Pulsed plasma chemical vapor deposition process and system

Abstract

The present invention provides a method and system for processing multiple containers to provide, for example, a gas barrier. [Solution] A method and system are disclosed for processing multiple containers to provide, for example, a gas barrier. The gas barrier can be deposited simultaneously in multiple containers using pulsed plasma chemical vapor deposition, with each container located within an opening in an RF electrode.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 064,831, filed on 12 August 2020.

[0002] The present invention relates to coated containers for storing pharmaceutical solutions, biologically active compounds, or blood, and to the technical field for manufacturing coated containers. For example, the present invention relates to a system for coating containers by plasma chemical vapor deposition (PECVD), a pulsed plasma chemical vapor deposition system for coating the inner surface of a container, a method for coating a container, for example, the inner surface of a container, by pulsed PECVD, and a container coated by the pulsed plasma chemical vapor deposition method and system described herein.

[0003] This disclosure also relates to improved methods for handling containers used for venipuncture and other medical sample collection, drug storage and delivery, and other purposes, such as multiple identical containers. Such containers must be used in large numbers for these purposes, be relatively economical to manufacture, have consistent properties from container to container, and be highly reliable in storage and use. [Background technology]

[0004] One important consideration when manufacturing pharmaceutical packaging or other containers that store or come into contact with fluids, such as vials and pre-filled syringes, is that the contents of the pharmaceutical packaging or other containers should preferably have a reasonable shelf life.

[0005] Conventional glass pharmaceutical packaging or other containers are prone to breakage or deterioration during manufacturing, filling, transport, and use, meaning that glass particles may enter the medication. The presence of glass particles has led to numerous FDA warnings and product recalls.

[0006] As a result, some companies have switched to plastic pharmaceutical packaging or other containers that offer higher dimensional tolerances and lower breakage than glass, but their use in primary pharmaceutical packaging remains limited due to gas (oxygen) permeability: plastics allow small molecular gases such as oxygen to permeate into (or out of) an article. In addition to oxygen, many plastic materials also allow moisture, i.e., water vapor, to permeate into (or out of) an article. The permeability of plastics to gases such as oxygen and water vapor is far higher than that of glass, and in many cases (such as for oxygen-sensitive drugs like epinephrine), plastics have been unacceptable for this reason.

[0007] The permeability problem has been addressed by using cyclic olefin polymer ("COP") resins or cyclic olefin copolymer ("COC") resins and adding an oxygen barrier film or layer to the area of ​​the plastic pharmaceutical packaging that comes into contact with the fluid contents. One such barrier layer is coated by plasma chemical vapor deposition, SiO2 as defined below. x This is an extremely thin coating. However, coating of this type of plastic packaging, such as syringe barrels and vials, has traditionally been performed on a container-by-container basis, with a single container or a small number (four or fewer) being coated at once by a given system. With the use of such systems, it is difficult to achieve consistency between the coatings applied to the containers. In addition to the small number of containers coated in a given time, the low power used in such systems results in a relatively long process (for example, about 1.5 minutes per layer, resulting in a process that takes about 4 minutes to coat four containers with the three-layer coating described herein). [Overview of the project] [Problems that the invention aims to solve]

[0008] Furthermore, resins such as COP and COC are relatively expensive and difficult to manufacture or obtain in large quantities. Therefore, the cost of these materials plays a significant role in the overall cost of manufacturing pharmaceutical packaging. And as the scale and speed of container coating increase according to the embodiments of this disclosure, the difficulty in manufacturing or obtaining COP and COC in large quantities can impose significant limitations on the overall scale and / or manufacturing speed of coated containers and pharmaceutical packaging utilizing those coated containers. [Means for solving the problem]

[0009] Summary of the Invention One aspect of the present invention is a container having a lumen at least partially defined by a wall, the wall having an inner surface facing the lumen, an outer surface, and a coating set on the inner surface, the coating set optionally including a tie coating or layer, a barrier coating or layer, and optionally a pH protective coating or layer.

[0010] The tie film or layer, if present, may contain SiOxCy or Si(NH)xCy. In either formula, x is approximately 0.5 to 2.4 and y is approximately 0.6 to 3. The tie film or layer has an inner surface facing the lumen and an outer surface facing the inner surface of the wall.

[0011] The barrier film or layer may contain SiOx, where x is 1.5 to 2.9. Alternatively, the barrier film or layer may contain one or more metals or metal oxides such as Al2O3, or a combination thereof. The barrier layer may be 2 to 1000 nm thick. The barrier film or layer may have an inner surface facing the lumen and an outer surface facing the inner surface of the film or layer. The barrier film or layer is effective in reducing the intrusion of atmospheric gas into the lumen compared to a container without a barrier film or layer. In some embodiments, the barrier film or layer is SiOx, where x is 1.5 to 2.9. x It may include one or more layers of SiO₂ and one or more layers of a metal or metal oxide such as Al₂O₃. xThe film or layer can be effective in reducing the ingress of oxygen into the lumen as compared to a container without a barrier film or layer, and the Al2O3 layer can be effective in reducing the ingress of water vapor (i.e., moisture) into the lumen as compared to a container without a barrier film or layer.

[0012] The pH protection film or layer, when present, can comprise SiOxCy or Si(NH)xCy, where x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3. The pH protection film or layer can have an inner surface facing the lumen and an outer surface facing the inner surface of the barrier film or layer.

[0013] In one embodiment, a container having a lumen is at least partially defined by a wall, the wall comprising a thermoplastic material and having an inner surface facing the lumen, an outer surface, and a film on the inner surface comprising at least one barrier film or layer and optionally at least one pH protection film or layer and / or at least one tie film or layer. At least one barrier film or layer comprising SiOx, where x is from 1.5 to 2.9, and the barrier film or layer is effective in reducing the ingress of atmospheric gases into the lumen as compared to a container without a barrier film or layer, and when present, SiO x C y or SiN x C[[ID=,15]] y At least one pH protection film or layer comprising, where x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3, and when present, SiO x C y or SiN x C yAt least one tie film or layer comprising, x is approximately 0.5 to approximately 2.4 and y is approximately 0.6 to approximately 3; at least one barrier film or layer and at least one pH protective film or layer and / or tie film or layer are applied by pulsed RF plasma chemical vapor deposition, optionally without an interface layer between the barrier layer and the pH protective layer and / or tie layer, exposed to air; at least the barrier film or layer has a thinner thickness than a conventional SiOx barrier film (e.g., less than 20 nm thick compared to a conventional barrier film with a thickness of approximately 80 nm) and has improved (i.e., lower) oxygen permeability compared to a conventional SiOx barrier film (e.g., having an oxygen permeability at a thickness of 15 nm that would not be obtained with a conventional SiOx barrier film until the conventional film reaches a thickness of approximately 80 nm).

[0014] In some embodiments, for example, the SiOx barrier film or layer may have an average thickness of less than 200 nm, optionally less than 150 nm, optionally less than 125 nm, optionally less than 100 nm, optionally less than 80 nm, optionally less than 60 nm, optionally less than 50 nm, optionally less than 40 nm, optionally less than 30 nm, optionally less than 25 nm, optionally less than 20 nm, optionally less than 15 nm, or optionally less than 10 nm, thereby enabling oxygen permeability of the container wall. The rate (d-1) may be less than 0.020, optionally less than 0.015, optionally less than 0.010, optionally less than 0.005, optionally less than 0.0025, optionally less than 0.0015, optionally less than 0.0010, optionally less than 0.0008, optionally less than 0.0006, optionally less than 0.0005, optionally less than 0.0004, optionally less than 0.0003, optionally less than 0.0002, or optionally less than 0.0001.

[0015] In addition to containers having improved oxygen permeability per coating thickness, containers prepared by the methods and systems described herein are provided with more consistent coating thickness and properties (e.g., oxygen permeability, silicon dissolution by a fluid of a given pH, etc.) throughout multiple containers manufactured over long periods, such as hours, days, weeks, or months. The cost of manufacturing each container can also be reduced by increasing the number of containers that can be coated by the system in a given time.

[0016] Furthermore, in some embodiments, the container, container wall, or at least a portion of the container wall can be made of a thermoplastic material that is less expensive than conventionally used COP and COC resins. In some embodiments, for example, the container, container wall, or at least a portion of the container wall may include or be made of a cyclic block copolymer (CBC). Cyclic block copolymers are styrene-based fully hydrogenated polymers and dienes conjugated via anionic polymerization. Examples of cyclic block copolymers include, for example, the VIVION® family, such as VIVION® 0510, VIVION® 0510HF, or VIVION® 1325, manufactured by USI Corporation (Taiwan). Cyclic block copolymers are less expensive than COP and COC resins, at least in part, due to their lower cost of raw materials (styrene, butadiene, hydrogen, and cyclohexane solvent) and the lower cost of catalysts used in polymerization and finishing processes. The use of cyclic block copolymers is limited by their much higher oxygen permeability compared to COP and COC resins. However, the improvement in oxygen permeability (d-1) provided by the embodiments of the present invention makes it possible for the first time to use cyclic block copolymers in the preparation of pharmaceutical containers and packaging such as vials and syringes that require high barrier properties.

[0017] Just as the methods and systems described herein provide an expansion of the container coating process in terms of both the amount of time required for the coating process and the number of containers that can be coated using a given system, the ability to transition from COP resin and COC resin to CBC resin provides a further improvement in the ability to expand the production of coated containers and filled pharmaceutical packaging.

[0018] Because the raw materials used in the manufacture of COP and COC resins, such as monomers and catalysts, are not readily available in large quantities, the number of COP or COC containers that can be produced within a defined time may be limited. Therefore, as the rate and scale of container coating increases with the methods and systems disclosed herein, the ability to manufacture COP or COC resins and containers may become a limiting factor to the scale and / or rate of production of the final product, i.e., coated (and optionally filled) containers. In contrast, the raw materials used in the manufacture and finishing of CBC resins, such as monomers and catalysts, are readily available in large quantities from multiple manufacturers and are of general-purpose grade. Therefore, by enabling the use of containers made from CBC resin, the methods and systems described herein can also eliminate additional limitations on the scale and / or rate of production, such as those related to the manufacture of the containers themselves.

[0019] Many additional and alternative aspects and embodiments of the present invention are also contemplated and described herein and in the subsequent claims. Some optional features contemplated in any embodiment include:

[0020] In any embodiment, the above-described container is intended to be made of, or composed of, at least a portion of the container wall, any cyclic olefin polymer such as cyclic olefin polymer ("COP") or cyclic olefin copolymer ("COC"), the low-cost cyclic block copolymer (CBC) resin described above, or any of the wide variety of other known thermoplastic materials such as PET, polyethylene, nylon, polypropylene, polyamide, polystyrene, polycarbonate, TRITAN® (a product of Eastman Chemical Company), thermoplastic olefin polymers, etc.

[0021] The above-mentioned containers, including syringe barrels, vials, or blister packaging or blood collection tubes, are intended in any embodiment.

[0022] The barrier film or layer is applied by pulsed radio frequency (RF) plasma chemical vapor deposition (PECVD), sometimes also known as pulsed plasma impulse chemical vapor deposition (pulsed PICVD), and the container described above is intended to be 1 to 50 nm thick, alternatively 1 to 20 nm thick, or alternatively 2 to 15 nm thick, in any embodiment.

[0023] In any embodiment, the above-described container is intended in which the tie layer and / or pH protective film or layer contains SiOxCy.

[0024] In any embodiment, the above-described container is intended to be coated by pulsed RF PECVD of a precursor feed comprising an acyclic siloxane, monocyclic siloxane, polycyclic siloxane, polysilsesquioxane, monocyclic silazane, polycyclic silazane, polysilsesquiazane, silatoran, silk asilatran, silproatrane, azasilatrane, azasilquasiatrane, azasilproatrane, or any two or more combinations thereof.

[0025] In any embodiment, the above-described container is intended to be coated by pulsed RF PECVD of a precursor feed containing a linear siloxane or linear silazane, such as hexamethyldisiloxane (HMDSO) or tetramethyldisiloxane (TMDSO), or a cyclic siloxane, such as octamethylcyclotetrasiloxane (OMCTS).

[0026] The container described above is intended in any embodiment, wherein the pH protective film or layer to be applied is 10 to 1000 nm thick.

[0027] In any embodiment, the above-described container is intended such that the erosion rate of the pH protective film or layer is less than 20% of the erosion rate of the barrier film or layer when in direct contact with a fluid composition having pH 8, under the same conditions and in direct contact with the same fluid composition.

[0028] In any embodiment, the above-described container is intended to have a pH protective film or layer having at least the same extent as the barrier film or layer.

[0029] In any embodiment, the above-described container is intended to remove the pH protective film or layer at a rate of 1 nm or less per 44 hours of contact with the fluid composition.

[0030] In any embodiment, the above-described container is intended to further include a lubricating film or layer applied between the pH film or layer and the lumen.

[0031] The FTIR absorbance spectrum of the pH protective film or layer is The maximum amplitude of the Si-O-Si symmetric stretching peak is approximately 1000-1040 cm⁻¹. Approximately 1060~1100cm -1 The maximum amplitude of the Si-O-Si symmetric stretching peak and In any embodiment, the above-described container having a ratio greater than 0.75 between the two is intended.

[0032] The above-described container is intended in any embodiment, in which the silicon dissolution rate with 50 mM potassium phosphate buffer containing 0.2 wt.% polysorbate 80 surfactant is less than 170 ppb / day, diluted with sterile water for injection, adjusted to pH 8 with concentrated nitric acid.

[0033] In any embodiment, the above-described container is intended to have a total silicon content of less than 66 ppm in the pH protective film or layer and barrier film when dissolved from the container in a 0.1N potassium hydroxide solution at 40°C.

[0034] The calculated storage life (total Si / Si dissolution rate) is more than 2 years, and the above-described container is intended in any embodiment.

[0035] The pH protective film or layer is O parameter = (1253cm) -1 Strength at 1000-1100cm -1 (Maximum intensity within the range) In any embodiment, the above-described vessel is intended to exhibit the O-parameter measured with a damped total internal reflection (ATR) of less than 0.4, as measured as follows.

[0036] The pH protective film or layer is N parameter = (840cm) -1 Strength at 799cm -1 (Intensity in) In any embodiment, the above-described container is intended to exhibit an N parameter measured by a damped total internal reflection (ATR) of less than 0.7, as measured as follows.

[0037] The pH protective film or layer and / or tie film or layer is applied by pulsed RF PECVD of a precursor feed containing octamethylcyclotetrasiloxane (OMCTS), tetramethyldisiloxane (TMDSO), or hexamethyldisiloxane (HMDSO), as intended in any embodiment of the above-described container.

[0038] In any embodiment, the above-described container is intended to have a tie film or layer, if present, with an average thickness of 5 to 200 nm.

[0039] In any embodiment, the above-described container is intended to have a tie film or layer having at least the same extent as the barrier film or layer.

[0040] The tie film or layer is applied by pulsed RF PECVD, and the above-described container is intended in any embodiment.

[0041] In any embodiment, the above-described container is intended to have a barrier film or layer that is 1 to 50 nm thick, alternatively 1 to 20 nm thick, or alternatively 2 to 15 nm thick.

[0042] The barrier film or layer is applied by pulsed RF PECVD, and the above-described container is intended in any embodiment.

[0043] The container has a lumen at least partially defined by a plastic wall, the plastic wall having an inner surface facing the lumen, an outer surface, and a coating set on the inner surface, the coating set comprising a barrier film or layer of SiOx, where x is 1.5 to 2.9 as measured by XPS, and optionally a tie film or layer of SiOxCy or SiNxCy, where x is approximately 0.5 to 2.4 and y is approximately 0.6 to 3, these respectively as measured by XPS, and a pH protective film or layer of SiOxCy or SiNxCy, where x is approximately 0.5 to 2.4 and y is approximately 0.6 to 3, these respectively as measured by XPS, and at least one or both of the pH protective film or layer, the container is made of cyclic block copolymer (CBC) resin, and the oxygen permeability of the container wall (d -1 The above-described Container is intended in any embodiment, wherein the coefficient of The barrier film or layer may have an average thickness of less than 500 nm, optionally less than 300 nm, optionally less than 200 nm, optionally less than 150 nm, optionally less than 125 nm, optionally less than 100 nm, optionally less than 80 nm, optionally less than 60 nm, optionally less than 50 nm, optionally less than 40 nm, optionally less than 30 nm, optionally less than 25 nm, optionally less than 20 nm, optionally less than 15 nm, and optionally less than 10 nm.

[0044] The container has a lumen at least partially defined by a plastic wall, the plastic wall having an inner surface facing the lumen, an outer surface, and a coating set on the inner surface, the coating set being a barrier coating or layer of SiOx, where x is 1.5 to 2.9 as measured by XPS, and optionally a tie coating or layer of SiOxCy or SiNxCy, where x is approximately 0.5 to 2.4 and y is approximately 0.6 to 3, these being measured by XPS, and a pH protective coating or layer of SiOxCy or SiNxCy, where x is approximately 0.5 to 2.4. The values ​​are such that y is approximately 0.6 to approximately 3, and these each include at least one or both of the pH protective film or layer, which is measured by XPS, and the SiOx barrier film or layer has an average thickness of less than 200 nm, optionally less than 150 nm, optionally less than 125 nm, optionally less than 100 nm, optionally less than 80 nm, optionally less than 60 nm, optionally less than 50 nm, optionally less than 40 nm, optionally less than 30 nm, optionally less than 25 nm, optionally less than 20 nm, optionally less than 15 nm, and optionally less than 10 nm, and the oxygen permeability of the container wall (d -1 The above-described Container is intended in any embodiment such that the coefficient of

[0045] In any embodiment, the above-described vessel is intended to include a member selected from the group consisting of the following:

