Pharmaceutical containers

Abstract

We provide containers for pharmaceuticals. [Solution] This container is particularly suitable for the storage and transport of delicate components of pharmaceuticals, such as mRNA, and is a pharmaceutical container having an inner surface and an outer surface, wherein at least a portion of the inner surface is coated with a coating, and the container has a relative lipid nanoparticle (LNP) incubation MCR score ratio of lipid factor 1 less than 0.67, less than 0.5, less than 0.3, or less than 0.13 based on negative-mode ToF-SIMS data.

Description

[Technical Field]

[0001] The present invention relates to a container for pharmaceuticals. This container is particularly suitable for the storage and transport of pharmaceutical compositions containing delicate components, such as mRNA-LNP-based pharmaceuticals.

[0002] Background technology Lipid-based carrier systems, such as lipid nanoparticles (LNPs), are cutting-edge drug delivery carriers used for pharmaceutically active and sensitive components such as mRNA.

[0003] LNPs used in mRNA vaccines against SarS-CoV-2 are based on chemically different types of lipids, such as phospholipids, cholesterol, PEG-modified lipids, and cationic lipids. Cationic lipids bind to mRNA due to their opposite molecular charge. mRNA molecules are chemically delicate and require high-pressure storage conditions to preserve the drug, such as temperatures well below -20°C in some cases.

[0004] Buschmann et al. (Vaccines 9, 2021, 65) describe an mRNA delivery system focusing on lipid nanoparticles used in clinical trials of SARS-CoV-2 vaccines that were underway at the time.

[0005] Therefore, high demands are placed on containers for the storage and transport of mRNA vaccines. RNA-based active agents are very potent drugs and require only very small doses. Currently, these drugs are available in multi-dose containers. It is important that each dose taken from the container contains the same amount of active agent, and that the active agent remains in its original form within the container even after long-term storage.

[0006] Therefore, there remains a need to provide containers for pharmaceutically active and delicate components that reduce and / or avoid adhesion and potential inactivation of lipid-based carrier systems.

[0007] Summary of the Invention In a first aspect, the disclosure relates to a pharmaceutical container having an inner surface and an outer surface, wherein at least a portion of the inner surface is coated with a coating, and the container has a relative lipid nanoparticle (LNP) incubation MCR score ratio of less than 0.67, less than 0.5, less than 0.3, or less than 0.13 for lipid factor 1 based on negative-mode ToF-SIMS data.

[0008] In a second aspect, the disclosure relates to a pharmaceutical container having an inner surface and an outer surface, wherein at least a portion of the inner surface is coated with a coating, and the container is configured such that the coated inner surface is subjected to 7 × 10⁻¹⁶ based on negative-mode ToF-SIMS data. 13 Less than 5 x 10 13 Less than, or 2 × 10 13 This relates to a pharmaceutical container having an absolute LNP-incubated MCR score of less than 1 for lipid factor 1.

[0009] In a third aspect, the disclosure relates to a pharmaceutical container having an inner surface and an outer surface, wherein at least a portion of the inner surface is coated with a coating, and the container is configured such that, based on negative-mode ToF-SIMS data, at least 1 × 10⁻¹⁶ of the coated inner surface 12 This relates to a pharmaceutical container having an absolute LNP incubation MCR score for organosilicon factor 1.

[0010] In a fourth aspect, the disclosure relates to a pharmaceutical container having an inner surface and an outer surface, wherein at least a portion of the inner surface is coated with a coating, and the container has a relative LNP-incubated MCR score ratio of at least 2, or at least 5, organosilicon factor 1 based on negative-mode ToF-SIMS data.

[0011] In a fifth aspect, the disclosure relates to a pharmaceutical container having an inner surface and an outer surface, wherein at least a portion of the inner surface is coated with a coating, and the container has an LNP incubation haze value of less than 50% or less than 30% measured on the coated inner surface in accordance with the ASTM D1003-13 standard using a light source D65 and a 2° observer, the LNP incubation haze value obtained after freezing to -80°C and incubating at -80°C for 4 weeks.

[0012] The container described herein is suitable for pharmaceutical compositions and overcomes the problems associated with containers known in the prior art. This container enables the storage and transport of compositions containing lipid-based carrier systems, such as lipid nanoparticles, specifically pharmaceutical compositions including mRNA, siRNA, or saRNA-containing formulations, including vaccines. The container overcomes the problems of uniformity across multiple doses and the preservation of pharmaceutical compositions in their original form even after long-term storage.

[0013] While a wide variety of coated containers are already known, the challenge remains of providing pharmaceutical containers suitable for the storage and transport of lipid-based carrier systems, particularly compositions containing lipid nanoparticles. The subject matter of this disclosure addresses this need by providing containers with coatings that have improved adhesion inhibition properties. In this context, "improved adhesion" means reduced adhesion. Even after long-term storage, adhesion of components of the lipid-based carrier system is minimal. Consequently, excellent dose uniformity is achieved, and the pharmaceutical composition remains undamaged and unchanged.

[0014] The improved adhesion properties of the container are embodied and represented by factors and their scores obtained using MCR, as described later in this specification.

[0015] In a sixth aspect, the present invention relates to a filled pharmaceutical container comprising a pharmaceutical container according to the present disclosure and a pharmaceutical composition comprising a lipid-based carrier system, particularly lipid nanoparticles.

[0016] In a seventh aspect, the disclosure relates to a pharmaceutical container having an inner surface and an outer surface, wherein at least a portion of the inner surface is coated with a coating, and the container is configured to coat the coated inner surface based on negative-mode ToF-SIMS data, particularly without LNP incubation. At least 3 × 10 12 The absolute MCR score of organosilicon factor 1, and / or The relative MCR score ratio of at least two organosilicon factors 1, or max 3×10 13 The absolute MCR score of inorganic silicon factor 1, and / or Relative MCR score ratio of inorganic silicon factor 1 with a maximum of 5 This relates to a container for pharmaceuticals that has the following characteristics.

[0017] The filled pharmaceutical containers offer advantages such as excellent dose uniformity due to minimal adhesion of pharmaceutical composition components to the inner surface of the container, and can also be inert to lipid-based carrier systems. Furthermore, when the pharmaceutical composition includes lipid-based carrier systems, particularly lipid nanoparticles, adhesion of lipids and / or lipid nanoparticles to the inner surface of the container can be reduced.

[0018] In an eighth aspect, the present invention relates to the use of pharmaceutical containers for the storage and / or transport of pharmaceutical compositions comprising lipid-based carrier systems, particularly lipid nanoparticles.

[0019] Detailed explanation The pharmaceutical containers according to the present invention may be syringes, cartridges, ampoules, or vials. The containers may be glass containers such as borosilicate glass containers, aluminosilicate glass containers, or boroaluminosilicate glass containers. Alternatively, the pharmaceutical containers may be manufactured from suitable polymers such as cycloolefin copolymers (COCs) or cycloolefin polymers (COPs). The inner surface of the pharmaceutical container is coated with a coating that imparts desirable surface properties for the adhesion of lipid-based carrier systems such as lipid nanoparticles (LNPs). For the purpose of establishing the factors and scores of this disclosure, the coated containers undergo negative-mode ToF-SIMS data acquisition and subsequent MCR (multivariate spectral decomposition) analysis, as outlined in more detail below. References to “LNP incubation” in this disclosure mean that the container or coating was incubated with LNPs before measurement. Where scores are presented as “relative” score ratios, each value should be understood as the relative ratio obtained by dividing the score value of the coated container by the score value of an uncoated reference container based on the same MCR factor. For example, to measure the relative LNP incubation MCR score ratio between a coated container and an uncoated container (the uncoated container being a reference container), both containers are incubated with the same specific LNP composition applied to the coated container. Both the coated container and the reference container are analyzed by ToF-SIMS and MCR to obtain absolute MCR scores, such as lipid factor 1. The relative LNP incubation MCR score ratio, for example lipid factor 1, is obtained by dividing the MCR score obtained for the coated container by the MCR score of the reference container. For example, the relative LNP incubation MCR score ratio for lipid factor 1 may be less than 0.5. As mentioned above, the reference container may be an uncoated container. The reference container may have the same dimensions, material, and bulk composition as the coated container (excluding the coating, of course).

