Pharmaceutical container with pH protective layer deposited by atomic layer deposition

Abstract

A pharmaceutical container comprising an inner cavity defined in part by a wall having an inner surface facing the inner cavity, an outer surface and at least one pH protective layer comprising an oxide of zirconium, titanium or magnesium, wherein the at least one pH protective layer is a layer produced by an atomic layer deposition (ALD) process.

Description

[0001] Cross-references to related applications

[0002] This patent application claims the benefits of U.S. Provisional Patent Application No. 63 / 550,319, filed February 6, 2024; U.S. Provisional Patent Application No. 63 / 648,604, filed May 16, 2024; U.S. Patent Application No. 18 / 666,677, filed May 16, 2024; and U.S. Provisional Patent Application No. 63 / 691,500, filed September 6, 2024, the disclosures of which are incorporated herein by reference in their entirety for all purposes. Background Technology

[0003] Pharmaceutical containers, such as vials and syringes, may have one or more barrier layers of one or more materials on their inner walls. These layers are designed to protect the pharmaceutical agent—a compound, biological agent, or other material—stored in the vial or syringe from contamination, such as from gases from outside the container or from the container's own material, which may degrade over time. In this way, pharmaceutical containers can be safely delivered to their final point of use without requiring excessive special handling during transport and storage, and the agent retains its effectiveness even during extended periods of transport and / or storage. However, known barrier layers tend to degrade over time when in contact with certain pharmaceutical agents; therefore, the shelf life of such containers is often shortened.

[0004] To develop pharmaceutical containers capable of providing long-term storage for stored pharmaceutical compositions, attempts have been made to reduce the degradation rate of barrier layers. One such attempt involves incorporating a pH-protective layer onto the barrier layer. However, an unmet need remains for pharmaceutical containers with a thin pH-protective layer and enhanced long-term drug storage capability. The invention disclosed herein provides such a pharmaceutical container. These and other advantages of the invention, as well as additional inventive features, will become apparent from the description of the invention provided herein. Summary of the Invention

[0005] In one aspect, the present invention provides a pharmaceutical container comprising an inner cavity partially defined by a wall having an inner surface facing the inner cavity, an outer surface and at least one pH protective layer comprising an oxide of zirconium, titanium or magnesium, wherein the at least one pH protective layer is a layer produced by an atomic layer deposition (ALD) process.

[0006] A pharmaceutical container with a pH protective layer applied by ALD technology according to one aspect of the invention offers one or more technical advantages. For example, a very thin pH protective layer can be applied by ALD technology. Furthermore, the pH protective layer applied by this technology is very dense, thus protecting the underlying gas barrier layer from unwanted pH exposure from the contents of the pharmaceutical container. Moreover, the pharmaceutical container can be provided with an even thinner pH protective layer, for example, the pH protective layer can be 20 nm to 50 nm, which is much smaller than the conventional thickness of about 250 to 400 nm, up to 10 or 12 times smaller. Furthermore, the mechanical properties of the pH protective layer applied by ALD technology impart significant crack resistance and / or flexural strength to the barrier layer. Additionally, the pH protective layer imparts thermal cycling resistance and / or mechanical flexural strength to the pharmaceutical container, particularly the barrier layer. Alternatively, or furthermore, because the pH protective layer and / or barrier layer are very thin, production time is saved when performing one or both of these steps in the manufacturing process of the pharmaceutical container, especially considering that the pH protective layer is constructed one atomic layer or molecular layer at a time by the ALD process. When exposed to conditions of 50°C and pH 3 to 9 for 72 hours, the pH protective layer reduces the dissolution rate of the gas barrier layer by >90%.

[0007] In another aspect, the present invention provides a pharmaceutical container having a wall having an inner side or inner surface, the pharmaceutical container comprising a nanolaminate coated on the inner side or inner surface of the container wall, wherein the nanolaminate comprises a plurality of thin pH protection layers and a plurality of thin gas barrier layers, wherein each of the pH protection layers and each of the gas barrier layers is alternately arranged, the nanolaminate further comprising a thick pH protection coating disposed on the alternately arranged layers and facing inward toward the container interior, wherein at least one of the thin pH protection layers comprises an oxide of zirconium, titanium or magnesium, and at least one of the thin gas barrier layers comprises an oxide of aluminum, and wherein the at least one pH protection layer and the at least one gas barrier layer are deposited by atomic layer deposition (ALD).

[0008] In another aspect, the present invention provides a pharmaceutical container that further contains a pharmaceutical composition.

[0009] Other and alternative aspects and features of the disclosed invention will become apparent from the following detailed description. It should be understood that the methods disclosed herein can be implemented and used in other different ways and can be modified in various aspects. Therefore, it should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and do not in any way limit the scope of the claimed invention. Attached Figure Description

[0010] Figure 1A This is an X-ray photoelectron spectroscopy (XPS) depth profile of a silicon wafer coated with a 20 nm thick Al₂O₃ layer. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and silicon (Si) were measured at different depths from the top surface of the wafer. The depth bar is estimated based on the Al₂O₃ rate.

[0011] Figure 1B This is an XPS depth profile of a silicon wafer coated with a 50 nm thick Al₂O₃ layer. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and silicon (Si) were determined at different depths. The depth bar is estimated based on the Al₂O₃ rate.

[0012] Figure 1C This is an XPS depth profile of a silicon wafer coated with a 50 nm thick ZrO2 coating over a 50 nm thick Al2O3 coating. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), silicon (Si), and zirconium (Zr) were determined at different depths. The depth bar is estimated based on the Al2O3 rate.

[0013] Figure 1D This is an XPS depth profile of a silicon wafer with a 20 nm thick Al₂O₃ coating and a 20 nm thick ZrO₂ layer deposited on top of the Al₂O₃ coating. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), silicon (Si), and zirconium (Zr) were determined at different depths. The depth bar is estimated based on the Al₂O₃ rate.

[0014] Figure 2A This is a schematic diagram of a pharmaceutical container, showing a pH protection layer, a barrier layer, and an optional binding layer deposited on a polymer substrate, wherein the pharmaceutical container is a vial.

[0015] Figure 2B This is a schematic diagram of a pharmaceutical container, showing a pH protection layer, a barrier layer, and an optional binding layer deposited on a polymer substrate, wherein the pharmaceutical container is a syringe.

[0016] Figure 3A This is a schematic diagram of the aluminum concentration in the collected pH 9 buffer solution, for Si wafers coated with a 20nm Al2O3 gas barrier layer and Si wafers coated with a 20nm Al2O3 barrier layer and a 20nm ZrO2 pH protection layer deposited on the 20nm Al2O3 barrier layer by ALD.

[0017] Figure 3BThis is a schematic diagram of the aluminum concentration in the collected pH 9 buffer solution, for Si wafers coated with a 50nm Al2O3 gas barrier layer and Si wafers coated with a 50nm Al2O3 barrier layer and a 50nm ZrO2 pH protection layer deposited on the 50nm Al2O3 barrier layer by ALD.

[0018] Figure 3C This is a schematic diagram of the aluminum concentration in the collected pH 3 buffer solution, for Si wafers coated with a 20nm Al2O3 gas barrier layer and Si wafers coated with a 20nm Al2O3 barrier layer and a 20nm ZrO2 pH protection layer deposited on the 20nm Al2O3 barrier layer by ALD.

[0019] Figure 3D This is a schematic diagram of the aluminum concentration in the collected pH 3 buffer solution, for Si wafers coated with a 50nm Al2O3 gas barrier layer and Si wafers coated with a 50nm Al2O3 barrier layer and a 50nm ZrO2 pH protection layer deposited on the 50nm Al2O3 barrier layer by ALD.

[0020] Figure 4A These are schematic STEM images of the polypropylene substrate and coating at different magnifications: (a) at 200 nm, (b) at 50 nm, and (c) at 20 nm. The sample surface is rough, and the coating thickness is approximately 10 nm to 15 nm.

[0021] Figure 4B This is a schematic diagram illustrating the energy dispersive spectroscopy (EDS) mapping of an Al2O3 barrier layer on a polypropylene substrate at a magnification of 300 nm. (a) is a HAADF-STEM image, (b) is the line scan mapping of aluminum (Al), (c) is the line scan mapping of oxygen (O), (d) is the line scan mapping of carbon (C), and (e) is the line scan mapping of a combination of Al, O, and C.

[0022] Figure 4C These are schematic diagrams using STEM to illustrate the ZrO2 pH protective layer deposited on Al2O3 on a polypropylene substrate at different magnifications: (a) at 200 nm and (b) at 50 nm. The thickness of the coating is approximately 25 to 35 nm.

[0023] Figure 4DThis is a schematic diagram illustrating the energy dispersive spectroscopy (EDS) mapping of a ZrO2 pH protective layer deposited on a polypropylene substrate via ALD at a magnification of 60 nm. (a) is a HAADF-STEM image, (b) is a line scan mapping of aluminum (Al), (c) is a line scan mapping of oxygen (O), (d) is a line scan mapping of zirconium (Zr), (e) is a line scan mapping of carbon (C), (f) is a line scan mapping of a combination of Al and Zr, and (g) is a line scan mapping of a combination of Al, O, C, and Zr.

[0024] Figure 5 This is a schematic diagram of the aluminum concentration in the collected pH 9 buffer solution, for both polypropylene samples coated with only an Al2O3 gas barrier layer and polypropylene samples coated with a ZrO2 pH protection layer applied over the Al2O3 gas barrier layer via ALD.

[0025] Figure 6 This is a schematic diagram illustrating the difference in thickness of the pH protective layer deposited using atomic layer deposition (ALD) and plasma-enhanced chemical vapor deposition (PECVD).

[0026] Figure 7 This is a schematic diagram illustrating a pharmaceutical container, showing a pH protection layer, a barrier layer, and an optional binding layer deposited on a polymer substrate, wherein the pharmaceutical container is a vial or syringe.

[0027] Figure 8A This is an X-ray photoelectron spectroscopy (XPS) depth profile of a cyclic olefin copolymer (COP) based vial coated with a 27 nm thick Al₂O₃ barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), and oxygen (O) were determined at different depths on the bottom surface of the vial. The depth bar is estimated based on the Al₂O₃ rate.

[0028] Figure 8B This is an XPS depth profile of a (COP)-based vial coated with a 27 nm thick Al₂O₃ barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), and oxygen (O) were determined at different depths on the vial wall surface. The depth bar is estimated based on the Al₂O₃ rate.

[0029] Figure 9A This is an XPS depth profile of a (COP)-based vial coated with a 41 nm thick Al₂O₃ barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), and oxygen (O) were measured at different depths on the bottom surface of the vial. The depth bar is estimated based on the Al₂O₃ rate.

[0030] Figure 9BThis is an XPS depth profile of a (COP)-based vial coated with a 61 nm thick Al₂O₃ barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), and oxygen (O) were measured at different depths on the outer surface of the vial's bottom. The depth bar is estimated based on the Al₂O₃ rate.

[0031] Figure 9C This is an XPS depth profile of a (COP)-based vial coated with an Al₂O₃ barrier layer of approximately 61 nm thickness. In this analysis, the concentrations of aluminum (Al), carbon (C), and oxygen (O) were determined at different depths on the inner surface of the vial wall. The depth bar is estimated based on the Al₂O₃ deposition rate. The inner surface of the vial wall appears to be slightly thinner than the bottom; however, due to instrumentation issues, this film was run on a different instrument than the bottom interior. Minor differences in deposition rates may exist.

[0032] Figure 10 This is an XPS depth profile of a (COP)-based vial coated with an Al₂O₃ barrier layer approximately 30 nm thick. In this analysis, the concentrations of aluminum (Al), carbon (C), and oxygen (O) were measured at different depths on the bottom surface of the vial. The depth bar is estimated based on the Al₂O₃ rate.

[0033] Figure 11A This is an XPS depth profile of a COP-based vial coated with a 35 nm thick Al₂O₃ barrier layer and a 35 nm thick ZrO₂ pH protective layer deposited on top of the Al₂O₃ barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and zirconium (Zr) were determined at different depths on the bottom surface of the vial.

[0034] Figure 11B This is an XPS depth profile of a COP-based vial coated with a 35 nm thick Al₂O₃ barrier layer and a 35 nm thick ZrO₂ pH protective layer deposited on top of the Al₂O₃ barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and zirconium (Zr) were determined at different depths on the outer surface of the vial's bottom.

[0035] Figure 12A This is an XPS depth profile of a (COP)-based vial coated with a 40 nm thick Al₂O₃ barrier layer and a 40 nm thick ZrO₂ pH protective layer deposited on top of the Al₂O₃ barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and zirconium (Zr) were determined at different depths on the bottom surface of the vial.

[0036] Figure 12BThis is a schematic diagram illustrating the water vapor transmission rate data of a (COP)-based vial coated with a 40 nm thick Al2O3 barrier layer and a 40 nm thick ZrO2 pH protective layer deposited on top of the Al2O3 barrier layer.

[0037] Figure 12C This is a schematic diagram illustrating the oxygen permeability data of a (COP)-based vial coated with a 40 nm thick Al2O3 barrier layer and a 40 nm thick ZrO2 pH protective layer deposited on top of the Al2O3 barrier layer.

[0038] Figure 12D This is a schematic diagram of the aluminum and zirconium concentrations in the collected pH 9 buffer solution, for both (COP)-based vials coated with a 40 nm thick Al2O3 barrier layer and (COP)-based vials coated with a 40 nm thick Al2O3 barrier layer and a 40 nm thick ZrO2 pH protective layer deposited on top of the Al2O3 barrier layer.

[0039] Figure 12E This is a schematic diagram of the aluminum and zirconium concentrations in the collected pH 3 buffer solution, for both (COP)-based vials coated with a 40 nm thick Al2O3 barrier layer and (COP)-based vials coated with a 40 nm thick Al2O3 barrier layer and a 40 nm thick ZrO2 pH protective layer deposited on top of the Al2O3 barrier layer.

[0040] Figure 13A This is an XPS depth profile of a (COP)-based syringe coated with an Al₂O₃ barrier layer of 40 nm to 50 nm thickness and a ZrO₂ pH protective layer of 40 nm to 50 nm thickness deposited on top of the Al₂O₃ barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and zirconium (Zr) were determined at different depths at the syringe needle tip.

[0041] Figure 13B This is an XPS depth profile of a (COP)-based syringe coated with an Al₂O₃ barrier layer of 40 nm to 50 nm thickness and a ZrO₂ pH protective layer of 40 nm to 50 nm thickness deposited on top of the Al₂O₃ barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and zirconium (Zr) were determined at different depths in the middle of the syringe.

[0042] Figure 13CThis is an XPS depth profile of a (COP)-based syringe coated with an Al₂O₃ barrier layer of 40 nm to 50 nm thickness and a ZrO₂ pH protective layer of 40 nm to 50 nm thickness deposited on top of the Al₂O₃ barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and zirconium (Zr) were determined at different depths at the syringe flange.

[0043] Figure 14 This is a schematic diagram of a pharmaceutical container, showing a nanolayer consisting of thin, alternating layers of a ZrO2 pH protective layer and an Al2O3 barrier layer, wherein a thick ZrO2 pH protective coating is disposed on top of the alternating layers, wherein the pharmaceutical container is a vial or syringe.

[0044] Figure 15A This is a schematic diagram of the aluminum and zirconium concentrations in the collected pH 9 buffer solution, for both (COP)-based vials coated with a 50 nm thick Al2O3 barrier layer and (COP)-based vials coated with a 50 nm nanolayer stack, wherein the nanolayer stack consists of thin, alternating layers of ZrO2 pH protective layer and Al2O3 barrier layer, wherein a thick ZrO2 pH protective coating layer is disposed on top of the alternating layers.

[0045] Figure 15B This is a schematic diagram of the aluminum and zirconium concentrations in the collected pH 3 buffer solution, for both (COP)-based vials coated with a 50 nm thick Al2O3 barrier layer and (COP)-based vials coated with a 50 nm nanolayer stack, wherein the nanolayer stack consists of thin, alternating layers of ZrO2 pH protective layer and Al2O3 barrier layer, wherein a thick ZrO2 pH protective coating layer is disposed on top of the alternating layers.

[0046] Figure 15C This is a schematic diagram of a high-resolution TEM image showing the nanocrystalline structure (circled areas) within an amorphous matrix of ZrO2 and Al2O3 layers. The thinner, alternating layers disrupt the formation of nanocrystals. Using alternating layers, a tortuous path for gas permeation is created due to the formation of nanocrystals.

[0047] Figure 16 These are STEM surface images of a silicon wafer sample coated with an Al2O3 barrier layer and a ZrO2 pH protective layer on top of the Al2O3 barrier layer via ALD, at different magnifications: (left) 200 nm, (middle) 150 nm, and (right) 50 nm. The ZrO2 pH protective layer is approximately 50 nm thick, and the Al2O3 barrier layer is approximately 40 nm thick.

[0048] Figure 17This is a superimposed schematic diagram of TEM micrographs and XPS depth analysis of a sample coated with a 50 nm Al2O3 barrier layer and a 50 nm ZrO2 pH protective layer on top of the Al2O3 barrier layer via ALD.

[0049] Specific embodiments of the present invention

[0050] The present invention provides a pharmaceutical container comprising an inner cavity partially defined by a wall having an inner surface facing the inner cavity, an outer surface and at least one pH protective layer comprising an oxide of zirconium, titanium or magnesium, wherein the at least one pH protective layer is a layer produced by an atomic layer deposition (ALD) process.