[0046] Biologics Abatacept; Absiximab; Avobotulinum toxin A; Adalimumab; Adalimumab-adaz; Adalimumab-adbm; Adalimumab-afzb; Adalimumab-atto; Adalimumab-bwwd; Ado-trastuzumab emtansine; Aflibercept; Agalsidase beta; Albiglutide; Chromated CR51 serum albumin; Aldesleukin; Alefacept; Alemtuzumab; Alglucosidase alfa; Alirocumab; Alteplase; Anakinra; Aprotinin; Asfotase alfa; Asparaginase; Asparagi Naze erwinia chrysanthemum; atezolizumab; avelumab; basiliximab; becaprelmin; belatacept; belimumab; benralizumab; belacant; bevacizumab; bevacizumab-awwb; bevacizumab-bvzr; bezlotoxumab; blinatumomab; brentuximab vedotin; brodalumab; brolucizumab-dbll; brosumab-twza; caraspargaze pegol-mknl; calfactant; canakinumab; capracizumab-yhdp; capromab pendetide; semiprimab-rwlc; senegermin-bkbj; cell Liponase alfa; certolizumab pegol; cetuximab; coligonadotropin alfa; chorionic gonadotropin; chymopapain; collagenase; collagenase Clostridium histolyticum; corticollein oubaiin triflutate; chryzanlizumab-tmca; dacrizumab; daratumumab; daratumumab and hyaluronidase-fihj; darbepoetin alfa; denileukin difutitox; denosumab; decilidine; dinutuximab; dorunase alfa; dorotrecogin alfa; dulaglutide; dupilumab; durvalumab Ecalantid; Eculizumab; Ephalizumab; Elapegademase-lvlr; Elosulfase alfa; Elotuzumab; Emapalmab-lzsg; Emicizumab-kxwh; Enfortumab vedotin-ejfv; Epoetin alfa; Epoetin alfa-epbx; Erenumab-aooe; Etanercept; Etanercept-szzs; Etanercept-ykro; Evolocumab; Fam-trastuzumab deruxtecan-nxki; Fibrinolysin and deoxyribonuclease mixture with chloramphenicol [bovine]; Filgrastim;Filgrastim-aafi; Filgrastim-sndz; Folitropin alfa; Folitropin beta; Fremanezumab-vfrm; Galcanezumab-gnlm; Galsulfase; Gemtuzumab ozogamicin; Glucarpidase; Golimumab; Guselkumab; Hyaluronidase; Human hyaluronidase; Ibalizumab-uiyk; Ibritumomab tiuxetan; Idarucizumab; Idursulfase; Imiglucerase; Incobotulinum toxin A; Innebilizumab-cdon; Infliximab; Infliximab-abda; Inflix Simab-AXXQ; Infliximab-DYYB; Infliximab-QBTX; Inotuzumab Ozogamicin; Insulin Aspart; Insulin Aspart Protamine / Insulin Aspart; Insulin Degludec; Insulin Degludec / Insulin Aspart; Insulin Degludec / Liraglutide; Insulin Detemir; Insulin Glargine; Insulin Glargine / Lixisenatide; Insulin Glurisine; Human Insulin; Human Isofenzyme Insulin; Human Isofenzyme Insulin / Human Insulin; Insulin Lispro; Insulin Lis Proprotamine, insulin lispro; insulin lispro-aabc; interferon alfa-2a; interferon alfa-2b; interferon alfacon-1; interferon alfa-n3 (derived from human leukocytes); interferon beta-1a; interferon beta-1b; interferon gamma-1b; ipilimumab; isatuximab-irfc; ixekizumab; lanadermab-flyo; laronidase; lixisenatide; ruspatercept-aamt; mecasermin; mecasermin linfaber; menotropins; Mepolizumab; Methoxypolyethylene glycol epoetin beta; Metreleptin; Mogamulizumab-kpkc; Moxetumomab pasudotox-tdfk; Muromanab-CD3; Natalizumab; Necitumumab; Nivolumab; Technetium; Oviltoxakimab; Obinutuzumab; Ocrelizumab; Ocliplasmin; Ofatumumab; Oralatumab; Omalizumab; Onabotulinum toxin A; Oprelbequin; Palifermin; Palivizumab; Pancrelipase; Panitumumab; Parathyroid hormone; Bovine pegademase;Pegaspargase; Pegfilgrastim; Pegfilgrastim-apgf; Pegfilgrastim-bmez; Pegfilgrastim-cbqv; Pegfilgrastim-jmdb; Peginterferon alfa-2a; Peginterferon alfa-2a and ribavirin; Peginterferon alfa-2b; Peginterferon alfa-2b and ribavirin; Peginterferon beta-1a; Pegroticase; Pegvariase-pqpz; Pegvisomant; Pembrolizumab; Pertuzumab; Polatuzumab vedotin-piiq; Polactant alfa; Prabotulinum toxin A-xvfs; Radiolabeled albumin technetium Tc -99m Albumin Colloid Kit; Ramucirumab; Ranibizumab; Rasburicase; Rabrizumab-CWVZ; Laxibakumab; Resulizumab; Leteplase; Rilonacept; Botulinum Toxin Type B; Risankizumab-RZAA; Rituximab; Rituximab and Human Hyaluronidase; Rituximab-ABBS; Rituximab-PVVR; Romiplostim; Romosozumab-AQQG; Sacituzumab Govitecan-HZIY; Sacrosidase; Sarglamostim; Sarirumab; Seberipase Alfa; Secukinumab; Siltuximab; Somatropin; Tagraxofusp-ERZS; Taliglucerase Alfa; TBO-Filgrastim; Technetium 99m tcphanoresomab; tenecteplase; teprotumumab-trbw; tesamorelin acetate; human thyrotropin alpha; tildrakizumab-asmn; tocilizumab; tocitumomab and iodine I-131 tocitumomab; trastuzumab; trastuzumab and hyaluronidase-oysk; rastuzumab-anns; rastuzumab-dkst; rastuzumab-dttb; rastuzumab-pkrb; rastuzumab-qyyp; urophorit Ropin; Urokinase; Ustekinumab; Vedolizumab; Veraglycerase alfa; Bestronidase alfa-vjbk; Ziv-Aflibercept; Amjevita (adalimumab-atto); Dupixent (dupilumab); Fulphila (pegfilgrastim-jmdb); Ilaris (canakinumab); Ixifi (infliximab-qbtx); Lyumjev (insulin lispro-aabc);Nyvepria (pegfilgrastim-apgf); Ogivri (trastuzumab-dkst); Semglee (insulin glargine); Uplizna (inebilizumab-cdon); APL (human chorionic gonadotropin); Abrillada (adalimumab-afzb); Accretropin (somatropin); Actemra (tocilizumab); Acthrel (corticolin oubintriflutate); Actimmune (interferon gamma-1b); Activase (alteplase); Adagen (bovine peg) Ademase); Adakveo (Cryzanlizumab-tmca); Adcetris (Brentuximab Vedotin); Adlyxin (Lixisenatide); Admelog (Insulin Lispro); Afrezza (Human Insulin); Aimovig (Erenumab-aooe); Ajovy (Fremanezumab-vfrm); Aldurazyme (Laronidase); Alferon N Injection (Interferon Alpha-n3 (Human Leukocyte Derived)); Amevive (Alefacept); Amphadase (Hyaluronidase); Anthim (Obi Lutoxaximab; Apidra (insulin glulisine); Aranesp (darbepoetin alfa); Arcalyst (lilonacept); Arzerra (ofatumumab); Asparlas (caraspargaze pegol-mknl); Avastin (bevacizumab); Avonex (interferon beta-1a); Avsola (infliximab-axxq); Basaglar (insulin glargine); Bavencio (avelumab); Benlysta (belimumab); Beovu (brolucizumab-dbll); Besp onsa (Inotuzumab ozogamicin); Betaseron (Interferon beta-1b); Bexxar (Tositumomab and Tositumomab iodine I-131); Blincyto (Blinatumomab); Botox (Onabotulinum toxin A); Botox Cosmetic (Onabotulinum toxin A); Bravelle (Urofolitropin); Brineura (Cerliponase alfa); Cabrivi (Caplacizumab-yhdp); Campath (Alemtuzumab); CathfloActivase (Alteplase);Cerezyme (imiglucerase); Chorionic Gonadotropin (human chorionic gonadotropin); Chromalbin (chromium-oxidized CR51 serum albumin); Chymodiactin (chymopapain); Cimzia (certolizumab pegol); Cinqair (resulizumab); Cosentyx (secukinumab); Cotazym (pancrelipase); Creon (pancrelipase); Crysvita (brosumab-twza); Curosurf (polactant alfa); Cyltezo (adalimumab) (adbm); Cyramza (ramucirumab); Darzalex (daratumumab); DarzalexFaspro (daratumumab and hyaluronider-fihj); DraximageMAA (kit for preparing technetium Tc-99m albumin agglutination); Dysport (avobotulinum toxin A); Egrifta (tesamorelin acetate); EgriftaSV (tesamorelin acetate); Elaprase (idursulfase); Elase-chloromycetin (fibrinolysin deoxyribonuclease) Combination drug [bovine], containing chloramphenicol); Elelyso (taliglucerase alfa); Elitek (rasburicase); Elspar (asparaginase); Elzonris (taglaxofusp-erzs); Emgality (galcanezumab-gnlm); Empliciti (elotuzumab); Enbrel (etanercept); EnbrelMini (etanercept); Enhertu (fam-trastuzumab deruxtecan-nxki); Entyvio (vedolizumab); Epogen / Procrit (epoeth Nalpha); Erbitux (Cetuximab); Erelzi (Etanercept-szzs); ErelziSensoready (Etanercept-szzs); Erwinaze (Asparaginase Erwinia chrysanthemum); Eticovo (Etanercept-ykro); Evenity (Romosozumab-aqqg); Extavia (Interferon beta-1b); Eylea (Aflibercept); Fabrazyme (Agalsidase beta); Fasenra (Benralizumab); Fiasp (Insulin aspart);Follistim (Follitropin beta); FollistimAQ (Follitropin beta); FollistimAQCartridge (Follitropin beta); Gamifant (Emapalmab-lzsg); Gazyva (Obinutuzumab); Genotropin (Somatropin); Gonal-f (Follitropin alpha); G; onal-fRFF (Folitropin alfa); Gonal-fRFFRediJect (Folitropin alfa); Granix (tbo-filgrastim); Hadlima (adalimumab-bwwd); Hemlibra (emisizumab-kxwh); Herceptin (trastuzumab); HerceptinHylecta (trastuzumab and hyaluronidase-oysk); Herzuma (trastuzumab-pkrb); Humalog insulin lispro; HumalogMix50 / 50 (insulin lispro protamine) (Insulin and Insulin Lispro); HumalogMix75 / 25 (Insulin Lispro, Protamine and Insulin Lispro); Humatrope (Somatropin); Humegon (Menotropins); Humira (Adalimumab); Humulin70 / 30 (Human Isophen Insulin and Human Insulin); HumulinN (Human Isophen Insulin); HumulinRU-100 (Human Insulin); HumulinRU-500 (Human Insulin); Hydase (Hyaluronidase); Hylenexrecombinant t (Borhyaluronidase alfa); Hyrimoz (adalimumab-adaz); Ilumya (tildrakizumab-asmn); Imfinzi (durvalumab); Increlex (mecasermin); Infasurf (calfactant); Infergen (interferon alpha-con-1); Inflectra (infliximab-dyyb); IntronA (interferon alpha-2b); Iplex (mecasermin linfaber); Iprivask (decilidine); Jeanatope (albumin iodide) I-125 kit); Jetrea (ocliplasmin); Jeuveau (prabotulinum toxin A-xvfs); Kadcyla (ado-trastuzumab emtansine); Kalbitor (ecalantide); Kanjinti (trastuzumab-anns); Kanuma (seberipase alfa); Kepivance (palifermin); Kevzara (sarilumab); Keytruda (pembrolizumab); Kineret (anakinra); Kinlytic (nasalpraze); Krystexxa (pegroticase);Lantus (insulin glargine); Lartruvo (olaratumab); Lemtrada (alemtuzumab); Leukine (salglamostim); Levemir (insulin detemir); Libtayo (semiprimab-rwlc); Lucentis (ranibizumab); Lumizyme (alglucosidase alfa); Lumoxiti (moxetumomab pasudotox-tdfk); Macrotec (kit for preparing technetium Tc-99m albumin agglutination); Megatope (iodide albumin I-131 kit); Menopur (menotropins); Mepsevii (vestronidase alfa-vjbk); Microlite (radiolabeled albumin technetium Tc-99m Albumin Colloid Kit); Mircera (Polyethylene Glycol Monomethyl Ester-Epoetin Beta); Mvasi (Bevacizumab-awwb); Myalept (Metreleptin); Mylotarg (Gemtuzumab Ozogamicin); Myobloc (Botulinum Toxin Type B); Myozyme (Alglucosidase Alpha); Myxredlin (Human Insulin); N / A (Laxibacumab); Naglazyme (Galsulfase); Natpara (Parathyroid Hormone); Neulasta (Pegfilgrastim); NeulastaOnpro (Pegfilgrastim); Neumega (Orelbequine); Neupogen (Filgrastim); NeutroSpec (Technetium-99m Tc-phanoresomab); Nivestym (filgrastim-aafi); Norditropin (somatropin); Novarel (human chorionic gonadotropin); Novolin 70 / 30 (human isophene insulin and human insulin); Novolin N (human isophene insulin); Novolin R (human insulin); Novolog (insulin aspart); Novolog Mix 50 / 50 (insulin aspart protamine and insulin aspart); Novolog Mix 70 / 30 (insulin aspart protamine and insulin aspart); Nplate (romiplostim); Nucala (mepolizumab); Nulojix (veratacept); Nutropin (somatropin);NutropinAQ (somatropin); Ocrevus (ocrelizumab); Omnitrope (somatropin); Oncaspar (peguaspar gauze); Ontak (denilouquin difutitox); Ontruzant (trastuzumab-dttb); Opdivo (nivolumab); Orencia (abatacept); OrthocloneOKT3 (muromanab-CD3); Ovidrel (choliogonadotropin alfa); Oxervate (senegermin-bkbj); Padcev (enforzumab vedocitr). n-ejfv); Palynziq (pegvariase-pqpz); Pancreaze (pancrelipase); Pegasys (peginterferon alfa-2a); PegasysCopegusCombinationPack (peginterferon alfa-2a and ribavirin); Pegintron (peginterferon alfa-2b); PegIntron / RebetolComboPack (peginterferon alfa-2b and ribavirin); Pergonal (menotropins); Perjeta (pertuzumab );Pertzye (pancrelipase);Plegridy (pegylated interferon beta-1a);Polivy (polatuzumab vedotin-piiq);Portrazza (necitumumab);Poteligeo (mogamulizumab-kpkc);Praluent (alirocumab);Praxbind (idarucizumab);Pregnyl (human chorionic gonadotropin);Procrit (epoetin alfa);Proleukin (aldesleukin);Prolia (denosumab);ProstaScint (capromab pendetide); Pulmolite (kit for preparing technetium Tc-99m albumin agglutination); PulmotechMAA (kit for preparing technetium Tc-99m albumin agglutination); Pulmozyme (dolnaze alfa); Raptiva (efalizumab); Rebif (interferon beta-1a); Reblozyl (ruspatercept-aamt); Regranex (becaprelmin); Remicade (infliximab); Renflexis (infliximab-abda); Reopro (absiximab);Repatha (evolocumab); Repronex (menotropins); Retacrit (epoetin alfa-epbx); Retavase (reteplase); Revcovi (erapegademase-lvlr); Rituxan (rituximab); Rituxan Hycela (rituximab and human hyaluronidase); Roferon-A (interferon alfa-2a); Ruxience (rituximab-pvvr); Ryzodeg70 / 30 (insulin degludec and insulin aspart); Saizen (somato Ropin); Santyl (collagenase); Sarclisa (isatuximab-irfc); Serostim (somatropin); Siliq (brodalumab); Simponi (golimumab); SimponiAria (golimumab); Simulect (basiliximab); Skyrizi (risankizumab-rzaa); Soliqua100 / 33 (insulin glargine and lixisenatide); Soliris (eculizumab); Somavert (pegvisomant); Stellara (ustekinumab); Strensiq (asfota) -ze alfa); Sucraid (sacrosidase); Survanta (bellactant); Sylvant (siltuximab); Synagis (palivizumab); Takhzyro (lanadelmab-flyo); Taltz (ixekizumab); Tanzeum (albiglutide); Tecentriq (atezolizumab); Tepezza (teprotumumab-trbw); Thyrogen (human thyrotropin alfa); TNKase (tenecteplase); Toujeo (insulin glargine); Trasylol (aprotinin); T razimera (trastuzumab-qyyp); Tremfya (guselkumab); Tresiba (insulin degludec); Trodelvy (sacituzumab govitecan-hziy); Trogarzo (ibalizumab-uiyk); Trulicity (dulaglutide); Truxima (rituximab-abbs); Tysabri (natalizumab); Udenyca (pegfilgrastim-cbqv); Ultomiris (ravulizumab-cwvz); Unituxin (dinutuximab); Vectibix (panitumumab);Verluma (Nofetumomab); Vimizim (Erosulfase alfa); Viokace (Panclelipase); Vitrase (Hyaluronidase); Voraxaze (Glucarpidase); VPRIV (Veraglucerase alfa); Xeomin (Incobotulinum Toxin A); Xgeva (Denosumab); Xiaflex (Collagenase Clostridium histolyticum); Xigris (Drotrecogin alfa); Xolair (Omalizumab); Xultophy100 / 3.6 (Insulin degludecyl and Relag) Lutide; Yervoy (ipilimumab); Zaltrap (Ziv-aflibercept); Zarcio (filgrastim-sndz); Zenapax (daclizumab); Zenpep (pancrelipase); Zevalin (ibritumomab tiuxetan); Ziextenzo (pegfilgrastim-bmez); Zinbryta (daclizumab); Zinplava (bezlotoxumab); Zirabev (bevacizumab-bvzr); Zomacton (somatropin); Zorbtive / Serostim (somatropin);mRNA containing any one or more of the following: mRNA-1647, mRNA-1653, mRNA-1893, mRNA-1345, mRNA-1851, mRNA-1944, mRNA-4157, mRNA-5671, mRNA-2416, mRNA-2752, MEDI1191, AZD8601, mRNA-3927, mRNA-1010, mRNA-1020, mRN A-1030, mRNA-1273, mRNA-1273.351 / -211, mRNA-1283, mRNA-1189, mRNA-1644, mRNA-1574, mRNA-0184 , mRNA-6981, mRNA-6231, mRNA-1215, mRNA-3705, mRNA-3283, mRNA-3745, BNT111, BNT112, BNT113, BNT 114, BNT115, BNT116, RO7198457 (BNT1223), SAR441000 (BNT131), BNT141, BNT142, BNT151, BNT152, BNT153, BNT211, BNT212, BNT221 (NEO-PTC-01), Gen1046 (BNT311), Gen1042 (BNT312), BNT321 (MVT-5873), BNT411, BNT161, BNT162, or BNT171; short interfering RNA (siRNA); microRNA (miRNA); CRISPR-based therapies, e.g., therapies containing Cas9 nuclease (enzyme) and one or more single guide RNAs (sgRNAs); plasmids, i.e., DNA-based molecules containing specific protein-coding transgenes; nonplasmids; DNA; one or more proteins or peptides; for example, antisense oligonucleotides (ASOs) including gapmer-based or mixed-mer-based ASOs; micronuclear RNA (U-RNA); micronucleolar RNA (snoRNA); Piwi-binding RNA (piRNA); repeat-associated siRNA (rasiRNA); ribosomal DNA-derived small RNA (srRNA); transfer RNA-derived small RNA (tsRNA); ribosomal RNA-derived small RNA (rsRNA); long non-coding RNA-derived small RNA (lncsRNA); messenger RNA-derived small RNA (msRNA); small hairpin RNA (shRNA); dicer-dependent siRNA (di-siRNA); double-stranded RNAs (dsRNA); single-stranded RNAi (ssRNAi); DNA-directed RNA interference (ddRNAi); RNA-activated oligonucleotides (RNAa); exon-skipping oligonucleotides;

[0047] Inhaled anesthetics Aliflurane; chloroform; cyclopropane; desflurane (Suprane); diethyl ether; enflurane (Ethrane); ethyl chloride; ethylene; halothane; isoflurane (Forane, Isoflo); isopropenyl vinyl ether; methoxyflurane; methoxyflurane; methoxypropane; nitrous oxide; loflurane; sevoflurane (Sevorane, Ultane, Sevoflo); teflurane; trichloroethylene; vinyl ether; xenon;

[0048] Injectable drug Ablavar (Gadophosbecet trisodium injection); Abarelix Depot; Avobotulinum toxin A injection (Dysport); ABT-263; ABT-869; ABX-EFG; Accretropin (Somatropin injection); Acetadote (Acetylcysteine ​​injection); Acetazolamide injection (Acetazolamide injection); Acetazolamide injection (Acetadote); Actemra (Tocilizumab injection); Acthrel (Corticolerin oubaiintriflutate for injection); Actumune; Activase; Acyclovir for injection (Zovirax injection); Adacel; Adalimumab; Adenoscan (Adenosine injection) Injectable drugs; Adenosine injection (Adenoscan); Adrenaclick; AdreView (Yobenguan I123 intravenous injection); Afluria; Ak-Fluor (Fluorescein injection); Audrazyme (Laronidase); Alglucerase injection (Ceredes); Alkeran injection (Melphalan HCl injection); Allopurinol sodium for injection (Aloprim); Aloprim (Allopurinol sodium for injection); Alprostadil; Alsuma (Sumatriptan injection); ALTU-238; Amino acid injection; Aminosyn; Apidra; Apremilast; Alprostadil dual chamber system for injection (Caverject) Impulse);AMG009;AMG076;AMG102;AMG108;AMG114;AMG162;AMG220;AMG221;AMG222;AMG223;AMG317;AMG379; AMG386;AMG403;AMG477;AMG479;AMG517;AMG531;AMG557;AMG623;AMG655;AMG706;AMG714;AMG745;AMG785;AM G811; AMG827; AMG837; AMG853; AMG951; Amiodarone HCl injection (Amiodarone HCl injection); Amobarbital sodium injection (Amytal sodium); Amytal sodium (Amobarbital sodium injection); Anakinra; Anti-Abeta; Anti-Beta7; Anti-Beta20; Anti-CD4; Anti-CD20; Anti-CD40;Anti-IFNalpha; Anti-IL13; Anti-OX40L; Anti-oxLDS; Anti-NGF; Anti-NRP1; Arixtra; Amphadase (Hyaluronidase Injection); Ammonul (Sodium Phenylacetate and Sodium Benzoate Injection); Anaprox; Anzemet Injection (Dracetron Mesylate Injection); Apidra (Insulin Glucisine [rDNA Derived] Injection); Apomab; Aranesp (Darbepoetin Alpha); Argatroban (Argatroban Injection); Arginine Hydrochloride Injection (R-Gene10); Aristospan; Arsenic Trioxide Injection (Trisenox); Articane HCl (Articane HCl) and epinephrine injection (Septocaine); Arzera (ofatumumab injection); Asclera (polidocanol injection); Atallen; Atallen-DMD; Atenolol injection (Tenormin IV injection); Atracurium besylate injection (Atracurium besylate injection); Avastin; Azactam injection (Aztreonam injection); Azithromycin (Zithromax injection); Aztreonam injection (Azactam injection); Baclofen injection (Lioresal intrathecal injection); Bacteriostatic water (Bacteriostatic water for injection); Baclofen injection (Lioresal intrathecal injection); Bal in Oil Ampules (Dimercarprol injection); BayHepB; BayTet; Benadryl; Bendamustine hydrochloride injection (Treanda); Benztropine mesylate injection (Cogentin); Betamethasone suspension injection (Celestone Soluspan); Bexal; Bicillin C-R900 / 300 (Penicillin G benzathine and Penicillin G procaine injection); Blenoxan (Bleomycin sulfate injection); Blenoxan (Bleomycin sulfate injection); Boniva injection (Ibandronate sodium injection); Botox Cosmetic (Botulinum toxin A for injection); BR3-FC; Bravelle (Urophoretropin injection); Bretilium (Bretylium tosylate injection); Brevital sodium (Methhexital sodium for injection); Brethine; Briobacept; BTT-1023; Bupivacaine HCl; Byetta;Ca-diethylenetriaminepentaacetic acid (calcium trisodium pentetate injection); cabazitaxel injection (jevtana); caffeine alkaloid (caffeine and sodium benzoate injection); calcigex injection (calcitriol); calcitriol (calcigex injection); calcium chloride (calcium chloride injection 10%); calcium disodium bersenate (calcium disodium edetate injection); Campus (altemtuzumab); Camptosar injection (irinotecan hydrochloride); canakinumab injection (iraris); capastat sulfate (capreomycin for injection); capreomycin for injection (capastat sulfate); cardiolite (technetium Tc99 cestamibi preparation kit for injection (Prep kit)); Carticel; Cathflo; Cefazolin and glucose for injection (Cefazolin injection); Cefepime hydrochloride; Cefotaxime; Ceftriaxone; Cerezyme; Carnitor injection; Caverject; Celestone Soluspan; Celsior; Cerebyx (Fosphenytoin sodium injection); Ceredese (Alglucerase injection); Ceretec (Technetium Tc99m examethadim injection); Certolizumab; CF-101; Chloramphenicol sodium succinate (Chloramphenicol sodium succinate injection); Chloramphenicol sodium succinate injection (Chloramphenicol sodium succinate); Cholestagel (Coleseveram HCl); Chlorogenic gonadotropin alpha injection (Ovidrel); Cimzia; Cisplatin (Cisplatin injection); Chloral (Clofarabine injection); Clomiphine citrate Citrate; Clonidine injection (Duraclon); Cogentin (Benztropine mesylate injection); Coly-Mycin M injection; Coly-Mycin M injection; Compath; Conivaptan HCl injection (Vaprisol); Conjugated estrogen for injection (Premarin injection); Copaxone; Corticorin oubaiintriflutate for injection (Acthrel);Colbert (ibutylide fumarate injection); Cubicin (daptomycin injection); CF-101; Cyanokit (hydroxocobalamin injection); cytarabine liposomal injection (Depotyte); cyanocobalamin; Cytoben (ganciclovir); DHE45; dasetuzumab; Dacogen (decitabine injection); dalteparin; Dantrium IV (dantrolene sodium injection); dantrolene sodium injection (Danttrium IV); daptomycin injection (Cubicin); darbepoetin alfa; DDAVP injection (desmopressin acetate injection); Decavax; decitabine injection (Dacogen); anhydrous alcohol (anhydrous alcohol injection); denosumab injection (Prolia); delatestril; delestrone; delteparin sodium; Depacon (sodium valproate injection); Depomelodol (methylprednisolone acetate suspension injection); Deposite (cytarabine liposomal injection); Depodul (morphine sulfate XR liposomal injection); Desmopressin acetate injection (DDAVP injection); Depoestradiol; Depopropera 104 mg / ml; Depopropera 150 mg / ml; Depotestosterone; Dexrazoxane for injection, intravenous only (Totect); Glucose / electrolytes; Glucose and sodium chloride injection (5% glucose in 0.9% sodium chloride); Glucose; Diazepam injection (diazepam injection); Digoxin injection (lanoxin injection); Dilaud-HP (hydromorphone hydrochloride injection); Dimercarprol injection (Bal in Oil Ampules); Diphenhydramine Injection (Benadryl Injection); Dipyridamole Injection (Dipyridamole Injection); DMOAD; Docetaxel Injection (Taxotere); Dracetron Mesylate Injection (Anzemet Injection); Doribax (Doripenem Injection); Doripenem Injection (Doribax); Doxelcalciferol Injection (Hectorol Injection); Doxil (Doxorubicin HCl Liposome Injection); Doxorubicin HCl Liposome Injection (Doxil); Duraclon (Clonidine Injection); Duramorph (Morphine Injection); Dysport (Avobotulinum Toxin A Injection); Ecalantide Injection (Kalbitor);EC-Naprosin (Naproxen); Calcium disodium edetate injection (Calcium disodium bersenate); Edex (Alprostadil for injection); Engerix; Edrophonium injection (Enlon); Eliglustat Tartate); Eloxatin (Oxaliplatin injection); Emend injection (Fosaprepitant dimeglumine injection); Enalaprilat injection (Enalaprilat injection); Enlon (Edrophonium injection); Enoxaparin sodium injection (Labnox); Eovist (Gadoxetate disodium injection); Enbrel (Etanercept); Enoxaparin; Epicel; Epinepherine; EpiPen; EpiPen Jr.; Epiratuzumab; Erbitux; Ertapenem injection (Invanz); Erythropoieten; Essential amino acid injection (Nephramine); Estradiol cypionate; Estradiol valerate; Etanercept; Exenatide injection (Byetta); Evlotra; Fabrazyme (Adalsidase beta) beta); Famotidine injection; FDG (Fludeoxyglucose F18 injection); Ferrahem (Fermoxytol injection); Feridex IV (Fermoxides injection solution); Fertinex; Fermoxides injection solution (Feridex IV); Fermoxytol injection (Ferahem); Flagyl injection (Metronidazole injection); Fluarix; Fludara (Fudarabine phosphate); Fludeoxyglucose F18 injection (FDG); Fluorescein injection (Ak-Fluor); Follistim AQ cartridge (Follitropin beta injection); Follitropin alpha injection (Gonal-f RFF); Follitropin beta injection (Follistim AQ cartridge); Forotin (Pralatrexate solution for intravenous injection); Fondaparinux; Forteo (Teriparatide (rDNA-derived) injection); Fostamatinib; Fosaprepitant dimeglumine injection (Emend injection); Fosphenytoin sodium injection (Foscavir); Foscavir (Fosphenytoin sodium injection);Fosphenytoin sodium injection (Cerebyx); fospropofol disodium injection (Lusedra); Fragmin; Fuzeon (Enfvirtide); GA101; gadopentate meglumine injection (Multihance); gadophosveset trisodium injection (Ablavar); gadoteridol injection solution (Prohance); cadvercetamide injection (Opti; MARK); Gadoxetate disodium injection (Eovist); Ganirelix (Ganirelix acetate injection); Gardasil; GC1008; GDFD; Gemtuzumab ozogamicin for injection (Mylotarg); Genotropin; Gentamicin injection; GENZ-112638; Golimumab injection (Simponi injection); Gonal-f RFF (Follitropin alpha injection); Granisetron hydrochloride (Kytril injection); Gentamicin sulfate; Gratilama - Acetate; Glucagen; Glucagon; HAE1; Haldol (haloperidol injection); Havrix; Hectorol injection (doxelcalciferol injection); Hedgehog pathway inhibitor; Heparin; Herceptin; hG-CSF; Humalog; Human growth hormone; Humatrope; HuMax; Humegon; Humira; Humulin; Ibandronate sodium injection (Boniva injection); Ibuprofen lysin injection (NeoProfe n); Ibutylide fumarate injection (Colbert); Idarubicin PFS (idarubicin hydrochloride injection); Idarubicin hydrochloride injection (idarubicin PFS); Ilaris (canakinumab injection); Imipenem and cilastatin for injection (Primaxin IV); Imitrex; Incobotulinum toxin A for injection (Xeomin); Increlex (Mecasermin [rDNA derived] injection); Indacin IV (Indomethacin injection); Indomethacin injection (Indacin IV); Infanrix; Inohep; Insulin; Insulin aspart [rDNA derived] injection (NovoLog); Insulin glargine [rDNA derived] injection (Lantus); Insulin glulisine [rDNA derived] injection (Apidra); Interferon alpha-2b, recombinant for injection (Intron A); Intron A (Interferon alpha-2b, recombinant for injection); Invanz (ertapenem injection); Invega Sustenna (paliperidone palmitate sustained-release suspension injection); Invirase (saquinavir mesylate); Yobenguan I123 intravenous injection (AdreView); Iopromide injection (Ultravist); Ioversol injection (Optiray injection); Iplex (mecasermin linfaber [rDNA derived] injection); Iprivask;Irinotecan hydrochloride (Camptosar injection); Iron oxide injection (Venofar); Istodax (for romidepsin injection); Itraconazole injection (Sporanox injection); Jevtana (cabazitaxel injection); Jonesa; Kalbitor (ecalantide injection); KCl in D5NS (Potassium Chloride in 5% Dextrose and Sodium Chloride injection); KCl in D5W; KCl in NS; Kenalog 10 injection (triamcinolone acetonide suspension injection); Kepivans (palifermin); Kepra injection (levetiracetam); Keratinocyte; KFG; Kinase inhibitor; Kineret (anakinra); Kinlytic (urokinase injection); Kinrix; Clonopine (clonazepam); Kytril injection (granisetron hydrochloride); Lacosamide tablets and injection (Vinpat); Ringer's lactate solution; La Noxine injection (digoxin injection); lansoprazole injection (prevacid IV); lantus; leucovorin calcium (leucovorin calcium injection); lente (L); leptin; levemir; leukain salglamostim; leuprolide acetate; levothyroxine; levetiracetam (keppra injection); labunox; levocarnitine injection (Carnitor injection); lexcan (legadenoson injection); liorexin Searle intrathecal injection (baclofen injection); liraglutide [rDNA] injection (Victoza); Labnox (enoxaparin sodium injection); Lucentis (ranibizumab injection); Lumizyme; Lupron (leuprolide acetate injection); Lusedra (fospropofol disodium injection); Maci; magnesium sulfate (magnesium sulfate injection); mannitol injection (mannitol IV); Marcaine (bupivacaine hydrochloride and epinephrine injection); Maxipime (cefepime hydrochloride injection); Technetium injection MDP multidose kit (technetium Tc99m medronate injection); mecasermin [rDNA derived] injection (Increlex); mecasermin linfaber [rDNA derived] injection (Iplex); melphalan HCl injection (Alkeran injection); methotrexate;Menactra; Menopur (Menotropins injection); Menotropins for injection (Repronex); Metohexital sodium for injection (Brevital sodium); Methyldopert hydrochloride injection, solution (Methyldopert HCl); Methylene blue (Methylene blue injection); Methylprednisolone acetate suspension injection (Depomelodol); MetMab; Metoclopramide injection (Reglan injection); Metrodin (Urophoretropin injection); Metronidazole injection (Flagyl injection); Miacalcin; Midazolam (Midazolam injection); Minpara (Cinacalet); Minosin injection (Minocycline injection); Minosin injection (Minosin injection); Mipomersen; Mitoxa Novantrone Injection Concentrate (Novantrone); Morphine Injection (Duramorph); Morphine Sulfate XR Liposome Injection (Depodul); Sodium Molinate (Sodium Molinate Injection); Motesanib; Mozovir (Prelixafor Injection); Multihance (Gadobenate Meglumine Injection); Polyelectrolyte and Glucose Injection; Polyelectrolyte Injection; Mylotarg (Gemtuzumab Ozogamicin for Injection); Myozyme (Alglucosidase Alpha); Nafcillin Injection (Nafcillin Sodium); Nafcillin Sodium (Nafcillin Injection); Naltrexone XR Injection (Vivitrol); Naprosin (Naproxen); NeoProfen (Ibuprofen Lysin Injection); Nandrol Decanoate; Neostigmine methylsulfate (Neostigmine methylsulfate injection); NEO-GAA; NeoTect (Technetium Tc99m depreotide injection); Nephramine (Essential amino acid injection); Neulasta (Pegfilgrastim); Neupogen (Filgrastim); Novolin; Novolog; NeoRecormon; Neutrexin (Trimethrexate gluconate injection); NPH(N); Nexterone (Amiodarone HCl injection); Norditropin (Somatropin injection); Physiological saline (Sodium chloride injection); Novantrone (Mitoxantrone concentrate for injection);Novolin 70 / 30 Innolet (70% NPH, human insulin isophene suspension and 30% regular, human insulin injection); NovoLog (insulin aspart [rDNA-derived] injection); Nplate (romiplostim); Neutropin (somatropin (rDNA-derived) for injection); Neutropin AQ; Neutropin Depot (somatropin (rDNA-derived) for injection); octreotide acetate injection (Sandostatin LAR); ocrelizumab; ofatumumab injection (Arzera); sustained-release olanzapine suspension injection (Zyprexa Relprevv); Omnitarg; Omnitrope (somatropin [rDNA-derived] injection); ondansetron hydrochloride injection (Zofran injection); OptiMARK (cadvercetamide injection); Optiray injection (iobersol injection); Orencia; Osmitrol injection, Aviva (mannitol injection, Aviva plastic drug); Osmitrol injection, Viaflex (mannitol injection, Viaflex plastic drug); osteoprotegrin; Ovidrel (human chorionic gonadotropin alpha injection); oxacillin (oxacillin for injection); oxaliplatin injection (eloxatin); oxytocin injection (pitosin); paliperidone palmitate sustained-release suspension injection (Invega Sustenna); Pamidronate disodium injection (Pamidronate disodium injection); Panitumumab for injection (Vectibix); Papaverine hydrochloride injection (Papaverine injection); Papaverine injection (Papaverine hydrochloride injection); Parathyroid hormone; Palicalcitol injection flip-top vial (Zemplar injection); PARP inhibitors; Pediarix; PegIntron; Peginterferon; Pegfilgrastim; Penicillin G benzathine and Penicillin G procaine; Calcium trisodium pentetate injection (Ca-diethylenetriaminepentaacetic acid); Zinc trisodium pentetate injection (Zn-diethylenetriaminepentaacetic acid); Pepsid injection (Famotidine injection); Pergonal; Pertuzumab; Pentolamine mesylate (Pentolamine mesylate for injection); Physostigmine salicylate (Physostigmine salicylate (injectable));Physostigmine salicylate (injectable); Piperacillin and tazobactam injection (Zosyn); Pitosin (oxytocin injection); Plasma-Lyte 148 (polyelectrolyte injection); Plasma-Lyte 56 and glucose (polyelectrolyte and glucose injection, Viaflex plastic drug packaging); PlasmaLyte; Prelixafor injection (Mozovir); Polidocanol injection (Asclera); Potassium chloride; Pralatrexate solution for intravenous injection (Forotin); Pramulintide acetate injection (Symlin); Premarin injection (conjugated estrogen for injection); Preparation kit for technetium Tc99 cestamivi for injection (Prep kit) (Cardiolite); Prevacid IV (Lansoprazole for injection); Primaxin IV (Imipenem and cilastatin for injection); Prochymal; Procrit; Progesterone; Prohans (Gadoteridol injection solution); Prolia (Denosumab injection); Promethazine HCl injection (Promethazine hydrochloride injection); Propranolol hydrochloride injection (Propranolol hydrochloride injection); Quinidine gluconate injection (Quinidine injection); Quinidine injection (Quinidine gluconate injection); R-Gene10 (Arginine hydrochloride injection); Ranibizumab injection (Lucentis); Ranitidine hydrochloride injection (Zantac injection); Raptiva; Reclast (Zoledronic acid injection); Recombivarix HB; Legadenoson injection (Lexcan); Reglan injection (Metoclopramide injection); Remicade; Renagel; Renvela (Sevelamer carbonate); Repronex (Menotropins injection); Retrovir IV (Zidovudine injection); rhApo2L / TRAIL; Ringer's solution and 5% glucose injection (Ringer's solution with glucose); Ringer's solution; Rituxan; Rituximab; Rocephin (Ceftriaxone); Rocuronium bromide injection (Zemuron); Roferon-A (Interferon alpha-2a); Romazicon (Flumazenil); Romidepsin injection (Istodax); Saizen (Somatropin injection); Sandostatin LAR (Octreotide acetate injection); Sclerostin Ab; Sensipar (Cinacalcet);Sensorcaine (bupivacaine HCl injection); Septocaine (articane HCl and epinephrine injection); Serostim LQ (somatropin (rDNA-derived) injection); Simponi injection (golimumab injection); sodium acetate (sodium acetate injection); sodium bicarbonate (5% sodium bicarbonate injection); sodium lactate (sodium lactate injection); Thorium injection, AVIVA); Sodium phenylacetate and sodium benzoate injection (Ammonul); Somatropin (rDNA-derived) injection (Neutropin); Sporanox injection (Itraconazole injection); Stelara injection (Ustekinumab); Stemgen; Sufenta (Sufentanyl citrate injection); Sufentanyl citrate injection (Sufenta); Sumavel; Sumatriptan injection (Alsuma); Symlin; Symlin Pen; Systemic Hedgehog (Systemic Hedgehog antagonist; Synvisc-One (Hylan G-F20 single intra-articular injection); Tarceva; Taxotere (Docetaxel injection); Technetium Tc99m; Teravancin injection (Vibative); Temsirolimus injection (Torisel); Tenormin IV injection (Atenolol injection); Teriparatide (rDNA-derived) injection (Forteo); Testosterone cypionate; Testosterone enanthate; Testosterone propionate; Tev-Tropin (Somatropin, rDNA-derived, for injection); tgAAC94; Thallium chloride; Theophylline; Thiotepa (Thiotepa injection); Thymoglobulin (Antithymocyte immunoglobulin (rabbit)); Thyrogen (Thyrotropin alpha injection); Ticalcillin sodium and clavulanate potassium Galaxy (Ga laxy) (Timentine injection); Tigan injection (Trimethobenzamide hydrochloride injectable); Timentine injection (Ticalcillin sodium and clavulanate potassium Galaxy); TNKase; Tobramycin injection (Tobramycin injection); Tocilizumab injection (Actemra); Torisel (Temsirolimus injection); Totect (Dexrazoxane for injection, intravenous only); Trastuzumab-DM1; Travasol (Amino acid (injectable)); Treanda (Bendamustine hydrochloride injection); Torelstar (Triptrelympamoate suspension injection); Triamcinolone acetonide; Triamcinolone acetate; Triamcinolone hexaacetonide suspension injection (Aristospan injection 20 mg); Triesence (Triamcinolone acetonide suspension injection);Trimethobenzamide hydrochloride (injectable) (Tigan injection); Trimethrexate gluconate injection (Neutrexin); Triptrelympamoate suspension injection (Torelstar); Twinject; Trivaris (Triamcinolone acetonide suspension injection); Trisenox (Arsenic trioxide injection); Twinrix; Typhoid Vi; Ultravist (Iopromide injection); Urofollicularin injection (Metrodin); Urokinase injection (Kinlytic); Ustekinumab (Stelara injection); Ultralente (U); Barium (diazepam); Sodium valproate injection (Depacon); Valtropin (somatropin injection); sodium valproate (sodium valproate injection); sodium valproate injection (sodium valproate); vaprizol (conivaptan HCl injection); VAQTA; vasovist (gadophosbecet trisodium for intravenous injection); vectibix (panitumumab for intravenous injection); venofar (ferric glucose injection); verteporfin injection (visudine); vivative (teravancin injection); victoza (liraglutide [rDNA] injection); vinpat (lacosamide tablets and injection); vinblastine sulfate (vinblastine sulfate injection); Vincasar PFS (Vincristine Sulfate Injection); Victoza; Vincristine Sulfate (Vincristine Sulfate Injection); Visudyne (Verteporfin Injection); Vitamin B-12; Vivitrol (Naltrexone XR Injection); Voluben (Hydroxyethyl Starch in Sodium Chloride) Chloride injection); Xeloda; Xenical (Orlistat); Xeomin (Incobotulinum toxin A injection); Xolair; Zantac injection (Ranitidine hydrochloride injection); Zemplar injection (Paricalcitol injection flip-top vial); Zemuron (Rocuronium bromide injection); Zenapax (Daclizumab); Zevalin; Zidovudine injection (Retrovir IV); Zithromax injection (Azithromycin); Zn-Diethylenetriaminepentaacetic acid (Zinc trisodium pentetate injection); Zofran injection (Ondansetron hydrochloride injection); Zingo;Zoledronic acid for injection (Zometa); Zoledronic acid injection (Reclast); Zometa (Zoledronic acid for injection); Zosyn (piperacillin and tazobactam injection); Zyprexa Relprevv (sustained-release olanzapine suspension injection);