[0020] Advantageously, lipids are less likely to adhere to coated containers. This is reflected in a lower relative LNP-incubated MCR score ratio for lipid factor 1 when the coated container is compared to the reference container.

[0021] In a similar embodiment, the disclosure provides a pharmaceutical container comprising an inner surface and an outer surface, wherein at least a portion of the inner surface is coated with a coating, the container having a relative LNP-incubated MCR score ratio of less than 0.5 for lipid factor 1 based on negative-mode ToF-SIMS data, the coated container being compared to a reference container, the relative LNP-incubated MCR score ratio for lipid factor 1 being obtained by dividing the absolute MCR score of lipid factor 1 of the coated container by the absolute MCR score of lipid factor 1 of the uncoated container.

[0022] In one embodiment, LNP incubation of a glass container, which is either an uncoated or coated glass container, includes the steps of washing the container with ultrapure water (equivalent to purity 1, DIN ISO3696, ≤0.1 μS / cm at 25°C), drying under laminar flow conditions, incubating the container containing the standard LNP composition by filling the container with the standard LNP composition, freezing to -80°C, incubating at -80°C for 12 hours, then thawing to 5°C within 12 hours, then emptying the contents and cleaning the inner surface of the container by rinsing 10 times with ultrapure water, and then drying under laminar flow.

[0023] In related embodiments, the incubation of LNP in a polymeric container, which is either an uncoated polymeric container or a coated polymeric container, involves incubating a container containing a standard LNP composition by filling the container with the standard LNP composition, freezing it to -80°C, incubating it at -80°C for 12 hours, then thawing it to 5°C within 12 hours, and then washing the inner surface of the container by emptying the contents and rinsing it 10 times with ultrapure water, and then drying it under laminar flow.

[0024] In one embodiment, the standard LNP composition is the Comirnaty® vaccine formulation (License number EU / 1 / 20 / 1528).

[0025] In an alternative embodiment, the standard LNP composition is in phosphate-buffered saline (PBS) (pH 7.4) with a sucrose content of 10 wt% and the following lipids in the indicated amounts: 7.2 mg / mL of (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.83 mg / mL of 2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1.5 mg / mL of 1,2-distearoyl-sn-glycero-3-phosphocholine, and 3.3 mg / mL of cholesterol; at the following concentrations

[0026] [Table 1] and contains.

[0027] In one embodiment, the container has an absolute LNP incubation MCR score of less than 7×10 13 less than, less than 5×10 13 less than, or less than 2×10 13 less than, and further less than 0.5×10 13 for lipid factor 1.

[0028] In one embodiment, the container has a relative LNP-incubated MCR score ratio of lipid factor 1 less than 0.67, less than 0.5, less than 0.3, or less than 0.13.

[0029] In one embodiment, the container is at least 1 × 10 12 , at least 2 × 10 12 , or at least 3 × 10 12 The absolute LNP incubation MCR score of organosilicon factor 1 is obtained. Optionally, the absolute LNP incubation MCR score of organosilicon factor 1 is obtained up to 9 × 10⁻⁶. 13 , up to 7×10 13 , or up to 6 x 10 13 It is possible to reach this point.

[0030] In one embodiment, the container has a relative LNP incubation MCR score ratio of at least 2, at least 3, or at least 5 for organosilicon factor 1. Optionally, the relative LNP incubation MCR score ratio of organosilicon factor 1 may be up to 20, up to 15, or up to 10. It has been found that when the MCR score of organosilicon factor 1 is within this range, lipid adhesion, particularly LNP adhesion, is significantly reduced.

[0031] In one embodiment, the container for pharmaceuticals has a maximum size of 1 × 10 13 , up to 5×10 12 , or up to 3 x 10 12 The inorganic silicon factor 1 has an absolute LNP incubation MCR score. Optionally, this score is at least 0.5 × 10⁻⁶. 12 That's fine.

[0032] In one embodiment, the relative LNP-incubated MCR score ratio of inorganic silicon factor 1 is up to 5, up to 3, or up to 1.5. Optionally, this score ratio is at least 0.1, or at least 0.2.

[0033] In one embodiment, the container is at least 1 × 10 12 , at least 2 × 10 12 , or at least 3 × 1012 Organic factor 1 has an absolute LNP-incubated MCR score and / or a relative LNP-incubated MCR score ratio of at least 0.2, at least 0.5, or at least 1.0. Optionally, the relative LNP-incubated MCR score ratio of organic factor 1 is up to 10, up to 5, or up to 2.0.

[0034] Optionally, the container can be up to 9 x 10 12 , up to 8×10 12 , or up to 6 x 10 12 It has an absolute LNP incubation MCR score for organic factor 1.

[0035] Alternatively, or in addition, the container may have a corresponding non-LNP incubation score value. These values ​​are obtained without LNP incubation ("non-incubation").

[0036] The absolute non-incubated MCR score for organosilicon factor 1 is at least 3 × 10⁻⁶. 12 , at least 5 × 10 12 , or at least 7 × 10 12 This may be the case. Optionally, the absolute non-incubation MCR score for organosilicon factor 1 is up to 9 × 10⁻⁶. 13 , up to 7×10 13 , or up to 6 x 10 13 It is possible to reach this point.

[0037] The relative non-incubated MCR score ratio of organosilicon factor 1 is at least 3 × 10⁻⁶. 12 , at least 5 × 10 12 , or at least 7 × 10 12 This may be the case. Optionally, the absolute LNP incubation MCR score for organosilicon factor 1 is up to 9 × 10⁻⁶. 13 , up to 7×10 13 , or up to 6 x 10 13 It is possible to reach this point.

[0038] The absolute non-incubated MCR score for inorganic silicon factor 1 is up to 1 × 10⁻⁶.13 , up to 5×10 12 , or up to 3 x 10 12 It may be so. Optionally, this score should be at least 0.5 × 10 12 That's fine.

[0039] The relative non-incubated MCR score ratio for inorganic silicon factor 1 may be up to 5, up to 3, or up to 1.5. Optionally, this score ratio is at least 0.1 or at least 0.2.

[0040] In one embodiment of a pharmaceutical container, the ToF-SIMS data includes n datasets consisting of ion-specific masses and their corresponding intensities, such that the ToF-SIMS results measured on a particular coating or container can be attributed to a specific location in an n-dimensional composition space, and one or more factors selected from lipid factor 1, organosilicon factor 1, inorganic silicon factor 1, and organic factor 1 have factor-specific MCR loadings, which represent the conceptual components in the n-dimensional composition space to which the one or more factors can be attributed, the factor-specific MCR loadings characterize one or more factors by enumerating the ions that contribute to the definition of the factor, and each of the absolute LNP-incubated MCR score or relative LNP-incubated MCR score ratio represents the abundance of the corresponding MCR factor in the coating or container. If a (pre-selected) ion species has an intensity of zero or has a value of zero in the factor loading, that ion species does not contribute to the loading and the associated factor.

[0041] Figures 2A, 3A, and 4A show MCR data generated from a bundle of ToF-SIMS spectra representing n datasets consisting of ion-specific masses. Figures 2A and 3A show characteristic lipid factor 1 loading and scoring obtained from the data matrix of negative ToF-SIMS spectra of adsorbed lipid-containing compounds. Figure 4A shows characteristic organosilicon factor 1 loading obtained from the data matrix of negative ToF-SIMS spectra, and Figure 4B shows the scoring of organosilicon compounds adsorbed on the inner surface of the container.

[0042] One or more factors can be selected from lipid factor 1, organosilicon factor 1, inorganic silicon factor 1, and organic factor 1, and each factor has a factor-specific MCR loading that indicates a conceptual component in the n-dimensional composition space to which the one or more factors can belong, and the factor-specific MCR loading characterizes each factor by enumerating the ions that contribute to the definition of the factor. Conceptual components correspond to classifications of compounds such as lipids, siloxanes, and silicon, which is typical of glass. Therefore, conceptual components are not present in the coating or on the container.

