining a barrel lumen 18.
  • the barrel or wall 14 can further include an opening 32 spaced from the dispensing portion 20 and communicating through the internal sliding surface.
  • Such an opening is conventional, for example, in a syringe or cartridge, where a typical example is the back opening 32 of a prefilled syringe barrel, through which the stopper, O-ring, plunger tip or piston 36 is inserted after the barrel lumen 18 is filled with a suitable pharmaceutical preparation or other fluid material 40 to be dispensed.
  • the barrel or wall 14 can be formed, for example, by molding, although the manner of its formation is not critical and it can also be formed, for example, by machining a solid preform.
  • the barrel is molded by injection molding thermoplastic material, although it can also be formed by blow molding or a combined method.
  • the barrel or wall 14 can be formed by placing a dispensing portion 20 as described below in an injection mold and injection molding thermoplastic material about the dispensing portion, thus forming the barrel and securing the dispensing portion to the barrel.
  • the dispensing portion and the barrel can be molded or otherwise formed as a single piece, or can be formed separately and joined in other ways.
  • the barrel of any embodiment can be made of any suitable material. Several barrel materials particularly contemplated are COC (cyclic olefin copolymer), COP (cyclic olefin polymer), PET (polyethylene terephthalate), and polypropylene.
  • the barrel or wall 14 can be made of any suitable glass, for example borosilicate glass.
  • the dispensing portion 20 of the container 12 is provided to serve as an outlet for fluid dispensed from the barrel lumen 18 of a completed article made from the container 12.
  • a suitable dispensing portion illustrated in the Figures is a hypodermic needle 20.
  • the dispensing portion 20 can instead be a needle-free dispenser.
  • a suitable needle-free dispenser is a blunt or flexible dispensing portion intended to be received in a complementary coupling to transfer fluid material 40.
  • blunt or flexible dispensing portions are well known for use in syringes, intravenous infusion systems, and other systems and equipment to dispense material while avoiding the hazard of working with a sharp needle that may accidentally stick a health professional or other person.
  • Another example of a needle- free dispenser is a fluid jet or spray injection system that injects a free jet or spray of fluid directly through a patient's skin, without the need for an intermediate needle. Any type of dispensing portion 20, whether a hypodermic needle or any form of needle-free dispenser, is contemplated for use according to any embodiment of the present invention.
  • the dispensing portion 20 is secured to the barrel or wall 14 and includes a proximal opening 22, a distal opening 24, and a dispensing portion lumen 26.
  • the proximal opening 22 communicates with the barrel lumen 18.
  • the distal opening 24 is located outside the barrel or wall 14.
  • the dispensing portion lumen 26 communicates between the proximal and distal openings 22, 24 of the dispensing portion 20.
  • the distal opening 24 is at the sharpened tip of a hypodermic needle 20.
  • the shield 28 is secured to the barrel or wall 14 and at least substantially isolates the distal opening 24 of the dispensing portion 20 from pressure conditions outside the shield 28.
  • the shield 28 sufficiently isolates portions of the container 12 to provide a sufficient bio-barrier to facilitate safe use of the capped container 12 for transdermal injections.
  • the shield 28 can isolate the distal opening 24 in various ways. Effective isolation can be provided at least partially due to contact between the shield 28 and the distal opening 24, as shown in present FIGS. 2, 3, 4, and 7. In the illustrated embodiment, the tip of the dispensing portion 20 is buried in the material of the shield 28. Alternatively in any embodiment, effective isolation can be provided at least partially due to contact between the shield 28 and the barrel or wall 14, as also shown in present FIGS. 2, 3, 4, and 7. In the illustrated embodiment, the primary line of contact between the shield 28 and the barrel or wall 14 is at a rib 42 (best seen in FIG. 3) encircling and seated against a generally cylindrical surface 44 at the nose of the barrel or wall 14.
  • the shield 28 of any embodiment optionally has a latching mechanism, best shown in FIG. 3, including a barb 46 and a catch 48 which engage to hold the shield 28 in place.
  • the catch 48 is made of sufficiently resilient material to allow the shield 28 to be removed and replaced easily.
  • the shield 28 can be a specially formed needle shield.
  • the original use of a needle shield is to cover the hypodermic needle before use, preventing accidental needle sticks and preventing contamination of the needle before it is injected in a patient or an injection port.
  • a comparable shield preferably is used, even if the dispensing portion 20 is a needle-free dispenser, to prevent contamination of the dispenser during handling.
  • the shield 28 can be formed in any suitable way.
  • the shield 28 can be formed by molding thermoplastic material.
  • the thermoplastic material is elastomeric material or other material that is suitable for forming a seal.
  • One suitable category of elastomeric materials is known generically as thermoplastic elastomer (TPE).
  • TPE thermoplastic elastomer
  • An example of a suitable thermoplastic elastomer for making a shield 28 is Stelmi® Formulation 4800 (flexible shield formulation). Any other material having suitable characteristics can instead be used in any embodiment.
  • the shield 28 can be sufficiently permeable to a sterilizing gas to sterilize the portions of the container 12 isolated by the shield.
  • a sterilizing gas is ethylene oxide.
  • Shields 28 are available that are sufficiently permeable to the sterilizing gas that parts isolated by the shield can nonetheless be sterilized.
  • An example of a shield formulation sufficiently permeable to accommodate ethylene oxide gas sterilization is Stelmi® Formulation 4800.
  • an optional step in the present methods is sterilizing the container 12 using a sterilizing gas. Sterilization can be performed at any suitable step, such as sterilizing the container 12 alone or sterilizing a complete pre-filled syringe after it is filled with a suitable pharmaceutical preparation or other material.
  • a vapor-deposited coating or layer 30 is applied directly or indirectly to at least a portion of the internal sliding surface of the barrel or wall 14.
  • the coating or layer 30 is applied while the container 12 is capped.
  • the coating or layer 30 is applied under conditions effective to maintain communication between the barrel lumen 18 and the dispensing portion lumen 26 via the proximal opening 22 at the end of the applying step.
  • the vapor-deposited coating or layer 30 optionally can be applied through the opening 32.
  • the vapor-deposited coating or layer 30 optionally can be applied by introducing a vapor-phase precursor material through the opening and employing chemical vapor deposition to deposit a reaction product of the precursor material on the internal wall of the barrel.
  • the vapor-deposited coating or layer (30) optionally can be applied by flowing a precursor reactant vapor material through the opening and employing chemical vapor deposition to deposit a reaction product of the precursor reactant vapor material on the internal wall of the barrel.
  • the reactant vapor material optionally can be a precursor.
  • the reactant vapor material for an oxygen barrier, pH protective, or lubricity coating or layer optionally can be an organosilicon precursor.
  • the reactant vapor material optionally can be an oxidant gas.
  • the reactant vapor material optionally can be oxygen.
  • the reactant vapor material optionally can include a carrier gas or diluent.
  • the reactant vapor material optionally can include helium, argon, krypton, xenon, neon, or a combination of two or more of these as a diluent or carrier gas.
  • the reactant vapor material optionally can include argon.
  • the reactant vapor material optionally can be a precursor material mixture with one or more oxidant gases in a partial vacuum through the opening and employing chemical vapor deposition to deposit a reaction product of the precursor material mixture on the internal wall of the barrel.
  • the reactant vapor material optionally can be passed through the opening at sub-atmospheric pressure.
  • the chemical vapor deposition optionally can be plasma- enhanced chemical vapor deposition.
  • the vapor-deposited coating or layer optionally can be a gas barrier coating or layer.
  • the vapor-deposited coating or layer optionally can be an oxygen barrier coating or layer.
  • the vapor-deposited coating or layer is a water vapor barrier coating or layer.
  • the vapor-deposited coating or layer optionally can be a solvent barrier coating or layer.
  • the vapor-deposited coating or layer optionally can be a water barrier coating or layer.
  • the vapor-deposited coating or layer optionally can be a solvent barrier coating or layer for a solvent comprising a co-solvent used to increase drug solubilization.
  • the vapor-deposited coating or layer optionally can be a barrier coating or layer for water, glycerin, propylene glycol, methanol, ethanol, n- propanol, isopropanol, acetone, benzyl alcohol, polyethylene glycol, cotton seed oil, benzene, dioxane, or combinations of any two or more of these.
  • the vapor-deposited coating or layer optionally can be a solute barrier coating or layer.
  • solutes in drugs usefully excluded by a barrier layer in any embodiment include antibacterial preservatives, antioxidants, chelating agents, pH buffers, and combinations of any of these.
  • the vapor-deposited coating or layer optionally can be a metal ion barrier coating or layer.
  • the vapor-deposited coating or layer optionally can be a barrel wall material barrier coating or layer, to prevent or reduce the leaching of barrel material such as any of the base barrel resins mentioned previously and any other ingredients in their respective compositions.
  • the vapor deposited coating or layer for any embodiment defined in this specification optionally can be a coating or layer, optionally applied by PECVD as indicated in U.S. Pat. No. 7,985,188.
  • the vapor deposited coating or layer can be a barrier coating or layer, optionally a barrier coating or layer characterized as an "SiO x " coating or layer containing silicon, oxygen, and optionally other elements, in which x, the ratio of oxygen to silicon atoms, optionally can be from about 1 .5 to about 2.9, or 1 .5 to about 2.6, or about 2.
  • the barrier coating or layer optionally can be applied, for example to the interior of a pharmaceutical package or other vessel, for example a sample collection tube, a syringe barrel, a vial, or another type of vessel.
  • the SiO x coating or layer is particularly contemplated as a barrier to oxygen ingress or egress and a solute barrier to prevent migration of drug constituents (as in the barrel lumen 18 of a prefilled syringe or cartridge) into the barrel wall or the migration of barrel wall constituents into the drug or other contents of the barrel lumen.
  • plasma optionally can be generated in the barrel lumen 18 by placing an inner electrode into the barrel lumen 18 through the opening 32, placing an outer electrode outside the barrel or wall 14 and using the electrodes to apply plasma-inducing electromagnetic energy which optionally can be microwave energy, radio frequency energy, or both in the barrel lumen 18.
  • the electromagnetic energy optionally can be direct current.
  • the electromagnetic energy optionally can be alternating current.
  • the alternating current optionally can be modulated at frequencies including audio, or microwave, or radio, or a combination of two or more of audio, microwave, or radio.
  • the electromagnetic energy optionally can be applied across the barrel lumen (18).
  • the method optionally can include applying another, either sole or second or further coating or layer of the same material or a different material.
  • a further coating or layer can be placed directly or indirectly over the glass or barrier coating or layer.
  • a further coating or layer useful in any embodiment is a pH protective coating or layer.
  • a pH protective coating or layer can be used in any embodiment, and is particularly useful if the internal sliding surface yields measurable dissolved silicon when contacted with 0.1 N aqueous potassium hydroxide at 40 °C. and the fluoropolymer layer functions as a pH protective coating or layer having an interior surface facing the lumen, the protective coating or layer being effective to increase the calculated shelf life of the article (total Si / Si dissolution rate). Additionally or instead in any embodiment, the rate of erosion of the protective coating or layer on the internal sliding surface 16, if directly contacted by a fluid composition having a pH at some point between 5 and 9, can be less than the rate of erosion of the internal sliding surface 16 without the protective coating or layerbarrier coating or layer, if directly contacted by the fluid composition.
  • the pH protective coating or layer optionally can be applied over at least a portion of the SiO x coating or layer to protect the SiO x coating or layer from contents stored in a vessel, where the contents otherwise would be in contact with the SiO x coating or layer.
  • the pH protective coating or layers or layers are particularly contemplated to protect an SiO x barrier layer of a prefilled syringe or cartridge that is exposed to contents, such as a pharmaceutical preparation, having a pH between 4 and 9, alternatively between 4 and 8, alternatively between 5 and 9.
  • contents such as a pharmaceutical preparation, having a pH between 4 and 9, alternatively between 4 and 8, alternatively between 5 and 9.
  • Such pharmaceutical preparations have been found to attack and remove the SiO x coating or layer if unprotected by a protective coating or layer.
  • another vapor-deposited coating 34 optionally can be applied directly or indirectly over the coating 30, while the container 12 is capped, under conditions effective to maintain communication between the barrel lumen 18 and the dispensing portion lumen 26 via the proximal opening 22 at the end of applying the second vapor-deposited coating 34.
  • the other vapor-deposited coating 34 can be a pH protective coating or layer.
  • the pH protective coating or layer can include or consist essentially of a parylene or halogenated polymer, for example a fluorinated polymer of a polyxylylene, for example a Parylene coating.
  • the pH protective coating or layer can include or consist essentially of SiO x C y or SiN x C y wherein x is from about 0.5 to about 2.4, optionally about 1 .1 , and y is from about 0.6 to about 3, optionally about 1 .1 .
  • the pH protective coating or layer can include or consist essentially of SiO x C y H z , in which x is from about 0.5 to about 2.4, optionally from about 0.5 to 1 , y is from about 0.6 to about 3, optionally from about 2 to about 3, and z is from about 2 to about 9, optionally from 6 to about 9.
  • the pH protective coating or layer can be applied as the first or sole vapor-deposited coating or layer (30), instead of or in addition to its application as a further layer.
  • This expedient may be useful, for example, where the barrel is made of glass, which is optional in any embodiment.
  • suitable glass is borosilicate glass of a type commonly used to fabricate syringe parts, vials, and other implements.
  • the presently disclosed pH protective coating or layer also reduces the dissolution of glass, for example borosilicate glass, by contents having the pH values indicated as attacking SiO x coatings or layers.
  • the precursor for the SiO x barrier coating or layer or for the alternative (non- parylene or halogenated polymer) pH protective coating or layer can include any of the following precursors useful for PECVD.
  • the precursor for the PECVD pH protective coating or layer of the present invention optionally can be broadly defined as an organometallic precursor.
  • An organometallic precursor is defined in this specification as comprehending compounds of metal elements from Group III and/or Group IV of the Periodic Table having organic residues, for example hydrocarbon, aminocarbon or oxycarbon residues.
  • Organometallic compounds as presently defined include any precursor having organic moieties bonded to silicon or other Group III/ IV metal atoms directly, or optionally bonded through oxygen or nitrogen atoms.
  • the relevant elements of Group III of the Periodic Table are Boron, Aluminum, Gallium, Indium, Thallium, Scandium, Yttrium, and Lanthanum, Aluminum and Boron being preferred.
  • the relevant elements of Group IV of the Periodic Table are Silicon, Germanium, Tin, Lead, Titanium, Zirconium, Hafnium, and Thorium, with Silicon and Tin being preferred.
  • Other volatile organic compounds can also be contemplated.
  • organosilicon compounds are preferred for performing present invention.
  • organosilicon precursor is contemplated, where an "organosilicon precursor" is defined throughout this specification most broadly as a compound having at least one of the linkages:
  • the first structure immediately above is a tetravalent silicon atom connected to an oxygen atom and an organic carbon atom (an organic carbon atom being a carbon atom bonded to at least one hydrogen atom).
  • the second structure immediately above is a tetravalent silicon atom connected to an -NH- linkage and an organic carbon atom (an organic carbon atom being a carbon atom bonded to at least one hydrogen atom).
  • the organosilicon precursor is selected from the group consisting of a linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a linear silazane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, and a combination of any two or more of these precursors.
  • a precursor though not within the two formulas immediately above, is an alkyl trimethoxysilane.
  • an oxygen-containing precursor for example a Siloxane
  • a representative predicted empirical composition resulting from PECVD under conditions forming a hydrophobic or lubricating pH protective coating or layer would be Si w O x C y H z or its equivalent SiO x C y as defined in the Definition Section
  • a representative predicted empirical composition resulting from PECVD under conditions forming a barrier coating or layer would be SiO x , where x in this formula is from about 1 .5 to about 2.9.
  • a nitrogen-containing precursor for example a silazane
  • the predicted composition would be Si w *N x *C y *H z *, i.e.
  • Si w O x C y H z or its equivalent SiO x C y as specified in the Definition Section O is replaced by N and the indices for H are adapted to the higher valency of N as compared to O (3 instead of 2.
  • the latter adaptation will generally follow the ratio of w, x, y and z in a Siloxane to the corresponding indices in its aza counterpart.
  • Si w *N x *C y *H z * (or its equivalent SiN x *C y * ) in which w * , x * , y * , and z * are defined the same as w, x, y, and z for the siloxane counterparts, but for an optional deviation in the number of hydrogen atoms.
  • One type of precursor starting material having the above empirical formula is a linear siloxane, for example a material having the following formula:
  • each R is independently selected from alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others, and n is 1 , 2, 3, 4, or greater, optionally two or greater.
  • alkyl for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others
  • n is 1 , 2, 3, 4, or greater, optionally two or greater.
  • HMDSO hexamethyldisiloxane
  • analogous silazanes in which -NH- is substituted for the oxygen atom in the above structure are also useful for making analogous pH protective coating or layers or coating or layers.
  • contemplated linear silazanes are octamethyltrisilazane, decamethyltetrasilazane, or combinations of two or more of these.
  • Another type of precursor starting material is a monocyclic siloxane, for example a material having the following structural formula:
  • R is defined as for the linear structure and "a" is from 3 to about 10, or the analogous monocyclic silazanes.
  • a is from 3 to about 10
  • contemplated hetero-substituted and unsubstituted monocyclic siloxanes and silazanes include
  • OCTS octamethylcyclotetrasiloxane
  • Another type of precursor starting material is a polycyclic siloxane, for example a material having one of the followin structural formulas:
  • Y can be oxygen or nitrogen
  • E is silicon
  • Z is a hydrogen atom or an organic substituent, for example alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others.
  • Y oxygen
  • the respective structures from left to right, are a Silatrane, a Silquasilatrane, and a Silproatrane.
  • Y is nitrogen
  • the respective structures are an azasilatrane, an azasilquasiatrane, and an azasilproatrane.
  • Another type of polycyclic siloxane precursor starting material is a polysilsesquioxane, with the empirical formula RSiOi. 5 and the structural formula:
  • each R is a hydrogen atom or an organic substituent, for example alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others.
  • alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others.
  • SST-eM01 poly(methylsilsesquioxane) in which each R is methyl
  • SST-3MH1 .1 poly(Methyl-Hydridosilsesquioxane) in which 90% of the R groups are methyl, 10% are hydrogen atoms.
  • This material is available in a 10% solution in tetrahydrofuran, for example. Combinations of two or more of these are also contemplated.
  • a contemplated precursor examples include methylsilatrane, CAS No. 2288-13-3, in which each Y is oxygen and Z is methyl, methylazasilatrane, poly(methylsilsesquioxane) (for example SST-eM01 poly(methylsilsesquioxane)), in which each R optionally can be methyl, SST-3MH1 .1 poly(Methyl- Hydridosilsesquioxane) (for example SST-3MH1 .1 poly(Methyl-Hydridosilsesquioxane)), in which 90% of the R groups are methyl and 10% are hydrogen atoms, or a combination of any two or more of these.
  • the analogous polysilsesquiazanes in which -NH- is substituted for the oxygen atom in the above structure are also useful for making analogous pH protective coating or layer.
