Pharmaceutical containers with coating layers deposited by atomic layer deposition

Abstract

Disclosed is a primary container for pharmaceutical packaging which includes a lumen defined in part by a wall, the wall having an inner surface facing the lumen and an outer surface, where the inner surface of the wall is coated with a metal oxide coating and provides improved drug compatibility, in particular compatibility with biologic drugs like proteins, when compared with primary containers without such a coating. The metal of the metal oxide coating is selected from the group consisting of zirconium, hafnium, titanium, tantalum, aluminum, and combinations thereof. The metal oxide coating is produced and applied by an atomic layer deposition (ALD) process.

Description

Leydig 7754171PHARMACEUTICAL CONTAINERS WITH COATING LAYERS DEPOSITED BY ATOMIC LAYER DEPOSITIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No.63 / 778,629, filed March 27, 2025 and U.S. Provisional Patent Application No. 63 / 890,456, filed September 30, 2025, the disclosures of which are incorporated herein in their entirety for all purposes.BACKGROUND OF THE INVENTION

[0002] Biologic drugs constitue a wide range of products, including vaccines, blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. The biologic drugs could also include one or more of buffers, tonicity modifiers, cryo-or lyoprotectants, surfactants, metal chelators, and antioxidants. Thus, most biologies are complex mixtures that are not easily precisely identified and / or characterized, and routine analytical testing often cannot readily detect changes in biologic drugs.

[0003] Although most biologic formulations are aqueous solutions or suspensions at neutral or near-neutral pH values, which minimizes leachables from glass, surfactants (such as polysorbate 80 and 20) and high ionic strength may enhance the risk of leaching. Additionally, many biologic products are injectable as liquids into a patient’s bloodstream or through the skin. When compared with small-molecule drugs, which are often dry powders and tablet, liquid formulations are more able to induce leaching, especially upon long-term storage.

[0004] Pharmaceutical containers such as vials and syringes can have one or more barrier layers of material(s) on their interior walls, such layers being designed to protect the pharmaceutical agent - compound, biologic, or other drug product, - that is stored in the vial or syringe from contamination or degradation over time. In this manner, pharmaceutical containers may be delivered safely to an end-use location without excessive requirements for special handling during transport and storage, and the pharmaceutical agent would maintain its safety and effectiveness even when transported and / or stored for extended periods of time. However, pharmaceutical agents, in particular biologic agents, tend to interact with known barrier layers,Leydig 7754172which often leads to degradation of the pharmaceutical agents over time. As a result, the shelflife, safety, or effectiveness of such pharmaceutical agents tend to diminish. The interior surface of the primary container can also cause biological products to adhere to the surface. Surface adhesion of protein-based biologic drugs can reduce the concentration of the drug in the container and cause the drug to denature (change), thereby resulting in an increase in sub-visible particles in the drug.

[0005] Pharmaceutical containers known in the art, when their interior surface is coated with a metal oxide, e.g., zirconium oxide (or zirconia), exhibit properties of low extractables and the elimination of glass delamination of a wide range of pH drug formulations. However, since many drug formulations are composed of complex protein-based molecules, the protein-based molecules can denature in the pharmaceutical container, due to changes in temperature, light and the drug contact surface, over the drug shelflife. Protein denaturing can occur when the protein adsorbs onto the surface of the pharmaceutical container.

[0006] Even though attempts have been made to reduce the degradation of pharmaceutical agents, particularly of biologic agents, there remains an unmet need to provide containers suitable for long-term storage of pharmaceutical compositions. The present invention, in an aspect, solves the above-mentioned problems.

[0007] These and other advantages of the invention, as well as additional inventive features, will be apparent to those of skill in the art from the following description of the invention provided herein.BRIEF SUMMARY OF THE INVENTION

[0008] In an aspect, the invention provides a primary container for pharmaceutical packaging comprising a lumen defined in part by a wall, the wall having an inner surface facing the lumen and an outer surface, where the inner surface of the wall is coated with a metal oxide layer. In an aspect, the metal of the metal oxide layer can be Zr, Hf, Ta, or Ti, or any combination thereof.

[0009] The coating provides improved drug compatibility when compared with primary containers without a zirconia coating on the inner surface facing the lumen of the wall. The enhanced biocompatibility due to such zirconia coatings disclosed herein holds both for solidLeydig 7754173(e g., lyophilized) proteins and for their aqueous solutions and suspensions. The present invention also provides a method of safely storing pharmaceutical agents in such primary containers.

[0010] In another aspect, the present invention provides a primary container for pharmaceutical packaging comprising a lumen defined in part by a wall, the wall having an inner surface facing the lumen and an outer surface, wherein the metal oxide layer is coated with a polymer layer, wherein the polymer layer is one that is coated by a vapor phase in-situ coating method. The polymer layer can be a polyethylene glycol (PEG) layer, an acrylate layer, or a phosphate layer.

[0011] In a further aspect, the present invention provides a primary container for pharmaceutical packaging comprising a lumen defined in part by a wall, the wall having an inner surface facing the lumen and an outer surface, wherein a metal oxide layer has been coated on the inner wall of the container, and the metal oxide layer is further coated with a hydrophilic polymer or oligomer layer coating by vapor phase coating method, the polymer or oligomer layer coating providing biological adhesion mitigation on (ALD) metal oxide surfaces.

[0012] The present invention further provides a pharmaceutical container comprising a lumen defined in part by a glass wall, the glass wall having an inner surface facing the lumen and an outer surface, wherein the inner surface of the wall has been coated with a zirconia coating by atomic layer deposition (ALD) coating process, wherein adsorption of a biological drug placed in the pharmaceutical container to the inner surface coated with the zirconia coating is at least 50% less compared to the adsorption of the biological drug stored in a pharmaceutical container composed of glass without the zirconia coating.

[0013] The improved compatibility features of the present invention include any or all of the following: diminished surface adsorption of proteins and / or lower extent of this adsorption's irreversibility; reduced aggregation and other modes of protein deterioration upon lyophilization; greater resistance to protein degradation induced by various stresses (e.g., mechanical agitation and / or thermal) and freezing-thawing cycles, as well as better protein storage stability resulting in longer shelf-life; reduced drug loss due to proteins adhering to the inner container walls; and reduced sub-visible particles - for example, when denatured proteins dislodge from the container walls and create particles in the liquid drug.Leydig 7754174

[0014] The present invention provides processes for providing the coatings. Thus, for example, the invention provides a process for applying zirconium oxide coatings, by ALD deposition, to 10 mL pharmaceutical glass container. The present invention supports a wide range of primary pharmaceutical containers, that include but are not limited to: vials ranging in size from 2mL to lOOmL, syringes from 0.5mL, ImL long, ImL standard, 3mL, 5mL, lOmL 20mL and 50mL and cartridges ImL, 3mL, 5mL and lOmL. It has been found that 20 nm zirconium oxide thickness is effective at preventing the dissolution of glass at pH 9. Moreover, the amount of crystallinity in the zirconium oxide coating is lower in a 20 nm thick coating compared to a 40nm thick coating. It has been found that a more amorphous layer of zirconium oxide coating provides a more effective barrier to dissolution than a crystalline layer. ALD coating techniques to minimize crystallization include but are not limited to: (1) use of alternating layers of AhCh / ZnCh that are 3-5 nm in thickness, processing temperatures <200°C and minimizing thickness of the drug contact layer. Experiments suggest that a top layer thickness of < 20nm is effective at reducing crystal formation in the coating.

[0015] Additionally, in accordance with an aspect of the present invention, the amount of adsorption for certain types of proteins (drugs) is reduced when the zirconium oxide coating is amorphous or not crystalline and the roughness of the coated surface is reduced. For example, the overall adsorption on a zirconium oxide coated surface is < 50% than adsorption on an untreated glass surface. Furthermore, surface roughness is less on a thinner coating of zirconium oxide compared to that on a thicker coating. Reduced surface roughness leads to reduced adsorption and reduced aggregation of proteins. It has also been found that certain protein-based drug compounds require a more hydrophilic surface compared to glass while others require a more hydrophobic surface compared to glass. The present invention describes techniques to achieve these surface properties with the coating.

[0016] Further and alternative aspects and features of the disclosed invention will be apparent from the following detailed description. As will be appreciated, the methods disclosed herein are capable of being carried out and used in other and different aspects, and also capable of being modified in various respects. Accordingly, it is to be understood that both the foregoing general description and the following detailed description are only exemplary and illustrative and do not restrict in any way the scope of the claimed invention.Leydig 7754175BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Fig. 1 is a graph demonstrating the X-ray photoelectron spectroscopy (XPS) depth profile of a syringe coated with a zirconia coating over an AI2O3 coating present on the surface of the syringe, wherein the concentrations of Al, C, O, and Zr were measured near the syringe needle end at various depths from the top surface of the wafer.

[0018] Fig. 2 is a graph demonstrating the XPS depth profile of a syringe coated with a zirconia coating over an AI2O3 coating present on the surface of the syringe, wherein the concentrations of Al, C, O, and Zr were measured at the middle of the syringe at various depths from the top surface of the wafer.

[0019] Fig. 3 is a graph demonstrating the XPS depth profile of a syringe coated with a zirconia coating over an AI2O3 coating present on the surface of the syringe, wherein the concentrations of Al, C, O, and Zr were measured at the flange end of the syringe at various depths from the top surface of the wafer.

[0020] Fig. 4 is a graph depicting the contact angle of water measured on zirconia films coated onto an alumina surface.

[0021] Fig. 5 depicts an expected dissolution profile of borosilicate glass vials which are coated with a zirconia layer when exposed to an aqueous solution at a pH of 9 at 50 °C for 72 hours. The profile on the left depicts the expected results of a vial without a protective alumina coating layer between the glass surface and the zirconia layer, whereas the profile on the right depicts the expected results of a vial with a protective alumina coating layer between the glass surface and the zirconia layer.

[0022] Fig. 6 depicts an expected dissolution profile of borosilicate glass vials which are coated with a zirconia layer when exposed to an aqueous solution at a pH of 3 at 50 °C for 72 hours. The profile on the left depicts the expected results of a vial without a protective alumina coating layer between the glass surface and the zirconia layer, whereas the profile on the right depicts the expected results of a vial with a protective alumina coating layer between the glass surface and the zirconia layer.Leydig 7754176

[0023] Fig. 7 depicts the measured concentration of Zr, Al, O, and C as a function of depth on a syringe coated with a zirconia layer, wherein the measurement was made at the top of the syringe.

[0024] Fig. 8 depicts the measured concentration of Zr, Al, O, and C as a function of depth on a syringe coated with a zirconia layer, wherein the measurement was made at the middle of the syringe.

[0025] Fig. 9 depicts the measured concentration of Zr, Al, O, and C as a function of depth on a syringe coated with a zirconia layer, wherein the measurement was made at the bottom of the syringe.

[0026] Fig. 10 depicts the water contact angles measured on zirconia films at different temperatures.

[0027] Fig. 11 depicts SEM images of the surface of 20 nm and 40 nm thick zirconium oxide coated surfaces for reducing adhesion of biological s. The thinner coating of zirconia (20 nm thick) provides superior performance over the thicker coating (40 nm). It is evident that the thinner coating has lower number of surface defects, as evidenced by the fewer number of 10 -15 nm diameter features on the surface of the thinner coating compared to such features on the surface of the thicker coating. Protein adsorption and aggregation are less when the coating is thinner due to the reduced amount of defects.

[0028] Fig. 12 depicts a proposed coating arrangement of aluminum oxide and zirconium oxide layers on a glass surface, including thicknesses of the layers, wherein zirconium oxide coating at the top surface is 15 nm thick.

[0029] Fig. 13 depicts a proposed coating arrangement of aluminum oxide and zirconium oxide layers on a glass surface, including thicknesses of the layers, wherein zirconium oxide coating at the top surface is 37 nm thick.

[0030] Fig. 14 depicts the microstructure of a 40 nm thick zirconia coating. The zirconia coated surface on the right provides a superior performance in reducing adhesion of biologicals over the uncoated surface on the left, where the biologicals tend to adhere in a greater amount.

[0031] Fig. 15 provides a higher magnified image of the microstructure of the thinner coating depicte in Fig. 14, showing reduced number of finer vertical microstructures, compared to such structures on the surface of the thicker coating.Leydig 7754177

[0032] Fig. 16 depicts a cross-section TEM image of the configuration shown in Fig. 15. Conical or tapered grain structure formed within the top ZrCh layer is revealed by the image; however, the amount of deposit is less compared to a glass surface without a ZrCh layer thereon.

[0033] Fig. 17 depicts a high magnification image depicted in Fig. 16.

[0034] Fig. 18 depicts some of the advantages of a ZrCh coated pharmaceutical container in terms of reducing the extraction of underlying coated glass surface. The extracted amounts of Al, B, Si, and Zr for uncoated and ZrCh coated glass surfaces are shown. The extracted amounts are much lower for the ZrCh coated glass surface.

[0035] Fig. 19A depicts measured contact angles of ZrCh coated glass surfaces depending on the position of the vial in the ALD coating chamber, as depicted in Fig. 19B. Substantially uniform contact angles are obtained irrespective of the position of the vial in the chamber.

[0036] Fig. 20 graphically depicts the contact angles of ZrCh coated glass surfaces as a function of temperature and number of cycles of ALD coating. Thus, contact angle can be controlled by the coating temperature and the number of coating cycles.

[0037] Fig. 21 schematically depicts deposition of aluminum oxide by ALD. In Fig. 21A, the flow of TMA and water vapor are depicted, and the resulting aluminum oxide is depicted in Fig. 21B. Fig. 21C depicts the conformal multiple layer deposition of deep silicon trenches.

[0038] Fig. 22A depicts a picture of Woollam M2000X elliposometer employed to measure the thickness of ALD coatings. Fig. 22B depicts the layout of the samples inside the ALD chamber. Fig. 22C depicts that the thickness of the coating could be controlled by adjusting the position of the vials in the ALD chamber.

[0039] Fig. 23 depicts concentration of Al, Na, O, Si, and Zr, as determined by X-ray photoelectron spectroscopy (XPS) in a coating at the bottom inside of the vial B6,V32.