[0043] Lipid factor 1 generally correlates with the presence of lipids. For example, a high MCR score for lipid factor 1 is interpreted as an abundance of lipids, including an evaluation of additional information from the MCR scores of other factors mentioned above. In one embodiment, lipid factor 1 contains the following ions within its factor-specific MCR loading: • Fatty acid ions; ·[C n H 2n-1 O2] - [n is 10, 12, 14, 16, or 18]; ·[C n H 2n-3 O2] - [n is 10, 12, 14, 16, or 18]; ·[C n H 2n-5 O2] - [n is either 16 or 18]; • Phosphatidylcholine ion; ·[(CH) n [H2O4P] - [n = 0, 1, 2, or 3] Includes one or more of the following.

[0044] Organosilicon factor 1 generally correlates with the presence of organosilicon compounds. For example, a high MCR score for organosilicon factor 1 is interpreted as indicating a high abundance of organosilicon compounds, including an evaluation of additional information from the MCR scores of other aforementioned factors. In one embodiment, organosilicon factor 1 contains the following ions within its factor-specific MCR loading: • Bletilla species, • Silicon-carbon species (i.e., species containing Si atoms and C atoms) ·Formula [OSiR1R2] n - Polysiloxane species having [wherein R1 and R2 are independently selected from methyl, ethyl, and propyl, and n is any integer from 2 to 10] Includes one or more of the following.

[0045] Inorganic silicon factor 1 generally correlates with the presence of inorganic compounds. For example, if the MCR score of inorganic silicon factor 1 is interpreted as high, including an evaluation of additional information from the MCR scores of other aforementioned factors, then a large amount of inorganic compounds (e.g., glass components or inorganic oxides) is present. In one embodiment, inorganic silicon factor 1 has the following ions in its factor-specific MCR loading: • Silicon species and / or silicon oxide species; • Aluminum oxide species and / or boron species and / or boron oxide species; • Halogen species; • Alkali oxide species and / or alkaline earth oxide species Includes one or more of the following.

[0046] In one embodiment, lipid factor 1, during the MCR loading specific to that factor, produces the following ions: [C 10 H 17 O2]- , [C 10 H 19 O2] - , [C 12 H 21 O2] - , [C 16 H 29 O2] - , [C 16 H 31 O2] - , [C 16 H 32 O2] - , [C 18 H 31 O2] - , [C 18 H 33 O2] - , [C 18 H 35 O2] - , [PO3] - , [PH2O4] - , [CH3O4P] - , [C2H4O4P] - : contains one or more of the following.

[0047] In one embodiment, the organosilicon factor 1 contains, during the MCR loading specific to that factor, the following: [SiC] - , [SiCH3O] - , [SiCH3O2] - , [SiC2H5O] - , [Si2CHO2] - , [SiC3H9O] - , [Si2C5H 15 O2] - , [Si3C5H 15 O4] - : contains one or more of the following ions.

[0048] In one embodiment, the inorganic silicon factor 1 contains, during the MCR loading specific to that factor, the following ions: OH - , Al - , Si - , P - , Cl - , NaO - , AlO - , BO2 - , SiHO- AlO2 - SiO2 - SiH5O2 - Si3H3O2 - Si2HO5 - Includes one or more of the following:

[0049] In one embodiment, lipid factor 1, during the MCR loading specific to that factor, produces the following ions: [C 10 H 17 O2] - [C 10 H 19 O2] - [C 12 H 21 O2] - [C 16 H 29 O2] - [C 16 H 31 O2] - [C 16 H 32 O2] - [C 18 H 31 O2] - [C 18 H 33 O2] - [C 18 H 35 O2] - ...PO3] - [PH2O4] - [CH3O4P] - [C2H4O4P] - This includes at least 5 of the following:

[0050] In one embodiment, organosilicon factor 1, during the MCR loading specific to that factor, contains the following ions: [SiC] - [SiCH3O] - [SiCH3O2] - [SiC2H5O] - [Si2CHO2] - [SiC3H9O] - [Si2C5H 15 O2] - [Si3C5H 15 O4]- This includes at least four of the following:

[0051] In one embodiment, inorganic silicon factor 1, during MCR loading specific to that factor, contains the following ions:OH - , Al - Si - , P - Cl - NaO - AlO - , BO2 - SiHO - AlO2 - SiO2 - SiH5O2 - Si3H3O2 - Si2HO5 - This includes at least 5 of the following:

[0052] In one embodiment, lipid factor 1, during the MCR loading specific to that factor, produces the following ions: [C 10 H 19 O2] - [C 12 H 21 O2] - [C 16 H 29 O2] - [C 16 H 31 O2] - , and [C 18 H 35 O2] - Includes:

[0053] In one embodiment, organosilicon factor 1, during its MCR loading, contains the following ion: [SiCH3O] - [SiCH3O2] - [SiC2H5O] - [SiC3H9O] - , and [Si2C5H 15 O2] - Includes:

[0054] In one embodiment, inorganic silicon factor 1, during MCR loading specific to that factor, contains the following ions:OH- Si - SiO2 - SiH5O2 - , and Si3H3O2 - Includes:

[0055] In one embodiment, the MCR score is calculated using an MCR having a total of 3, 4, or 5 MCR factors.

[0056] In one embodiment, a container for pharmaceuticals has an inner surface and an outer surface, at least a portion of the inner surface is coated with a coating, and the container has the following conditions on the coated inner surface: LNP incubation haze values ​​of less than 50% or less than 30% measured according to ASTM D1003-13 standard using light source D65 and 2° observers, obtained after freezing to -80°C and incubation at -80°C for 4 weeks; and / or • Water contact angle of at least 105° as measured according to DIN 55660-2-2011-12 One or more of the following conditions must be met.

[0057] In one embodiment, the haze value measured according to the ASTM D1003-13 standard using a light source D65 and a 2° observer is less than 50%, less than 40%, less than 30%, or less than 20%. In one embodiment, the haze value measured according to the ASTM D1003-13 standard using a light source D65 and a 2° observer is at least 1%, at least 2%, at least 3%, or at least 5%. The LNP incubation haze value is determined after incubation of the container with the LNP composition, and the LNP incubation haze value is obtained after freezing at -80°C and incubation at -80°C for 4 weeks. Other processing is as described above for the LNP incubation MCR score.

[0058] In one embodiment, the water contact angle is at least 105° or at least 110° when measured according to DIN 55660-2-2011-12. In one embodiment, the water contact angle is 125° or less or 120° or less when measured according to DIN 55660-2-2011-12. The water contact angle is determined on the container without prior LNP incubation.

[0059] In one embodiment, the container is made of glass or polymer.

[0060] In one embodiment, the container contains a cyclic olefin copolymer.

[0061] In one embodiment, the container has the following characteristics: • Wall thickness of 0.50 to 10.0 mm, or 1.00 to 4.00 mm; and / or • 0.1ml to 1000ml, 0.5ml to 500ml, 1ml to 250ml, 2ml to 30ml, 2ml to 15ml, or approximately 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml, 11ml, 12ml, 13ml, 14ml, or 15ml; optionally, container volumes of 5 to 15ml. It has one or more of the following.

[0062] In one embodiment, the container has a wall thickness of 0.50 mm or more, 1.00 mm or more, or 2.0 mm or more. In another embodiment, the container has a wall thickness of 10.0 mm or less, 7.00 mm or less, or 4.0 mm or less.

[0063] In one embodiment, the container is a syringe, cartridge, ampoule, or vial.

[0064] glass composition In one embodiment, the container comprises a glass composition containing 50-90% by weight of SiO2 and 3-25% by weight of B2O3.

[0065] In one embodiment, the container comprises a glass composition containing an aluminosilicate, optionally comprising 55-75% by weight of SiO2 and 11.0-25.0% by weight of Al2O3.

[0066] In one embodiment, the container comprises a glass composition containing 70-81% by weight of SiO2, 1-10% by weight of Al2O3, 6-14% by weight of B2O3, 3-10% by weight of Na2O, 0-3% by weight of K2O, 0-1% by weight of Li2O, 0-3% by weight of MgO, 0-3% by weight of CaO, and 0-5% by weight of BaO.

[0067] In one embodiment, the container comprises a glass composition containing 72-82% by weight of SiO2, 5-8% by weight of Al2O3, 3-6% by weight of B2O3, 2-6% by weight of Na2O, 3-9% by weight of K2O, 0-1% by weight of Li2O, 0-1% by weight of MgO, and 0-1% by weight of CaO.