  • contemplated polysilsesquiazanes are a poly(methylsilsesquiazane), in which each R is methyl, and a poly(Methyl- Hydridosilsesquiazane, in which 90% of the R groups are methyl, 10% are hydrogen atoms. Combinations of two or more of these are also contemplated.
  • One particularly contemplated precursor for the barrier coating or layer according to the present invention is a linear siloxane, for example is HMDSO.
  • One particularly contemplated precursor for the pH protective coating or layer and the pH protective coating or layer according to the present invention is a cyclic siloxane, for example octamethylcyclotetrasiloxane (OMCTS).
  • the OMCTS or other cyclic siloxane molecule provides several advantages over other siloxane materials.
  • its ring structure results in a less dense pH protective coating or layer (as compared to pH protective coating or layer prepared from HMDSO).
  • the molecule also allows selective ionization so that the final structure and chemical composition of the pH protective coating or layer can be directly controlled through the application of the plasma power.
  • Other organosilicon molecules are readily ionized (fractured) so that it is more difficult to retain the original structure of the molecule.
  • the applying step optionally can be carried out by vaporizing the precursor and providing it in the vicinity of the substrate.
  • OMCTS is usually vaporized by heating it to about 50 °C before applying it to the PECVD apparatus.
  • Cyclic organosilicon precursors in particular monocyclic organosilicon precursors (like the monocyclic precursors listed elsewhere in present description), and specifically OMCTS, are particularly suitable to achieve a pH protective coating or layer.
  • O 2 can be present as a coreactant in an amount (which can, for example be expressed by the flow rate in seem) which is less than one order of magnitude greater than the organosilicon amount.
  • the amount of O 2 typically is at least one order of magnitude higher than the amount of organosilicon precursor.
  • the volume ratio (in seem) of organosilicon precursor to O 2 for a pH protective coating or layer can be in the range from 0.1 : 1 to 10 : 1 , optionally in the range from 0.3 : 1 to 8 : 1 , optionally in the range from 0.5 : 1 to 5 : 1 , optionally from 1 : 1 to 3 : 1 .
  • the presence of the precursor and 0 2 in the volume ratios as given in Tables 9-1 1 is specifically suitable to achieve a pH protective coating or layer.
  • a carrier or diluent gas is absent in the reaction mixture, in another aspect of the invention, it is present.
  • Suitable carrier or diluent or diluent gases include Argon, Helium and other noble gases such as Neon and Xenon.
  • the carrier or diluent gas is typically present in a volume (in seem) exceeding the volume of the organosilicon precursor.
  • the ratio of the organosilicon precursor to carrier or diluent gas can be from 1 : 1 to 1 : 50, optionally from 1 : 5 to 1 : 40, optionally from 1 : 10 to 1 : 30.
  • One function of the carrier or diluent gas is to dilute the reactants in the plasma, encouraging the formation of a coating or layer on the substrate instead of powdered reaction products that do not adhere to the substrate and are largely removed with the exhaust gases.
  • one preferred combination of process gases includes octamethylcyclotetrasiloxane (OMCTS) or another cyclic siloxane as the precursor, in the presence of oxygen as an oxidizing gas and argon as a carrier or diluent gas.
  • O 2 , N 2 O, or another oxidizing gas and/or of a carrier or diluent gas, in particular of a carrier or diluent gas, for example a noble gas, for example Argon (Ar) is contemplated to improve the resulting pH protective coating or layer.
  • a PECVD apparatus suitable for performing the present invention includes a vessel holder 50, an inner electrode defined by the probe108, an outer electrode 160, and a power supply 162.
  • the container 12 seated on the vessel holder 50 defines a plasma reaction chamber, which optionally can be a vacuum chamber.
  • a source of vacuum 98, a reactant gas source 144, a gas feed (probe 108) or a combination of two or more of these can be supplied.
  • the PECVD apparatus can be used for atmospheric-pressure PECVD, in which case the plasma reaction chamber defined by the container 12 does not need to function as a vacuum chamber.
  • the vessel holder 50 optionally can comprise a gas inlet port 104 for conveying a gas into the container 12 seated on the opening 82.
  • the gas inlet port 104 has a sliding seal provided for example by at least one O-ring 106, or two O-rings in series, or three O-rings in series, which can seat against a cylindrical probe 108 when the probe 108 is inserted through the gas inlet port 104.
  • the probe 108 can be a gas inlet conduit that extends to a gas delivery port at its distal end 1 10.
  • the distal end 1 10 of the illustrated embodiment can be inserted deep into the container 12 for providing one or more PECVD reactants and other precursor feed or process gases.
  • FIG. 4 shows additional optional details of the coating station 60 that are usable, for example, with all the illustrated embodiments.
  • the coating station 60 can also have a main vacuum valve 574 in its vacuum line 576 leading to the pressure sensor 152.
  • a manual bypass valve 578 is provided in the bypass line 580.
  • a vent valve 582 controls flow at the vent 404.
  • Flow out of the PECVD gas or precursor source 144 is controlled by a main reactant gas valve 584 regulating flow through the main reactant feed line 586.
  • One component of the gas source 144 is the organosilicon liquid reservoir 588.
  • the contents of the reservoir 588 are drawn through the organosilicon capillary line 590, which is provided at a suitable length to provide the desired flow rate.
  • Flow of organosilicon vapor is controlled by the organosilicon shut-off valve 592.
  • Pressure is applied to the headspace 614 of the liquid reservoir 588, for example a pressure in the range of 0-15 psi (0 to 78 cm.
  • the reservoir 588 is sealed and the capillary connection 620 is at the bottom of the reservoir 588 to ensure that only neat organosilicon liquid (not the pressurized gas from the headspace 614 flows through the capillary tube 590.
  • the organosilicon liquid optionally can be heated above ambient temperature, if necessary or desirable to cause the organosilicon liquid to evaporate, forming an organosilicon vapor.
  • the pH protective coating or layer apparatus can advantageously include heated delivery lines from the exit of the precursor reservoir to as close as possible to the gas inlet into the syringe. Preheating is useful, for example, when feeding OMCTS.
  • Oxygen is provided from the oxygen tank 594 via an oxygen feed line 596 controlled by a mass flow controller 598 and provided with an oxygen shut-off valve 600.
  • other precursor, reactant, and/or carrier or diluent gas reservoirs such as 602 can be provided to supply additional materials if needed for a particular deposition process.
  • Each such reservoir such as 602 has the appropriate feed line 604 and shut-off valve 606.
  • the processing station 28 can include an electrode 160 fed by a radio frequency power supply 162 for providing an electric field for generating plasma within the container 12 during processing.
  • the probe 108 is also electrically conductive and is grounded, thus providing a counter- electrode within the container 12.
  • the outer electrode 160 can be grounded and the probe 108 directly connected to the power supply 162.
  • the outer electrode 160 can either be generally cylindrical as illustrated in FIGS. 4 and 5 or a generally U-shaped elongated channel as illustrated in FIG. 6 (FIG. 5 being an embodiment of the section taken along section line A— A of FIG. 4).
  • Each illustrated embodiment has one or more sidewalls, such as 164 and 166, and optionally a top end 168, disposed about the container 12 in close proximity.
  • the plasma in the PECVD process is generated at RF frequency.
  • the plasma of any embodiment can be generated with an electric power of from 0.1 to 500 W, optionally from 0.1 to 400 W, optionally from 0.1 to 300 W, optionally from 1 to 250 W, optionally from 1 to 200 W, even optionally from 10 to 150 W, optionally from 20 to 150 W, for example of 40 W, optionally from 40 to 150 W, even optionally from 60 to 150 W.
  • the ratio of the electrode power to the plasma volume can be less than 100 W/ml, optionally is from 5 W/ml to 75 W/ml, optionally is from 6 W/ml to 60 W/ml, optionally is from 10 W/ml to 50 W/ml, optionally from 20 W/ml to 40 W/ml.
  • These power levels are suitable for applying pH protective coating or layers or coating or layers to syringes and cartridges and sample tubes and pharmaceutical packages or other vessels of similar geometry having a void volume of 5 ml_ in which PECVD plasma is generated. It is contemplated that for larger or smaller objects the power applied, in Watts, should be increased or reduced accordingly to scale the process to the size of the substrate.
  • a method for applying the coating or layer includes several steps.
  • a vessel wall is provided, as is a reaction mixture comprising plasma forming gas, i.e. an organosilicon compound gas, optionally an oxidizing gas, and optionally a hydrocarbon gas.
  • Plasma can be formed in the reaction mixture that is substantially free of hollow cathode plasma.
  • the vessel wall is contacted with the reaction mixture, and the pH protective coating or layer of SiO x is deposited on at least a portion of the vessel wall.
  • Uniform plasma means regular plasma that does not include a substantial amount of hollow cathode plasma (which has a higher emission intensity than regular plasma and is manifested as a localized area of higher intensity interrupting the more uniform intensity of the regular plasma).
  • Another useful coating or layer in any embodiment is a tie coating or layer between the injection molded barrel substrate and the barrier layer as described in this specification.
  • the tie coating or layer can be formed under similar conditions, using similar equipment and material feeds, to those used to deposit the pH protective coating or layer, although normally the tie coating or layer can be relatively thin compared to the pH protective coating or layer.
  • the tie coating or layer promotes adhesion of the barrier layer to the substrate, and also has been found to reduce the rate at which the SiOx barrier coating or layer is attacked, in an embodiment in which the coatings on the barrel substrate include a tie coating or layer, an SiOx barrier coating or layer, and a pH protective coating or layer.
  • the inventors further theorize that if a tie coating or layer similar in composition to the pH protective layer underlies the barrier layer, the barrier layer is sandwiched between a tightly adherent, pH resistant layer on both sides. In the event of a pinhole in the pH protective coating or layer, the immediately underlying portion of the barrier layer can be attacked, but the superior adhesion of the tie layer to both the barrier layer and the substrate, plus the resistance to erosion of the pH protective composition of the tie coating or layer, prevents such flakes or particles from separating and prevents acceleration of the attack.
  • the internal sliding surface 16, the external sliding surface 268, or both of any embodiment can be made at least in part of a parylene or halogenated polymer.
  • a parylene or halogenated polymer can be used as a coating or layer, which includes a situation in which the entire part is made of the parylene or halogenated polymer.
  • parylene or halogenated polymer sliding surface 268 of a stopper, O-ring, plunger tip or piston 36 can be provided in various ways in any embodiment.
  • an entire stopper, O-ring, plunger tip or piston 36 can be injection molded of a parylene or halogenated polymer.
  • a parylene or halogenated polymer film can be inserted into an injection mold for the stopper, O-ring, plunger tip or piston 36, adjacent to a wall of the mold, prior to molding another material in the mold.
  • the other material can be a resilient polymer, for example a natural or (preferably) synthetic rubber composition such as filled rubber or filled thermoplastic elastomer (TPE). This method is commonly referred to as insert molding or in mold labelling.
  • a parylene or halogenated polymer provided for example as a film or sheet, can be laminated or wrapped about an already-molded stopper, O-ring, plunger tip or piston 36 made of another material such as filled rubber or filled TPE.
  • the parylene or halogenated polymer can be applied either locally as just the external sliding surface 268 or more generally, for example defining the external sliding surface 268 and also the leading or lumen-facing surface of the stopper, O-ring, plunger tip or piston, alternatively as all surfaces of the stopper, O-ring, plunger tip or piston.
  • a coating of a parylene or halogenated polymer can be applied to a stopper, O-ring, plunger tip or piston.
  • the coating can be applied either locally as just the external sliding surface 268 or more generally, for example defining the external sliding surface 268 and also the leading or lumen-facing surface, alternatively every surface, of the stopper, O-ring, plunger tip or piston.
  • the coating can be applied by dip coating or spray coating of a coating material, which in some cases can be heated or dissolved or dispersed in a solvent or diluent for ease of application.
  • the coated material can be appropriately dried, crosslinked, or otherwise cured or fixed to form a coating.
  • the coating can be applied by vapor deposition, as by evaporation of a coating material and deposition of the material on the stopper, O-ring, plunger tip or piston.
  • the coating can be applied by any variant of chemical vapor deposition (CVD), which is broadly defined as exposing a substrate to a gaseous precursor, optionally with other gaseous reactants present, such that the precursor engages in a chemical reaction, yielding a coating on the substrate of modified material.
  • CVD chemical vapor deposition
  • PECVD plasma enhanced chemical vapor deposition
  • heat-initiated chemical vapor deposition for which the chemical reaction is promoted by heating the precursor.
  • HWCVD hot filament chemical vapor deposition
  • iCVD initiated chemical vapor deposition
  • Parylene Process Another example of heat-initiated chemical vapor deposition is the heat- initiated polymerization of Parylene, sometimes known as the Parylene Process, practiced for example by Specialty Coating Systems, Inc., discussed for example in Lonny Wolgemuth, Challenges With Prefilled Syringes: The Parylene Solution, www.ondrugdelivery.com, pp. 44-45 (Frederick Furness Publishing, 2012). The documents mentioned in this paragraph are incorporated by reference here.
  • the Parylene Process can be carried out using several different species of Parylene, four of which are:
  • Parylene HT® or the similar compound Parylene HTX poly(tetrafluoroparaxylylene).
  • parylene or halogenated polymer coating may find use in the present invention, although the parylene or halogenated polymer, Parylene HT® (trademark of Specialty Coating Systems, Inc) or poly(tetrafluoroparaxylylene), is presently preferred.
  • Parylene HT® trademark of Specialty Coating Systems, Inc
  • poly(tetrafluoroparaxylylene) is presently preferred.
  • Parylene coatings are optically clear, there is an inherent level of difficulty involved in identifying if a component has been coated with Parylene. In the military and aerospace industries, for example, customers require a method to guarantee that a component is indeed Parylene coated. SCS Parylene C-UVF coatings are available containing a flourescent marker incorporated into the Parylene C deposition process. The result is a coating that fluoresces under a ultraviolet ("black") light, verifying that components are coated and ready for use, while maintaining the same electrical, mechanical and physical properties of Parylene C film.
  • black ultraviolet
  • Parylene HT® Parylene lubricated syringe
  • the present inventors further contemplate the use of a Parylene coating or layer to provide pH protective properties comparable to those of the organosilicon pH protective coatings or layers defined in this specification
  • fluorinated co-monomer can be any of the primary parylene or halogenated polymer precursors identified in this disclosure, such as hexafluoropropylene oxide (HFPO) or the dimer used to make Parylene HT®, to make fluorinated co-polymers.
  • HFPO hexafluoropropylene oxide
  • perfluoropropene epoxide and a fluorinated co-monomer can be reacted to produce perfluorinated copolymers via thermal CVD.
  • free radical polymerization initiators such as t-butyl peroxide can be reacted with a fluorinated co-monomer e.g. perfluoropropene to produce perfluroropolymers.
  • branching of the (co)polymers could be accomplished.
  • perfluoropropene epoxide, a fluorinated co-monomer, and DVB can be reacted to provide branched fluorinated (co)polymers via thermal CVD.
  • t-butyl peroxide can be reacted with a fluorinated co-monomer e.g. perfluoropropene and DVB to produce branched perfluororopolymers.
  • T-butylperoxide has also been proposed as an initiator to polymerize fluorinated alkyl(methy)acrylates using iCVD as a thermal cracking source for TBPO radical formation.
  • iCVD thermal cracking source for TBPO radical formation.
  • HWCVD relatively cool wire temperature in HWCVD (270 °C)
  • the TBPO reaction with a fluorinated alkyl(methy)acrylate forms a radical and generates a fluoropolymer chain with its orientation parallel with the surface.
  • the TBPO is cracked to form methyl radicals ( * CH 3 ), resulting in a reaction with a fluorinated alkyl(methy)acrylate to generate a parylene or halogenated polymer chain alignment perpendicular to the surface.
  • Coating the selected substrate with a parylene or halogenated polymer by this chemistry is contemplated to cause the formation of PTFE oriented in either a parallel or perpendicular orientation.
  • POSS polyhedral oligomeric silsesquioxane
  • a parylene or halogenated polymer can be used as a coating or layer defining the internal sliding surface 16.
  • the parylene or halogenated polymer can be applied to the internal sliding surface 16 in any of the same ways as described above for making the external sliding surface 268 at least in part of a parylene or halogenated polymer.
  • a parylene or halogenated polymer can be used as a coating or layer defining both the internal sliding surface 16 and the external sliding surface 268.
  • FIGS. 1 and 2 Other details of construction of the syringe shown in FIGS. 1 and 2, for example the provision or details of a Luer tip or staked hypodermic needle on the front end 260, a shield 28, a plunger rod, ears or finger grips, or a thumb pad are not part of the invention and are not required in any embodiment.
  • the lumen 18 can be prefilled with a fluid, for example a parenteral drug.
  • the syringe of FIG. 1 optionally can have a fixed injection needle permanently installed.
  • any embodiment of the syringe shown in FIG. 1 optionally can have a barrier coating or layer 30 and/or a protective coating or layer, or both, as further described below.
  • the parylene or halogenated polymer optionally can be a parylene polymer including a halogen element bonded to a carbon atom, either in the aromatic ring or ethylene chain.
  • Parylene C and HT processes have been found in some testing to provide a low precision in reproducible coating thicknesses (+/- 20%).
  • the Parylene HTX process has been found in some testing to provide higher precision in reproducible coating thicknesses.
  • the parylene or halogenated polymer coating applied for example by the Parylene HTX process, can be applied with a precision in reproducible coating thicknesses of +/- 1 -15%, optionally +/- 1 -10%, optionally +/- 1 to 5%, optionally +/- 2% or less.
  • the parylene or halogenated polymer optionally can comprise a polymer having the structure:
  • each CXmHn and CX q H r moiety is a methylene or substituted methylene moiety
  • each -C 6 X 0 U P - moiety is a benzene or substituted benzene nucleus
  • each U is hydrogen or lower alkyl, in which lower alkyl is methyl, ethyl, propyl, isopropyl, butyl, i-butyl, or t-butyl,
  • n & r are independently (2-m) and (2-q),
  • • s is from 3 to 100,000, optionally from 10 to 100,000, optionally from 10-10,000.
  • the parylene or halogenated polymer optionally can be applied by hot filament chemical vapor deposition.
  • the parylene or halogenated polymer optionally can be applied by pyrolysis chemical vapor deposition, carried out by decomposing a precursor (182) in a pyrolysis (high heat) step/region such as a cracking pipe, cracking tube, or cracking capillary (190) and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus (198) to form at least one of the internal and external sliding surfaces.
  • a precursor (182) in a pyrolysis (high heat) step/region such as a cracking pipe, cracking tube, or cracking capillary (190)
  • the precursor for the parylene or halogenated polymer optionally can comprise xylene or its ethyl, propyl, or butyl-substituted analog, fully halogenated on each pendant alkyl moiety.
  • each pendant alkyl moiety optionally can be trihalogenated methyl.
  • each pendant alkyl moiety optionally can be trifluoromethyl.
  • the halogen optionally can be one nonfluoro halogen terminal moiety selected from chloro, bromo, or iodo and the balance fluoro.
  • the alkyl moieties optionally can be bromodifluoromethyl.