[0049] Liquid formulation (non-injectable) Abilify; AccuNeb (albuterol sulfate inhalation solution); Actidose Aqua (medicinal charcoal suspension); Medicinal charcoal suspension (Actidose Aqua); Advere; Agenerase oral solution (amprenavir oral solution); Akten (lidocaine hydrochloride ophthalmic gel); Alamast (pemilorast potassium eye drops); Albumin (human) 5% solution (Buminate 5%); Albuterol sulfate inhalation solution; Alinia; Alocril; Alphagan; Alrex; Alvesco; Amprenavir oral solution; Analpram-HC; Alformoterol tartrate inhalation solution (Brovana); Aristospan injection 20 mg (triamcinolone hexaacetonide suspension injection) Asacol; Azmanex; Astepro; Astepro (azelastine hydrochloride nasal spray); Atrovent nasal spray (ipratropium bromide nasal spray); Atrovent nasal spray 0.06; Augmentin ES-600; Azasite (azithromycin eye drops); Azelaic acid (Finacea gel); Azelastine hydrochloride nasal spray (Astepro); Azelex (azelaic acid cream); Azopt (brinzolamide suspension eye drops); Bacteriostatic saline; Balanced salt; Bepotastine; Bactroban nasal; Bactroban; Beclovent; Benzac W; Betimol; Betoptic S; Bepreve; Bimatoprost eye drops; Bleph 10 (Sulfacetamide sodium ophthalmic solution 10%); Brinzolamide suspension ophthalmic solution (Azopt); Bromfenac ophthalmic solution (Xibrom); Bromhist; Brovana (Alformoterol tartrate inhalation solution); Budesonide inhalation suspension (Palmi film inhalation solution); Cambia (Diclofenac potassium oral solution); Capex; Carac; Carboxine-PSE; Carnitor; Cayston (Aztreonam inhalation solution); CellCept; Centany; Cerumenex; Ciprodex ophthalmic solution (Ciprofloxacin HCl ophthalmic solution); Ciprodex; Ciprofloxacin HCl ophthalmic solution (Ciloxan ophthalmic solution); Clemastine fumarate syrup (Clemastine fumarate syrup); CoLyte (PEG electrolyte solution);Combiven; Comtan; Condylox; Cordran; Cortisporin suspension eye drops; Cortisporin ear suspension; Cromolyn sodium inhalation solution (IntalNebulizer solution); Romolyn sodium eye drops (Opticrom); Crystalline Amino Acid Solution with Electrolytes (Aminosyn Electrolytes); Cutivate; Cuvposa (Glycopyrrollate oral solution); Cyanocobalamin (CaloMist nasal spray); Cyclosporine oral solution (Gengraf oral solution); Cyclozil; Cysview (Hexaminolevulinate hydrochloride intravesical solution); DermOtic oil (Fluocinolone acetonide oil ear drops) Drops); Desmopressin acetate nasal spray; DDAVP; Derma-Smoothe / FS; Dexamethasone Intensol; Dianyl hypocalcium; Dianyl PD; Diclofenac potassium oral solution (Cambia); Didanosine pediatric powder oral solution (Videx); Differin; Dirantin 125 (phenytoin oral suspension); Ditropan; Dorzolamide hydrochloride eye drops (Trusopt); Dorzolamide hydrochloride-timolol maleate eye drops (Cosopt); Dovonex Scalp (calcipotriene solution); Doxycycline calcium oral suspension (Vibramycin oral); Efudex; Elaprace (idursulfase solution); Elestat (Epinastine HCl eye drops); Elocon; Epinastine HCl eye drops (Elestat); Epivir HBV; Epogen (Epoetin alfa); Erythromycin topical solution 1.5% (Staticin); Ethiodol (Ethiodized oil); Ethosuximide oral solution (Zarontin oral solution); Oylax; Extranal (Icodexistrin peritoneal dialysis solution); Felbatol; Feridex IV (Fermoxides injectable solution); Flovent; Floxin ear medicine (Ofloxacin ear solution); Flo-Pred (Prednisolone acetate oral suspension); Fluoroplex; Flunisolid nasal spray (Flunisolid nasal spray 0.025%);Fluorometholone suspension eye drops (FML); Flurbiprofen sodium eye drops (Ocufen); FML; Foradil; Formoterol fumarate inhalation solution (Perforomist); Fosamax; Fladantin (nitrofurantoin oral suspension); Floxone; Gammaguard solution (10% human immunoglobulin for intravenous injection); Gantrisin (acetylsulfisoxazole suspension for children); Gatifloxacin eye drops (Zymar); Gengraf oral solution (cyclosporine oral solution); Glycopyrrolate oral solution (Cuvposa); Halog solution (halcinonide topical solution); Halog solution (halcinonide topical solution); HEP-LOCK U / P (preservative-free heparin lock flush solution); Heparin lock flush solution (Hepflush 10); Hexaminorebrinate hydrochloride intravesical solution (Intravesical (Cysview Solution); Hydrocodone hydrogen tartrate and acetaminophen oral solution (Lortab Elixir); Hydroquinone 3% topical solution (Melquin-3 topical solution); IAP antagonist; Isopto; Ipratropium bromide nasal spray (Atrovent nasal spray); Itraconazole oral solution (Sporanox oral solution); Ketrolactromethamine eye drops (Acular LS); Kaletra; Lanoxin; Lexiva; Leuprolide acetate depot suspension (Lupron Depot 11.25 mg); Levobetaxolol hydrochloride suspension eye drops (Betaxone); Levocarnitine tablets, oral solution, sugar-free (Carnitor); Levofloxacin eye drops 0.5% (Quixin); Lidocaine HCl sterile solution (Xylocaine MPF sterile solution); Lok Pak (Flush solution for heparin lock); Lorazepam Intensol; Lortab Elixir (hydrocodone hydrogen tartrate and acetaminophen oral solution); Lotemax (loteprednol ethavone suspension eye drops); loteprednol ethavone suspension eye drops (Alrex); hypocalcium peritoneal dialysis solution (Dianyl hypocalcium); Lumigan (bimatoprost eye drops 0.03% for glaucoma); Lupron Depot 11.25 mg (leuprolide acetate depot suspension); megestrol acetate oral suspension (megestrol acetate oral suspension); MEK inhibitors; Mepron; Mesnex; Mestinon;Mesalamine Rectal Suspension Enema (Rowasa); Melquin-3 Topical Solution (Hydroquinone 3% Topical Solution); MetMab; Methyldopert HCl (Methyldopert Hydrochloride Injection, Solution); Methylin Oral Solution (Methylphenidate HCl Oral Solution 5 mg / 5 mL and 10 mg / 5 mL); Methylprednisolone Acetate Suspension Injection (Depo Melodol); Methylphenidate HCl Oral Solution 5 mg / 5 mL and 10 mg / 5 mL (Methylin Oral Solution); Methylprednisolone Sodium Succinate (Solmedrol); Metipranolol Ophthalmic Solution (Optipranolol); Migranal; Miochol-E (Acetylcholine Chloride Intraocular Solution (Intraocular) Solution)); Micro-K liquid suspension (for potassium chloride sustained-release liquid suspension); Minosin (minocycline hydrochloride oral suspension); Nasa film; Neomycin sulfate and polymyxin B sulfate and hydrocortisone; Nepafenac suspension eye drops (Nevanac); Nevanac (Nepafenac suspension eye drops); Nitrofurantoin oral suspension (Fladantin); Noxafil (posaconazole oral suspension); Nistatin (oral) (Nistatin oral suspension); Nistatin oral suspension (Nistatin (oral)); Ocufen (flurbiprofen sodium eye drops); Ofloxacin eye drops (Ofloxacin eye drops); Ofloxacin otological solution (Floxin otological medicine); Olopatadine hydrochloride eye drops (Pataday); Opticr om (Cromolin sodium eye drops); Optipranolol (Metipranolol eye drops); Patanol; Pediapred; PerioGard; Phenytoin oral suspension (Dilantin 125); Phisohex; Posaconazole oral suspension (Noxafil); Potassium chloride sustained-release liquid suspension (Micro-K liquid suspension); Pataday (Olopatadine hydrochloride eye drops); Patanase nasal spray (Olopatadine hydrochloride nasal spray); PEG electrolyte solution (CoLyte); Pemirolast potassium eye drops (Alamast); Penlac (Cyclopirox topical solution); PENNSAID (Diclofenac sodium topical solution); Perforomist (Formoterol fumarate inhalation solution); Peritoneal dialysis solution;Phenylephrine hydrochloride eye drops (Neosynephrine); Phosphorine iodide (Ecothiopart iodide eye drops); Podophyllox (Podophyllox topical solution); Pred Forte (Prednisolone acetate suspension eye drops); Pralatrexate solution for intravenous injection (Forotin); Pred Mild; Prednisone Intensol; Prednisolone acetate suspension eye drops (Pred Forte); Prevacid; PrismaSol solution (Sterile hemofiltration; Hemodiafiltration solution) Solution); Proair; Proglycem; ProHance (Gadoteridol Injection Solution); Proparacaine Hydrochloride Eye Drops (Alcaine); Propine; Palmi Film; Pulmozyme; Quixin (Levofloxacin Eye Drops 0.5%); QVAR; Rapammune; Rebetol; Relacon-HC; Rotarix (Oral Live Rotavirus Vaccine Suspension); Oral Live Rotavirus Vaccine Suspension (Rotarix); Rowasa (Mesalamine Rectal Suspension Enema); Sabril (Vigabatrin Oral Solution); Sacrosidase Oral Solution (Sucraid); Sandimmun; Sepra; Serevent Diskus; Solu-Cortef (hydrocortisone sodium succinate); Solu-Medrol (methylprednisolone sodium succinate); Spiriva; Sporanox oral solution (itraconazole oral solution); Staticin (erythromycin topical solution 1.5%); Starlix; Sterile hemofiltration (hemodiafiltration solution) (PrismaSol solution); Stimate; Sucralfate (Calafate suspension); Sulfacetamide sodium eye drops 10% (Bleph 10); Synarel nasal spray (nafarelin acetate nasal spray for endometriosis); Taclonex Scalp (calcipotriene and betamethasone dipropionate topical suspension); Tamiflu; TobraDex; Tobradex ST (tobramycin / dexamethasone suspension eye drops 0.3% / 0.05%);Tobramycin / dexamethasone suspension eye drops 0.3% / 0.05% (Tobradex ST); Timolol; Timoptic; Travatans; Treprostinil inhalation solution (Tyvaso); Trusopt (dorzolamide hydrochloride eye drops); Tyvaso (treprostinil inhalation solution); Ventolin; Vfend; Vibramycin; Oral use (Doxycycline calcium oral suspension); Videx (Didanosine for pediatric oral powder); Vigabatrin oral solution (Sabril); Viokase; Viracept; Viramune; Vitamin K1 (Vitamin K1 fluid colloidal solution); Voltaren ophthalmic medicine (Diclofenac sodium eye drops); Zarontin oral solution (Ethosuximide oral solution); Ziagen; Zyvox; Zymar (Gatifloxacin eye drops); Zymaxid (Gatifloxacin eye drops)

[0050] Types of drugs 5α-reductase inhibitors; 5-aminosalicylates; 5HT3 receptor antagonists; adamantane antiviral drugs; corticosteroids; corticosteroid inhibitors; adrenergic bronchodilators; drugs for hypertensive emergencies; drugs for pulmonary hypertension; aldosterone receptor antagonists; alkylating agents; α-adrenergic receptor antagonists; α-glucosidase inhibitors; alternative drugs; amoebicides; aminoglycosides; aminopenicillins; aminosalicylates; amylin analogs; analgesic combination drugs; analgesics; androgens and anabolic steroids; angiotensin-converting enzyme inhibitors; an Geotensin II inhibitors; anorectal preparations; appetite suppressants; antacids; anthelmintics; anti-vasogenic ophthalmic agents; anti-CTLA-4 monoclonal antibodies; anti-infective drugs; centrally acting anti-adrenergic agonists; peripherally acting anti-adrenergic agonists; anti-androgens; anti-angina drugs; antiarrhythmic drugs; anti-asthmatic combination drugs; antibiotics / antineoplastic drugs; anticholinergic antiemetics; anticholinergic antiparkinsonian drugs; anticholinergic bronchodilators; anticholinergic chronotropic drugs; anticholinergic agonists / antispasmodics; anticoagulants; anticonvulsants; antidepressants; antidiabetic drugs; antidiabetic combination drugs; antidiarrheals; antidiuretic hormones; detoxification agents; antiemetics / anti-vertigo drugs Antifungal drugs; antigonadotropins; gout treatment drugs; antihistamines; drugs for hyperlipidemia; combination drugs for hyperlipidemia; antihypertensive combination drugs; uric acid lowering drugs; antimalarial drugs; combination antimalarial drugs; quinolines for antimalarial drugs; antimetabolites; antimigraine drugs; antitumor antidotes; antitumor interferons; antitumor monoclonal antibodies; antitumor drugs; antiparkinson's drugs; antiplatelet drugs; anti-Pseudomonas penicillin drugs; antipsoriasis drugs; antipsychotic drugs; antirheumatic drugs; antiseptics and antibacterial drugs; antithyroid drugs; antitoxins and antisnake venom; antituberculosis drugs; combination antituberculosis drugs; antitussives; antiviral drugs; antiviral combination drugs; antiviral Centaferon; anxiolytics, sedatives, and hypnotics; aromatase inhibitors; atypical antipsychotics; azol antifungals; bacterial vaccines; barbiturate anticonvulsants; barbiturates; BCR-ABL tyrosinase inhibitors; benzodiazepine anticonvulsants; benzodiazepines; β-adrenergic blockers; β-lactamase inhibitors; bile acid metal ion chelating agents; biological agents; bisphosphonate preparations; bone resorption inhibitors; bronchodilator combinations; bronchodilators; calcitonin; calcium channel blockers; carbamate anticonvulsants; carbapenems; carbonic anhydrase inhibitor anticonvulsants;Carbonic anhydrase inhibitors; cardiac stressing agents; cardiac-selective beta-blockers; cardiovascular agents; catecholamines; CD20 monoclonal antibodies; CD33 monoclonal antibodies; CD52 monoclonal antibodies; central nervous system drugs; cephalosporins; earwax solution; chelating agents; chemokine receptor antagonists; chloride channel activators; cholesterol absorption inhibitors; cholinergic agonists; cholinergic muscle stimulants; cholinesterase inhibitors; central nervous system stimulants; coagulation regulators; colony-stimulating factors; contraceptives; adrenocorticotropic hormones; coumarins and indanedions; Cox-2 inhibitors; decongestants; Topical drugs; diagnostic radiopharmaceuticals; dibenzazepine anticonvulsants; digestive enzymes; dipeptidyl peptidase-4 inhibitors; diuretics; dopaminergic antiparkinsonian drugs; drugs used for alcohol dependence; echinocandin; EGFR inhibitors; estrogen receptor antagonists; estrogens; expectorants; factor Xa inhibitors; fatty acid derivative anticonvulsants; fibrinate derivatives; first-generation cephalosporins; fourth-generation cephalosporins; functional bowel disease drugs; gallstone solubilizers; GABA analogs; GABA reuptake inhibitors; GABA transaminase inhibitors; gastrointestinal drugs; all Anesthetics; urogenital tract agents; gastrointestinal stimulants; glucocorticoids; glucose-raising agents; glycopeptide antibiotics; glycoprotein platelet inhibitors; glycylcyclines; gonadotropin hormones; gonadotropin-releasing hormone antagonists; gonadotropins; Class I antiarrhythmics; Class II antiarrhythmics; Class III antiarrhythmics; Class IV antiarrhythmics; Class V antiarrhythmics; growth hormone receptor blockers; growth hormone; Helicobacter pylori eradication agents; H2 antagonists; hematopoietic stem cell mobilizers; heparin antagonists; heparin; HER2 inhibitors Plant products; Histone deacetylase inhibitors; Hormone replacement therapy; Hormones; Hormones / antineoplastic drugs; Hydantoin anticonvulsants; Illegal (street) drugs; Immunoglobulins; Immunotherapy drugs; Immunosuppressants; Impotence drugs; In vivo diagnostic biological agents; Incretin mimetics; Inhaled infection drugs; Inhaled corticosteroids; Cardiotonic drugs; Insulin; Insulin-like growth factors; Integrase chain transfer inhibitors; Interferon; Intravenous nutritional products; Iodine contrast agents; Ionized iodine contrast agents; Iron products; Ketolides; Laxatives; Leukotriene inhibitors; Leukotriene regulators;Lincomycin derivatives; lipid-derived glycopeptides; local injection anesthetics; loop diuretics; pulmonary surfactants; lymphatic staining agents; lysosomal enzymes; macrolide derivatives; macrolides; magnetic resonance imaging contrast agents; mast cell stabilizers; medical gases; meglitinides; metabolites; methylxanthines; mineralocorticoids; minerals and electrolytes; other drugs; other analgesics; other antibiotics; other anticonvulsants; other antidepressants; other antidiabetic drugs; other antiemetics; other antifungal drugs; other drugs for hyperlipidemia; other antimalarial drugs; other antitumor drugs; other antiparkinsonian drugs; Other antipsychotics; other antituberculosis drugs; other antiviral drugs; other anxiolytics, sedatives and hypnotics; other biological preparations; other bone resorption inhibitors; other cardiovascular drugs; other central nervous system drugs; other coagulation regulators; other diuretics; other urogenital drugs; other GI drugs; other hormones; other metabolites; other ophthalmic drugs; other ophthalmic drugs; other ophthalmic drugs; other respiratory drugs; other sex hormones; other topical drugs; other unclassified drugs; other vaginal drugs; mitotic inhibitors; monoamine oxidase inhibitors; monoclonal antibodies; oral and throat products; mTOR inhibitors; mTOR kinase inhibitors; mucolytics; mal Thikinase inhibitors; muscle relaxants; mydriatics; narcotic analgesic combinations; narcotic analgesics; nasal anti-infection agents; nasal antihistamines and decongestants; nasal lubricants and irrigants; nasal preparations; nasal steroids; natural penicillin derivatives; neuraminidase inhibitors; neuromuscular blockers; next-generation cephalosporins; nicotinic acid derivatives; nitrates; non-nucleoside reverse transcriptase inhibitors; non-cardiac selective beta-blockers; non-iodine contrast agents; non-ionic iodine contrast agents; non-sulfonylurea; nonsteroidal anti-inflammatory drugs; norepinephrine reuptake inhibitors; norepinephrine-dopamine reuptake inhibitors; nucleo NRTIs (Northostatic Reverse Transcriptase Inhibitors); Nutritional Supplements; Nutritional Products; Ocular Anesthetics; Ocular Infectious Diseases; Ocular Anti-inflammatory Drugs; Ocular Antihistamines and Decongestants; Ocular Diagnostic Agents; Ocular Glaucoma Drugs; Ocular Lubricants and Irrigants; Ocular Preparations; Ocular Steroids; Additional Ocular Steroids for Infectious Diseases; Ocular Surgical Drugs; Oral Nutritional Supplements; Otorhinolary Anesthetics; Otorhinolary Infectious Diseases; Otorhinolary Preparations; Otorhinolary Steroids; Additional Otorhinolary Steroids for Infectious Diseases; Oxazolidinedione Anticonvulsants; Parathyroid Hormone and Analogues; Penicillinase-Resistant Penicillin; Penicillin-Based Drugs; Peripheral Opioid Receptor Antagonists; Peripheral Vasodilators;Peripheral-acting anti-obesity drugs; phenothiazine antiemetics; phenothiazine antipsychotics; phenylpiperazine antidepressants; plasma expanders; platelet aggregation inhibitors; platelet stimulants; polyenes; potassium-sparing diuretics; probiotics; progestins; prolactin inhibitors; prostaglandin D2 antagonists; protease inhibitors; proton pump inhibitors; psoralens; psychotropic drugs; psychotropic combination drugs; purine nucleosides; pyrrolidine anticonvulsants; quinolones; contrast agents; radioactive adjuvants; radioactive agents; radioactive conjugates Agents; radiopharmaceuticals; RANK ligand inhibitors; recombinant human erythropoietin; renin inhibitors; respiratory drugs; inhaled respiratory drugs; rifamycin derivatives; salicylates; sclerosing agents; second-generation cephalosporins; selective estrogen receptor modulators; selective serotonin reuptake inhibitors; serotonin-norepinephrine reuptake inhibitors; serotonergic neurointestinal modulators; sex hormone complexes; sex hormones; skeletal muscle relaxant complexes; skeletal muscle relaxants; smoking cessation drugs; somatostatin and somatostatin analogs; spermicides; statins; sterile washing solutions Liquid; Streptomyces derivatives; Succinimide anticonvulsants; Sulfonamides; Sulfonylureas; Synthetic ovulation inducers; Tetracyclic antidepressants; Tetracyclines; Therapeutic radiopharmaceuticals; Thiazide diuretics; Thiazolidinediones; Thioxanthene; Third-generation cephalosporins; Thrombin inhibitors; Thrombolytic agents; Thyroid agents; Labor suppressants; Topical acne medications; Topical medications; Local anesthetics; Topical infection medications; Topical antibiotics; Topical antifungal agents; Topical antihistamines; Topical antipsoriasis drugs; Topical antiviral drugs; Topical astringents; Topical pus-draining agents; Topical depigments; Topical skin softeners Drugs; topical keratolytic agents; topical steroids; additional topical steroids for infections; toxoids; triazine anticonvulsants; tricyclic antidepressants; trifunctional monoclonal antibodies; tumor necrosis factor (TNF) inhibitors; tyrosinase inhibitors; ultrasound contrast agents; upper respiratory tract combination agents; urea anticonvulsants; urinary tract infection drugs; urinary tract antispasmodics; urine pH adjusters; uterine contraction drugs; vaccines; combination vaccines; vaginal antiinfectives; vaginal suppositories; vasodilators; vasopressin antagonists; vasopressors; VEGF / VEGFR inhibitors; viral vaccines; intra-articular replacement drugs; vitamin and mineral complexes; vitamins;