[0068] In one embodiment, the container comprises a glass composition containing 60-78% by weight of SiO2, 7-15% by weight of B2O3, 0-4% by weight of Na2O, 3-12% by weight of K2O, 0-2% by weight of Li2O, 0-2% by weight of MgO, 0-2% by weight of CaO, 0-3% by weight of BaO, and 4-9% by weight of ZrO2.

[0069] In one embodiment, the container comprises a glass composition containing 50-70% by weight of SiO2, 10-26% by weight of Al2O3, 1-14% by weight of B2O3, 0-15% by weight of MgO, 2-12% by weight of CaO, 0-10% by weight of BaO, 0-2% by weight of SrO, 0-8% by weight of ZnO, and 0-2% by weight of ZrO2.

[0070] In one embodiment, the container comprises a glass composition containing 55-70% by weight of SiO2, 11-25% by weight of Al2O3, 0-10% by weight of MgO, 1-20% by weight of CaO, 0-10% by weight of BaO, 0-8.5% by weight of SrO, 0-5% by weight of ZnO, 0-5% by weight of ZrO2, and 0-5% by weight of TiO2.

[0071] In one embodiment, the container comprises a glass composition containing 65-72% by weight of SiO2, 11-17% by weight of Al2O3, 0.1-8% by weight of Na2O, 0-8% by weight of K2O, 3-8% by weight of MgO, 4-12% by weight of CaO, and 0-10% by weight of ZnO.

[0072] In one embodiment, the container comprises a glass composition containing 64-78% by weight of SiO2, 4-14% by weight of Al2O3, 0-4% by weight of B2O3, 6-14% by weight of Na2O, 0-3% by weight of K2O, 0-10% by weight of MgO, 0-15% by weight of CaO, 0-2% by weight of ZrO2, and 0-2% by weight of TiO2.

[0073] coating In one embodiment, the coating comprises the elemental species Si, C, O, and H.

[0074] In one embodiment, the coating comprises at least one layer having a carbon content of at least 55%.

[0075] In one embodiment, the coating is derived and / or generated from one or more of the following: hexamethyldisiloxane (HMDSO), hexamethyldisilazane (HMDS), tetramethylsilane (TMS), trimethylborazole (TMB), tri(dimethylaminosilyl)amino-di(dimethylamino)borane (TDADB), tris(trimethylsilyl)borate (TMSB), hexamethylcyclotrisiloxane (HMCTSO), octamethylcyclotetrasiloxane (OMCTS), decamethylcyclopentasiloxane (DMCPS), dodecamethylcyclohexasiloxane (DMCHS), diacetoxy-di-t-butoxysilane (DADBS), tetraethoxysilane (TEOS), tris(trimethylsilyloxy)vinylsilane (TTMSVS), vinyltriethoxysilane (VTES), and / or combinations thereof.

[0076] In one embodiment, the coating comprises at least one layer, and the coating, or at least one layer of the coating, [Si2C5H 15 O2 - ] 20 / [Si2C5H 15 O2 - ] 80 ≥x1 [Si2C5H15O2-] Satisfying the parameters, [Si2C5H in the formula 15 O2 - ] 20 This is measured by TOF-SIMS at 20% of the time required for the sputtering gun beam to reach the glass surface [Si2C5H 15 O2 - This is the ion count; [Si2C5H in the formula 15 O2 - ] 80 This is measured by TOF-SIMS at 80% of the time required for the sputtering gun beam to reach the glass surface [Si2C5H 15 O2 - ] 80 This is the ion count; x1 [Si2C5H15O2-] It is 1.2, 1.5, 2, 3, 5, 8, or 12.

[0077] In one embodiment, the coating comprises at least one layer, the at least one layer of the coating having the following parameters: [Si2C3H9O3 - ] 20 / [Si2C3H9O3 - ] 80 ≥x1 [Si2C3H9O3-] [In the formula, x1 [Si2C3H9O3-] is 1.1, preferably 1.5, more preferably 2, more preferably 3, and / or [Si2C3H9O3 - ] 20 / [Si2C3H9O3 - ] 80 ≤ x² [Si2C3H9O3-] [In the formula, x2 [Si2C3H9O3-][The values ​​are 100, preferably 75, more preferably 50, more preferably 40, more preferably 30, more preferably 20, more preferably 10, more preferably 8, more preferably 6, more preferably 5, and more preferably 4.] Satisfying the conditions, [Si2C3H9O3 in the formula - ] 20 This is measured by TOF-SIMS at 20% of the time required for the sputtering gun beam to reach the glass surface [Si2C3H9O3 - This is the ion count; [Si2C3H9O3 in the formula - ] 80 [Si2C3H9O3] is measured by TOF-SIMS at 80% of the time required for the sputtering gun beam to reach the glass surface. - ] 80 This is the ion count.

[0078] This analysis used the ToF-SIMS depth profiling measurement process, which was started at 0% of the time required for the sputtering analysis process to reach the glass surface. At this point, [Si + [Al for the number of ions] + The ratio of ion counts can preferably be 0.00. After a certain analysis time (sputtering time) has elapsed, [Si + [Al for the number of ions] + The ratio of ion counts will be 0.10 or greater. Since aluminum is usually attributed as an element of glass, this point indicates the time required for the sputtering gun beam to reach the glass surface. This point is set to 100%, in relation to 100% of the time required for the sputtering analysis process to reach the glass surface.

[0079] The ToF-SIMS depth profiling process used in this measurement differs from the static ToF-SIMS method used to obtain the MCR dataset.

[0080] Filled containers for pharmaceuticals In one embodiment, the present invention provides a filled pharmaceutical container comprising one of the first to fifth embodiments of the present disclosure and a pharmaceutical composition comprising a lipid-based carrier system, particularly lipid nanoparticles.

[0081] In one embodiment, the lipid-based carrier system or lipid nanoparticles are classified as follows: a.) Phospholipids; and / or b.)C 24 Cholesterol or steroid functionalized with a linear or branched alkyl chain at position C, wherein the linear or branched alkyl chain contains 1 to 50 C atoms, 24 Cholesterol or steroids whose position is defined according to IUPAC nomenclature; and / or c.) PEG-modified lipids; and / or d.) Cationic lipids Includes one or more of the following.

[0082] In one embodiment, the pharmaceutical composition is a liquid or a frozen liquid. a.) Phospholipids in concentrations of 1.05 mg / mL to 1.95 mg / mL; and / or b.) Cholesterol of 2.3 mg / mL to 4.3 mg / mL; and / or c.) PEG-modified lipids in concentrations of 0.56 mg / mL to 1.05 mg / mL; and / or d.) Cationic lipids in concentrations of 0.50 mg / mL to 9.40 mg / mL Includes.

[0083] In one embodiment, lipid nanoparticles possess the following properties, as measured by dynamic light scattering (DLS) using a Malvern zetasizing meter: i) The polyvariance index (PDI) value is <0.5 or ≤0.1; and ii) The z-average diameter is up to 200 nm, up to 150 nm, or up to 100 nm, for example, 10 nm to 200 nm, 20 nm to 150 nm, or 50 nm to 100 nm. Characterized by one or more of the following:

[0084] In one embodiment, the z-average diameter of the lipid nanoparticles is 10 nm or more, 20 nm or more, or 50 nm or more.

[0085] Particle size and PDI were determined at room temperature using a Malvern® (Malvern Instruments Ltd., Worcestershire, United Kingdom) zetasizing Nano ZS. Size and PDI were measured using the automated mode after diluting the lipid concentration to 0.07 mg / ml in 10 mM phosphate buffer at pH 7.4. The default settings for the automated mode of the Malvern® (Malvern Instruments Ltd., Worcestershire, United Kingdom) zetasizing Nano ZS were as follows: Number of measurements = 3; Run time = 60 seconds; Number of runs = 10; Equilibrium time = 60 seconds; Refractive index solvent = 1.45; Refractive index dispersant = 1.335; Viscosity = 1.02 cP; Temperature = 24.9 °C; Dielectric constant = 78.5 F / m; Backscattering mode (173°); Auto-voltage selection; Smoluchowski formula:

[0086] In one embodiment, the pharmaceutical composition comprises RNA, such as mRNA, siRNA, or saRNA.