[0040] Fig. 24 depicts the compositional depth profile determined XPS, wherein alternate layers of AI2O3 and ZrCh have been deposited on the glass with a thick ZrCh layer being deposited on the top as a cap.

[0041] Fig. 25 depicts the thickness of ZrCh films deposited on glass, showing that the films have a thickness of 21.1 nm. Carbon films were deposited as part of the TEM sample preparation technique to protect the ZrCh films.Leydig 7754178

[0042] Fig. 26 depicts the compositional depth profile determined by XPS, wherein alternating thin layers of AI2O3 and ZrCh have been deposited on the glass with a 40 nm thick ZrCh layer being deposited on the top. Carbon films were deposited as part of the TEM sample preparation technique to protect the ZrCh films.

[0043] Fig. 27 depicts the uniformity of the ZrCh cap of 40 nm thickness placed over alternating thin layers of AI2O3 and ZrCh.

[0044] Fig. 28 depicts the thickness distribution of the respective elements of the coatings, i.e., C, O, Na, Al, Si, and Zr, as measured via electron density distribution using TEM-EDS method.

[0045] Fig. 29 depicts the advantageous effect of a zirconium oxide coating on glass when exposed to a pH 9 buffer solution at 70°C for 72 hours. Uncoated glass vial showed significant depletion as evidenced by the high concentrations of Al, B, Si, and Zr from uncoated glass, whereas the extract from the coated glass showed very low concentrations of Al, B, Si, and Zr.

[0046] Fig. 30 depicts the results from five zirconium oxide coated 10 mb vials, confirming consistent performance throughout the coating batch. Fig. 30A depicts the viail. Fig. 30B depicts the the concentration of B, Al, Si, and Zr. Fig. 30C depicts the position of the vials in the ALD chamber.

[0047] Fig. 31 depicts results of contact angle measurements on ZrCh coated and uncoated vials. The contact angle measurements confirm that surface wetting of the pharmaceutical container can be reliably engineered.

[0048] Fig. 32 depicts the results of protein adsorption measurements using a fluorescent dye on ZrCh coated glass surface and on glass surface without ZrCh coating. The tested proteins adsorbed less on ZrCh coated glas surface compared to uncoated borosilicate glass surface.

[0049] Fig. 33 A depicts an advantage of ZrCh coated glass surface over Type 1 borosilicate glass surface in reducing the adsorption of biomolecules, in particular, P-galactosidase tetramer (or P-gal tetramer, shown in Fig. 33B). A 4-times reduction in adsorption was observed on ZrCh coated glass surface compared to the adsorption on uncoated borosilicate glass. See Fig. 33D and 33E. However, comparable adsorption was observed for the lower molecular weight compound, Green Fluorescent Monomer (GFP, shown in Fig. 33C), for the coated and uncoated glassLeydig 7754179surfaces. Fig. 33F and 33G depict the images of different views of borosilicate glass and ZrCh coated borosilicate glass.

[0050] Fig. 34 depicts SEM images of the surfaces of ZrCh coatings of 40 nm and 20 nm thicknesses on glass vials, showing that thicker coating would lead to rougher surface.

[0051] Fig. 35 depicts fluorescent images of the surface with 40 nm coating from Fig. 34 when evaluated for protein aggregation. Protein adsorption was observed on the surface of the 40 nm (thicker) ZrCh coating.

[0052] Fig. 36 depicts fluorescent images of the surface with 20 nm coating from Fig. 34 when evaluated for protein aggregation. Less protein adsorption was observed on the surface of the 20 nm (thinner) ZrCh coating.

[0053] Fig. 37 depicts a method of modification, e.g., pegylation, of the surface of zirconium oxide with ethylene oxide.DETAILED DESCRIPTION OF ASPECTS OF THE INVENTION

[0054] The invention provides, in an aspect, a primary container for pharmaceutical packaging comprising a lumen defined in part by a wall, the wall having an inner surface facing the lumen and an outer surface, where the inner surface of the wall is coated with a metal oxide coating and provides improved drug compatibility when compared with primary containers without a metal oxide coating on the inner surface facing the lumen of the wall, wherein the metal oxide is an oxide of a metal selected from the group consisting of zirconium, hafnium, titanium, tantalum, aluminum, and combinations thereof. A primary container of the invention provides improved drug compatibility when compared with primary containers without a metal oxide coating on the inner surface facing the lumen of the wall.

[0055] The primary container may be made of various types of glass or plastic. There is significant variation in the composition of the surface of such primary containers manufactured by different manufacturers. For example, Table 1 below sets forth the composition of borosilicate glass tubular syringes manufactured by six different manufacturers. The composition of a moulded syringe is also set forth in Table 1.Leydig 77541710

[0056] Table 1. Composition of borosilicate glass tubular and moulded syringestabular Moulded SCHOTT Gerresheifner Nipro SCHOTT Gerresheimer Nipro SCHOTT Wheaton CompositionGX-33 | W-33 Fiolax* j GX-S1 NSV-S'l NGC 400 _ SiOz _ SI _ _ SO _ | _ SO _ A _ B _ _ 73 73. B . ......... B .............^ j i .f .M. 11 r 12. 10 ZIL . it .4- 7 1 9 7 to 10 AhtOi 2 3 3 . ? .1. ' . g 5 6MgO / CaO / 8aO 0 <0.1 | 0 2 1 3 5 4* Data take?; / root ^niffocterei's sheets

[0057] The inner surface of the glass or plastic can be coated with a layer of aluminum oxide (AI2O3) and the metal oxode coating is placed on a coating of AI2O3 in turn placed on a glass. In the case of a polymer or plastic container, the layer of AI2O3 serves as a gas barrier layer, thereby protecting the contents of the pharmaceutical container. The metal oxide coating placed on the layer of aluminum oxide prevents the aluminum oxide from dissolving in the pharmaceutical composition and damaging the said pharmaceutical composition. Alternatively, the metal oxide coating is placed directly on a glass surface, such as a borosilicate glass surface. In this case, the metal oxide coating prevents dissolution of glass surface and leaching of its silica and other glass’s silicon components into the pharmaceutical composition that could damage the said pharmaceutical composition.

[0058] In an aspect, the metal oxide coating is applied to the inner surface of the wall by atomic layer deposition (ALD) process. The ALD process is based on typically self-limiting reactions, whereby sequential and alternating pulses of reactants are utilized to deposit one monolayer of deposit per cycle. The deposition conditions and precursors are chosen to provide self-saturating reactions, such that an adsorbed layer of one reactant leaves a surface termination that is non-reactive with the vapor phase reactants of the same reactant. The substrate surface is subsequently contacted with a different reactant that reacts with the previous termination to enable continued deposition. Thus, each cycle of alternating pulsed reactants generally 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 detailed procedures involving ALD.Leydig 77541711

[0059] ALD is a coating deposition technology that yields exceptional conformity and allows for tunable coating compositions, wherein the coating thicknesses can be controlled at the atomic level. ALD operates via chemical reactions of two or more precursors which are added into a chamber where a substrate is placed at a given temperature and pressure to enable the deposition of a material on the surface of a substrate layer by layer. ALD is a technique where chemical precursors are introduced one after other to the surface of the substrate where they chemically react directly with the surface to form sub-monolayers of film. While traditional techniques, such as chemical vapor deposition (CVD), rely on high temperatures to decompose the precursor at the surface of the substrate, ALD can be performed at lower temperatures. Moreover, when compared to CVD and physical vapor deposition (PVD), ALD can produce high quality coatings with conformality and uniformity and is highly reproducible and easily scalable to an industrial process level. In certain aspects, plasma enhanced atomic layer deposition may be used to deposit the barrier layer or pH-protective layer at lower temperatures.

[0060] In some aspects, the pharmaceutical container comprises a coating of an oxide of zirconium deposited by ALD by utilizing tetrakisdimethylamidozirconium (Zr(N e2)4), tetrakisethylmethylamidozirconium (Zr(NMeEt)4), tetrakisdiethylamidozirconium (Zr(NEt2)4), or a combination thereof, as reactant(s). Alternatively, Zr[OCH(CH3)3]4 can be used as a precursor. Specific examples of ALD ZrCh coatings can be found in US 12303461 Bl and US 12109173 Bl, which are incorporated herein in their entirety. The HfCh layer can be coated or grown using tetrakisdimethylamidohafnium (Hf(N e2)4), tetrakisethylmethylamidohafnium (Hf(NMeEt)4), tetrakisdi ethyl amidohafnium (Hf(NEt2)4), or a combination thereof, as reactants. Alternatively, Hf(OCH(CH3)3)4 can be used as a reactant. See, e.g., Seweryn et al., Surfaces and Interfaces 55 (2024) 105311; www.sciencedirect.com / iournal / surfaces-and-interfaces; see alsoenhanced-atomic-layer-deposition-appiication-electronic-materials.

[0061] Optionally, mixed metal (Zr / Hf) ALD precursors can be utilized to create mixed metal oxide coatings to control coating properties including crystallinity, surface roughness, surface wettability and barrier performance.Leydig 77541712

[0062] Other ALD metals and metal systems (oxides, nitrides, sulfides) and core / shell nanoparticles can be coated onto medical containers toward offering performance attributes including control of color, clarity and security (material ID, anti-fraud) elements.

[0063] ALD coatings can generate vibrant structural colors by creating precise, nanometerthick dielectric coatings that cause light interference more effectively than dyes. By controlling the number of cycles, films of materials like TiCh, Ta2Os, or AI2O3 are deposited with subangstrom precision, allowing for tuned, durable, and brilliant colors across complex, 3D, or flexible substrates. See, e.g., Materials Today, Volume 17, Number 5 June 2014 RESEARCH, “A brief review of atomic layer deposition: from fundamentals to applications;” Richard W. Johnson, Adam Hultqvist and Stacey F. Bent; and US 2020 / 0066927 Al, Control of Surface properties by Deposition of Particle Monolayers, Greer et al.

[0064] The metal oxide layer can be deposited using ALD at any suitable temperature, e.g., at a temperature of 200 °C or less, e.g., 195 °C or less, 190 °C or less, 185 °C or less, 180 °C or less, 175 °C or less, 170 °C or less, 165 °C or less, 160 °C or less, 155 °C or less, 150 °C or less, 145 °C or less, 140 °C or less, 135 °C or less, 130 °C or less, 125 °C or less, 120 °C or less, 115 °C or less, 110 °C or less, 105 °C or less, 100 °C or less, 95 °C or less, 90 °C or less, 85 °C or less, 80 °C or less, 75 °C or less, 70 °C or less, 65 °C or less, 60 °C or less, 55°C or less, 50 °C or less, 45 °C or less, or 40 °C or less. In some aspects, the oxide layer is applied by ALD at a temperature that is less than the Tg of the material comprising the pharmaceutical container.

[0065] The metal oxide layer has any suitable thickness, e.g., a thickness of 50 nm or less, e.g., 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, the layer has a thickness of 1 to 5 nm, e.g., 1 nm, 1.5 nm, 2 nm, 2.5 nm, 3 nm, 3.5 nm, 4 nm, 4.5 nm, or 5 nm. In certain aspects, the layer has a thickness of 1 to 3 nm or 3 to 5 nm. In some aspects, the layer has a thickness of 40 to 50 nm, e.g., 41 nm, 42 nm, 43 nm, 44 nm, 45 nm, 46 nm, 47 nm, 48 nm, 49 nm, or 50 nm. The thickness of the oxide layer can be measured using any suitable method, for example, transmission electron microscopy (TEM) or X-ray photoelectron spectroscopy (XPS).

[0066] In accordance with another aspect, the primary container of the invention can be a vial, syringe, cartridge, or ampoule. In another aspect, the primary container is made of glass, in particular type 1 borosilicate glass. In yet another aspect, the primary container is made of aLeydig 77541713plastic, e.g., a cyclo olefin copolymer, a cyclo olefin polymer, polypropylene, or polyethylene, or a combination thereof.

[0067] In a further aspect, the present invention provides a pharmaceutical container comprising a lumen defined in part by a glass wall, the glass wall having an inner surface facing the lumen and an outer surface, wherein the inner surface of the wall has been coated with a zirconia coating by atomic layer deposition (ALD) coating process, wherein adsorption of a biological drug placed in the pharmaceutical container to the inner surface coated with the zirconia coating is at least 50% less compared to the adsorption of the biological drug stored in a pharmaceutical container composed of glass without the zirconia coating. In an aspect, the metal oxide coating has a thickness of about 15 nm to about 20 nm, about 6 nm to about 18 nm, or about 17 nm.

[0068] In an aspect, the metal oxide, e.g., zirconium oxide, coating has a surface roughness defined by an arithmetical mean height of 0.61 ± 0.03 nm, a root mean square height of 0.80 ± 0.03 nm, and / or a maximum peak to valley height of 8.8 ± 0.4 nm, wherein the arithmetical mean height, root mean square height, and peak to valley height are defined as set forth in the table set forth below:

[0069] Table 2. Various types of heights of the zirconia coating surface roughness NameArithmeUcd mean height (pm) S,, * | [ .“ixa s sh'hrRoot mean sguam height (gm) I )Maximum peak m w&y height (gm) mm urn)

[0070] In an aspect, the thickness of the zirconia coating is about 20 nm to 40 nm, e g., 25, 30, or 35 nm.

[0071] In any of the above aspects, the metal oxide coating, e.g., zirconia coating, is amorphous.Leydig 77541714

[0072] The metal oxide layer can be coated with a polymer layer, wherein the polymer layer is one that is coated by a vapor phase in-situ coating method. The polymer layer can be a polyethylene glycol (PEG) layer, an acrylate layer, or a phosphate layer. The presence poly(ethylene oxide) (PEO / PEG) oligomers (ca. MW=400) on medical container surfaces can significantly reduce the interaction (wall adhesion, fouling, activity reduction) of biologic active ingredients. PEG layers can be created on the surface of inorganic oxides via fluid phase solution and solgel methods using non-volatile reactive PEG oligomers.

[0073] In an aspect, non-fluid phase methods can be used for creating PEG surfaces coupled with ALD metal oxides and coating methods. Since preformed PEG molecules exhibit limited volatility, utilizing in-situ formed PEG molecules (from volatile ethylene oxide (EO) precursors) on ALD metal oxide surfaces is a preferred option.