[0051] The present invention also provides a pharmaceutical container having a wall having an inner side, the pharmaceutical container comprising a nanolayer coated on the inner side of the container wall, wherein the nanolayer comprises a plurality of thin pH protection layers and a plurality of thin gas barrier layers, wherein each of the pH protection layers and each of the gas barrier layers is alternately arranged, the nanolayer further comprising a thick pH protection coating layer disposed on the alternately arranged layers and facing inward toward the container interior, wherein at least one of the thin pH protection layers comprises an oxide of zirconium, titanium or magnesium, and at least one of the thin gas barrier layers comprises an oxide of aluminum, and wherein the at least one pH protection layer and the at least one gas barrier layer are deposited by atomic layer deposition (ALD).

[0052] This invention particularly relates to a coating applied to an alumina barrier layer used in medical packaging. While this disclosure relates to any suitable type of packaging in which the purity and stability of the stored material are critical for efficacy, safety, etc., in some aspects, medical packaging in which an alumina barrier layer coating with an additional coating layer is applied can include a variety of containers (e.g., including a cavity), such as vials, syringes (e.g., syringe barrels), blister packs, blood collection tubes, cartridges, bottles, stents, catheters, etc.

[0053] In one aspect, the medical container is a vial. For example, the vial typically has an open spout that can be sealed with a closure, allowing the contents of the vial to be accessed using a needle. Such vials are typically made of glass or plastic. In some aspects, the vial comprises polypropylene, cyclic olefin polymers, cyclic olefin copolymers, polyethylene, or polyethylene terephthalate. Furthermore, the closure of the vial may comprise an elastomer, such as a vulcanized elastomer and a styrene-based block copolymer thermoplastic elastomer, and also includes natural rubber, acrylate-butadiene rubber, cis-polybutadiene, chlorinated butyl or brominated butyl rubber, chlorinated polyethylene elastomers, polyepoxide polymers, ethylene-vinyl acetate, fluorosilicone rubber, hexafluoropropylene-vinylidene fluoride-tetrafluoroethylene terpolymer, butyl rubber, polyisobutylene, synthetic polyisoprene rubber, silicone rubber, styrene-butadiene rubber, tetrafluoroethylene-propylene copolymer, thermoplastic copolyester, thermoplastic elastomer, or combinations thereof.

[0054] On the other hand, the medical container is a syringe. For example, a syringe typically has a cylindrical barrel made of glass or plastic, wherein the barrel can be operated by a plunger to expel the contents of the barrel through the nozzle of the syringe. In some aspects, the syringe is made of cyclic olefin polymers (COP), cyclic olefin copolymers (COC), acrylonitrile-butadiene-styrene (ABS), polycarbonate (PC), polyoxymethylene (POM), polystyrene (PS), polybutylene terephthalate (PBT), polypropylene (PP), polyethylene (PE), polyamide (PA), thermoplastic elastomers (TPE), or combinations thereof. In some aspects, the plunger is made of an elastomer, such as a vulcanized elastomer and a styrene-based block copolymer thermoplastic elastomer, also including natural rubber, acrylate-butadiene rubber, cis-polybutadiene, chlorinated butyl or brominated butyl rubber, chlorinated polyethylene elastomer, polyepoxide polymer, ethylene-vinyl acetate, fluorosilicone rubber, hexafluoropropylene-vinylidene fluoride-tetrafluoroethylene terpolymer, butyl rubber, polyisobutylene, synthetic polyisoprene rubber, silicone rubber, styrene-butadiene rubber, tetrafluoroethylene-propylene copolymer, thermoplastic copolyester, thermoplastic elastomer, or combinations thereof. In some aspects, the syringe is pre-filled with a pharmaceutical composition, allowing for rapid administration of a precise dose to a patient. In some aspects, the pharmaceutical container includes a syringe and a cartridge, wherein the cartridge is a dedicated container that can be inserted into a pen-type or auto-injector to act as a drug delivery device.

[0055] In some aspects, the pharmaceutical container is a blister pack. For example, blister packs can be used to package pharmaceuticals and medical devices, such as solid dosage forms (tablets, capsules, etc.), transdermal patches, syringes, etc. The blister pack of the present invention includes a rigid bottom web base having one or more grooves adapted to it for stabilizing the contents of the package. The blister pack of the present invention also includes a top web laminate, which is heat-sealed to the blister and acts as a "lid" to allow access to the contents of the package.

[0056] Alumina barrier layers and coatings can be applied to a variety of materials used in such medical packaging, such as glass, plastics (e.g., thermoplastics), rubber, polymers, and ceramics. Therefore, materials such as pharmaceuticals, vaccines, bodily fluids, compounds, and biological agents can be safely stored and transported under various conditions while maintaining safety and efficacy for a longer period compared to previously uncoated barrier layers.

[0057] In some aspects, the pharmaceutical container includes an oxygen barrier layer disposed on the inner wall of the container and a pH protection layer disposed on the gas barrier layer. In some aspects, the inner surface of the pharmaceutical container includes an inner cavity.

[0058] In some aspects, the wall of the pharmaceutical container comprises a polymer. In some aspects, the wall of the pharmaceutical container may be composed of polypropylene, cyclic olefin polymer (COP), cyclic olefin copolymer (COC), polyethylene, and / or polyethylene terephthalate. In some aspects, the cyclic olefin copolymer may include copolymers of cyclic olefins with ethylene or α-olefins, such as copolymers of ethylene and norbornene or copolymers of ethylene and tetracyclododecene. In some aspects, the cyclic olefin polymer or cyclic olefin copolymer comprises at least one cyclic olefin selected from the group consisting of cyclobutene, cyclopentene, cyclooctene, norbornene, 5-methylnorbornene, 3-methylnorbornene, ethylnorbornene, phenylnorbornene, dimethylnorbornene, diethylnorbornene, dicyclopentadiene, tetracyclododecene, methyltetracyclododecene, 6-methylnorbornene, 6-ethylnorbornene, 6-n-butylnorbornene, 5-propylnorbornene, 1-methylnorbornene, 7-methylnorbornene, 5,6-dimethylnorbornene, 5-phenylnorbornene, 5-benzylnorbornene, 8-methyltetracyclo-3-dodecene, 8-ethyltetracyclo-3-dodecene, 8-hexyltetracyclo-3-dodecene, 2,10-dimethyltetracyclo-3-dodecene, and 5,10-dimethyltetracyclo-3-dodecene. In some respects, the polymer does not contain voids, defects or pores.

[0059] For example, some of these polymers are commercially available from Avient, under the trade name Edgetek. TM Polyplastics, product name TOPAS® (COC), Zeonex, trade name ZEONOR ® (COP), and Mitsui, with the product name APEL TM (COC). In some respects, the cyclic olefin copolymer is Edgetek. TM COC BLEND-15GF Natural (COC-GF15, Avient), TOPAS ® 5013F-04 (COC, Polyplastics), TOPAS ® 6013S-04 (COC, Polyplastics), TOPAS ® 5013L-10 (COC, Polyplastics), TOPAS ® 6013F-04 (COC, Polyplastics), TOPAS ® 6013M-07 (COC, Polyplastics), TOPAS ® 6015S-04 (COC, Polyplastics), TOPAS ® 8007F-04 (COC, Polyplastics), TOPAS ® 8007F-600 (COC, Polyplastics), TOPAS ® 8007S-04 (COC, Polyplastics), TOPAS ® 8007X10 (COC, Polyplastics), TOPAS ® 9506F-500 (COC, Polyplastics), Topas ® 5013F-04 (COC, Topas), Topas ® 5013L-10 (COC, Topas), Topas ® 5013S-04 (COC, Topas), Topas ® 6013F-04 (COC, Topas), Topas ® 6013M-07 (COC, Topas), Topas ® 6015S-04 (COC, Topas), Topas ® 6017S-04 (COC, Topas), Topas ®7010F-600 (COC, Topas), Topas ® 8007F-04 (COC, Topas), Topas ® 8007F-600 (COC, Topas), Topas ® 8007S-04 (COC, Topas), Topas ® 8007X10 (COC, Topas), Topas ® 9506F-500 (COC, Topas), Topas ® 9903D-10 (COC, Topas), Topas ® ELASTOMER E-140 (COC, Topas)、APEL TM APL5014DP(COC, Mitsui Chemicals America)、APEL TM APL5514ML (COC, Mitsui ChemicalsAmerica), APEL TM APL6011T (COC, Mitsui Chemicals America), APEL TM APL6013T (COC,Mitsui Chemicals America)、APEL TM APL6015T (COC, Mitsui Chemicals America), APEL TM APL6509T (COC, Mitsui Chemicals America), APEL TM APL8008T (COC, MitsuiChemicals America) or a combination thereof.

[0060] In some respects, the cyclic olefin polymer is Zeonex. ® 330R (COP, Zeon Corporation), Zeonex ® 480 (COP, Zeon Corporation), Zeonex ® 480R (COP, Zeon Corporation), Zeonex ® 5000 (COP, Zeon Corporation), Zeonex ®690R (COP, Zeon Corporation), Zeonex ® 790R (COP, Zeon Corporation), Zeonex ® E48R (COP, Zeon Corporation), Zeonex ® F52R (COP, Zeon Corporation), Zeonex ® RS420 (COP, Zeon Corporation), Zeonor ® 1020R (COP, Zeon Corporation), Zeonor ® 1060R (COP, Zeon Corporation), Zeonor ® 1420R (COP, Zeon Corporation), ARTON F4520 (COP, JSR Corporation), ARTON F3500 (COP, JSR Corporation), ARTON D4000 (COP, JSR Corporation), ARTONFBK80 (COP, JSR Corporation), ARTON R5000 (COP, JSR Corporation), ARTON RX4500 (COP, JSR Corporation), Zeonex ® RS420-LDS (COP, Zeon Corporation), Zeonex ® 350R (COP, Zeon Corporation), Zeonex ® K26R (COP, Zeon Corporation), Zeonor ® 1430R (COP, Zeon Corporation) or a combination thereof.

[0061] The COC or COP may have a strength of 1000 kg / m³ according to ISO 1183 or ASTM D792. 3 Up to 1030kg / m 3 The density is preferably 1010 kg / m³. 3 and 1020kg / m 3 According to ISO 1183, 2cm 3 / 10min to 20cm 3Melt volumetric rate (MVR) of 10 min, preferably 4 cm 3 / 10min and 13cm 3 / 10min; according to ISO 1183, a melt flow rate of 1 g / 10min to 20 g / 10min (MFR, 260°C, 2.16 kg), preferably 3.6 g / 10min and 12 g / 10min; according to JIS K6719, a melt flow rate of 1 g / 10min to 20 g / 10min (MFR, 280°C, 21.18 N), preferably 6 g / 10min and 17 g / 10min; and / or according to ASTM D 1238, a melt flow index of 1 g / 10min to 20 g / 10min (MFI, 280°C, 2.16 kg), preferably 6 g / 10min and 17 g / 10min.

[0062] The COC or COP may have a water absorption rate of 0.03% or less according to ISO 62 or ASTM D570, preferably 0.01% and 0.01% or less; a tensile modulus (1 mm / min) of 410 kpsi to 450 kpsi according to ISO 527-3, preferably 420 kpsi and 440 kpsi; a flexural modulus of 2000 MPa to 2800 MPa according to ASTM D790, preferably 2200 MPa and 2600 MPa; and a tensile stress at break (5 mm / min) of 8500 psi to 9300 psi according to ISO 527-3, preferably 8700 psi and 9100 psi; according to ISO 2.3% to 2.8% of the tensile strain at break (5 mm / min) according to ISO 527-3, preferably 2.5% and 2.6%; 5% to 25% of the tensile strain at break (5 mm / min) according to ISO 527-3, preferably 10% and 20%; 6.5 ft-lbs / in according to ISO 179 / 1eU. 2 Up to 7.35 ft-lbs / in 2 Charpy impact strength at 23°C, preferably 6.7 ft-lbs / in. 2 and 7.1 ft-lbs / in 2 According to ISO 11357-1,-2,-3, the glass transition temperature is 250℉ to 330℉ (10℃ / min), preferably 288℉ and 316℉; according to JIS K7121 or ASTM E 1356, the glass transition temperature is 120℃ to 180℃, preferably 136℃ and 163℃; according to ISO 13468-2 or ASTM D1003 (3mm), the light transmittance is 90% to 95%, preferably 91% and 92%; and / or according to JISD648, the heat distortion temperature is 120℃ to 180℃, preferably 136℃ and 161℃.

[0063] In some aspects, the walls of the pharmaceutical container are composed of glass. The glass used for pharmaceutical containers is typically type I borosilicate glass. Borosilicate glass consists of 25% to 30% by mass of metal. These metals include boron, aluminum, and iron. For type I borosilicate glass, a pH-protective layer helps prevent the dissolution of Si at both high and low pH levels and prevents metal ions from leaching into the drug.

[0064] The pH barrier layer can be applied by any suitable method, particularly by atomic layer deposition (ALD). ALD is typically based on a self-limiting reaction, thereby utilizing sequential and alternating pulses of reactants to deposit one monolayer of deposit per cycle. Deposition conditions and precursors are selected to provide a self-saturating reaction, such that an adsorbed layer of one reactant leaves a surface termination that does not react with the gaseous reactant of the same reactant. The substrate surface is then brought into contact with different reactants, which react with the previous termination to achieve continuous deposition. Thus, each cycle of alternating pulse reactants typically leaves no more than about one monolayer of the desired material. See, for example, US 11,244,825 B2; Di Mauro et al., Applied Catalysis B: Environmental 196 (2016) 68-76; Ahmed et al., AIP Advances 14, 035133 (2024); and Oviroh et al., Science and Technology of Advanced Materials, 20(1):465-496 (2019) for steps involving atomic layer deposition.

[0065] ALD (Atomic Layer Deposition) is a coating deposition technique that produces excellent conformability and allows for tunable coating compositions, where coating thickness can be controlled at the atomic level. ALD operates through the chemical reaction of two or more precursors, which are added to a chamber containing a substrate, to achieve layer-by-layer deposition of material on the substrate surface at a given temperature and pressure. While traditional techniques such as chemical vapor deposition (CVD) rely on high temperatures to decompose the precursors on the substrate surface, ALD can be performed at lower temperatures. Furthermore, compared to CVD and physical vapor deposition (PVD), ALD can produce high-quality coatings with conformability and uniformity, and is highly reproducible and easily scaled up to industrial process levels. In some aspects, plasma-enhanced atomic layer deposition can be used to deposit barrier layers or pH-protective layers at lower temperatures.

[0066] In some aspects, the pharmaceutical container includes a nanolayer coated on the inner side of the container wall, wherein the nanolayer comprises a plurality of thin pH protective layers and a plurality of thin gas barrier layers, wherein each of the pH protective layers and each of the gas barrier layers is alternately arranged, and the nanolayer further includes a thick pH protective coating disposed on the alternately arranged layers facing inward toward the container interior, wherein at least one of the thin pH protective layers comprises an oxide of zirconium, titanium, or magnesium, and at least one of the thin gas barrier layers comprises an oxide of aluminum, and wherein the at least one pH protective layer and the at least one gas barrier layer are deposited by atomic layer deposition (ALD), for example, as... Figure 14 As shown.

[0067] In some aspects, the thin, alternating layers comprise 2 to 60 layers of pH protection layers and 2 to 60 layers of gas barrier layers, for example, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 layers. In other aspects, the thin, alternating layers comprise 10 to 20 layers, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 layers.

[0068] In some aspects, the pH barrier layer may be a compound of aluminum and oxygen, such as aluminum oxide (Al2O3) or Al3O5 (e.g., each compound is referred to herein as "aluminum oxide" unless otherwise explicitly stated). The barrier layer may be applied to a package or a portion thereof using a process such as atomic layer deposition, and may include, as needed, additional precursor steps and bonding layers to continuously apply an aluminum oxide coating with the desired deposition pattern, thickness, consistency, and other properties desired for a particular application.

[0069] The barrier layer of the present invention is deposited using atomic layer deposition at temperatures of 200°C or below, for example, 195°C or below, 190°C or below, 185°C or below, 180°C or below, 175°C or below, 170°C or below, 165°C or below, 160°C or below, 155°C or below, 150°C or below, 145°C or below, 140°C or below, 135°C or below, 130°C or below, or below. The gas barrier layer is applied at temperatures of 130°C, 125°C or below, 120°C or below, 115°C or below, 110°C or below, 105°C or below, 100°C or below, 95°C or below, 90°C or below, 85°C or below, 80°C or below, 75°C or below, 70°C or below, 65°C or below, 60°C or below, 55°C or below, 50°C or below, 45°C or below, or 40°C or below. In some aspects, the gas barrier layer is applied by atomic layer deposition at a temperature below the Tg of the material contained in the medical container.

[0070] In one aspect of the invention, the thickness of the barrier layer is 50 nm or less, for example, 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, 25 nm or less, 20 nm or less, 15 nm or less, 10 nm or less, or 5 nm or less. In some aspects, each of the thin barrier layers has a thickness of 1 nm to 5 nm, for example, 1 nm, 1.5 nm, 2 nm, 2.5 nm, 3 nm, 3.5 nm, 4 nm, 4.5 nm, or 5 nm. In some aspects, each of the thin barrier layers has a thickness of 1 nm to 3 nm or 3 nm to 5 nm.

[0071] The pharmaceutical container of the present invention may include a bonding layer. In some aspects, the bonding layer comprises aluminum oxide and is deposited between the barrier layer and the inner lumen. In some aspects, the bonding layer may be deposited using atomic layer deposition at temperatures of 100°C or below, for example, 95°C or below, 90°C or below, 85°C or below, 80°C or below, 75°C or below, 70°C or below, 65°C or below, 60°C or below, 55°C or below, 50°C or below, 45°C or below, or 40°C or below.

