Materials and methods for mitigating presence of nitrosamines in packaging using activated carbon or derivatives thereof

Abstract

Disclosed herein are materials, articles, and methods for reducing, mitigating, or excluding the formation and / or amount of nitrosylating agents and / or N-nitroso compounds, including N-nitrosamines, in a package containing an active agent and a pharmaceutical dosage form in a shell, wherein the active agent can be effective to reduce, mitigate, or exclude the formation and / or amount of nitrosylating agents and / or N-nitroso compounds in the shell and / or in the pharmaceutical dosage form. There is provided a drug delivery system comprising a blister pack configured to contain a plurality of drug dosage forms, the blister pack comprising an active ingredient, the active ingredient may be effective to reduce, mitigate, or exclude the formation and / or amount of nitrosylating agents and / or N-nitroso compounds in the outer shell of the blister pack and / or in the pharmaceutical dosage form.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 493,622, filed March 31, 2023, entitled “MATERIALS AND METHODS FOR SCAVENGING OF N-NITROSO COMPOUNDS IN PACKAGING,” U.S. Provisional Application No. 63 / 493,654, filed March 31, 2023, entitled “MATERIALS AND METHODS FOR SCAVENGING OF N-NITROSAMINES IN PACKAGING,” and U.S. Provisional Application No. 63 / 580,592, filed September 5, 2023, entitled “BLOWN FILMS WITH VOLATILE ORGANIC COMPOUND SCAVENGING AGENT AND METHODS OF MAKING THE SAME.” Each of the aforementioned priority applications are hereby incorporated by reference in their entirety. TECHNICAL FIELD

[0003] The disclosed concepts include materials, articles, and methods for scavenging N-nitroso compounds, such as N-nitrosamines, from packaging containing an amount of product susceptible to contamination by N-nitroso compounds to reduce the amount of N-nitroso compounds, such as N-nitrosamines, or to mitigate (or eliminate) their formation. BACKGROUND

[0004] A group of compounds known as N-nitroso compounds (NOCs) share the >N-N=O moiety. This group of compounds can be further divided into two subgroups: (i) N-nitrosamines and (ii) N-nitrosamides and related compounds. N-nitrosamines are N-nitroso derivatives of secondary amines; N-nitrosamides and related compounds are those substituted ureas, amides, carbamates, guanidines, and similar compounds.

[0005] This group of compounds has received much attention due to evidence that its members have mutagenic and carcinogenic properties. Most NOCs induce cancer in experimental animals and can be associated with the etiology of several human cancers. The wide range of human exposure sources (exogenous and endogenous) has led to regulatory and legislative actions and the development of advanced and sensitive analytical methods.

[0006] Reaction of primary and secondary amines with nitrite or nitrous acid can lead to the formation of NOC, in which the N-H moiety is replaced by the N-N=0 moiety.

[0007] Thus, pharmaceuticals and food products containing primary and secondary amines are susceptible to reaction with nitrite or nitrous acid over time, thereby becoming contaminated with N-nitrosamines. Therefore, strategies to reduce the rate of formation of NOC or to preclude its formation can reduce or minimize the health risks associated with consumption of these products. Materials and methods for reducing or eliminating N-nitrosamines and / or nitrosating agents (e.g., nitrite and / or nitrous acid) in the packaging of these commodities and reducing or eliminating the amount of N-nitrosamines present in the commodities themselves can in turn be used to minimize the health risks associated with exposure to NOC contaminants in these products.

[0008] Pharmaceutical compositions are intended to be safe and, in general, meet the requirements of government regulatory rules, such as those of the U.S. FDA. In addition, the levels of impurities present in a pharmaceutical composition should meet the requirements outlined by the U.S. FDA. The FDA has been investigating the presence of nitrosamine impurities in some types of pharmaceuticals. The FDA has set an acceptable daily intake limit for nitrosamines. See “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities”, U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research, Pharmacology / Toxicology, August 4, 2023. The acceptable intake (AI) limit determined by the FDA is as follows:

[0009]

[0010] The AI limit is the exposure to the compound as described above that, after 70 years of exposure, results in a cancer risk of approximately 1 in 100,000. See “Control of Nitrosamine Impurities in Human Drugs / Guidance for Industry”, Pharmaceutical Quality / Manufacturing Standards / Current Good Manufacturing Practices / Version 1, February 2021.