[0074] In any of the above aspects, the pharmaceutical container includes a biological drug which is a peptide drug or a combination of peptide drugs. For example, the peptide drug is selected from the group consisting of liraglutide, ranibizumab, and bevacizumab, or any combination thereof. As a further example, the biological drug comprises a lipid loaded nanoparticle (LNP), e.g., wherein the LNP is GFP RNA loaded LNP. In another aspect, the biological drug comprises a humanized IgG.

[0075] In an aspect, the pharmaceutical container includes a biological drug comprising a bacteriophage, for example, wherein the biological drug comprises Botulinus neurotoxin.

[0076] The present invention further provides a method of storing a biological drug in a pharmaceutical container, the method comprising placing the biological drug in the pharmaceutical container described such that the biological drug is in contact with the metal oxide coating.

[0077] Thus, the invention provides a method of storing a pharmaceutical agent in a primary container, the method comprising providing a primary container comprising a lumen defined in part by a wall, the wall having an inner surface facing the lumen and an outer surface, where the inner surface of the wall is coated with a metal oxide coating and provides improved drug compatibility when compared with primary containers without a metal oxide coating on the inner surface facing the lumen of the wall, and storing the pharmaceutical agent in the primaryLeydig 77541715container, wherein the metal oxide is an oxide of a metal selected from the group consisting of zirconium, hafnium, titanium, tantalum, aluminum, and combinations thereof.

[0078] The primary container of the invention is used to store a pharmaceutical composition, which can be a drug product. In another aspect, the drug is a biologic. An example of a biologic is a protein. Examples of proteins include a hormone, a cytokine, a blood constituent, a monoclonal antibody, or a derivative thereof. The primary container of the invention in another aspect exhibits a diminished surface adsorption of a protein and / or a lower extent of irreversibility of surface adsorption of a protein when compared to glass and / or plastic containers without the zirconia coating. In another aspect, the primary container of the invention exhibits reduced aggregation and / or other modes of protein deterioration upon lyophilization when compared to glass and / or plastic containers without the zirconia coating.

[0079] The primary container of the invention exhibits greater protection against protein degradation induced by internal or external stresses than a container that does not have the zirconia coating. The primary container imparts greater resistance to protein degradation induced by a mechanical agitation, thermal stress, or freeze-thaw cycle. In another aspect, the primary container exhibits enhanced storage stability shelf-life to the protein, when compared to glass and / or plastic containers without the zirconia coating. The primary container according to the invention exhibits reduced drug loss due to proteins adhering to the container wall when compared to glass and / or plastic containers without the zirconia coating. The primary container according to the invention, in another aspect, exhibits reduced number of sub-visible particles of denatured proteins that dislodge from the container wall when compared to the number of sub-visible particles of glass and / or plastic containers which have not been coated with the zirconia coating. Sub-visible particles may be measured using the following techniques:

[0080] (1) light obscuration (example is a HIAC 9703+ Laboratory Particle Counter) that that measures particle size and concentration by detecting the shadow (blockage) a particle creates as it passes through a laser beam, (2) membrane microscopy an analytical technique used to isolate, count, and characterize sub-visible particles typically from 10 - 500 microns pharmaceutical liquids, emulsions, and drugs by filtration and (3) microflow imaging is a sensitive, image-based technique used to detect, count, and characterize subvisible particles (1-100 microns) in biopharmaceuticals. Examples of instruments to measure particles by microflowLeydig 77541716imaging include: Bio-Techne MFI 5000 series (5100 / 5200) and Fluid Imaging Technologies FlowCam.

[0081] Sub-visible particles for pharmaceutical packaging are tested using USP 788 / USP789.

[0082] The primary container according to the invention contains or is used to store a drug product which can be a pharmaceutical composition comprising a peptide, a protein, a monoclonal antibody, or a blood constituent.

[0083] In another aspect, the primary container of the invention contains or is used to store a pharmaceutical composition that comprises a biologic drug selected from abatacept; abciximab; abobotulinumtoxin A; adalimumab; adalimumab-adaz; adalimumab-adbm; adalimumab-afzb; adalimumab-atto; adalimumab-bwwd; ado-trastuzumab emtansine; aflibercept; agalsidase beta; albiglutide; albumin chromated CR-51 serum; aldesleukin; alefacept; alemtuzumab; alglucosidase alfa; alirocumab; alteplase; anakinra; aprotinin; asfotas alfa; asparaginase; asparaginase Erwinia chrysanthemi; atezolizumab; avelumab; basiliximab; becaplermin; belatacept; belimumab; benralizumab; beractant; bevacizumab; bevacizumab-awwb; bevacizumab-bvzr; bezlotoxumab; blinatumomab; brentuximab vedotin; brodalumab; brolucizumab-dbll; burosumab-twza; calaspargase pegol-mknl; calfactant; canakinumab; caplacizumab-yhdp; capromab pendetide; cemiplimab-rwlc; cenegermin-bkbj ; cerliponase alfa; certolizumab pegol; cetuximab; choriogonadotropin alfa; chorionic gonadotropin; chymopapain; collagenase; collagenase Clostridium histolyticum; corticorelin ovine triflutate; crizanlizumab-tmca; daclizumab; daratumumab; daratumumab and hyaluronidase-fihj; darbepoetin alpha; denileukin diftitox; denosumab; desirudin; dinutuximab; dornase alfa; drotrecogin alfa; dulaglutide; dupilumab; durvalumab; ecallantide; eculizumab; efalizumab; elapegademase-lvlr; elosulfase alfa; elotuzumab; emapalumab-lzsg; emicizumab-kxwh; enfortumab vedotin-ejfv; epoetin alfa; epoetin alfa-epbx; erenumab-aooe; etanercept; etanercept-szzs; etanercept-ykro; evolocumab; fam-trastuzumab deruxetecan-nxki; fibrinolysin and desoxyribonuclease combined [bovine], with chloramphenicol; filgrastim; filgrastim-aafi; filgrastim-sndz; follitropin alfa; follitropin beta; fremanezumab-vfrm; galcanezumab-gnlm; galsulfase; gemtuzumab ozogamicin; glucarpidase; golimumab; guselkumab; hyaluronidase; hyaluronidase human; ibalizumab-uiyk; ibritumomab tiuxetan; idarucizumab; idursulfase; imiglucerase; incobotulinumtoxinA; inebilizumab-cdon; infliximab; infliximab-abda; infliximab-axxq; infliximab-dyyb; infliximab-Leydig 77541717qbtx; inotuzumab ozogamicin; insulin aspart; insulin aspart protamine and insulin aspart; insulin degludec; insulin degludec and insulin aspart; insulin degludec and liraglutide; insulin detemir; insulin glargine; insulin glargine and lixisenatide; insulin glulisine; insulin human; insulin isophane human; insulin isophane human and insulin human; insulin lispro; insulin lispro protamine and insulin lispro; insulin lispro-aabc; interferon alfa-2a; interferon alfa-2b; interferon alfacon-1; interferon alfa-n3 (human leukocyte derived); interferon beta- la; interferon beta- lb; interferon gamma-lb; ipilimumab; isatuximab-irfc; ixekizumab; lanadelumab-flyo; laronidase; lixisenatide; luspatercept-aamt; mecasermin; mecasermin rinfabate; menotropins; mepolizumab; methoxy polyethylene glycol-epoetin beta; metreleptin; mogamulizumab-kpkc; moxetumomab pasudotox-tdfk; muromanab-CD3; natalizumab; necitumumab; nivolumab; nofetumomab; obiltoxaximab; obinutuzumab; ocrelizumab; ocriplasmin; ofatumumab; olaratumab; omalizumab; onabotulinumtoxin A; oprelvekin; palifermin; palivizumab; pancrelipase; panitumumab; parathyroid hormone; pegademase bovine; pegaspargase; pegfilgrastim; pegfilgrastim-apgf; pegfilgrastim-bmez; pegfilgrastim-cbqv; pegfilgrastim-jmdb; peginterferon alfa-2a; peginterferon alfa-2a and ribavirin; peginterferon alfa-2b; peginterferon alfa-2b and ribavirin; peginterferon beta-la; pegloticase; pegvaliase-pqpz; pegvisomant; pembrolizumab; pertuzumab; polatuzumab vedotin-piiq; poractant alfa; prabotulinumtoxin A-xvfs; radiolabeled albumin technetium Tc-99m albumin colloid kit; ramucirumab; ranibizumab; rasburicase; ravulizumab-cwvz; raxibacumab; reslizumab; reteplase; rilonacept; rimabotulinumtoxinB; risankizumab-rzaa; rituximab; rituximab and hyaluronidase human; rituximab-abbs; rituximab-pvvr; romiplostim; romosozumab-aqqg; sacituzumab govitecan-hziy; sacrosidase; sargramostim; sarilumab; sebelipase alfa; secukinumab; siltuximab; somatropin; tagraxofusp-erzs; taliglucerase alfa; tbo-filgrastim; technetium 99m tc fanolesomab; tenecteplase; teprotumumab-trbw; tesamorelin acetate; thyrotropin alfa; tildrakizumab- asmn; tocilizumab; tositumomab and iodine 1-131 tositumomab; 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; Amj evita (adalimumab-atto); Dupixent (dupilumab); Fulphila (pegfilgrastim-jmdb); Haris (canakinumab); Ixifi (infliximab-qbtx); Lyumjev (insulin lispro-aabc); Nyvepria (pegfilgrastim-apgf); Ogivri (trastuzumab-dkst); Semglee (insulin glargine); UpliznaLeydig 77541718(inebilizumab-cdon); A.P.L. (chorionic gonadotropin); Abrilada (adalimumab-afzb); Aduhelm (aducanumab-avwa); Accretropin (somatropin); Actemra (tocilizumab); Acthrel (corticorelin ovine triflutate); Actimmune (interferon gamma- 1 b); Activase (alteplase); Adagen (pegademase bovine); Adakveo (crizanlizumab-tmca); Adbry (tralokinumab-ldrm); Adcetris (brentuximab vedotin); Adlyxin (lixisenatide); Admelog (insulin lispro); Afrezza (insulin human); Aimovig (erenumab-aooe); Ajovy (fremanezumab-vfrm); Aldurazyme (laronidase); Alferon N Injection (interferon alfa-n3 (human leukocyte derived)); Amevive (alefacept); Amphadase (hyaluronidase); Anthim (obiltoxaximab); Apidra (insulin glulisine); Aranesp (darbepoetin alpha); Arcalyst (rilonacept); Arzerra (ofatumumab); Asparlas (calaspargase pegol-mknl);Avastin (bevacizumab); Avonex (interferon beta- la); Avsola (infliximab-axxq); Basaglar (insulin glargine); Bavencio (avelumab); Benlysta (belimumab); Beovu (brolucizumab-dbll); Besponsa (inotuzumab ozogamicin); Besremi (ropeginterferon-alfa-2b-njft); Betaseron (interferon beta-lb); Bexxar (tositumomab and iodine 1-131 tositumomab); Beyfortus (nirsevimab-alip); Bimzelx (bimekizumab); Blincyto (blinatumomab); Botox (onabotulinumtoxinA); Botox Cosmetic (onabotulinumtoxinA); Bravelie (urofollitropin);Brineura (cerliponase alfa); Briumvi (ublituximab-xiiy); Cablivi (caplacizumab-yhdp); Campath (alemtuzumab); Cathflo Activase (alteplase); Cerezyme (imiglucerase); Chorionic Gonadotropin (chorionic gonadotropin); Chromalbin (albumin chromated CR-51 serum); Chymodiactin (chymopapain); Cimzia (certolizumab pegol); Cinqair (reslizumab); Columvi (glofitamab-gxbm); Cosentyx (secukinumab); Cotazym (pancrelipase); Creon (pancrelipase); 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 the preparation of technetium Tc-99m albumin aggregated); Dysport (abobotulinumtoxinA); Egrifta (tesamorelin acetate); Egrifta SV (tesamorelin acetate); Elahere (mirvetuximab soravtansine-gynx); Elaprase (idursulfase); Elase-chloromycetin (fibrinolysin and desoxyribonuclease combined [bovine], with chloramphenicol); Elelyso (taliglucerase alfa); Elfabrio (pegunigalsidase alfa-iwxj); Elitek (rasburicase); Elrexfio (elranatamab-bcmm); Elspar (asparaginase); Elzonris (tagraxofusp-erzs); Emgality (galcanezumab-gnlm); Empliciti (elotuzumab); Enbrel (etanercept); Enbrel Mini (etanercept); Enhertu (fam -trastuzumab deruxetecan-nxki); Enjaymo (sutimlimab-jome); EntyvioLeydig 77541719(vedolizumab); Epkinly (epcoritamab-bysp); Epogen / Procrit (epoetin alfa); Erbitux (cetuximab); Erelzi (etanercept-szzs); Erelzi Sensoready (etanercept-szzs); Erwinaze (asparaginase Erwinia chrysanthemi); Eticovo (etanercept-ykro); Evenity (romosozumab-aqqg); Evkeeza (evinacumab-dgnb), Extavia (interferon beta-lb); Eylea (aflibercept); Fabrazyme (agalsidase beta); Fasenra (benralizumab); Fiasp (insulin aspart); Follistim (follitropin beta); Follistim AQ (follitropin beta); Follistim AQ Cartridge (follitropin beta); Gamifant (emapalumab-lzsg); Gazyva (obinutuzumab); Genotropin (somatropin); Gonal-f (follitropin alfa); Gonal-f RFF (follitropin alfa); Gonal-f RFF RediJect (follitropin alfa); Granix (tbo-filgrastim); Hadlima (adalimumab-bwwd); Hemlibra (emicizumab-kxwh); Herceptin (trastuzumab); Herceptin Hylecta (trastuzumab and hyaluronidase-oysk); Herzuma (trastuzumab-pkrb); Humalog (insulin lispro); Humalog Mix 50 / 50 (insulin lispro protamine and insulin lispro); Humalog Mix 75 / 25 (insulin lispro protamine and insulin lispro); Humatrope (somatropin); Humegon (menotropins); Humira (adalimumab); Humulin 70 / 30 (insulin isophane human and insulin human); Humulin N (insulin isophane human); Humulin RU-100 (insulin human); Humulin RU-500 (insulin human); Hydase (hyaluronidase); Hylenex recombinant (hyaluronidase human); Hyrimoz (adalimumab-adaz); llumya (tildrakizumab-asmn); Imfinzi (durvalumab); Imjudo (tremelimumab-actl); Increlex (mecasermin); Infasurf (calfactant); Infergen (interferon alfacon-1); Inflectra (infliximab- dyyb); Intron A (interferon alfa-2b); Iplex (mecasermin rinfabate); Iprivask (desirudin); Jeanatope (kit for iodinated 1-125 albumin); Jemperli (dostarlimab-gxly); Jetrea (ocriplasmin); Jeuveau (prabotulinumtoxinA-xvfs); Kadcyla (ado-trastuzumab emtansine); Kalbitor (ecallantide);Kanjinti (trastuzumab-anns); Kanuma (sebelipase alfa); Kepivance (palifermin); Kevzara (sarilumab); Keytruda (pembrolizumab); Kimmtrak (tebentafusp-tebn); Kineret (anakinra); Kinlytic (urokinase); Krystexxa (pegloticase); Lamzede (velmanase alfa-tycv); Lantus (insulin glargine); Lartruvo (olaratumab); Lemtrada (alemtuzumab); Leqembi (lecanemab-irmb);Leukine (sargramostim); Levemir (insulin detemir); Libtayo (cemiplimab- rwlc); Loqtorzi (toripalimab-tpzi); Lucentis (ranibizumab); Lumizyme (alglucosidase alfa); Lumoxiti (moxetumomab pasudotox-tdfk); Lunsumio (mosunetuzumab-axgb); Macrotec (kit for the preparation of technetium Tc-99m albumin aggregated); Megatope (kit for iodinated 1-131 albumin); Menopur (menotropins); Mepsevii (vestronidase alfa-vjbk); Microlite (radiolabeled albumin technetium Tc-99m albumin colloid kit); Mircera (methoxy polyethylene glycol-epoetinLeydig 77541720beta); Mvasi (bevacizumab-awwb); Myalept (metreleptin); Mylotarg (gemtuzumab ozogamicin); Myobloc (rimabotulinumtoxinB); Myozyme (al glucosidase alfa); Myxredlin (insulin human); N / A (raxibacumab); Naglazyme (galsulfase); Natpara (parathyroid hormone); Neulasta (pegfilgrastim); Neulasta Onpro (pegfilgrastim); Neumega (oprelvekin); Neupogen (filgrastim); NeutroSpec (technetium 99m tc fanolesomab); Nexobrid (anacaulase-bcdb); Nexviazyme (avalglucosidase alfa-ngpt); Ngenla (somatrogon-ghla); Nivestym (filgrastim-aafi); Norditropin (somatropin); Novarel (chorionic gonadotropin); Novolin 70 / 30 (insulin isophane human and insulin human); Novolin N (insulin isophane human); Novolin R (insulin human); Novolog (insulin aspart); Novolog Mix 50 / 50 (insulin aspart protamine and insulin aspart); Novolog Mix 70 / 30 (insulin aspart protamine and insulin aspart); Nplate (romiplostim); Nucala (mepolizumab); Nulojix (belatacept); Nutropin (somatropin); Nutropin AQ (somatropin);Ocrevus (ocrelizumab); Omnitrope (somatropin); Omvoh (mirikizumab-mrkz); Oncaspar (pegaspargase); Ontak (denileukin diftitox); Ontruzant (trastuzumab-dttb); Opdivo (nivolumab); Opdualag (nivolumab and relatlimab-rmbw); Orencia (abatacept); Orthoclone OKT3 (muromanab-CD3); Ovidrel (choriogonadotropin alfa); Oxervate (cenegermin-bkbj); Padcev (enfortumab vedotin-ejfv); Palynziq (pegvaliase-pqpz); Pancreaze (pancrelipase); Pegasys (peginterferon alfa-2a); Pegasys Copegus Combination Pack (peginterferon alfa-2a and ribavirin); Pegintron (peginterferon alfa-2b); Peglntron / Rebetol Combo Pack (peginterferon alfa-2b and ribavirin); Pergonal (menotropins); Perjeta (pertuzumab); Pertzye (pancrelipase);Plegridy (peginterferon beta- la); Polivy (polatuzumab vedotin-piiq); Pombiliti (cipaglucosidase alfa-atga); Portrazza (necitumumab); Poteligeo (mogamulizumab-kpkc); Praluent (alirocumab); Praxbind (idarucizumab); Pregnyl (chorionic gonadotropin); Procrit (epoetin alfa); Proleukin (aldesleukin); Prolia (denosumab); ProstaScint (capromab pendetide); Pulmolite (kit for the preparation of technetium Tc-99m albumin aggregated); Pulmotech MAA (kit for the preparation of technetium Tc-99m albumin aggregated); Pulmozyme (domase alfa); Raptiva (efalizumab); Rebif (interferon beta- la); Reblozyl (luspatercept-aamt); Regranex (becaplermin); Remicade (infliximab); Renflexis (infliximab-abda); Reopro (abciximab); Repatha (evolocumab);Repronex (menotropins); Retacrit (epoetin alfa-epbx); Retavase (reteplase); Revcovi (elapegademase-lvlr); Rituxan (rituximab); Rituxan Hycela (rituximab and hyaluronidase human); Roferon-A (interferon alfa-2a); Rolvedon (eflapegrastim-xnst); Ruxience (rituximab-Leydig 77541721pvvr); Rybrevant (amivantamab-vmjw); Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn); Ryzneuta; Rystiggo (rozanolixizumab-noli); Ryzodeg 70 / 30 (insulin degludec and insulin aspart); Saizen (somatropin); Santyl (collagenase); Saphnelo (anifrolumab-fnia); Sarclisa (isatuximab-irfc); Serostim (somatropin); Siliq (brodalumab); Simponi (golimumab); Simponi Aria (golimumab); Simulect (basiliximab); Skyrizi (risankizumab-rzaa); Skytrofa (lonapegsomatropin-tcgd); Soliqua 100 / 33 (insulin glargine and lixisenatide); Soliris (eculizumab); Somavert (pegvisomant); Spevigo (spesolimab-sbzo); Stelara (ustekinumab); Strensiq (asfotas alfa); Sucraid (sacrosidase); Survanta (beractant); Susvimo (ranibizumab); Sylvant (siltuximab); Synagis (palivizumab); Takhzyro (lanadelumab-flyo); Taltz (ixekizumab); Talvey (talquetamab-tgvs); Tanzeum (albiglutide); Tecentriq (atezolizumab); Tecvayli (teclistamab-cqyv); Tepezza (teprotumumab-trbw); Tezspire (tezepelumab-ekko); Thyrogen (thyrotropin alfa); Tivdak (tisotumab vedotin-tftv); TNKase (tenecteplase); Toujeo (insulin glargine); Trasylol (aprotinin); Trazimera (trastuzumab-qyyp); Tremfya (guselkumab); Tresiba (insulin degludec); Trodelvy (sacituzumab govitecan-hziy); Trogarzo (ibalizumab-uiyk);Trulicity (dulaglutide); Truxima (rituximab-abbs); Tysabri (natalizumab); Tzield (teplizumab-mzwv); Udenyca (pegfilgrastim-cbqv); Ultomiris (ravulizumab-cwvz); Unituxin (dinutuximab); Vabysmo (faricimab-svoa); Vectibix (panitumumab); Veopoz (pozeilimab-bbfg); Verluma (nofetumomab); Vimizim (elosulfase alfa); Viokace (pancrelipase); Vitrase (hyaluronidase); Voraxaze (glucarpidase); VPRIV (velaglucerase alfa); Vyvgart (efgartigimod alfa-fcab); Vyvgart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc); Xenpozyme (olipudase alfa-rpcp); Xeomin (incobotulinumtoxinA); Xgeva (denosumab); Xiaflex (collagenase Clostridium histolyticum); Xigris (drotrecogin alfa); Xolair (omalizumab); Xultophy 100 / 3.6 (insulin degludec and liraglutide); Yervoy (ipilimumab); Zaltrap (Ziv-Aflibercept); Zarxio (filgrastim-sndz); Zenapax (daclizumab); Zenpep (pancrelipase); Zevalin (ibritumomab tiuxetan); Ziextenzo (pegfilgrastim-bmez); Zinbryta (daclizumab); Zinplava (bezlotoxumab); Zirabev (bevacizumab-bvzr);Zomacton (somatropin); Zorbtive / Serostim (somatropin); Zymfentra (infliximab); Zynlonta (locastuximab tesirine-lpyl); or Zynyz (retifanlimab-dlwr), or any combination thereof.