[0072] In some aspects, the pH protective layer of the present invention can be deposited on the barrier layer and can be titanium oxide (e.g., TiO2), zirconium oxide (e.g., ZrO2 or zirconium oxide), magnesium oxide (e.g., MgO or magnesium oxide) or variations and combinations thereof, which are applied on the alumina oxide barrier layer using atomic layer deposition.

[0073] In some respects, titanium dioxide can be applied in its naturally occurring form. In some respects, titanium dioxide is deposited via an ALD process using tetra(dimethylamino)titanium (TDMAT), tetra(diethylamino)titanium (TDEAT), or tetra(ethylmethylamino)titanium (TEMAT), or combinations thereof, as one or more reactants. In some respects, the titanium dioxide precursor requires a process temperature above 225°C. In some respects, the titanium dioxide precursor is used in conjunction with water or an ozone oxidant.

[0074] In some respects, zirconium dioxide is deposited via an ALD process using tetra(dimethylamino)zirconium (Zr(NMe2)4), tetra(ethylmethylamino)zirconium (Zr(NMeEt)4), or tetra(diethylamino)zirconium (Zr(NEt2)4), or combinations thereof, as one or more reactants.

[0075] In some respects, magnesium oxides are deposited via an ALD process using Mg(thd)2 (2,2,6,6-tetramethyl-3,5-heptanedionate magnesium), Mg(Cp)2 (bis(cyclopentadienyl)magnesium), or Mg(EtCp)2 (bis(ethylcyclopentadienyl)magnesium), or combinations thereof, as one or more reactants.

[0076] The pH protective layer of the present invention is deposited using atomic layer deposition at temperatures of 200°C or below, for example, 195°C or below, 190°C or below, 185°C or below, 180°C or below, 175°C or below, 170°C or below, 165°C or below, 160°C or below, 155°C or below, 150°C or below, 145°C or below, 140°C or below, 135°C or below, 130°C or below. Below 130°C, 125°C or below 125°C, 120°C or below 120°C, 115°C or below 115°C, 110°C or below 110°C, 105°C or below 105°C, 100°C or below 100°C, 95°C or below 95°C, 90°C or below 90°C, 85°C or below 85°C, 80°C or below 80°C, 75°C or below 75°C, 70°C or below 70°C, 65°C or below 65°C, 60°C or below 60°C, 55°C or below 55°C, 50°C or below 50°C, 45°C or below 45°C, or 40°C or below 40°C. In some aspects, the pH protective layer is applied by atomic layer deposition at a temperature below the Tg of the contained material of the pharmaceutical container.

[0077] The thickness of the pH protective layer of the present invention is 50 nm or less, for example, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, 25 nm or less, 20 nm or less, 15 nm or less, 10 nm or less, or 5 nm or less. In some aspects, each of the thin pH protective layers has a thickness of 1 nm to 5 nm, for example, 1 nm, 1.5 nm, 2 nm, 2.5 nm, 3 nm, 3.5 nm, 4 nm, 4.5 nm, or 5 nm. In some aspects, each of the thin barrier layers has a thickness of 1 nm to 3 nm or 3 nm to 5 nm. In some aspects, the thick pH protective coating has a thickness of 40 nm to 50 nm, for example, 41 nm, 42 nm, 43 nm, 44 nm, 45 nm, 46 nm, 47 nm, 48 nm, 49 nm, or 50 nm.

[0078] In some respects, the thickness of the barrier layer and the pH protection layer is measured using transmission electron microscopy (TEM) or X-ray photoelectron spectroscopy (XPS).

[0079] The pharmaceutical container of this application is suitable for containing pharmaceutical compositions. In some aspects, the pH of the pharmaceutical composition is from 3 to 12, for example, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12. In some aspects, the pharmaceutical composition comprises peptides, proteins, monoclonal antibodies, or blood components.

[0080] In other respects, the pharmaceutical composition comprises a biological agent, such as those selected from: abatacept; abciximab; botulinum toxin type A; adalimumab; adalimumab-adaz; adalimumab-adbm; adalimumab-afzb; adalimumab-atto; adalimumab-bwwd; ado-trastuzumab emtansine; aflibercept; agalsidase β; abiglutide; chromated CR-51 serum; interleukin; levacecept; alenzusab; aglucosidase α; alicurumab; alteplase; anapeptidase; afotas alfa; asparaginase; Erwinia chrysogena asparaginase. Chrysanthemi; Atezolizumab; Avelumab; Baliximab; Becaprolem; Beracip; Belimumab; Benralizumab; Beraactant; Bevacizumab; Bevacizumab-AWWB; Bevacizumab-BVZR; Bezlotoxumab; Bonatumab; Bentuximab-Vidotine; Brodalumab; Brolurumab-DBLL; Broxol-TWZA; Calaspargase Pegol-MKNL; Calfactant; Canakinumab; Caplacizumab-YHDP; Capromab Pendetide; Seplimab-Rwlc (cemiplimab-rwlc); Cenegermin-bkbj; cerliponase alfa; cetozumab (polyethylene glycol); cetuximab; recombinant human chorionic gonadotropin alpha (choriogonadotropin alfa); chorionic gonadotropin; chymopapain; collagenase; Clostridium histolytica collagenase; corticotropin-releasing factor sheep trifluoroacetate; crizanlizumab-tmca; dacrolimus; daratumumab; daratumumab and hyaluronidase-fihj; dabepoetin alpha; denileukin diftitox; dinoxicam; dinutuximab; streptococcal enzyme alpha;drotrecogin alfa; dulaglutide; dupilumab; durvalumab; icaralotide; eculizumab; efalizumab; elapegademase-lvlr; elosulfase alfa; erlotinumab; emapalumab-lzsg; emicizumab-kxwh; enfortumab vedotin-ejfv; epoetin afa; epoetin afa-epbx; eoretin aoe (erenumab-aooe); etanercept; etanercept-szzs; etanercept-ykro; evolocumab; fam-trastuzumab-drutecan-nxki; plasmin and deoxyribonuclease combination [bovine], containing chloramphenicol; filgrastim; filgrastim-aafi; filgrastim-sndz; follicle-stimulating hormone α; follicle-stimulating hormone β; remanezumab-vfrm (fremanezumab-vfrm); galcanezumab-gnlm (galcanezumab-gnlm); galsulfase; gemtruzumab-orzomicin; glucarpidase; golimumab; gusecurumab; hyaluronidase; human hyaluronidase; ebalizumab-uiyk (ibalizumab-uiyk); teimozumab; idazumab; idursulfase; imiglucinase; incobotulinumtoxin A; inebilizumab-cdon; infliximab; infliximab-abda; infliximab-axxq; infliximab-dyyb; infliximab-qbtx; oxaituzumab; insulin aspart; protamine zinc insulin aspart and insulin aspart; insulin degludec; insulin degludec and insulin aspart; insulin degludec and liraglutide; insulin detemir; insulin glargine; insulin glargine islets Liximab and liximab-2a; lisin insulin; human insulin; zinc protamine human insulin; zinc protamine human insulin and human insulin; lispro insulin; zinc protamine lispro insulin and lispro insulin; lispro insulin-aabc; interferon α-2a; interferon α-2b; interferon alfacon-1; interferon α-n3 (human leukocyte-derived); interferon β-1a; interferon β-1b; interferon γ-1b; ipilimumab; isatuximab-irfc; ixekizumab; lanadelumab-flyo; laronidase; liximab-2a; luspatercept-aamt;mecasermin; mecaserminrinfabate; menotropins; mepolizumab; methoxy polyethylene glycol-eportin β; metreleptin; mogamulizumab-kpkc; moxetumomab pasudotox-tdfk; muromanab-CD3; nastatin; nexituzumab; nivolumab; nofetumomab; obiltoxaximab; obinutuzumab; ocrelizumab; ocriplasmin; ofatumumab; olaratumab; omalizumab; onabotulinumtoxin A; oprelvekin; palifermin; pallizumab; pancreatic lipase; panitumumab; parathyroid hormone; pegademase bovine; peglucosamine; peglucosamine-apgf; peglucosamine-bmez; peglucosamine-cbqv; peglucosamine-jmdb; interferon α-2a; interferon α-2a and ribavirin; interferon α-2b; interferon α-2b and ribavirin; interferon β-1a; pegloticase; pegvaliase-pqpz; pegvaliase; pembrolizumab; pertuzumab; vedotin-piiq; poractant alfa; prabotulinumtoxinA-xvfs; radiolabeled albumin technetium Tc-99m albumin colloid kit; ramucirumab; ranibizumab; raburicase; ravulizumab-cwvz; raxibacumab; reslizumab; reteplase; rilonacept; rimabotulinumtoxinB; risankizumab-rzaa; rituximab; rituximab and human hyaluronidase; rituximab-abbs; rituximab-pvvr; romiplostim; romosozumab-aqqg; goxatozumab-hziy (sacituzumab govitecan-hziy); sacrosidase; sargramostim;Sarilumab; sebelipase alfa; secukinumab; siltuximab; growth hormone; tagraxofusp-erzs; taliglucerase alfa; TBO-filgrastim; technetium 99m TC fanolesomab; tenepase; teprotumumab-trbw; tesamorelin Acetate; Thyroid-stimulating hormone alpha; Tildrakizumab-asmn; Tocilizumab; Tosimomab and Iodine I-131 Tosimomab; Trastuzumab; Trastuzumab and Hyaluronidase-oysk; Trastuzumab-anns; Trastuzumab-dkst; Trastuzumab-dttb; Trastuzumab-pkrb; Trastuzumab-qyyp; Urofollitropin; Urokinase; Ustekinumab; Vedolizumab; Velaglucerase alfa; Vestronidase alfa-vjbk; Ziv-Aflibercept; Amjevita (Adalimumab-atto); Dupixent (Dupilumab); Fulphila (Pefilgrastim-jmdb); Llarris (Kanamab); Ixifi (Infliximab-qbtx); Lyumjev (Insulin Lispro-aabc); Nyvepria (Pegfilgrastim-apgf); Ogivri (Trastuzumab-dkst); Semglee (Insulin Glargine); Uplizna (Innerzalizumab-cdon); APL (Human Chorionic Gonadotropin); Abrilada (Adalimumab-afzb); Aduhelm (Adunazumab-avwa); Accretropin (Growth Hormone); Actemra (Tocilizumab); Acthrel (Corticotropin-releasing factor sheep trifluoroacetate); Actimmune (Interferon-γ-1b); Activase (Alteplase); Adagen (Pegademase Bovine); Adakveo (Krazinzumab-tmca); Addbry (Tralokinumab-ldrm); Adcetris (Bentuximab-Vidotin); Adlyxin (Lixisenatide); Admelog (lispro insulin); Afrezza (human insulin); Aimovig (elemenexumab-aooe); Ajovy (remanexumab-vfrm); Aldurazyme (laronidase);Alferon N Injection (interferon α-n3 (human leukocyte-derived)); Amevive (levacecept); Amphadase (hyaluronidase); Anthim (obiltoxaximab); Apira (insulin lysine); Aranesp (dabepoetin α); Arcalyst (linacecept); Arzerra (olfatumumab); Asparlas (calaspargase pegol-mknl); Avastin (bevacizumab); Avonex (interferon β-1a); Avsola (infliximab-axxq); Basaglar (insulin glargine); Bavencio (averumab); Benlysta (belimumab); Beovu (brolucizumab-dbll); Besponsa (ogaituzumab); Besremi (ropeginterferon-alfa-2b-njft); Betaseron (Interferon β-1b); Bexxar (tosimomab and iodine I-131 tosimomab); Beyfortus (nirsevimab-alip); Bimzelx (bimekizumab); Blincyto (bonatoxin); Botox (onabotulinumtoxin A); Botox Cosmetic (onabotulinumtoxin A); Bravelle (urofollitropin); Brineura (alpha lipase); Briumvi (ublituximab-xiiy); Cablivi (caracizumab-yhdp); Campath (alendizumab); Cathflo Activase (alteplase); Cerezyme (imiglycidase); Chorionic Gonadotropin (human chorionic gonadotropin); Chromalbin (chromium [51Cr] albumin); Chymodiactin (papain); Cimzia (Cetuzumab (polyethylene glycol)); Cinqair (Retizumab); Columvi (glofitamab-gxbm); Cosentyx (Secukinumab); Cotazym (pancreatic lipase); Creon (pancreatic lipase); Crysvita (burosumab-twza); Curosurf (poractant alfa); Cyltezo (adalimumab-adbm); Cyramza (ramucirumab); Darzalex (daratumumab);Darzalex Faspro (darazolizumab and hyaluronidase-fihj); Daxxify (daxibotulinumtoixna-lanm); Draximage MAA (kit for preparing technetium Tc-99m albumin aggregates); Dysport (botulinum toxin type A); Egrifta (tesamorelin acetate); EgriftaSV (tesamorelin acetate); Elahere (mirvetuximab soravtansine-gynx); Elaprase (elaporase); Elase-chloromycetin (fibrinolytic enzyme and deoxyribonuclease combination [bovine], containing chloramphenicol); Ellyso (taliglucerase alfa); Elfabrio (pegunigalsidase alfa-iwxj); Elitek (raburicase); Elrexfio (elranatamab-bcmm); Elspar (Asparaginase); Elzonris (tagraxofusp-erzs); Emgality (gacanezumab-gnlm); Empliciti (erlotuzumab); Enbrel (etanercept); Enbrel Mini (etanercept); Enhertu (fam-trastuzumab-drutecan-nxki); Enjaymo (sutimlimab-jome); Entyvio (veduzumab); Epkinly (epcoritamab-bysp); Epogen / Procrit (eporitine afa); Erbitux (cetuximab); Erelzi (etanercept-szzs); Erelzi Sensoready (etanercept-szzs); Erwinaze (Erwinia chrysanthemum asparaginase); Eticovo (etanercept-ykro); Evenity (romoxozumab-aqqg); Evkeeza (evinacumab-dgnb); Extavia (interferon beta-1b); Eylea (aflibercept); Fabrazyme (agalsidase beta); Fasenra (benlaribumab); Fiasp (insulin aspart); Follistim (follicle-stimulating hormone beta); Follistim AQ (follicle-stimulating hormone beta); Follistim AQ Cartridge (follicle-stimulating hormone beta); Gamifant (imalimumab-lzsg); Gazyva (octobitumab);Genotropin (growth hormone); Gonal-f (follicle-stimulating hormone alpha); Gonal-f RFF (follicle-stimulating hormone alpha); Gonal-f RFF RediJect (follicle-stimulating hormone alpha); Granix (tbo-filgrastim); Hadlima (adalimumab-bwwd); Hemlibra (emecizumab-kxwh); Herceptin (trastuzumab); HerceptinHylecta (trastuzumab and hyaluronidase-oysk); Herzuma (trastuzumab-pkrb); Humalog (lispro insulin); Humalog Mix 50 / 50 (protamine zinc lispro insulin and lispro insulin); Humalog Mix 75 / 25 (protamine zinc lispro insulin and lispro insulin); Humatrope (growth hormone); Humegon (menotropins); Humira (adalimumab); Humulin 70 / 30 (Protamine Zinc Human Insulin and Human Insulin); Humulin N (Protamine Zinc Human Insulin); Humulin RU-100 (Human Insulin); Humulin RU-500 (Human Insulin); Hydase (Hyaluronidase); Hylenex recombinant (Human Hyaluronidase); Hyrimoz (Adalimumab - adaz); Ilumya (Trecitracin - asmn); Imfinzi (Dulvarubab); Imjudo (Tremelimumab - actl); Increlex (mecasermin); Infasurf (Carfaktan); Infergen (Interferon alfacon-1); Inflectra (Infliximab - dyyb); Intron A (Interferon α-2b); Iplex (mecaserminrinfabate); Iprivask (Disiludin); Jeanatope (Kit for I-125 albumin iodide); Jemerli (dostarlimab-gxly); Jetrea (Octokinase); Jeuveau (prabotulinumtoxinA-xvfs); Kadcyla (trastuzumab emtansine); Kalbitor (Icaratide); Kanjinti (trastuzumab-anns); Kanuma (sebelipase alfa); Kepivance (palifermin); Kevzara (thalidomab); Keytruda (pembrolizumab);Kimmtrak (tebentafusp-tebn); Kinret (anabolic acid); Kinlytic (urokinase); Krystexxa (precocis); Lamzede (velmanase alfa-tycv); Lantus (insulin glargine); Lartruvo (olaramab); Lemtrada (alendumab); Leqembi (lecanemab-irmb); Leukine (saxaglastine); Leafmir (insulin detemir); Libtayo (teplimab-rwlc); Loqtorzi (toripalimab-tpzi); Lucentis (ranibizumab); Lumizyme (moxetumomab pasudotox-tdfk); Lunsumio (mosunetuzumab-axgb); Macrotec (kit for preparing technetium Tc-99m albumin aggregates); Megatope (kit for iodinated I-131 albumin); Menopur (menotropins); Mepsevii (vestronidase alfa-vjbk); Microlite (radiolabeled albumin technetium Tc-99m albumin colloid kit); Mircera (methoxy-polyethylene glycol-epotine β); Mvasi (bevacizumab-awwb); Myalept (metreleptin); Mylotarg (geutzumab-orzomicin); Myobloc (rimabotulinumtoxin B); Myozyme (glucosidase α); Myxredlin (human insulin); N / A (raxibacumab); Naglazyme (sulfonase); Natpara (parathyroid hormone); Neulasta (Pefilgrastim); Neulasta Onpro (Pefilgrastim); Neumega (Neupogen); Neupogen (Nefilgrastim); NeutroSpec (Technetium 99m tc fanolesomab); Nexobrid (anacaulase-bcdb); Nexviazyme (avalglucosidase alfa-ngpt); Ngenla (somatrogon-ghla); Nivestym (Nefilgrastim-aafi); Norditropin (Growth Hormone); Novalel (Human Chorionic Gonadotropin); Novolin 70 / 30 (Protamine Zinc Human Insulin and Human Insulin);Novolin N (Zinc Protamine Insulin); Novolin R (Human Insulin); Novolog (Insulin Aspart); Novolog Mix 50 / 50 (Zinc Protamine Insulin Aspart and Insulin Aspart); Novolog Mix 70 / 30 (Zinc Protamine Insulin Aspart and Insulin Aspart); Nplate (Roprostine); Nucala (Mepolilimab); Nulojix (Beraceptide); Nutropin (Growth Hormone); Nutropin AQ (Growth Hormone); Ocrevus (Orelizumab); Omnitrope (Growth Hormone); Omvoh (mirikizumab-mrkz); Oncaspar (Pegasparase); Ontak (Dennis Interleukin-Diphtheria Toxin Conjugate); Ontruzant (Trastuzumab-dttb); Opdivo (Nivolumab); Opdualag (Nivolumab and relatlimab-rmbw); Orencia (Abatacept); Orthoclone OKT3 (muromanab-CD3); Ovidrel (Recombinant Human Chorionic Gonadotropin Alpha); Oxervate (Cenegemin-bkbj); Padcev (Ventumumab-ejfv); Palynziq (pegvaliase-pqpz); Pancreaze (Pancrease); Pegasys (Interferon Alpha-2a); Pegasys Copegus Combination Pack (Interferon Alpha-2a and Ribavirin); Pegintron (Interferon Alpha-2b); Pegintron / Rebetol Combo Pack (Interferon Alpha-2b and Ribavirin); Pergonal (menotropins); Perjeta (Pertuzumab); Pertzye (Pancrease); Plegridy (Interferon Beta-1a); Polivy (Verpottuzumab-piiq); Pombiliti (cipaglucosidasealfa-atga); Portrazza (nexituzumab); Poteligeo (moglizumab-kpkc); Praluent (alikumab); Praxbind (idazumab); Pregnyl (human chorionic gonadotropin); Procrit (eportin afa); Proleukin (aldeleukin); Prolia (denomab); ProstaScint (carosumab pendiptide); Pulmolite (kit for preparing technetium Tc-99m albumin aggregates);Pulmotech MAA (Kit for preparing technetium Tc-99m albumin aggregates); Pulmozyme (Streptococcus alpha); Raptiva (Efazolizumab); Rebif (Interferon β-1a); Reblozyl (luspatercept-aamt); Regrannex (Becaprelamine); Remicade (Infliximab); Renflexis (Infliximab-abda); Reopro (Abciximab); Repatha (Evologumab); Repronex (Menotropins); Retacrit (Epobine-epbx); Retavase (Reteplase); Revcovi (elapegademase-lvlr); Rituxan (Rituximab); Rituxan Hycela (Rituximab and Human Hyaluronidase); Roferon-A (Interferon alpha-2a); Rolvedon (eflapegrastim-xnst); Ruxience (rituximab-pvvr); Rybrevant (amivantamab-vmjw); Rylaze (Erwinia chrysanthemum asparaginase (recombinant)-rywn); Ryzneuta; Rystiggo (rozanolixizumab-noli); Ryzodeg 70 / 30 (insulin degludec and insulin aspart); Saizen (growth hormone); Santyl (collagenase); Saphnelo (anifrolumab-fnia); Sarclisa (isatuximab-irfc); Serostim (growth hormone); Siliq (brodamarab); Simponi (golimumab); Simponi Aria (golimumab); Simulect (baliximab); Skyrizi (rzaa); Skytrofa (lonapegsomatropin-tcgd); Soliqua 100 / 33 (insulin glargine and lixisenatide); Soliris (eculizumab); Somavert (pevisomone); Spevigo (spesolimab-sbzo); Stelara (ustekinumab); Streniq (afotazyme α); Sucraid (sacrosidase); Survanta (belatan); Susvimo ​​(ranibizumab); Sylvant (staxicumab); Synagis (palizumab); Takhzyro (lanadelumab-flyo);Taltz (Ikrazizumab); Talvey (talquetamab-TGVS); Tanzeum (Abiglutide); Tecentriq (Tetelizumab); Tecvayli (teclistamab-CQYV); Tepezza (Tetramumab-TRBW); Tezspire (Tezepelumab-Ekko); Thyrogen (Thyroid-stimulating hormone alpha); Tivdak (tisotumab vedotin-TFTV); TNKase (Tenneplase); Toujeo (Insulin Glargine); Trasylol (Aprotinin); Trazimera (Trastuzumab-QYYP); Tremfya (Gusecurumab); Tresiba (Insulin Degludec); Trodelvy (Gosaxutuzumab-HZIY); Trogarzo (Ebalizumab-UIYK); Trulicity (Dulaglutide); Truxima (Rituximab-abbs); Tysabri (Natazumab); Tzield (teplizumab-mzwv); Udenyca (pefragilamine-cbqv); Ultomiris (relizumab-cwvz); Unituxin (denutuximab); Vabysmo (faricimab-svoa); Vectibix (panitumumab); Veopoz (pozeilimab-bbfg); Verluma (nofetumomab); Vimizim (evolactase α); Viokace (pancreatic lipase); Vitrase (hyaluronidase); Voraxaze (carboxypeptidase); VPRIV (vilaradinase α); Vyvgart (efgartigimod alfa-fcab); Vyvgart Hytrulo (efgartigimod Alfa and hyaluronidase-qvfc); Xenpozyme (olipudase alfa-rpcp); Xeomin (incobotulinumtoxin A); Xgeva (denomab); Xiaflex (clostridium histolyticum collagenase); Xigris (trichomoniasis α); Xolair (omalizumab); Xultophy 100 / 3.6 (insulin degludec and liraglutide); Yervoy (ipilimumab); Zaltrap (Ziv-aflibercept); Zarxio (filgrastim-sndz); Zenapax (dacrolimus); Zenpep (pancreatic lipase); Zevalin (tieimomab);Ziextenzo (pefragstatin-bmez); Zinbryta (dacrolimus); Zinplava (bezotocilizumab); Zirabev (bevacizumab-bvzr); Zomacton (growth hormone); Zorbtive / Serostim (growth hormone); Zymfentra (infliximab); Zynlonta (locastuximab tesirine-lpyl); or Zynyz (retifanlimab-dlwr).