  • the precursor vapor optionally can be decomposed in the presence of a catalyst.
  • “Decomposed” is broadly defined to include activation of a precursor without necessarily removing any atoms.
  • the catalyst optionally can comprise copper, zinc, magnesium, titanium, cadmium, silver, indium, tin, aluminum, or other solid reducing agent, or a combination of two or more of these.
  • the catalyst optionally can comprise zinc or a zinc halide, for example zinc bromide.
  • the catalyst optionally can comprise copper or a copper halide, for example copper bromide.
  • the precursor vapor optionally can be decomposed in the presence of an initiator different from the precursor.
  • the initiator optionally can comprise xylene (a methyl-substituted compound) or its ethyl, propyl, or butyl- substituted analog, at least partially halogenated on each pendant alkyl moiety.
  • the methyl pendant groups optionally can be di- or tri-halogen-substituted.
  • the initiator optionally can comprise m-bis-(dibromomethyl)benzene.
  • the initiator optionally can comprise p-bis-(dibromomethyl)benzene.
  • the initiator optionally can comprise m-bis-(difluorobromo)benzene.
  • the initiator optionally can comprise p-bis-(difluorobromo)benzene.
  • the parylene or halogenated polymer optionally can be applied by pyrolysis chemical vapor deposition, carried out by decomposing a precursor comprising p-bis(trifluoromethyl)benzene in a cracking pipe or other pyrolysis apparatus and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus (198) to form at least the external sliding surface.
  • the pyrolysis can be carried out in the presence of an initiator comprising bis(difluorobromomethyl)benzene and a catalyst as previously defined.
  • the deposition equipment optionally can incorporate stacked plunger holder trays in the coating chamber to increase output.
  • the stopper, O-ring, plunger tip or piston optionally can consist essentially of an elastomeric seal having a molded external sliding surface directly coated by chemical vapor deposition with the parylene or halogenated polymer.
  • the F, and F m values for advance of the external sliding surface along the internal sliding surface optionally each can be from 1 to 20 N, alternatively from 3 to 18 N, optionally from 5 to 15 N, respectively after a park time of at least one day, optionally one week, optionally one month, alternatively three months, alternatively six months, alternatively 12 months, alternatively 18 months, alternatively 24 months.
  • the F, and F m values for advance of the external sliding surface along the internal sliding surface optionally do not increase more than 50 percent, alternatively more than 40 percent, alternatively more than 30 percent, alternatively more than 20 percent, alternatively more than 10 percent, alternatively at all, and optionally decrease up to 10%, optionally up to 20%, optionally up to 30%, after a park time of at least one day, optionally one week, optionally one month, alternatively three months, alternatively six months, alternatively 12 months, alternatively 18 months, alternatively 24 months.
  • a substrate supporting the parylene or halogenated polymer optionally can be molded, the parylene or halogenated polymer optionally can be applied to the supporting substrate by chemical vapor deposition, and the presence of the parylene or halogenated polymer optionally can reduce the extractables obtainable from the injection molded substrate.
  • the parylene or halogenated polymer optionally can comprise poly(tetrafluoro-p-xylylene), and the extractables obtainable from the injection molded substrate by isopropanol extraction optionally can be reduced by at least 10%, optionally at least 25%, optionally at least 30%, optionally at least 40%, optionally at least 47%, optionally at least 50%, optionally at least 60%, optionally at least 70%, optionally at least 80%, optionally at least 90%, optionally from 10% to 95%, optionally from 10% to 90%, optionally from 10% to 80%, optionally from 10% to 70%, optionally from 10% to 60%, optionally from 10% to 50%, optionally from 25% to 50%, compared to the uncoated substrate.
  • the parylene or halogenated polymer optionally can be applied as a coating on an elastomeric stopper, O-ring, plunger tip or piston 36 as a substrate and the container closure integrity (CCI) result for the parylene or halogenated polymer coated substrate, measured using the Bonfiglioli or other vacuum decay test, optionally can be a vacuum decay of less than 50 mbar (500 N/cm 2 ), alternatively less than 40 mbar (400 N/ cm 2 ), alternatively less than 30 mbar (300 N/cm 2 ), alternatively less than 20 mbar (200 N/cm 2 ), as an upper limit, and at least 3 mbar (30 N/cm 2 ), alternatively at least 5 mbar (50 N/cm 2 ), alternatively at least 7 mbar (70 N/cm 2 ), alternatively at least 10 mbar (100 N/cm 2 ), alternatively at least 12 mbar (120 N/cm 2 ).
  • CCI container closure integrity
  • the parylene or halogenated polymer coating optionally can be 0.5-20 microns thick, optionally 0.5-10 microns thick, optionally 0.5-4.5 microns thick, optionally 1 to 5 microns thick, optionally 1 to 4.5 microns thick, optionally 1 -3 microns thick.
  • the parylene or halogenated polymer coating optionally consists essentially of Poly[1 ,4- phenylene(1 ,1 ,2,2-tetrafluoro-1 ,2-ethanediyl), which can be generated, for example, using the Parylene HT or HTX process conditions.
  • the parylene or halogenated polymer optionally can be provided in the form of a coating having a crystallinity of greater than 10%, optionally from 15% to 50%, optionally from 20 to 40%, optionally 20 to 30%.
  • Coatings of SiO x are deposited by plasma enhanced chemical vapor deposition (PECVD) or other chemical vapor deposition processes on the vessel of a pharmaceutical package, in particular a thermoplastic package, to serve as a barrier coating or layer 30) preventing oxygen, carbon dioxide, or other gases from entering the vessel and/or to prevent leaching of the pharmaceutical material into or through the package wall.
  • PECVD plasma enhanced chemical vapor deposition
  • other chemical vapor deposition processes on the vessel of a pharmaceutical package, in particular a thermoplastic package, to serve as a barrier coating or layer 30) preventing oxygen, carbon dioxide, or other gases from entering the vessel and/or to prevent leaching of the pharmaceutical material into or through the package wall.
  • the barrier coating 30 optionally can comprise or consist essentially of SiO x , wherein x is from 1 .5 to 2.9, from 2 to 1000 nm thick, the barrier coating 288 of SiO x having an interior surface facing the lumen and an outer surface facing the barrel internal sliding surface 16, the barrier coating being effective to reduce the ingress of atmospheric gas into the lumen compared to an uncoated vessel such as the syringe 250.
  • x is from 1 .5 to 2.9, from 2 to 1000 nm thick
  • the barrier coating 288 of SiO x having an interior surface facing the lumen and an outer surface facing the barrel internal sliding surface 16, the barrier coating being effective to reduce the ingress of atmospheric gas into the lumen compared to an uncoated vessel such as the syringe 250.
  • One suitable barrier composition is one where x is 2.3, for example.
  • barrier layers or coatings of SiOx as well as borosilicate and other glass substrates are eroded or dissolved at some rate by some fluid compositions, for example aqueous compositions having a pH above about 5. Since coatings applied by chemical vapor deposition can be very thin - tens to hundreds of nanometers thick - even a relatively slow rate of erosion can remove or reduce the effectiveness of the barrier layer in less time than the desired shelf life of a product package. Additionally, while a glass substrate normally will not be compromised as quickly as a barrier layer, the erosion of glass can cause flaking during the shelf life of a vial.
  • organosilicon pH protective coating or layers 272 are those made from cyclic siloxanes and silazanes as described in this disclosure.
  • SiO x C y or SiN x C y coatings deposited from linear siloxane or linear silazane precursors, for example hexamethyldisiloxane (HMDSO) are believed to contain fragments of the original precursor to a large degree and low organic content.
  • Such SiOxCy or SiN x C y coatings have a degree of water miscibility or swellability, allowing them to be attacked by aqueous solutions.
  • the protective coating or layer is made of SiO x C y or SiN x C y wherein x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3.
  • the protective coating or layer has an interior surface facing the lumen and an outer surface facing the interior surface of the barrier coating.
  • the protective coating or layer can be formed by chemical vapor deposition of a precursor selected from a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, a Silatrane, a Silquasilatrane, a Silproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a combination of any two or more of these precursors. This process is described in more detail throughout this specification.
  • the rate of erosion of the protective coating or layer, if directly contacted by the fluid composition is less than the rate of erosion of the barrier coating, if directly contacted by the fluid composition.
  • the protective coating or layer is effective to isolate the fluid composition from the barrier coating 30).
  • the syringe, cartridge, or similar article 12 optionally can comprise a barrel 250) including a lumen 18) defined at least in part by a internal sliding surface 16; and a stopper, O-ring, plunger tip or piston 36 within the lumen comprising a sliding surface 268 slidable in the lumen at least substantially in contact with the internal sliding surface 16.
  • the internal sliding surface 16, the external sliding surface 268, or both is made at least in part of a parylene or halogenated polymer.
  • the parylene or halogenated polymer can be deposited directly or with intervening or subsequent layers on the external sliding surface 268, the internal sliding surface 16, or both.
  • the parylene or halogenated polymer optionally is applied by chemically modifying a precursor, while on or in the vicinity of the fluid receiving interior surface.
  • the precursor optionally can comprise:
  • parylene or halogenated polymer is:
  • the parylene or halogenated polymer optionally can be applied by vapor deposition, for example chemical vapor deposition.
  • the parylene or halogenated polymer can be applied by chemical vapor deposition of dimeric tetrafluoroparaxylylene.
  • An example of a suitable parylene or halogenated polymer is polytetrafluoroparaxylylene.
  • the parylene or halogenated polymer consists essentially of polytetrafluoroparaxylylene.
  • the parylene or halogenated polymer coating or layer optionally can comprise polytetrafluoroethylene.
  • the parylene or halogenated polymer coating or layer optionally can consist essentially of polytetrafluoroethylene.
  • the polytetrafluoroethylene optionally can comprise or consist essentially of linear polytetrafluoroethylene with little or no branching.
  • the parylene or halogenated polymer can comprise a composite of polytetrafluoroethylene 34 and a fluorine substituted derivative of poly(paraxylylene) 31 .
  • the parylene or halogenated polymer can comprise: polytetrafluoroethylene particles (as in Fig. 9) or a layer (34) (as in Fig. 10) defining at least one of the internal 16 and external (268 sliding surfaces, and a fluorine substituted derivative of poly(paraxylylene) (31 ) between the polytetrafluoroethylene particles or layer and the substrate 14.
  • Fig. 9 (as well as Fig. 10) is to be understood for present purposes as an instance of a fluorine substituted derivative of poly(paraxylylene) 30 between the polytetrafluoroethylene particles 34 and the substrate 14, even though both the particles 34 and layer 30 of Fig. 9 both are shown in contact with the substrate 14, as line segments like 56 can be drawn in Fig. 9 between the particles 34 and the substrate 14 (diagonally in Fig. 9) with portions of the layer 30 between the particles 34 and the substrate 14.
  • Fig. 9 (but not Fig. 10) is also to be understood for present purposes as an instance of polytetrafluoroethylene particles 34 between the fluorine substituted derivative of poly(paraxylylene) 30 and the substrate 14, even though both the particles 34 and layer 30 both are shown in contact with the substrate 14, as line segments like 58 can be drawn in Fig. 9 between the layer 30 and the substrate 14 (diagonally in Fig. 9) with portions of the particles 34 between the layer 30 and the substrate 14.
  • the parylene or halogenated polymer can comprise polytetrafluoroethylene particles or a layer (34) effective to improve the lubricity between the internal sliding surface 16 and the external sliding surface.
  • the parylene or halogenated polymer of at least one of the internal and external sliding surfaces (16, 268 can comprise a composite layer (30) of polytetrafluoroethylene and a fluorine substituted derivative of poly(paraxylylene) (34), formed by at least partial co-deposition or sequential deposition of the polytetrafluoroethylene and a fluorine substituted poly(paraxylylene).
  • the composite layer (30) can be formed by sequential deposition of polytetrafluoroethylene and a fluorine substituted derivative of poly(paraxylylene).
  • the composite layer (30) can be formed at least in part by overlapping deposition of polytetrafluoroethylene and a fluorine substituted derivative of poly(paraxylylene).
  • a gradient composition can be formed transitioning from predominantly the previously deposited composition, optionally the fluorine substituted derivative of poly(paraxylylene), to predominantly the later deposited composition, optionally polytetrafluoroethylene.
  • the composite layer can be formed by substantially simultanous deposition of polytetrafluoroethylene and a fluorine substituted derivative of poly(paraxylylene).
  • the parylene or halogenated polymer coating or layer can be applied by chemically modifying a precursor, while on or in the vicinity of the fluid receiving interior surface, to produce the parylene or halogenated polymer coating or layer on the fluid receiving interior surface.
  • the parylene or halogenated polymer coating or layer can be applied by chemical vapor deposition, for example by chemical vapor deposition of polytetrafluoroethylene, or by chemical vapor deposition of dimeric tetrafluoroparaxylylene, or both.
  • the parylene or halogenated polymer coating or layer can be applied by heated wire chemical vapor deposition (HWCVD), althernatively the same process being known as hot filament chemical vapor deposition.
  • HWCVD heated wire chemical vapor deposition
  • the parylene or halogenated polymer coating or layer can be applied by plasma enhanced chemical vapor deposition (PECVD). Mixed processes or other processes for applying a suitable coating are also contemplated, in any embodiment.
  • FIG. 12 Another useful process for applying the parylene or halogenated polymer coating in any embodiment is pyrolysis chemical vapor deposition, as illustrated in FIG. 12 which is reproduced with annotations from Jun Wang, Xue Song, Rui li, Jinpeng Shen, Guangcheng Yang, Hui Huang, Fluorocarbon Thin Film With Superhydrophobic Property Prepared By Pyrolysis Of Hexafluoropropylene Oxide, APPLIED SURFACE SCIENCE 258 (2012) 9782-9785.
  • the substrate 198 can be a surface within the vessel or syringe 12 without a reaction chamber, as illustrated in more detail in FIGS. 3 and 4.
  • the illustrated apparatus further can include a pressure releasing valve 186, a flow meter 188, heating tape 194 or other suitable apparatus for heating the cracking pipe 190 or its various parts, and a thermocouple wrap 192 or other apparatus for determining the temperature of the cracking pipe 190 or its various parts.
  • a temperature controller 196 can be provided to control the heating tape 194 according to the data obtained from the thermocouple 192.
  • a vessel or reactor 12 can be provided where chemical vapor deposition will occur.
  • the cracking pipe 190 has an inlet generally indicated as 181 and an outlet generally indicated at 183.
  • the outlet 183 of the cracking pipe and the treated substrate 198 on the reaction vessel 12 or other surface to be treated are connected via a conduit 197.
  • the substrate 198 can be cooled as necessary or convenient to prevent distortion of the vessel or other workpiece as it is treated with the decomposition products produced in the cracking tube 190, as by a cooling jacket 199.
  • the gases departing from the outlet 183 of the cracking tube 190 also can be allowed to cool to an appropriate degree by selecting an appropriate length, diameter, material, and ambient or applied temperature for the conduit 197 separating the outlet 183 from the treated substrate 198.
  • the pyrolysis chemical vapor deposition process can be carried out, for example, by decomposing a precursor vapor 184 in the cracking pipe 190 and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus 198 to form at least one of the internal and external sliding surfaces 16, 268.
  • the internal sliding surfaces can be formed in any embodiment by connecting the vessel 12 as the reactor 198 and forming the internal sliding surfaces inside the vessel 12.
  • the chemical vapor deposition apparatus 198 optionally can comprise the barrel 14 functioning as its own reaction vessel.
  • the external sliding surfaces can be formed in any embodiment by placing the stopper, O-ring, plunger tip or piston 36 to be provided with an external sliding surface into a separate reactor 198.
  • reaction conditions can be used, varied as appropriate for a specific process, vessel 12 and materials.
  • the temperature within the cracking pipe 190 can be maintained, for example, between150°C and 1300°C during decomposition.
  • a difluorocarbene precursor vapor 184 can be decomposed in the cracking pipe 190 to generate difluorocarbene free radicals.
  • the difluorocarbene precursor vapor can be one or more of hexafluoroepoxypropane, trifluoromethane and difluorochloromethane.
  • a polytetrafluoroethylene coating film can be formed on the substrate due to polymerization of the difluorocarbene free radicals.
  • the difluorocarbene precursor vapor can be fed at the flow rate of 5-600 seem.
  • the minimum distance through the conduit 197 between the outlet 183 of the cracking pipe and the treated substrate 198 can be from 1 to 60 cm, alternatively from 1 to 50 cm, alternatively from 1 to 40 cm, alternatively from 1 to 30 cm, alternatively from 1 to 20 cm, alternatively from 10 to 60 cm, alternatively from 10 to 50 cm, alternatively from 10 to 40 cm, alternatively from 10 to 30 cm, alternatively from 10 to 20 cm, alternatively from 20 to 60 cm, alternatively from 20 to 50 cm, alternatively from 20 to 40 cm, alternatively from 20 to 30 cm, alternatively from 30 to 60 cm, alternatively from 30 to 50 cm, alternatively from 30 to 40 cm. Longer distances in this area provide more cooling, and vice versa.
  • the polymerization reaction can be performed at a temperature controlled to be below 100°C, alternatively below 90 °C, alternatively below 80° C, alternatively below 70° C, alternatively below 60° C, alternatively below 50 °C at the substrate 198.
  • the polymerization reaction can be performed under a reaction environment selected from vacuum environment or an environment filled with a filler gas.
  • the filler gas can be nitrogen and can have a pressure within 10 standard atmosphere pressures.
  • acid gases can be generated when the difluorocarbene precursor vapor is decomposed in a cracking pipe to generate difluorocarbene free radicals.
  • the other acid gases can be removed from the effluent by freezing them in a cold trap 201 such as a Dewar bottle or by absorbing them with a basic solution.
  • a dimeric tetrafluoroparaxylylene precursor vapor can be decomposed in the cracking pipe to generate tetrafluoroparaxylyl free radicals.
  • the polytetrafluoroparaxylylene coating film can be formed on the substrate due to polymerization of tetrafluoroparaxylylene free radicals.
  • the dimeric tetrafluoroparaxylylene precursor vapor can be fed at the flow rate of 5-600 seem and the minimum distance through the conduit, between the outlet of the cracking pipe and the treated substrate, can be from 1 to 60 cm, alternatively from 1 to 50 cm, alternatively from 1 to 40 cm, alternatively from 1 to 30 cm, alternatively from 1 to 20 cm, alternatively from 10 to 60 cm, alternatively from 10 to 50 cm, alternatively from 10 to 40 cm, alternatively from 10 to 30 cm, alternatively from 10 to 20 cm, alternatively from 20 to 60 cm, alternatively from 20 to 50 cm, alternatively from 20 to 40 cm, alternatively from 20 to 30 cm, alternatively from 30 to 60 cm, alternatively from 30 to 50 cm, alternatively from 30 to 40 cm.
  • the polytetrafluoroparaxylylene polymerization reaction can be performed at a temperature controlled to be below 100° C, alternatively 30 below 90° C, alternatively 30 below 80° C, alternatively 30 below 70° C, alternatively 30 below 60° C, alternatively 30 below 50 °C at the substrate.