[0051] Diagnostic test 17-Hydroxyprogesterone; ACE (Angiotensin I-converting enzyme); Acetaminophen; Acid phosphatase; Adrenocorticotropic hormone; Active clotting time; Activated protein C resistance; Adrenocorticotropic hormone (ACTH); Alanine aminotransferase (ALT); Albumin; Aldolase; Aldosterone; Alkaline phosphatase; Alkaline phosphatase (ALP); α1-Antitrypsin; α-Fetoprotein; α-Fetoprotein (fetoprotien); Ammonia level; Amylase; ANA (Antinuclear Antbody (antinuclear) antbodies); ANA (antinuclear antibody); angiotensin-converting enzyme (ACE); anion gap; anticardiolipin antibody; anticardiolipin antibodies (ACA); anticentromere antibody; antidiuretic hormone; anti-DNA; anti-deoxyribonuclease B; anti-gliadin antibody; anti-glomerular basement membrane antibody; anti-HBc (hepatitis B core antibody); anti-HBs (hepatitis B surface antibody); antiphospholipid antibody; anti-RNA polymerase; anti-Smith (Sm) antibody; anti-smooth muscle antibody; anti-streptolysin O value (ASO); anti-thrombin III; anti-Xa activity; anti-Xa assay; apolipoprotein; arsenic; aspartate aminotransferase (AST); B12; basophilic leukocytes; β2-microglobulin; β-hydroxybutyrate; B-HCG; bilirubin; direct bilirubin; indirect bilirubin; total bilirubin Bottle; bleeding time; blood gas (arterial); blood urea nitrogen (BUN); blood urea nitrogen; BUN; CA125; CA15-3; CA19-9; calcitonin; calcium; calcium (ionized); carbon monoxide (CO); CEA (carcinoembryonic antigen); complete blood count (value), complete blood count; carcinoembryonic antigen; CEA; ceruloplasmin; CH50 chloride; cholesterol; cholesterol, HDL; thrombolysis time; clot regression time; CMP; CO2; cold agglutinin; complement component 3; copper; corticotropin-releasing hormone (CRH) stimulation test; cortisol; capsule rosin stimulation test; C peptide; CPK (total); CPK-MB; C-reactive protein; creatinine; creatinine kinase (CK); cryoglobulin; DAT (direct antiglobulin test); D-dimer; dextamethasone suppression test; DHEA-S;Diluted Russell's chain snake venom; oval erythrocytes; eosinophils; erythrocyte sedimentation rate (ESR); estradiol; estriol; ethanol; ethylene glycol; euglobulin solubil; factor V Leiden; factor VIII inhibitor; factor VIII level; ferritin; fibrin degradation products; fibrinogen; folate; folate (serum); sodium fractional excretion rate (FENA); FSH (follicle-stimulating factor); FTA-ABS; gamma-glutamyltransferase (GGT); gastrin; GGTP (gamma-glutamyltransferase); glucon Growth hormone; haptoglobin; HBeAg (hepatitis B e antigen); HBs-Ag (hepatitis B surface antigen); Helicobacter pylori; hematocrit (red blood cell volume); hematocrit (HCT); hemoglobin; hemoglobin A1C; hemoglobin electrophoresis; hepatitis A antibody; hepatitis C antibody; IAT (indirect antiglobulin test); immunofixation (IFE); iron; lactate dehydrogenase (LDH); lactate (lactate); LDH; LH (leutinizing hormone); lipase; lupus anticoagulant; lymph Spheres; Magnesium; MCH (Mean corpuscular hemoglobin); MCHC (Mean corpuscular hemoglobin concentration); MCV (Mean corpuscular volume); Methyl malonate; Monocytes; MPV (Mean platelet volume); Myoglobin; Neutrophils; Parathyroid hormone; Phosphorus; Platelets (plt); Potassium; Prealbumin; Prolactin; Prostate-specific antigen (PSA); Protein C; Protein S; PSA (Prostate-specific antigen); PT (Prothrombin time); PTT (Partial thromboplastin time); RDW (Red blood cell distribution width); Renin; Rennin; Reticulocyte count Reticulocytes; Rheumatoid factor (RF); ESR; Serum glutamate pyruvate transaminase (SGPT); Serum protein electrophoresis (SPEP); Sodium; T3 resin uptake (T3RU); Free T4; Thrombin time; Thyroid-stimulating hormone (TSH); Thyroxine (T4); Total iron-binding capacity (TIBC); Total protein; Transferrin (iron-binding globulin); Transferrin saturator; Triglycerides (TG); Troponin; Uric acid; Cyanocobalamin (vitamin B12); White blood cells (WBC); Widar test.

[0052] Another aspect of the present invention relates to a container, particularly a container having a lumen at least partially defined by a wall, and more particularly to a method of coating one or more films on the inner surface of a container wall, wherein the plastic wall has an inner and outer surface facing the lumen. The one or more films may include any combination of the films described above.

[0053] In one embodiment, the method includes coating at least one, optionally each of one or more coatings or layers, by steps including applying sufficient power to generate plasma in a lumen, supplying a precursor gas over a deposition time to generate a film or layer, and then extinguishing the plasma. The plasma may be generated using a pulsed RF power supply, which may have at least 100 W of power and at least 5 Hz of pulse frequency.

[0054] The use of relatively high power and frequency provides a high-density coating or layer with desired properties that can be applied with shorter deposition times and / or thinner thicknesses compared to conventional PECVD coating methods used in the field. The use of relatively high power also allows for coating a larger number of vessels, e.g., at least 12 or at least 16 vessels, simultaneously using the same RF power supply, and enables better control over plasma conditions and stability within the lumen of each vessel, thereby allowing for greater consistency between vessel coatings. When operating at relatively high power, pulses are used to prevent overheating and deformation of the thermoplastic material constituting the vessel walls.

[0055] In some embodiments, pulsed RF power may also be used to improve the gas distribution within the vessel lumen. In conventional methods of coating the inner surface of a vessel, such as those described above, the precursor gas is introduced into the lumen by a component having multiple outlets that extend into the lumen and allow the precursor gas to flow relatively uniformly throughout the entire length of the lumen. Direct introduction of the precursor gas into the lumen through the vessel opening is necessary because it results in a relatively uniform coating where the thickness of the coating near the vessel opening is much thicker than the thickness of the coating further away from the vessel opening, for example, near the closed end of the vessel. However, the use of gas outlet components that extend into the lumen leads to the undesirable result that after several coating cycles, the component needs to be removed, cleaned, and / or replaced due to the accumulation of the coating on the component itself. For example, in a conventional process, the coating process may need to be stopped every 1.5 hours of operation to remove and replace the gas outlet component, the process may take about 10 minutes, and about 10% of the vessel coating throughput will be lost.

[0056] In some embodiments, the precursor gas flow rate and RF power pulses can be controlled to improve the distribution of the precursor gas within the lumen, by allowing the precursor gas to be directly supplied into the lumen through the open end of the vessel without any gas outlet components located within the lumen. For example, the RF power pulse rate can be controlled by the time between pulses to distribute the gas introduced into the lumen substantially uniformly throughout the lumen, resulting in a coating with substantially uniform thickness. In some embodiments, a compartment, such as an aluminum screen, is placed between the gas inlet (located outside the vessel lumen) and the vessel lumen, allowing the precursor gas to pass through but preventing the plasma from igniting outside the lumen.

[0057] Embodiments of the method of the present disclosure include the steps of: a. providing a container having a lumen at least partially defined by a plastic wall, the plastic wall having an inner surface and an outer surface facing the lumen; b. drawing a partial vacuum into the lumen; and c. optionally coating a tie film or layer of SiOxCy by a tie PECVD coating step, which includes applying sufficient power to generate a plasma in the lumen and supplying a precursor gas containing siloxane, optionally oxygen, and optionally an inert gas diluent over a deposition time to generate a tie film or layer on the inner surface, and then extinguishing the plasma, wherein x is approximately 0.5 to approximately 2.4 and y is approximately 0.6 to approximately 3, each of which is measured by X-ray photoelectron spectroscopy (XPS); and d. applying sufficient power to generate a plasma in the lumen and supplying a precursor gas containing siloxane and oxygen over a deposition time to generate a burr e. A step of coating a barrier film or layer of SiOx while maintaining a partial vacuum in the lumen without disrupting it, by a barrier PECVD coating step comprising generating a film or layer on an inner surface, optionally on an inner surface treated according to step c to have a film or layer, and then extinguishing the plasma, wherein x is 1.5 to 2.9 as measured by XPS; and e. A step of optionally coating a pH protective film or layer of SiOxCy by a pH protective PECVD coating step comprising applying sufficient power to generate a plasma in the lumen, supplying a precursor gas containing siloxane, optionally oxygen, and optionally an inert gas diluent over a deposition time to generate a pH protective film or layer, and then extinguishing the plasma, wherein x is approximately 0.5 to approximately 2.4 and y is approximately 0.6 to approximately 3, each of which is measured by XPS.The plasma in step d may be generated using pulsed RF having a power of at least 200 W, optionally at least 225 W, optionally at least 250 W, optionally at least 275 W, optionally at least 300 W, optionally at least 325 W, optionally at least 350 W, optionally at least 375 W, optionally at least 400 W and pulse frequencies of at least 50 Hz, at least 75 Hz, at least 100 Hz, at least 125 Hz, at least 150 Hz, at least 175 Hz, at least 200 Hz, at least 225 Hz, and at least 250 Hz.

[0058] If steps c and / or e are performed, the plasma in those steps may also be generated using pulsed RF having power and pulse frequency within any of the identified ranges. Furthermore, if steps c and / or e are performed, the same siloxane precursor may be used in each of steps c, d, and / or e. In some embodiments, the siloxane precursor may include HMDSO, TMDSO, or a combination thereof. In some embodiments, the siloxane precursor may be HMDSO. Furthermore, if steps c and / or e are performed, steps c, d, and / or e may be performed without breaking the partial vacuum in the vessel or moving the vessel between separate coating stations.

[0059] The deposition time in step d can be selected to provide a barrier layer having a desired thickness, i.e., a thickness that provides a vessel with a desired oxygen permeability (OTR). For example, the deposition time in step d may be 20 seconds or less, optionally 15 seconds or less, optionally 10 seconds or less, optionally 2 to 15 seconds, optionally 3 to 10 seconds, or optionally 3 to 7 seconds. In connection therewith, the deposition time can be selected to produce a barrier film or layer having an average thickness of at least 10 nm, optionally at least 15 nm, optionally at least 20 nm, optionally 10 to 100 nm, optionally 10 to 75 nm, optionally 10 to 50 nm, optionally 15 nm to 50 nm, or optionally 20 nm to 45 nm (based on power, pulse frequency, etc.).

[0060] The deposition time in step c can also be selected to provide a tie layer with a desired thickness. For example, the deposition time in step c may be 15 seconds or less, optionally 10 seconds or less, optionally 5 seconds or less, optionally 2 to 12 seconds, optionally 3 to 10 seconds, or optionally 3 to 7 seconds. In connection with this, the deposition time can be selected to produce a tie film or layer having an average thickness of at least 5 nm, optionally at least 10 nm, optionally 5 to 30 nm, optionally 10 to 30 nm, optionally 10 to 25 nm, or optionally 15 to 25 nm (based on power, pulse frequency, etc.).

[0061] The deposition time in step e can also be selected to provide a tie layer of a desired thickness. For example, the deposition time in step e may be 25 seconds or less, optionally 20 seconds or less, optionally 15 seconds or less, optionally 10 seconds or less, optionally 4 to 20 seconds, optionally 5 to 20 seconds, optionally 5 to 15 seconds, or optionally 5 to 10 seconds. In connection with this, the deposition time can be selected to produce a pH protective film or layer having an average thickness of at least 30 nm, optionally at least 40 nm, or optionally at least 50 nm (based on power, pulse frequency, etc.).

[0062] In some embodiments, the method includes a lubrication PECVD coating step which involves applying sufficient power to generate plasma in the lumen, supplying a precursor gas containing siloxane, optionally oxygen, and optionally an inert gas diluent over a deposition time to generate a lubricating film or layer, and then extinguishing the plasma, thereby creating a barrier film or layer, or if present, a pH protective film or layer, between the barrier film or layer and the lumen. x C yStep f may further include applying a lubricating film or layer, where x is approximately 0.5 to approximately 2.4 and y is approximately 0.6 to approximately 3, each of which is measured by X-ray photoelectron spectroscopy (XPS). The plasma in step f may also be generated using pulsed RF having power of at least 200 W, optionally at least 225 W, optionally at least 250 W, optionally at least 275 W, optionally at least 300 W, optionally at least 325 W, optionally at least 350 W, optionally at least 375 W, optionally at least 400 W and pulse frequencies of at least 50 Hz, at least 75 Hz, at least 100 Hz, at least 125 Hz, at least 150 Hz, at least 175 Hz, at least 200 Hz, at least 225 Hz, and at least 250 Hz.

[0063] The plasma in steps c, d, e, and / or f may be generated using pulsed RF with duty cycles of at least 25%, optionally at least 30%, optionally at least 35%, optionally at least 40%, optionally at least 45%, optionally at least 50%, and optionally at least 55%. In some embodiments, for example, the plasma may have a duty cycle of 25% to 99%. In some embodiments, the plasma in steps c, d, e, and / or f may be generated using pulsed RF having pulsed high-power levels of 250W to 1000W and / or pulsed low-power levels of 0W. In some embodiments, the plasma in steps c, d, e, and / or f may have pulse train frequencies of 150kHz to 500kHz.

[0064] In some embodiments, one or more precursor gases may be introduced into the lumen of the container through a gas delivery device or gas inlet probe extending into the lumen of the container.

[0065] In other embodiments, one or more precursor gases may be supplied directly to the lumen of the vessel through an opening in the vessel, e.g., an open end. For example, the plasma pulse rate may be controlled so that the gas delivery device or gas outlet is located inside the vessel lumen. Alternatively, for example, the gas outlet may be located outside the vessel opening (e.g., below in the illustrated system), and the vessel opening and one or more precursor gases may enter the lumen after passing through a compartment. The compartment may be configured to allow one or more precursor gases to pass through but to prevent plasma ignition outside the vessel lumen, i.e., to act as a plasma screen. For example, the compartment may include a metal mesh or a perforated metal plate.

[0066] Using a system such as those described herein, eight or more containers can be coated simultaneously, optionally twelve or more containers, or optionally sixteen or more containers, using the method described above. When multiple containers are coated simultaneously, the plasma in the lumen of each of the multiple containers can be generated by the same power source. For example, each container can be placed in a separate cavity of the same electrode. When multiple containers are coated simultaneously, one or more precursor gases introduced into the lumen of each of the multiple containers may come from the same gas source and be equally distributed to each of the multiple containers by a gas manifold, the vacuum drawn into the lumen of each of the multiple containers may come from the same vacuum source and be equally distributed to each of the multiple containers by a vacuum manifold, or both.

[0067] In some embodiments, the method may include: positioning each of a plurality of vessels at one of the openings of a plurality of metal RF electrodes; evacuating the internal volume of each of the plurality of vessels using an exhaust manifold operably connected to a single vacuum and / or vacuum line; introducing one or more source gases into each of the plurality of vessels using a gas inlet manifold operably connected to a single precursor gas supply line; generating plasma within each of the plurality of vessels using one or more source gases and pulsed RF signals applied to the metal RF electrodes; and using the plasma to deposit a film in each of the plurality of vessels, including at least one barrier film or layer.

[0068] In some embodiments in which multiple containers are coated simultaneously, the combination of steps c, d, and e—i.e., the application of the three-layer coating set described herein to each of the multiple containers—can be carried out in less than 120 seconds, optionally less than 110 seconds, optionally less than 100 seconds, optionally less than 90 seconds, optionally less than 80 seconds, optionally less than 75 seconds, optionally less than 70 seconds, and optionally less than 65 seconds.

[0069] Due to the uniformity of the coating provided, in some embodiments in which multiple containers are coated simultaneously, each coated container may have substantially the same oxygen permeability constant as each of the other coated containers. Similarly, due to the uniformity of the coating provided, in some embodiments in which multiple containers are coated simultaneously, each coated container may have substantially the same silicon dissolution amount and / or silicon dissolution rate as each of the other coated containers when in contact with a solution having pH 9 for 72 hours.

[0070] In some embodiments, the method may further include the step of applying one or more coatings to the outer surface of the container wall by pulsed RF PECVD. The step of applying one or more coatings to the outer surface of the container wall may be performed in the same system as the inner wall coating described above, for example, without moving the container to a separate coating station. The one or more coatings applied to the outer surface of the container wall may include, for example, an antistatic and / or scratch-resistant coating as described in U.S. Patent Application Publication No. 2018 / 0049945A1, which is incorporated herein by reference in whole.

[0071] In any embodiment, the method may provide a desired coating on one or more plastic containers, including a plastic wall which comprises a COP resin or COC resin, is basically made of a COP resin or COC resin, or is made of a COP resin or COC resin. In any embodiment, the method can provide a desired coating on one or more plastic containers, including a plastic wall comprising a cyclic block copolymer (CBC) resin, basically consisting of or made of a CBC resin, optionally comprising or made of a CBC resin selected from the group consisting of VIVION® 0510, VIVION® 0510HF, and VIVION® 1325, optionally comprising or made of such CBC resins, optionally comprising or made of a CBC resin selected from the group consisting of VIVION® 0510 and VIVION® 0510HF, optionally comprising or made of VIVION® 0510, optionally comprising or made of VIVION® 0510HF.

[0072] Another aspect of the present invention is a container, particularly a container having a lumen at least partially defined by a plastic wall, more particularly a system for coating one or more films on the inner surface of the container wall, the plastic wall having an inner surface and an outer surface facing the lumen. The one or more films may include any combination of the films described above.

[0073] In some embodiments, the system may utilize a gas outlet located within the container lumen. In other embodiments, the system may utilize a gas outlet located outside the container lumen, for example, below the container opening, so that the precursor gas flows directly into the container lumen through the container opening.

[0074] Accordingly, embodiments of the system of the present disclosure may comprise a radio frequency (RF) power supply, an RF electrode having a plurality of openings, each configured to receive a vessel, an inlet gas manifold operable to divide a single gas inlet into a plurality of gas source inputs, one for each vessel, and an exhaust manifold operable to exhaust each vessel into a single exhaust line. The system may be operable to receive the plurality of vessels at the openings of the RF electrode, to exhaust the internal volume of each of the plurality of vessels using a single vacuum line via the exhaust manifold, to introduce one or more source gases into each of the plurality of vessels using a single source line via the gas inlet manifold, to generate plasma in each of the plurality of vessels using one or more source gases and pulsed RF signals applied to the metal RF electrode by the RF power supply, and to use the plasma to deposit a film on each of the plurality of vessels, including at least one barrier film or layer. [Brief explanation of the drawing]

[0075] [Figure 1] This is a schematic cross-sectional view of a container according to any embodiment of the present invention. [Figure 2] Figure 1 is a magnified detailed view of a portion of the container wall and coating. [Figure 3] These are schematic diagrams of pharmaceutical packaging in the form of a syringe barrel as a container, as shown in Figures 1 and 2, containing a fluid and closed with a plunger-type closure. [Figure 4] These are schematic diagrams of pharmaceutical packaging in the form of vials, which are containers containing fluid and sealed with a closure, as shown in Figures 1 and 2. [Figure 5] These are schematic diagrams of pharmaceutical packaging in the form of blister packaging as containers, as shown in Figures 1 and 2, containing fluid and closed with a closure in the form of a covering sheet that defines an additional container wall. [Figure 6] This invention shows a pulsed RF PECVD reactor according to one embodiment of this disclosure. [Figure 7] This shows a side view of a pulsed RF PECVD reactor according to one embodiment of the present disclosure. [Figure 8]This shows a top view of a pulsed RF PECVD reactor according to one embodiment of the present disclosure. [Figure 9] Various diagrams of an RF electrode according to one embodiment of this disclosure are shown. [Figure 10] Various diagrams of an RF electrode according to one embodiment of this disclosure are shown. [Figure 11] This disclosure shows a pulsed RF PECVD container deposition apparatus according to one embodiment. [Figure 12] This invention illustrates a pulse RF PECVD container deposition apparatus without an inlet probe according to one embodiment of this disclosure. [Figure 13] This disclosure shows a pulse RF PECVD syringe deposition apparatus without an inlet probe according to one embodiment of this disclosure. [Figure 14] This disclosure shows a pulsed RF PECVD apparatus for both internal and external vessel deposition according to one embodiment of this disclosure. [Figure 15] This disclosure shows a pulsed RF PECVD apparatus for both internal and external vessel deposition according to one embodiment of this disclosure. [Figure 16] This diagram shows a cross-sectional view of a single-container pulsed RF PECVD apparatus in both internal and external container deposition according to one embodiment of the present disclosure. [Figure 17] This shows the relationship between layer thickness and layer growth time in a pulsed RF PECVD system in which 16 containers are simultaneously coated, according to one embodiment of the present disclosure. [Figure 18] This shows the relationship between the oxygen permeability and the thickness of the barrier layer of a vial having a barrier layer according to one embodiment of the present disclosure. [Figure 19] This shows a contour map of vial growth in a 16-container pulsed RF PECVD system according to one embodiment of the present disclosure. [Figure 20] This shows a contour map of vial growth in a 16-container pulsed RF PECVD system according to one embodiment of the present disclosure. [Figure 21] This shows a design scatter plot of the dissolution rate of coated vials in a pulsed RF PECVD system according to one embodiment of the present disclosure. [Figure 22]This disclosure shows the relationship between oxygen barrier performance and plasma pulse rate according to one embodiment of this disclosure. [Figure 23] This disclosure shows the relationship between oxygen barrier performance and plasma pulse rate according to one embodiment of this disclosure. [Figure 24] This exhibits pressure uniformity between vessels in a pulsed RF PECVD system according to one embodiment of the present disclosure. [Figure 25] This invention demonstrates pressure uniformity between vessels under gas flow in a pulsed RF PECVD system according to one embodiment of this disclosure. [Figure 26] This shows the coating integrity of a coated container in a pulsed RF PECVD system according to one embodiment of the present disclosure. [Figure 27] This plot compares pulsed RF PECVD processes in two different systems over 8 hours of continuous operation, according to one embodiment of the present disclosure. [Figure 28] This is a plot showing the oxygen permeability (OTR) of various container wall materials in both an uncoated state and a state in which a barrier layer is applied, according to one embodiment of the present disclosure. [Figure 29] This is a perspective view of an RF electrode according to one embodiment of the present disclosure. [Modes for carrying out the invention]

[0076] The following definitions and abbreviations are used in relation to the present invention.

[0077] Pulsed RF PECVD is a pulsed radio frequency plasma chemical vapor deposition method that utilizes plasma to enhance deposition by dissociating precursor materials using plasma pulsed at RF frequencies. In other scenarios, the plasma can be pulsed at microwave frequencies.

[0078] In the context of this invention, the term "at least" means the integer "greater than or equal to" that follows it. The term "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude plurals unless otherwise specified. Whenever a parameter range is given, it is intended to disclose the parameter values ​​given as limits to the range and all parameter values ​​that fall within that range.

[0079] For example, “first” and “second” or similar references to lubricant deposits, processing stations, or processing devices refer to the minimum number of deposits, processing stations, or devices present, and do not necessarily represent an order or total number of deposits, processing stations, and devices, nor do they require additional deposits, processing stations, and devices beyond the number described. These terms do not limit the number of processing stations or the specific processing performed at each station. For example, “first” deposit, in the context of this specification, may be, without limitation, a single deposit or any one of several deposits. In other words, the “first” deposit description may, but does not require, embodiments having second or further deposits.

[0080] For the purposes of the present invention, the "organosilicon precursor" is a compound having at least one of the following bonds, wherein the tetravalent silicon atom is bonded to an oxygen atom or nitrogen atom and an organic carbon atom (an organic carbon atom is a carbon atom bonded to at least one hydrogen atom). [ka] Volatile organosilicon precursors are defined as precursors that can be supplied as vapor to a PECVD apparatus and are optional organosilicon precursors. Optionally, organosilicon precursors are selected from the group consisting of linear siloxanes, monocyclic siloxanes, polycyclic siloxanes, polysilsesquioxanes, alkyltrimethoxysilanes, linear silazanes, monocyclic silazanes, polycyclic silazanes, polysilsesquiazanes, and any two or more combinations of these precursors.