[0081] For example, preferred classifications of biologics include those for use with: tumor necrosis factor-α (TNF) inhibitors, interleukin inhibitors, selective co-stimulatory modulators, glucagon-like peptide-1 (GLP-1) agonists or GLP-1 receptor agonists, mRNA-based formulations, allergens, tissues, recombinant proteins, personalized medicines (e.g., CAR-T; cell and gene therapy), and biologics listed in the FDA Purple Book (Purple Book: List of Approved Biologics and Reference Drug Exclusivity / Biosimilar Interchangeability Assessment). In some aspects, the personalized medicine is a CAR-T drug or a cell or gene therapy drug.

[0082] The aspects of the invention described herein can be used alone or in combination with one or more other aspects. Without limiting the foregoing description, certain non-limiting aspects, numbered 1-44, are provided below. As will be apparent to those skilled in the art upon reading this disclosure, each individually numbered aspect can be used in combination with any of the foregoing or subsequently individually numbered aspects. This is intended to support all such combinations of aspects, and is not limited to the combinations of aspects explicitly provided below:

[0083] (1) A pharmaceutical container comprising an inner cavity partially defined by a wall having an inner surface facing the inner cavity, an outer surface and at least one pH protection layer comprising an oxide of zirconium, titanium or magnesium, wherein the at least one pH protection layer is a layer produced by an atomic layer deposition (ALD) process.

[0084] (2) The pharmaceutical container according to aspect (1) further includes at least one gas barrier layer disposed between the inner surface and the at least one pH protection layer.

[0085] (3) The pharmaceutical container according to aspect (2), wherein the at least one gas barrier layer comprises Al2O3 and / or Al3O5.

[0086] (4) The pharmaceutical container according to any one of aspects (1) to (3), wherein the wall of the pharmaceutical container comprises a polymer.

[0087] (5) The pharmaceutical container according to aspect (4), wherein the polymer of the pharmaceutical container is selected from polypropylene, cyclic olefin polymer (COP), cyclic olefin copolymer (COC), polyethylene, polyethylene terephthalate and combinations thereof.

[0088] (6) The pharmaceutical container according to aspect (5), wherein the polymer is COP, COC or a combination thereof.

[0089] (7) The pharmaceutical container according to aspect (5) or (6), wherein the COP or COC comprises at least one cycloolefin selected from the group consisting of cyclobutene, cyclopentene, cyclooctene, norbornene, 5-methylnorbornene, 3-methylnorbornene, ethylnorbornene, phenylnorbornene, dimethylnorbornene, diethylnorbornene, dicyclopentadiene, tetracyclododecene, and methyltetracyclododecene.

[0090] (8) The pharmaceutical container according to aspect (5) or (6), wherein the COP or COC comprises at least one cycloolefin selected from the group consisting of norbornene, 6-methyl norbornene, 6-ethyl norbornene, 6-n-butyl norbornene, 5-propyl norbornene, 1-methyl norbornene, 7-methyl norbornene, 5,6-dimethyl norbornene, 5-phenyl norbornene, 5-benzyl norbornene, 8-methyltetracyclo-3-dodecene, 8-ethyltetracyclo-3-dodecene, 8-hexyltetracyclo-3-dodecene, 2,10-dimethyltetracyclo-3-dodecene, and 5,10-dimethyltetracyclo-3-dodecene.

[0091] (9) The pharmaceutical container according to aspect (1), wherein the wall of the pharmaceutical container comprises glass.

[0092] (10) A pharmaceutical container according to any one of aspects (4) to (8), wherein the at least one pH protection layer and / or the at least one gas barrier layer is applied by ALD at a temperature below the Tg of the polymer wall.

[0093] (11) A pharmaceutical container according to any one of aspects (2) to (9), wherein the at least one gas barrier layer and / or the at least one pH protection layer is deposited by ALD at a temperature of 150°C, 140°C, 130°C, 120°C, 110°C or 100°C or below 100°C.

[0094] (12) The pharmaceutical container according to any one of aspects (2) to (11), wherein the at least one gas barrier layer provides a barrier against carbon dioxide, nitrogen, oxygen and / or water vapor.

[0095] (13) The pharmaceutical container according to any one of aspects (2) to (12), wherein the thickness of the at least one gas barrier layer is 50 nm or less.

[0096] (14) The pharmaceutical container according to any one of aspects (1) to (13), wherein the thickness of the at least one pH protective layer is 50 nm or less.

[0097] (15) The medical container according to aspect (13), wherein the thickness of the at least one gas barrier layer is measured by TEM or XPS.

[0098] (16) The pharmaceutical container according to aspect (14), wherein the thickness of the at least one pH protective layer is measured by TEM or XPS.

[0099] (17) The pharmaceutical container according to any one of aspects (2) to (16), wherein when exposed to conditions of 50°C and pH 3 to 9 for 72 hours, the at least one pH protective layer reduces the dissolution rate of the at least one gas barrier layer by >90%.

[0100] (18) The pharmaceutical container according to any one of aspects (2) to (17) further includes a nanolayer coated on the inner surface of the wall of the container, wherein the nanolayer includes a plurality of thin pH protection layers and a plurality of thin gas barrier layers, wherein each of the pH protection layers and each of the gas barrier layers are arranged alternately, and the nanolayer further includes a thick pH protection coating disposed on the alternately arranged layers and facing the interior of the container.

[0101] (19) The pharmaceutical container according to aspect (18), wherein the thin, alternating layers comprise 2 to 60 layers of pH protection layer and / or 2 to 60 layers of gas barrier layer.

[0102] (20) The pharmaceutical container according to aspect (18) or (19), wherein at least one of the thin pH protection layers comprises an oxide of zirconium, titanium or magnesium, and at least one of the thin gas barrier layers comprises an oxide of aluminum, and wherein at least one pH protection layer and at least one gas barrier layer are deposited by atomic layer deposition (ALD).

[0103] (21) A pharmaceutical container according to any one of aspects (18) to (20), wherein the thin gas barrier layer and / or the thin pH protection layer is deposited at a temperature below the Tg of the material contained in the wall of the pharmaceutical container.

[0104] (22) A pharmaceutical container according to any one of aspects (18) to (21), wherein the thin gas barrier layer and / or the thin pH protection layer are deposited by ALD at a temperature of 150°C, 140°C, 130°C, 120°C, 110°C or 100°C or below 100°C.

[0105] (23) A pharmaceutical container according to any one of aspects (18) to (22), wherein the thin gas barrier layer provides a barrier against carbon dioxide, nitrogen, oxygen and / or water vapor.

[0106] (24) A pharmaceutical container according to any one of aspects (18) to (23), wherein each of the thin gas barrier layers has a thickness of 3 nm to 5 nm.

[0107] (25) A pharmaceutical container according to any one of aspects (18) to (24), wherein each of the thin pH protective layers has a thickness of 3 nm to 5 nm.

[0108] (26) The pharmaceutical container according to any one of aspects (18) to (25), wherein the thick pH protective coating has a thickness of 40 nm to 50 nm.

[0109] (27) A pharmaceutical container according to any one of aspects (24) to (26), wherein the thickness of any of the layers is measured by TEM and / or XPS.

[0110] (28) The pharmaceutical container according to any one of aspects (18) to (27), wherein when exposed to conditions of 50°C and pH 3 to 9 for 72 hours, the thin pH protective layer reduces the dissolution rate of the thin barrier layer by at least 60%.

[0111] (29) The pharmaceutical container according to aspect (28), wherein when exposed to conditions of 50°C and pH 3 to 9 for 72 hours, the thin pH protective layer reduces the dissolution rate of the thin barrier layer by up to 90% or more.

[0112] (30) A pharmaceutical container according to any one of aspects (1) to (29), wherein the zirconium oxide is ZrO2.

[0113] (31) A pharmaceutical container according to any one of aspects (1) to (29), wherein the oxide of said titanium is TiO2.

[0114] (32) A pharmaceutical container according to any one of aspects (1) to (29), wherein the oxide of said magnesium is MgO.

[0115] (33) The pharmaceutical container according to aspect (30), wherein the ZrO2 is deposited by an ALD process using tetra(dimethylamino)zirconium (Zr(NMe2)4), tetra(ethylmethylamino)zirconium (Zr(NMeEt)4) or tetra(diethylamino)zirconium (Zr(NEt2)4) or a combination thereof as one or more reactants.

[0116] (34) The pharmaceutical container according to aspect (31), wherein the TiO2 is deposited by an ALD process using tetra(dimethylamino)titanium (TDMAT), tetra(diethylamino)titanium (TDEAT) or tetra(ethylmethylamino)titanium (TEMAT) or a combination thereof as one or more reactants.

[0117] (35) The pharmaceutical container according to aspect (32), wherein the MgO is deposited by an ALD process using Mg(thd)2 (magnesium 2,2,6,6-tetramethyl-3,5-heptadecanoate), Mg(Cp)2 (bis(cyclopentadienyl)magnesium) or Mg(EtCp)2 (bis(ethylcyclopentadienyl)magnesium) or a combination thereof as one or more reactants.

[0118] (36) The pharmaceutical container according to any one of aspects (1) to (35) further includes a bonding layer deposited on the inner cavity.

[0119] (37) The pharmaceutical container according to aspect (36), wherein the bonding layer comprises aluminum oxide.

[0120] (38) The pharmaceutical container according to any one of aspects (1) to (37) contains a pharmaceutical composition.

[0121] (39) The pharmaceutical container according to aspect (38), wherein the pH of the pharmaceutical composition is 3 to 12.

[0122] (40) The pharmaceutical container according to aspect (39), wherein the pH of the pharmaceutical composition is 3 to 9 or 6 to 9.

[0123] (41) A pharmaceutical container according to any one of aspects (38) to (40), wherein the pharmaceutical composition comprises a peptide, a protein, a monoclonal antibody or a blood component.