[0011] There are multiple reasons for the presence of nitrosamines in pharmaceuticals. Sources of nitrosamines have been found to potentially be related to the manufacturing process of the drug or its chemical structure or even the storage or packaging conditions of the drug. If a person is exposed to nitrosamine impurities above the acceptable level for a long period of time, the risk of developing cancer can increase.

[0012] Several NOCs are important environmental and workplace pollutants and can be found in smoke, including smoke produced by tobacco combustion.

[0013] It is desirable to reduce the levels of nitrosamines in pharmaceutical and drug compositions and their packaging to meet safety standards and reduce the risk of exposure of patients taking the drugs to nitrosamines. Therefore, there remains a need for materials, articles, and methods that can scavenge N-nitroso compounds and / or nitrosating agents (e.g., nitrite and / or nitrous acid) from packaging and / or commodities enclosed therein to reduce the amount of N-nitroso compounds in the commodities and / or packaging, or to mitigate (or eliminate) the formation of N-nitroso compounds in the commodities and / or packaging, where the commodities comprise an amount of a product (e.g., a drug or food) susceptible to contamination by N-nitroso compounds. There is also a need for a solution that does not require reformulation of the pharmaceutical composition (e.g., by adding a mitigating agent in the composition itself) or changes to the process of manufacturing the pharmaceutical composition. The desired materials, articles, and methods can reduce the levels of free N-nitroso compounds in a product (e.g., a pharmaceutical composition) and thereby reduce the hazards associated with these compounds. SUMMARY

[0014] Provided herein is a container comprising a scavenging material capable of removing a nitrosating agent and / or an N-nitroso compound from a headspace within the container.

[0015] Also provided herein is a method for manufacturing a container comprising a scavenging material capable of removing a nitrosating agent and / or an N-nitroso compound from a headspace within the container.

[0016] Provided is a method for treating a patient having a medical condition with a pharmaceutical dosage form comprising or capable of forming a nitrosating agent and / or an N-nitroso compound, the method configured to mitigate potential adverse effects on the patient associated with the nitrosating agent and / or the N-nitroso compound, the method comprising:

[0017] (a) providing a package comprising a housing and one or more pharmaceutical dosage forms contained within the housing, wherein a headspace is formed within the volume of the housing that is not occupied by the one or more pharmaceutical dosage forms;

[0018] (b) providing an amount of activated carbon and / or a derivative thereof in the headspace effective to reduce or inhibit the rate of formation of a nitrosating agent and / or an N-nitroso compound in the headspace and / or in the pharmaceutical dosage forms within the package, the amount of activated carbon and / or a derivative thereof being separate and spaced apart from the one or more pharmaceutical dosage forms;

[0019] (c) opening the housing to dispense the one or more drug dosage forms; and

[0020] (d) administering the one or more drug dosage forms to provide a therapeutically effective amount of a drug to the patient to treat the medical condition with improved patient safety by mitigating the potential adverse effects associated with the drug dosage forms by reducing the nitrosating agent and / or N-nitroso compound with the amount of activated carbon or derivative thereof.

[0021] A method of reducing, mitigating, or eliminating the formation and / or amount of a nitrosating agent and / or N-nitroso compound in a drug package is provided, the method comprising:

[0022] providing a housing;

[0023] positioning at least one drug dosage form in the housing;

[0024] forming a headspace in the housing that is not occupied by the at least one drug dosage form; and

[0025] positioning activated carbon and / or a derivative thereof within the headspace,

[0026] wherein the activated carbon and / or derivative thereof is effective to reduce, mitigate, or eliminate the formation and / or amount of a nitrosating agent and / or N-nitroso compound in the headspace and / or in the drug dosage form.