[0087] use In one embodiment, the present invention relates to the use of pharmaceutical containers for the storage and / or transport of pharmaceutical compositions comprising lipid-based carrier systems, particularly lipid nanoparticles.

[0088] A benefit of (filled) pharmaceutical containers is that less of the pharmaceutical composition's components adhere to the inner surface of the container. Furthermore, if the pharmaceutical composition contains a lipid-based carrier system, particularly lipid nanoparticles, less lipid and / or lipid nanoparticle adhesion to the inner surface of the container is possible. Thus, dose uniformity and the unchanging pharmaceutical composition are protected.

[0089] Lipid nanoparticles (LNPs) In this disclosure, “lipid-based carrier systems” include lipid-containing drug delivery systems such as liposomes, micelles, SEDDSs, and lipid nanoparticles.

[0090] Solid lipid nanoparticles, or lipid nanoparticles (LNPs), are nanoparticles composed of lipids.

[0091] In one embodiment, the lipid nanoparticles comprise one or more ionizable lipids as disclosed in Table 2 of Buschmann et al. (Vaccines 9, 2021, 65, which is incorporated herein by reference).

[0092] In one embodiment, the lipid nanoparticles include PEG lipids, which can be obtained by PEGylation of lipids.

[0093] In relation to this disclosure, PEGylation refers to the process of covalently and noncovalently bonding polyethylene glycol (PEG) polymer chains to (macro) molecules, such as lipids that will be subsequently PEGylated.

[0094] In one embodiment, the lipid nanoparticles include one or more cationic lipids disclosed in Tables 2 and 3 of International Publication No. 2017 / 075531, which is incorporated herein by reference.

[0095] In relation to this disclosure, lipids can be understood as one of four types of compounds or classifications of compounds: cholesterol; fatty acids with chain lengths ranging from 12 or more carbon atoms to 26 carbon atoms; triglycerides based on condensation products of glycerol with three fatty acids, which may be the same or different; sphingolipids and phospholipids.

[0096] In one embodiment, the lipid nanoparticles include ionizable lipids, DSPC (distearoylphosphatidylcholine), cholesterol, and PEG lipids.

[0097] In one embodiment, the lipid nanoparticles further comprise polynucleotides, particularly RNA. [Brief explanation of the drawing]

[0098] [Figure 1] The figure shows photographs obtained from uncoated and coated glass vials. The glass vials were prepared using glass tubes (Fiolax® clear, Schott AG, Germany) and exposed to standard solutions and solutions containing LNP. [Figure 2A] This figure shows characteristic lipid factor 1 loading obtained from the data matrix of negative ToF-SIMS spectra of lipid-containing compounds adsorbed on the inner surface of a glass vial. [Figure 2B] This figure shows the score values ​​obtained for coated and uncoated glass vials from MCR analysis based on lipid factor 1 during loading, as shown in Figure 2A. Each experiment was performed in double layers on both the bottom wall and the wall near the bottom of the inner surface of the glass vial. [Figure 3A] This figure shows characteristic lipid factor 1 loading, obtained from the negative ToF-SIMS spectrum data matrix of lipid-containing compounds adsorbed on the inner surfaces of coated and uncoated polymer syringes manufactured from COC polymers. [Figure 3B] Figure 3A shows the score values ​​obtained from MCR analysis based on lipid factors during loading for coated polymer syringes and uncoated polymer syringes. Each experiment was performed in double layers on both the inner bottom wall and the wall near the bottom. [Figure 4A]This figure shows characteristic organosilicon factor 1 loadings obtained from a data matrix of negative ToF-SIMS spectra for organosilicon compounds on the inner surfaces of coated and uncoated glass vials, as well as glass and polymer syringes. [Figure 4B] This figure shows the score values ​​obtained from the MCR analysis of the data matrix shown in Figure 4A for coated and uncoated containers. Each experiment was performed in duplicate on both the inner bottom wall and the wall near the bottom. [Figure 5A] This figure shows a list of ion species selected from raw ToF-SIMS data, including intensity, obtained from glass containers. [Figure 5B] This figure shows a list of ion species selected from raw ToF-SIMS data, including strength, obtained from polymer containers. [Figure 6A] This figure shows the characteristic loading of inorganic silicon factor 1, obtained from the data matrix of negative ToF-SIMS spectra of inorganic silicon compounds on the inner surfaces of coated and uncoated glass vials. [Figure 6B] This figure shows the score values ​​obtained for coated and uncoated containers from the MCR analysis of the data matrix shown in Figure 6A. Each experiment was performed in double layers on both the inner bottom wall and the wall near the bottom. [Figure 7A] This figure shows the loading of characteristic organic factor 1, obtained from the data matrix of negative ToF-SIMS spectra of organic compounds on the inner surfaces of coated and uncoated glass vials. [Figure 7B] This figure shows the score values ​​obtained from the MCR analysis of the data matrix shown in Figure 7A for coated and uncoated glass vials. Each experiment was performed in double layers on both the inner bottom wall and the wall near the bottom.

[0099] method Manufacturing of glass containers A coated glass container and an uncoated glass container (the latter serving as a reference container), both having the same dimensions, the same type of glass, and the same glass composition, are processed under exactly the same conditions.

[0100] To measure the LNP incubation MCR score, each container is washed with ultrapure water (equivalent to purity 1, DIN ISO3696, ≤0.1 μS / cm at 25°C) and dried under laminar flow conditions. The containers are then filled with a standard LNP composition, frozen to -80°C, incubated at -80°C for 12 hours, and then thawed to 5°C within 12 hours.

[0101] In the first variant, the standard LNP composition is Comirnaty vaccine (license number EU / 1 / 20 / 1528).

[0102] In the second variant, standard LNP contains the following lipids in the indicated amounts in phosphate-buffered saline (PBS) (pH 7.4) with a sugar content of 10% by weight: 7.2 mg / mL of (4-hydroxybutyl)azandiyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.83 mg / mL of 2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1.5 mg / mL of 1,2-distearoyl-sn-glycero-3-phosphocholine, and 3.3 mg / mL of cholesterol; and the following concentrations

[0103] [Table 2] That is the case.

[0104] All containers are analyzed by ToF-SIMS and MCR analysis (see next section).

[0105] The absolute LNP incubator MCR score refers to the MCR score for one specific factor obtained from a single container, either a coated glass container or an uncoated (reference) glass container, where the factors are selected from lipid factor 1, organosilicon factor 1, inorganic silicon factor 1, and organic factor 1, and each factor has its own unique MCR loading.

[0106] The relative LNP incubator MCR score ratio refers to the quotient of the MCR scores for a specific factor between coated glass containers and uncoated (reference) glass containers.

[0107] Manufacturing of polymer containers Coated polymer containers and uncoated polymer containers, both having the same dimensions, the same type of glass, and the same glass composition, are processed under exactly the same conditions.

[0108] The manufacturing process for polymer containers is the same as that for glass containers, except that washing with ultrapure water (equivalent to purity 1, DIN ISO3696, ≤0.1 μS / cm at 25°C) and drying under laminar flow conditions are omitted.

[0109] ToF-SIMS (time-of-flight secondary ion mass spectrometry) The following sections describe in detail the measurement methods and data evaluation for specific ToF-SIMS measurements. Iontof's TOF.SIMS4 was used for the measurements. Unless otherwise specified, ToF-SIMS measurements are performed according to ASTM E1829 and ASTM E2695.

[0110] measurement The following parameter settings are required for ToF-SIMS analysis: Primary ion: Ga + ;(or TOF.SIMS5 and Bi + Use; (Primary ion) energy: 25000V; Measurement area: 100×100μm 2 ; Primary ion dose density: 6 × 10⁻⁶ 12 cm -2 ; Surface discharge: caused by low-energy electrons I used it.

[0111] Spectral data was acquired for 100 seconds and then integrated.

[0112] Sample preparation Each sample in the (coated) container was cut lengthwise in half, and positioned so that the centerline of the primary ion gun of the ToF-SIMS instrument struck the inner surface of the sample. The resulting essentially ionized secondary ions were analyzed by time-of-flight analysis and separated into different detectable mass / charge ratios. This yielded high-resolution mass spectra (Δm / m > 3000 for Si) covering both atomic and molecular ionic species. Die surface sensitivity covers several monolayers.