[0124] (42) A pharmaceutical container according to any one of aspects (38) to (41), wherein the pharmaceutical composition comprises a biological drug selected from: abatacept; abciximab; botulinum toxin type A; adalimumab; adalimumab-adaz; adalimumab-adbm; adalimumab-afzb; adalimumab-atto; adalimumab-bwwd; trastuzumab emtansine; aflibercept; agalsidase β; abiglutide; chromium [51Cr] albumin; interleukin; levacecept; alenzusumab; aglucosidase. Alteplase; Alteplase; Anaprostol; Aprotinin; Afotazone α; Asparaginase; Erwinia chrysogena asparaginase; Atezolizumab; Avelumab; Baliximab; Becaprolem; Beracip; Belimumab; Benlazolizumab; Belatan; Bevacizumab; Bevacizumab-AWWB; Bevacizumab-BVZR; Bezotocilizumab; Bonatumab; Bentuximab; Brodatumab; Brodatumab-DBLL; Broxolumab-TWZA; Calaspargase pegol-mknl; carfaxtam; cannabinoid; carracizumab-yhdp; calcitumab pendiptide; ceprelimumab-rwlc; senegiline-bkbj; alpha lipase; cetolizumab-polyethylene glycol; cetuximab; recombinant human chorionic gonadotropin α; chorionic gonadotropin; papain; collagenase; clostridium histolyticum collagenase; corticotropin-releasing factor sheep trifluoroacetate; crizolinium-tmca; dacrolimus; daracetam Tomotumab; Daratumab and Hyaluronidase-fihj; Dabepoetin Alpha; Denisulin-Diphtheria Toxin Conjugate; Denotumab; Desirudin; Denutoximab; Streptomycin Alpha; Triclocarpine Alpha; Dulaglutide; Dupilumab; Duvalumab; Icaratide; Eculizumab; Efazumab; Elapegademase-lvlr; Elotrinase Alpha; Erlotinumab; Imalimumab-lzsg; Emicycin Anti-kxwh; Verentumab-ejfv; Epoetin afa; Epoetin afa-epbx; Erenedumab-aooe; Etanercept; Etanercept-szzs; Etanercept-ykro; Evocloburot; FAM-Trastuzumab-Drutec-nxki; Fibrinolytic enzyme and deoxyribonuclease combination [bovine], containing chloramphenicol; Filgrastim; Filgrastim-aafi; Filgrastim-sndz; Follicle-stimulating hormone α; Follicle-stimulating hormone Follicle-stimulating hormone β; Remannetumab-vfrm; Gardanazumab-gnlm; Thionase; Gelatinumab-orzomicin; Carboxypeptidase; Golimumab; Gusecurumab; Hyaluronidase; Human Hyaluronidase; Ebalizumab-uiyk; Tiimumab; Idazumab; Iduthiopeptidase; Imiglucerase; Incobotulinumtoxin A; Inellizumab-cdon; Infliximab-abda;Infliximab-AXXQ; Infliximab-DYYB; Infliximab-QBTX; Ogaituzumab; Insulin Aspart; Protamine Zinc Insulin Aspart and Insulin Aspart; Insulin Degludec; Insulin Degludec and Insulin Aspart; Insulin Degludec and Liraglutide; Insulin Detemir; Insulin Glargine; Insulin Glargine and Lixinus; Insulin Lispro; Human Insulin; Protamine Zinc Human Insulin; Protamine Zinc Human Insulin and Human Insulin; Insulin Lispro; Insulin Lispro; Protamine Zinc Lispro; Insulin Lispro Insulin-aabc; Interferon α-2a; Interferon α-2b; Interferon alfacon-1; Interferon α-n3 (human leukocyte-derived); Interferon β-1a; Interferon β-1b; Interferon γ-1b; Ipilimumab; isatuximab-irfc; Ixekizumab; lanadelumab-flyo; laronidase; liximab; luspatercept-aamt; mecasermin; mecasermin Rinfabate; Menotropins; Meporibumab; Metreleptin; Mogliflozin-KPKC; Moxetumomab; Pasudotox-TDFK; Muromanab-CD3; Natazolizumab; Nexituzumab; Nivolumab; Nofetumomab; Obiltoxaximab; Obiltoxaximab; Oligolizumab; Octocin; Olatumab; Omalizumab; Onabotulinumtoxin A; Interleukin; Palifermin; Palolizumab; Pancreatic Lipase; Panitumumab; Parathyroid Hormone; Pegademase bovine; pegvaliase; pegfilgrastim; pegfilgrastim-apgf; pegfilgrastim-bmez; pegfilgrastim-cbqv; pegfilgrastim-jmdb; interferon α-2a; interferon α-2a and ribavirin; interferon α-2b; interferon α-2b and ribavirin; interferon β-1a; pegvaliase-pqpz; pegfilgrastim; pembrolizumab; pertuzumab; veporactantalfa; prabo Tulinumtoxin A-XVFS; Radiolabeled Technetium Albumin Tc-99m Albumin Colloid Kit; Ramucirumab; Ranibizumab; Raburicase; Relizumab-CWVZ; Raxibacumab; Relizumab; Reliplase; Linasicept; Rimabotulinumtoxin B; Rizaaa; Rituximab; Rituximab and Human Hyaluronidase; Rituximab-ABBS; Rituximab-PVVR; Roprostadil; Romosulzumab-AQQG;Sacrosidase; Saxaglucerase; Salilurumab; Sebelipase Alfa; Secukinumab; Secukinumab; Growth Hormone; Tagraxofusp-erzs; Taliglucerase Alfa; TBO-Figrasil; Technetium 99M TC Fanolesomab; Tenecteplase; Tiltumumab-TRBW; Tesamorelin Acetate; Thyroid-stimulating hormone alpha; Tiraginumab - asmn; Tocilizumab; Tosimomab and Iodine I-131 Tosimomab; Trastuzumab; Trastuzumab and Hyaluronidase - oysk; Trastuzumab - anns; Trastuzumab - dkst; Trastuzumab - dttb; Trastuzumab - pkrb; Trastuzumab - qyyp; Urofollitropin; Urokinase; Ustekinumab; Vedolizumab; Verasidase alpha; Vestronidasealfa - vjbk; Ziv - Aflibercept; Amjevita (Adalimumab - atto); Dupixent (Dupilumab); Fulphila (Pefilgrastim - jmdb); Llarris (Kanamab); Ixifi (Infliximab - qbtx); Lyumjev (Insulin lispro-aabc); Nyvepria (pefraglucinil-apgf); Ogivri (trastuzumab-dkst); Semglee (insulin glargine); Uplizna (innerazolizumab-cdon); APL (human chorionic gonadotropin); Abrilada (adalimumab-afzb); Aduhelm (adunazumab-avwa); Accretropin (growth hormone); Actemra (tocilizumab); Acthrel (corticotropin-releasing factor sheep trifluoroacetate); Actimmune (interferon-γ-1b); Activase (alteplase); Adagen (pegademase bovine); Adakveo (clozalinumab-tmca); Addbry (tralokinumab-ldrm); Adcetris (bentuximab-vitoline); Adlyxin (lixisenatide); Admelog (insulin lispro); Afrezza (Human insulin); Aimovig (Erenezumab-aooe); Ajovy (Remannetumab-vfrm); Aldurazyme (laronidase); Alferon N Injection (Interferon α-n3 (human leukocyte-derived)); Amevive (Levacercept); Amphadase (hyaluronidase);Anthim (obiltoxaximab); Apira (insulin lisigludec); Aranesp (dabepoetin alpha); Arcalyst (linasip); Arzerra (olfatumumab); Asparlas (calaspargase pegol-mknl); Avastin (bevacizumab); Avonex (interferon beta-1a); Avsola (infliximab-axxq); Basaglar (insulin glargine); Bavencio (averumab); Benlysta (belimumab); Beovu (brolucizumab-dbll); Besponsa (ogaituzumab); Besremi (ropeginterferon-alfa-2b-njft); Betaseron (interferon beta-1b); Bexxar (tosimomab and iodine I-131 tosimomab); Beyfortus (nirsevimab-alip); Bimzelx (bimekizumab); Blincyto (bonatoxin); Botox (onabotulinumtoxinA); Botox Cosmetic (onabotulinumtoxinA); Bravelle (urofollitropin); Brineura (alpha lipase); Briumvi (ublituximab-xiiy); Cablivi (caralacilizumab-yhdp); Camppath (alendumab); Cathflo Activase (alteplase); Cerezyme (imiglycidase); Chorionic Gonadotropin (human chorionic gonadotropin); Chromalbin (chromium [51Cr] albumin); Chymodiactin (papain); Cimzia (cetuzumab polyethylene glycol); Cinqair (reteizumab); Columvi (glofitamab-gxbm); Cosentyx (secukinumab); Cotazym (pancreatic lipase); Creon (pancreatic lipase); Crysvita (burosumab-twza); Curosurf (poractant alfa); Cyltezo (adalimumab-adbm); Cyramza (ramucirumab); Darzalex (daratumumab); Darzalex Faspro (daratumumab and hyaluronidase-fihj); Daxxify (daxibotulinumtoixna-lanm);Draximage MAA (Kit for preparing technetium Tc-99m albumin aggregates); Dysport (Botulinum toxin type A); Egrifta (tesamorelin acetate); Egrifta SV (tesamorelin acetate); Elahere (mirvetuximab soravtansine-gynx); Elaprase (Idasulfan); Elase-chloromycetin (a combination of plasmin and deoxyribonuclease [bovine], containing chloramphenicol); Ellyso (taliglucerase alfa); Elfabrio (pegunigalsidase alfa-iwxj); Elitek (raburicase); Elrexfio (elranatamab-bcmm); Elspar (asparaginase); Elzonris (tagraxofusp-erzs); Emgality (cananezumab-gnlm); Empliciti (erlotinib); Enbrel (Etanercept); Enbrel Mini (Etanercept); Enhertu (fam-trastuzumab-drutecan-nxki); Enjaymo (sutimlimab-jome); Entyvio (Vetrazil); Epkinly (epcoritamab-bysp); Epogen / Procrit (eporitine afa); Erbitux (cetuximab); Erelzi (Etanercept-szzs); Erelzi Sensoready (Etanercept-szzs); Erwinaze (Erwinia chrysanthemum asparaginase); Eticovo (Etanercept-ykro); Evenity (romosuzumab-aqqg); Evkeeza (evinacumab-dgnb); Extavia (interferon β-1b); Eylea (aflibercept); Fabrazyme (agalsidase β); Fasenra (Benlalizumab); Fiasp (Insulin Aspart); Follistim (Follicle-stimulating hormone beta); Follistim AQ (Follicle-stimulating hormone beta); Follistim AQ Cartridge (Follicle-stimulating hormone beta); Gamifant (Imalimumab-lzsg); Gazyva (Oxtozumab); Genotropin (Growth Hormone); Gonal-f (Follicle-stimulating hormone alpha); Gonal-f RFF (Follicle-stimulating hormone alpha); Gonal-f RFF RediJect (Follicle-stimulating hormone alpha);Granix (TBO - Fibrazil); Hadlima (Adalimumab - BWWD); Hemlibra (Emicizumab - KXWH); Herceptin (Trastuzumab); Herceptin Hylecta (Trastuzumab and Hyaluronidase - OYSK); Herzuma (Trastuzumab - PKRB); Humalog (Lispro insulin); Humalog Mix 50 / 50 (Protamine Zinc Lispro insulin and Lispro insulin); Humalog Mix 75 / 25 (Protamine Zinc Lispro insulin and Lispro insulin); Humatrope (Growth Hormone); Humegon (Menotropins); Humira (Adalimumab); Humulin 70 / 30 (Protamine Zinc Human Insulin and Human Insulin); Humulin N (Protamine Zinc Human Insulin); Humulin RU-100 (Human Insulin); Humulin RU-500 (Human Insulin); Hydase; Hylenex recombinant (Human Hyaluronidase); Hyrimoz (Adalimumab - adaz); Ilumya (Trecitrazumab - asmn); Imfinzi (Dulvarumab); Imjudo (Tremelimumab - actl); Increlex (mecasermin); Infasurf (Carfaktan); Infergen (Interferon alfacon-1); Inflectra (Infliximab - dyyb); Intron A (Interferon α-2b); Iplex (mecasermin rinfabate); Iprivask (Disiludin); Jeanatope (Kit for I-125 Albumin Iodide); Jemerli (Dostarlimab - gxly); Jetrea (Octokinase); Jeuveau (prabotulinumtoxin A-xvfs); Kadcyla (trastuzumab emtansine); Kalbitor (Icaratide); Kanjinti (trastuzumab-anns); Kanuma (sebelipase alfa); Kepivance (palifermin); Kevzara (thalidomab); Keytruda (pembrolizumab); Kimmtrak (tebentafusp-tebn); Kinoret (analexin); Kinlytic (urokinase); Krystexxa (precex); Lamzede (velmanase alfa-tycv);Lantus (insulin glargine); Lartruvo (olaramab); Lemtrada (alenduzumab); Leqembi (lecanemab-irmb); Leukine (saxaglastine); Leafmir (insulin detemir); Libtayo (teplimab-rwlc); Loqtorzi (toripalimab-tpzi); Lucentis (ranibizumab); Lumizyme (glucosidase α); Lumoxiti (moxetumomab pasudotox-tdfk); Lunsumio (mosunetuzumab-axgb); Macrotec (kit for preparing technetium Tc-99m albumin aggregates); Megatope (kit for iodinated I-131 albumin); Menopur (menotropins); Mepsevii (vestronidasealfa-vjbk); Microlite (Radiolabeled albumin technetium Tc-99m albumin colloid kit); Mircera (methoxy-polyethylene glycol-eportine β); Mvasi (bevacizumab-awwb); Myalept (metreleptin); Mylotarg (gemtuzumab-orzomicin); Myobloc (rimabotulinumtoxin B); Myozyme (aglucosidase α); Myxredlin (human insulin); N / A (raxibacumab); Naglazyme (sulfonase); Natpara (parathyroid hormone); Neulasta (pefragil); Neulasta Onpro (pefragil); Neumega (interleukin); Neupogen (fragil); NeutroSpec (technetium 99m tc fanolesomab); Nexobrid (anacaulase-bcdb); Nexviazyme (avalglucosidase) alfa-ngpt); Ngenla (somatrogon-ghla); Nivestym (filastatin-aafi); Norditropin (growth hormone); Novalel (human chorionic gonadotropin); Novolin 70 / 30 (protamine zinc human insulin and human insulin); Novolin N (protamine zinc human insulin); Novolin R (human insulin); Novolog (aspart insulin); Novolog Mix 50 / 50 (protamine zinc aspart insulin and aspart insulin);Novolog Mix 70 / 30 (Protamine Zinc Aspart Insulin and Aspart Insulin); Nplate (Roprostine); Nucala (Mepolilimab); Nulojix (Beraccept); Nutropin (Growth Hormone); Nutropin AQ (Growth Hormone); Ocrevus (Orelizumab); Omnitrope (Growth Hormone); Omvoh (mirikizumab-mrkz); Oncaspar (Pegasparase); Ontak (Dennis Interleukin-Diphtheria Toxin Conjugate); Ontruzant (Trastuzumab-dttb); Opdivo (Nivolumab); Opdualag (Nivolumab and Relatlimab-rmbw); Orencia (Abatacept); Orthoclone OKT3 (Muromanab-CD3); Ovidrel (Recombinant human chorionic gonadotropin α); Oxervate (xenegiline-bkbj); Padcev (vemtotuzumab-ejfv); Palynziq (pegvaliase-pqpz); Pancreaze (pancreatic lipase); Pegasys (pegvaliase α-2a); Pegasys Copegus Combination Pack (pegvaliase α-2a and ribavirin); Pegintron (pegvaliase α-2b); Pegintron / Rebetol ComboPack (pegvaliase α-2b and ribavirin); Pergonal (menotropins); Perjeta (pertuzumab); Pertzye (pancreatic lipase); Plegridy (pegvaliase β-1a); Polivy (vemtotuzumab-piiq); Pombiliti (cipaglucosidase alfa-atga); Portrazza (nexituzumab); Poteligeo (Moglitumumab-kpkc); Praluent (Alikumab); Praxbind (Idazumab); Pregnyl (Human Chorionic Gonadotropin); Procrit (Epoetin Alfa); Proleukin (Interleukin Aldehyde); Prolia (Denosumab); ProstaScint (Carolomab-Penditin); Pulmolite (Kit for Preparing Technetium Tc-99m Albumin Aggregates); PulmotechMAA (Kit for Preparing Technetium Tc-99m Albumin Aggregates); Pulmozyme (Streptococcal Enzyme Alpha); Raptiva (Efazumab); Rebif (Interferon β-1a);Reblozyl (luspatercept-aamt); Regranex (becapremin); Remicade (infliximab); Renflexis (infliximab-abda); Reopro (abciximab); Repatha (evolocumab); Repronex (menotropins); Retacrit (epbx); Retavase (reteplase); Revcovi (elapegademase-lvlr); Rituxan (rituximab); RituxanHycela (rituximab and human hyaluronidase); Roferon-A (interferon alpha-2a); Rolvedon (eflapegrastim-xnst); Ruxience (rituximab-pvvr); Rybrevant (amivantamab-vmjw); Rylaze (Recombinant Erwinia chrysanthemi asparaginase-rywn); Ryzneuta; Rystiggo (rozanolixizumab-noli); Ryzodeg 70 / 30 (insulin degludec and insulin aspart); Saizen (growth hormone); Santyl (collagenase); Saphnelo (anifrolumab-fnia); Sarclisa (isatuximab-irfc); Serostim (growth hormone); Siliq (brodamarumab); Simponi (golimumab); Simponi Aria (golimumab); Simulect (baliximab); Skyrizi (rzaa); Skytrofa (lonapegsomatropin-tcgd); Soliqua 100 / 33 (insulin glargine and liximab); Soliris (eculizumab); Somavert (pevisomone); Spevigo (spesolimab-sbzo); Stelara (ustekinumab); Streniq (afotazyme α); Sucraid (sacrosidase); Survanta (belatan); Susvimo ​​(ranibizumab); Sylvant (staxicumab); Synagis (palizumab); Takhzyro (lanadelumab-flyo); Taltz (ixekizumab); Talvey (talquetamab-tgvs); Tanzeum (albiglutide); Tecentriq (atelizumab);Tecvayli (teclistamab-cqyv); Tepezza (tetotumab-trbw); Tezspire (tezepelumab-ekko); Thyrogen (thyroid-stimulating hormone alpha); Tivdak (tisotumab vedotin-tftv); TNKase (tenectinase); Toujeo (insulin glargine); Trasylol (aprotinin); Trazimera (trastuzumab-qyyp); Tremfya (gucecurumab); Tresiba (insulin degludec); Trodelvy (goxatotumab-hziy); Trogarzo (eebalizumab-uiyk); Trulicity (dulaglutide); Truxima (rituximab-abbs); Tysabri (natezumab); Tzield (teplizumab-mzwv); Udenyca (Peffiglastin-cbqv); Ultomiris (Relizumab-cwvz); Unituxin (Denotoximab); Vabysmo (faricimab-svoa); Vectibix (panitumumab); Veopoz (pozeilimab-bbfg); Verluma (nofetumomab); Vimizim (epilepsin α); Viokace (pancreatic lipase); Vitrase (hyaluronidase); Voraxaze (carboxypeptidase); VPRIV (vilaradinase α); Vyvgart (efgartigimod alfa-fcab); Vyvgart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc); Xenpozyme (olipudase alfa-rpcp); Xeomin (incobotulinumtoxin A); Xgeva (denotumab); Xiaflex (Clostridium histolytica collagenase); Xigris (Trueclosporine α); Xolair (Omalizumab); Xultophy 100 / 3.6 (Insulin degludec and liraglutide); Yervoy (Ipilimumab); Zaltrap (Ziv-Aflibercept); Zarxio (Filgrastim-sndz); Zenapax (Dacoxetine); Zenpep (Pancreatic lipase); Zevalin (Imoxicillin); Ziextenzo (Pefilgrastim-bmez); Zinbryta (Dacoxetine); Zinplava (Bezotocillin); Zirabev (Bevacizumab-bvzr);Zomacton (growth hormone); Zorbtive / Serostim (growth hormone); Zymfentra (infliximab); Zynlonta (locastuximab tesirine-lpyl); or Zynyz (retifanlimab-dlwr).