[0084] In an aspect, the pharmaceutical composition comprises a biologic drug selected from the group consisting of liraglutide, ranibizumab, and bevacizumab, or any combination thereof.Leydig 77541722

[0085] In another aspect, the pharmaceutical container is used to store a pharmaceutical composition that comprises a biologic for tumor necrosis, a factor-a (TNF) inhibitor, a interleukin inhibitor, a selective co-stimulation modulator, a glucagon-like peptide-1 (GLP-1) agonist or GLP-1 receptor agonist, an mRNA based formulation, an allergen, a tissue, a recombinant protein, a personalized medicine, a CAR-T cell thereapy medicine, a gene therapy medicine, or a biologic listed in the FDA Purple Book, or any combination thereof; in particular, the pharmaceutical composition comprises CAR-T cell therapy medicine or a gene therapy medicine.

[0086] The present invention further provides a method of storing a pharmaceutical agent in a primary container, the method comprising providing a primary container comprising a lumen defined in part by a wall, the wall having an inner surface facing the lumen and an outer surface, where the inner surface of the wall is coated with a zirconia coating and provides improved drug compatibility when compared with primary containers without a zirconia coating on the inner surface facing the lumen of the wall, and storing the pharmaceutical agent in the primary container.

[0087] The invention also provides a pharmaceutical container of any suitable packaging type where purity and stability of a stored biological material is critical for effectiveness, safety, and the like, in some aspects medical packaging in which an alumina barrier layer with an additional coating layer is applied may include a variety of vessels (e.g., including a lumen), such as vials, syringes (e.g., syringe barrels), blister packages, blood tubes, cartridges, bottles, stents, catheters, and the like.

[0088] In another aspect, the pharmaceutical container is a vial. For example, a vial will generally have an open mouth which may be sealed with a closure, wherein the contents of the vial may be accessed using a needle. Such vials are usually made of glass or plastic. In some aspects, the vial comprises polypropylene, cyclo olefin polymer, cyclo olefin co-polymer, polyethylene, or polyethylene terephthalate. In some aspects the vial comprises Type 1 Borosilicate Glass. Moreover, the closure of said vial may comprise an elastomer, such as vulcanized elastomers and styrenic block copolymer thermoplastic elastomers, but also natural rubber, acrylate-butadiene rubber, cis-polybutadiene, chloro or bromobutyl rubber, chlorinated polyethylene elastomers, polyalkylene oxide polymers, ethylene vinyl acetate, fluorosiliconeLeydig 77541723rubbers, hexafluoropropylene-vinylidene fluoride-tetrafluoroethylene terpolymers, butyl rubbers, polyisobutene, synthetic polyisoprene rubber, silicone rubbers, styrene-butadiene rubbers, tetrafluoroethylene propylene copolymers, thermoplastic copolyesters, thermoplastic elastomers, or a combination thereof.

[0089] In another aspect, the pharmaceutical container is a syringe. For example, a syringe will generally have a cylindrical barrel made of glass or plastic, wherein the barrel of the syringe can be operated with a plunger in order to eject the contents of the barrel via the nozzle of the syringe. In some aspects, the syringe is composed of cyclic olefin polymers (COP), cyclic olefin co-polymers (COC), acrylonitrile butadiene styrene (ABS), polycarbonate (PC), polyoxymethylene (POM), polystyrene (PS), polybutylene terephthalate (PBT), polypropylene (PP), polyethylene (PE), polyamide (PA), thermoplastic elastomer (TPE), or combinations thereof. In some aspects the syringe comprises Type 1 Borosilicate Glass. In some aspects, the plunger is composed of an elastomer, such as vulcanized elastomers and styrenic block copolymer thermoplastic elastomers, but also natural rubber, acrylate-butadiene rubber, cispolybutadiene, chloro or bromobutyl rubber, chlorinated polyethylene elastomers, polyalkylene oxide polymers, ethylene vinyl acetate, fluorosilicone rubbers, hexafluoropropylene-vinylidene fluoride-tetrafluoroethylene terpolymers, butyl rubbers, polyisobutene, synthetic polyisoprene rubber, silicone rubbers, styrene-butadiene rubbers, tetrafluoroethylene propylene copolymers, thermoplastic-copolyesters, thermo-plastic elastomers, or a combination thereof. In some aspects, the syringe is pre-filled with a pharmaceutical composition, allowing for the quick administration of an exact dose to a patient. In some aspects, the pharmaceutical container comprises a syringe and a cartridge, wherein the cartridge is a specialized container that can be inserted into a pen or an auto-injector to act as a pharmaceutical delivery device.

[0090] The zirconia barrier layer and coating may be applied to variety of materials used in medical packaging, such as glass, plastics (e.g., thermoplastics), rubbers, polymers, and ceramics. Accordingly, materials such as pharmaceuticals, vaccines, bodily fluids, compounds, biologies, and the like may be safely stored and transported in a variety of conditions while maintaining safety and effectiveness for longer than with prior uncoated barrier layers.Leydig 77541724

[0091] In some aspects, the pharmaceutical container contains an oxygen barrier layer disposed on an inner wall of the container and a pH-protective layer disposed on a gas barrier layer. In some aspects, the internal surface of the pharmaceutical container comprises a lumen.