  • the polytetrafluoroparaxylylene polymerization reaction can be performed under a reaction environment selected from vacuum environment or an environment filled with a filler gas.
  • the filler gas can be nitrogen and can have a pressure within 10 standard atmosphere pressures.
  • the effluent gases for formation of polytetrafluoroparaxylylene can be frozen by a cold trap Dewar bottle or absorbed with a basic solution, or both.
  • the polytetrafluoropara- xylylene component will provide a pinhole free composite coating providing an excellent solute barrier, and both the polytetrafluoroethylene component and the polytetrafluoroparaxylylene component will provide a lubricious coating.
  • the composite coatings will provide simultaneous (a) solute barrier performance (inhibition of organic and inorganic extractables/leachables) and (b) lubricity performance to parenteral medical devices including syringe assemblies and cartridges, as well as any contained material to be delivered through a mechanical delivery device.
  • the invention can provide a pH protective coating or layer contributing dissolution protection of SiO x gas barrier coatings to alkaline pH media.
  • the non-wetting nature of the coating can provide superior air bubble removal in filling operations and high delivery transfer efficiency for expensive drugs or payloads.
  • At least a portion of the wall of the syringe barrel or plunger or other substrate optionally can comprise or consist essentially of a polymer, for example a polyolefin (for example a cyclic olefin polymer, a cyclic olefin copolymer, or polypropylene), a polyester, for example polyethylene terephthalate, a polycarbonate, or any combination or copolymer of any of these.
  • at least a portion of the barrel or plunger optionally can comprise or consist essentially of glass, for example borosilicate glass. A combination of any two or more of the materials in this paragraph can also be used.
  • the fluid composition has a pH between 5 and 6, optionally between 6 and 7, optionally between 7 and 8, optionally between 8 and 9, optionally between 6.5 and 7.5, optionally between 7.5 and 8.5, optionally between 8.5 and 9.
  • the fluid composition is a liquid at 20 °C and ambient pressure at sea level, which is defined as a pressure of 760 mm Hg.
  • the fluid composition is an aqueous liquid.
  • the barrier coating is from 4 nm to 500 nm thick, optionally from 7 nm to 400 nm thick, optionally from 10 nm to 300 nm thick, optionally from 20 nm to 200 nm thick, optionally from 30 nm to 100 nm thick.
  • the protective coating or layer 272 optionally can comprise or consist essentially of SiO x C y .
  • the protective coating or layer optionally can comprise or consist essentially of SiN x C y .
  • the precursor optionally can comprise a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a combination of any two or more of these precursors.
  • the precursor optionally can comprise a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a Silatrane, a Silquasilatrane, a Silproatrane, or a combination of any two or more of these precursors.
  • the precursor optionally can comprise octamethylcyclotetrasiloxane (OMCTS) or consists essentially of OMCTS.
  • OMCTS octamethylcyclotetrasiloxane
  • Other precursors described elsewhere in this specification or known in the art are also contemplated for use according to the invention.
  • the precursor optionally can comprise a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a combination of any two or more of these precursors.
  • the protective coating or layer as applied is between 10 and 1000 nm thick, optionally between 50 and 800 nm thick, optionally between 100 and 700 nm thick, optionally between 300 and 600 nm thick.
  • the thickness does not need to be uniform throughout the vessel, and will typically vary from the preferred values in portions of a vessel.
  • the protective coating or layer contacting the fluid composition is between 10 and 1000 nm thick, optionally between 50 and 500 nm thick, optionally between 100 and 400 nm thick, optionally between 150 and 300 nm thick two years after the pharmaceutical package is assembled.
  • the rate of erosion of the protective coating or layer, if directly contacted by a fluid composition having a pH of 8, is less than 20%, optionally less than 15%, optionally less than 10%, optionally less than 7% , optionally from 5% to 20% , optionally 5% to 15% , optionally 5% to 10%, optionally 5% to 7%, of the rate of erosion of the barrier coating 288, if directly contacted by the same fluid composition under the same conditions.
  • the protective coating or layer is at least coextensive with the barrier coating.
  • the protective coating or layer alternatively can be less extensive than the barrier coating, as when the fluid composition does not contact or seldom is in contact with certain parts of the barrier coating absent the protective coating or layer.
  • the protective coating or layer alternatively can be more extensive than the barrier coating, as it can cover areas that are not provided with a barrier coating.
  • the pharmaceutical package can have a shelf life, after the pharmaceutical package 210 is assembled, of at least one year, alternatively at least two years.
  • the shelf life is measured at 3°C, alternatively at 4°C or higher, alternatively at 20°C or higher, alternatively at 23°C, alternatively at 40 °C.
  • the pH of the fluid composition is between 5 and 6 and the thickness by TEM of the protective coating or layer is at least 80 nm at the end of the shelf life.
  • the pH of the fluid composition is between 6 and 7 and the thickness by TEM of the protective coating or layer is at least 80 nm at the end of the shelf life.
  • the pH of the fluid composition is between 7 and 8 and the thickness by TEM of the protective coating or layer is at least 80 nm at the end of the shelf life.
  • the pH of the fluid composition is between 8 and 9 and the thickness by TEM of the protective coating or layer is at least 80 nm at the end of the shelf life.
  • the pH of the fluid composition is between 5 and 6 and the thickness by TEM of the protective coating or layer is at least 150 nm at the end of the shelf life.
  • the pH of the fluid composition is between 6 and 7 and the thickness by TEM of the protective coating or layer is at least 150 nm at the end of the shelf life.
  • the pH of the fluid composition is between 7 and 8 and the thickness by TEM of the protective coating or layer is at least 150 nm at the end of the shelf life.
  • the pH of the fluid composition is between 8 and 9 and the thickness by TEM of the protective coating or layer is at least 150 nm at the end of the shelf life.
  • the fluid composition removes the protective coating or layer at a rate of 1 nm or less of lubricity and/or protective coating or layer thickness per 44 hours of contact with the fluid composition 200 nm per year), alternatively 1 nm or less of lubricity and/or protective coating or layer thickness per 88 hours of contact with the fluid composition (100 nm per year), alternatively 1 nm or less of lubricity and/or protective coating or layer thickness per 175 hours of contact with the fluid composition (50 nm per year), alternatively 1 nm or less of lubricity and/or protective coating or layer thickness per 250 hours of contact with the fluid composition (35 nm per year), alternatively 1 nm or less of lubricity and/or protective coating or layer thickness per 350 hours of contact with the fluid composition 25 nm per year).
  • the rate of removing the protective coating or layer can be determined by TEM from samples exposed to the fluid composition for known periods.
  • the protective coating or layer is effective to provide a lower frictional resistance than the uncoated interior surface 16.
  • the frictional resistance is reduced by at least 25 %, more preferably by at least 45%, even more preferably by at least 60% in comparison to the uncoated interior surface 16.
  • the protective coating or layer preferably is effective to reduce the frictional resistance between a portion of the wall contacted by the fluid composition and a relatively sliding part 36 after the pharmaceutical package 210 is assembled.
  • the protective coating or layer is effective to reduce the frictional resistance between the wall and a relatively sliding part 36 at least two years after the pharmaceutical package 210 is assembled.
  • the fluid composition optionally can comprise a member or a combination of two or more members selected from the group consisting of the compositions described in the claims.
  • the fluid composition can be an inhalation anesthetic, a drug, or a diagnostic test material. Any of these fluid compositions can be an injectable material, a volatile material capable of being inhaled, or otherwise capable of being introduced into a subject.
  • the pharmaceutical package 210 can be a syringe.
  • the syringe can comprise a syringe barrel or wall 14 and a stopper, O-ring, plunger tip or piston 36.
  • the wall can define at least a portion of the syringe barrel or wall 14syringe barrel or wall 14syringe barrel or wall 14.
  • the stopper, O-ring, plunger tip or piston 36 can be a relatively sliding part of the syringe, with respect to the syringe barrel or wall 14.
  • syringe is broadly defined to include cartridges, injection “pens,” and other types of barrels or reservoirs adapted to be assembled with one or more other components to provide a functional syringe.
  • Syringe is also broadly defined to include related articles such as auto-injectors, which provide a mechanism for dispensing the contents.
  • Another aspect of the invention is an article such as any pharmaceutical package or other vessel such as the vial 170 as shown in FIG. 8.
  • the wall has an inner or interior surface 16.
  • the fluid composition is contained in the lumen and has a pH between 5 and 9.
  • the barrier coating or layer 30 is made at least in part of SiO x , wherein x is from 1 .5 to 2.9, from 2 to 1000 nm thick.
  • the barrier coating or layer 30 of SiO x has an interior surface 220 facing the lumen 212 and an outer surface 222 facing the wall inner or interior surface 16.
  • the barrier coating or layer 30 is effective to reduce the ingress of atmospheric gas into the lumen 212, compared to an uncoated container otherwise the same as the pharmaceutical package or other vessel 210.
  • the protective coating or layer can be made of a parylene or halogenated polymer, for example the fluorinated Parylene previously described.
  • the protective coating or layer can be made at least in part of SiO x C y or SiN x C y where x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3.
  • the protective coating or layer has an interior surface facing the lumen and an outer surface facing the barrier coating or layer 30.
  • the protective coating or layer can be formed by chemical vapor deposition of a precursor selected from a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a combination of any two or more of these precursors.
  • a suitable protective coating or layer precursor of this type is octamethylcyclotetrasiloxane or OMCTS. Other specific examples of precursors within this broad definition are provided elsewhere in this specification.
  • the rate of erosion, dissolution, or leaching (different names for related concepts) of the protective coating or layer, if directly contacted by the fluid composition, is less than the rate of erosion of the barrier coating or layer 30, if directly contacted by the fluid composition.
  • the protective coating or layer is effective to isolate the fluid composition from the barrier coating or layer 30, at least for sufficient time to allow the barrier coating to act as a barrier during the shelf life of the pharmaceutical package or other vessel 210.
  • a pharmaceutical package or other vessel 210 including a thermoplastic wall having an inner or interior surface 220 enclosing a lumen 212.
  • a fluid composition contained in the lumen 212 has a pH greater than 5.
  • a barrier coating or layer 30 of SiO x in which x is between 1 .5 and 2.9, is applied by plasma enhanced chemical vapor deposition (PECVD) directly or indirectly to the thermoplastic wall so that in the filled pharmaceutical package or other vessel 210 the barrier coating or layer 30 is located between the inner or interior surface 220 of the thermoplastic wall and the fluid composition.
  • the barrier coating or layer 30 of SiO x is supported by the thermoplastic wall.
  • the barrier coating or layer 30 has the characteristic of being subject to being measurably diminished in barrier improvement factor in less than six months as a result of attack by the fluid composition.
  • the barrier coating or layer 30 as described elsewhere in this specification, or in U.S. Patent No. 7,985,188, can be used in any embodiment.
  • the barrier improvement factor (BIF) of the barrier layer can be determined by providing two groups of identical containers, adding a barrier layer to one group of containers, testing a barrier property (such as the rate of outgassing in micrograms per minute or another suitable measure) on containers having a barrier, doing the same test on containers lacking a barrier, and taking a ratio of the properties of the materials with versus without a barrier. For example, if the rate of outgassing through the barrier is one-third the rate of outgassing without a barrier, the barrier has a BIF of 3.
  • a barrier property such as the rate of outgassing in micrograms per minute or another suitable measure
  • a protective coating or layer of SiO x C y in which x is between 0.5 and 2.4 and y is between 0.6 and 3, is applied by PECVD directly or indirectly to the barrier coating or layer 30 so it is located between the barrier coating or layer 30 and the fluid composition in the finished article.
  • the protective coating or layer is supported by the thermoplastic wall.
  • the protective coating or layer is effective to keep the barrier coating or layer 30 at least substantially undissolved as a result of attack by the fluid composition for a period of at least six months.
  • Any embodiment can further optionally include a lubricity layer 287.
  • the lubricity layer 287 can be applied between the protective coating or layer and the lumen. Lubricity layers 287 as described elsewhere in this specification, or in U.S. Patent No. 7,985,188, can be used in any embodiment.
  • Any embodiment can further optionally include a further coating applied adjacent to the inner surface of the protective coating or layer, the further coating having an outer surface facing the interior surface of the thermoplastic wall and an inner surface facing the lumen.
  • any embodiment can further include a fluid composition in contact with the protective coating or layer [292]
  • the protective and lubricity layers 286 and 287 of any embodiment can be either separate layers with a sharp transition or a single, graduated layer that transitions between the protective coating or layer and the lubricity layer 287, without a sharp interface between them.
  • an FTIR absorbance spectrum of the protective coating or layer of any organosilicon embodiment has a ratio greater than 0.75 between the maximum amplitude of the Si-O-Si symmetrical stretch peak normally located between about 1000 and 1040 cm-1 , and the maximum amplitude of the Si-O-Si assymmetric stretch peak normally located between about 1060 and about 1 100 cm-1 .
  • this ratio can be at least 0.8, or at least 0.9, or at least 1 .0, or at least 1 .1 , or at least 1 .2.
  • this ratio can be at most 1 .7, or at most 1 .6, or at most 1 .5, or at most 1 .4, or at most 1 .3. Any minimum ratio stated here can be combined with any maximum ratio stated here, as an alternative embodiment of the invention.
  • the protective coating or layer in the absence of the medicament, has a non-oily appearance. This appearance has been observed in some instances to distinguish an effective protective coating or layer from a lubricity layer, which in some instances has been observed to have an oily (i.e. shiny) appearance.
  • the silicon dissolution rate by a 50 mM potassium phosphate buffer diluted in water for injection, adjusted to pH 8 with concentrated nitric acid, and containing 0.2 wt. % polysorbate-80 surfactant, (measured in the absence of the medicament, to avoid changing the dissolution reagent), at 40 °C, is less than 170 ppb/day.
  • the silicon dissolution rate is measured by determining the total silicon leached from the vessel into its contents, and does not distinguish between the silicon derived from the protective coating or layer, the lubricity layer 287, the barrier coating or layer 30, or other materials present.
  • the silicon dissolution rate is less than 160 ppb/day, or less than 140 ppb/day, or less than 120 ppb/day, or less than 100 ppb/day, or less than 90 ppb/day, or less than 80 ppb/day.
  • the silicon dissolution rate is more than 10 ppb/day, or more than 20 ppb/day, or more than 30 ppb/day, or more than 40 ppb/day, or more than 50 ppb/day, or more than 60 ppb/day. Any minimum rate stated here can be combined with any maximum rate stated here, as an alternative embodiment of the invention.
  • the total silicon content of the protective coating or layer and barrier coating, upon dissolution into a test composition with a pH of 8 from the vessel is less than 66 ppm, or less than 60 ppm, or less than 50 ppm, or less than 40 ppm, or less than 30 ppm, or less than 20 ppm.
  • the calculated shelf life of the package is more than six months, or more than 1 year, or more than 18 months, or more than 2 years, or more than 21 ⁇ 2 years, or more than 3 years, or more than 4 years, or more than 5 years, or more than 10 years, or more than 20 years.
  • the calculated shelf life of the package is less than 60 years.
  • the protective coating or layer is applied by PECVD at a power level per of more than 22,000 kJ/kg of mass of precursor, or more than 30,000 kJ/kg of mass of precursor, or more than 40,000 kJ/kg of mass of precursor, or more than 50,000 kJ/kg of mass of precursor, or more than 60,000 kJ/kg of mass of precursor, or more than 62,000 kJ/kg of mass of precursor, or more than 70,000 kJ/kg of mass of precursor, or more than 80,000 kJ/kg of mass of precursor, or more than 100,000 kJ/kg of mass of precursor, or more than 200,000 kJ/kg of mass of precursor, or more than 300,000 kJ/kg of mass of precursor, or more than 400,000 kJ/kg of mass of precursor, or more than 500,000 kJ/kg of mass of precursor.
  • the protective coating or layer is applied by PECVD at a power level per of less than 2,000,000 kJ/kg of mass of precursor, or less thanl ,000,000 kJ/kg of mass of precursor, or less than 700,000 kJ/kg of mass of precursor, or less than 500,000 kJ/kg of mass of precursor, or less than 100,000 kJ/kg of mass of precursor, or less than 90,000 kJ/kg of mass of precursor, or less than 81 ,000 kJ/kg of mass of precursor.
  • thermoplastic wall is a syringe barrel.
  • a stopper, O-ring, plunger tip or piston is positioned for sliding in the barrel and a lubricity coating or layer is present on at least a portion of the stopper, O-ring, plunger tip or piston.
  • the lubricity coating or layer is configured to provide a lower piston sliding force or breakout force than the uncoated substrate.
  • the lubricity layer has one of the atomic ratios previously defined for the lubricity and/or protective coating or layer, measured by X-ray photoelectron spectroscopy (XPS).
  • the lubricity layer has a thickness by transmission electron microscopy (TEM) between 10 and 500 nm; the lubricity layer deposited by plasma enhanced chemical vapor deposition (PECVD) under conditions effective to form a coating from a precursor selected from a linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a linear silazane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane,
  • TEM transmission electron micro
  • Even another aspect of the invention is a composite material including a substrate such as a wall, a barrier coating or layer 30 disposed on the substrate or wall, and a passivation layer or protective coating or layer on the barrier layer or coating 288.
  • a substrate such as a wall
  • a barrier coating or layer 30 disposed on the substrate or wall
  • a passivation layer or protective coating or layer on the barrier layer or coating 288.
  • articles made from such a composite material are a syringe barrel, a vial, and a medical device of any kind.
  • the passivation layer or protective coating or layer is deposited by PECVD using a source material comprising a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a combination of any two or more of these precursors.
  • a source material comprising a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane
  • the passivation layer or protective coating or layer taking into account the H atoms, may thus in one aspect have the formula SiwOxCyHz, for example where w is 1 , x is from about 0.5 to about 2.4, y is from about 0.6 to about 3, and z is from about 2 to about 9.
  • the formula SiwOxCy the atomic ratios of Si, O, and C are, as several options:
  • Si 100 O 90-120 : C 90-140, or
  • the passivation layer or protective coating or layer shows an O-Parameter measured with attenuated total reflection (ATR) of less than 0.4, measured as:
  • the O-Parameter is defined in U.S. Patent No. 8,067,070, which claims an O-parameter value of most broadly from 0.4 to 0.9. It can be measured from physical analysis of an FTIR amplitude versus wave number plot to find the numerator and denominator of the above expression, as shown in Fig. 27, which is the same as Fig. 5 of U.S. Patent No. 8,067,070, except annotated to show interpolation of the wave number and absorbance scales to arrive at an absorbance at 1253 cm "1 of .0424 and a maximum absorbance at 1000 to 1 100 cm "1 of 0.08, resulting in a calculated O-parameter of 0.53.
  • the O- Parameter can also be measured from digital wave number versus absorbance data.
  • U.S. Patent No. 8,067,070 asserts that the claimed O-parameter range provides a superior protective coating or layer, relying on experiments only with HMDSO and HMDSN, which are both non-cyclic siloxanes.
  • the PECVD precursor is a cyclic siloxane, for example OMCTS
  • OMCTS cyclic siloxane
  • the O-parameter has a value of from 0.1 to 0.39, or from 0.15 to 0.37, or from 0.17 to 0.35.