[0081] In this specification and in the claims, the supply quantities of PECVD precursors, gaseous reactants or process gases and carrier gases may be expressed in "standard volume." The standard volume of a charge gas or any other fixed amount of gas is the volume occupied by that fixed amount of gas at a standard temperature and pressure (without considering the actual delivery temperature and pressure). The standard volume can be measured using various units of volume, but still remain within the scope of this disclosure and the claims. For example, the same fixed amount of gas can be expressed as a value in standard cubic centimeters, standard cubic meters, or standard cubic feet. The standard volume can also be defined using various standard temperatures and pressures, but still remain within the scope of this disclosure and the claims. For example, the standard temperature may be 0°C and the standard pressure 760 Torr (conventional), or the standard temperature may be 20°C and the standard pressure 1 Torr. However, in any given case, when comparing the relative volumes of two or more different gases without specifying any particular parameters, the same units of volume, standard temperature, and standard pressure are used for each gas unless otherwise specified.

[0082] In this specification, the corresponding supply rates of PECVD precursors, gaseous reactants or process gases, and carrier gases are expressed in standard volume per unit time. For example, in the examples, the flow rate is expressed as standard cubic centimeters / minute and abbreviated as sccm. As with other parameters, other units of time such as seconds or hours may be used, but when comparing the flow rates of two or more gases, a consistent parameter should be used unless otherwise specified.

[0083] In the context of this invention, “container” can be any type of container having at least one opening and a wall defining its inner surface or inner surface. The substrate can be the wall of a container having a lumen. While this invention is not necessarily limited to drug packaging or other containers of a specific capacity, drug packaging or other containers having a lumen with a void capacity of 0.5 to 50 mL, optionally 1 to 10 mL, optionally 0.5 to 5 mL, or optionally 1 to 3 mL are envisioned. The substrate surface can be a part or all of the inner surface or inner surface of a container having at least one opening and an inner surface or inner surface. Some examples of drug packaging include, but are not limited to, vials, plastic-coated vials, syringes, plastic-coated syringes, blister packs, ampoules, plastic-coated ampoules, cartridges, bottles, plastic-coated bottles, pouches, pumps, sprayers, stoppers, needles, plungers, caps, stents, catheters, or implants.

[0084] In the context of the present invention, the term "at least" means "greater than or equal to" the integer following the preceding term. Therefore, a container in the context of the present invention has one or more openings. One or two openings are preferred, such as the opening of a sample tube (one opening) or the opening of a syringe barrel (two openings). If a container has two openings, they may be the same size or different sizes. If there are two or more openings, one opening may be used for gas inhalation in the PECVD coating method described in the present invention, while the other openings may be covered or left open. The containers described in the present invention may be, for example, a sample tube for collecting or storing biological fluids such as blood or urine, a syringe (or part thereof such as a syringe barrel) for storing / transporting biologically active compounds or compositions, such as drugs or pharmaceutical compositions, a vial for storing biomaterials or biologically active compounds or compositions, a conduit for transporting biomaterials or biologically active compounds or compositions, such as a catheter, or a cuvette for holding a fluid such as a biomaterial or biologically active compound or composition.

[0085] The container can be of any shape, but a container having a substantially cylindrical wall adjacent to at least one of its open ends is preferred. Generally, the inner wall of the container is cylindrical, for example, inside a sample tube or syringe barrel. Sample tubes and syringes or their components (e.g., syringe barrels) are intended.

[0086] In the context of this invention, "hydrophobic layer" means that a film or layer reduces the wetting tension of the surface covered by the film or layer compared to the corresponding uncoated surface. Hydrophobicity is therefore a feature of both the uncoated substrate and the film or layer. The same applies to appropriate substitutes in other contexts in which the term "hydrophobic" is used. The term "hydrophilic" is the opposite, meaning that the wetting tension is increased compared to a reference sample. This hydrophobic layer is primarily defined by its hydrophobicity and the process conditions that provide it.

[0087] These values ​​of w, x, y, and z are used throughout this specification for the experimental composition Si w O x C y H z Applicable to: The values ​​of w, x, y, and z used throughout this specification should be understood as ratios or empirical formulas (e.g., coatings or layers), not as limitations on the number or type of atoms in the molecule. For example, molecular composition Si4O4C8H 24 Octamethylcyclotetrasiloxane having the following empirical formula: Si1O1C2H6, obtained by dividing each of the molecular formula's w, x, y, and z by their greatest common divisor, 4. The values ​​of w, x, y, and z are not limited to integers. For example, the molecular composition of (acyclic) octamethyltrisiloxane is Si3O2C8H 24 is Si1O 0.67 C 2.67 It is convertible to H8. Also, SiO x C y H z is SiO x C y It is described as an equivalent to SiO x C yTo demonstrate its presence, it is not necessary to show the presence of hydrogen in any arbitrary proportion.

[0088] "Wetting tension" is a specific measure of the hydrophobicity or hydrophilicity of a surface. In the context of this invention, an optional method for measuring wetting tension is ASTMD2578 or an improved version of the method described therein. This method uses a standard wetting tension solution (called Dyne solution) to determine how close the solution approaches the wet state of the plastic film surface in exactly 2 seconds. This is the wetting tension of the film. The procedure used herein differs from that in ASTMD2578 in that the substrate is not a flat plastic film, but a tube manufactured according to the "Protocol for Forming PET Tubes" and coated (except for the control) according to the protocol for coating the inside of the tube with a hydrophobic coating or layer (see Example 9 of European Patent Application Publication No. 2251671A2).

[0089] The atomic ratio can be determined by XPS. Therefore, taking into account the H atoms that are not measured by XPS, the film or layer is, in one embodiment, of the chemical formula Si w O x C y H z (or equivalent SiO x C y ) has such that, for example, w is 1, x is approximately 0.5 to approximately 2.4, y is approximately 0.6 to approximately 3, and z is approximately 2 to approximately 9. Typically, such a film or layer contains 36% to 41% carbon normalized to 100% carbon + oxygen + silicon.

[0090] The term “syringe” is broadly defined to include cartridges, “pen” type syringes, and other types of barrels or reservoirs that are assembled with one or more other components to provide a functional syringe. “Syringe” is also broadly defined to include related articles such as autoinjectors that provide a mechanism for dispensing contents.

[0091] A coating, layer, or treatment is defined as "hydrophobic" if it reduces the surface wetting tension compared to the corresponding uncoated or untreated surface. Therefore, hydrophobicity is a feature of both the untreated substrate and the treated surface.

[0092] The term "comprising" does not exclude other elements or steps.

[0093] The indefinite article "a" or "an" does not exclude the plural.

[0094] Detailed explanation The present invention will be described more fully hereby with reference to the accompanying drawings, which illustrate several embodiments. However, the present invention can be carried out in many different forms and should not be construed as being limited to the embodiments described herein. Rather, these embodiments are examples of the present invention, and the present invention has the entire scope as indicated by the language of the claims. Similar numbers refer to similar or corresponding elements throughout. The following disclosure relates to all embodiments unless specifically noted as being limited to a particular embodiment.

[0095] Embodiments of the present disclosure relate to coatings of containers made at least partially from thermoplastic materials to achieve coated containers suitable for, for example, containing injectable solutions. This can be achieved by using a pulsed RF PECVD coating process to coat a variety of layers that function as oxygen barriers, optionally water vapor permeability (or moisture) barriers, optionally tie layers, and optionally pH protective layers. By using pulsed RF PECVD, coating defects can be minimized and process time can be reduced as the number of containers coated at one time increases. A pulsed RF PECVD system may comprise a single source supplying gas to each container via an input manifold and a single vacuum line discharging each container / chamber via an exhaust manifold. In this way, a high degree of layer uniformity is possible across multiple containers. Furthermore, pulsed RF PECVD can be controlled to provide a higher density layer that enables similar or improved layer performance using thinner, higher density layers.

[0096] Container and coating set One aspect of the present invention, most broadly shown in the detailed drawings of Figures 1 and 2, is a container 210 comprising a wall 214 surrounding a lumen 212 and a container coating or layer set 285 on at least a portion of the wall 214 facing the lumen 212. More specifically, the container may be a vial, syringe, blister pack, ampoule, cartridge, bottle, pouch, pump, spray, stopper, needle, plunger, cap, stent, catheter, implant, or any other type of container or conduit for fluids. Figures 1 to 5 show containers having at least one opening, and it should be understood that this includes containers having two or more openings, such as syringe barrels, or containers without openings, such as pouches, blister packs, or ampoules.

[0097] One embodiment of the container coating or layer set 285 is shown in Figures 1 and 2, comprising at least one tie coating or layer 289, at least one barrier coating or layer 288, and at least one pH protective coating or layer 286. This embodiment of the container coating or layer set is sometimes known as a “three-layer coating,” in which the SiOx barrier coating or layer 288 is interposed between the pH protective coating or layer 286 and the tie coating or layer 289, each being an organic layer of SiOxCy as defined herein, thereby protecting it from contents having a pH sufficiently high to otherwise remove it. Specific examples of this three-layer coating are provided herein. The intended thickness of each layer in nm (preferred range in parentheses) is given in the three-layer thickness table.

[0098] [Table 1]

[0099] Several specific adjustment coating sets 285, 285a, and 285b for container 210 and the closure in Figure 1 are shown in the coating set table.

[0100] [Table 2]

[0101] [Table 3]

[0102] [Table 4]

[0103] Sets 1-4 and 7, 8, and 10 in the coating set table are considered useful alternatives for syringes. Set 1, the syringe barrel wall (left column), is an example of the three-layer coating described above, and Set 7 is a variation of the three-layer coating where the pulsed RF PECVD lubricating coating is the top layer of the set.

[0104] The three-layer coating set 285 of set 1 is shown in Figure 2 and, in one embodiment, is applied to a plastic, for example, a COP syringe barrel.

[0105] The three-layer coating set 285 of set 1 includes, as the first layer, an adhesion or tie coating or layer 289 that improves the adhesion of the barrier coating or layer to the plastic substrate. The adhesion or tie coating or layer 289 is also thought to reduce stress on the barrier coating or layer 288, so that the barrier layer is less susceptible to damage from thermal expansion or contraction or mechanical shock. The adhesion or tie coating or layer 289 is also thought to decouple defects between the barrier coating or layer 288 and the plastic substrate. This is thought to occur because any pinholes or other defects that may form when the adhesion or tie coating or layer 289 is applied tend not to persist when the barrier coating or layer 288 is applied, and therefore pinholes or other defects in one coating do not align with defects in another coating. The adhesion or tie coating or layer 289 has some effect as a barrier layer and is therefore blocked by the adhesion or tie coating or layer 289, even defects that would provide a leakage path extending through the barrier coating or layer 289.

[0106] The three-layer coating set 285 of set 1 includes a barrier coating or layer 288 as the second layer, which provides a barrier to oxygen that has permeated the barrel wall and a barrier to moisture that may optionally permeate the plastic barrel wall. The barrier coating or layer 288 also serves as a barrier to the extraction of the composition of the barrel wall 214 by the contents of the lumen 214.

[0107] The three-layer coating set 285 of Set 1 includes a pH protective coating or layer 286 as a third layer, which provides protection for the underlying barrier coating or layer 288 from the contents of the syringe with a pH of 4 to 8, including in the presence of surfactants. For pre-filled syringes that are in contact with the contents of the syringe from manufacturing to use, the pH protective coating or layer 286 prevents or inhibits attack on the barrier coating or layer 288 to the extent that it maintains an effective oxygen and / or moisture barrier over the intended storage life of the pre-filled syringe.

[0108] Sets 5, 6, and 9 are useful, for example, for vials. The lubricant deposition as coating set 285b represents a siliconized partition where the entire surface is coated with lubricant to facilitate insertion into the vial neck, and therefore the coating is not required on the contact surface of the closure, but is coated.

[0109] The container wall coating set 285, represented by set 6, is another three-layer coating set, also shown in Figure 2, and in one embodiment is applied to a plastic, for example, a COP vial. The three-layer coating has the same layers as the syringe three-layer coating of set 1 described above and provides the same performance.

[0110] In some embodiments, at least a portion of the container wall may contain a cyclic block copolymer (CBC) resin such as VIVION® 0510, VIVION® 0510HF, or VIVION® 1325 from the VIVION® family, manufactured by USI Corporation (Taiwan). Cyclic block copolymers are styrene-based fully hydrogenated polymers and dienes conjugated via anionic polymerization. Cyclic block copolymers are less expensive than COP and COC resins, at least in part due to low-cost raw materials and low-cost catalysts used in polymerization and finishing processes. Embodiments of the PECVD coating process and system described herein can be used to coat a set of coatings that provide a CBC container wall with sufficient barrier properties, such as oxygen barrier properties, to function as pharmaceutical packaging, e.g., vials, syringe barrels, etc., as described herein.

[0111] film or layer The tie film or layer 289 has at least two functions. One function of the tie film or layer 289 is to improve the adhesion of the barrier film or layer 288 to a substrate, particularly a thermoplastic substrate, but the tie layer can also be used to improve adhesion to a glass substrate or another film or layer. For example, the tie film or layer, also called an adhesion film or layer, can be applied to a substrate, and a barrier layer can be applied to an adhesion layer to improve the adhesion of the barrier layer or film to the substrate.

[0112] Another function of the tie film or layer 289 has been discovered: the tie film or layer 289 applied beneath the barrier film or layer 288 can improve the function of the pH protective film or layer 286 applied on top of the barrier film or layer 288.

[0113] The tie film or layer 289 can be composed of SiOxCy, contain SiOxCy, or consist primarily of SiOxCy, where x is 0.5 to 2.4 and y is 0.6 to 3. Alternatively, the atomic ratio can be expressed as the formula SiwOxCy, and the atomic ratios of Si, O, and C in the tie film or layer 289 are, among several options, ·Si 100:O 50~150:C 90~200 (i.e. w=1, x=0.5~1.5, y=0.9~2); ·Si 100:O 70~130:C 90~200 (i.e. w=1, x=0.7~1.3, y=0.9~2) ·Si 100:O 80~120:C 90~150 (i.e. w=1, x=0.8~1.2, y=0.9~1.5) ·Si 100:O 90~120:C 90~140 (i.e., w=1, x=0.9~1.2, y=0.9~1.4), or ·Si 100:O 92~107:C 116~133 (i.e. w=1, x=0.92~1.07, y=1.16~1.33) That is the case.

[0114] The atomic ratio can be determined by XPS. Therefore, in one embodiment, considering the H atoms that are not measured by XPS, the tie film or layer 289 is of the formula Siw O x C y H z (or equivalent SiO x C y ) may have, for example, in the formula, w is 1, x is approximately 0.5 to approximately 2.4, y is approximately 0.6 to approximately 3, and z is approximately 2 to approximately 9. Typically, the tie film or layer 289 contains 36% to 41% carbon normalized to 100% carbon + oxygen + silicon.

[0115] Optionally, the tie film or layer may have a composition similar to or identical to pH protective film or layer 286 described elsewhere in this specification, but this is not a requirement.

[0116] The tie film or layer 289 is generally intended to be 5 nm to 100 nm thick, preferably 5 nm to 20 nm thick, in any embodiment, especially when applied by chemical vapor deposition. These thicknesses are not critical. Generally, the tie film or layer 289 is relatively thin, but not necessarily so, as its function is to alter the surface properties of the substrate.

[0117] In some embodiments, the tie film or layer 289 may be omitted. In other embodiments, a thin tie film or layer 289 may be applied by pulsed RF PECVD. In addition to SiOxCy, the tie film or layer 289 applied by pulsed RF PECVD may be any material that is effective in improving the adhesion between the subsequently applied barrier film or layer 288 and the container wall 214 or any film already applied thereto. Such materials include metals and metal oxides, for example, Al2O3, TiO2, ZrO2, HfO2, Ta2O5, Nb2O5, Y2O3, MgO, CeO2, La2O3, SrTiO3, BaTiO3, Bi x Ti y O z , In2O3, In2O3:Sn, In2O3:F, In2O3:Zr, SnO2, SnO2:Sb, ZnO, ZnO:Al, Ga2O3, NiO, CoO x YBa2Cu3O 7-xThese include LaCoO3, LaNiO3, Si, Ge, Cu, Mo, Ta, and W. In some embodiments, zinc oxide (ZnO) or aluminum oxide (Al2O3) may be applied as a tie film or layer 289 by pulsed RF PECVD. Due to its adhesion to the polymer film, zinc oxide (ZnO) in particular can function as a high-quality tie film or layer 289.

[0118] When the tie film or layer 289 is coated by pulsed RF PECVD, the thickness of the tie film or layer can generally be 2 nm to 100 nm thick, preferably 2 to 20 nm thick. These thicknesses are not critical. Generally, the tie film or layer 289 is relatively thin, but not necessarily so, as its function is to alter the surface properties of the substrate.

[0119] In some embodiments, the barrier film or layer 288 may be divided into an oxygen barrier layer 301 and a moisture barrier layer 300, which may or may not be applied as adjacent films. Therefore, in some embodiments, the tie film or layer 289 may be applied between the container wall 214 and the barrier film 288, which includes both the oxygen barrier layer and the moisture barrier layer, by pulsed RF PECVD. However, in other embodiments, the film or layer 289 may be applied between the oxygen barrier layer 301 and the moisture barrier layer 300 by pulsed RF PECVD. For example, the moisture barrier layer 300 may be applied to the container wall 214 by pulsed RF PECVD, then the tie film or layer 289 may be applied, and then the oxygen barrier layer 301 may be applied.

[0120] For example, pulsed RF PECVD is used to create a moisture barrier layer (e.g., Al2O3), a tie film or layer 289, SiO2O3. x The oxygen barrier layer and the pH protective film or layer 286 are applied.

[0121] In other embodiments, multiple tie films or layers 289 may be applied. For example, a first tie film or layer 289 may be applied by pulsed RF PECVD, followed by a first barrier layer such as a moisture barrier (e.g., Al2O3), followed by a second tie film or layer, followed by a second barrier layer such as an oxygen barrier (e.g., SiOx), followed by a pH protective film or layer 286.

[0122] In yet another example, a moisture barrier layer (e.g., Al2O3) is coated onto the container wall by pulsed RF PECVD, and then SiO2O3 is applied. x An oxygen barrier layer is applied, followed by a pH protective film or layer 286.

[0123] Barrier layer The barrier film or layer 288 can optionally be deposited on the container of a pharmaceutical package, particularly a thermoplastic package, by pulsed RF PECVD to prevent oxygen, carbon dioxide, or other gases from entering the container and / or prevent pharmaceutical materials from entering into or through the packaging wall.

[0124] In any embodiment defined herein (unless otherwise specified in specific cases), the barrier film or layer is optionally a film or layer applied by pulsed RF PECVD as described herein. The barrier layer is optionally "SiO x Characterized as a film, comprising silicon, oxygen, and optionally other elements, where x is the ratio of oxygen atoms to silicon atoms, which is about 1.5 to about 2.9 or 1.5 to about 2.6 or about 2. These alternative definitions of x are as follows in this specification: SiO x This applies to any use of the term. The barrier film or layer is applied, for example, to the inside of pharmaceutical packaging or other containers, such as sample collection tubes, syringe barrels, vials, or other types of containers.

[0125] Barrier film 288 is SiO x Includes, or basically SiO xThe SiOx barrier film 288 can consist of a SiOx barrier film with a value of 1.5 to 2.9 and a thickness of 2 to 1000 nm, and has an inner surface 220 facing the lumen 212 and an outer surface 222 facing the wall 214 and the surface 254 of the article, and the barrier film 288 is effective in reducing the intrusion of atmospheric gas into the lumen 212 compared to an uncoated container 250. One suitable barrier composition is, for example, a composition in which x is 2.3.

[0126] For example, a barrier film or layer such as 288 of any embodiment can be applied with a thickness of at least 2 nm, at least 4 nm, at least 7 nm, at least 10 nm, at least 20 nm, at least 30 nm, at least 40 nm, at least 50 nm, at least 100 nm, at least 150 nm, at least 200 nm, at least 300 nm, at least 400 nm, at least 500 nm, at least 600 nm, at least 700 nm, at least 800 nm, or at least 900 nm. The barrier film or layer can have a maximum thickness of 1000 nm, a maximum of 900 nm, a maximum of 800 nm, a maximum of 700 nm, a maximum of 600 nm, a maximum of 500 nm, a maximum of 400 nm, a maximum of 300 nm, a maximum of 200 nm, a maximum of 100 nm, a maximum of 90 nm, a maximum of 80 nm, a maximum of 70 nm, a maximum of 60 nm, a maximum of 50 nm, a maximum of 40 nm, a maximum of 30 nm, a maximum of 20 nm, a maximum of 10 nm, or a maximum of 5 nm. A range of 2 to 100 nm, and optionally a range of 5 to 20 nm, is particularly intended, in which case the barrier film or layer is coated by pulsed RF plasma PECVD. A specific thickness range consisting of any one of the minimum thicknesses above plus any one of the maximum thicknesses above is also explicitly intended.

[0127] When the barrier film or layer is applied by pulsed RF PECVD, the thickness of the barrier film or layer may be, for example, 1 to 50 nm thick, alternatively 1 to 20 nm thick, alternatively 2 to 19 nm thick, or alternatively 2 to 15 nm thick.

[0128] The thickness of SiOx or other barrier films or layers can be measured, for example, by transmission electron microscopy (TEM), and their composition can be measured by X-ray photoelectron spectroscopy (XPS). The primer films or layers described herein can be applied to a variety of pharmaceutical packaging or other containers made from plastic or glass, such as plastic tubes, vials, and syringes.

[0129] A barrier film or layer 288 of SiOx with x = 1.5 to 2.9 is applied directly or indirectly to the thermoplastic wall 214 by pulsed RF PECVD (for example, a tie film or layer 289 may be interposed between them) in the filled pharmaceutical packaging or other container 210, such that the barrier film or layer 288 is positioned between the inner surface or inner surface 220 of the thermoplastic wall 214 and the fluid 218.

[0130] The SiOx barrier film or layer 288 is supported by the thermoplastic wall 214. The barrier film or layer 288 described elsewhere in this specification or in U.S. Patent No. 7,985,188 may be used in any embodiment.

[0131] Certain barrier coatings or layers 288, such as SiOx as defined herein, have been found to exhibit a measurable decrease in barrier improvement within six months when attacked by certain contents with relatively high pH in coated containers, particularly those in which the barrier coating or layer is in direct contact with the contents, as described elsewhere herein. This problem can be addressed using pH-protective coatings or layers discussed herein.

[0132] SiO x The barrier film or layer 288 can also function as a primer film or layer 283, as discussed elsewhere in this specification.

[0133] In some embodiments, the barrier film or layer 288 has a higher density and fewer defects than similar barrier films deposited by other methods, and is made of the aforementioned SiO xIt can be applied by pulsed RF PECVD, such as for barrier coatings. As a result, the barrier film or layer 288 can have a thinner thickness while still providing the same oxygen barrier properties compared to a barrier film or layer applied by conventional PECVD. It has also been shown that even when the barrier film or layer 288 applied by pulsed RF PECVD according to the embodiments of this disclosure is applied in a thin thickness, it can have improved gas barrier properties compared to a barrier film or layer of the same composition applied by conventional (non-pulsed) PECVD.

[0134] In some embodiments, the barrier film or layer 288 may include one or more layers in addition to the SiOx layer described above. For example, in some embodiments, one or more additional barrier layers may be applied.

[0135] In some embodiments, it may be desirable to apply an additional moisture barrier layer, i.e., a water vapor barrier layer, in addition to the SiOx oxygen barrier. For example, some plastic materials that can constitute a container wall may themselves possess suitable moisture barrier properties, while other plastic materials may require the application of one or more moisture barrier films or layers. In some embodiments, the moisture barrier film or layer may be applied by pulsed RF PECVD as described herein.

[0136] In some embodiments, for example, the barrier film or layer 288 may include both (i) an oxygen barrier layer of SiOx applied by pulsed RF PECVD and (ii) a moisture barrier layer of Al2O3 applied by pulsed RF PECVD. Depositing these layers in the same process reduces the number of process steps, thereby improving yield and shortening process time. The oxygen barrier layer and the moisture barrier layer may be applied sequentially adjacent to each other, or separated by one or more films or layers (e.g., the tie films or layers described above). When applied sequentially, SiO x The oxygen barrier layer may be applied first, followed by the moisture barrier layer, or vice versa.

[0137] In alternative embodiments, the barrier film or layer 288 may include, or essentially consist of, any one or more materials that provide adequate oxygen and / or moisture barrier properties to the container. Such materials include metals and metal oxides, e.g., Al2O3, TiO2, ZrO2, HfO2, Ta2O5, Nb2O5, Y2O3, MgO, CeO2, La2O3, SrTiO3, BaTiO3, Bi x Ti y O z , In2O3, In2O3:Sn, In2O3:F, In2O3:Zr, SnO2, SnO2:Sb, ZnO, ZnO:Al, Ga2O3, NiO, CoO x YBa2Cu3O 7-x These may include LaCoO3, LaNiO3, Si, Ge, Cu, Mo, Ta, and W. In some embodiments, one or more materials may be provided by atomic layer deposition (ALD).

[0138] pH protective film or layer The inventors of the present invention have found that SiO x It has been found that the barrier layer or coating can be corroded or dissolved by certain fluids, such as aqueous compositions with a pH greater than approximately 5. Because coatings applied by chemical vapor deposition can be very thin—tens to hundreds of nanometers thick—even relatively slow corrosion can render the barrier layer ineffective or reduce its effectiveness in a shorter time than the desired shelf life of the product packaging. This is particularly problematic in the case of fluid pharmaceutical compositions, as many of them have a pH of approximately 7 or more broadly in the range of 5 to 9, similar to the pH of blood and other human or animal fluids. The higher the pH of the pharmaceutical, the more SiO2 x The coating corrodes or dissolves more rapidly. Optionally, this problem can be addressed by protecting the barrier coating or layer 288 or other pH-sensitive materials with a pH-protective coating or layer 286.

[0139] Optionally, the pH protective film or layer 286 is made of the previously defined Si w O x C y Hz (or its equivalent, SiO x C y ) or Si w N x C y H z Or its equivalent Si(NH) x C y It is composed of, contains, or can essentially consist of. The atomic ratio of Si:O:C: or Si:N:C can be determined by XPS (X-ray photoelectron spectroscopy). Taking the H atom into account, the pH protective film or layer is therefore, in one embodiment, of the formula Si w O x C y H z or its equivalent SiO x C y It can have such that, for example, in the formula, w is 1, x is approximately 0.5 to approximately 2.4, y is approximately 0.6 to approximately 3, and z is approximately 2 to approximately 9.

[0140] Typically, formula Si w O x C y When expressed as such, the atomic ratios of Si, O, and C are, among several options, ·Si 100:O 50~150:C 90~200 (i.e. w=1, x=0.5~1.5, y=0.9~2); ·Si 100:O 70~130:C 90~200 (i.e. w=1, x=0.7~1.3, y=0.9~2) ·Si 100:O 80~120:C 90~150 (i.e. w=1, x=0.8~1.2, y=0.9~1.5) ·Si 100:O 90~120:C 90~140 (i.e. w=1, x=0.9~1.2, y=0.9~1.4), ·Si 100:O 92~107:C 116~133 (i.e., w=1, x=0.92~1.07, y=1.16~1.33), or Si 100:O 80~130:C 90~150 That is the case.