[0027] In some embodiments, one or more of the headspace and the at least one drug dosage form includes a nitrosating agent and / or N-nitroso compound.

[0028] A drug delivery system for mitigating potential adverse effects associated with a drug is also provided, the system comprising:

[0029] (a) a blister pack configured to contain one or more drug dosage forms, the blister pack comprising:

[0030] (i) a backing;

[0031] (ii) a cover attached to the backing, the cover and the backing in combination forming at least one housing, the at least one housing configured to contain a single drug dosage form;

[0032] (b) a single drug dosage form contained within the at least one housing;

[0033] (c) a headspace formed within the volume of the housing that is not occupied by the one or more drug dosage forms; and

[0034] (d) activated carbon or a derivative thereof dispersed in a base polymer to form an entrained polymer film capable of reducing or inhibiting the rate of formation of a nitrosylating agent and / or an N-nitrosyl compound in the headspace within the package and / or in the pharmaceutical dosage form,

[0035] wherein the entrained polymer film is separate and spaced apart from the single pharmaceutical dosage form. BRIEF DESCRIPTION OF DRAWINGS

[0036] The foregoing summary of the technology of the present disclosure and the following detailed description of illustrated embodiments will be better understood when read in conjunction with the appended drawings. Like reference numerals designate identical elements throughout the several views. For the purpose of illustrating the technology of the present disclosure, various illustrative embodiments are shown in the drawings. It should be understood, however, that the technology of the present disclosure is not limited to the precise arrangements and instrumentalities shown. In the drawings:

[0037] Figure 1 is a schematic illustration of a representative apparatus and process for forming a blown film in accordance with optional embodiments of the disclosed concept; and

[0038] Figure 2 is a schematic illustration of a blister pack for storing a pharmaceutical product in accordance with optional embodiments of the disclosed concept. DETAILED DESCRIPTION

[0039] While systems, apparatuses, and methods are described herein by way of example and embodiments, those skilled in the art will recognize that systems, apparatuses, and methods of the presently disclosed technology are not limited to the embodiments or drawings described. Rather, the present technology covers all modifications, equivalents, and alternatives falling within the spirit and scope of the appended claims. Any headings used herein are for organizational purposes only and are not intended to be used to limit the scope of the description or the claims. In this document, the terms "chaotic" and "chaotic state" refer to a state of matter that is not in thermodynamic equilibrium.

[0040] Accordingly, provided herein is a container comprising scavenging material capable of removing N-nitrosyl compounds and / or nitrosylating agents (e.g., nitrite and / or nitrous acid) from the headspace within the container and / or the commodity of merchandise enclosed by the container. Also provided herein is a method for scavenging N-nitrosyl compounds and / or nitrosylating agents (e.g., nitrite and / or nitrous acid) in order to reduce the rate of N-nitrosyl compounds and / or nitrosylating agents (e.g., nitrite or nitrous acid), or to inhibit their formation, or to remove them from the container and / or the commodity of merchandise enclosed therein. Optionally, the scavenging material can reduce the amount of N-nitrosyl compounds. Optionally, the scavenging material can reduce the amount of nitrite and / or nitrous acid.

[0041] Optionally, the disclosed concepts include a system for mitigating the presence of nitrosamine impurities in a pharmaceutical product and the potential adverse effects on patients using the pharmaceutical product. The system includes a package comprising a housing and one or more pharmaceutical dosage forms having or tending to form or release N-nitroso compounds and / or nitrosating agents (e.g., nitrite or nitrous acid) therein or thereon. A headspace is formed within the volume of the housing that is not occupied by the one or more pharmaceutical dosage forms. An effective amount of an active agent is placed within the headspace to inhibit the formation of and / or reduce the presence of N-nitroso compounds and / or nitrosating agents in or on the one or more pharmaceutical dosage forms and / or in the headspace.