  • FIGS. 24-26 Even another aspect of the invention is a composite material as just described, exemplified in FIGS. 24-26, wherein the passivation layer shows an N- Parameter measured with attenuated total reflection (ATR) of less than 0.7, measured as:
  • N-Parameter Intensity at 840 cm "1
  • the N-Parameter is also described in U.S. Patent No. 8,067,070, and is measured analogously to the O-Parameter except that intensities at two specific wave numbers are used - neither of these wave numbers is a range.
  • U.S. Patent No. 8,067,070 claims a passivation layer with an N-Parameter of 0.7 to 1 .6. Again, the present inventors have made better coatings employing a protective coating or layer having an N- Parameter lower than 0.7, as described above.
  • the N-parameter has a value of at least 0.3, or from 0.4 to 0.6, or at least 0.53.
  • the dissolution rate of the SiO x barrier layer is believed to be dependent on SiO bonding within the layer. Oxygen bonding sites (silanols) are believed to increase the dissolution rate.
  • the OMCTS-based protective coating or layer bonds with the silanol sites on the SiO x barrier layer to "heal" or passivate the SiO x surface and thus dramatically reduces the dissolution rate.
  • the thickness of the OMCTS layer is not the primary means of protection - the primary means is passivation of the SiOx surface.
  • a protective coating or layer as described in this specification can be improved by increasing the crosslink density of the protective coating or layer.
  • the protective coating or layer described in this specification can be applied in many different ways.
  • the low-pressure PECVD process described in U.S. Patent No. 7,985,188 can be used.
  • atmospheric PECVD can be employed to deposit the protective coating or layer.
  • the coating can be simply evaporated and allowed to deposit on the SiO x layer to be protected.
  • the coating can be sputtered on the SiO x layer to be protected.
  • the protective coating or layer can be applied from a liquid medium used to rinse or wash the SiOx layer.
  • HMDZ hexamethylene disilazane
  • HMDZ has the advantage of containing no oxygen in its molecular structure.
  • This passivation treatment is contemplated to be a surface treatment of the SiO x barrier layer with HMDZ. To slow down and/or eliminate the decomposition of the silicon dioxide coatings at silanol bonding sites, the coating must be passivated. It is contemplated that passivation of the surface with HMDZ (and optionally application of a few mono layers of the HMDZ-derived coating) will result in a toughening of the surface against dissolution, resulting in reduced decomposition.
  • HMDZ will react with the -OH sites that are present in the silicon dioxide coating, resulting in the evolution of NH 3 and bonding of S-(CH 3 )3 to the silicon (it is contemplated that hydrogen atoms will be evolved and bond with nitrogen from the HMDZ to produce NH 3 ).
  • this HMDZ passivation can be accomplished through several possible paths.
  • One contemplated path is dehydration/vaporization of the HMDZ at ambient temperature.
  • an SiO x surface is deposited, for example using hexamethylene disiloxane (HMDSO).
  • HMDSO hexamethylene disiloxane
  • the as-coated silicon dioxide surface is then reacted with HMDZ vapor.
  • the vacuum is maintained.
  • the HMDSO and oxygen are pumped away and a base vacuum is achieved. Once base vacuum is achieved, HMDZ vapor is flowed over the surface of the silicon dioxide (as coated on the part of interest) at pressures from the mTorr range to many Torr.
  • the HMDZ is then pumped away (with the resulting NH 3 that is a byproduct of the reaction).
  • the amount of NH 3 in the gas stream can be monitored (with a residual gas analyzer - RGA - as an example) and when there is no more NH 3 detected, the reaction is complete.
  • the part is then vented to atmosphere (with a clean dry gas or nitrogen).
  • the resulting surface is then found to have been passivated. It is contemplated that this method optionally can be accomplished without forming a plasma.
  • the vacuum can be broken before dehydration/vaporization of the HMDZ.
  • Dehydration/vaporization of the HMDZ can then be carried out in either the same apparatus used for formation of the SiO x barrier coating or layer 30) or different apparatus.
  • Dehydration/vaporization of HMDZ at an elevated temperature is also contemplated.
  • the above process can alternatively be carried out at an elevated temperature exceeding room temperature up to about 150°C.
  • the maximum temperature is determined by the material from which the coated part is constructed. An upper temperature should be selected that will not distort or otherwise damage the part being coated.
  • Dehydration/ vaporization of HMDZ with a plasma assist is also contemplated. After carrying out any of the above embodiments of dehydration/vaporization, once the HMDZ vapor is admitted into the part, a plasma is generated.
  • the plasma power can range from a few watts to 100+ watts (similar powers as used to deposit the SiO x ). The above is not limited to HMDZ and could be applicable to any molecule that will react with hydrogen, for example any of the nitrogen-containing precursors described in this specification.
  • Another way of applying the protective coating or layer is to apply as the protective coating or layer an amorphous carbon or parylene or halogenated polymer coating, or a combination of the two.
  • Amorphous carbon coatings can be formed by PECVD using a saturated hydrocarbon, (e.g. methane or propane) or an unsaturated hydrocarbon (e.g. ethylene, acetylene) as a precursor for plasma polymerization
  • parylene or halogenated polymer coatings can be derived from parylene or halogenated polymers (for example, hexafluoroethylene or tetrafluoroethylene).
  • Either type of coating, or a combination of both, can be deposited by vacuum PECVD or atmospheric pressure PECVD.
  • an amorphous carbon and/or parylene or halogenated polymer coating will provide better passivation of an SiO x barrier layer than a siloxane coating since an amorphous carbon and/or parylene or halogenated polymer coating will not contain silanol bonds.
  • fluorosilicon precursors can be used to provide a protective coating or layer over an SiO x barrier layer. This can be carried out by using as a precursor a fluorinated silane precursor such as hexafluorosilane and a PECVD process. The resulting coating would also be expected to be a non-wetting coating.
  • any embodiment of the protective coating or layer processes described in this specification can also be carried out without using the article to be coated to contain the plasma.
  • external surfaces of medical devices for example catheters, surgical instruments, closures, and others can be protected or passivated by sputtering the coating, employing a radio frequency target.
  • Yet another coating modality contemplated for protecting or passivating an SiOx barrier layer is coating the barrier layer using a polyamidoamine epichlorohydrin resin.
  • the barrier coated part can be dip coated in a fluid polyamidoamine epichlorohydrin resin melt, solution or dispersion and cured by autoclaving or other heating at a temperature between 60 and 100°C.
  • a coating of polyamidoamine epichlorohydrin resin can be preferentially used in aqueous environments between pH 5-8, as such resins are known to provide high wet strength in paper in that pH range.
  • wet strength is the ability to maintain mechanical strength of paper subjected to complete water soaking for extended periods of time, so it is contemplated that a coating of polyamidoamine epichlorohydrin resin on an SiO x barrier layer will have similar resistance to dissolution in aqueous media. It is also contemplated that, because polyamidoamine epichlorohydrin resin imparts a lubricity improvement to paper, it will also provide lubricity in the form of a coating on a thermoplastic surface made of, for example, COC or COP.
  • Suitable methods and apparatus for applying a barrier or protective coating or layer such as 90 of SiO x , SiO x C y , or SiN x C y to a substrate such as the vessel 80 (FIG. 1 ) or a vial are described, for example, in U.S. Patent No. 7,985,188 or the EP applications cited in paragraph [002], under conditions effective to form a coating or layer.
  • a precursor feed or process gas can be employed having a standard volume ratio of, for example:
  • Another embodiment is a protective coating or layer of the type made by the above process.
  • FIG. 1 Another embodiment is a vessel such as the vessel 80 (FIG. 1 ) including a lumen defined by a surface defining a substrate.
  • a protective coating or layer is present on at least a portion of the substrate, typically deposited over an SiO x barrier layer to protect the barrier layer from dissolution.
  • the protective coating or layer is made by the previously defined process.
  • the organosilicon precursor for the protective coating or layer can include any of the following precursors useful for PECVD.
  • the precursor for the PECVD protective coating or layer of the present invention is broadly defined as an organometallic precursor.
  • An organometallic precursor is defined in this specification as comprehending compounds of metal elements from Group III and/or Group IV of the Periodic Table having organic residues, for example hydrocarbon, aminocarbon or oxycarbon residues.
  • Organometallic compounds as presently defined include any precursor having organic moieties bonded to silicon or other Group III/ IV metal atoms directly, or optionally bonded through oxygen or nitrogen atoms.
  • the relevant elements of Group III of the Periodic Table are Boron, Aluminum, Gallium, Indium, Thallium, Scandium, Yttrium, and Lanthanum, Aluminum and Boron being preferred.
  • the relevant elements of Group IV of the Periodic Table are Silicon, Germanium, Tin, Lead, Titanium, Zirconium, Hafnium, and Thorium, with Silicon and Tin being preferred.
  • Other volatile organic compounds can also be contemplated.
  • organosilicon compounds are preferred for performing present invention.
  • organosilicon precursor is contemplated, where an "organosilicon precursor" is defined throughout this specification most broadly as a compound having at least one of the linkages:
  • the first structure immediately above is a tetravalent silicon atom connected to an oxygen atom and an organic carbon atom (an organic carbon atom being a carbon atom bonded to at least one hydrogen atom).
  • the second structure immediately above is a tetravalent silicon atom connected to an -NH- linkage and an organic carbon atom (an organic carbon atom being a carbon atom bonded to at least one hydrogen atom).
  • the organosilicon precursor is selected from the group consisting of a linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a linear silazane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, and a combination of any two or more of these precursors.
  • a precursor though not within the two formulas immediately above, is an alkyl trimethoxysilane.
  • an oxygen-containing precursor for example a Siloxane
  • a representative predicted empirical composition resulting from PECVD under conditions forming a hydrophobic or lubricating protective coating or layer would be Si w O x C y H z or its equivalent SiO x C y as defined in the Definition Section
  • a representative predicted empirical composition resulting from PECVD under conditions forming a barrier coating or layer 30 would be SiO x , where x in this formula is from about 1 .5 to about 2.9.
  • a nitrogen-containing precursor for example a silazane
  • the predicted composition would be Si w *N x *C y *H z *, i.e.
  • Si w O x C y H z or its equivalent SiO x C y as specified in the Definition Section O is replaced by N and the indices for H are adapted to the higher valency of N as compared to O (3 instead of 2.
  • the latter adaptation will generally follow the ratio of w, x, y and z in a Siloxane to the corresponding indices in its aza counterpart.
  • Si w *N x *Cy*H z * (or its equivalent SiN x *C y * ) in which w*, x*, y*, and z* are defined the same as w, x, y, and z for the siloxane counterparts, but for an optional deviation in the number of hydrogen atoms.
  • One type of precursor starting material having the above empirical formula is a linear siloxane, for example a material having the following formula:
  • each R is independently selected from alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others, and n is 1 , 2, 3, 4, or greater, optionally two or greater.
  • alkyl for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others
  • n is 1 , 2, 3, 4, or greater, optionally two or greater.
  • HMDSO hexamethyldisiloxane
  • analogous silazanes in which -NH- is substituted for the oxygen atom in the above structure are also useful for making analogous protective coating or layers or layers.
  • contemplated linear silazanes are octamethyltnsilazane, decamethyltetrasilazane, or combinations of two or more of these.
  • R is defined as for the linear structure and "a" is from 3 to about 10, or the analogous monocyclic silazanes.
  • a is from 3 to about 10
  • contemplated hetero-substituted and unsubstituted monocyclic siloxanes and silazanes include
  • OCTS octamethylcyclotetrasiloxane
  • dodecamethylcyclohexasilazane or combinations of any two or more of these.
  • Another type of precursor starting material is a polycyclic siloxane, for example a material having one of the followin structural formulas:
  • Y can be oxygen or nitrogen
  • E is silicon
  • Z is a hydrogen atom or an organic substituent, for example alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others.
  • Y oxygen
  • the respective structures from left to right, are a Silatrane, a Silquasilatrane, and a Silproatrane.
  • Y is nitrogen
  • the respective structures are an azasilatrane, an azasilquasiatrane, and an azasilproatrane.
  • polysilsesquioxane Another type of polycyclic siloxane precursor starting material, among the preferred starting materials in the present context, is a polysilsesquioxane, with the empirical formula RSiOi. 5 and the structural formula:
  • each R is a hydrogen atom or an organic substituent, for example alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others.
  • a contemplated precursor examples include methylsilatrane, CAS No. 2288-13-3, in which each Y is oxygen and Z is methyl, methylazasilatrane, poly(methylsilsesquioxane) (for example SST-eM01 poly(methylsilsesquioxane)), in which each R optionally can be methyl, SST-3MH1 .1 poly(Methyl- Hydridosilsesquioxane) (for example SST-3MH1 .1 poly(Methyl-Hydridosilsesquioxane)), in which 90% of the R groups are methyl and 10% are hydrogen atoms, or a combination of any two or more of these.
  • analogous polysilsesquiazanes in which -NH- is substituted for the oxygen atom in the above structure are also useful for making analogous protective coating or layer.
  • contemplated polysilsesquiazanes are a poly(methylsilsesquiazane), in which each R is methyl, and a poly(Methyl- Hydridosilsesquiazane, in which 90% of the R groups are methyl, 10% are hydrogen atoms. Combinations of two or more of these are also contemplated.
  • One particularly contemplated precursor for the barrier coating or layer 30) according to the present invention is a linear siloxane, for example is HMDSO.
  • One particularly contemplated precursor for the lubricity coating or layer and the protective coating or layer according to the present invention is a cyclic siloxane, for example octamethylcyclotetrasiloxane (OMCTS).
  • the OMCTS or other cyclic siloxane molecule provides several advantages over other siloxane materials.
  • the molecule also allows selective ionization so that the final structure and chemical composition of the protective coating or layer can be directly controlled through the application of the plasma power.
  • Other organosilicon molecules are readily ionized (fractured) so that it is more difficult to retain the original structure of the molecule.
  • the applying step optionally can be carried out by vaporizing the precursor and providing it in the vicinity of the substrate.
  • OMCTS is usually vaporized by heating it to about 50 °C before applying it to the PECVD apparatus.
  • Cyclic organosilicon precursors in particular monocyclic organosilicon precursors (like the monocyclic precursors listed elsewhere in present description), and specifically OMCTS, are particularly suitable to achieve a protective coating or layer.
  • O 2 can be present in an amount (which can, for example be expressed by the flow rate in seem) which is less than one order of magnitude greater than the organosilicon amount.
  • the amount of O 2 typically is at least one order of magnitude higher than the amount of organosilicon precursor.
  • the volume ratio (in seem) of organosilicon precursor to O 2 for a protective coating or layer can be in the range from 0.1 : 1 to 10 : 1 , optionally in the range from 0.3 : 1 to 8 : 1 , optionally in the range from 0.5 : 1 to 5 : 1 , optionally from 1 : 1 to 3 : 1 .
  • the presence of the precursor and O 2 in the volume ratios as given in Tables 9-1 1 is specifically suitable to achieve a protective coating or layer.
  • a carrier or diluent gas is absent in the reaction mixture, in another aspect of the invention, it is present.
  • Suitable carrier or diluent gases include Argon, Helium and other noble gases such as Neon and Xenon.
  • the carrier or diluent gas is typically present in a volume (in seem) exceeding the volume of the organosilicon precursor.
  • the ratio of the organosilicon precursor to carrier or diluent gas can be from 1 : 1 to 1 : 50, optionally from 1 : 5 to 1 : 40, optionally from 1 : 10 to 1 : 30.
  • One function of the carrier or diluent gas is to dilute the reactants in the plasma, encouraging the formation of a coating on the substrate instead of powdered reaction products that do not adhere to the substrate and are largely removed with the exhaust gases.
  • one preferred combination of process gases includes octamethylcyclotetrasiloxane (OMCTS) or another cyclic siloxane as the precursor, in the presence of oxygen as an oxidizing gas and argon as a carrier or diluent gas.
  • OCTS octamethylcyclotetrasiloxane
  • argon a carrier or diluent gas.
  • a PECVD apparatus suitable for performing the present invention includes a vessel holder, an inner electrode, an outer electrode, and a power supply.
  • a vessel seated on the vessel holder defines a plasma reaction chamber, which optionally can be a vacuum chamber.
  • a source of vacuum, a reactant gas source, a gas feed or a combination of two or more of these can be supplied.
  • a gas drain not necessarily including a source of vacuum, is provided to transfer gas to or from the interior of a vessel seated on the port to define a closed chamber.
  • the PECVD apparatus can be used for atmospheric-pressure PECVD, in which case the plasma reaction chamber does not need to function as a vacuum chamber.
  • the vessel holder 50 optionally can comprise a gas inlet port 104 for conveying a gas into a vessel seated on the vessel port.
  • the gas inlet port 104 has a sliding seal provided by at least one O-ring 106, or two O-rings in series, or three O-rings in series, which can seat against a cylindrical probe 108 when the probe 108 is inserted through the gas inlet port 104.
  • the probe 108 can be a gas inlet conduit that extends to a gas delivery port at its distal end 1 10.
  • the distal end 1 10 of the illustrated embodiment can be inserted deep into the vessel 80 for providing one or more PECVD reactants and other precursor feed or process gases.
  • FIG. 1 1 of U.S. Patent No. 7,985,188 shows additional optional details of the coating or layer station 28 that are usable, for example, with all the illustrated embodiments.
  • the coating or layer station 28 can also have a main vacuum valve 574 in its vacuum line 576 leading to the pressure sensor 152.
  • a manual bypass valve 578 is provided in the bypass line 580.
  • a vent valve 582 controls flow at the vent 404.
  • Flow out of the PECVD gas or precursor source 144 is controlled by a main reactant gas valve 584 regulating flow through the main reactant feed line 586.
  • One component of the gas source 144 is the organosilicon liquid reservoir 588.
  • the contents of the reservoir 588 are drawn through the organosilicon capillary line 590, which is provided at a suitable length to provide the desired flow rate.
  • Flow of organosilicon vapor is controlled by the organosilicon shut-off valve 592.
  • Pressure is applied to the headspace 614 of the liquid reservoir 588, for example a pressure in the range of 0-15 psi (0 to 78 cm. Hg), from a pressure source 616 such as pressurized air connected to the headspace 614 by a pressure line 618 to establish repeatable organosilicon liquid delivery that is not dependent on atmospheric pressure (and the fluctuations therein).
  • the reservoir 588 is sealed and the capillary connection 620 is at the bottom of the reservoir 588 to ensure that only neat organosilicon liquid (not the pressurized gas from the headspace 614 flows through the capillary tube 590.
  • the organosilicon liquid optionally can be heated above ambient temperature, if necessary or desirable to cause the organosilicon liquid to evaporate, forming an organosilicon vapor.
  • the protective coating or layer apparatus can advantageously include heated delivery lines from the exit of the precursor reservoir to as close as possible to the gas inlet into the syringe. Preheating is useful, for example, when feeding OMCTS.
  • Oxygen is provided from the oxygen tank 594 via an oxygen feed line 596 controlled by a mass flow controller 598 and provided with an oxygen shut-off valve 600.