[0092] In some aspects, the pharmaceutical container has a wall comprising a polymer. In some aspects, the wall of the pharmaceutical container can be composed of polypropylene, cyclo olefin polymer (COP), cyclo olefin co-polymer (COC), polyethylene, and / or polyethylene terephthalate. In some aspects, the cyclo olefin co-polymer can include copolymers of a cyclo olefin with ethylene or a-olefin, such as ethylene and norbomene or ethylene and tetracyclodecene. In some aspects, the cyclo olefin polymer or cyclo olefin copolymer comprises at least one cyclic olefin selected from cyclobutene, cyclopentene, cyclooctene, norbomene, 5-methylnorbornene, 3-methylnorbomene, ethylnorbornene, phenylnorbomene, dimethylnorbomene, diethylnorbornene, dicyclopentadiene, tetracycloclododecene, methyltetracyclododecene, 6-methylnorbornene, 6-ethylnorbornene, 6-n-butylnorbornene, 5-propylnorbornene, 1 -methylnorbornene, 7-methylnorbornene, 5,6-di-methylnorbornene, 5-phenylnorbornene, 5-benzylic norbomene, 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 aspects, the polymer is substantially free of voids, defects, or holes.

[0093] For example, some such polymers are commercially available from Avient Corporation as Edgetek™, Polyplastics as TOPAS® (COC), Zeonex as ZEONOR® (COP), and Mitsui as APEL™ (COC). In some aspects, the cyclo olefin copolymer is Edgetek™ 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,Leydig 77541725Topas), 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™ APL5014DP (COC, Mitsui Chemicals America), APEL™ APL5514ML (COC, Mitsui Chemicals America), APEL™ APL601 IT (COC, Mitsui Chemicals America), APEL™ APL6013T (COC, Mitsui Chemicals America), APEL™ APL6015T (COC, Mitsui Chemicals America), APEL™ APL6509T (COC, Mitsui Chemicals America), APEL™ APL8008T (COC, Mitsui Chemicals America), or combinations thereof.

[0094] In some aspects, the cyclo 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), ARTON FBK80 (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 combinations thereof.

[0095] The COC or COP can have a density of 1000 kg / m3to 1030 kg / m3according to ISO 1183 or ASTM D 792, and preferably 1010 kg / m3and 1020 kg / m3; a melt volume rate (MVR) according to ISO 1183 of 2 cm3 / 10 min to 20 cm3 / 10 min, preferably 4 cm3 / 10 min and 13 cm3 / 10 min; a melt flow rate (MFR, 260 °C, 2.16 kg) according to ISO 1183 of 1 g / 10 min to 20 g / 10 min, preferably 3.6 g / 10 min and 12 g / 10 min; a melt flow rate (MFR, 280 °C, 21.18 N) according to JIS K6719 of 1 g / 10 min to 20 g / 10 min, preferably 6 g / 10 min and 17 g / 10 min; and / or a melt flow index (MFI, 280 °C, 2.16 kg) according to ASTM D 1238 of 1 g / 10 min to 20 g / 10 min, preferably 6 g / 10 min and 17 g / 10 min.

[0096] The COC or COP can have a water absorption according to either ISO 62 or ASTM D570 of 0.03% or less, preferably 0.01% and 0.01% or less; a tensile modulus (1 mm / min) according to ISO 527-3 of 410 kpsi to 450 kpsi; preferably 420 kpsi and 440 kpsi; a flex modulusLeydig 77541726according to ASTM D790 of 2000 MPa to 2800 MPa, preferably 2200 MPa and 2600 MPa; a tensile stress at break (5 mm / min) according to ISO 527-3 of 8500 psi to 9300 psi, preferably 8700 psi and 9100 psi; a tensile strain at break (5 mm / min) according to ISO 527 of 2.3% to 2.8%, preferably 2.5% and 2.6%; a tensile strain at break (5 mm / min) according to ISO 527-3 of 5% to 25%, preferably 10% and 20%; a Charpy impact strength at 23 °C according to ISO 179 / leU of 6.5 ft-lbs / in2to 7.35 ft-lbs / in2, preferably 6.7 ft-lbs / in2and 7.1 ft-lbs / in2; a glass transition temperature (10 °C / min) according to ISO 11357-1,-2,-3 of 250 °F to 330 °F, preferably 288 °F and 316 °F; a glass transition temperature (Tg) according to JIS K7121 or ASTM E 1356 of 120 °C to 180 °C, preferably 136 °C and 163 °C; a degree of light transmittance according to ISO 13468-2 or ASTM DI 003 (3 mm) of 90% to 95%, preferably 91% and 92%; and / or a heat distortion temperature according to JIS D648 of 120 °C to 180 °C preferably 136 °C and 161 °C.

[0097] In some aspects, the the pharmaceutical container has a wall comprising glass. The glass used for a pharmaceutical container is typically, Type 1 borosilicate glass. Borosilicate glass is composed of 25-30% metals by mass. These metals include boron, aluminum, and iron. A pH protective layer is advantageuous for Type 1 borosilicate glass to prevent Si dissolution at high and low pH values and to prevent metal ions from leaching into the drug.

[0098] The barrier layer can be deposited using atomic layer deposition at a temperature of 200 °C or less, e.g., 195 °C or less, 190 °C or less, 185 °C or less, 180 °C or less, 175 °C or less, 170 °C or less, 165 °C or less, 160 °C or less, 155 °C or less, 150 °C or less, 145 °C or less, 140 °C or less, 135 °C or less, 130 °C or less, 125 °C or less, 120 °C or less, 115 °C or less, 110 °C or less, 105 °C or less, 100 °C or less, 95 °C or less, 90 °C or less, 85 °C or less, 80 °C or less, 75 °C or less, 70 °C or less, 65 °C or less, 60 °C or less, 55°C or less, 50 °C or less, 45 °C or less, or 40 °C or less. In some aspects, the gas barrier layer is applied by ALD at a temperature that is less than the Tg of the material comprising the pharmaceutical container.

[0099] The barrier layer, in an aspect has a thickness of 50 nm or less, e.g., 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 to 5 nm, e.g., 1 nm, 1.5 nm, 2 nm, 2.5 nm, 3 nm, 3.5 nm, 4 nm, 4.5 nm, or 5 nm. In certain aspects, each of the thin barrier layers a thickness of 1 to 3 nm or 3 to 5 nm.Leydig 77541727

[0100] The pharmaceutical container of the present invention may comprise a binding layer. In some aspects, the binding layer comprises alumina and is deposited between the barrier layer and the lumen. In certain aspects, the binding layer can be deposited using ALD at a temperature of 100 °C or less, e.g., 95 °C or less, 90 °C or less, 85 °C or less, 80 °C or less, 75 °C or less, 70 °C or less, 65 °C or less, 60 °C or less, 55°C or less, 50 °C or less, 45 °C or less, or 40 °C or less.

[0101] The metal oxide layer of the present invention is deposited using ALD at a temperature of 200 °C or less, e.g., 195 °C or less, 190 °C or less, 185 °C or less, 180 °C or less, 175 °C or less, 170 °C or less, 165 °C or less, 160 °C or less, 155 °C or less, 150 °C or less, 145 °C or less, 140 °C or less, 135 °C or less, 130 °C or less, 125 °C or less, 120 °C or less, 115 °C or less, 110 °C or less, 105 °C or less, 100 °C or less, 95 °C or less, 90 °C or less, 85 °C or less, 80 °C or less, 75 °C or less, 70 °C or less, 65 °C or less, 60 °C or less, 55°C or less, 50 °C or less, 45 °C or less, or 40 °C or less. In some aspects, the pH-protective layer is applied by ALD at a temperature that is less than the Tg of the material comprising the pharmaceutical container.

[0102] The zirconia layer of the present invention has a thickness of 50 nm or less, e.g., 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 to 5 nm, e.g., 1 nm, 1.5 nm, 2 nm, 2.5 nm, 3 nm, 3.5 nm, 4 nm, 4.5 nm, or 5 nm. In certain aspects, each of the thin barrier layers a thickness of 1 to 3 nm or 3 to 5 nm. In some aspects, the layer has a thickness of 40 to 50 nm, e.g., 41 nm, 42 nm, 43 nm, 44 nm, 45 nm, 46 nm, 47 nm, 48 nm, 49 nm, or 50 nm.

[0103] In an aspect, the pharmaceutical container has a top layer which comes into contact with the pharmaceutical composition comprises a layer ZrCh (top layer) as described above, and five pairs of alternating combination of AI2O3 and ZrCh layers, each layer being 3 nm or more, e.g., 3-5 nm, in thickness, with the top layer being about 20 - 50 nm, preferably less than 30 - 40 nm, in thickness.

[0104] In an aspect, the pharmaceutical container has a top layer which comes into contact with the pharmaceutical composition comprises a metal oxide layer (top layer) as described above, and five pairs of alternating combination of another metal oxide layer, each layer being 3 nm or more, e.g., 3-5 nm, in thickness, with the top layer being about 20 - 50 nm, preferably lessLeydig 77541728than 20 nm, in thickness. For example, the combination of metal oxide layers can be zirconia and alumina, zirconia and hafnium oxide, zirconia and tantalum oxide, zirconia and titanium oxide, and hafnia and aluminum oxide.

[0105] Any of the metal oxide coating can be amorphous or crystalline.

[0106] In an aspect, any of the metal oxide coating can be coated further with an organic coating layer, e.g., a polyphosphate layer or a polymer or oligomer of ethylene oxide or ethylene glycol. For example, a polyphosphate layer or a polymer or oligomer of ethylene oxide or ethylene glycol can be grafted onto the metal oxide layer. Any suitable method can be used to graft the polyphosphate layer. In an aspect, the grafting can be carried out by utilizing plasma activated vapor phase cyclic trimetaphosphate.

[0107] In an aspect, any of the metal oxide coating can be coated further with a polymer of hydroxyalkyl acrylate, for example, C1-C5 hydroxy alkyl acrylate. In a further aspect, the hydroxyalkyl acrylate can be hydroxyethyl acrylate and / or hydroxypropyl acrylate.

[0108] In an aspect, any of the metal oxide coating can be grafted with a polyphosphate grafted. For example, a polyphosphate could be grafted onto the metal oxide coating by utilizing vapor phase plasma activated cyclic trimetaphosphate.

[0109] In an aspect, the polyphosphate can be grafted onto the metal oxide coating by plasma activated vapor phase activated cyclic trimetaphosphate.

[0110] The thickess of the barrier layer can be measured by any suitable method. In some aspects, the thicknesses of the barrier layer and pH-protective layer are measured using transmission electron microscopy (TEM) or X-ray photoelectron spectroscopy (XPS).

[0111] The pharmaceutical container of the present application is suitable for holding an aqueous pharmaceutical composition. In some aspects, the pharmaceutical composition has a pH of from about 3 to about 12, e.g., 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 a peptide, protein, monoclonal antibody, or a blood constituent.EXAMPLESLeydig 77541729

[0112] The following examples illustrate aspects of the invention but should not be construed as in any way limiting its scope.EXAMPLE 1

[0113] This example illustrates a method of applying zirconia coatings to pharmaceutical containers. Zirconia coatings were applied to pharmaceutical containers containing an AI2O3 barrier layer that served as a model for the surface of a pharmaceutical container, which was a syringe. The atomic concentrations of Al, C, O, and Zr present in a layer deposited by the ALD process were measured by XPS. The results obtained at different locations, i.e., top, middle, and bottom region of the syringe are shown in Figs. 1-3. The zirconia layer was found to be present up to depth of about 80 nm in all three areas of the syringe.EXAMPLE 2

[0114] This example illustrates a surface property of the zirconia coated surface. Water contact angles were measured on zirconia films at different temperatures and at varying cycles, and the results obtained are shown in Fig. 4. All water contact angles of the samples were found to be larger than 90° regardless of the thickness and deposition temperatures, indicating that the zirconia thin films are relatively hydrophobic. For the same thickness of zirconia thin films, the water contact angles decreased with increasing coating temperatures. In other words, the zirconia thin films are more hydrophobic at lower temperatures. At each temperature, the thicker films would result in larger water contact angles, that is, the thicker films are more hydrophobic than the thinner ones at 50, 150, and 225 °C. The surface wettability is related to surface microstructures and surface functional groups. By varying the thickness (i.e., by the number of coating cycles), the surface water contact angle can be adjusted.EXAMPLE 3

[0115] This example shows expected or measured results of dissolution of a 2-ml borosilicate glass vial when exposed to a solution containing a drug at a pH of 9 and at a pH of 3 at 50 °C for 72 hours. The results show that the zirconia provides protection to the underlying alumina layer, and it is expected that the pharmaceutical composition contained in the vial will be more stable.Leydig 77541730

[0116] Fig. 5 depicts an expected dissolution profile of a comparative borosilicate glass vials without an aluminum oxide binder layer between the zirconia layer and the glass surface when exposed to a liquid at a pH of 9 at 50 °C for 72 hours. The amount of silicon leached from the vial in the presence of the zirconia protective layer is minimized.

[0117] Fig. 6 depicts an expected dissolution profile of borosilicate glass with an aluminum oxide binder layer between the zirconia layer and the glass surface, as another aspect of the invention, when exposed to a liquid at a pH of 3 at 50 °C for 72 hours. The amount of aluminum leached from the alumina binder layer in the presence of a zirconia protective layer is minimized.

[0118] Fig. 7 depicts the measured concentrations of Zr, O, C, and Al at the needle end portion of the syringe in accordance with another aspect of the invention.

[0119] Fig. 8 depicts the measured concentrations of Zr, O, C, and Al at the middle portion of the syringe in accordance with another aspect of the invention.

[0120] Fig. 9 depicts the measured concentrations of Zr, O, C, and Al at the bottom portion of the syringe in accordance with another aspect of the invention.