[0125] (43) A pharmaceutical container according to any one of aspects (38) to (42), wherein the pharmaceutical composition comprises a biological agent for use with: a tumor necrosis factor-α (TNF) inhibitor, an interleukin inhibitor, a selective co-stimulatory modulator, a glucagon-like peptide-1 (GLP-1) agonist or a GLP-1 receptor agonist, an mRNA-based formulation, an allergen, tissue, a recombinant protein, a personalized medicine (e.g., CAR-T; cell and gene therapy), or a biological agent listed in the FDA Purple Book.

[0126] (44) The pharmaceutical container according to aspect (43), wherein the personalized medicine is a CAR-T drug, a cell therapy drug, or a gene therapy drug. Example

[0127] The following examples further illustrate the invention, but should not be construed as limiting its scope in any way.

[0128] Example 1

[0129] This embodiment illustrates a method for preparing a pH-protective coating using atomic layer deposition (ALD) technology. Therefore, a pH-protective layer is applied to a silicon wafer containing an Al2O3 barrier layer, the silicon wafer serving as a model of the surface of a medical container.

[0130] Therefore, pH protection layers are applied to the following silicon wafers (each 1 cm × 1 cm): (i) a Si wafer with a 20 nm Al2O3 barrier layer, (ii) a Si wafer with a 50 nm Al2O3 barrier layer, (iii) a 50 nm ZrO2 pH protection layer deposited on top of the 50 nm Al2O3 barrier layer, and (iv) a Si wafer with a 20 nm Al2O3 barrier layer and a 20 nm ZrO2 pH protection layer deposited on top of the 20 nm Al2O3 barrier layer.

[0131] Samples were evaluated to determine the coating stack at multiple locations on a Si wafer using XPS. XPS experiments were performed using a Physical Electronics VersaProbe III instrument equipped with a monochromatic Al kα X-ray source (hν = 1486.6 eV) and a concentric hemispherical analyzer. Charge neutralization was performed using low-energy electrons (<5 eV) and argon ions. The binding energy axis was determined using sputter-cleaned Cu (Cu 2p) material. 3 / 2 = 932.62 eV, Cu 3p 3 / 2 = 75.1 eV) and Au foil (Au 4f) 7 / 2 Calibration was performed at 83.96 eV. Peak position was referenced to CH in the carbon 1s spectrum. x Charge correction was performed at 284.8 eV. Measurements were taken at a 45° exit angle relative to the sample surface plane. This resulted in a typical sampling depth of 3 nm to 6 nm (95% of the signal originates from this depth or shallower). Quantification was performed using the instrument's relative sensitivity factor (RSF), which takes into account the electron's X-ray cross-section and inelastic mean free path. On homogeneous samples, the standard deviation for major elements (>5 atomic%) is typically <3%, while trace elements may have significantly higher deviations. The analysis size was approximately 200 µm in diameter. Ion sputtering was performed using a 2 kV Ar+ grating scan over a 2 mm × 2 mm area. The Al2O3 sputtering rate was 1.4 nm / min, based on an assumed 50 nm thickness.

[0132] Figures 1A to 1D XPS depth profiling of different samples is shown.

[0133] This study shows that silicon becomes less visible as the thickness of Al2O3 increases.

[0134] Example 2

[0135] This embodiment illustrates an exemplary method for developing a functional pH protection layer on a silicon wafer by measuring the dissolution of the Al2O3 barrier layer at pH 3 and 9.

[0136] In this study, samples were placed in HCl pH 3 or pH 9 phosphate buffer solutions and incubated at 50°C for 72 hours. After 72 hours, the pH 3 or pH 9 buffer solutions were collected, and the aluminum concentration was determined using inductively coupled plasma mass spectrometry (ICP-MS) or optical emission spectroscopy (OES). The analyzed samples included: (i) Si wafers with a 20 nm Al2O3 barrier layer, (ii) Si wafers with a 50 nm Al2O3 barrier layer, (iii) Si wafers with a 20 nm Al2O3 barrier layer and a 20 nm ZrO2 pH protective layer deposited on top of the 20 nm Al2O3 barrier layer, and (iv) Si wafers with a 50 nm Al2O3 barrier layer and a 50 nm ZrO2 pH protective layer deposited on top of the 50 nm Al2O3 barrier layer.

[0137] Figure 3A This is a schematic diagram of the aluminum concentration in the collected pH 9 buffer solution, for Si wafers coated with a 20nm Al2O3 gas barrier layer and Si wafers coated with a 20nm Al2O3 barrier layer and a 20nm ZrO2 pH protection layer deposited on the 20nm Al2O3 barrier layer by ALD. Figure 3B This is a schematic diagram of the aluminum concentration in the collected pH 9 buffer solution, for Si wafers coated with a 50nm Al2O3 gas barrier layer and Si wafers coated with a 50nm Al2O3 barrier layer and a 50nm ZrO2 pH protection layer deposited on the 50nm Al2O3 barrier layer by ALD. Figure 3C This is a schematic diagram of the aluminum concentration in the collected pH 3 buffer solution, for Si wafers coated with a 20nm Al2O3 gas barrier layer and Si wafers coated with a 20nm Al2O3 barrier layer and a 20nm ZrO2 pH protection layer deposited on the 20nm Al2O3 barrier layer by ALD. Figure 3D This is a schematic diagram of the aluminum concentration in the collected pH 3 buffer solution, for Si wafers coated with a 50nm Al2O3 gas barrier layer and Si wafers coated with a 50nm Al2O3 barrier layer and a 50nm ZrO2 pH protection layer deposited on the 50nm Al2O3 barrier layer by ALD.

[0138] This embodiment provides an exemplary method for determining the solubility of a coating system deposited on a silicon wafer at pH 3 or pH 9. Data shows that when the silicon wafer is coated with only a 20 nm Al₂O₃ barrier layer or a 50 nm Al₂O₃ barrier layer, the aluminum concentration in the pH 9 buffer solution is 8.9 µg and 55 µg, respectively. Conversely, when a 20 nm ZrO₂ pH protective layer or a 50 nm ZrO₂ pH protective layer is deposited on top of the 20 nm Al₂O₃ barrier layer or the 50 nm Al₂O₃ gas barrier layer, the aluminum concentration in the pH 9 buffer solution is 0.7 µg and <0.5 µg, respectively. Furthermore, data shows that when the silicon wafer is coated with only a 20 nm Al₂O₃ barrier layer or a 50 nm Al₂O₃ barrier layer, the aluminum concentration in the pH 3 buffer solution is 11 µg and 36 µg, respectively. Conversely, when a 20 nm ZrO2 pH protective layer or a 50 nm ZrO2 pH protective layer is deposited on top of a 20 nm Al2O3 barrier layer or a 50 nm Al2O3 gas barrier layer, the concentration of aluminum in the pH 3 buffer solution is <0.5 µg and 2.2 µg, respectively.

[0139] Example 3

[0140] This embodiment illustrates an exemplary method for characterizing a gas barrier layer and a pH protection layer deposited on a polypropylene substrate by atomic layer deposition using scanning transmission electron microscopy (STEM) and energy dispersive spectroscopy (EDS).

[0141] In this study, STEM and EDS were used to analyze the samples to characterize the gas barrier layer and pH protection layer. The polypropylene membrane samples used in this study ranged in length from 1.08 cm to 1.57 cm, width from 0.88 cm to 1.25 cm, and had an area of ​​0.95 cm². 2 Up to 1.86cm 2 .

[0142] Figures 4A to 4D This is a schematic diagram of a gas barrier layer and / or pH protection layer on a polypropylene substrate.

[0143] This embodiment illustrates an exemplary method for characterizing a gas barrier layer and a pH protection layer deposited on a polypropylene substrate by atomic layer deposition using scanning transmission electron microscopy (STEM). Data show that the Al2O3 gas barrier layer is approximately 10 nm to 15 nm thick, and the coating including the Al2O3 gas barrier layer and the ZrO2 pH protection layer is 25 nm to 35 nm thick.

[0144] Example 4

[0145] This embodiment illustrates an exemplary method for developing a functional pH-protective layer on a polypropylene substrate by measuring the dissolution of the Al2O3 barrier layer at pH 9.

[0146] In this study, samples were placed in a pH 9 phosphate buffer solution and incubated at 50°C for 72 hours. The pH 9 buffer solution was collected, and the aluminum concentration was determined using inductively coupled plasma mass spectrometry (ICP-MS) or optical emission spectroscopy (OES). The polypropylene membrane samples used in this study ranged in length from 1.08 cm to 1.57 cm, width from 0.88 cm to 1.25 cm, and area from 0.95 cm². 2 Up to 1.86cm 2 .

[0147] Figure 5 This is a schematic diagram of the aluminum concentration in the collected pH 9 buffer solution, for samples coated only with an Al2O3 gas barrier layer and samples coated with a ZrO2 pH protective layer on top of the Al2O3 gas barrier layer.

[0148] This embodiment provides an exemplary method for determining the solubility of a coating system deposited on a polypropylene substrate at pH 9. Data shows that the concentration of aluminum in the pH 9 buffer solution is 35 µg in the absence of a pH protection layer. Conversely, the concentration of aluminum in the pH 9 buffer solution is 23 µg when a ZrO2 pH protection layer is deposited over an Al2O3 gas barrier layer.

[0149] Example 5

[0150] This example illustrates the differences between depositing a pH protective layer using atomic layer deposition (ALD) and plasma-enhanced chemical vapor deposition (PECVD).

[0151] In this study, a pH protective layer was deposited on top of a gas barrier layer, and the thickness of the pH protective layer was measured for both application methods. For the ALD system, the pH protective layer was found to be 20 nm to 50 nm thick, while for the PECVD system, the pH protective layer was found to be 250 nm to 400 nm thick.

[0152] Figure 6 This is a schematic diagram illustrating the difference between depositing a pH protective layer using atomic layer deposition (ALD) and plasma-enhanced chemical vapor deposition (PECVD).

[0153] This example illustrates the difference between using ALD or PECVD to deposit a pH protective layer. Data shows that the ZrO2 pH protective layer deposited using ALD is approximately 10 times thinner than that applied using PECVD, without any change in function. The advantage of the thinner coating is that it provides a more robust polymer pharmaceutical container that can withstand thermal cycling and mechanical flexing without the risk of the pH protective coating cracking or being damaged.

[0154] Example 6

[0155] This embodiment illustrates a method for preparing a barrier layer using atomic layer deposition (ALD) technology. Therefore, an Al₂O₃ barrier layer is coated onto a (COP)-based vial using ALD.

[0156] Therefore, the Al2O3 barrier layer was deposited at 100°C.

[0157] Figure 8A and Figure 8B XPS depth profiles of the bottom and walls of the vial are displayed separately.

[0158] This study shows that the mold walls and bottom contain an Al2O3 coating layer with no detectable carbon in the oxide and a clear Al2O3-polymer interface. The film thickness was determined to be approximately 27 nm.

[0159] Example 7

[0160] This embodiment illustrates a method for preparing a barrier layer using atomic layer deposition (ALD) technology. Therefore, an Al₂O₃ barrier layer is coated onto a (COP)-based vial using ALD.

[0161] Therefore, the Al2O3 barrier layer was deposited at 100°C.

[0162] Figures 9A to 9C XPS depth profiles of the inner bottom surface, outer bottom surface, and inner wall surface of the vial are displayed separately.

[0163] This study indicates that the film thickness on the inner bottom surface is approximately 41 nm, while that on the outer bottom surface is approximately 61 nm. The sidewalls appear to be slightly thinner than the bottom; however, due to instrumentation issues, this film was processed on a different instrument than the one used for the inner bottom surface. A slight difference in deposition rate may exist.

[0164] Example 8

[0165] This embodiment illustrates a method for preparing a barrier layer using atomic layer deposition (ALD) technology. Therefore, an Al₂O₃ barrier layer is coated onto a (COP)-based vial using ALD.

[0166] Therefore, the Al2O3 barrier layer was deposited at 100°C.

[0167] Figure 10 XPS depth profile of the inner surface of the bottom of the vial is shown.

[0168] This study is a repeat of Example 7, used to confirm the depth of the Al2O3 barrier layer on the inner surface of the bottom of the vial.

[0169] Example 9

[0170] This embodiment illustrates a method for preparing a pH-protective coating using atomic layer deposition (ALD) technology. Therefore, an Al2O3 barrier layer is deposited on a (COP)-based vial using ALD, and then a ZrO2 pH-protective layer is deposited on top of the Al2O3 barrier layer using ALD.

[0171] An Al2O3 barrier layer and a ZrO2 pH protective layer were deposited at 100°C.

[0172] Figure 11A and Figure 11B XPS depth profiles of the inner and outer surfaces of the bottle bottom are displayed separately.

[0173] This study shows that the ZrO2 pH protective layer is extremely thin or patchy inside the vial. Analysis of the outside of the vial (sidewall region) revealed intact ZrO2 and Al2O3 films, each approximately 35 nm in size.

[0174] Example 10

[0175] This embodiment illustrates a method for preparing a pH-protective coating using atomic layer deposition (ALD) technology. Therefore, an Al2O3 barrier layer is deposited on a (COP)-based vial using ALD, and then a ZrO2 pH-protective layer is deposited on top of the Al2O3 barrier layer using ALD.

[0176] An Al2O3 barrier layer and a ZrO2 pH protective layer were deposited at 100°C.

[0177] Figure 12A XPS depth profile of the inner surface of the bottom of the vial is shown.

[0178] This study shows that the inner surface of the bottom of the vial has a ZrO2 layer of about 40 nm on top of an Al2O3 layer of about 40 nm.

[0179] Example 11

[0180] This embodiment illustrates a method for determining the water vapor transmission rate and oxygen transmission rate of the coated (COP)-based vial of Example 10.

[0181] Figure 12B and Figure 12C The water vapor transmission rate and oxygen transmission rate of the coated (COP)-based vial of Example 10 are shown.

[0182] This study showed that the water vapor transmission rate of the coated (COP)-based vials was 0.0000250 g / packet-day, while that of the uncoated (COP)-based vials was 0.0000780 g / packet-day. Furthermore, the oxygen transmission rate of the coated (COP)-based vials was 0.0002100 cc / packet-day, while that of the uncoated (COP)-based vials was 0.0120000 cc / packet-day.

[0183] Example 12

[0184] This embodiment illustrates an exemplary method for determining the dissolution of an Al2O3 barrier layer at pH 3 and 9.

[0185] In this study, samples were placed in HCl pH 3 or pH 9 phosphate buffer solutions and incubated at 50°C for 72 hours. After 72 hours, the pH 3 or pH 9 buffer solutions were collected, and the concentrations of aluminum and zirconium were determined using inductively coupled plasma mass spectrometry (ICP-MS) or optical emission spectroscopy (OES). The analyzed samples included vials with a 40 nm Al₂O₃ barrier layer and vials with a 40 nm Al₂O₃ barrier layer and a 40 nm ZrO₂ pH protective layer deposited on top of the 40 nm Al₂O₃ barrier layer.

[0186] Figure 12D This is a schematic diagram of the aluminum and zirconium concentrations in the collected pH 9 buffer solution, for both (COP)-based vials coated with a 40 nm thick Al2O3 barrier layer and (COP)-based vials coated with a 40 nm thick Al2O3 barrier layer and a 40 nm thick ZrO2 pH protective layer deposited on top of the Al2O3 barrier layer.

[0187] Figure 12E This is a schematic diagram of the aluminum and zirconium concentrations in the collected pH 3 buffer solution, for both (COP)-based vials coated with a 40 nm thick Al2O3 barrier layer and (COP)-based vials coated with a 40 nm thick Al2O3 barrier layer and a 40 nm thick ZrO2 pH protective layer deposited on top of the Al2O3 barrier layer.