  • the processing station 28 can include an electrode 160 fed by a radio frequency power supply 162 for providing an electric field for generating plasma within the vessel 80 during processing.
  • the probe 108 is also electrically conductive and is grounded, thus providing a counter-electrode within the vessel 80.
  • the outer electrode 160 can be grounded and the probe 108 directly connected to the power supply 162.
  • the outer electrode 160 can either be generally cylindrical as illustrated in FIGS. 1 and 2 or a generally U- shaped elongated channel as illustrated in FIG. 1 (FIG. 2 being an embodiment of the section taken along section line A— A of FIG. 1 ).
  • Each illustrated embodiment has one or more sidewalls, such as 164 and 166, and optionally a top end 168, disposed about the vessel 80 in close proximity.
  • FIGS. 8 and 9 of U.S. Patent No. 7,985,188 a specific adaptation of the PECVD process is described for applying PECVD coatings to a vessel such as a syringe barrel that is open at both ends.
  • FIGS. 8 and 9 of U.S. Patent No. 7,985,188 show a method and apparatus generally indicated at 290 for coating or layer an inner or interior surface 292 of a restricted opening 294 of a generally tubular vessel 250 to be processed, for example the restricted front opening 294 of a syringe barrel or wall 14syringe barrel or wall 14syringe barrel or wall 14, by PECVD.
  • the previously described process is modified by connecting the restricted opening 294 to a processing vessel 296 and optionally making certain other modifications.
  • the generally tubular vessel 250 to be processed includes an outer surface 298, an inner or inner or interior surface 16 defining a lumen 300, a larger opening 302 having an inner diameter, and a restricted opening 294 that is defined by an inner or interior surface 292 and has an inner diameter smaller than the inner diameter of the larger opening 302.
  • the processing vessel 296 has a lumen 304 and a processing vessel opening 306, which optionally is the only opening, although in other embodiments a second opening can be provided that optionally is closed off during processing.
  • the processing vessel opening 306 is connected with the restricted opening 294 of the vessel 250 to be processed to establish communication between the lumen 300 of the vessel 250 to be processed and the processing vessel lumen via the restricted opening 294.
  • At least a partial vacuum is drawn within the lumen 300 of the vessel 250 to be processed and lumen 304 of the processing vessel 296.
  • a PECVD reactant is flowed from the gas source 144 through the first opening 302, then through the lumen 300 of the vessel 250 to be processed, then through the restricted opening 294, then into the lumen 304 of the processing vessel 296.
  • the PECVD reactant can be introduced through the larger opening 302 of the vessel 250 by providing a generally tubular inner electrode 308 having an interior passage 310, a proximal end 312, a distal end 314, and a distal opening 316, in an alternative embodiment multiple distal openings can be provided adjacent to the distal end 314 and communicating with the interior passage 310.
  • the distal end of the electrode 308 can be placed adjacent to or into the larger opening 302 of the vessel 250 to be processed.
  • a reactant gas can be fed through the distal opening 316 of the electrode 308 into the lumen 300 of the vessel 250 to be processed.
  • the reactant will flow through the restricted opening 294, then into the lumen 304, to the extent the PECVD reactant is provided at a higher pressure than the vacuum initially drawn before introducing the PECVD reactant.
  • Plasma 318 is generated adjacent to the restricted opening 294 under conditions effective to deposit a coating or layer of a PECVD reaction product on the inner or interior surface 292 of the restricted opening 294.
  • the plasma in the PECVD process is generated at RF frequency.
  • the plasma of any embodiment can be generated with an electric power of from 0.1 to 500 W, optionally from 0.1 to 400 W, optionally from 0.1 to 300 W, optionally from 1 to 250 W, optionally from 1 to 200 W, even optionally from 10 to 150 W, optionally from 20 to 150 W, for example of 40 W, optionally from 40 to 150 W, even optionally from 60 to 150 W.
  • the ratio of the electrode power to the plasma volume can be less than 100 W/ml, optionally is from 5 W/ml to 75 W/ml, optionally is from 6 W/ml to 60 W/ml, optionally is from 10 W/ml to 50 W/ml, optionally from 20 W/ml to 40 W/ml.
  • These power levels are suitable for applying protective coating or layers or layers to syringes, cartridges, or similar articles and sample tubes and pharmaceutical packages or other vessels of similar geometry having a void volume of 5 ml_ in which PECVD plasma is generated. It is contemplated that for larger or smaller objects the power applied, in Watts, should be increased or reduced accordingly to scale the process to the size of the substrate.
  • a method for applying the coating includes several steps.
  • a vessel wall is provided, as is a reaction mixture comprising plasma forming gas, i.e. an organosilicon compound gas, optionally an oxidizing gas, and optionally a hydrocarbon gas.
  • Plasma can be formed in the reaction mixture that is substantially free of hollow cathode plasma.
  • the vessel wall is contacted with the reaction mixture, and the protective coating or layer of SiO x is deposited on at least a portion of the vessel wall.
  • Uniform plasma means regular plasma that does not include a substantial amount of hollow cathode plasma (which has a higher emission intensity than regular plasma and is manifested as a localized area of higher intensity interrupting the more uniform intensity of the regular plasma).
  • the protective or lubricity coating or layer of Si w O x C y or its equivalent SiO x C y also can have utility as a hydrophobic layer.
  • a coating or layer of this kind is contemplated to be hydrophobic, independent of whether it also functions as a lubricity and/or protective coating or layer.
  • a coating or layer or treatment is defined as "hydrophobic" if it lowers the wetting tension of a surface, compared to the corresponding uncoated or untreated surface. Hydrophobicity is thus a function of both the untreated substrate and the treatment.
  • Suitable hydrophobic coatings or layers and their application, properties, and use are described in U.S. Patent No. 7,985,188. Dual functional protective / hydrophobic coatings or layers having the properties of both types of coatings or layers can be provided for any embodiment of the present invention.
  • the thickness of a PECVD coating or layer such as the protective coating or layer, the barrier coating or layer 30), the lubricity coating or layer, and/or a composite of any two or more of these layers can be measured, for example, by transmission electron microscopy (TEM).
  • TEM transmission electron microscopy
  • An exemplary TEM image for a lubricity and/or protective coating or layer is shown in Fig. 21 .
  • Fig. 22 An exemplary TEM image for an Si0 2 barrier coating or layer 30) is shown in Fig. 22.
  • the TEM can be carried out, for example, as follows.
  • Samples can be prepared for Focused Ion Beam (FIB) cross-sectioning in two ways. Either the samples can be first coated with a thin layer of carbon (50-1 OOnm thick) and then coated with a sputtered coating or layer of platinum (50-1 OOnm thick) using a K575X Emitech protective coating or layer system, or the samples can be coated directly with the protective sputtered Pt layer.
  • the coated samples can be placed in an FEI FIB200 FIB system.
  • An additional coating or layer of platinum can be FIB-deposited by injection of an organometallic gas while rastering the 30kV gallium ion beam over the area of interest.
  • the area of interest for each sample can be chosen to be a location half way down the length of the syringe barrel.
  • Thin cross sections measuring approximately 15 m ("micrometers") long, 2 m wide and 15 m deep can be extracted from the die surface using an in-situ FIB lift-out technique.
  • the cross sections can be attached to a 200 mesh copper TEM grid using FIB-deposited platinum.
  • One or two windows in each section, measuring about 8 m wide, can be thinned to electron transparency using the gallium ion beam of the FEI FIB.
  • Cross-sectional image analysis of the prepared samples can be performed utilizing either a Transmission Electron Microscope (TEM), or a Scanning Transmission Electron Microscope (STEM), or both. All imaging data can be recorded digitally.
  • TEM Transmission Electron Microscope
  • STEM Scanning Transmission Electron Microscope
  • the grid with the thinned foils can be transferred to a Hitachi HD2300 dedicated STEM.
  • Scanning transmitted electron images can be acquired at appropriate magnifications in atomic number contrast mode (ZC) and transmitted electron mode (TE). The following instrument settings can be used.
  • ZC atomic number contrast mode
  • TE transmitted electron mode
  • sample grids can be transferred to a Hitachi HF2000 transmission electron microscope. Transmitted electron images can be acquired at appropriate magnifications.
  • the relevant instrument settings used during image acquisition can be those given below.
  • a suitable barrier or other type of protective coating or layer usable in conjunction with the PECVD-applied protective coating or layer or other PECVD treatment as disclosed here, can be a liquid barrier, lubricant, surface energy tailoring, or protective coating or layer 90 applied to the inner or interior surface of a pharmaceutical package or other vessel, either directly or with one or more intervening PECVD-applied coatings or layers described in this specification, for example SiO x , a lubricity coating or layer and/or a protective coating or layer, or both.
  • a suitable liquid barrier, lubricity, or protective coating or layer 90 also optionally can be applied, for example, by applying a liquid monomer or other polymerizable or curable material to the inner or interior surface of the vessel 80 and curing, polymerizing, or crosslinking the liquid monomer to form a solid polymer, or by applying a solvent-dispersed polymer to the surface 88 and removing the solvent.
  • Any of the above methods can include as a step forming a protective coating or layer 90 on the interior 88 of a vessel 80 via the vessel port 92 at a processing station or device 28.
  • a liquid protective coating or layer for example of a curable monomer, prepolymer, or polymer dispersion
  • the prior art describes polymer protective coating or layer technology as suitable for treating plastic blood collection tubes.
  • any of the above methods can also include as a step forming a coating or layer on the exterior outer wall of a vessel 80.
  • the exterior coating or layer optionally can be a barrier coating or layer 30), optionally an oxygen barrier coating or layer 30), or optionally a water barrier coating or layer 30).
  • the exterior coating or layer can also be an armor layer that protects the outer wall of a vessel 80.
  • a suitable exterior coating or layer is polyvinylidene chloride, which functions both as a water barrier and an oxygen barrier.
  • the exterior coating or layer can be applied as a water-based coating or layer.
  • the exterior coating or layer optionally can be applied by dipping the vessel in it, spraying it on the pharmaceutical package or other vessel, or other expedients.
  • compositions or other vessels such as a prefilled syringe are contemplated having a barrier coating or layer 30) at least partially covered by a protective coating or layer such as 286.
  • the pharmaceutical package 210 optionally can comprise a vessel or vessel part such as 250; optionally a barrier coating or layer 30) such as 288 on the vessel or vessel part; a protective coating or layer such as 286 on the vessel, vessel part, or barrier coating or layer 30); and a pharmaceutical composition or preparation such as contained within the vessel.
  • a vessel or vessel part such as 250
  • a barrier coating or layer 30 such as 288 on the vessel or vessel part
  • a protective coating or layer such as 286 on the vessel, vessel part, or barrier coating or layer 30
  • a pharmaceutical composition or preparation such as contained within the vessel.
  • the barrier coating or layer 30) such as 288 can be an SiO x barrier coating or layer 30) applied as described in any embodiment of this specification or in U.S. Patent No. 7,985,188.
  • the barrier coating or layer 30) such as 288 of any embodiment can be applied at a thickness of at least 2 nm, or at least 4 nm, or at least 7 nm, or at least 10 nm, or at least 20 nm, or at least 30 nm, or at least 40 nm, or at least 50 nm, or at least 100 nm, or at least 150 nm, or at least 200 nm, or at least 300 nm, or at least 400 nm, or at least 500 nm, or at least 600 nm, or at least 700 nm, or at least 800 nm, or at least 900 nm.
  • the barrier coating or layer 30 can be up to 1000 nm, or at most 900 nm, or at most 800 nm, or at most 700 nm, or at most 600 nm, or at most 500 nm, or at most 400 nm, or at most 300 nm, or at most 200 nm, or at most 100 nm, or at most 90 nm, or at most 80 nm, or at most 70 nm, or at most 60 nm, or at most 50 nm, or at most 40 nm, or at most 30 nm, or at most 20 nm, or at most 10 nm, or at most 5 nm thick.
  • the thickness of the SiO x or other barrier coating or layer 30 can be measured, for example, by transmission electron microscopy (TEM), and its composition can be measured by X-ray photoelectron spectroscopy (XPS).
  • TEM transmission electron microscopy
  • XPS X-ray photoelectron spectroscopy
  • the protective coating or layer described herein can be applied to a variety of pharmaceutical packages or other vessels made from plastic or glass, for example to plastic tubes, vials, and syringes, cartridges, or similar articles.
  • the protective coating or layer such as 286 can be an SiO x C y protective coating or layer applied as described in any embodiment of this specification.
  • the protective coating or layer such as 286 of any embodiment optionally can comprise or consist essentially of a coating or layer of SiO x C y applied over the barrier coating or layer 30 to protect at least a portion of the barrier coating or layer 30) from the pharmaceutical preparation such as in FIGS. 24-26.
  • the protective coating or layer such as 286 is provided, for example, by applying one of the described precursors on or in the vicinity of a substrate in a PECVD process, providing a protective coating or layer.
  • the coating can be applied, for example, at a thickness of 1 to 5000 nm, or 10 to 1000 nm, or 10 to 500 nm, or 10 to 200 nm, or 20 to 100 nm, or 30 to 1000 nm, or 30 to 500 nm thick, or 30 to 1000 nm, or 20 to 100 nm, or 80 to 150 nm, and crosslinking or polymerizing (or both) the protective coating or layer, optionally in a PECVD process, to provide a protected surface.
  • the protective coating or layer applied over an SiOx barrier layer on a vessel wall, functions at least in part by passivating the SiO x barrier layer surface against attack by the contents of the vessel, as well as providing a more resistant or sacrificial independent layer to isolate the SiO x barrier layer from the contents of the vessel. It is thus contemplated that the protective coating or layer can be very thin, and even so improve the shelf life of the pharmaceutical package.
  • a lubricity coating or layer can be applied after applying an SiO x barrier layer and/or a protective coating or layer to the inner or interior surface or to other parts of the pharmaceutical package, as described in U.S. Patent No. 7,985,188.
  • the barrier coating or layer 30) of SiO x can be deposited at a location more remote from the protective coating or layer, with at least one intervening coating or layer of another material.
  • Another expedient contemplated here, for adjacent layers of SiO x and a lubricity and/or protective coating or layer, is a graded composite of SiO x and Si w O x C y , or its equivalent SiO x C y , as defined in the Definition Section.
  • a graded composite can be separate layers of a lubricity and/or protective and/or barrier layer or coating with a transition or interface of intermediate composition between them, or separate layers of a lubricity and/or protective and/or hydrophobic layer and SiO x with an intermediate distinct protective coating or layer of intermediate composition between them, or a single coating or layer that changes continuously or in steps from a composition of a lubricity and/or protective and/or hydrophobic layer to a composition more like SiO x , going through the protective coating or layer in a normal direction.
  • the grade in the graded composite can go in either direction.
  • the composition of SiO x can be applied directly to the substrate and graduate to a composition further from the surface of a protective coating or layer, and optionally can further graduate to another type of coating or layer, such as a hydrophobic coating or layer or a lubricity coating or layer.
  • an adhesion coating or layer for example Si w O x C y , or its equivalent SiO x C y , optionally can be applied directly to the substrate before applying the barrier layer.
  • a graduated protective coating or layer is particularly contemplated if a layer of one composition is better for adhering to the substrate than another, in which case the better-adhering composition can, for example, be applied directly to the substrate. It is contemplated that the more distant portions of the graded protective coating or layer can be less compatible with the substrate than the adjacent portions of the graded protective coating or layer, since at any point the protective coating or layer is changing gradually in properties, so adjacent portions at nearly the same depth of the protective coating or layer have nearly identical composition, and more widely physically separated portions at substantially different depths can have more diverse properties.
  • a protective coating or layer portion that forms a better barrier against transfer of material to or from the substrate can be directly against the substrate, to prevent the more remote protective coating or layer portion that forms a poorer barrier from being contaminated with the material intended to be barred or impeded by the barrier.
  • the applied coatings or layers instead of being graded, optionally can have sharp transitions between one layer and the next, without a substantial gradient of composition.
  • Such protective coating or layer can be made, for example, by providing the gases to produce a layer as a steady state flow in a non-plasma state, then energizing the system with a brief plasma discharge to form a coating or layer on the substrate. If a subsequent protective coating or layer is to be applied, the gases for the previous protective coating or layer are cleared out and the gases for the next protective coating or layer are applied in a steady-state fashion before energizing the plasma and again forming a distinct layer on the surface of the substrate or its outermost previous protective coating or layer, with little if any gradual transition at the interface.
  • One non-limiting aspect of the invention is a syringe, for example any of the syringes described in this specification, including a barrel; a stopper, O-ring, plunger tip or piston 36; a barrier coating and pH protective layer on the barrel; and a lubricity and optionally solute barrier layer on the stopper, O-ring, plunger tip or piston.
  • the barrel can be an injection molded barrel or wall 14 including a lumen 18, a vessel substrate defining at least a portion of the lumen 18, and an internal sliding surface 16 on the vessel substrate adjacent to the lumen.
  • the stopper, O-ring, plunger tip or piston 36 is operatively connected with the lumen and can include a substrate having an external sliding surface 268 slidable in the lumen at least substantially in contact with the internal sliding surface 16 and a surface exposed to the lumen.
  • the barrier coating or layer is disposed on the internal sliding surface, with or without additional intervening layers.
  • the pH protective layer comprises SiO x C y , where x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3, disposed between the barrier coating or layer and the lumen.
  • the barrier layer and pH protective layer combined are alternatively referred to as a "bilayer” or “bilayer coating.”
  • the parylene coating or layer is provided on the external sliding surface 268 of the stopper, O-ring, plunger tip or piston.
  • the parylene coating is arranged to be effective to reduce the F, and F m of the stopper, O-ring, plunger tip or piston respecting relative movement of the inner and outer sliding surfaces.
  • the syringe further comprises a tie coating or layer of SiOxCy as an intervening layer between the barrier coating or layer and the internal sliding surface.
  • the stopper, O-ring, plunger tip or piston 36 comprises elastomeric material defining the external sliding surface.
  • the parylene coating or layer is effective to reduce the leaching of solutes from the stopper, O-ring, plunger tip or piston 36.
  • the parylene coating or layer comprises fluorinated parylene.
  • the parylene coating or layer is deposited by vapor deposition.
  • the parylene coating or layer is deposited by chemical vapor deposition.
  • the parylene coating or layer comprises polytetrafluoroparaxylylene.
  • the parylene coating or layer consists essentially of polytetrafluoroparaxylylene.
  • the barrier coating or layer comprises SiOx, where x is from 1 .5 to 2.9.
  • the barrier coating or layer consists essentially of SiOx, where x is from 1 .5 to 2.9.
  • the parylene coating or layer is from at least 0.1 micrometers to at most 10 micrometers thick
  • the barrier coating or layer is deposited by vapor deposition.
  • the barrier coating or layer is deposited by chemical vapor deposition.
  • the barrier coating or layer is deposited by plasma enhanced chemical vapor deposition.
  • the pH protective coating or layer is deposited by vapor deposition.
  • the pH protective coating or layer is deposited by chemical vapor deposition.
  • the pH protective coating or layer is deposited by plasma enhanced chemical vapor deposition.