[0042] Optionally, the disclosed concepts include a method of reducing, mitigating, or eliminating the formation of and / or controlling the amount of N-nitroso compounds and / or nitrosating agents in a pharmaceutical package. The method includes forming a headspace in a housing that is not occupied by a pharmaceutical dosage form and positioning an active agent within the housing. Optionally, one or both of the headspace and the pharmaceutical dosage form includes N-nitroso compounds and / or nitrosating agents. The active agent can be effective to reduce, mitigate, or eliminate the formation of and / or the amount of N-nitroso compounds and / or nitrosating agents in the headspace and / or in the pharmaceutical dosage form.

[0043] Optionally, the active agent can be effective to reduce, mitigate, or eliminate the formation of and / or the amount of N-nitroso compounds in the headspace to less than 1500 ppm, optionally less than 400 ppm, optionally less than 100 ppm, optionally less than 95 ppm, optionally less than 90 ppm, optionally less than 85 ppm, optionally less than 80 ppm, optionally less than 75 ppm, optionally less than 70 ppm, optionally less than 65 ppm, optionally less than 60 ppm, optionally less than 55 ppm, optionally less than 50 ppm, optionally less than 45 ppm, optionally less than 40 ppm, optionally less than 35 ppm, optionally less than 25 ppm, optionally less than 20 ppm, optionally less than 15 ppm, optionally less than 14 ppm, optionally less than 13 ppm, optionally less than 12 ppm, optionally less than 11 ppm, optionally less than 10 ppm, optionally less than 9 ppm, optionally less than 8 ppm, optionally less than 7 ppm, optionally less than 6 ppm, optionally less than 5 ppm, optionally less than 4 ppm, optionally less than 3 ppm, optionally less than 2 ppm, optionally less than 1 ppm, optionally less than 0.9 ppm, optionally less than 0.8 ppm, optionally less than 0.7 ppm, optionally less than 0.6 ppm, optionally less than 0.5 ppm, optionally less than 0.4 ppm, optionally less than 0.3 ppm, optionally less than 0.2 ppm, or optionally less than 0.1 ppm.

[0044] Optionally, the active agent can be effective to reduce, mitigate, or eliminate the formation and / or amount of N-nitroso compounds in the pharmaceutical dosage form to less than 1500 ppm, optionally less than 400 ppm, optionally less than 100 ppm, optionally less than 95 ppm, optionally less than 90 ppm, optionally less than 85 ppm, optionally less than 80 ppm, optionally less than 75 ppm, optionally less than 70 ppm, optionally less than 65 ppm, optionally less than 60 ppm, optionally less than 55 ppm, optionally less than 50 ppm, optionally less than 45 ppm, optionally less than 40 ppm, optionally less than 35 ppm, optionally less than 25 ppm, optionally less than 20 ppm, optionally less than 15 ppm, optionally less than 14 ppm, optionally less than 13 ppm, optionally less than 12 ppm, optionally less than 11 ppm, optionally less than 10 ppm, optionally less than 9 ppm, optionally less than 8 ppm, optionally less than 7 ppm, optionally less than 6 ppm, optionally less than 5 ppm, optionally less than 4 ppm, optionally less than 3 ppm, optionally less than 2 ppm, optionally less than 1 ppm, optionally less than 0.9 ppm, optionally less than 0.8 ppm, optionally less than 0.7 ppm, optionally less than 0.6 ppm, optionally less than 0.5 ppm, optionally less than 0.4 ppm, optionally less than 0.3 ppm, optionally less than 0.2 ppm, or optionally less than 0.1 ppm.