[0113] Data creation The ToF-SIMS data includes n datasets consisting of ion-specific masses and their corresponding intensities. Ion species / mass are selected from the raw ToF-SIMS data, including intensities, shown in Figures 5A and 5B for the glass and polymer containers, respectively. Since the experiment is performed in negative mode, ion-specific masses are relevant only to anions. The IONTOF GmbH spectral library can be used for mass interpretation. All ion species / masses are normalized according to their respective variances.

[0114] Multivariate spectral decomposition (MCR) To identify MCR factors, multivariate analysis using MCR (Multivariate Spectral Decomposition) is performed on the ToF-SIMS results. MCR is a statistical analysis method, and in the most common approach, a two-way data matrix D (m × n) is converted into two matrices C (m × k) containing the pure concentration profiles and pure spectra of k types of the unknown mixture, respectively, and S T (k × n) and the equation D = CS TThe data is decomposed according to +E, where E is the error matrix containing the residuals of the data (Ruckebusch & Blanchet, Analytica Chimica Acta 765, 2013, 28-36). The MCR method has been applied to the decomposition and analysis of ToF-SIMS. For this task, commercially available software such as SurfaceLab Ver 7.1, for example, can be used, where the number of factors can be arbitrarily set to 3, 4, or 5. A general description of a method that can analyze spectral information in detail is provided by Juan & Tauler (Analytica Chimica Acta 1145, 2021, 59-78).

[0115] In summary, ToF-SIMS results measured on a particular coating or container can be attributed to a specific location in an n-dimensional composition space. MCR is used to reduce the complexity of ToF-SIMS results by grouping the dataset into a more limited number of variables, so-called "factors." The MCR results consist of a set of factors, loadings, and corresponding scores. Each factor has an MCR loading specific to that factor, which indicates a conceptual component in the n-dimensional composition space to which the factor can be attributed, and the loading characterizes the factor in that it enumerates the ions that contribute to the definition of the factor. Each factor relates to a substance present in or on the coating or container. To be clear, the conceptual component does not actually exist in the coating or container. Each score indicates the intensity of the corresponding factor, which correlates with the abundance of the substance in or on the coating or container.

[0116] ToF-SIMS depth profiling using a sputter gun For example, ions [Al + ] 20 [Al + ] 80 [Si2C5H 15 O2 - ] 20 , and [Si2C5H 15 O2 -] 80 Depth profiling values ​​of ions such as these can be obtained according to the following method.

[0117] Measurement method For measurement, TOF-SIMS (Iontof's TOF.SIMS5) may be used. Unless otherwise specified, TOF-SIMS measurements are performed according to ASTM E1829 and ASTM E2695.

[0118] TOF-SIMS has the following parameter settings: For analysis: Primary ion: Bi 3+ ; Energy: 30,000 eV; Measurement area: 200×200μm 2 ; Pattern: 128x128 random; Bismuth analysis current: 0.3 pA, For sputter guns (argon cluster source): Sputter ion: Ar1051 (argon); Energy: 5000 eV; Sputtering area: 500 × 500 μm 2 ; Sputtering current of Ar cluster source: 1nA, moreover: Cycle time: 200 μs; Analyzer extractor: 2160V; Analyzer detector: 9000V; Charge compensation: Flood gun; Primary ion time of flight correction: On; Gas flooding: 9 x 10 -7 mbar I used it.

[0119] A sample of a coated glass element, such as half of a container with an inner coating cut lengthwise in half, is positioned such that the centerline of the sputtering gun and the centerline of the TOF-SIMS liquid metal ion gun strike the coated area of ​​the sample, and the sputtered area covers the entire measurement area, preferably so that the centerlines of the sputtering gun and the centerline of the TOF-SIMS liquid metal ion gun strike the same point on the coated area of ​​the sample. TOF-SIMS measures either cations or anions. To obtain both types of ions, two measurements can be performed using a new area of ​​the same sample, or a new sample, such as the first half and the remaining half of a coated container cut lengthwise in half, for each measurement.

[0120] Data Evaluation For data evaluation, the counts of all ions were calculated as follows: [Si + ] ions and [Si - ] is normalized to an ion, thereby [Si + ] ions and [Si - Each ion is set to 1.

[0121] Furthermore, the point at which TOF SIMS analysis begins (sputtering time) is set to 0%, and the point at which it reaches the glass surface is set to 100%. [Al + ] Signal and [AlO 2- The signal can be clearly attributed to glass, therefore this is [Al + ] Signal and [AlO 2- These are indicated by the signals, respectively.

[0122] When measuring cations, the point at which the sputter gun reaches the glass surface is [Si + [Al for the number of ions] + This can be the point at which the ratio of ion counts first becomes 0.10 or greater, and preferably such a point in time.

[0123] When measuring anions, the point at which the sputter gun reaches the glass surface is [Si- [AlO] for the number of ions 2- This can be the point at which the ratio of ion counts first becomes 0.10 or greater, and preferably such a point in time.

[0124] The point at which the analysis, i.e., measurement process was started was set to 0% of the time required for the sputtering analysis process to reach the glass surface. At this point, [Si + [Al for the number of ions] + The ratio of ion counts can be 0.00, preferably 0.00. After a certain analysis time (sputtering time), [Si + [Al for the number of ions] + The ratio of ion counts is greater than or equal to 0.10. Since aluminum is clearly attributed as an element of glass, this point indicates the time required for the sputtering gun beam to reach the glass surface. Up until this point, this ratio had never been greater than 0.10. As a result, this point was set to 100%. This is because it represents 100% of the time required for the sputtering analysis process to reach the glass surface.

[0125] Examples Coated glass vials 20R vials (glass vials manufactured from glass tubes, Fiolax® clear, Schott AG, Germany) were prepared. As an initial pretreatment, the vials were pre-washed in a laboratory dishwasher (HAMO AG LS-2000) with ultrapure water at ≤10 μS / cm at 25°C for 2 minutes at room temperature, 6 minutes at 40°C, and then 25 minutes at room temperature. The vials were then dried at 300°C for 20 minutes. Subsequently, the vials were processed and simultaneously coated using the apparatus described in International Publication No. 03 / 015122. Microwave irradiation at a frequency of 2.45 GHz was used for all plasma treatments. The reaction chamber was inside the vial. The outside of the vial was exposed to ambient conditions.

[0126] First, the vial was evacuated until the pressure reached 0.05 mbar. Then, oxygen was added to the vial at a flow rate of 25 sccm until the pressure reached 5 mbar, after which plasma pretreatment was initiated. The plasma was excited in pulse mode with an input power of 5500 W, a pulse duration of 0.5 ms, and a pulse pause time of 1.8 ms. Plasma pretreatment was performed for 17 seconds until the vial temperature reached 250°C, which was measured with a pyrometer at the center of the cylindrical portion of the vial.

[0127] The coating process was performed immediately afterward. The vial was filled with HMDSO (hexamethyldisiloxane) at a flow rate of 12.5 sccm, and the pressure was set to 0.8 mbar. The vial was then irradiated for 0.2 seconds (pressure: 0.8 mbar, flow rate of 12.5 sccm of HMDSO, input power: 6000 W, pulse duration: 0.050 ms, pulse pause time: 30 ms), followed by 13 seconds of irradiation (pressure: 0.8 mbar, flow rate of 12.5 sccm of HMDSO, input power: 4500 W, pulse duration: 0.008 ms, pulse pause time: 1 ms).

[0128] Subsequently, post-processing was performed. Specifically, the vials were filled with oxygen, cooled to room temperature in the presence of oxygen, and coated vials were obtained.

[0129] Alternatively, the coating may be provided as described in European Patent Application No. 21164784.7, which is incorporated herein by reference.

[0130] Coated polymer vials A polymer syringe (1 mL in volume) made from a Luer-lock type COC (cyclic olefin copolymer) was used. A silicon-containing fluid was applied to the inner surface of the container via a spray process or a bath process. The silicon-containing fluid may be a mixture of different organosilicon compounds such as poly(organo)siloxane, in which at least one reactive component can be thermoset to form a network.

[0131] Alternatively, the coating may be prepared in accordance with the description of European Patent Application No. 21164784.7, which is incorporated herein by reference.