[0121] Fig. 10 depicts the contact angle of water measured on zirconia films. All the water contact angles of the samples are larger than 90° regardless of the thickness and deposition temperatures, indicating that the zirconia thin films are relatively hydrophobic. For the same thickness of zirconia thin films, the water contact angles decreased with the increasing temperatures. In other words, the zirconia thin films are more hydrophobic at lower temperatures. At each temperature, the thicker films would result in larger water contact angles, that is, the thicker films are more hydrophobic than the thinner ones at 50, 150, and 225 °C. The surface wettability is related to surface microstructures and surface functional groups.EXAMPLE 4

[0122] This Example depicts the height measurements of zirconia coatings prepared by ALD process, which had thicknesses of 17 nm in accordance with an aspect of the invention and 37 nm (comparative).Leydig 77541731Sample Sa (nm) Sq (nm) Sz (nm) Sample Sa (nm) Sq (nm) Sz (nm) B1-W2-3 0.62 0.81 9.4 B6-W1-2 0.79 1.11 17.9 B1-W2-4 0.57 0.76 8.4 B6-W1-3 0.71 0.98 13.9 B1-W2-5 0.64 0.83 8.7B6-W1-4 0.71 0.99 13.6Average Average Stnd. Dev. 0.03 0.03 0.4 Stnd. Dev.0.04 0.06 2.0

[0123] Fig. 11(A)-(C) depict height images of the surface of a 17 nm thick zirconium oxide coated surface in accordance with an aspect of the invention, which were obtained at three different locations of the surface. Fig. 12 depicts three height images of a comparative surface of a 37 nm thick zirconium oxide coated surface obtained at three different locations of the surface.EXAMPLE 5

[0124] This Example illustrates a configuration of a zirconia coated aluminum oxide surface in accordance with an aspect of the invention, wherein five AI2O3 and ZrCh layers, each 5 nm thick, were placed one on top of another, followed by a ZrCh layer of 15 nm being placed on to of the first 5 nm thick ZrCh layer, as illustrated in Fig. 13. The contact angle of the top layer surface was measured by five different persons, and the average value of the measurements was 81.2 dynes / cm.

[0125] Fig. 14 depicts a cross section TEM image of the configuration. Conical or tapered grain structure formed within the top ZrCh layer is revealed by the image. The bottom layer is amorphous as shown by the TEM image.EXAMPLE 6

[0126] This Example illustrates aspects of ZrCh surface functionalization for storing biological drugs in accordance with an aspect of the invention. The modification of a hydroxylated zirconium oxide ZrCh surface grown by ALD primarily relies on ligand exchange and substitution reactions with a gaseous metal precursor. A ligand is a molecule, ion, or atom that binds specifically to a larger molecule (usually a protein or metal ion) to initiate a biological response or form a coordination complex. Acting as signal messengers in cells or as electron donors in chemistry, they are essential for processes like neurotransmission, enzyme regulation,Leydig 77541732and immune responses. These reactions are the fundamental steps in the ALD half-cycle, leading to the growth of the ZrCh film or the functionalization of its surface.

[0127] Core Reaction Types include chemistries that utilize the surface hydroxyl (-OH) groups for modification or film growth include: Ligand Exchange and Substitution Reactions.

[0128] The substitution reaction is a defining reaction for the first half-cycle of ZrO2by ALD. The hydroxyl group on ZrO2(-OH) on the surface reacts with a gaseous zirconium precursor. The precursor’s ligand (L) is substituted by the surface oxygen, forming a new ZrO bond to the surface and releasing a gaseous by-product (HL). A common reaction, using a metal amide precursor like tetrakis(dimethylamino)zirconium(IV) (TDMAZr) or Zr(NMe2)4 with a hydroxylated surface, can be generalized as:ZrO2-OH + Zr(NMe2)4> ZrO2+ O + Zr(NMe2)3*+ HN (CH3)2.

[0129] In the above reaction scheme, * indicates the surface site. This reaction attaches a new zirconium species to the surface and releases dimethylamine as the by-product, a phenomenon confirmed by density functional theory calculations.

[0130] Metal halide precursors, such as zirconium tetrachloride ZrCL, also react via an exchange mechanism with the surface hydroxyls, releasing hydrochloric acid HC1 as the byproduct.

[0131] Dehydration / Condensation Reactions: The surface hydroxyl groups can react with each other to form a condensed surface and release water, which decreases the total hydroxyl density on the surface. This process is more prominent at higher temperatures.

[0132] Common Precursor Chemistries: The type of precursor dictates the specific chemistry and the nature of the reaction products, for example: Metal Amides (e.g., TDMAZr): These are highly reactive toward hydroxylated surfaces and are often preferred for low-temperature ALD processes (e.g., 150-250°C), as their bonds ZrN are weaker than metal-halide bonds.

[0133] Another example is metal halides (e.g., ZrCh): They react vigorously with -OH groups, releasing HC1. These often require higher temperatures and can sometimes lead to greater film crystallinity and surface roughness.Leydig 77541733

[0134] Cyclopentadi enyl-based Precursors (e.g., Zr(MeCp)2 , Me-O-Me): These use different ligands (such as methylcyclopentadienyl, methyl, and methoxy) that combine with surface protons and desorb during the ALD process, with the kinetics determined by the relative bond strengths.

[0135] While ALD itself is a gas-phase process, an already formed hydroxylated ZrCh surface can be further functionalized using various wet chemistries, primarily relying on the high reactivity of the surface hydroxyl -OH groups.

[0136] In a further example, wet chemistries can be utilized, e.g., an effective wet chemistries for modifying the ZrO2 surface are based on organosilane and phosphonic acid coupling agents.

[0137] Silanization using organosilanes: This is one of the most widely used methods for functionalizing metal oxide surfaces. The chemistry is as follows: Organosilane molecules, typically alkoxysilanes R-Si-OR? or chlorosilanes R-SiCh, react with the surface -OH groups in a liquid solvent.

[0138] The reaction steps include hydrolysis, wherein alkoxysilanes first react with trace water (either in the solvent or on the surface) to form reactive silanol RSi(OH)s species, and condensation / Covalent Bonding, wherein the silanol groups react with the ZrO2 surface -OH groups via a condensation reaction, forming stable zirconium-oxygen-silicon ZrO-Si covalent bonds and releasing water or alcohol, that is: ZrO2(-OH) + HOsSiR > ZrO2-O-Si(OH)2+R+H2O.

[0139] The functionalization takes place as follows. The R-group on the silane dictates the final surface functionality, allowing the attachment of chemical groups like amine NH2, epoxide, thiol SH, or fluorocarbon chains. As an example of a precursor: 3 -aminopropyltri ethoxy silane (APTES) is used to introduce primary amine groups.

[0140] Phosphonylation can be carried out using phosphonic acids. Phosphonic acids (R-PO3H2) are exceptional ligands for ZrCh and other high-k metal oxides, often forming robust self-assembled monolayers (SAMs). The chemistry is as follows: The phosphonic acid head group exhibits strong, direct coordination with the surface Zr atoms. Bonding takes place as follows: Phosphonic acids react with the surface -OH groups and adjacent Zr atoms to form highly stable, often bidentate or tridentate, zirconium-phosphonate complexes Zr-O-P. ThisLeydig 77541734bonding is typically stronger than the siloxane bond, offering higher thermal and chemical stability. During functionalization, the phosphonic acid group deprotonates and binds to the surface Zr atoms, displacing the surface -OH groups and creating a stable anchoring layer:ZrO2- Zr-(OH)n+ R-PO3H2 > ZrO2- Zr-O2(PR)m + nH2O.

[0141] Functionalization: As with silanes, the R-group can be tailored to introduce various functionalities (e.g., long alkyl chains for hydrophobicity, aromatic rings for chemical resistance).

[0142] Carboxylic acids can also be used especially in non-polar solvents, though the resulting bond strength can be weaker than phosphonates. The chemistry as follows. They react with the surface -OH groups or coordinate directly with the surface Zr atoms, forming a zirconium carboxylate linkage (Zr-O-CO-R). The binding is often rapid and can be a good method for physisorption or forming weaker layers compared to phosphonates.EXAMPLE 7

[0143] This Example illustrates a method of preparing zirconia coated container in accordance with an aspect of the invention. The ALD hardware and processes described in US12303461B1 and US12109173 (and references therein) are utilized. Thus, a container comprising a zirconia (ZrCh) coating on the inner container surface is exposed to a vapor concentration of ethylene oxide (EO) [20 to 40 mmol / cm2] vapor to sufficient to react with the zirconia surface and polymerize, providing a dense packed PEG oligomer (equivalent weight approximately to a PEG-400). EO vapor concentration and time are important process parameters. The presence of the grafted surface PEG moiety can be characterized with XPS, FT-IR, AFM, and water contact angle measurement.

[0144] The reaction scheme is illustrated in Fig. 37. Pegylation with Ethylene Oxide (EO) Vapor.EXAMPLE 8

[0145] This Example illustrates a method of preparing zirconia coated container in accordance with an aspect of the invention. Utilizing the ALD hardware and processes described in US12303461B1 and US12109173 (and references therein), a container comprising a zirconiaLeydig 77541735(ZrCh) coating on the inner container surface, wherein the Zr surface comprises an unoxidized ZrCh precursor (e.g. [surface-O-(Zr(NR2)x]y) bound to the ZrCh surface). This surface is exposed to (a) a vapor concentration of boron trifluoride (BF3) [10 to 20 mmol / cm2] sufficient react with the amine (-NR.2) moieties on the surface, followed by (b) a vapor concentration of ethylene oxide (EO) [20 to 40 mmol / cm2] vapor sufficient displace the amine / boron surface complexes surface and polymerize providing a dense packed PEG oligomer (equivalent weight approximately to a PEG-400). See Fig. 37. EO vapor concentration and time are the key process parameters. The presence of the surface PEG moiety is characterized with XPS, FT-IR, AFM, and water contact angle measurement.EXAMPLE 9

[0146] Utilizing ALD hardware and processes described in US12303461B1 and US12109173 (and references therein), a container comprising a zirconia (ZrO2) coating on the inner container surface, wherein the Zr surface comprises an unoxidized ZrO2 precursor (e.g. [surface-O-(Zr(NR2)x]y) bound to the ZrO2 surface). This surface is exposed to (a) a vapor concentration of boron trifluoride (BF3) [10 to 20 mmol / cm2] sufficient react with the amine (-NR2) moieties on the surface, followed by (b) a vapor concentration of ethylene oxide (EO) [20 to 40 mmol / cm2] vapor sufficient displace the amine / boron surface complexes surface and polymerize providing a dense packed PEG oligomer (equivalent weight approximately to a PEG-400). See Fig. 37. EO vapor concentration and time are key process parameters. The presence of the surface PEG moiety can be characterized with XPS, FT-IR, AFM, and water contact angle measurement.EXAMPLE 10

[0147] This Example illustrates a further method of preparing zirconia (ZrO2) coating on the inner container surface. The container surface is exposed to (a) a vapor concentration [4 mmol / cm2] of trimethoxy(aminopropyl)silane [(MeO^S^CFLCFECFENFL)] sufficient to react with surface oxygen atoms, followed by (b) a vapor concentration of boron trifluoride (BF3) [10 to 20 mmol / cm2] sufficient react with the amine (-NH2) moieties on the surface, followed by (c) a vapor concentration [20 to 40 mmol / cm2] of ethylene oxide (EO) to sufficient displace the amine / boron surface complexes surface and polymerize providing a dense packed PEG oligomerLeydig 77541736(equivalent weight approximately to a PEG-400). See Fig. 37. EO vapor concentration and time are key process parameters. The presence of the surface PEG moiety can be characterized with XPS, FT-IR, AFM, and water contact angle measurement.

[0148] In Examples 8-10, the bonding of EO to metal oxide surfaces is via metal oxide surface oxygen atoms. Further, in Example 8- Treatment is on a ALD finished ZrO2 surface is essentially comprised of polar Zr(4+) atoms in a matrix of Oxygen (2-) atoms, the former acting as a Lewis acid site which can activate the EO reactant toward reaction with an adjacent oxygen atom, either as a dangling -OH moiety or complexed -O- moiety. If required, Zr-OH surface formation can be accomplished via numerous plasma activation methods. This approach utilizes only EO monomer after the ALD oxidation cycle (water, air, oxygen, ozone) of the bound metal oxide precursor. See US US 8,609,193 B2.

[0149] Example 9 - This example leverages the presence of the bound, unoxidized metal oxide surface precursor to react with only EO monomer BEFORE the ALD oxidation cycle (water, air, oxygen, ozone) of the bound metal oxide precursor.

[0150] Example 10 also example leverages the presence of the bound, unoxidized metal oxide surface precursor, with the addition of BF3 (a Lewis Acid), to complex with the amine of the unoxidized metal oxide surface precursor, further activating the site for oxygen reaction with EO monomer.EXAMPLE 11

[0151] This Example illustrates a method of preparing zirconia (ZrOs) coating on the inner container surface. The example incorporates a silane amine bridging agent, with EO bonding to the trimethylene bridging agent moiety. The degree of EO surface grafting (and subsequent PEG growth) will be a function of degree of crystallinity (amorphous over crystalline surface is good), dangling hydroxyls [-O-Zr(OH)i-3] versus -Zr-O-Zr- moieties (lower reaction temperatures preferred) and lower surface roughness (surface access).

[0152] Utilizing ALD hardware and processes described in US12303461B1 and US12109173 (and references therein), a container comprising a zirconia (ZrO ) coating on theLeydig 77541737inner container surface is exposed to (a) a vapor concentration [4 mmol / cm2] of trimethoxy(aminopropyl)silane [(MeO)3Si(CH2CH2CH2NH2)] sufficient to react with surface oxygen atoms, followed by (b) a vapor concentration of boron trifluoride (BF3) [10 to 20 mmol / cm2] sufficient react with the amine (-NH2) moieties on the surface, followed by (c) a vapor concentration [20 to 40 mmol / cm2] of ethylene oxide (EO) to sufficient displace the amine / boron surface complexes surface and polymerize providing a dense packed PEG oligomer (equivalent weight approximately to a PEG-400). EO vapor concentration and time are key process parameters. The presence of the surface PEG moiety can be characterized with XPS, FT-IR, AFM, and water contact angle measurement. Example 11 mimics the pror repulsion of biocess of glass (SiO2) surface activation with a reactive amine-functional siloxane coupling agent [trimethoxy(aminopropyl)silane [(MeO)3Si(CH2CH2CH2NH2)] with the methoxysilane moieties exchanging with the surface metal hydroxyls (Zr-O-Si-), followed by BF3 amine activation of the amine and EO grafting / oligomerization. See, e.g., “Vapor Deposited Poly(ethylene glycol) Films for Surface Modification of Microfluidic Systems”, Ketul C. Popata et al., Presented at Lab Automation 2002, Palm Springs, CA.EXAMPLE 12

[0153] This Example illustrates additional methods of incorporating hydrophilic surfaces. A-potential vapor phase hydroxy(ethyl, propyl) acrylate (HEA, HP A) polymerization grafting to metal oxide surfaces (see US 20240353400 Al):HO O[CH2CH2(CO2CH2CH2OH)]n j + HEA (vapor) ■Coating -[O-Zr-O-Zr-O]- -[O-Zr-O-Zr-OJ- surface Plasma activationIn a further aspect, vapor phase polyphosphate grafting to metal oxide can be utilized ; see, e.g., US 20210129179. In another aspect, vapor phase cyclic trimetaphosphate, produced from decomposition of ammonium polyphosphate, can be utilized:Leydig 77541738HO O' [(P(«O)(OH)-O]0H * Cyclic (HPO3)3(vapor)Coating -[O-Zr-O-Zr-O]- ™A -[O-Zr-O-Zr-OJ- surface Plasma activationSee, e.g., (1) Rafal Franski, et al., Gas phase conversion of triphosphate to trimetaphosphate Journal of Mass Spectrometry, Volume 51, Issue 2 pp. 165-168 (2016) and (2) https: / / chemistry-europe.onlinelibrary.wiley.com / doi / epdf / 10.1002 / chem.201904433.