[0141] Alternatively, the pH protective film or layer may have atomic concentrations of less than 50% carbon and more than 25% silicon, normalized to 100% carbon, oxygen, and silicon, as determined by X-ray photoelectron spectroscopy (XPS). Alternatively, the atomic concentrations may be 25-45% carbon, 25-65% silicon, and 10-35% oxygen.

[0142] Alternatively, the atomic concentrations are 30-40% carbon, 32-52% silicon, and 20-27% oxygen. Alternatively, the atomic concentrations are 33-37% carbon, 37-47% silicon, and 22-26% oxygen.

[0143] The thickness of the pH protective film or layer can be, for example, 10nm to 1000nm; alternatively 10nm to 1000nm; alternatively 10nm to 900nm; alternatively 10nm to 800nm; alternatively 10nm to 700nm; alternatively 10nm to 600nm; alternatively 10nm to 500nm; alternatively 10nm to 400nm; alternatively 10nm to 300nm; alternatively 10nm to 200nm; alternatively 10nm to 100nm; alternatively 10nm to 50nm; alternatively 20nm to 1000nm; alternatively 50nm to 1000nm; alternatively 10nm to 1000nm; alternatively 50nm to 800nm; alternatively 100nm to 700nm; or alternatively 300nm to 600nm.

[0144] Optionally, the atomic concentration of carbon in the protective layer, normalized to 100% carbon, oxygen, and silicon as determined by X-ray photoelectron spectroscopy (XPS), can be greater than the atomic concentration of carbon in the atomic formula of the organosilicon precursor. For example, embodiments are envisioned in which the atomic concentration of carbon is increased by 1 to 80 atomic percent, alternatively 10 to 70 atomic percent, alternatively 20 to 60 atomic percent, alternatively 30 to 50 atomic percent, alternatively 35 to 45 atomic percent, and alternatively 37 to 41 atomic percent.

[0145] Optionally, the atomic ratio of carbon to oxygen in the pH protection film or layer can be increased compared to the organosilicon precursor, and / or the atomic ratio of oxygen to silicon can be reduced compared to the organosilicon precursor.

[0146] Optionally, the pH protection film or layer can have a silicon atomic concentration lower than that in the atomic formula of the feed gas, normalized to 100% carbon, oxygen, and silicon, as determined by X-ray photoelectron spectroscopy (XPS). For example, embodiments are contemplated where the silicon atomic concentration is reduced by 1-80 atomic percent, alternatively 10-70 atomic percent, alternatively 20-60 atomic percent, alternatively 30-55 atomic percent, alternatively 40-50 atomic percent, alternatively 42-46 atomic percent.

[0147] As another option, in any embodiment, a pH protection film or layer is contemplated that can be characterized by a total formula that increases the atomic ratio C:O and / or decreases the atomic ratio Si:O compared to the total formula of the organosilicon compound precursor.

[0148] The pH protection film or layer 286 is generally disposed between the barrier film or layer 288 and the fluid 218 in the finished product. The pH protection film or layer 286 is supported by the thermoplastic wall 214.

[0149] The pH protection film or layer 286 is optionally effective to maintain the barrier film or layer 288 from substantially dissolving, at least, upon exposure to the fluid 218 for a period of at least six months.

[0150] The pH protection film or layer has a density of 1.25 - 1.65 g / cm 3 , alternatively 1.35 - 1.55 g / cm 3 , alternatively 1.4 - 1.5 g / cm 3 , alternatively 1.4 - 1.5 g / cm 3 , alternatively 1.44 - 1.48 g / cm 3It can have a density of octamethylcyclotetrasiloxane as the organosilicon compound, and the pH protective film or layer can have a density that is higher than that of the pH protective film or layer made from HMDSO as the organosilicon compound under the same PECVD reaction conditions.

[0151] The pH protective film or layer can optionally prevent or reduce precipitation of compounds or components of compositions in contact with the pH protective film or layer compared to an uncoated surface and / or a barrier coating surface using HMDSO as a precursor, and in particular can prevent or reduce insulin precipitation or blood coagulation.

[0152] The pH protective film or layer may optionally have an RMS surface roughness value (measured by AFM) of approximately 5 to 9, optionally 6 to 8, or optionally 6.4 to 7.8. The Ra surface roughness value of the pH protective film or layer, measured by AFM, may be approximately 4 to 6, or optionally 4.6 to 5.8. The Rmax surface roughness value of the pH protective film or layer, measured by AFM, may be approximately 70 to 160, optionally 84 to 142, or optionally 90 to 130.

[0153] The inner surface of the pH protection can have a contact angle (with distilled water) of 90° to 110°, optionally 80° to 120°, or optionally 70° to 130°, when measured by goniometer angle measurement of a water droplet on the pH protection surface, in accordance with ASTM D7334-08 "Standard Practice for Surface Wettability of Coatings, Substrates and Pigments by Advancing Contact Angle Measurement".

[0154] The passivation layer or pH protective film or layer 286 may be optionally selected. O parameter = (1253cm) -1Intensity at 1000 - 1100 cm -1 (maximum intensity within the range of) shows an O parameter of less than 0.4, measured using attenuated total reflection (ATR), as measured.

[0155] The O parameter is defined in U.S. Patent No. 8,067,070, which claims an O parameter value most broadly in the range of 0.4 - 0.9. 1253 cm -1 with an absorbance of 0.0424 at 1000 - 1100 cm -1 annotated to show an O parameter of 0.53, calculated as a result of interpolation of the wavenumber and absorbance scale to obtain a maximum absorbance of 0.08 at 1000 - 1100 cm

[0156] <> In U.S. Patent No. 8,067,070, it is claimed that the claimed range of the O parameter provides an excellent pH - protecting film or layer, relying on experiments with only HMDSO and HMDSN, both of which are acyclic siloxanes. Surprisingly, the inventors have found that when the PECVD precursor is a cyclic siloxane, such as OMCTS, the O parameter of using OMCTS outside the range claimed in U.S. Patent No. 8,067,070 can provide even better results than those obtained in U.S. Patent No. 8,067,070 using HMDSO.

[0157] Alternatively, in the embodiments of FIGS. 1 - 5, the O parameter has a value of 0.1 - 0.39, or 0.15 - 0.37, or 0.17 - 0.3

[0158] Yet another aspect of the present invention is the composite material described above and illustrated in FIGS. 1 - 5, wherein the passivation layer is N parameter = (850 cm -1Strength at 799cm -1 (Intensity in) This shows the N-parameter, which is less than 0.7, measured using attenuated total reflection (ATR).

[0159] The N parameter is also described in U.S. Patent No. 8,067,070 and is measured similarly to the O parameter, except that the intensity at two specific wavenumbers—neither of which is within the range—is used. U.S. Patent No. 8,067,070 claims an inactivating layer having an N parameter of 0.7 to 1.6. Similarly, the inventors have produced better coatings using pH protective coatings or layer 286 having an N parameter below 0.7, as described above. Alternatively, the N parameter may have a value of at least 0.3, or 0.4 to 0.6, or at least 0.53.

[0160] The rate of corrosion, melting, or elution of the pH protective film or layer 286 when in direct contact with the fluid 218 (different names in related concepts) is less than the corrosion rate of the barrier film or layer 288 when in direct contact with the fluid 218.

[0161] In any embodiment, the thickness of the pH protective film or layer is intended to be in the range of 50 to 500 nm, preferably 100 to 200 nm.

[0162] The pH protective film or layer 286 is effective in separating the fluid 218 from the barrier film or layer 288 for at least a sufficient amount of time to allow the barrier film to function as a barrier throughout the storage life of the pharmaceutical packaging or other container 210.

[0163] SiO formed from a polysiloxane precursor, where the pH protective film or layer has a considerable amount of organic components. x C y or Si(NH) x C yCertain pH protective coatings or layers do not erode rapidly when exposed to fluids; in fact, erosion or dissolution is relatively slow when the fluid has a high pH in the range of 5-9. For example, at pH 8, the dissolution rate of pH protective coatings or layers made from the precursor octamethylcyclotetrasiloxane, i.e., OMCTS, is very slow. Therefore, SiOxC y or Si(NH) x C y These pH-protective films or layers can be used to coat the SiOx barrier layer, preserving the benefits of the barrier layer by protecting it from fluids within the pharmaceutical packaging. The protective layer is applied to at least a portion of the SiOx layer, protecting the SiOx layer from contents stored in the container, otherwise the contents would come into contact with the SiOx layer.

[0164] Although this invention does not rely on the accuracy of the following theory, it is believed that a pH protective film or layer effective in avoiding erosion can be produced from the siloxanes and silazanes described herein. A cyclic siloxane or linear silazane precursor, for example, SiO deposited from octamethylcyclotetrasiloxane (OMCTS) x C y or Si(NH) x C y The coating is thought to contain relatively long, continuous repeating units of intact cyclic siloxane rings and precursor structures. These coatings are thought to be nanoporous, yet structured and hydrophobic, and these properties are thought to contribute to their success as pH-protective coatings or layers, and as protective coatings or layers. This is illustrated, for example, in U.S. Patent No. 7,901,783.

[0165] SiO x C y or Si(NH) x C y The coating can also be deposited from linear siloxanes or linear silazane precursors, such as hexamethyldisiloxane (HMDSO) or tetramethyldisiloxane (TMDSO).

[0166] Optionally, the FTIR absorbance spectrum of the pH protective film or layer 286 of any embodiment is greater than 0.75, typically around 1000 cm⁻¹. -1 and 1040cm -1 The maximum amplitude of the Si-O-Si symmetric stretching peak located between these two points is typically around 1060 cm. -1 and approximately 1100cm -1 It has a ratio with respect to the Si-O-Si asymmetric stretching peak located at . Alternatively, in any embodiment, this ratio can be at least 0.8, at least 0.9, at least 1.0, at least 1.1, or at least 1.2. Alternatively, in any embodiment, this ratio can be at most 1.7, at most 1.6, at most 1.5, at most 1.4, or at most 1.3. Any minimum ratio described herein can be combined with any maximum ratio described herein.

[0167] Optionally, in any embodiment, the pH protective film or layer 286 in the absence of the agent has a non-oily appearance. This appearance has been shown to distinguish, in some cases, an effective pH protective film or layer from a lubricating layer which may have an oily (i.e., glossy) appearance.

[0168] Optionally, for any pH protective coating or layer 286 in any embodiment, the silicon dissolution rate in 50 mM potassium phosphate buffer at 40°C is less than 170 ppb / day, diluted with sterile 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 agent to avoid changes in the dissolving reagent). (Polysorbate 80 is a common formulation ingredient available, for example, as Tween®-80 from Uniqema Americas LLC, Wilmington, Delaware.)

[0169] Optionally, for any embodiment of the pH protective coating or layer 286, the silicon dissolution rate is less than 160 ppb / day, less than 140 ppb / day, less than 120 ppb / day, less than 100 ppb / day, less than 90 ppb / day, or less than 80 ppb / day. Optionally, in any embodiment, the silicon dissolution rate is greater than 10 ppb / day, or greater than 20 ppb / day, greater than 30 ppb / day, greater than 40 ppb / day, greater than 50 ppb / day, or greater than 60 ppb / day. For any embodiment of the pH protective coating or layer 286, any minimum rate described herein can be combined with any maximum rate described herein.

[0170] Optionally, for any embodiment of the pH protective coating or layer 286, the total silicon content of the pH protective film or layer and barrier film when dissolved from the container into the pH 8 test composition is less than 66 ppm, less than 60 ppm, less than 50 ppm, less than 40 ppm, less than 30 ppm, or less than 20 ppm.

[0171] The inventors of this invention provide the following theory of action of the pH protective film or layer described herein. The present invention is not limited to the accuracy of this theory or to the embodiments that can be predicted by using this theory.

[0172] SiO x The dissolution rate of the barrier layer is thought to depend on the SiO bonds within the layer. Oxygen-bonded sites (silanols) are thought to increase the dissolution rate.

[0173] The pH protective film or layer is thought to dramatically reduce the dissolution rate by binding to the silanol moieties of the SiOx barrier layer and "repairing," i.e., passivating, the SiOx surface. In this hypothesis, the thickness of the pH protective layer is not the primary protective measure—the primary measure is passivation of the SiOx surface. In any embodiment, it is intended that the pH protective film or layer described herein can be improved by increasing the crosslinking density of the pH protective film or layer.

[0174] Hydrophobic layer Si w Ox C y or its equivalent SiO x C y Suitable hydrophobic films or layers, and their uses, properties, and applications, are described in U.S. Patent No. 7,985,188. Dual-function protective / hydrophobic films or layers having the properties of both types of films or layers can be provided in any embodiment of the present invention.

[0175] One embodiment can be carried out under conditions effective for forming a hydrophobic pH protective film or layer on a substrate. Optionally, the hydrophobic properties of the pH protective film or layer can be set by setting the ratio of O2 to the organosilicon precursor in the gas reactant and / or by setting the power used to generate the plasma. Optionally, the pH protective film or layer may have a lower wetting tension than the uncoated surface, optionally 20-72 dyne / cm, optionally 30-60 dyne / cm, optionally 30-40 dyne / cm, or optionally 34 dyne / cm. Optionally, the pH protective film or layer may have higher hydrophobicity than the uncoated surface.

[0176] The use of a film or layer according to any described embodiment is intended in any embodiment to be (i) a lubricating film having lower frictional resistance than an uncoated surface, (ii) a pH-protective film or layer that prevents dissolution of a barrier film in contact with a fluid, and / or (iii) a hydrophobic layer that is more hydrophobic than an uncoated surface.

[0177] Pulsed RF PECVD System Figure 6 shows a pulsed RF PECVD reactor according to one embodiment of the present disclosure. Referring to Figure 6, a pulsed RF PECVD reactor 600 is shown, comprising an RF power supply 601, an RF electrode 603, a container cavity 605, a camera 607, an exhaust manifold 609, a gas inlet manifold 611, and a vacuum line 613. At the bottom of each container cavity 605 are container holders 1105, 1107, with container openings positioned thereto, through which precursor gas flows into the container (from the gas inlet manifold 611) and exhaust gas flows out of the container (to the exhaust manifold 609).

[0178] The RF power supply 601 may include, for example, a circuit suitable for supplying an RF signal of a desired power level, duty cycle, pulse duration, and frequency to the RF electrode 603. The RF power supply 601 may include an adjustable matching impedance network to adjust the output impedance to match the RF electrode 603. The RF power supply 601 may provide an RF voltage with a resolution of 100 mV to optimally control the plasma. In addition, the generated RF signal may have high-power pulses of 250 W to 1000 W, but the power can be increased to several kW depending on other parameters. Low-power pulses may be 0 W, and the power frequency may be, for example, 13.65 MHz. The duty cycle may vary between 1% and 99%, preferably between 50% and 99%. The pulse train frequency may be in the range of 250 Hz to 5000 Hz, and the range may be extended up to 10000 Hz.

[0179] The RF electrode 603 may include a metal component that transmits an RF signal from an RF power source to individual PECVD chambers defined by the container cavity 605 and the container itself. The RF electrode 603 has a plurality of orifices on its upper surface, within which the covered containers are positioned in the individual container cavities 605.

[0180] The vessel cavity 605 contains portions of the vessel to be covered, each comprising portions of RF electrodes 603 that substantially surround the vessel wall. The potential between the RF electrodes 603 and a grounding plate (not shown) is configured to generate plasma using the input gas provided by the gas inlet manifold 611. In this example, there are 16 vessel cavities 605 in two rows of eight, but the disclosure is not limited thereto.

[0181] In some embodiments, the vessel cavity 605 may have a “window” opening 603A in the wall of the RF electrode 603 that defines the vessel cavity, allowing a camera 607 to view the plasma generated in each vessel by the applied RF signal, as shown, for example, in Figure 29. In some embodiments, each vessel cavity 605 is provided with only one window opening. Conventional systems have multiple windows, for example, to improve plasma stability. However, the planar electrode 603 and vessel cavity 605 of this design allow the wall of the RF electrode defining each vessel cavity to have only one window. Since gaps in electrodes, such as windows, generally reduce coating uniformity, this reduction to only one window allows for a more uniform coating applied to the inner surface of the vessel wall.

[0182] Camera 607 may include, for example, a CCD or CMOS imaging sensor for monitoring deposition. Camera 607 may be used to monitor the plasma intensity, uniformity, and / or color to ensure, for example, that the plasma conditions are correctly configured for deposition and / or maintained during film deposition. In some embodiments, such as those shown in Figures 6 to 10, two or more cameras may be required to monitor the deposition in all, for example, 16 chambers. In the illustrated embodiment, for example, camera 607 may be positioned on each side of electrode 603. In other embodiments, including, for example, those shown in Figure 29, the vessel cavities 605 may be positioned and configured so that a single camera 607 can be used to monitor the plasma in all vessels during coating. For example, as shown in Figure 29, by alternating the vessel cavities 605 in the first row with the vessel cavities in the second row, each cavity may have a single window 603a, and all windows face the same direction. Therefore, one or more cameras 607, preferably the cameras shown in the illustrated embodiments, may be positioned on one side of the electrode 603 and used to monitor the plasma conditions in the vessels contained in the cavities of both rows during the PECVD coating process.

[0183] In one embodiment, camera 607 can capture and examine images of plasma in the visible light range. In another embodiment, camera 607 can capture and examine images of plasma in the infrared range. In yet another embodiment, camera 607 can capture and examine images of plasma in the ultraviolet (UV) range. By capturing and examining light within one or more of these wavelength ranges, the quality of the plasma process can be assessed.

[0184] The captured images may be examined by a processor operably linked to camera 607 and optionally further operably linked to a display and / or user interface. Examination of the images captured by camera 607 may alert the operator if the plasma in one or more vessels is outside a predefined and acceptable range of one or more properties, such as intensity, uniformity, or color, and may allow adjustment of one or more PECVD variables (e.g., gas flow rate, vacuum level, RF power level, pulse rate, etc.) and / or halt the process for system maintenance. Vessels in which the plasma is deemed unacceptable may be discarded.

[0185] The discharge manifold 609 allows multiple discharge outputs to be combined into one, enabling a single vacuum system / pump to equally vacuum multiple chambers, and thus providing a network of gas flow lines that deliver a uniform, consistently reproducible vacuum within each of the multiple vessel lumens. In this example, each of the discharge manifolds 609 on either side combines the outputs from the eight vessel lumens into a single output line, and each output line is coupled together in the vacuum line 613.

[0186] The vacuum line 613 can provide a vacuum to the container cavity via the discharge manifold 609, and the vacuum can be enabled by one or more pumps (not shown). By providing the same pressure to each container, inter-container uniformity in the deposition process can be ensured.

[0187] The gas inlet manifold 611 divides a single input gas line into multiple input lines to supply gas to the covered vessels, so that a single input port 611A can supply gas equally to each vessel, and thus provides a network of gas flow lines that provide a uniform, consistently reproducible precursor gas flow in each of the multiple vessel lumens. In this example, the gas inlet manifold divides the output of the gas input port 611A equally among 16 vessels.

[0188] Figure 7 shows a side view of a pulsed RF PECVD reactor according to one embodiment of the present disclosure. Referring to Figure 7, a pulsed RF PECVD reactor 600 is shown, comprising an RF electrode 603, a camera 607, an exhaust manifold 609, a gas inlet manifold 611, and a vacuum line 613.

[0189] This side view of the pulsed RF PECVD reactor 600 shows the orientation of the gas inlet manifold 611 and the exhaust manifold 609, which is also located on the opposite side of the inlet manifold. In other embodiments, the gas inlet manifold 611 and the exhaust manifold 609 may be oriented in the opposite direction to that shown in the illustrated embodiment, such that the exhaust manifold is substantially centrally located and the gas inlet manifold is located on two opposing sides of the exhaust manifold.

[0190] Figure 8 shows a top view of a pulsed RF PECVD reactor according to one embodiment of the present disclosure. Referring to Figure 8, a pulsed RF PECVD is shown comprising an RF electrode 603, a vessel cavity 605, and a camera 607.

[0191] The top view of the pulsed RF PECVD reactor 600 shows the vessel cavity 605 at the RF electrode 603. The two rows of vessel cavities, each containing eight vessels, allow for the simultaneous processing of 16 vessels. In addition, the RF electrode 603 extends from the interconnect on the RF power supply 601 to the upper plate on which the portion of the RF electrode defining the vessel cavity 605 extends.

[0192] Figures 9 and 10 show various diagrams of an RF electrode according to one embodiment of the present disclosure. Referring to Figure 9, a side view and a top view of the RF electrode 603 are shown, the top view showing 16 container cavities 605 in which the covered containers are arranged, and the side view showing the vertical spread of the container cavities below the top surface of the RF electrode 603. In one scenario example, the RF electrode contains copper, but other metals are also possible depending on the desired conductivity.

[0193] Figure 10 is an oblique view of the RF electrode 603 showing 16 vessel cavities 605. The figure shows cylindrical vessel cavities that enable a uniform plasma in the covered vessel.

[0194] Figure 11 shows a pulsed RF PECVD vessel deposition apparatus according to one embodiment of the present disclosure. Referring to Figure 11, a cross-sectional view and an enlarged cross-sectional view of a vessel 210, here in a vial, is shown, with the opening of the vessel 210 facing downward in the vessel holder 1105 and positioned within the vessel cavity 605. In this example, a gas delivery probe 1101 for supplying one or more precursor gases to the vessel 210 during the pulsed PECVD deposition process is also shown. In addition, the gas delivery probe 1101 may function as an internal electrode (which may include, for example, metal and be grounded), so that an electric field is generated with the RF electrode 603 providing an RF signal, thereby igniting plasma inside the vessel 210 during the deposition process.

[0195] Figure 11 also shows a plasma screen 1107 that extends across the opening of the vacuum port 1103, ensuring that the plasma is confined above the screen 1107 and within the container 210. In any embodiment, the plasma screen 1107 may take any of a variety of forms. In some embodiments, for example, the plasma screen 1107 may include a perforated grid, such as a perforated metal disc or perforated metal plate, as shown in the illustrated embodiment. In other embodiments, the plasma screen 1107 may include a metal mesh.

[0196] During the pulsed plasma PECVD coating process, one or more precursor gases flow from the gas inlet manifold 611 to the gas delivery probe 1101 and into the vessel 210, where a plasma can be generated by a pulsed RF signal, thereby causing the deposition of the desired film on the inner surface of the vessel's walls. A desired level of vacuum is maintained by the gas flow through the vacuum port 1103 to the discharge manifold 609 described above. Since the outlet of the gas delivery probe 1101 is located near the end of the vessel opposite the opening being vacuumed, the precursor gas flows along the length of the vessel, providing a substantially uniform gas distribution and allowing the film to be applied substantially uniformly along the vessel walls.

[0197] While the gas delivery probe 1101 can provide a uniform gas distribution within the container 210, in other embodiments, the probe 1101 can be eliminated by pulsing the RF field that generates the plasma, because the pulses (and precursor gas flow) can be controlled to provide sufficient time between pulses for the precursor gas to disperse within the container before each pulse. An example of such an embodiment is shown in Figure 12.

[0198] Figure 12 shows a pulsed RF PECVD vessel coating system without a gas delivery probe according to one embodiment of the present disclosure. Referring to Figure 12, similar to Figure 11, but without a gas delivery probe inside the vessel 210, the vessel 210 is located in the vessel cavity 605, and cross-sectional and enlarged cross-sectional views of the vial are shown here. In this example, a precursor gas inlet line 1201 is present but does not extend into the lumen of the vessel 210. Instead, the gas inlet line 1201 extends across the opening of the gas inlet line and is separated from the lumen of the vessel by a plasma screen 1107, which ensures that the plasma is confined above the screen 1107 and inside the vessel 210.

[0199] Similar to the apparatus shown in Figure 11, the opening of the container 210 is oriented downward in the container holder 1105. In this example, with the RF electrode 603 providing an RF signal, an electric field is generated between the RF electrode 603 and the plasma screen 1107, which can function as an “internal” (in this case, not inside the container) electrode (which may include, for example, metal and be grounded) to ignite the plasma within the container 210 during the deposition process. In the illustrated embodiment, the plasma screen 1107 extends over both the outlet of the gas inlet line 1201 and the inlet of the vacuum port 1103. However, in other embodiments, the first plasma screen 1107 may be associated with the gas inlet line 1201 and the second plasma screen 1107 may be associated with the vacuum port 1103.

[0200] Figure 13 shows a pulsed RF PECVD barrel coating system configured to coat the inner surface of a syringe barrel and without an inlet probe, according to one embodiment of the present disclosure. Referring to Figure 13, a cross-sectional and enlarged cross-sectional view of a syringe barrel 252 located in a vessel cavity 605 is shown, similar to that shown in Figure 12, but without a gas inlet probe. In this example, the gas inlet line 1201 is rather separated from the lumen of the syringe barrel 252 from the screen 1107. In another (non-limiting) embodiment, the pulsed RF PECVD syringe barrel coating system may include a gas inlet probe extending into the lumen of the syringe barrel 252, similar to the system shown in Figure 11.

[0201] Similar to the apparatus shown in Figures 11 and 12, the rear opening of the syringe barrel 252 is directed downward in the container holder 1105. In this example, with the RF electrode 603 providing an RF signal, an electric field is generated between the RF electrode 603 and the plasma screen 1107, which can function as an "internal" (in this case, not inside the container) electrode (which may contain, for example, metal and be grounded) to ignite the plasma within the lumen of the syringe barrel 252 during the deposition process.

[0202] Figures 14, 15, and 16 show a pulsed RF PECVD system configured to provide a coating on both the inner and outer surfaces of a container, according to one embodiment of the present disclosure. Referring to Figure 14, a pulsed RF PECVD system 1400 is shown having four container chambers 1401A to 1401D, each chamber operable to deposit one or more coatings or layers on the inner surface of the container and one or more coatings or layers on the outer surface of the container. An example of a coating that is desired to be applied to the outer surface of the container 201 is an antistatic coating, as static charge could lead to contaminants being drawn into the container. Figure 15 shows a cross-sectional view of the quad pulsed RF PECVD coating system 1400 of Figure 14, having deposit chambers 1401A and 1401B. Figure 16 shows a cross-sectional view of a single container coating system, further detailing, for example, a single deposit chamber 1401A.

[0203] In addition to the components described above with respect to any embodiment shown in Figures 6 to 13 (or the alternative embodiments not shown above), the system may also include an upper sealing element 1411 which covers and closes the container 210 when the container is inserted into the container cavity 605 of the electrode 603. In this way, the covering chamber 1413 may be formed around the outer wall of the container 210.

[0204] At least a portion of the upper sealing element 1411 may be a metallic component that acts as part of the PECVD coating process of the electrode 603. In the illustrated embodiment, for example, element 1411A, which contacts the electrode 603 and forms part of the wall of the coating chamber 1413, is a metallic component that functions as part of the outer electrode during the PECVD coating process. Preferably, element 1411A is made of the same metal as the electrode 603. For example, if the electrode 603 is copper, then element 1411A is also preferably copper. Alternatively, if the electrode 603 is aluminum, then element 1411A is also preferably aluminum.