[0132] Standard lipid nanoparticles (LNPs) Coated glass vials were treated with either phosphate-buffered saline (PBS) solution or standard-LNP in the same PBS solution. ToF-SIMS measurements were performed on the coated glass vials treated with the different methods, and data were extracted according to the MCR analysis described above.

[0133] In the first variant, the standard LNP composition was Comirnaty vaccine (license number EU / 1 / 20 / 1528).

[0134] In the second variant, standard LNP is prepared in phosphate-buffered saline (PBS) (pH 7.4) with a sugar content of 10% by weight, containing the following lipids in the indicated amounts: 7.2 mg / mL of (4-hydroxybutyl)azandiyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.83 mg / mL of 2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1.5 mg / mL of 1,2-distearoyl-sn-glycero-3-phosphocholine, and 3.3 mg / mL of cholesterol; at the following concentrations

[0135] [Table 3] It included that.

[0136] Further LNP formulations Alternatively, LNPs with a similar formulation may be used, although this formulation may deviate by up to 30% by weight from the specified amounts of individual lipid components.

[0137] Furthermore, LNPs include RNA such as mRNA based on polynucleotides, particularly adenine.

Claims

1. A pharmaceutical container having an inner surface and an outer surface, wherein at least a portion of the inner surface is coated with a coating, A pharmaceutical container wherein the container has a coated inner surface having a relative lipid nanoparticle (LNP) incubation MCR score ratio of less than 0.67 for lipid factor 1, based on negative-mode ToF-SIMS data.

2. The aforementioned container is 7 x 10 １３ Less than 5 x 10 １３ Less than, or 2 x 10 １３ A pharmaceutical container according to claim 1, having an absolute LNP incubation MCR score of less than 1 for lipid factor 1.

3. The aforementioned container at least 1 × 10 １２ The absolute LNP incubation MCR score of organosilicon factor 1, and / or Relative LNP incubation MCR score ratio of at least two organosilicon factors 1 A container for pharmaceuticals according to claim 1 or 2, having the following features.

4. The aforementioned container for pharmaceuticals at least 1 × 10 １３ The absolute LNP incubation MCR score of inorganic silicon factor 1, and / or Relative LNP incubation MCR score ratio of up to 5 inorganic silicon factors 1 A container for pharmaceuticals according to any one of claims 1 to 3, having the following:

5. The aforementioned container at least 1 × 10 １２ The absolute LNP incubation MCR score of organic factor 1, and / or Relative LNP incubation MCR score ratio of organic factor 1 of at least 0.2 A container for pharmaceuticals according to claim 1 or 2, having the following features.

6. The ToF-SIMS data includes n datasets consisting of ion-specific masses and their corresponding intensities, such that ToF-SIMS results measured on a particular coating or container can be attributed to a specific position in an n-dimensional composition space. One or more factors selected from lipid factor 1, organosilicon factor 1, inorganic silicon factor 1, and organic factor 1 have an MCR loading specific to the factor, the MCR loading specific to the factor represents a conceptual component in the n-dimensional composition space that can belong to the one or more factors, and the MCR loading specific to the factor characterizes the one or more factors by enumerating the ions that contribute to the definition of the factor. The absolute LNP incubation MCR score or the relative LNP incubation MCR score ratio each represents the amount of the corresponding factor present in the coating or container. A container for pharmaceuticals according to any one of claims 1 to 5.

7. - Lipid factor 1 contains, within the MCR loading specific to that factor, the following ions: fatty acid ions; [C ｎ H ２ｎ－１ O ２ － [n is 10, 12, 14, 16, or 18]; [C ｎ H ２ｎ－３ O ２ － [n is 10, 12, 14, 16, or 18]; [C ｎ H ２ｎ－５ O ２ － [n is 16 or 18]; phosphatidylcholine ions; [(CH) ｎ H ２ O ４ P] － [n = 0, 1, 2, or 3], and / or​​​ • Organosilicon factor 1 contains the following ions in its factor-specific MCR loading: silane species; silicon-carbon species; formula [OSiR １ R ２ ] ｎ － Polysiloxane species based on [wherein R １ and R ２ [independently, one or more of methyl, ethyl, and propyl, where n is any integer from 2 to 10] and / or - Inorganic silicon factor 1 contains one or more of the following ions in its MCR loading: silicon species; silicon oxide species; aluminum species, aluminum oxide species and / or boron species and / or boron oxide species; halogen species; alkali oxide species; alkaline earth oxide species. A container for pharmaceuticals according to any one of claims 1 to 6.

8. Lipid factor 1, during its MCR loading, produces the following ions: [C] １０ H １７ O ２ ] － [C １０ H １９ O ２ ] － [C １２ H ２１ O ２ ] － [C １６ H ２９ O ２ ] － [C １６ H ３１ O ２ ] － [C １６ H ３２ O ２ ] － [C １８ H ３１ O ２ ] － [C １８ H ３３ O ２ ] － [C １８ H ３５ O ２ ] － [PO ３ ] － [PH ２ O ４ ] － some CH ３ O ４ P) － [C ２ H ４ O ４ P) － Includes one or more of the following, and / or ・ During the MCR loading specific to the organic silicon factor 1, the following ions: [SiC] － , [SiCH ３ O] － , [SiCH ３ O ２ － , [SiC ２ H ５ O] － , [Si ２ CHO ２ － , [SiC ３ H ９ O] － , [Si ２ C ５ H １５ O ２ － , [Si ３ C ５ H １５ O ４ － include one or more of, and / or​​​​ • Inorganic silicon factor 1, during its MCR loading, produces the following ions: OH － Al － Si － , P － , Cl － NaO － AlO － , BO ２ － SiHO － AlO ２ － SiO ２ － SiH ５ O ２ － Si ３ H ３ O ２ － Si ２ HO ５ － Including one or more of the following: A container for pharmaceuticals according to any one of claims 1 to 7.

9. Lipid factor 1, during its MCR loading, produces the following ions: [C] １０ H １９ O ２ ] － [C １２ H ２１ O ２ ] － [C １６ H ２９ O ２ ] － [C １６ H ３１ O ２ ] － , and [C １８ H ３５ O ２ ] － Including, and / or • Organosilicon factor 1, during its MCR loading, produces the following ion: [SiCH] ３ O] － someSi CH ３ O ２ ] － [SiC ２ H ５ O] － [SiC ３ H ９ O] － , and [Si ２ C ５ H １５ O ２ ] － Including, and / or • Inorganic silicon factor 1, during its MCR loading, produces the following ions: OH － Si － SiO ２ － SiH ５ O ２ － , and Si ３ H ３ O ２ － including, A container for pharmaceuticals according to any one of claims 1 to 8.

10. A pharmaceutical container according to any one of claims 1 to 9, wherein the MCR score is calculated using an MCR having a total of three, four, or five MCR factors.

11. A pharmaceutical container having an inner surface and an outer surface, wherein at least a portion of the inner surface is coated with a coating, and the container is provided with the following conditions on the coated inner surface: - LNP incubation haze values ​​of less than 50% or less than 30% measured according to the ASTM D1003-13 standard using a light source D65 and a 2° observer, wherein the LNP incubation includes freezing to -80°C and incubating at -80°C for 4 weeks, and / or - A water contact angle of at least 105°, as measured according to DIN 55660-2-2011-12. A container for pharmaceuticals that meets one or more of the following criteria.

12. A container for pharmaceuticals according to any one of claims 1 to 11, wherein the container is made of glass or polymer.

13. The container has the following characteristics: - Wall thickness of 0.50 to 10.0 mm, preferably 1.00 to 4.00 mm; and / or - Volume capacity of the container: 0.1 ml to 1000 ml, preferably 0.5 ml to 500 ml, more preferably 1 ml to 250 ml, more preferably 2 ml to 30 ml, more preferably 2 ml to 15 ml, more preferably about 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 11 ml, 12 ml, 13 ml, 14 ml, or 15 ml; more preferably 5 to 15 ml A container for pharmaceuticals according to any one of claims 1 to 12, having one or more of the above.

14. A container for a pharmaceutical product according to any one of claims 1 to 13, wherein the container is a syringe, cartridge, ampoule, or glass vial.