[0188] This embodiment provides an exemplary method for determining the solubility of a coating system deposited on a (COP)-based vial at pH 3 or pH 9. Data shows that when the (COP)-based vial is coated with only a 40 nm Al₂O₃ barrier layer, the aluminum concentration in the pH 9 buffer solution is 100 µg. Conversely, when a 40 nm ZrO₂ pH protective layer is deposited on top of the 40 nm Al₂O₃ barrier layer, the aluminum concentration in the pH 9 buffer solution is 14 µg. Furthermore, data shows that when the (COP)-based vial is coated with only a 40 nm Al₂O₃ barrier layer, the aluminum concentration in the pH 3 buffer solution is 175 µg. Conversely, when a 40 nm ZrO₂ pH protective layer is deposited on top of the 40 nm Al₂O₃ barrier layer, the aluminum concentration in the pH 3 buffer solution is 2.7 µg.

[0189] Example 13

[0190] This embodiment illustrates a method for preparing a pH-protective coating using atomic layer deposition (ALD) technology. Therefore, an Al2O3 barrier layer is deposited on a (COP)-based syringe using ALD, and then a ZrO2 pH-protective layer is deposited on top of the Al2O3 barrier layer using ALD.

[0191] Therefore, the Al2O3 barrier layer and the ZrO2 pH protective layer were deposited at 100°C.

[0192] Figures 13A to 13C XPS depth profiles of the syringe needle tip, middle section, and flange.

[0193] The study shows that all regions contain well-defined layers of ZrO2 with a thickness of 40 nm to 50 nm on top of Al2O3.

[0194] Example 14

[0195] This embodiment illustrates an exemplary method for determining the dissolution of the Al2O3 barrier layer at pH 3 and 9 when a nanolayer stack comprising alternating layers of Al2O3 barrier layer and ZrO2 pH protection layer is deposited on a (COP)-based vial.

[0196] In this study, samples were placed in HCl pH 3 or pH 9 phosphate buffer solutions and incubated at 50°C for 72 hours. After 72 hours, the pH 3 or pH 9 buffer solutions were collected, and the concentrations of aluminum and zirconium were determined using inductively coupled plasma mass spectrometry (ICP-MS) or optical emission spectroscopy (OES). The analyzed samples included vials with a 50 nm Al2O3 barrier layer and vials with a 50 nm nanolayer stack consisting of alternating layers of Al2O3 barrier layer and ZrO2 pH protective layer.

[0197] Figure 15A This is a schematic diagram of the aluminum and zirconium concentrations in the collected pH 9 buffer solution, for both (COP)-based vials coated with a 50 nm thick Al2O3 barrier layer and (COP)-based vials coated with a 50 nm nanolayer stack, wherein the nanolayer stack consists of thin, alternating layers of ZrO2 pH protective layer and Al2O3 barrier layer, wherein a thick ZrO2 pH protective coating layer is disposed on top of the alternating layers.

[0198] Figure 15B This is a schematic diagram of the aluminum and zirconium concentrations in the collected pH 3 buffer solution, for both (COP)-based vials coated with a 50 nm thick Al2O3 barrier layer and (COP)-based vials coated with a 50 nm nanolayer stack, wherein the nanolayer stack consists of thin, alternating layers of ZrO2 pH protective layer and Al2O3 barrier layer, wherein a thick ZrO2 pH protective coating layer is disposed on top of the alternating layers.

[0199] This embodiment provides an exemplary method for determining the solubility of a coating system deposited on a (COP)-based vial at pH 3 or pH 9. Data shows that when the (COP)-based vial is coated with only a 50 nm Al₂O₃ barrier layer, the aluminum concentration in the pH 9 buffer solution is 100 µg. Conversely, when a 50 nm nanolayer stack (including alternating layers of Al₂O₃ barrier layer and ZrO₂ pH protective layer) is present, the aluminum concentration in the pH 9 buffer solution is 0.8 µg. Furthermore, data shows that when the (COP)-based vial is coated with only a 50 nm Al₂O₃ barrier layer, the aluminum concentration in the pH 3 buffer solution is 175 µg. Conversely, when a 50 nm nanolayer stack (including alternating layers of Al₂O₃ barrier layer and ZrO₂ pH protective layer) is present, the aluminum concentration in the pH 3 buffer solution is 9.2 µg.

[0200] All references cited in this article, including publications, patent applications and patents, are incorporated herein by reference to the same extent that each reference is individually and specifically cited and fully elaborated herein.

[0201] In the context of describing the invention (especially in the context of the following claims), terms without quantifiers and the use of the term "at least one" and similar references should be interpreted as covering both singular and plural, unless otherwise stated herein or the context explicitly contradicts. The term "at least one" followed by a list of one or more items (e.g., "at least one of A and B") should be interpreted as meaning one item selected from the listed items (A or B) or any combination of two or more listed items (A and B), unless otherwise stated herein or the context explicitly contradicts. The terms "comprising," "having," "including," and "containing" should be interpreted as open-ended terms (i.e., meaning "including but not limited to"), unless otherwise stated. The enumeration of numerical ranges herein is intended only as a shorthand method for individually referring to each individual value falling within that range, unless otherwise stated herein, and each individual value is incorporated into the specification as if it were individually enumerated herein. Unless otherwise stated herein or the context explicitly contradicts, all methods described herein may be performed in any suitable order. Unless otherwise required, the use of any and all examples or exemplary language (e.g., "for example") provided herein is intended only to better illustrate the invention and does not constitute a limitation on the scope of the invention. No language in the specification should be construed as indicating that any unclaimed element is necessary for the practice of the invention.

[0202] This document describes preferred aspects of the invention, including the best modes known to the inventors for carrying out the invention. After reading the foregoing description, variations of those preferred aspects may become apparent to those skilled in the art. The inventors expect those skilled in the art to appropriately employ such variations, and the inventors intend that the invention be practiced in a manner different from that specifically described herein. Therefore, the invention includes all modifications and equivalents of the subject matter described in the appended claims permitted under applicable law. Furthermore, unless otherwise stated herein or the context clearly contradicts it, the invention covers any combination of the foregoing elements in all possible variations.

Claims

1. A pharmaceutical container comprising an inner cavity partially defined by a wall having an inner surface facing the inner cavity, an outer surface, and at least one pH protective layer comprising an oxide of zirconium, titanium, or magnesium, wherein the at least one pH protective layer is a layer produced by an atomic layer deposition (ALD) process.

2. The pharmaceutical container according to claim 1, further comprising at least one gas barrier layer disposed between the inner surface and the at least one pH protection layer.

3. The pharmaceutical container according to claim 2, wherein the at least one gas barrier layer comprises Al2O3 and / or Al3O5.

4. The pharmaceutical container according to any one of claims 1 to 3, wherein the wall of the pharmaceutical container comprises a polymer.

5. The pharmaceutical container according to claim 4, wherein the polymer of the pharmaceutical container is selected from polypropylene, cyclic olefin polymer (COP), cyclic olefin copolymer (COC), polyethylene, polyethylene terephthalate, and combinations thereof.

6. The pharmaceutical container of claim 5, wherein the polymer is COP, COC, or a combination thereof.

7. The pharmaceutical container according to claim 5 or 6, wherein the COP or COC comprises at least one cycloolefin selected from the group consisting of cyclobutene, cyclopentene, cyclooctene, norbornene, 5-methylnorbornene, 3-methylnorbornene, ethylnorbornene, phenylnorbornene, dimethylnorbornene, diethylnorbornene, dicyclopentadiene, tetracyclododecene, and methyltetracyclododecene.

8. The pharmaceutical container according to claim 5 or 6, wherein the COP or COC comprises at least one cycloolefin selected from the group consisting of: norbornene, 6-methyl norbornene, 6-ethyl norbornene, 6-n-butyl norbornene, 5-propyl norbornene, 1-methyl norbornene, 7-methyl norbornene, 5,6-dimethyl norbornene, 5-phenyl norbornene, 5-benzyl norbornene, 8-methyltetracyclo-3-dodecene, 8-ethyltetracyclo-3-dodecene, 8-hexyltetracyclo-3-dodecene, 2,10-dimethyltetracyclo-3-dodecene, and 5,10-dimethyltetracyclo-3-dodecene.

9. The pharmaceutical container of claim 1, wherein the wall of the pharmaceutical container comprises glass.

10. The pharmaceutical container according to any one of claims 4 to 8, wherein the at least one pH protection layer and / or the at least one gas barrier layer is applied by ALD at a temperature lower than the Tg of the polymer wall.

11. The pharmaceutical container according to any one of claims 2 to 8 or 10, wherein the at least one gas barrier layer and / or the at least one pH protection layer is deposited by ALD at a temperature of 150°C, 140°C, 130°C, 120°C, 110°C, or 100°C or below 100°C.

12. The pharmaceutical container of claim 11, wherein the at least one gas barrier layer provides a barrier against carbon dioxide, nitrogen, oxygen and / or water vapor.

13. The pharmaceutical container according to any one of claims 2 to 8 and 10 to 12, wherein the thickness of the at least one gas barrier layer is 50 nm or less.

14. The pharmaceutical container according to any one of claims 1 to 13, wherein the thickness of the at least one pH protective layer is 50 nm or less.

15. The pharmaceutical container of claim 13, wherein the thickness of the at least one gas barrier layer is measured by TEM or XPS.

16. The pharmaceutical container of claim 14, wherein the thickness of the at least one pH protective layer is measured by TEM or XPS.

17. The pharmaceutical container according to any one of claims 2 to 16, wherein when exposed to conditions of 50°C and pH 3 to 9 for 72 hours, the at least one pH protective layer reduces the dissolution rate of the at least one gas barrier layer by >90%.

18. The pharmaceutical container according to any one of claims 2 to 17, further comprising a nanolayer coated on the inner surface of the wall of the container, wherein the nanolayer comprises a plurality of thin pH protection layers and a plurality of thin gas barrier layers, wherein each of the pH protection layers and each of the gas barrier layers are alternately arranged, and the nanolayer further comprises a thick pH protection coating disposed on the alternately arranged layers and facing inward toward the interior of the container.

19. The pharmaceutical container of claim 18, wherein the thin, alternating layers comprise 2 to 60 layers of pH protection layers and / or 2 to 60 layers of gas barrier layers.

20. The pharmaceutical container of claim 18 or 19, wherein at least one of the thin pH protection layers comprises an oxide of zirconium, titanium or magnesium, and at least one of the thin gas barrier layers comprises an oxide of aluminum, and wherein at least one pH protection layer and at least one gas barrier layer are deposited by atomic layer deposition (ALD).

21. The pharmaceutical container according to any one of claims 18 to 20, wherein the thin gas barrier layer and / or the thin pH protection layer is deposited at a temperature lower than the Tg of the material contained in the wall of the pharmaceutical container.

22. The pharmaceutical container according to any one of claims 18 to 21, wherein the thin gas barrier layer and / or the thin pH protection layer are deposited by ALD at a temperature of 150°C, 140°C, 130°C, 120°C, 110°C, or 100°C or below 100°C.

23. The pharmaceutical container according to any one of claims 18 to 22, wherein the thin gas barrier layer provides a barrier against carbon dioxide, nitrogen, oxygen and / or water vapor.

24. The pharmaceutical container according to any one of claims 18 to 23, wherein each of the thin gas barrier layers has a thickness of 3 nm to 5 nm.

25. The pharmaceutical container according to any one of claims 18 to 24, wherein each of the thin pH protective layers has a thickness of 3 nm to 5 nm.

26. The pharmaceutical container according to any one of claims 18 to 25, wherein the thick pH protective coating has a thickness of 40 nm to 50 nm.

27. The pharmaceutical container according to any one of claims 24 to 26, wherein the thickness of any of the layers is measured by TEM and / or XPS.

28. The pharmaceutical container according to any one of claims 18 to 27, wherein when exposed to conditions of 50°C and pH 3 to 9 for 72 hours, the thin pH protective layer reduces the dissolution rate of the thin barrier layer by at least 60%.

29. The pharmaceutical container of claim 28, wherein when exposed to conditions of 50°C and pH 3 to 9 for 72 hours, the thin pH protective layer reduces the dissolution rate of the thin barrier layer by up to 90% or more.

30. The pharmaceutical container according to any one of claims 1 to 29, wherein the zirconium oxide is ZrO2.

31. The pharmaceutical container according to any one of claims 1 to 29, wherein the oxide of said titanium is TiO2.

32. The pharmaceutical container according to any one of claims 1 to 29, wherein the magnesium oxide is MgO.

33. The pharmaceutical container of claim 30, wherein the ZrO2 is deposited by an ALD process using tetratetra(dimethylamino)zirconium (Zr(NMe2)4), tetratetra(ethylmethylamino)zirconium (Zr(NMeEt)4), or tetratetra(diethylamino)zirconium (Zr(NEt2)4), or a combination thereof, as one or more reactants.

34. The pharmaceutical container of claim 31, wherein the TiO2 is deposited by an ALD process using tetra(dimethylamino)titanium (TDMAT), tetra(diethylamino)titanium (TDEAT), or tetra(ethylmethylamino)titanium (TEMAT), or a combination thereof, as one or more reactants.

35. The pharmaceutical container according to claim 32, wherein the MgO is deposited by an ALD process using Mg(thd)2 (2,2,6,6-tetramethyl-3,5-heptanedionate magnesium), Mg(Cp)2 (bis(cyclopentadienyl)magnesium), or Mg(EtCp)2 (bis(ethylcyclopentadienyl)magnesium), or a combination thereof as one or more reactants.

36. The pharmaceutical container according to any one of claims 1 to 35, further comprising a bonding layer deposited on the inner cavity.

37. The pharmaceutical container of claim 36, wherein the bonding layer comprises aluminum oxide.

38. The pharmaceutical container according to any one of claims 1 to 37, comprising a pharmaceutical composition.

39. The pharmaceutical container of claim 38, wherein the pH of the pharmaceutical composition is from 3 to 12.

40. The pharmaceutical container of claim 39, wherein the pH of the pharmaceutical composition is 3 to 9 or 6 to 9.

41. The pharmaceutical container according to any one of claims 38 to 40, wherein the pharmaceutical composition comprises a peptide, a protein, a monoclonal antibody, or a blood component.