  • the fluorinated parylene is applied by pyrolysis chemical vapor deposition, carried out by decomposing a precursor (182) in a cracking pipe (190) and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus (198) to form at least one of the internal and external sliding surfaces.
  • the precursor for the fluorinated parylene comprises xylene or its ethyl, propyl, or butyl-substituted analog, fully halogenated on each pendant alkyl moiety.
  • each pendant alkyl moiety is trihalogenated methyl.
  • each pendant alkyl moiety is trifluoromethyl.
  • the halogen is one nonfluoro halogen terminal moiety selected from chloro, bromo, or iodo and the balance fluoro.
  • the alkyl moieties are bromodifluoromethyl.
  • the precursor gasprecursor vapor is decomposed in the presence of a catalyst.
  • the catalyst comprises copper, zinc, magnesium, titanium, cadmium, silver, indium, tin, aluminum, or a combination of two or more of these.
  • the catalyst comprises zinc or a zinc halide, for example zinc bromide.
  • the catalyst comprises copper or a copper halide, for example copper bromide.
  • the precursor gasprecursor vapor is decomposed in the presence of an initiator different from the precursor.
  • the initiator comprises xylene or its ethyl, propyl, or butyl-substituted analog, at least partially halogenated on each pendant alkyl moiety.
  • the methyl pendant groups are di- or tri-halogen-substituted.
  • the initiator comprises m-bis- (dibromomethyl)benzene.
  • the initiator comprises p-bis- (dibromomethyl)benzene.
  • the initiator comprises m-bis- (difluorobromo)benzene.
  • the initiator comprises p-bis- (difluorobromo)benzene.
  • the fluorinated parylene is applied by pyrolysis chemical vapor deposition, carried out by decomposing a precursor comprising p-bis(trifluoromethyl)benzene in a cracking pipe in the presence of an initiator comprising bis(difluorobromomethyl)benzene and a catalyst comprising zinc metal and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus (198) to form at least the external sliding surface.
  • the Fi and Fm values for advance of the external sliding surface along the internal sliding surface are each from 1 to 20 N, alternatively from 3 to 18 N, optionally from 5 to 15 N after a park time of at least one day, optionally one week, optionally one month, alternatively three months, alternatively six months, alternatively 12 months, alternatively 18 months, alternatively 24 months.
  • the F, and F m values for advance of the external sliding surface along the internal sliding surface do not increase more than 50 percent, alternatively more than 40 percent, alternatively more than 30 percent, alternatively more than 20 percent, alternatively more than 10 percent, alternatively at all, and optionally decrease 10%, optionally 20%, optionally 30%, after a park time of at least one day, optionally one week, optionally one month, alternatively three months, alternatively six months, alternatively 12 months, alternatively 18 months, alternatively 24 months.
  • the stopper, O-ring, plunger tip or piston 36 is injection molded.
  • the parylene polymer comprises poly(tetrafluoro-p-xylylene), and the extractables obtainable from the injection molded substrate by isopropanol extraction are reduced by at least 10%, optionally at least 25%, optionally at least 30%, optionally at least 40%, optionally at least 47%, optionally at least 50%, optionally at least 60%, optionally at least 70%, optionally at least 80%, optionally at least 90%, optionally from 10% to 95%, optionally from 10% to 90%, optionally from 10% to 80%, optionally from 10% to 70%, optionally from 10% to 60%, optionally from 10% to 50%, optionally from 25% to 50%.
  • the parylene polymer is applied as a coating on an elastomeric stopper, O-ring, plunger tip or piston 36 as a substrate and the Bonfiglioli container closure integrity result for the parylene polymer coated substrate is a vacuum decay of less than 50 mbar, alternatively less than 40 mbar, alternatively less than 30 mbar, alternatively less than 20 mbar, as an upper limit, and at least 3 mbar, alternatively at least 5 mbar, alternatively at least 7 mbar, alternatively at least 10 mbar, alternatively at least 12 mbar, as a lower limit.
  • the parylene coating is 0.5-20 microns thick, optionally 0.5-10 microns thick, optionally 0.5-4.5 microns thick, optionally 1 to 5 microns thick, optionally 1 to 4.5 microns thick, optionally 1 -3 microns thick.
  • the parylene coating is applied with a precision in reproducible coating thicknesses of +/- 1 -15%, optionally +/- 1 -10%, optionally +/- 1 to 5%, optionally +/- 2%.
  • the parylene coating consists essentially of Parylene HTX.
  • the parylene is provided in the form of a coating having a crystallinity of greater than 10%, optionally from 15% to 50%, optionally from 20 to 40%, optionally 20 to 30%.
  • a vessel with a protective coating or layer as described herein and/or prepared according to a method described herein can be used for reception and/or storage and/or delivery of a compound or composition.
  • the compound or composition can be sensitive, for example air-sensitive, oxygen-sensitive, sensitive to humidity and/or sensitive to mechanical influences. It can be a biologically active compound or composition, for example a pharmaceutical preparation or medicament like insulin or a composition comprising insulin. In another aspect, it can be a biological fluid, optionally a bodily fluid, for example blood or a blood fraction.
  • the compound or composition can be a product to be administrated to a subject in need thereof, for example a product to be injected, like blood (as in transfusion of blood from a donor to a recipient or reintroduction of blood from a patient back to the patient) or insulin.
  • a product to be injected like blood (as in transfusion of blood from a donor to a recipient or reintroduction of blood from a patient back to the patient) or insulin.
  • a vessel with a protective coating or layer as described herein and/or prepared according to a method described herein can further be used for protecting a compound or composition contained in its interior space against mechanical and/or chemical effects of the surface of the vessel material. For example, it can be used for preventing or reducing precipitation and/or clotting or platelet activation of the compound or a component of the composition, for example insulin precipitation or blood clotting or platelet activation.
  • It can further be used for protecting a compound or composition contained in its interior against the environment outside of the pharmaceutical package or other vessel, for example by preventing or reducing the entry of one or more compounds from the environment surrounding the vessel into the interior space of the vessel.
  • Such environmental compound can be a gas or liquid, for example an atmospheric gas or liquid containing oxygen, air, and/or water vapor.
  • a vessel with a protective coating or layer as described herein can also be evacuated and stored in an evacuated state.
  • the protective coating or layer allows better maintenance of the vacuum in comparison to a corresponding vessel without a protective coating or layer.
  • the vessel with a protective coating or layer is a blood collection tube.
  • the tube can also contain an agent for preventing blood clotting or platelet activation, for example EDTA or heparin.
  • any of the above-described embodiments can be made, for example, by providing as the vessel a length of tubing from about 1 cm to about 200 cm, optionally from about 1 cm to about 150 cm, optionally from about 1 cm to about 120 cm, optionally from about 1 cm to about 100 cm, optionally from about 1 cm to about 80 cm, optionally from about 1 cm to about 60 cm, optionally from about 1 cm to about 40 cm, optionally from about 1 cm to about 30 cm long, and processing it with a probe electrode as described below.
  • relative motion between the probe and the vessel can be useful during protective coating or layer formation. This can be done, for example, by moving the vessel with respect to the probe or moving the probe with respect to the vessel.
  • the barrier coating or layer 30 can be thinner or less complete than would be preferred to provide the high gas barrier integrity needed in an evacuated blood collection tube.
  • the protective coating or layer can be thinner or less complete than would be preferred to provide the long shelf life needed to store a liquid material in contact with the barrier layer for an extended period.
  • the vessel has a central axis.
  • the vessel wall is sufficiently flexible to be flexed at least once at 20 °C, without breaking the wall, over a range from at least substantially straight to a bending radius at the central axis of not more than 100 times as great as the outer diameter of the vessel.
  • the bending radius at the central axis is not more than 90 times as great as, or not more than 80 times as great as, or not more than 70 times as great as, or not more than 60 times as great as, or not more than 50 times as great as, or not more than 40 times as great as, or not more than 30 times as great as, or not more than 20 times as great as, or not more than 10 times as great as, or not more than 9 times as great as, or not more than 8 times as great as, or not more than 7 times as great as, or not more than 6 times as great as, or not more than 5 times as great as, or not more than 4 times as great as, or not more than 3 times as great as, or not more than 2 times as great as, or not more than, the outer diameter of the vessel.
  • the vessel wall can be a fluid-contacting surface made of flexible material.
  • the vessel lumen can be the fluid flow passage of a pump.
  • the vessel can be a blood bag adapted to maintain blood in good condition for medical use.
  • the polymeric material can be a silicone elastomer or a thermoplastic polyurethane, as two examples, or any material suitable for contact with blood, or with insulin.
  • the vessel has an inner diameter of at least 2 mm, or at least 4 mm.
  • the vessel is a tube.
  • the lumen has at least two open ends. Relative proportions of gases of any embodiment
  • the process gas can contain this ratio of gases for preparing a lubricity and/or protective coating or layer:
  • the organosilicon compound can in certain aspects, particularly when a lubricity and/or protective coating or layer can be formed, comprise octamethylcyclotetrasiloxane (OMCTS).
  • OCTS octamethylcyclotetrasiloxane
  • the organosilicon compound for any embodiment of said certain aspects optionally can consist essentially of octamethylcyclotetrasiloxane (OMCTS).
  • the organosilicon compound can in certain aspects, particularly when a barrier coating or layer can be formed, be or comprise hexamethyldisiloxane.
  • the reaction gas can also include a hydrocarbon.
  • the hydrocarbon can comprise methane, ethane, ethylene, propane, acetylene, or a combination of two or more of these.
  • the organosilicon precursor can be delivered at a rate of equal to or less than 10 seem, optionally equal to or less than 6 seem, optionally equal to or less than 2.5 seem, optionally equal to or less than 1 .5 seem, optionally equal to or less than 1 .25 seem. Larger pharmaceutical packages or other vessels or other changes in conditions or scale may require more or less of the precursor.
  • the precursor can be provided at less than 1 Torr absolute pressure.
  • the carrier or diluent gas can comprise or consist of an inert gas, for example argon, helium, xenon, neon, another gas that is inert to the other constituents of the process gas under the deposition conditions, or any combination of two or more of these.
  • an inert gas for example argon, helium, xenon, neon, another gas that is inert to the other constituents of the process gas under the deposition conditions, or any combination of two or more of these.
  • the oxidizing gas can comprise or consist of oxygen (0 2 and/or 0 3 (commonly known as ozone)), nitrous oxide, or any other gas that oxidizes the precursor during PECVD at the conditions employed.
  • the oxidizing gas optionally can comprise about 1 standard volume of oxygen.
  • the gaseous reactant or process gas can be at least substantially free of nitrogen.
  • the plasma of any PECVD embodiment can be formed in the vicinity of the substrate.
  • the plasma can in certain cases, especially when preparing a barrier coating or layer 30), be a non-hollow-cathode plasma. In other certain cases, especially when preparing a lubricity coating or layer, a non-hollow-cathode plasma is not desired.
  • the plasma can be formed from the gaseous reactant at reduced pressure. Sufficient plasma generation power input can be provided to induce protective coating or layer formation on the substrate. IV. RF POWER OF ANY EMBODIMENT
  • the precursor can be contacted with a plasma made by energizing the vicinity of the precursor with electrodes powered at a frequency of 10 kHz to 2.45 GHz, alternatively from about 13 to about 14 MHz.
  • the precursor can be contacted with a plasma made by energizing the vicinity of the precursor with electrodes powered at radio frequency, optionally at a frequency of from 10 kHz to less than 300 MHz, optionally from 1 to 50 MHz, even optionally from 10 to 15 MHz, optionally at 13.56 MHz.
  • the precursor can be contacted with a plasma made by energizing the vicinity of the precursor with electrodes supplied with electric power at from 0.1 to 25 W, optionally from 1 to 22 W, optionally from 1 to 10 W, even optionally from 1 to 5 W, optionally from 2 to 4 W, for example of 3 W, optionally from 3 to 17 W, even optionally from 5 to 14 W, for example 6 or 7.5 W, optionally from 7 to 1 1 W, for example of 8 W, from 0.1 to 500 W, optionally from 0.1 to 400 W, optionally from 0.1 to 300 W, optionally from 1 to 250 W, optionally from 1 to 200 W, even optionally from 10 to 150 W, optionally from 20 to 150 W, for example of 40 W, optionally from 40 to 150 W, even optionally from 60 to 150 W.
  • a plasma made by energizing the vicinity of the precursor with electrodes supplied with electric power at from 0.1 to 25 W, optionally from 1 to 22 W, optionally from 1 to 10 W, even optionally from 1 to 5 W,
  • the precursor can be contacted with a plasma made by energizing the vicinity of the precursor with electrodes supplied with electric power density at less than 10 W/ml of plasma volume, alternatively from 6 W/ml to 0.1 W/ml of plasma volume, alternatively from 5 W/ml to 0.1 W/ml of plasma volume, alternatively from 4 W/ml to 0.1 W/ml of plasma volume, alternatively from 2 W/ml to 0.2 W/ml of plasma volume, alternatively from 10 W/ml to 50 W/ml, optionally from 20 W/ml to 40 W/ml.
  • a plasma made by energizing the vicinity of the precursor with electrodes supplied with electric power density at less than 10 W/ml of plasma volume, alternatively from 6 W/ml to 0.1 W/ml of plasma volume, alternatively from 5 W/ml to 0.1 W/ml of plasma volume, alternatively from 4 W/ml to 0.1 W/ml of plasma volume, alternatively from 2 W/ml to 0.2 W
  • the plasma can be formed by exciting the reaction mixture with electromagnetic energy, alternatively microwave energy.
  • the applying step for applying a protective coating or layer to the substrate can be carried out by vaporizing the precursor and providing it in the vicinity of the substrate.
  • the chemical vapor deposition employed can be PECVD and the deposition time can be from 1 to 30 sec, alternatively from 2 to 10 sec, alternatively from 3 to 9 sec.
  • the purposes for optionally limiting deposition time can be to avoid overheating the substrate, to increase the rate of production, and to reduce the use of process gas and its constituents.
  • the purposes for optionally extending deposition time can be to provide a thicker protective coating or layer for particular deposition conditions.
  • An embodiment can be carried out under conditions effective to form a hydrophobic protective coating or layer on the substrate.
  • the hydrophobic characteristics of the protective coating or layer can be set by setting the ratio of the O 2 to the organosilicon precursor in the gaseous reactant, and/or by setting the electric power used for generating the plasma.
  • the protective coating or layer can have a lower wetting tension than the uncoated surface, optionally a wetting tension of from 20 to 72 dyne/cm, optionally from 30 to 60 dynes/cm, optionally from 30 to 40 dynes/cm, optionally 34 dyne/cm.
  • the protective coating or layer can be more hydrophobic than the uncoated surface.
  • the protective coating or layer can have a thickness determined by transmission electron microscopy (TEM), of any amount stated in this disclosure.
  • TEM transmission electron microscopy
  • the lubricity and/or protective coating or layer can be composed of SiwOxCyH z (or its equivalent SiO x C y ) or Si w N x C y H z or its equivalent SiN x C y ), each as defined previously.
  • the atomic ratio of Si : O : C can be determined by XPS (X-ray photoelectron spectroscopy).
  • the protective coating or layer may thus in one aspect have the formula Si w O x C y H z , or its equivalent SiO x C y , for example where w is 1 , x is from about 0.5 to about 2.4, y is from about 0.6 to about 3, and z is from about 2 to about 9.
  • the protective coating or layer can have atomic concentrations normalized to 100% carbon, oxygen, and silicon, as determined by X-ray photoelectron spectroscopy (XPS) of less than 50% carbon and more than 25% silicon.
  • the atomic concentrations are from 25 to 45% carbon, 25 to 65% silicon, and 10 to 35% oxygen.
  • the atomic concentrations are from 30 to 40% carbon, 32 to 52% silicon, and 20 to 27% oxygen.
  • the atomic concentrations are from 33 to 37% carbon, 37 to 47% silicon, and 22 to 26% oxygen.
  • the atomic concentration of carbon in the protective coating or layer can be greater than the atomic concentration of carbon in the atomic formula for the organosilicon precursor.
  • the atomic concentration of carbon increases by from 1 to 80 atomic percent, alternatively from 10 to 70 atomic percent, alternatively from 20 to 60 atomic percent, alternatively from 30 to 50 atomic percent, alternatively from 35 to 45 atomic percent, alternatively from 37 to 41 atomic percent.
  • the atomic ratio of carbon to oxygen in the protective coating or layer can be increased in comparison to the organosilicon precursor, and/or the atomic ratio of oxygen to silicon can be decreased in comparison to the organosilicon precursor.
  • the protective coating or layer can have an atomic concentration of silicon, normalized to 100% of carbon, oxygen, and silicon, as determined by X-ray photoelectron spectroscopy (XPS), less than the atomic concentration of silicon in the atomic formula for the feed gas.
  • XPS X-ray photoelectron spectroscopy
  • the atomic concentration of silicon decreases by from 1 to 80 atomic percent, alternatively by from 10 to 70 atomic percent, alternatively by from 20 to 60 atomic percent, alternatively by from 30 to 55 atomic percent, alternatively by from 40 to 50 atomic percent, alternatively by from 42 to 46 atomic percent.
  • a protective coating or layer is contemplated that can be characterized by a sum formula wherein the atomic ratio C : O can be increased and/or the atomic ratio Si : O can be decreased in comparison to the sum formula of the organosilicon precursor.
  • the protective coating or layer can have a density between 1 .25 and 1 .65 g/cm 3 , alternatively between 1 .35 and 1 .55 g/cm 3 , alternatively between 1 .4 and 1 .5 g/cm 3 , alternatively between 1 .4 and 1 .5 g/cm 3 , alternatively between 1 .44 and 1 .48 g/cm 3 , as determined by X-ray reflectivity (XRR).
  • XRR X-ray reflectivity
  • the organosilicon compound can be octamethylcyclotetrasiloxane and the protective coating or layer can have a density which can be higher than the density of a protective coating or layer made from HMDSO as the organosilicon compound under the same PECVD reaction conditions.
  • the protective coating or layer optionally can prevent or reduce the precipitation of a compound or component of a composition in contact with the protective coating or layer, in particular can prevent or reduce insulin precipitation or blood clotting, in comparison to the uncoated surface and/or to a barrier coated surface using HMDSO as precursor.
  • the substrate can be a pharmaceutical package or other vessel, for protecting a compound or composition contained or received in the vessel with a protective coating or layer against mechanical and/or chemical effects of the surface of the uncoated substrate.
  • the substrate can be a pharmaceutical package or other vessel, for preventing or reducing precipitation and/or clotting of a compound or a component of the composition in contact with the inner or interior surface of the vessel.
  • the compound or composition can be a biologically active compound or composition, for example a medicament, for example the compound or composition can comprise insulin, wherein insulin precipitation can be reduced or prevented.
  • the compound or composition can be a biological fluid, for example a bodily fluid, for example blood or a blood fraction wherein blood clotting can be reduced or prevented.
  • the protective coating or layer optionally can have an RMS surface roughness value (measured by AFM) of from about 5 to about 9, optionally from about 6 to about 8, optionally from about 6.4 to about 7.8.