15. The aforementioned container 50-90% by weight of SiO ２ and 3-25% by weight of B ２ O ３ A glass composition containing, or - Contains aluminosilicate, preferably 55 to 75% by weight of SiO ２ and 11.0–25.0% by weight of Al ２ O ３ Glass composition containing A container for pharmaceuticals according to any one of claims 1 to 14, including the following:

16. The container contains 70-81% by weight of SiO ２ , 1-10% by weight of Al ２ O ３ , 6-14% by weight of B ２ O ３ , 3-10% by weight of Na ２ O, 0-3% by weight of K ２ O, 0-1% by weight of Li ２ A container for pharmaceuticals according to any one of claims 1 to 15, comprising a glass composition containing 0 to 3% by weight of MgO, 0 to 3% by weight of CaO, and 0 to 5% by weight of BaO.

17. The container contains 72-82% by weight of SiO ２ , 5-8% by weight of Al ２ O ３ , 3-6% by weight of B ２ O ３ , 2-6% by weight of Na ２ O, 3-9% by weight of K ２ O, 0-1% by weight of Li ２ A container for pharmaceuticals according to any one of claims 1 to 15, comprising a glass composition containing O, 0 to 1% by weight of MgO, and 0 to 1% by weight of CaO.

18. The container contains 60-78% by weight of SiO ２ , 7-15% by weight of B ２ O ３ , 0-4% by weight of Na ２ O, 3-12% by weight of K ２ O, 0-2% by weight of Li ２ O, 0-2 wt% MgO, 0-2 wt% CaO, 0-3 wt% BaO, 4-9 wt% ZrO ２ A container for pharmaceuticals according to any one of claims 1 to 15, comprising a glass composition containing the following.

19. The container contains 50 to 70% by weight of SiO ２ , 10-26% by weight of Al ２ O ３ , 1-14% by weight of B ２ O ３ , 0-15 wt% MgO, 2-12 wt% CaO, 0-10 wt% BaO, 0-2 wt% SrO, 0-8 wt% ZnO, 0-2 wt% ZrO ２ A container for pharmaceuticals according to any one of claims 1 to 15, comprising a glass composition containing the following.

20. The container contains 55-70% by weight of SiO ２ , 11-25% by weight of Al ２ O ３ , 0-10 wt% MgO, 1-20 wt% CaO, 0-10 wt% BaO, 0-8.5 wt% SrO, 0-5 wt% ZnO, 0-5 wt% ZrO ２ , 0-5% by weight TiO ２ A container for pharmaceuticals according to any one of claims 1 to 15, comprising a glass composition containing the following.

21. The container contains 65-72% by weight of SiO ２ , 11-17% by weight of Al ２ O ３ , 0.1 to 8% by weight of Na ２ O, 0-8% by weight of K ２ A container for pharmaceuticals according to any one of claims 1 to 15, comprising a glass composition containing 0, 3 to 8% by weight of MgO, 4 to 12% by weight of CaO, and 0 to 10% by weight of ZnO.

22. The container contains 64 to 78% by weight of SiO ２ , 4-14% by weight of Al ２ O ３ , 0-4% by weight of B ２ O ３ , 6-14% by weight of Na ２ O, 0-3% by weight of K ２ O, 0-10% by weight of MgO, 0-15% by weight of CaO, 0-2% by weight of ZrO ２ , 0-2% by weight TiO ２ A container for pharmaceuticals according to any one of claims 1 to 15, comprising a glass composition containing the following.

23. A pharmaceutical container according to any one of claims 1 to 22, wherein the coating comprises the element species Si, C, O, and H.

24. A pharmaceutical container according to any one of claims 1 to 23, wherein the coating comprises at least one layer having a carbon content of at least 55%.

25. The coating comprises at least one layer, The coating, or at least one layer of the coating, [Si] ２ C ５ H １５ O ２ － ] ２０ / [Yes ２ C ５ H １５ O ２ － ] ８０ ≧x1 ［Ｓｉ２Ｃ５Ｈ１５Ｏ２－］ Satisfying the parameters, [Si in the formula] ２ C ５ H １５ O ２ － ] ２０ [Si] is measured by TOF-SIMS at 20% of the time required for the sputtering gun beam to reach the glass surface. ２ C ５ H １５ O ２ － This is the number of ions, [Si in the formula] ２ C ５ H １５ O ２ － ] ８０ [Si] is measured by TOF-SIMS at 80% of the time required for the sputtering gun beam to reach the glass surface. ２ C ５ H １５ O ２ － ] ８０ This is the ion count, x1 ［Ｓｉ２Ｃ５Ｈ１５Ｏ２－］ It is 1.2, 1.5, 2, 3, 5, 8, or 12. A container for pharmaceuticals according to any one of claims 1 to 24.

26. The coating comprises at least one layer, and the at least one layer of the coating is [Si] ２ C ３ H ９ O ３ － ] ２０ / [Yes ２ C ３ H ９ O ３ － ] ８０ ≧x1 ［Ｓｉ２Ｃ３Ｈ９Ｏ３－］ [In the formula, x1 ［Ｓｉ２Ｃ３Ｈ９Ｏ３－］ is 1.1, preferably 1.5, more preferably 2, more preferably 3, and / or [Si] ２ C ３ H ９ O ３ － ] ２０ / [Yes ２ C ３ H ９ O ３ － ] ８０ ≦x2 ［Ｓｉ２Ｃ３Ｈ９Ｏ３－］ [In the formula, x2 ［Ｓｉ２Ｃ３Ｈ９Ｏ３－］ [The values ​​are 100, preferably 75, more preferably 50, more preferably 40, more preferably 30, more preferably 20, more preferably 10, more preferably 8, more preferably 6, more preferably 5, and more preferably 4.] Satisfying the parameters, [Si in the formula] ２ C ３ H ９ O ３ － ] ２０ [Si] is measured by TOF-SIMS at 20% of the time required for the sputtering gun beam to reach the glass surface. ２ C ３ H ９ O ３ － This is the number of ions, [Si in the formula] ２ C ３ H ９ O ３ － ] ８０ [Si] is measured by TOF-SIMS at 80% of the time required for the sputtering gun beam to reach the glass surface. ２ C ３ H ９ O ３ － ] ８０ The number of ions, A container for pharmaceuticals according to any one of claims 1 to 25.

27. A filled container for pharmaceuticals, A container for pharmaceuticals according to any one of claims 1 to 26, • Lipid-based carrier systems, particularly pharmaceutical compositions containing lipid nanoparticles and A filled container for pharmaceuticals, including the contents.

28. The aforementioned lipid-based carrier system or lipid nanoparticles fall under the following compound classifications: a.) Phospholipids, and / or b.) C ２４ Cholesterol or steroid functionalized with a linear or branched alkyl chain at position C, wherein the linear or branched alkyl chain contains 1 to 50 C atoms, ２４ Cholesterol or steroids, and / or c. PEG-modified lipids, and / or d.) Cationic lipids A filled pharmaceutical container according to claim 27, comprising one or more of the above.

29. The pharmaceutical composition is a liquid or a frozen liquid, a. ) 1.05 mg / mL to 1.95 mg / mL of phospholipids, and / or b.) Cholesterol in a concentration of 2.3 mg / mL to 4.3 mg / mL, and / or c. 0.56 mg / mL to 1.05 mg / mL of PEG-modified lipids, and / or d. 0.50 mg / mL to 9.40 mg / mL of cationic lipids A filled container for pharmaceuticals according to claim 27, including the above.

30. The lipid nanoparticles exhibit the following properties, as measured by dynamic light scattering (DLS) using a Malvern zetasizer: i) The polyvariance index (PDI) value is <0.5 or ≤0.1, and ii) The z-average diameter is 50 nm to 200 nm, or 50 nm to 100 nm. A filled pharmaceutical container according to any one of claims 27 to 29, characterized by one or more of the above.

31. A filled pharmaceutical container according to any one of claims 27 to 30, wherein the pharmaceutical composition comprises RNA, for example mRNA, siRNA, or saRNA.

32. Use of a pharmaceutical container according to any one of claims 1 to 26 for the storage and / or transport of a lipid-based carrier system, particularly a pharmaceutical composition comprising lipid nanoparticles.

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