[0205] In some embodiments, such as those shown in Figures 14-15, the upper sealing element 1411 may comprise, or be operably connected to, a precursor gas inlet manifold 1405 for supplying one or more precursor gases to the chamber 1413, a vacuum / discharge manifold 1403 for providing a desired vacuum to the chamber 1413. For example, the upper sealing element 1411 in the illustrated embodiment comprises (a) a gas inlet manifold 1405 and associated gas inlet 1201 for introducing one or more precursor gases to the chamber 1413, and (b) a discharge manifold 1403 and associated vacuum port 1103 for discharging exhaust gas from the chamber 1413 to maintain a desired vacuum. The precursor gas inlet 1201 and the exhaust gas outlet, i.e., the vacuum port 1103, may be configured similarly to those shown in Figures 12 and 13 (for coating the inner surface of the container). For example, both the precursor gas inlet and the exhaust gas outlet can be separated from the chamber 1413 by the plasma screen 1107, as described herein.

[0206] In other (not shown) embodiments, a gas inlet manifold 1405 and associated gas inlet 1201 for introducing one or more precursor gases into chamber 1413, an exhaust manifold 1403 and associated outlet 1103 for expelling exhaust gases from chamber 1413, or both, may be associated with a container holder 1105 instead of an upper sealing element 1411. In some embodiments, for example, the gas inlet manifold 1405 and associated inlet for introducing one or more precursor gases into chamber 1403 may be located at one end of the container, for example, in association with one of the upper sealing element 1411 and the container holder 1105, and the exhaust manifold 1403 and associated outlet for creating a vacuum in chamber 1403 may be located at the other end of the container, for example, in association with the other of the upper sealing element and the container holder. In such an embodiment, the precursor gases travel along the length of the container between the gas inlet and the exhaust outlet.

[0207] The RF electrode 603 (and optionally 1411A as described above) may provide an RF electric field to ignite a plasma inside the container 210 for coating one or more PECVD films on the inner surface of the container as described above. In this embodiment, the RF electrode 603 (and optionally 1411A as described above) may also provide an RF electric field to ignite a plasma inside the chamber 1413 for coating one or more PECVD films on the outer surface of the container. The plasma inside the chamber 1413 may be ignited, for example, by generating an electric field using the gas probe inlet 1101 and / or plasma screen 1107 as grounded "internal" electrodes (although the screen itself is not inside either the container or the chamber). The plasma may be formed inside either the container 210 or the chamber 1413 by controlling the gas flow to each (for example, if there is no gas flow in the chamber 1413, no plasma will be formed in that chamber, and if there is no gas flow in the container 210, no plasma will be formed in the container).

[0208] Figure 16 shows a cross-sectional view of a single-container pulsed RF PECVD coating system 1600 configured to coat both the inner and outer surfaces of a container, according to one embodiment of the present disclosure. Gas inlets at the top and bottom provide source gas to the outer and inner surfaces of the container 210, respectively. An inlet gas probe 1101 may provide source gas to the interior of the container 201. As with the other embodiments described above, an RF electrode such as the RF electrode 603 (and optionally an element 1411A of the upper sealing element) may provide an RF signal such that an electric field is generated between the RF electrode 603 and the inlet gas probe 1101, thereby igniting a plasma within the container 210 during deposition. In alternative embodiments, the system may be configured without the gas inlet probe 1101, as described above with respect to the embodiments shown in Figures 12 and 13.

[0209] PECVD coating process To execute the process, basically, a container 210 is provided that includes a wall 214 made of a thermoplastic polymer material that defines an inner cavity 212. Optionally, in any embodiment, the wall comprises polyester, polyethylene terephthalate (PET), polyethylene naphthalate (PEN); polyolefin, cyclic block copolymer (CBC), cyclic olefin polymer (COP), cyclic olefin copolymer (COC), polypropylene (PP), or polycarbonate, preferably COP, COC, or CBC. Optionally, in any embodiment, the container inner cavity has a volume of 2 to 12 mL, optionally 3 to 5 mL, optionally 8 to 10 mL. The wall 214 has an inner surface 303 facing the inner cavity and an outer surface 305.

[0210] A partial vacuum is drawn into the inner cavity. In some embodiments, for example, the partial vacuum can be from about 20 to about 60 millitorr, alternatively from about 30 to about 50 millitorr.

[0211] While maintaining the partial vacuum within the inner cavity without breaking it, the SiOxCy thin film or layer 289 is optionally applied by a pulsed PECVD thin layer coating step that includes applying pulsed RF power (alternatively, the same concept is referred to herein as "energy") sufficient to generate a plasma within the inner cavity while supplying a siloxane precursor, preferably a linear siloxane precursor, optionally a precursor gas containing oxygen, and optionally an inert gas diluent to stabilize the plasma. In some embodiments, the precursor gas can be introduced and the ratio of the gas components can be stabilized prior to plasma ignition. Then, while maintaining the partial vacuum within the inner cavity without breaking it, the plasma can be extinguished, which has the effect of stopping the application of the SiO x C y thin film or layer.

[0212] After the plasma used in the TiPECVD coating process has disappeared and before the barrier PECVD coating process is started, stop the supply of the gas employed in the TiPECVD coating process, for example, increase the ratio of oxygen to the siloxane precursor, and optionally replace or simply change to a gas supply more suitable for the deposition of the barrier film or layer by reducing or eliminating an inert gas (such as argon) from the gas supply.

[0213] While maintaining the partial vacuum inside the cavity without breaking it, the barrier film or layer 288 is applied by a pulsed PECVD barrier coating step that includes applying a pulsed RF power sufficient to generate a plasma inside the cavity while supplying a precursor gas containing siloxane, preferably linear siloxane and oxygen. In some embodiments, the precursor gas can be introduced and the ratio of the gas components can be stabilized before plasma ignition. After applying the barrier film or layer, the plasma can be extinguished while maintaining the partial vacuum inside the cavity without breaking it, which has the effect of stopping the application of the barrier film or layer. A barrier film or layer of SiOx where x is between 1.5 and 2.9 as measured by XPS is generated between the Ti film or layer and the cavity as a result of the barrier coating step.

[0214] After the plasma used in the barrier PECVD coating process has disappeared and optionally if a pH protection PECVD coating process is used, before the pH protection PECVD coating process is started, stop the supply of the gas employed in the barrier PECVD coating process, for example, decrease the ratio of oxygen to the siloxane precursor, and optionally replace or simply change to a gas supply more suitable for the deposition of the pH protection film or layer by increasing or introducing an inert gas (such as argon) to the gas supply.

[0215] Then, while maintaining the partial vacuum inside the cavity without breaking it, SiO x C yThe pH protective film or layer 286 can be applied by a pulsed RF PECVD pH protective coating step. The pH protective film or layer is optionally applied between the barrier film or layer and the lumen. The pH protective PECVD step involves applying sufficient pulsed RF power to generate plasma in the lumen while supplying a precursor gas containing a siloxane precursor, preferably a linear siloxane precursor, optionally oxygen, and optionally an inert gas diluent for stabilizing the plasma. In some embodiments, the precursor gas may be introduced and the ratio of gas components may be stabilized before plasma ignition.

[0216] If the pH protective coating layer is the last layer, the vacuum can be broken and the coated container can be removed. On the other hand, if another layer such as a lubricating layer is applied, the partial vacuum inside the lumen can be maintained without breaking, SiO x C y A lubricating film or layer can be applied by a pulsed RF PECVD lubrication coating step. The lubrication PECVD step involves applying sufficient pulsed RF power to generate a plasma in the lumen while supplying a precursor gas containing a siloxane precursor, preferably a linear siloxane precursor, optionally oxygen, and optionally an inert gas diluent for plasma stabilization. After the lubricating film is applied, the plasma can be extinguished while maintaining a partial vacuum in the lumen without disrupting it, which has the effect of stopping the application of the lubricating film or layer.

[0217] In any optional embodiment, each linear siloxane precursor used for the deposition of an optional tie film or layer, barrier film or layer, and optional pH protective film or layer may be hexamethyldisiloxane (HMDSO) or tetramethyldisiloxane (TMDSO), preferably HMDSO. In any optional embodiment, the same linear siloxane precursor is used in each coating process, which may be, for example, a tie PECVD coating process, a barrier PECVD coating process, and optionally a pH protective PECVD coating process. The use of the same siloxane allows for the use of the same coating equipment, eliminating the need for valve devices to supply different siloxanes and increasing the throughput of the coating process (by eliminating the time required to switch between gases). In any optional embodiment, the technology can be further generalized to the use of any plasma chemical vapor deposition process using any precursor to produce multiple films by employing the processes described herein or in the claims.

[0218] In any optional embodiment, the high-power RF pulses provided for generating plasma in the lumen to coat a barrier film or layer in the 16 upcoater such as those shown herein are 218–600 watts, optionally 218–436 watts, optionally 450–500 watts, and optionally 250–300 watts.

[0219] In any optional embodiment, the high-power RF pulses provided for generating plasma in the lumen to coat a tie film or layer in the 16 upcoater such as those shown herein are 100–350 watts, optionally 200–270 watts, optionally 135–350 watts, and optionally 100–200 watts.

[0220] In any optional embodiment, the high-power RF pulses provided to generate plasma in the lumen for coating a pH protective film or layer in the 16 upcoater such as those shown herein are 100–350 watts, optionally 200–270 watts, optionally 135–350 watts, and optionally 100–200 watts.

[0221] In any optional embodiment, the high-power RF pulses provided for generating plasma in the lumen to coat a lubricating film or layer in the 16 upcoater, such as those shown herein, are 2 to 1000 watts, and optionally 3 to 50 watts.

[0222] In any optional embodiment, the RF power provided to generate plasma in the lumen for coating a barrier film or layer in the 16 upcoater such as those shown herein may be pulsed at pulse train frequencies of 2 to 10,000 Hz, optionally 250 to 10,000 Hz, optionally 30 to 500 Hz, and optionally 2 to 25 Hz.

[0223] In any optional embodiment, the RF power provided to generate plasma in the lumen for coating a tie film or layer in the 16 upcoater such as those shown herein may be pulsed at pulse train frequencies of 10 to 10,000 Hz, optionally 250 to 10,000 Hz, optionally 30 to 500 Hz, and optionally 2 to 25 Hz.

[0224] In any optional embodiment, the RF power provided to generate plasma in the lumen for coating a pH protective film or layer in the 16 upcoater such as those shown herein may be pulsed at pulse train frequencies of 10 to 10,000 Hz, optionally 250 to 10,000 Hz, optionally 20 to 400 Hz, and optionally 10 to 20 Hz.

[0225] In any optional embodiment, the RF power provided to generate plasma in the lumen for coating a lubricating film or layer in the 16 upcoater such as those shown herein may be pulsed at pulse train frequencies of 1 to 10,000 Hz, and optionally 100 to 10,000 Hz.

[0226] In any optional embodiment, the RF power provided to generate plasma in the lumen for coating a barrier film or layer in a 16 upcoater such as those shown herein may be pulsed at a power frequency of 13.56 to 72 MHz.

[0227] In any optional embodiment, the RF power provided to generate plasma in the lumen for coating a tie film or layer in a 16 upcoater such as those shown herein may be pulsed at a power frequency of 13.56 to 72 MHz.

[0228] In any optional embodiment, the RF power provided to generate plasma in the lumen for coating a pH protective film or layer in the 16 upcoater such as those shown herein may be pulsed at a power frequency of 13.56 to 72 MHz.

[0229] In any optional embodiment, the RF power provided to generate plasma in the lumen for coating a lubricating film or layer in the 16 upcoater such as those shown herein may be pulsed at a power frequency of 13.56 to 72 MHz.

[0230] In any optional embodiment, the pulsed RF power provided to generate plasma in the lumen for coating a barrier film or layer in a 16 upcoater such as those shown herein may have duty cycles of 20-99%, optionally 80-99%, optionally 96-99%, or optionally 20-50%.

[0231] Optionally, in any embodiment, the pulsed RF power provided to generate plasma in the lumen to apply a Ti coating or layer in a 16-up coater as shown herein may have a duty cycle of 15-99%, optionally 25-80%, optionally 80-99%, optionally 15-25%.

[0232] Optionally, in any embodiment, the pulsed RF power provided to generate plasma in the lumen to apply a pH-protective coating or layer in a 16-up coater as shown herein may have a duty cycle of 15-99%, optionally 25-80%, optionally 80-99%, optionally 15-25%.

[0233] Optionally, in any embodiment, the pulsed RF power provided to generate plasma in the lumen to apply a lubricating coating or layer in a 16-up coater as shown herein may have a duty cycle of 10-99%, optionally 60-80%.

[0234] Optionally, in any embodiment, the plasma generated to apply a barrier coating or layer may be applied over a deposition time of 3-40 seconds, optionally 6-40 seconds, optionally 6-30 seconds, optionally 6-25 seconds, optionally 6-20 seconds, optionally 6-15 seconds, optionally 7-40 seconds, optionally 7-30 seconds, optionally 7-25 seconds, optionally 7-20 seconds, optionally 7-15 seconds, optionally 10-40 seconds, optionally 10-30 seconds, optionally 10-25 seconds, optionally 10-20 seconds, optionally 10-15 seconds.

[0235] Optionally, in any embodiment, the plasma generated to apply a Ti coating or layer may be applied over a deposition time of 2-5 seconds, optionally 2-3.5 seconds, optionally 3.5-5 seconds.

[0236] In any optional embodiment, the plasma generated for coating the pH protective film or layer may be applied over a deposition time of 10-40 seconds, optionally 10-30 seconds, optionally 10-20 seconds, optionally 10-15 seconds, and optionally 15-20 seconds.

[0237] In any optional embodiment, the plasma generated for coating a lubricating film or layer may be applied over a deposition time of 10 to 120 seconds, or optionally 30 to 90 seconds.

[0238] In any optional embodiment, the three-layer (tie layer, barrier layer, pH protective layer) coating may be applied simultaneously to 16 containers using a 16-up coater such as those shown herein, in less than 120 seconds, optionally less than 110 seconds, optionally less than 100 seconds, optionally less than 90 seconds, optionally less than 80 seconds, optionally less than 75 seconds, optionally less than 70 seconds, or optionally less than 65 seconds.

[0239] In any optional embodiment, the barrier film or layer may be applied with a 16-up coater such as those shown herein, using an optional supply rate of HMDSO siloxane precursor of 1 to 10 sccm, or optionally 3 to 5 sccm, and an optional supply rate of oxygen precursor of 10 to 100 sccm, or optionally 20 to 50 sccm.

[0240] In any optional embodiment, the tie film or layer may be coated with a 16-up coater such as those shown herein, using an optional supply rate of 6-10 sccm, optionally 8-9 sccm, of HMDSO siloxane precursor, an optional supply rate of 1.7-4 sccm, optionally 2.5-4 sccm, of oxygen precursor, and an optional supply rate of 50-100 sccm, optionally 80-100 sccm, of inert gas (e.g., argon).

[0241] In any optional embodiment, the pH protective film or layer may be applied with a 16-up coater such as those shown herein, using an optional supply rate of 6-10 sccm, optionally 8-9 sccm, of HMDSO siloxane precursor, an optional supply rate of 1.7-4 sccm, optionally 2.5-4 sccm, of oxygen precursor, and an optional supply rate of 50-100 sccm, optionally 80-100 sccm, of inert gas (e.g., argon).

[0242] In any optional embodiment, the lubricating film or layer may be applied with a 16-up coater such as those shown herein, using an optional siloxane precursor supply rate of 1 to 30 sccm, optionally 25 to 30 sccm, optional OMCTS; an oxygen precursor supply rate of 0 to 100 sccm, optionally 0 to 10 sccm; a nitrogen precursor supply rate of 0 to 100 sccm; and an inert gas (e.g., argon) supply rate of 0 to 100 sccm, optionally 0 to 20 sccm.

[0243] In any optional embodiment, at least 12 vessels, or alternatively at least 16 vessels, can be simultaneously coated using the same RF power supply, the same vacuum source, the same precursor gas source, or any combination thereof (e.g., in a 12-upcoater, 16-upcoater, 24-upcoater, 32-upcoater, etc.). Optionally, during each coating step, the precursor gas can be equally distributed to all vessels by a gas manifold. Optionally, during each coating step, the vacuum can be equally distributed to all vessels by a vacuum manifold.

[0244] In any optional embodiment, the precursor gas may be supplied directly to the lumen through a container opening, such as the open end of the container. In other embodiments, the precursor gas may be supplied through a gas outlet probe located within the lumen of the container. In any optional embodiment, the outer surface of the container may be coated with an antistatic and / or scratch-resistant coating, etc., by PECVD and optionally pulsed PECVD.

[0245] Pulsed RF plasma enables a more stable plasma between vessels and between runs. Similarly, the vessel cladding systems described herein enable greater resolution of measured inputs such as vacuum pressure, gas flow, and power. The adjustable RF generator provides a 100mV resolution, which offers better plasma control. In addition, the RF generator's matching network provides improved adjustability, covering a wide range of conductances, which can be adjusted to accommodate any changes in the reactor layout, such as electrode geometry. The RF power supply 601's matching network can be adjusted to adapt the system design to process inputs that may vary in vessels of different sizes and / or shapes, such as vials and syringes.

[0246] As described above, increasing the capacity filled using a single gas source and a single exhaust source in the 16-container coating system increases resolution and reduces inter-run variability errors in the mass flow controller and pressure gauge. Furthermore, pulsing the plasma RF power minimizes the effects of thermal load during the coating process, thereby enabling higher power than conventional systems and achieving the best possible barrier performance. Depositing a three-layer coating without breaking the vacuum significantly reduces process time and improves layer quality because there is no inter-layer exposure to the environment that occurs with separate layer coatings.

[0247] Furthermore, the RF electrode design with a single electrode and connection leads to improved plasma uniformity compared to having electrodes on every vessel being coated, and minimizes parasitic effects when an RF signal is applied. The goal of the coating layer is to provide a barrier that can mimic the performance of glass as a gas barrier, such as an oxygen barrier. The optimized barrier reduced defects associated with high-density coating growth using a stable plasma, efficient hardware, and control. Increasing the system capacity to 16 or more vessels allows for electrically improved stability using stable process pressure and gas delivery control. The RF power supply 601 can provide RF power of 1 kW or more, at which point the RF energy is more reproducible and 100 mV resolution control is possible.

[0248] Figure 21 shows a design of experiment scatter plot of the dissolution rate of coated vials in a pulsed RF PECVD system according to one embodiment of the present disclosure. Referring to Figure 21, the design of experiment shows that with a pH protective layer, the cycle time can be 10 or 15 seconds in the 300–350 W power range, and the performance per dissolution Si(μg) is equal across all 16 parts, indicated by a basically flat Si(μg) plot at each chuck position 1–16. In contrast, it is shown that some variability in coating performance may occur at lower powers such as 200 W. [Examples]

[0249] Example 1 To characterize the performance of the barrier layer on 10 mL vials coated using one embodiment of the method and system described herein, 80 COP containers were coated with the barrier layer over one of nine different defined time periods (while keeping all other coating parameters the same). Five containers were coated in each time period. Two of the five containers were used for thickness testing, and three of the five containers were used for OTR testing. In each container, a 2-second adhesive (tie) layer was first applied to ensure that the plasma ignited in the barrier layer with minimal delay. The coating parameters are shown in Table 1 below.

[0250] [Table 5]

[0251] Next, the coated samples were tested for barrier layer thickness (measured by a filmmetrics sensor) and oxygen permeability (OTR). From the thickness data, the general trend was that the layer thickness increased at a fairly stable rate as the deposition time of the barrier layer increased.

[0252] The results are shown in Figure 17. In particular, Figure 17 shows the relationship between layer thickness and layer growth time in a pulsed RF PECVD system in which 16 containers are coated simultaneously, according to one embodiment of the present disclosure. Referring to Figure 17, a thickness plot is shown that exhibits a substantially linear thickness variation with time, with some nonlinearity at long deposition times, such as more than 20 seconds.

[0253] The results of the oxygen permeability test are shown in Figure 18. In particular, Figure 18 shows the relationship between the oxygen permeability and layer thickness of a vial having a barrier layer according to one embodiment of the present disclosure. Referring to Figure 18, the OTR results show that as the deposition time increases, the OTR decreases to around 10 seconds, and at that point, the OTR remains low even if the deposition time is increased further, and beyond 10 seconds, the performance does not increase even if the time is increased further.

[0254] As part of the thickness test, a contour map of the coating was also created. The results are shown in Figures 19 and 20. Referring to the figures, the contour map shows that the thickness variation is random, rather than due to a gradual transition along the length of the vial.

[0255] Example 2 The pulse rate (frequency and duty cycle) can affect the barrier performance of a coating set, such as the three-layer coating described herein. To demonstrate the effect of pulse rate, the three layers (tie layer, barrier layer, and pH protection layer) were coated onto a 10 mL COP container using various pulse rates. The coating parameters for applying the barrier layer using various duty cycles and frequencies are shown in the table below.

[0256] Pulse at 25% DC:

[0257] [Table 6]

[0258] Pulse at 50% DC:

[0259] [Table 7]

[0260] Pulse at 80% DC:

[0261] [Table 8]

[0262] Various DC pulses:

[0263] [Table 9]

[0264] The oxygen permeability (OTR) test was used on coated samples to evaluate the barrier layer performance. To perform the test, a sensor was placed inside the coated vial, and the vial was bonded to a glass slide in a glove box with epoxy resin. The partial pressure of oxygen at various points was measured using a Mocon-Optech oxygen-platinum system. These readings were then converted macroscopically to an OTR constant, a measure of the barrier layer performance of the vial. Typically, uncoated vials have an OTR constant of approximately 0.007. Glass has a reference value of 0.

[0265] The results are shown in Figures 22 and 23, which illustrate the relationship between the OTR constant and the plasma pulse rate. Figure 22 shows that the OTR improves with increasing frequency, with an improvement of 0.00025d -1 For OTR constants less than 0.00025d, the frequency plateaus above 200Hz. Similarly, Figure 23 shows that OTR improves with increasing duty cycle, with the improvement being 0.00025d -1For OTR constants below a certain value, the effect plateaus above 50%. The results demonstrate that a significant improvement in barrier layer OTR can be achieved through control of the RF power pulse frequency. Specifically, as the frequency and duty cycle pulse increase, the OTR constant decreases and barrier performance improves, but the effect plateaus beyond certain frequencies and duty cycles.

[0266] Example 3 To obtain consistency between coatings on containers coated in a high-capacity system such as one embodiment of the 16-cavity system described herein, it is important that the vacuum pressure in each container is substantially the same as the vacuum pressure in all other containers in the multi-cavity system. It is also important that the amount of precursor gas introduced into each container during each coating step is substantially the same as the amount of precursor gas introduced into all other containers in the multi-cavity system.

[0267] Figure 24 shows the vacuum pressure uniformity achieved between vessels arranged in a 16-cavity pulsed RF PECVD system according to one embodiment of the present disclosure. Referring to Figure 24, the under-vacuum pressure readings for each vessel in the 16-cavity pulsed RF PECVD system with an exhaust manifold are shown as described above. As can be seen from the plot, the pressure is highly uniform across all 16 vessels (also called components) in the coating, with a standard deviation of 0.07% and a mean of 0.0174 Torr.

[0268] Figure 25 shows the pressure uniformity achieved under a precursor gas flow between vessels arranged in a 16-cavity pulsed RF PECVD system according to one embodiment of the present disclosure. Referring to Figure 25, the pressure readings under a 30 sccm monomer gas flow in each vessel within the 16-cavity pulsed RF PECVD system with the gas distribution manifold described above are shown. As can be seen from the plot, the pressure is highly uniform across all 16 vessels (also called components) in the coating, with a standard deviation of 0.54% and a mean of 0.1021 Torr.

[0269] Example 4 Further tests were performed to analyze the consistency and coating integrity of the coatings applied across coated containers in a 16-cavity pulsed RF PECVD system according to one embodiment of the present disclosure. Sample vials were coated in a 16-cavity pulsed RF PECVD system according to one embodiment of the present disclosure, and each coated container was then tested for total silicon dissolution after 3 days in contact with a fluid having pH 9.

[0270] The container was coated according to the following parameters:

[0271] [Table 10]

[0272] A 5-second start delay (i.e., the time before the RF power is turned on in each sheathing step) was included to ensure stabilization of pressure and gas flow within each vessel for test purposes. While the start delay time could likely be minimized to less than 5 seconds, perhaps even much shorter, this would come at a significant cost to consistency.

[0273] Next, the containers were tested for total silicon dissolution. The test method quantifies silicon using inductively coupled plasma emission spectrometry (ICP-OES). Using a pH 9 solution, silicon is extracted from the container coating over a set time period under controlled conditions to provide information on lot-to-lot variability and the compositional consistency of the protective layer of the coating. This method also provides a means to confirm the presence and / or function of the adhesive layer through visual assessment of delamination.

[0274] For testing, each container was filled with a 50 mM potassium phosphate solution adjusted to pH 9. A stopper (treated to remove any silicone oil) was then inserted into the lumen opening. The filled and sealed containers were then placed in a 40°C incubator and left there for approximately 72 hours. Visual inspection was used to confirm the absence of particulate matter or detachment. The containers were then opened, and the contents were poured into a polypropylene centrifuge tube and diluted with 2% nitric acid. The diluted solutions were then analyzed by ICP-OES, for example, using an ESI autosampler or an ICP-OES Perkin Elmer Optima 8300 with an equivalent, ensuring accurate measurements using calibration standards.

[0275] The results of the coating integrity and consistency tests are shown in Figure 26. Referring to Figure 26, the total mass of dissolved silicon in each of the 16 vessels coated using a 16-cavity pulsed RF PECVD system according to one embodiment of the present disclosure is shown. The results in Figure 26 demonstrate substantially equal coating integrity performance within the error of the test method.

[0276] Example 5 Additional tests were conducted to analyze the consistency of the oxygen barrier properties of coatings applied to vessels using multiple 16-cavity pulsed RF PECVD systems over 8 hours of continuous production.

[0277] The vials were coated according to the following parameters.

[0278] [Table 11]

[0279] A 5-second start delay (i.e., the time before the RF power is turned on in each sheathing step) was included to ensure stabilization of pressure and gas flow within each vessel for test purposes. While the start delay time could likely be minimized to less than 5 seconds, perhaps even much shorter, this would come at a significant cost to consistency.

[0280] Sixteen containers coated with each of the two different systems were selected and tested for oxygen permeability (OTR) as described above. The test results are shown in Figure 27. Referring to Figure 27, the measured OTR constants for the coated containers, identified by cavity or pack position #1 to #16, in the two different coating systems, i.e., the coaters, operated for 8 hours are shown. The results show equal oxygen barrier performance between the containers, and the OTR differences are within the error of the test method. Some negative values ​​are due to no change in oxygen ingress and mean perfect barrier performance over the duration of the oxygen permeability test.