42. The pharmaceutical container according to any one of claims 38 to 41, wherein the pharmaceutical composition comprises a biological drug selected from: abatacept; abciximab; botulinum toxin type A; adalimumab; adalimumab-adaz; adalimumab-adbm; adalimumab-afzb; adalimumab-atto; adalimumab-bwwd; trastuzumab emtansine; aflibercept; agalsidase β; abiglutide; chromium [51Cr] albumin; interleukin; levacecept; alenzusumab; aglucosidase. Alteplase; Alteplase; Anaprostol; Aprotinin; Afotazone α; Asparaginase; Erwinia chrysogena asparaginase; Atezolizumab; Avelumab; Baliximab; Becaprolem; Beracip; Belimumab; Benlazolizumab; Belatan; Bevacizumab; Bevacizumab-AWWB; Bevacizumab-BVZR; Bezotocilizumab; Bonatumab; Bentuximab; Brodatumab; Brodatumab-DBLL; Broxolumab-TWZA; Calaspargase pegol-mknl; carfaxtam; cannabinoid; caralacilizumab-yhdp; calcitazol-pentetate; ceprelimumab-rwlc; sinegiline-bkbj; alpha lipase; cetuzumab-polyethylene glycol; cetuximab; recombinant human chorionic gonadotropin α; chorionic gonadotropin; papain; collagenase; Clostridium histolyticum collagenase; Corticotropic hormone-releasing factor sheep trifluoroacetate; Kezanilizumab-TMCA; Dacrolimus; Daratumumab; Daratumumab and hyaluronidase-FIHJ; Dabepoetin Alpha; Dinitroleum-diphtheria toxin conjugate; Dinosumab; Disiludin; Denutoximab; Streptase Alpha; Triclosan Alpha; Dulaglutide; Duprexumab; Duvalumab; Icaratide; Eculizumab; Eclazumab; Elapegademase-LVLR; Eloturase Alpha; Elan-Val-L; Rotocilizumab; Imalitumab-lzsg; Emycinumab-kxwh; Verentumab-ejfv; Epoetin afa; Epoetin afa-epbx; Erenedumab-aooe; Etanercept; Etanercept-szzs; Etanercept-ykro; Evolomab; FAM-Trastuzumab-drutecan-nxki; Plasmin and deoxyribonuclease combination [bovine], containing chloramphenicol; Filgrastim; Filgrastim-aafi; Filgrastim-sndz; Follicle-stimulating hormone (FSH) α; Follicle-stimulating hormone (FSH) β; Remannetumab-vfrm; Garcinia galenazumab-gnlm; Thionase; Gemtuzumab-orzomicin; Carboxypeptidase; Golimumab; Gusecurumab; Hyaluronidase; Human hyaluronidase; Ebalizumab-uiyk; Tiimumab; Idazumab; Iduthiase; Imiglucinase; Incobotulinumtoxin A; Inelolizumab-cdon; Infliximab; Infliximab-abda; Infliximab-axxq; Infliximab-dyyb; Infliximab-qbtx; Oga-ituzumab; Insulin aspart; Protamine zinc insulin aspart and insulin aspart; Insulin degludec; Insulin degludec and insulin aspart; Insulin degludec and liraglutide Detemir insulin; Glargine insulin; Glargine insulin and liximabide; Lissin insulin; Human insulin; Zinc protamine human insulin; Zinc protamine human insulin and human insulin; Lispro insulin; Zinc protamine lispro insulin and lispro insulin; Lispro insulin-aabc; Interferon α-2a; Interferon α-2b; Interferon alfacon-1; Interferon α-n3 (human leukocyte-derived); Interferon β-1a; Interferon β-1b; Interferon γ-1b; Ipilimumab; Isatuximab-irfc; Ixekizumab; Lanadelumab-flyo; Laronidase; Liximabide; Luspatercept-aamt; Mecasermin; Mecasermin rinfabate; Menotropins; Mepocilimab; Metreleptin; Mogliflozin-kpkc; Moxetumomabpasudotox-tdfk; muromanab-CD3; natamuzumab; nexituzumab; nivolumab; nofetumomab; obiltoxaximab; ozotuzumab; ozotuzumab; plasmin; ozotuzumab; ozotuzumab; ozotuzumab; ozotuzumab; ozotuzumab; onabotulinumtoxin A; ozotuzumab; interleukin; palifermin; palituzumab; pancreatic lipase; panitumumab; parathyroid hormone; pegademase Bovine; Pegaspargase; Pefilgrastim; Pefilgrastim-APGF; Pefilgrastim-BMEZ; Pefilgrastim-CBQV; Pefilgrastim-JMDB; Interferon α-2a; Interferon α-2a and Ribavirin; Interferon α-2b; Interferon α-2b and Ribavirin; Interferon β-1a; Pegvaliase; Pegvaliase-PQPZ; Pevisomycin; Pembrolizumab; Pertuzumab; Verpotentumab-piiq; poractantalfa; prabotulinumtoxinA-xvfs; radiolabeled technetium albumin Tc-99m albumin colloid kit; ramucirumab; ranibizumab; raburicase; relizumab-cwvz; raxibacumab; reteizumab; reteplase; linacip; rimabotulinumtoxinB; rizotinib-rzaa; rituximab; rituximab and human hyaluronidase; rituximab-abbs; rituximab-pvvr; roprostadil; romosulzumab-aqqg; goxatozumab-hziy; sacrosidase; saxaglastine; thalidomide; sebelipase alfa; secukinumab; secukinumab; growth hormone; tagraxofusp-erzs; taliglucerase alfa; tbo-filgrastim; technetium 99m tc fanolesomab; tenepase; tetrumab-trbw; tesamorelin acetate; thyroid-stimulating hormone alpha; tretinoin-asmn; tocilizumab; tosimomab and iodine I-131 tosimomab; trastuzumab; trastuzumab and hyaluronidase-oysk; trastuzumab-anns; trastuzumab-dkst; trastuzumab-dttb; trastuzumab-pkrb; trastuzumab-qyyp; urofollitropin; urokinase; ustekinumab; velidezumab; verasidase alpha; vestronidasealfa-vjbk; Ziv-aflibercept; Amjevita (adalimumab-atto); Dupixent (dupilumab); Fulphila (Pefilgrastim-jmdb); llaris (cananaximab); Ixifi (infliximab-qbtx); Lyumjev (insulin lispro-aabc); Nyvepria (pefilgrastim-apgf); Ogivri (trastuzumab-dkst); Semglee (insulin glargine); Uplizna (innerazumab-cdon); APL (human chorionic gonadotropin); Abrilada (adalimumab-afzb); Aduhelm (adalimumab-avwa); Accretropin (growth hormone); Actemra (tocilizumab); Acthrel (corticotropin-releasing factor sheep trifluoroacetate); Actimmune (interferon-γ-1b); Activase (alteplase); Adagen (pegademase bovine); Adakveo (kelzalizumab-tmca); Addbry (tralokinumab-ldrm); Adcetris (bentuximab-vitoline); Adlyxin (liximab-vitoline); Admelog (lispro insulin); Afrezza (human insulin); Aimovig (elemeneumab-aooe); Ajovy (remanemuzumab-vfrm); Aldurazyme (laronidase); Alferon N Injection (Interferon α-n3 (human leukocyte-derived)); Amevive (levacecept); Amphadase (hyaluronidase); Anthim (obiltoxaximab); Apira (insulin lisgu); Aranesp (dabepoetin α); Arcalyst (linacecept); Arzerra (olfatumumab); Asparlas (calaspargase pegol-mknl); Avastin (bevacizumab); Avonex (interferon β-1a); Avsola (infliximab-axxq); Basaglar (insulin glargine); Bavencio (avelumab); Benlysta (belimumab); Beovu (brolucizumab-dbll); Besponsa (ogaituzumab); Besremi (ropeginterferon-alfa-2b-njft); Betaseron (interferon β-1b); Bexxar (tosimomab and iodine I-131 tosimomab); Beyfortus (nirsevimab-alip); Bimzelx (bimekizumab); Blincyto (bonatoxin); Botox (onabotulinumtoxin A); Botox Cosmetic (onabotulinumtoxin A); Bravelle (urofollitropin); Brineura (alpha lipase); Briumvi (ublituximab-xiiy);Cablivi (caracizumab-yhdp); Campath (alenduzumab); Cathflo Activase (alteplase); Cerezyme (imiglucerase); Chorionic Gonadotropin (human chorionic gonadotropin); Chromalbin (chromium [51Cr] albumin); Chymodiactin (papain); Cimzia (cetuzumab-polyethylene glycol); Cinqair (reteuzumab); Columvi (glofitamab-gxbm); Cosentyx (secukinumab); Cotazym (pancreatic lipase); Creon (pancreatic lipase); Crysvita (burosumab-twza); Curosurf (poractant alfa); Cyltezo (adalimumab-adbm); Cyramza (ramucirumab); Darzalex (darazolizumab); Darzalex Faspro (daratumumab and hyaluronidase-fihj); Daxxify (daxibotulinumtoixna-lanm); Draximage MAA (kit for preparing technetium Tc-99m albumin aggregates); Dysport (botulinum toxin type A); Egrifta (tesamorelin acetate); Egrifta SV (tesamorelin acetate); Elahere (mirvetuximab soravtansine-gynx); Elaprase (idoxetine); Elase-chloromycetin (fibrinolytic enzyme and deoxyribonuclease combination [bovine], containing chloramphenicol); Ellyso (taliglucerase alfa); Elfabrio (pegunigalsidase alfa-iwxj); Elitek (raburicase); Elrexfio (elranatamab-bcmm); Elspar (asparaginase); Elzonris (tagraxofusp-erzs); Emgality (gacanetuzumab-gnlm); Empliciti (erlotuzumab); Enbrel (etanercept); Enbrel Mini (etanercept); Enhertu (fam-trastuzumab-drutecan-nxki); Enjaymo (sutimlimab-jome); Entyvio (vedelizumab); Epkinly (epcoritamab-bysp);Epogen / Procrit (Epogen); Erbitux (Cetuximab); Erelzi (Etanercept-szzs); Erelzi Sensoready (Etanercept-szzs); Erwinaze (Erwinia chrysanthemum asparaginase); Eticovo (Etanercept-ykro); Evenity (Romosuzumab-aqqg); Evkeeza (evinacumab-dgnb); Extavia (Interferon β-1b); Eylea (Aflibercept); Fabrazyme (Agarsidase β); Fasenra (Benlalizumab); Fiasp (Insulin Aspart); Follistim (Follicle-stimulating hormone β); Follistim AQ (Follicle-stimulating hormone β); Follistim AQ Cartridge (Follicle-stimulating hormone β); Gamifant (Imarilumab-lzsg); Gazyva (Oxtuzumab); Genotropin (growth hormone); Gonal-f (follicle-stimulating hormone alpha); Gonal-f RFF (follicle-stimulating hormone alpha); Gonal-f RFF RediJect (follicle-stimulating hormone alpha); Granix (tbo-filgrastim); Hadlima (adalimumab-bwwd); Hemlibra (emecizumab-kxwh); Herceptin (trastuzumab); Herceptin Hylecta (trastuzumab and hyaluronidase-oysk); Herzuma (trastuzumab-pkrb); Humalog (insulin lispro); Humalog Mix 50 / 50 (protamine zinc lispro insulin and lispro insulin); Humalog Mix 75 / 25 (protamine zinc lispro insulin and lispro insulin); Humatrope (growth hormone); Humegon (menotropins); Humira (Adalimumab); Humulin 70 / 30 (Protamine Zinc Human Insulin and Human Insulin); Humulin N (Protamine Zinc Human Insulin); Humulin RU-100 (Human Insulin); Humulin RU-500 (Human Insulin); Hydase (Hyaluronase); Hylenex recombinant (Human Hyaluronase); Hyrimoz (Adalimumab-adaz); Ilumya (Treligizumab-asmn); Imfinzi (Dulvarubab); Imjudo (Tremelimumab-actl); Incelex (mecasermin); Infasurf (Carfaktan);Infergen (interferon alfacon-1); Inflectra (infliximab-dyyb); Intron A (interferon α-2b); Iplex (mecasermin rinfabate); Iprivask (diasildenafil); Jeanatope (kit for iodinated I-125 albumin); Jemerli (dostarlimab-gxly); Jetrea (octane plasmin); Jeuveau (prabotulinumtoxinA-xvfs); Kadcyla (trastuzumab emtansine); Kalbitor (icaralotide); Kanjinti (trastuzumab-anns); Kanuma (sebelipase alfa); Kepivance (palifermin); Kevzara (thalidomab); Keytruda (pembrolizumab); Kimmtrak (tebentafusp-tebn); Kinoret (anaspirin); Kinlytic (urokinase); Krystexxa (precex); Lamzede (velmanase alfa-tycv); Lantus (insulin glargine); Lartruvo (olaramab); Lemtrada (alendumab); Leqembi (lecanemab-irmb); Leukine (saxaglastine); Leafmir (insulin detemir); Libtayo (teplimab-rwlc); Loqtorzi (toripalimab-tpzi); Lucentis (ranibizumab); Lumizyme (glucosidase α); Lumoxiti (moxetumomab pasudotox-tdfk); Lunsumio (mosunetuzumab-axgb); Macrotec (Kit for preparing technetium Tc-99m albumin aggregates); Megatope (Kit for iodinated I-131 albumin); Menopur (menotropins); Mepsevii (vestronidasealfa-vjbk); Microlite (Radiolabeled albumin technetium Tc-99m albumin colloid kit); Mircera (Methoxylated polyethylene glycol-epotine β); Mvasi (Bevacizumab-awwb); Myalept (metreleptin); Mylotarg (Gemtuzumab-orzomicin); Myobloc (rimabotulinumtoxin B); Myozyme (Aglucosidase α); Myxredlin (Human insulin); N / A (raxibacumab); Naglazyme (Thiolactin); Natpara (Parthyroid hormone); Neulasta (Pefilgrastim); Neulasta Onpro (Pefilgrastim); Neumega (Oprene Interleukin); Neupogen (Fingrasil); NeutroSpec (Technetium 99m tc fanolesomab); Nexobrid (anacaulase-bcdb); Nexviazyme (avalglucosidase alfa-ngpt); Ngenla (somatrogon-ghla); Nivestym (Fingrasil-aafi); Norditropin (Growth Hormone); Novalel (Human Chorionic Gonadotropin);Novolin 70 / 30 (Protamine Zinc Human Insulin and Human Insulin); Novolin N (Protamine Zinc Human Insulin); Novolin R (Human Insulin); Novolog (Insulin Aspart); Novolog Mix 50 / 50 (Protamine Zinc Aspart Insulin and Aspart Insulin); Novolog Mix 70 / 30 (Protamine Zinc Aspart Insulin and Aspart Insulin); Nplate (Roprostadil); Nucala (Mepolilimab); Nulojix (Beracip); Nutropin (Growth Hormone); Nutropin AQ (Growth Hormone); Ocrevus (Orelizumab); Omnitrope (Growth Hormone); Omvoh (mirikizumab-mrkz); Oncaspar (Pegasparase); Ontak (Dennisin-Diphtheria Toxin Conjugate); Ontruzant (Trastuzumab-dttb); Opdivo (Nivolumab); Opdualag (Nivolumab and Relatlimab-rmbw); Orencia (Abatacept); Orthoclone OKT3 (muromanab-CD3); Ovidrel (Recombinant Human Chorionic Gonadotropin Alpha); Oxervate (Cenegemin-bkbj); Padcev (Ventureumab-ejfv); Palynziq (pegvaliase-pqpz); Pancreaze (Pancreatic lipase); Pegasys (interferon α-2a); Pegasys Copegus Combination Pack (interferon α-2a and ribavirin); Pegintron (interferon α-2b); Pegintron / Rebetol ComboPack (interferon α-2b and ribavirin); Pergonal (menotropins); Perjeta (pertuzumab); Pertzye (pancreatic lipase); Plegridy (interferon β-1a); Polivy (verpottuzumab-piiq); Pombiliti (cipaglucosidase alfa-atga); Portrazza (nexituzumab); Poteligeo (moglituzumab-kpkc); Praluent (alikumab); Praxbind (idazumab); Pregnyl (human chorionic gonadotropin); Procrit (eportin alfa); Proleukin (Adeleukin); Prolia (Denoxin); ProstaScint (Carolomumab / Penditin); Pulmolite (Kit for preparing Technetium Tc-99m albumin aggregates); PulmotechMAA (Kit for preparing Technetium Tc-99m albumin aggregates); Pulmozyme (Streptococcal enzyme α); Raptiva (Efazolizumab); Rebif (Interferon β-1a); Reblozyl (luspatercept-aamt); Regranex (Becappelleramine); Remicade (Infliximab);Renflexis (infliximab-abda); Reopro (abxiximab); Repatha (evolocumab); Repronex (menotropins); Retacrit (epbx); Retavase (reteplase); Revcovi (elapegademase-lvlr); Rituxan (rituximab); RituxanHycela (rituximab and human hyaluronidase); Roferon-A (interferon α-2a); Rolvedon (eflapegrastim-xnst); Ruxience (rituximab-pvvr); Rybrevant (amivantamab-vmjw); Rylaze (Erwinia chrysanthemum asparaginase (recombinant)-rywn); Ryzneuta; Rystiggo (rozanolixizumab-noli); Ryzodeg 70 / 30 (Insulin Degludec and Insulin Aspart); Saizen (Growth Hormone); Santyl (Collagenase); Saphnelo (Anifrolumab-Fnia); Sarclisa (Isatuximab-IRFC); Serostim (Growth Hormone); Siliq (Brodamab); Simponi (Golimumab); Simponi Aria (Golimumab); Simulect (Baliximab); Skyrizi (RZA); Skytrofa (Lonapegsomatropin-TCGD); Soliqua 100 / 33 (Insulin Glargine and Liximab); Soliris (Eculizumab); Somavert (pevisom); Spevigo (spesolimab-sbzo); Stelara (ustekinumab); Streniq (afotazyme α); Sucraid (sacrosidase); Survanta (belatan); Susvimo ​​(ranibizumab); Sylvant (struximab); Synagis (palizumab); Takhzyro (lanadelumab-flyo); Taltz (ixekizumab); Talvey (talquetamab-tgvs); Tanzeum (albiglutide); Tecentriq (atelizumab); Tecvayli (teclistamab-cqyv); Tepezza (tetotemumab-trbw); Tezspire (tezepelumab-ekko); Thyrogen (thyroid-stimulating hormone α); Tivdak (tisotumab) vedotin-tftv); TNKase (tenectin); Toujeo (insulin glargine); Trasylol (aprotinin); Trazimera (trastuzumab-qyyp); Tremfya (gucecurumab); Tresiba (insulin degludec); Trodelvy (goxatozumab-hziy); Trogarzo (eebalizumab-uiyk); Trulicity (dulaglutide); Truxima (rituximab-abbs); Tysabri (natezumab); Tzield (teplizumab-mzwv); Udenyca (pefragstatin-cbqv); Ultomiris (relizumab-cwvz); Unituxin (denutuximab); Vabysmo (faricimab-svoa); Vectibix (panitumumab); Veopoz (pozeilimab-bbfg); Verluma (nofetumomab); Vimizim (epirosulfatase α); Viokace (pancreatic lipase); Vitrase (hyaluronidase); Voraxaze (carboxypeptidase); VPRIV (viragaside α); Vyvgart (efgartigimod alfa-fcab); Vyvgart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc); Xenpozyme (olipudase alfa-rpcp); Xeomin (incobotulinumtoxin A); Xgeva (denomab); Xiaflex (Clostridium histolytica collagenase); Xigris (Trekolol α); Xolair (Omalizumab); Xultophy 100 / 3.6 (Insulin degludec and liraglutide); Yervoy (Ipilimumab); Zaltrap (Ziv-Aflibercept); Zarxio (Filgrastim-SNDZ); Zenapax (Dacoxetine); Zenpep (Pancreatic lipase); Zevalin (Tieimomab); Ziextenzo (Pefilgrastim-BMEZ); Zinbryta (Dacoxetine); Zinplava (Bezotocilizumab); Zirabev (Bevacizumab-BVZR); Zomacton (Growth hormone); Zorbtive / Serostim (Growth hormone); Zymfentra (Infliximab); Zynlonta (Locastuximab) tesirine-lpyl); or Zynyz (retifanlimab-dlwr).

43. The pharmaceutical container according to any one of claims 38 to 42, wherein the pharmaceutical composition comprises a biological agent for use with: a tumor necrosis factor-α (TNF) inhibitor, an interleukin inhibitor, a selective co-stimulatory modulator, a glucagon-like peptide-1 (GLP-1) agonist or a GLP-1 receptor agonist, an mRNA-based formulation, an allergen, tissue, a recombinant protein, a personalized medicine, a CAR-T, a cell therapy drug, a gene therapy drug, or a biological agent listed in the FDA Purple Book.

44. The pharmaceutical container of claim 43, wherein the personalized medicine is a CAR-T drug, a cell therapy drug, or a gene therapy drug.

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