[0154] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0155] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.Leydig 77541739

[0156] Preferred aspects of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred aspects may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein.Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

Leydig 77541740CLAIMS:

1. A primary container for pharmaceutical packaging comprising a lumen defined in part by a wall, the wall having an inner surface facing the lumen and an outer surface, where the inner surface of the wall is coated with a metal oxide coating and provides improved drug compatibility when compared with primary containers without a metal oxide coating on the inner surface facing the lumen of the wall, wherein the metal oxide is an oxide of a metal selected from the group consisting of zirconium, hafnium, titanium, tantalum, aluminum, and combinations thereof.

2. The primary container of claim 1, wherein the metal of the metal oxide is zirconium.

3. The primary container of claim 1, wherein the metal of the metal oxide is hafnium.

4. The primary container of any one of claims 1-3, wherein the coating is one applied by an atomic layer deposition (ALD) process.

5. The primary container of any one of claims 1-4, which is a vial, syringe, cartridge, or ampule.

6. The primary container of any one of claims 1-5, where the container is made of glass.

7. The primary container of claim 6, wherein the glass container is made of type 1 borosilicate glass.

8. The primary container of any one of claims 1-5, wherein the container is made of a plastic.

9. The primary container of claim 8, wherein the plastic is cyclo olefin copolymer, cyclo olefin polymer, polypropylene, polyethylene, or any combination thereof.

10. The primary container of any one of claims 1-9, wherein the drug is a biologic.Leydig 7754174111. The primary container of claim 10, wherein the biologic drug is a protein.

12. The primary container of claim 11, wherein the protein is a therapeutic, a vaccine, a monoclonal antibody, or a derivative thereof.

13. The primary container according to any one of claims 1-12, which exhibits a diminished surface adsorption of a protein and / or a lower extent of irreversibility of surface adsorption of a protein when compared to glass or plastic containers without the metal oxide coating.

14. The primary container according to any one of claims 1-13, that exhibits reduced aggregation and / or other modes of protein deterioration upon lyophilization when compared to glass or plastic containers without the metal oxide coating.

15. The primary container according to any one of claims 1-14, that exhibits greater resistance to protein degradation induced by an internal or external stress.

16. The primary container according to claim 14, that exhibits greater resistance to protein degradation induced by mechanical agitation, thermal stress, or freeze-thaw cycle.

17. The primary container according to any one of claims 1-14, which imparts enhanced storage stability shelf-life to the protein, when compared to a glass or plastic container without the metal oxide coating.

18. The primary container according to any one of claims 1-14, which exhibits reduced drug loss due to proteins adhering to the container wall when compared to glass or plastic container without the metal oxide coating.

19. The primary container according to any one of claims 1-14, which exhibits reduced number of sub-visible particles of denatured proteins that dislodge from the container wall when compared to the number of sub-visible particles of glass or plastic containers which have not been coated with the metal oxide coating, tested by US Pharmacopeia 788 / 789.Leydig 7754174220. The primary container according to any one of claims 1-19, which contains a drug product which is a pharmaceutical composition that comprises a peptide, protein, monoclonal antibody, or a constituent of blood.

21. The primary container of any one of claims 1-20, wherein the pharmaceutical composition comprises a biologic drug selected from abatacept; abciximab; abobotulinumtoxinA; adalimumab; adalimumab-adaz; adalimumab-adbm; adalimumab-afzb; adalimumab-atto; adalimumab-bwwd; ado-trastuzumab emtansine; aflibercept; agalsidase beta; albiglutide; albumin chromated CR-51 serum; aldesleukin; alefacept; alemtuzumab; alglucosidase alfa; alirocumab; alteplase; anakinra; aprotinin; asfotas alfa; asparaginase; asparaginase Erwinia chrysanthemi; atezolizumab; avelumab; basiliximab; becaplermin; belatacept; belimumab; benralizumab; beractant; bevacizumab; bevacizumab-awwb; bevacizumab-bvzr; bezlotoxumab; blinatumomab; brentuximab vedotin; brodalumab; brolucizumab-dbll; burosumab-twza; calaspargase pegol-mknl; calfactant; canakinumab; caplacizumab-yhdp; capromab pendetide; cemiplimab-rwlc; cenegermin-bkbj ; cerliponase alfa; certolizumab pegol; cetuximab; choriogonadotropin alfa; chorionic gonadotropin; chymopapain; collagenase; collagenase Clostridium histolyticum; corticorelin ovine triflutate; crizanlizumab-tmca; daclizumab; daratumumab; daratumumab and hyaluronidase-fihj; darbepoetin alpha; denileukin diftitox; denosumab; desirudin; dinutuximab; dornase alfa; drotrecogin alfa; dulaglutide; dupilumab; durvalumab; ecallantide; eculizumab; efalizumab; elapegademase-lvlr; elosulfase alfa; elotuzumab; emapalumab-lzsg; emicizumab-kxwh; enfortumab vedotin-ejfv; epoetin alfa; epoetin alfa-epbx; erenumab-aooe; etanercept; etanercept-szzs; etanercept-ykro; evolocumab; fam-trastuzumab deruxetecan-nxki; fibrinolysin and desoxyribonuclease combined [bovine], with chloramphenicol; filgrastim; filgrastim-aafi; filgrastim-sndz; follitropin alfa; follitropin beta; fremanezumab-vfrm; galcanezumab-gnlm; galsulfase; gemtuzumab ozogamicin; glucarpidase; golimumab; guselkumab; hyaluronidase; hyaluronidase human; ibalizumab-uiyk; ibritumomab tiuxetan; idarucizumab; idursulfase; imiglucerase; incobotulinumtoxinA; inebilizumab-cdon; infliximab; infliximab-abda; infliximab-axxq; infliximab-dyyb; infliximab-qbtx; inotuzumab ozogamicin; insulin aspart; insulin aspart protamine and insulin aspart; insulin degludec; insulin degludec and insulin aspart; insulin degludec and liraglutide; insulin detemir; insulin glargine; insulin glargine and lixisenatide; insulin glulisine; insulin human; insulinLeydig 77541743isophane human; insulin isophane human and insulin human; insulin lispro; insulin lispro protamine and insulin lispro; insulin lispro-aabc; interferon alfa-2a; interferon alfa-2b; interferon alfacon-1; interferon alfa-n3 (human leukocyte derived); interferon beta- la; interferon beta- lb; interferon gamma-lb; ipilimumab; isatuximab-irfc; ixekizumab; lanadelumab-flyo; laronidase; lixisenatide; luspatercept-aamt; mecasermin; mecasermin rinfabate; menotropins; mepolizumab; methoxy polyethylene glycol-epoetin beta; metreleptin; mogamulizumab-kpkc; moxetumomab pasudotox-tdfk; muromanab-CD3; natalizumab; necitumumab; nivolumab; nofetumomab; obiltoxaximab; obinutuzumab; ocrelizumab; ocriplasmin; ofatumumab; olaratumab; omalizumab; onabotulinumtoxinA; oprelvekin; palifermin; palivizumab; pancrelipase; panitumumab; parathyroid hormone; pegademase bovine; pegaspargase; pegfilgrastim; pegfilgrastim-apgf; pegfilgrastim-bmez; pegfilgrastim-cbqv; pegfilgrastim-jmdb; peginterferon alfa-2a; peginterferon alfa-2a and ribavirin; peginterferon alfa-2b; peginterferon alfa-2b and ribavirin; peginterferon beta-la; pegloticase; pegvaliase-pqpz; pegvisomant; pembrolizumab; pertuzumab; polatuzumab vedotin-piiq; poractant alfa; prabotulinumtoxinA-xvfs; radiolabeled albumin technetium Tc-99m albumin colloid kit; ramucirumab; ranibizumab; rasburicase; ravulizumab-cwvz; raxibacumab; reslizumab; reteplase; rilonacept; rimabotulinumtoxinB; risankizumab-rzaa; rituximab; rituximab and hyaluronidase human; rituximab-abbs; rituximab-pvvr; romiplostim; romosozumab-aqqg; sacituzumab govitecan-hziy; sacrosidase; sargramostim; sarilumab; sebelipase alfa; secukinumab; siltuximab; somatropin; tagraxofusp-erzs; taliglucerase alfa; tbo-filgrastim; technetium 99m tc fanolesomab; tenecteplase; teprotumumab-trbw; tesamorelin acetate; thyrotropin alfa; tildrakizumab- asmn; tocilizumab; tositumomab and iodine 1-131 tositumomab; 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; Amj evita (adalimumab-atto); Dupixent (dupilumab); Fulphila (pegfilgrastim-jmdb); Haris (canakinumab); Ixifi (infliximab-qbtx); Lyumjev (insulin lispro-aabc); Nyvepria (pegfilgrastim-apgf); Ogivri (trastuzumab-dkst); Semglee (insulin glargine); Uplizna (inebilizumab-cdon); A.P.L. (chorionic gonadotropin); Abrilada (adalimumab-afzb); Aduhelm (aducanumab-avwa); Accretropin (somatropin); Actemra (tocilizumab); Acthrel (corticorelin ovine triflutate); Actimmune (interferon gamma-lb); Activase (alteplase); Adagen (pegademaseLeydig 77541744bovine); Adakveo (crizanlizumab-tmca); Adbry (tralokinumab-ldrm); Adcetris (brentuximab vedotin); Adlyxin (lixisenatide); Admelog (insulin lispro); Afrezza (insulin human); Aimovig (erenumab-aooe); Ajovy (fremanezumab-vfrm); Aldurazyme (laronidase); Alferon N Injection (interferon alfa-n3 (human leukocyte derived)); Amevive (alefacept); Amphadase (hyaluronidase); Anthim (obiltoxaximab); Apidra (insulin glulisine); Aranesp (darbepoetin alpha); Arcalyst (rilonacept); Arzerra (ofatumumab); Asparlas (calaspargase pegol-mknl);Avastin (bevacizumab); Avonex (interferon beta- la); Avsola (infliximab-axxq); Basaglar (insulin glargine); Bavencio (avelumab); Benlysta (belimumab); Beovu (brolucizumab-dbll); Besponsa (inotuzumab ozogamicin); Besremi (ropeginterferon-alfa-2b-njft); Betaseron (interferon beta-1 b); Bexxar (tositumomab and iodine 1-131 tositumomab); Beyfortus (nirsevimab-alip); Bimzelx (bimekizumab); Blincyto (blinatumomab); Botox (onabotulinumtoxinA); Botox Cosmetic (onabotulinumtoxinA); Bravelle (urofollitropin);Brineura (cerliponase alfa); Briumvi (ublituximab-xiiy); Cablivi (caplacizumab-yhdp); Campath (alemtuzumab); Cathflo Activase (alteplase); Cerezyme (imiglucerase); Chorionic Gonadotropin (chorionic gonadotropin); Chromalbin (albumin chromated CR-51 serum); Chymodiactin (chymopapain); Cimzia (certolizumab pegol); Cinqair (reslizumab); Columvi (glofitamab-gxbm); Cosentyx (secukinumab); Cotazym (pancrelipase); Creon (pancrelipase); 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 the preparation of technetium Tc-99m albumin aggregated); Dysport (abobotulinumtoxinA); Egrifta (tesamorelin acetate); Egrifta SV (tesamorelin acetate); Elahere (mirvetuximab soravtansine-gynx); Elaprase (idursulfase); Elase-chloromycetin (fibrinolysin and desoxyribonuclease combined [bovine], with chloramphenicol); Elelyso (taliglucerase alfa); Elfabrio (pegunigalsidase alfa-iwxj); Elitek (rasburicase); Elrexfio (elranatamab-bcmm); Elspar (asparaginase); Elzonris (tagraxofusp-erzs); Emgality (galcanezumab-gnlm); Empliciti (elotuzumab); Enbrel (etanercept); Enbrel Mini (etanercept); Enhertu (fam -trastuzumab deruxetecan-nxki); Enjaymo (sutimlimab-jome); Entyvio (vedolizumab); Epkinly (epcoritamab-bysp); Epogen / Procrit (epoetin alfa); Erbitux (cetuximab); Erelzi (etanercept-szzs); Erelzi Sensoready (etanercept-szzs); Erwinaze (asparaginase Erwinia chrysanthemi); Eticovo (etanercept-ykro); Evenity (romosozumab-aqqg); Evkeeza (evinacumab-Leydig 77541745dgnb), Extavia (interferon beta-lb); Eylea (aflibercept); Fabrazyme (agalsidase beta); Fasenra (benralizumab); Fiasp (insulin aspart); Follistim (follitropin beta); Follistim AQ (follitropin beta); Follistim AQ Cartridge (follitropin beta); Gamifant (emapalumab-lzsg); Gazyva (obinutuzumab); Genotropin (somatropin); Gonal-f (follitropin alfa); Gonal-f RFF (follitropin alfa); Gonal-f RFF RediJect (follitropin alfa); Granix (tbo-filgrastim); Hadlima (adalimumab-bwwd); Hemlibra (emicizumab-kxwh); Herceptin (trastuzumab); Herceptin Hylecta (trastuzumab and hyaluronidase-oysk); Herzuma (trastuzumab-pkrb); Humalog (insulin lispro); Humalog Mix 50 / 50 (insulin lispro protamine and insulin lispro); Humalog Mix 75 / 25 (insulin lispro protamine and insulin lispro); Humatrope (somatropin); Humegon (menotropins); Humira (adalimumab); Humulin 70 / 30 (insulin isophane human and insulin human); Humulin N (insulin isophane human); Humulin RU-100 (insulin human); Humulin RU-500 (insulin human); Hydase (hyaluronidase); Hylenex recombinant (hyaluronidase human); Hyrimoz (adalimumab-adaz); llumya (tildrakizumab-asmn); Imfinzi (durvalumab); Imjudo (tremelimumab-actl); Increlex (mecasermin); Infasurf (calfactant); Infergen (interferon alfacon-1); Inflectra (infliximab- dyyb); Intron A (interferon alfa-2b); Iplex (mecasermin rinfabate); Iprivask (desirudin); Jeanatope (kit for iodinated 1-125 albumin); Jemperli (dostarlimab-gxly); Jetrea (ocriplasmin); Jeuveau (prabotulinumtoxinA-xvfs); Kadcyla (ado-trastuzumab emtansine); Kalbitor (ecallantide);Kanjinti (trastuzumab-anns); Kanuma (sebelipase alfa); Kepivance (palifermin); Kevzara (sarilumab); Keytruda (pembrolizumab); Kimmtrak (tebentafusp-tebn); Kineret (anakinra); Kinlytic (urokinase); Krystexxa (pegloticase); Lamzede (velmanase alfa-tycv); Lantus (insulin glargine); Lartruvo (olaratumab); Lemtrada (alemtuzumab); Leqembi (lecanemab-irmb);Leukine (sargramostim); Levemir (insulin detemir); Libtayo (cemiplimab- rwlc); Loqtorzi (toripalimab-tpzi); Lucentis (ranibizumab); Lumizyme (alglucosidase alfa); Lumoxiti (moxetumomab pasudotox-tdfk); Lunsumio (mosunetuzumab-axgb); Macrotec (kit for the preparation of technetium Tc-99m albumin aggregated); Megatope (kit for iodinated 1-131 albumin); Menopur (menotropins); Mepsevii (vestronidase alfa-vjbk); Microlite (radiolabeled albumin technetium Tc-99m albumin colloid kit); Mircera (methoxy polyethylene glycol-epoetin beta); Mvasi (bevacizumab-awwb); Myalept (metreleptin); Mylotarg (gemtuzumab ozogamicin); Myobloc (rimabotulinumtoxinB); Myozyme (alglucosidase alfa); Myxredlin (insulin human); N / A (raxibacumab); Naglazyme (galsulfase); Natpara (parathyroid hormone); NeulastaLeydig 77541746(pegfilgrastim); Neulasta Onpro (pegfilgrastim); Neumega (oprelvekin); Neupogen (filgrastim); NeutroSpec (technetium 99m tc fanolesomab); Nexobrid (anacaulase-bcdb); Nexviazyme (avalglucosidase alfa-ngpt); Ngenla (somatrogon-ghla); Nivestym (filgrastim-aafi); Norditropin (somatropin); Novarel (chorionic gonadotropin); Novolin 70 / 30 (insulin isophane human and insulin human); Novolin N (insulin isophane human); Novolin R (insulin human); Novolog (insulin aspart); Novolog Mix 50 / 50 (insulin aspart protamine and insulin aspart); Novolog Mix 70 / 30 (insulin aspart protamine and insulin aspart); Nplate (romiplostim); Nucala (mepolizumab); Nulojix (belatacept); Nutropin (somatropin); Nutropin AQ (somatropin);Ocrevus (ocrelizumab); Omnitrope (somatropin); Omvoh (mirikizumab-mrkz); Oncaspar (pegaspargase); Ontak (denileukin diftitox); Ontruzant (trastuzumab-dttb); Opdivo (nivolumab); Opdualag (nivolumab and relatlimab-rmbw); Orencia (abatacept); Orthoclone OKT3 (muromanab-CD3); Ovidrel (choriogonadotropin alfa); Oxervate (cenegermin-bkbj); Padcev (enfortumab vedotin-ejfv); Palynziq (pegvaliase-pqpz); Pancreaze (pancrelipase); Pegasys (peginterferon alfa-2a); Pegasys Copegus Combination Pack (peginterferon alfa-2a and ribavirin); Pegintron (peginterferon alfa-2b); Peglntron / Rebetol Combo Pack (peginterferon alfa-2b and ribavirin); Pergonal (menotr opins); Perjeta (pertuzumab); Pertzye (pancrelipase);Plegridy (peginterferon beta- la); Polivy (polatuzumab vedotin-piiq); Pombiliti (cipaglucosidase alfa-atga); Portrazza (necitumumab); Poteligeo (mogamulizumab-kpkc); Praluent (alirocumab); Praxbind (idarucizumab); Pregnyl (chorionic gonadotropin); Procrit (epoetin alfa); Proleukin (aldesleukin); Prolia (denosumab); ProstaScint (capromab pendetide); Pulmolite (kit for the preparation of technetium Tc-99m albumin aggregated); Pulmotech MAA (kit for the preparation of technetium Tc-99m albumin aggregated); Pulmozyme (domase alfa); Raptiva (efalizumab); Rebif (interferon beta- la); Reblozyl (luspatercept-aamt); Regranex (becaplermin); Remicade (infliximab); Renflexis (infliximab-abda); Reopro (abciximab); Repatha (evolocumab);Repronex (menotropins); Retacrit (epoetin alfa-epbx); Retavase (reteplase); Revcovi (elapegademase-lvlr); Rituxan (rituximab); Rituxan Hycela (rituximab and hyaluronidase human); Roferon-A (interferon alfa-2a); Rolvedon (eflapegrastim-xnst); Ruxience (rituximab-pvvr); Rybrevant (amivantamab-vmjw); Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn); Ryzneuta; Rystiggo (rozanolixizumab-noli); Ryzodeg 70 / 30 (insulin degludec and insulin aspart); Saizen (somatropin); Santyl (collagenase); Saphnelo (anifrolumab-Leydig 77541747fnia); Sarclisa (isatuximab-irfc); Serostim (somatropin); Siliq (brodalumab); Simponi (golimumab); Simponi Aria (golimumab); Simulect (basiliximab); Skyrizi (risankizumab-rzaa); Skytrofa (lonapegsomatropin-tcgd); Soliqua 100 / 33 (insulin glargine and lixisenatide); Soliris (eculizumab); Somavert (pegvisomant); Spevigo (spesolimab-sbzo); Stelara (ustekinumab); Strensiq (asfotas alfa); Sucraid (sacrosidase); Survanta (beractant); Susvimo (ranibizumab); Sylvant (siltuximab); Synagis (palivizumab); Takhzyro (lanadelumab-flyo); Taltz (ixekizumab); Talvey (talquetamab-tgvs); Tanzeum (albiglutide); Tecentriq (atezolizumab); Tecvayli (teclistamab-cqyv); Tepezza (teprotumumab- trbw); Tezspire (tezepelumab-ekko); Thyrogen (thyrotropin alfa); Tivdak (tisotumab vedotin-tftv); TNKase (tenecteplase); Toujeo (insulin glargine); Trasylol (aprotinin); Trazimera (trastuzumab-qyyp); Tremfya (guselkumab); Tresiba (insulin degludec); Trodelvy (sacituzumab govitecan-hziy); Trogarzo (ibalizumab-uiyk);Trulicity (dulaglutide); Truxima (rituximab-abbs); Tysabri (natalizumab); Tzield (teplizumab-mzwv); Udenyca (pegfilgrastim-cbqv); Ultomiris (ravulizumab-cwvz); Unituxin (dinutuximab); Vabysmo (faricimab-svoa); Vectibix (panitumumab); Veopoz (pozeilimab-bbfg); Verluma (nofetumomab); Vimizim (elosulfase alfa); Viokace (pancrelipase); Vitrase (hyaluronidase); Voraxaze (glucarpidase); VPRIV (velaglucerase alfa); Vyvgart (efgartigimod alfa-fcab); Vyvgart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc); Xenpozyme (olipudase alfa-rpcp); Xeomin (incobotulinumtoxinA); Xgeva (denosumab); Xiaflex (collagenase Clostridium histolyticum); Xigris (drotrecogin alfa); Xolair (omalizumab); Xultophy 100 / 3.6 (insulin degludec and liraglutide); Yervoy (ipilimumab); Zaltrap (Ziv-Aflibercept); Zarxio (filgrastim-sndz); Zenapax (daclizumab); Zenpep (pancrelipase); Zevalin (ibritumomab tiuxetan); Ziextenzo (pegfilgrastim-bmez); Zinbryta (daclizumab); Zinplava (bezlotoxumab); Zirabev (bevacizumab-bvzr);Zomacton (somatropin); Zorbtive / Serostim (somatropin); Zymfentra (infliximab); Zynlonta (locastuximab tesirine-lpyl); orZynyz (retifanlimab-dlwr).