  • the R a surface roughness value of the protective coating or layer, measured by AFM can be from about 4 to about 6, optionally from about 4.6 to about 5.8.
  • the R ma x surface roughness value of the protective coating or layer, measured by AFM can be from about 70 to about 160, optionally from about 84 to about 142, optionally from about 90 to about 130.
  • the substrate can be a vessel having an inner or interior surface defining a lumen and an exterior surface
  • the protective coating or layer can be on the inner or interior surface of the pharmaceutical package or other vessel
  • the vessel can contain a compound or composition in its lumen, for example citrate or a citrate containing composition, or for example insulin or an insulin containing composition.
  • a prefilled syringe is especially considered which contains injectable or other liquid drugs like insulin.
  • the conditions given here are for a COC syringe barrel, and can be modified as appropriate for syringe barrels made of other materials.
  • the apparatus as generally shown in FIGS. 8 and 9 is used to hold a syringe barrel with butt sealing at the base of the syringe barrel. Additionally a shield 28 is provided that seals the end of the syringe barrel (illustrated in FIG. 8).
  • the syringe barrel is carefully moved into the sealing position over the extended probe or counter electrode 108 and pushed against a plasma screen.
  • the plasma screen is fit snugly around the probe or counter electrode 108 insuring good electrical contact.
  • the probe or counter electrode 108 is grounded to the casing of the RF matching network.
  • the gas delivery port 1 10 is connected to a manual ball valve or similar apparatus for venting, a thermocouple pressure gauge and a bypass valve connected to the vacuum pumping line.
  • the gas system is connected to the gas delivery port 1 10 allowing the gaseous reactant or process gas, octamethylcyclotetrasiloxane (OMCTS) (or the specific gaseous reactant or process gas reported for a particular example) to be flowed through the gas delivery port 1 10 (under process pressures) into the interior of the syringe barrel.
  • OCTS octamethylcyclotetrasiloxane
  • the gas system is comprised of a commercially available heated mass flow vaporization system that heats the OMCTS to about 100°C.
  • the heated mass flow vaporization system is connected to liquid octamethylcyclotetrasiloxane (Alfa Aesar® Part Number A1 160, 98%).
  • the OMCTS flow rate is set to the specific organosilicon precursor flow reported for a particular example. To ensure no condensation of the vaporized OMCTS flow past this point, the gas stream is diverted to the pumping line when it is not flowing into the interior of the COC syringe barrel for processing.
  • the vacuum pump valve is opened to the vessel holder 50 and the interior of the COC syringe barrel.
  • a vacuum pump and blower comprise the vacuum pump system.
  • the pumping system allows the interior of the COC syringe barrel to be reduced to pressure(s) of less than 100 mTorr while the gaseous reactant or process gases is flowing at the indicated rates.
  • the vessel holder 50 assembly is moved into the electrode 160 assembly.
  • the gas stream (OMCTS vapor) is flowed into the gas delivery port 1 10 (by adjusting the 3-way valve from the pumping line to the gas delivery port 1 10.
  • Pressure inside the COC syringe barrel is approximately 140 mTorr as measured by a capacitance manometer (MKS) installed on the pumping line near the valve that controls the vacuum.
  • MKS capacitance manometer
  • the pressure inside the gas delivery port 1 10 and gas system is also measured with the thermocouple vacuum gauge that is connected to the gas system. This pressure is typically less than 6 Torr.
  • the RF power supply is turned on to its fixed power level.
  • a 600 Watt RF power supply is used (at 13.56 MHz) at a fixed power level indicated in a specific example.
  • the RF power supply is connected to an auto match which matches the complex impedance of the plasma (to be created in the vessel) to the output impedance of the RF power supply.
  • the forward power is as stated and the reflected power is 0 Watts so that the stated power is delivered to the interior of the vessel.
  • the RF power supply is controlled by a laboratory timer and the power on time set to 10 seconds (or a different time stated in a given example).
  • a uniform plasma is established inside the interior of the vessel.
  • the plasma is maintained for the entire protective coating or layer time, until the RF power is terminated by the timer.
  • the plasma produces a protective coating or layer on the interior of the vessel.
  • the gas flow is diverted back to the vacuum line and the vacuum valve is closed.
  • the vent valve is then opened, returning the interior of the COC syringe barrel to atmospheric pressure (approximately 760 Torr).
  • the treated vessel is then carefully removed from the vessel holder 50 assembly (after moving the vessel holder 50 assembly out of the electrode 160 assembly).
  • This protocol is used to determine the total amount of silicon coatings present on the entire vessel wall.
  • a supply of 0.1 N potassium hydroxide (KOH) aqueous solution is prepared, taking care to avoid contact between the solution or ingredients and glass.
  • the water used is purified water, 18 ⁇ quality.
  • a Perkin Elmer Optima Model 7300DV ICP-OES instrument is used for the measurement except as otherwise indicated.
  • each device (vial, syringe, tube, or the like) to be tested and its shield and crimp (in the case of a vial) or other closure are weighed empty to 0.001 g, then filled completely with the KOH solution (with no headspace), capped, crimped, and reweighed to 0.001 g.
  • each vial is placed in a sonicating water bath at 40 °C for a minimum of 8-10 hours. The digestion step is carried out to quantitatively remove the silicon coatings from the vessel wall into the KOH solution. After this digestion step, the vials are removed from the sonicating water bath and allowed to cool to room temperature. The contents of the vials are transferred into 15 ml ICP tubes. The total Si concentration is run on each solution by ICP/OES following the operating procedure for the ICP/OES.
  • the total Si concentration is reported as parts per billion of Si in the KOH solution. This concentration represents the total amount of silicon coatings that were on the vessel wall before the digestion step was used to remove it.
  • the total Si concentration can also be determined for fewer than all the silicon layers on the vessel, as when an SiO x barrier layer is applied, an SiO x C y second layer (for example, a lubricity layer or a protective coating or layer) is then applied, and it is desired to know the total silicon concentration of just the SiO x C y layer.
  • This determination is made by preparing two sets of vessels, one set to which only the SiO x layer is applied and the other set to which the same SiO x layer is applied, followed by the SiOxCy layer or other layers of interest.
  • the total Si concentration for each set of vessels is determined in the same manner as described above. The difference between the two Si concentrations is the total Si concentration of the SiO x C y second layer.
  • the amount of silicon dissolved from the wall of the vessel by a test solution is determined, in parts per billion (ppb), for example to evaluate the dissolution rate of the test solution.
  • This determination of dissolved silicon is made by storing the test solution in a vessel provided with an SiO x and/or SiOxCy coating or layer under test conditions, then removing a sample of the solution from the vessel and testing the Si concentration of the sample.
  • the test is done in the same manner as the Protocol for Total Silicon Measurement, except that the digestion step of that protocol is replaced by storage of the test solution in the vessel as described in this protocol.
  • the total Si concentration is reported as parts per billion of Si in the test solution Protocol for Determining Average Dissolution Rate
  • the average dissolution rates reported in the working examples are determined as follows.
  • a series of test vessels having a known total total silicon measurement are filled with the desired test solution analogous to the manner of filling the vials with the KOH solution in the Protocol for Total Silicon Measurement.
  • the test solution can be a physiologically inactive test solution as employed in the present working examples or a physiologically active pharmaceutical preparation intended to be stored in the vessels to form a pharmaceutical package).
  • the test solution is stored in respective vessels for several different amounts of time, then analyzed for the Si concentration in parts per billion in the test solution for each storage time.
  • the respective storage times and Si concentrations are then plotted. The plots are studied to find a series of substantially linear points having the steepest slope.
  • the calculated shelf life values reported in the working examples below are determined by extrapolation of the total silicon measurements and average dissolution rates, respectively determined as described in the Protocol for Total Silicon Measurement and the Protocol for Determining Average Dissolution Rate. The assumption is made that under the indicated storage conditions the SiO x C y protective coating or layer will be removed at the average dissolution rate until the coating is entirely removed. Thus, the total silicon measurement for the vessel, divided by the dissolution rate, gives the period of time required for the test solution to totally dissolve the SiOxCy coating. This period of time is reported as the calculated shelf life. Unlike commercial shelf life calculations, no safety factor is calculated. Instead, the calculated shelf life is the calculated time to failure.
  • the sample was mounted onto the sample holder with conductive graphite adhesive, then put into a Denton Desk IV SEM Sample Preparation System, and a thin (approximately 50 A) gold protective coating or layer was sputtered onto the inner or interior surface of the syringe.
  • the gold protective coating or layer is required to eliminate charging of the surface during measurement.
  • the sample was removed from the sputter system and mounted onto the sample stage of a Jeol JSM 6390 SEM (Scanning Electron Microscope). The sample was pumped down to at least 1 x 10 "6 Torr in the sample compartment. Once the sample reached the required vacuum level, the slit valve was opened and the sample was moved into the analysis station.
  • Jeol JSM 6390 SEM Sccanning Electron Microscope
  • the sample was imaged at a coarse resolution first, then higher magnification images were accumulated.
  • the SEM images provided in the Figures are 5 ⁇ edge-to- edge (horizontal and vertical).
  • AFM Anatomic Force Microscopy
  • AFM images were collected using a NanoScope III Dimension 3000 machine (Digital Instruments, Santa Barbara, California, USA). The instrument was calibrated against a NIST traceable standard. Etched silicon scanning probe microscopy (SPM) tips were used. Image processing procedures involving auto-flattening, plane fitting or convolution were employed. One 10 ⁇ x 10 ⁇ area was imaged. Roughness analyses were performed and were expressed in: (1 ) Root-Mean-Square Roughness, RMS; 2 Mean Roughness, Ra; and (3) Maximum Height (Peak-to-Valley), Rmax, all measured in nm (see Table 5 and Figs. 18 to 20.
  • each sample was imaged over the 10 ⁇ x 10 ⁇ area, followed by three cross sections selected by the analyst to cut through features in the 10 ⁇ x 10 ⁇ images.
  • the vertical depth of the features was measures using the cross section tool.
  • a Root-Mean-Square Roughness (RMS) in nanmeters was reported.
  • the Digital Instruments Nanoscope III AFM/STM acquires and stores 3- dimensional representations of surfaces in a digital format. These surfaces can be analyzed in a variety of ways.
  • the Nanoscope III software can perform a roughness analysis of any AFM or STM image.
  • the product of this analysis is a single page reproducing the selected image in top view.
  • To the upper right of the image is the "Image Statistics” box, which lists the calculated characteristics of the whole image minus any areas excluded by a stopband (a box with an X through it). Similar additional statistics can be calculated for a selected portion of the image and these are listed in the "Box Statistics” in the lower right portion of the page. What follows is a description and explanation of these statistics.
  • RMS (R q ) This is the standard deviation of the Z values (or RMS roughness) in the image. It is calculated according to the formula:
  • Z avg is the average Z value within the image
  • Zi is the current value of Z
  • N is the number of points in the image. This value is not corrected for tilt in the plane of the image; therefore, plane fitting or flattening the data will change this value.
  • R a [1 /(L x L y )]Jo Ly io Lx ⁇ f(x,y) ⁇ dxdy
  • Max height (R ma x) This is the difference in height between the highest and lowest points of the surface relative to the Mean Plane.
  • Center Plane A flat plane that is parallel to the Mean Plane. The volumes enclosed by the image surface above and below the center plane are equal.
  • Table 8 shows a summary of the above OMCTS coatings or layers and their Fj and F m values. It should be understood that the initial lubricity and/or protective coating or layer work (C-K; roughness not known) was to identify the lowest possible stopper, O-ring, plunger tip or piston force attainable. From subsequent market input, it was determined that the lowest achievable stopper, O-ring, plunger tip or piston force was not necessarily most desirable, for reasons explained in the generic description (for example premature release). Thus, the PECVD reaction parameters were varied to obtain a stopper, O-ring, plunger tip or piston force of practical market use.
  • Sample A Stelmi tips coated 2 microns thick by heat-initiated chemical vapor deposition with Parylene C.
  • Sample B Stelmi tips coated 2 microns thick by heat-initiated chemical vapor deposition with Parylene HT®, shown in Figs. 7 and 1 5, respectively compared to PDMS and PTFE.
  • Sample C Stelmi tips coated 0.2 microns thick by heat-initiated chemical vapor deposition with Parylene HT®.
  • the syringes used were thermoplastic syringes having an internal barrier coating and coating and pH protective coating applied by PECVD as described in this specification (the two coatings being referred to below as a "bilayer coating").
  • Parylene HT® coated plunger had a much lower breakout force than the Parylene C coated plunger, since the Wolgemuth article cited in this specification states, at page 45, "Parylene N, C, and Parylene HT® offer similar lubricity capabilities." It is also surprising that a Parylene coated plunger provides a lower breakout force than the industry standard - a glass barrel syringe lubricated with silicone oil.
  • Parylene or halogenated polymer Coated Plunger Providing a Lower Plunger Breakout Force That is More Consistent Throughout Shelf Life
  • thermoplastic staked syringes, cartridges, or similar articles were provided with Stelmi plungers having elastomeric plunger tips, threaded plunger rods, and barrels.
  • the syringe barrels were coated with a PECVD SiO x barrier coating or layer and a PECVD protective coating or layer on the interior surfaces. These coatings or layers are referred to in the legend on FIG. 3 as a "Bilayer.”
  • the plunger tips were coated using the GVD Corporation hot wire or filament chemical vapor deposition (HWCVD) equipment and a method similar to those described in U.S. Publ. Appl. 2012/0003497.
  • the coating was applied 10 microns (micrometers) thick with a parylene or halogenated polymer characterized as polytetrafluoroethylene (PTFE), at a maximum temperature of the tip of 100°C, over a period of 2 hours, allowing intermediate time for the plunger tips to cool to maintain the maximum temperature. There was no evidence of melting or distortion to the tips.
  • Each plunger was assembled on the plunger rod until it bottomed out on the plunger rod shoulder.
  • the plunger assembly was then inserted into the syringe barrel to the appropriate depth and allowed to dwell or park undisturbed for 100 sec, one hour, three hours, or 24 hours (86,400 seconds).
  • a third comparative example was carried out as described in the working example above, except that a glass syringe and no bi-layer coating was used, and instead of applying a PTFE coating the glass syringe was siliconized conventionally by applying silicone oil to lubricate it.
  • the resulting plot and extrapolation are shown in FIG. 3 with the legend, "glass syringe with silicone oil” (etc). As shown the slope was 0.2072, the intercept was 0.51 18, and the two-year extrapolation of breakout force was 12.7 N.
  • This invention thus addresses and (based on extrapolation of short-term data) largely solves the problem of providing a lubricity coating that maintains a consistent breakloose force over the pre-filled syringe shelf life - approximately 2-3 years.
  • Test solutions - 50 mM buffer solutions at pH 3, 6, 7, 8, 9, and 12 are prepared. Buffers are selected having appropriate pKa values to provide the pH values being studied. A potassium phosphate buffer is selected for pH 3, 7, 8 and 12, a sodium citrate buffer is utilized for pH 6 and tris buffer is selected for pH 9. 3 ml of each test solution is placed in borosilicate glass 5 ml pharmaceutical vials and SiO x coated 5 ml thermoplastic pharmaceutical vials. The vials are all closed with standard coated stoppers and crimped.
  • the vials are placed in storage at 20 - 25 °C and pulled at various time points for inductively coupled plasma spectrometer (ICP) analysis of Si content in the solutions contained in the vials, in parts per billion (ppb) by weight, for different storage times.
  • ICP inductively coupled plasma spectrometer
  • the Protocol for Determining Average Dissolution Rate Si content is used to monitor the rate of glass dissolution, except as modified here.
  • the data is plotted to determine an average rate of dissolution of borosilicate glass or SiO x coating at each pH condition. Representative plots at pH 6 through 8 are FIGS 27-29.
  • the rate of Si dissolution in ppb is converted to a predicted thickness (nm) rate of Si dissolution by determining the total weight of Si removed, then using a surface area calculation of the amount of vial surface (1 1 .65 cm 2 ) exposed to the solution and a density of SiO x of 2.2 g/cm 3 .
  • the predicted initial thickness of the SiO x coating is about 36 nm at pH 5, about 80 nm at pH 6, about 230 nm at pH 7, about 400 nm at pH 7.5, about 750 nm at pH 8, and about 2600 nm at pH 9.
  • the coating thicknesses in FIG. 30 represent atypically harsh case scenarios for pharma and biotech products. Most biotech products and many pharma products are stored at refrigerated conditions and none are typically recommended for storage above room temperature. As a general rule of thumb, storage at a lower temperature reduces the thickness required, all other conditions being equivalent.
  • vessels coated with SiO x coating + OMCTS lubricity layer to test the lubricity layer for its functionality as a protective coating or layer.
  • the vessels are 5 mL vials (the vials are normally filled with product to 5 mL; their capacity without headspace, when capped, is about 7.5 mL) composed of cyclic olefin co-polymer (COC, Topas® 6013M-07).
  • Coating time 12 seconds (includes a 2-sec RF power ramp-up time)
  • the SiO x coated vials are coated over the SiO x with an SiO x C y coating produced in a PECVD process using an OMCTS precursor vapor according to the Protocol for Coating COC Syringe Barrel Interior with OMCTS Lubricity Coating set forth above, except that the same coating equipment is used as for the SiO x coating.
  • the special adaptations in the protocol for coating a syringe 12 are not used. The following conditions are used.

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  • Pharmacology & Pharmacy (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Anesthesiology (AREA)
  • Inorganic Chemistry (AREA)
  • Physical Vapour Deposition (AREA)

Abstract

L'invention concerne un récipient, par exemple une seringue, une cartouche, un flacon ou un article similaire comprenant un corps ou d'autre récipient et un bouchon, un joint torique, une pointe de piston ou un piston. Le substrat de récipient définit une lumière et une surface de glissement interne sur le substrat de récipient adjacent à la lumière. Le bouchon, le joint torique, la pointe de piston ou le piston a une surface de glissement externe pouvant glisser dans la lumière au moins sensiblement en contact avec la surface de glissement interne. La surface de glissement interne, la surface de glissement externe ou les deux sont faites au moins en partie d'un polymère de parylène ou halogéné qui peut être sous la forme d'un revêtement ou d'une matière massique. L'invention concerne également des procédés de fabrication de la seringue, de la cartouche ou d'un article similaire à l'aide de dépôt chimique en phase vapeur, par exemple par dépôt du polymère de parylène ou halogéné directement ou avec des couches intermédiaires pour définir la surface de glissement externe, la surface de glissement interne ou les deux.
PCT/US2013/062247 2012-09-28 2013-09-27 Revêtement de polymère halogéné ou de parylène WO2014052792A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US201261707810P 2012-09-28 2012-09-28
US61/707,810 2012-09-28
US201261716381P 2012-10-19 2012-10-19
US61/716,381 2012-10-19
US201361753348P 2013-01-16 2013-01-16
US61/753,348 2013-01-16
US201361768334P 2013-02-22 2013-02-22
US61/768,334 2013-02-22

Publications (1)

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WO2014052792A1 true WO2014052792A1 (fr) 2014-04-03

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