[0281] Example 6 Additional tests were performed to analyze the oxygen barrier properties of CBC vessels coated using a 16-cavity pulsed RF PECVD system according to one embodiment of the present disclosure, and compared their oxygen barrier properties to those of COP vessels coated under the same conditions.

[0282] 10 mL vials of (1) VIVION® 0510 CBC, (2) VIVION® 0510 HF CBC, and (3) ZEONEX® 690R COP (manufactured by Zeon Chemicals LP) were coated according to the following parameters.

[0283] [Table 12]

[0284] A 5-second start delay (i.e., the time before the RF power is turned on in each sheathing step) was included to ensure stabilization of pressure and gas flow within each vessel for test purposes. While the start delay time could likely be minimized to less than 5 seconds, perhaps even much shorter, this would come at a significant cost to consistency.

[0285] Next, the coated vials were tested for oxygen permeability (OTR) as described above. Uncoated samples of each type of vial were also tested for OTR as a control, demonstrating the improvement in OTR provided by the coating set.

[0286] Figure 28 is a plot showing the results. The results demonstrated that vials made from the two CBC resins had a much higher oxygen permeability constant than those made from COP resin, particularly by about four times. However, in particular, coating the vials made from the two CBC resins reduced the oxygen permeability constant of the vials to about 2% to 5% of that of the uncoated CBC vials, i.e., a reduction of about 95% to 98%, producing CBC containers with an oxygen permeability constant relatively close to that of the coated COP vials. Furthermore, it is thought that the OTR constant of vials made from CBC resin can be further reduced by changing the thickness of the barrier film.

[0287] In some embodiments, for example, a barrier coating can be applied to a container, such as a vial, having a wall made of CBC resin, to provide a wall having an oxygen permeability constant (d-1) of less than 0.0020, alternatively less than 0.0015, alternatively less than 0.0013, alternatively less than 0.0010, alternatively less than 0.0009, alternatively less than 0.0008, alternatively less than 0.0007, alternatively less than 0.0006, alternatively less than 0.0005, alternatively less than 0.0004, alternatively less than 0.0003, alternatively less than 0.0002, or alternatively less than 0.0001.

[0288] It will be found that the embodiments described provide unique and novel methods, systems, and covering containers that have several advantages over those in the art. Although specific structures for carrying out the present invention are shown and described herein, it will be apparent to those skilled in the art that various modifications and rearrangements of components can be made without departing from the spirit and scope of the underlying concept of the present invention, and that the invention is not limited to the specific forms shown and described herein, except as indicated by the appended claims. [Explanation of Symbols]

[0289] The following reference numerals are used in the drawings: 210 Pharmaceutical packaging 212 Lumen 214 Wall 216 Exterior 218 Fluid 220 Inner surface (of 288) 222 Outer surface (of 288) 224 Inner surface (of 286) 226 Outer surface (of 286) 228 vials 230 blister packs 250 syringe barrels 252 syringes 254 Inner surface or inner surface (of 250) 256 Rear end (of 250) 258 Plunger (of 252) (part that slides relative to 252) 259 Lubricant 260 Front end (of 250) 262 Closure 264 Inner surface or inner surface (of 262) 268 Container 270 Closure 272 Surface facing the interior 600 pulsed plasma PECVD reactor 601 RF power supply 603 RF electrode 605 Container Cavity 607 Camera 609 Exhaust Manifold 611 Gas Inlet Manifold 611A Input Port 613 Vacuum Line 274 Lumen 276 Wall contact surface 278 Inner surface or inner surface (of 280) 280 Container wall 281 Lubricating film or layer 282 Stopper 283 Primer film or layer 284 Shields 285 Container coating or layer set 286 pH protective film or layer 287 Lubricant deposits 288 Barrier layer 289 Tie Coat film or layer 290 Coating device, for example 250 292 Inner surface or inner surface (of 294) 294 Restricted opening (250) 296 Processing containers 298 Outer surface (of 250) 1101 Gas delivery probe 1105 Container holder 1107 Plasma Screen 1201 Entrance Line 1400 Quad-Pulse RF PECVD 1401A-C Deposition Chamber 1405 Manifold 1407 Manifold 1600 pulse RF PECVD 1607 Manifold

Claims

1. A container, a method for preparing a coating set in a container according to any one of the preceding claims, a. To provide a container having a lumen defined at least partially by a plastic wall, wherein the plastic wall has an inner surface and an outer surface facing the lumen, b. Partially vacuuming the lumen, c. Optionally coating the tie film or layer of SiOxCy by a tie PECVD coating step, which includes applying sufficient power to generate a plasma in the lumen, supplying a precursor gas containing siloxane, optionally oxygen, and optionally an inert gas diluent over a deposition time to generate a tie film or layer on the inner surface, and then extinguishing the plasma, wherein x is approximately 0.5 to approximately 2.4 and y is approximately 0.6 to approximately 3, each of which is measured by X-ray photoelectron spectroscopy (XPS), and optionally coating the tie film or layer. d. Applying a barrier PECVD coating step, which includes applying sufficient power to generate a plasma in the lumen, supplying a precursor gas containing siloxane and oxygen over the deposition time to generate a barrier film or layer on the inner surface, optionally having a tie film or layer on the inner surface treated according to step c, and then extinguishing the plasma, while maintaining the partial vacuum in the lumen without disrupting it, wherein x is 1.5 to 2.9 as measured by XPS, and applying a barrier film or layer. e. The pH protective PECVD coating step comprises applying sufficient power to generate plasma in the lumen, supplying a precursor gas containing siloxane, optionally oxygen, and optionally an inert gas diluent over a deposition time to generate a pH protective film or layer, and then extinguishing the plasma, thereby optionally coating the pH protective film or layer of SiOxCy between the barrier film or layer and the lumen, wherein x is approximately 0.5 to approximately 2.4 and y is approximately 0.6 to approximately 3, each of which is measured by XPS, and optionally coating the pH protective film or layer. Includes, The plasma in step d is generated using pulsed RF having a power of at least 200 W, optionally at least 225 W, optionally at least 250 W, optionally at least 275 W, optionally at least 300 W, optionally at least 325 W, optionally at least 350 W, optionally at least 375 W, optionally at least 400 W and pulse frequencies of at least 50 Hz, optionally at least 75 Hz, optionally at least 100 Hz, optionally at least 125 Hz, optionally at least 150 Hz, optionally at least 175 Hz, optionally at least 200 Hz, optionally at least 225 Hz, and optionally at least 250 Hz, in a method.

2. The method according to claim 1, wherein step c is performed.

3. The method according to claim 2, wherein the plasma in step c is generated using pulsed RF having a power of at least 200 W, optionally at least 225 W, optionally at least 250 W, optionally at least 275 W, optionally at least 300 W, optionally at least 325 W, optionally at least 350 W, optionally at least 375 W, optionally at least 400 W and pulse frequencies of at least 50 Hz, optionally at least 75 Hz, optionally at least 100 Hz, optionally at least 125 Hz, optionally at least 150 Hz, optionally at least 175 Hz, optionally at least 200 Hz, optionally at least 225 Hz, and optionally at least 250 Hz.

4. The method according to any one of claims 1 to 3, wherein step e is performed.

5. The method according to claim 4, wherein the plasma in step e is generated using a pulsed RF having a power of at least 200 W, optionally at least 225 W, optionally at least 250 W, optionally at least 275 W, optionally at least 300 W, optionally at least 325 W, optionally at least 350 W, optionally at least 375 W, optionally at least 400 W and a pulse frequency of at least 50 Hz, optionally at least 75 Hz, optionally at least 100 Hz, optionally at least 125 Hz, optionally at least 150 Hz, optionally at least 175 Hz, optionally at least 200 Hz, optionally at least 225 Hz, optionally at least 250 Hz.

6. The method according to any one of claims 1 to 5, wherein the same siloxane precursor is used in each step.

7. The method according to claim 6, wherein the siloxane precursor comprises HMDSO, TMDSO, or a combination thereof, and optionally HMDSO.

8. The method according to any one of claims 1 to 7, wherein each step is performed without disrupting the partial vacuum or moving the container.

9. The method according to any one of claims 1 to 8, wherein the deposition time in step d is 20 seconds or less, optionally 15 seconds or less, optionally 10 seconds or less, optionally 2 to 15 seconds, optionally 3 to 10 seconds, optionally 3 to 7 seconds, and a barrier film or layer having an average thickness of at least 10 nm, optionally at least 15 nm, optionally at least 20 nm, optionally 10 to 100 nm, optionally 10 to 75 nm, optionally 10 to 50 nm, optionally 15 nm to 50 nm, and optionally 20 nm to 45 nm.

10. The method according to any one of claims 1 to 9, wherein the deposition time in step c is 15 seconds or less, optionally 10 seconds or less, optionally 5 seconds or less, optionally 2 to 12 seconds, optionally 3 to 10 seconds, optionally 3 to 7 seconds, and a tie film or layer having an average thickness of at least 5 nm, optionally at least 10 nm, optionally 5 to 30 nm, optionally 10 to 30 nm, optionally 10 to 25 nm, or optionally 15 to 25 nm.

11. The method according to any one of claims 1 to 10, wherein the deposition time in step e is 25 seconds or less, optionally 20 seconds or less, optionally 15 seconds or less, optionally 10 seconds or less, optionally 4 to 20 seconds, optionally 5 to 20 seconds, optionally 5 to 15 seconds, optionally 5 to 10 seconds, and the method produces a pH protective film or layer having an average thickness of at least 30 nm, optionally at least 40 nm, optionally at least 50 nm, optionally 40 nm to 110 nm, optionally 40 nm to 100 nm, optionally 50 nm to 110 nm, and optionally 50 nm to 100 nm.

12. f. A lubricating PECVD coating step comprising applying sufficient power to generate plasma in the lumen, supplying a precursor gas containing siloxane, optionally oxygen, and optionally an inert gas diluent over the deposition time to generate a lubricating film or layer, and then extinguishing the plasma, thereby creating a barrier film or layer, or if present, a pH protective film or layer, between the barrier film or layer and the lumen. x C y The method according to any one of claims 1 to 11, further comprising applying the lubricating film or layer, wherein x is about 0.5 to about 2.4 and y is about 0.6 to about 3, each of which is measured by XPS.

13. The method according to claim 12, wherein the plasma in step f is generated using a pulsed RF having a power of at least 200 W, optionally at least 225 W, optionally at least 250 W, optionally at least 275 W, optionally at least 300 W, optionally at least 325 W, optionally at least 350 W, optionally at least 375 W, optionally at least 400 W and a pulse frequency of at least 50 Hz, optionally at least 75 Hz, optionally at least 100 Hz, optionally at least 125 Hz, optionally at least 150 Hz, optionally at least 175 Hz, optionally at least 200 Hz, optionally at least 225 Hz, optionally at least 250 Hz.

14. The method according to any one of claims 1 to 13, wherein the precursor gas is supplied directly into the lumen through the open end of the container.

15. The method according to any one of claims 1 to 14, wherein the gas outlet is not located within the lumen.

16. The method according to claim 14 or 15, wherein the precursor gas flows through a compartment immediately before entering the lumen, and the compartment permeates the precursor gas but prevents the plasma from being ignited outside the lumen.

17. The method according to claim 16, wherein the compartment is provided with a plasma screen.

18. The method according to any one of claims 14 to 17, wherein the gas outlet is located below the open end of the container and, if the compartment exists, below the compartment.

19. The container undergoes each coating step simultaneously with at least 11, and optionally at least 15 other containers. The method according to any one of claims 1 to 18, wherein the plasma in the lumen of each of the containers is generated by the same power source.

20. The method according to claim 19, wherein the precursor gas introduced into each of the lumens of the containers comes from the same gas supply source.

21. The method according to claim 20, wherein the precursor gas is equally distributed to each of the containers by a gas manifold.

22. The method according to any one of claims 1 to 21, wherein the vacuum drawn into each of the lumens of the containers is from the same vacuum source.

23. The method according to claim 22, wherein the vacuum is distributed equally to each of the containers by a vacuum manifold.

24. The method according to any one of claims 19 to 23, wherein each of the containers is placed in a separate cavity of the same electrode.

25. The method according to any one of claims 19 to 24, wherein the combination of steps c, d, and e is performed in less than 120 seconds, optionally less than 110 seconds, optionally less than 100 seconds, optionally less than 90 seconds, optionally less than 80 seconds, optionally less than 75 seconds, optionally less than 70 seconds, and optionally less than 65 seconds.

26. The method according to any one of claims 1 to 25, further comprising the step of applying a coating to the outer surface of the container wall by PECVD.

27. The method according to claim 26, wherein the step of applying the film to the outer surface of the container is performed simultaneously with at least one of steps c to f.

28. The method according to claim 26 or 27, wherein the coating applied to the outer surface of the container is an antistatic and / or scratch-resistant coating.

29. The method according to any one of claims 1 to 28, wherein the plastic wall comprises COP resin or COC resin, or is made of COP resin or COC resin.

30. The plastic wall comprises or consists of a cyclic block copolymer (CBC) resin, optionally comprising a CBC resin selected from the group consisting of VIVION® 0510, VIVION® 0510HF, and VIVION® 1325, optionally comprising a CBC resin, optionally comprising VIVION® 051 The method according to any one of claims 1 to 29, comprising or consisting of a CBC resin selected from the group consisting of 0 and VIVION (trademark) 0510HF, optionally comprising VIVION (trademark) 0510 or consisting of VIVION (trademark) 0510, optionally comprising VIVION (trademark) 0510HF or consisting of VIVION (trademark) 0510HF.

31. The method according to any one of claims 1 to 30, wherein the plasma in step d is generated using pulsed RF with duty cycles of at least 25%, optionally at least 30%, optionally at least 35%, optionally at least 40%, optionally at least 45%, optionally at least 50%, and optionally at least 55%.

32. The method according to any one of claims 1 to 31, wherein the plasma in step c is generated using pulsed RF with duty cycles of at least 25%, optionally at least 30%, optionally at least 35%, optionally at least 40%, optionally at least 45%, optionally at least 50%, and optionally at least 55%.

33. The method according to any one of claims 1 to 32, wherein the plasma in step e is generated using pulsed RF with duty cycles of at least 25%, optionally at least 30%, optionally at least 35%, optionally at least 40%, optionally at least 45%, optionally at least 50%, and optionally at least 55%.

34. The method according to any one of claims 1 to 33, wherein each of the coated containers has substantially the same oxygen permeability constant as each of the other coated containers.

35. The method according to any one of claims 1 to 34, wherein each of the coated containers, when in contact with a solution having pH 9 for 72 hours, has substantially the same silicon dissolution rate as each of the other coated containers.

36. A method for covering a container, Placing multiple containers at the opening of the metal RF electrode, Evaporating the internal volume of each of the multiple containers using a single vacuum line via a discharge manifold, Introducing one or more source gases to each of the multiple containers using a single source line via a gas inlet manifold, Using the one or more source gases and the pulsed RF signals applied to the metal RF electrodes, a plasma is generated in each of the multiple containers. Using the plasma, a film comprising at least one barrier film or layer is deposited on each of the plurality of containers, Methods that include...

37. The method according to claim 36, wherein the pulse RF signal has a pulse high power level of 250 W to 1000 W.

38. The method according to claim 36 or 37, wherein the pulse RF signal has a pulse low power level of 0W.

39. The method according to any one of claims 36 to 38, wherein the pulse RF signal has a duty cycle of 25% to 99%.

40. The method according to any one of claims 36 to 39, wherein the pulse RF signal has a pulse train frequency of 150 kHz to 500 kHz.

41. The method according to any one of claims 36 to 40, comprising introducing the one or more source gases into each container without a gas inlet probe into the container.

42. The method according to any one of claims 36 to 41, comprising introducing the one or more source gases into each container using a gas inlet probe in the container.

43. The method according to any one of claims 36 to 42, wherein the coating further comprises a tie coating or layer, and the tie coating or layer has an inner surface facing the barrier coating or layer and an outer surface facing the inner surface of the wall.

44. The aforementioned tie film or layer is SiO x C y or SiN x C y The method according to claim 43, wherein x is approximately 0.5 to approximately 2.4 and y is approximately 0.6 to approximately 3.

45. The method according to any one of claims 36 to 44, wherein the film further comprises a pH film or layer, and the pH film or layer has an inner surface facing the lumen and an outer surface facing the barrier film or layer.

46. The pH protection film or layer is SiO x C y or SiN x C y The method according to claim 45, comprising, where x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3.

47. The coated container wall contains or is made of a thermoplastic material, optionally, the coated container wall contains or is made of a cyclic block copolymer (CBC) resin, optionally, the coated container wall contains or is made of a CBC resin selected from the group consisting of VIVION® 0510, VIVION® 0510HF, and VIVION® 1325, optionally, the coated The method according to any one of claims 36 to 46, wherein the container wall comprises or consists of a CBC resin selected from the group consisting of VIVION® 0510 and VIVION® 0510HF, optionally comprising VIVION® 0510 or VIVION® 0510, optionally comprising VIVION® 0510HF or VIVION® 0510HF.

48. A container, a system for preparing a coating set in a container according to any one of the preceding claims, Radio frequency (RF) power supply and An RF electrode having multiple openings that can operate to receive a container, An inlet gas manifold that can operate to split a single gas inlet into multiple gas source inputs, one for each vessel, A discharge manifold that can operate to discharge each container into a single discharge line, Equipped with, The aforementioned system, The RF electrode is designed to receive multiple containers at its opening, The internal volume of each of the multiple containers is evacuated using a single vacuum line via the aforementioned discharge manifold, Introducing one or more source gases to each of the multiple containers using a single source line via the gas inlet manifold, Using the one or more source gases and the RF power supply, pulsed RF signals applied to the metal RF electrodes are used to generate plasma in each of the multiple containers. Using the plasma, a film comprising at least one barrier film or layer is deposited on each of the plurality of containers, A system capable of performing the following actions.

49. The system according to claim 48, wherein the pulse RF signal has a pulse high power level of 250 W to 1000 W.

50. The system according to claim 48 or 49, wherein the pulse RF signal has a pulse low power level of 0 W.

51. The system according to any one of claims 48 to 50, wherein the pulse RF signal has a duty cycle of 25% to 99%.

52. The system according to any one of claims 48 to 51, wherein the pulse RF signal has a pulse train frequency of 150 kHz to 500 kHz.

53. The system according to any one of claims 48 to 52, comprising introducing the one or more source gases into each container without a gas inlet probe in the container.

54. The system according to any one of claims 48 to 53, comprising introducing the one or more source gases into each container using a gas inlet probe in the container.

55. The system according to any one of claims 48 to 54, wherein the coating further comprises a tie coating or layer, and the tie coating or layer has an inner surface facing the barrier coating or layer and an outer surface facing the inner surface of the wall.

56. The aforementioned tie film or layer is SiO x C y or SiN x C y The system according to claim 55, wherein x is approximately 0.5 to approximately 2.4 and y is approximately 0.6 to approximately 3.

57. The system according to any one of claims 48 to 56, wherein the film further comprises a pH film or layer, and the pH film or layer has an inner surface facing the lumen and an outer surface facing the barrier film or layer.

58. The pH protective film or layer is SiO x C y or SiN x C y The system according to claim 57, wherein x is approximately 0.5 to approximately 2.4 and y is approximately 0.6 to approximately 3.

59. A container having a lumen at least partially defined by a plastic wall, wherein the plastic wall has an inner surface facing the lumen, an outer surface, and a coating set on the inner surface, the coating set is A SiOx barrier film or layer, where x is 1.5 to 2.9 as measured by XPS, Optionally, A tie film or layer of SiOxCy or SiNxCy, where x is approximately 0.5 to approximately 2.4 and y is approximately 0.6 to approximately 3, and these are measured by XPS, respectively, for the tie film or layer and A pH protective film or layer of SiOxCy or SiNxCy, where x is approximately 0.5 to approximately 2.4 and y is approximately 0.6 to approximately 3, each measured by XPS. At least one, preferably both, Includes, The aforementioned container is made from a cyclic block copolymer (CBC) resin. The oxygen permeability (d) of the wall of the container -1 A container whose ) is less than 0.020, optionally less than 0.015, optionally less than 0.010, optionally less than 0.005, optionally less than 0.0025, optionally less than 0.0015, optionally less than 0.0010, optionally less than 0.0008, optionally less than 0.0006, and optionally less than 0.0005.

60. The container according to claim 59, wherein the container is made of a CBC resin selected from the group consisting of VIVION® 0510, VIVION® 0510HF, and VIVION® 1325, and optionally the container is made of a CBC resin selected from the group consisting of VIVION® 0510 and VIVION® 0510HF, optionally the container is made of VIVION® 0510, and optionally the container is made of VIVION® 0510HF.

61. The container according to claim 59 or 60, wherein the barrier film or layer is applied by pulsed RF PECVD.

62. The container according to claim 61, wherein the deposition time of the barrier film or layer is less than 40 seconds, optionally less than 30 seconds, optionally less than 25 seconds, optionally less than 20 seconds, optionally less than 15 seconds, or optionally less than 10 seconds.

63. The container according to any one of claims 59 to 62, wherein the barrier film or layer has an average thickness of less than 500 nm, optionally less than 400 nm, optionally less than 300 nm, optionally less than 200 nm, optionally less than 150 nm, optionally less than 125 nm, optionally less than 100 nm, optionally less than 80 nm, optionally less than 60 nm, optionally less than 50 nm, optionally less than 40 nm, optionally less than 30 nm, optionally less than 25 nm, optionally less than 20 nm, optionally less than 15 nm, and optionally less than 10 nm.

64. The container according to any one of claims 59 to 63, wherein the coating set includes the tie coating or layer.

65. The container according to any one of claims 59 to 64, wherein the coating set includes the pH protective coating or layer.

66. The container according to any one of claims 59 to 65, wherein the coating set includes both the tie coating or layer and the pH protective coating or layer.

67. The container according to any one of claims 59 to 66, wherein the container is a syringe barrel, a vial, or a blood collection tube.

68. The container according to any one of claims 59 to 67, wherein the container is a syringe barrel.

69. The container according to any one of claims 59 to 67, wherein the container is a vial.

70. The container is a blood collection tube, according to any one of claims 59 to 67.

71. The container according to any one of claims 59 to 70, wherein the coating set further comprises a lubricating coating.

72. The container according to any one of claims 59 to 71, further comprising at least one coating on the outer surface.

73. The container according to claim 72, wherein the coating on the outer surface includes an antistatic coating, a scratch-resistant coating, or a combination thereof.

74. The container according to any one of claims 59 to 73, further comprising a fluid contained in the lumen and having a pH greater than 5.

75. The container according to claim 74, wherein the pH protective film or layer and the tie film or layer together are effective in keeping the barrier film or layer at least substantially insoluble as a result of attack by the fluid for a period of at least six months.

76. The container according to claim 74 or 75, wherein the fluid contained in the lumen has a pH of 5 to 9, and the calculated storage life of the packaging is more than 6 months at a storage temperature of 4°C.

77. The container according to any one of claims 74 to 76, wherein the combination of the tie film or layer and the pH protective film or layer is effective in extending the calculated storage life of the packaging (total Si / Si dissolution rate).

78. A container having a lumen defined at least partially by a plastic wall, wherein the plastic wall has an inner surface facing the lumen, an outer surface, and a coating set on the inner surface, the coating set is A SiOx barrier film or layer, where x is 1.5 to 2.9 as measured by XPS, Optionally, A tie film or layer of SiOxCy or SiNxCy, where x is approximately 0.5 to approximately 2.4 and y is approximately 0.6 to approximately 3, and these are measured by XPS, respectively, for the tie film or layer and A pH protective film or layer of SiOxCy or SiNxCy, where x is approximately 0.5 to approximately 2.4 and y is approximately 0.6 to approximately 3, each measured by XPS. At least one, preferably both, Includes, The SiOx barrier film or layer has an average thickness of less than 200 nm, optionally less than 150 nm, optionally less than 125 nm, optionally less than 100 nm, optionally less than 80 nm, optionally less than 60 nm, optionally less than 50 nm, optionally less than 40 nm, optionally less than 30 nm, optionally less than 25 nm, optionally less than 20 nm, optionally less than 15 nm, and optionally less than 10 nm. The oxygen permeability (d) of the wall of the container -1 A container whose ) is less than 0.020, optionally less than 0.015, optionally less than 0.010, optionally less than 0.005, optionally less than 0.0025, optionally less than 0.0015, optionally less than 0.0010, optionally less than 0.0008, optionally less than 0.0006, optionally less than 0.0005, optionally less than 0.0004, optionally less than 0.0003, optionally less than 0.0002, and optionally less than 0.0001.

79. The container according to claim 78, wherein the barrier film or layer is applied by pulsed RF PECVD.

80. The container according to claim 79, wherein the deposition time of the barrier film or layer is less than 30 seconds, optionally less than 25 seconds, optionally less than 20 seconds, optionally less than 15 seconds, or optionally 10 seconds or less.

81. The container according to any one of claims 78 to 80, wherein the coating set includes the tie coating or layer.

82. The container according to any one of claims 78 to 81, wherein the coating set includes the pH protective coating or layer.

83. The container according to any one of claims 78 to 82, wherein the coating set includes both the tie coating or layer and the pH protective coating or layer.

84. The container according to any one of claims 78 to 83, wherein the container is a syringe barrel, a vial, or a blood collection tube.

85. The container according to any one of claims 78 to 84, wherein the container is a syringe barrel.

86. The container according to any one of claims 78 to 84, wherein the container is a vial.

87. The container is a blood collection tube, according to any one of claims 78 to 84.

88. The container according to any one of claims 78 to 87, wherein the coating set further comprises a lubricating coating.

89. The container according to any one of claims 78 to 88, further comprising at least one coating on the outer surface.

90. The container according to claim 89, wherein the coating on the outer surface includes an antistatic coating, a scratch-resistant coating, or a combination thereof.

91. The container according to any one of claims 78 to 90, further comprising a fluid contained in the lumen and having a pH greater than 5.

92. The container according to claim 91, wherein the pH protective film or layer and the tie film or layer together are effective in keeping the barrier film or layer at least substantially insoluble as a result of attack by the fluid for a period of at least six months.

93. The container according to claim 91, wherein the fluid contained in the lumen has a pH of 5 to 9, and the calculated storage life of the packaging is more than 6 months at a storage temperature of 4°C.

94. The container according to claim 91, wherein the combination of the tie film or layer and the pH protective film or layer is effective in extending the calculated storage life of the packaging (total Si / Si dissolution rate).

95. The container according to any one of claims 78 to 94, wherein the plastic wall contains COP resin or COC resin, or is made of COP resin or COC resin.

96. The container according to any one of claims 78 to 94, wherein the plastic wall contains or is made of a cyclic block copolymer (CBC) resin.

97. The container according to claim 96, wherein the plastic wall comprises or consists of a CBC resin selected from the group consisting of VIVION® 0510, VIVION® 0510HF, and VIVION® 1325, and optionally comprises or consists of a CBC resin selected from the group consisting of VIVION® 0510 and VIVION® 0510HF, and optionally comprises or consists of a CBC resin, and optionally comprises or consists of VIVION® 0510, and optionally comprises or consists of VIVION® 0510HF.

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