22. The pharmaceutical container of any one of claims 1-21, wherein the pharmaceutical composition comprises a biologic for tumor necrosis, a factor-a (TNF) inhibitor, a interleukin inhibitor, a selective co-stimulation modulator, a glucagon-like peptide-1 (GLP-1) agonist or GLP-1 receptor agonist, an mRNA based formulation, an allergen, a tissue, a recombinant protein, a personalized medicine, a CAR-T cell thereapy medicine, a gene therapy medicine, or a biologic listed in the FDA Purple Book.Leydig 7754174823. The pharmaceutical container of claim 22, wherein the pharmaceutical composition comprises CAR-T cell therapy medicine or a gene therapy medicine.

24. A method of storing a pharmaceutical agent in a primary container, the method comprising providing a primary container comprising a lumen defined in part by a wall, the wall having an inner surface facing the lumen and an outer surface, where the inner surface of the wall is coated with a metal oxide coating and provides improved drug compatibility when compared with primary containers without a metal oxide coating on the inner surface facing the lumen of the wall, and storing the pharmaceutical agent in the primary container, wherein the metal oxide is an oxide of a metal selected from the group consisting of zirconium, hafnium, titanium, tantalum, aluminum, and combinations thereof.

25. The method of claim 24, wherein the oxide of zirconium is ZrCh, the oxide of titanium is TiCh, the oxide of tantalum is Ta2Os, the oxide of hafnium is HfCh, and the oxide of aluminum is AI2O3.

26. The method of claim 24 or 25, wherein the metal oxide coating has a thickness of about 15 nm to about 20 nm.

27. A pharmaceutical container comprising a lumen defined in part by a glass wall, the glass wall having an inner surface facing the lumen and an outer surface, wherein the inner surface of the wall has been coated with a metal oxide coating by atomic layer deposition (ALD) coating process, wherein adsorption of a biological drug placed in the pharmaceutical container to the inner surface coated with the metal oxide coating is at least 50% less compared to the adsorption of the biological drug stored in a pharmaceutical container composed of glass without the metal oxide coating, wherein the metal oxide is an oxide of a metal selected from the group consisting of zirconium, hafnium, titanium, tantalum, aluminum, and combinations thereof.

28. The pharmaceutical container of claim 27, wherein the metal oxide coating has a thickness of about 15 nm to about 20 nm.

29. The pharmaceutical container of claim 28, wherein the metal oxide coating has a thickness of about 6 nm to about 18 nm.Leydig 7754174930. The pharmaceutical container of claim 29, wherein the metal oxide coating has a thickness of about 17 nm.

31. The pharmaceutical container of any one of claims 27-30, wherein the metal oxide coating has a surface roughness defined by an arithmetical mean height of 0.61 ± 0.03 nm, a root mean square height of 0.80 ± 0.03 nm, and / or a maximum peak to valley height of 8.8 ± 0.4 nm.

32. The pharmaceutical container of any one of claims 27-31, wherein the metal oxide coating is amorphous.

33. The pharmaceutical container of any one of claims 27-32, wherein the biological drug is a peptide drug or a combination of peptide drugs.

34. The pharmaceutical container of claim 33, wherein the peptide drug is selected from the group consisting of liraglutide, ranibizumab, and bevacizumab, or any combination thereof.

35. The pharmaceutical container of any one of claims 27-34, wherein the biological drug comprises a lipid loaded nanoparticle (LNP).

36. The pharmaceutical container of claim 35, wherein the LNP is GFP RNA loaded LNP.

37. The pharmaceutical container of any one of claims 27-34, wherein the biological drug comprises a humanized IgG.

38. The pharmaceutical container of any one of claims 27-34, wherein the biological drug comprises a bacteriophage.

39. The pharmaceutical container of any one of claims 27-34, where the biological drug comprises Botulinus neurotoxin.Leydig 7754175040. A method of storing a biological drug in a pharmaceutical container, the method comprising placing the biological drug in the pharmaceutical container according to any one of claims 27-39 such that the biological drug is in contact with the metal oxide coating.

41. The pharmaceutical container of any one of claims 27-39, which further includes a layer or coating of a polymer or an oligomer of ethylene oxide or ethylene glycol deposited on the metal oxide coating.

42. A method of storing a biological drug in a pharmaceutical container according to claim 42, wherein the biological drug is in contact with the layer or coating of the polymer or oligomer of ethylene oxide or ethylene glycol.

43. The pharmaceutical container of any one of claims 27-39, which further includes a layer or coating of a polymer of hydroxyalkyl acrylate deposited on the metal oxide coating.

44. The pharmaceutical container of claim 43, wherein the hydroxyalkyl acrylate is a C1-C5 alkyl acrylate.

45. The pharmaceutical container of claim 43, wherein the hydroxyalkyl acrylate is hydroxyethyl acrylate and / or hydroxypropyl acrylate.

46. The pharmaceutical container of any one of claims 27-39, wherein the metal oxide coating further includes a polyphosphate grafted thereto.

47. The pharmaceutical container of claim 46, wherein the polyphosphate has been grafted onto the metal oxide coating by utilizing plasma activated vapor phase cyclic trimetaphosphate.

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