[0045] Optionally, the active agent can be effective to reduce, mitigate, or eliminate the formation and / or amount of nitroso compounds in the headspace to less than 1500 ppm, optionally less than 400 ppm, optionally less than 100 ppm, optionally less than 95 ppm, optionally less than 90 ppm, optionally less than 85 ppm, optionally less than 80 ppm, optionally less than 75 ppm, optionally less than 70 ppm, optionally less than 65 ppm, optionally less than 60 ppm, optionally less than 55 ppm, optionally less than 50 ppm, optionally less than 45 ppm, optionally less than 40 ppm, optionally less than 35 ppm, optionally less than 25 ppm, optionally less than 20 ppm, optionally less than 15 ppm, optionally less than 14 ppm, optionally less than 13 ppm, optionally less than 12 ppm, optionally less than 11 ppm, optionally less than 10 ppm, optionally less than 9 ppm, optionally less than 8 ppm, optionally less than 7 ppm, optionally less than 6 ppm, optionally less than 5 ppm, optionally less than 4 ppm, optionally less than 3 ppm, optionally less than 2 ppm, optionally less than 1 ppm, optionally less than 0.9 ppm, optionally less than 0.8 ppm, optionally less than 0.7 ppm, optionally less than 0.6 ppm, optionally less than 0.5 ppm, optionally less than 0.4 ppm, optionally less than 0.3 ppm, optionally less than 0.2 ppm, or optionally less than 0.1 ppm.

[0046] Optionally, the active agent is effective to reduce, mitigate, or eliminate the formation and / or amount of nitroso compounds in the pharmaceutical dosage form to less than 1500 ppm, optionally less than 400 ppm, optionally less than 100 ppm, optionally less than 95 ppm, optionally less than 90 ppm, optionally less than 85 ppm, optionally less than 80 ppm, optionally less than 75 ppm, optionally less than 70 ppm, optionally less than 65 ppm, optionally less than 60 ppm, optionally less than 55 ppm, optionally less than 50 ppm, optionally less than 45 ppm, optionally less than 40 ppm, optionally less than 35 ppm, optionally less than 25 ppm, optionally less than 20 ppm, optionally less than 15 ppm, optionally less than 14 ppm, optionally less than 13 ppm, optionally less than 12 ppm, optionally less than 11 ppm, optionally less than 10 ppm, optionally less than 9 ppm, optionally less than 8 ppm, optionally less than 7 ppm, optionally less than 6 ppm, optionally less than 5 ppm, optionally less than 4 ppm, optionally less than 3 ppm, optionally less than 2 ppm, optionally less than 1 ppm, optionally less than 0.9 ppm, optionally less than 0.8 ppm, optionally less than 0.7 ppm, optionally less than 0.6 ppm, optionally less than 0.5 ppm, optionally less than 0.4 ppm, optionally less than 0.3 ppm, optionally less than 0.2 ppm, or optionally less than 0.1 ppm.

[0047] Optionally, the active agent comprises a scavenging material. Optionally, the scavenging material comprises a microporous material. Optionally, the microporous material is carbon. Optionally, the microporous material is activated carbon or a derivative thereof. Optionally, the activated carbon or derivative thereof is in the form of a powder, granule, or bead.

[0048] Optionally, the scavenging material comprises a base. Optionally, the base is an organic amine. Optionally, the organic amine comprises at least one hydroxyl group. Optionally, the organic amine contains up to 8 carbons, optionally up to 6 carbons, optionally up to 4 carbons. Optionally, the organic amine contains up to 3 nitrogens, optionally up to 2 nitrogens, optionally 1 nitrogen. Optionally, the organic amine contains 3 or fewer oxygens, optionally 2 or fewer oxygens, optionally up to 1 oxygen. Optionally, all of the nitrogens in the organic amine are amino nitrogens. Optionally, all of the oxygens in the organic amine are hydroxyl oxygens. Optionally, the pKa of the conjugate acid of the organic amine is between 6 and 11, optionally between 6 and 10, optionally between 6.5 and 10, optionally between 6.5 and 9.5, optionally between 6.5 and 9, optionally between 6.5 and 8.5. Optionally, the organic amine is selected from the group consisting of ethanolamine, diethanolamine, triethanolamine, and tris(hydroxymethyl)aminomethane. Optionally, the organic base is a monovalent base. Optionally, the scavenging material further comprises the conjugate acid of the monovalent base. Optionally, the monovalent base and the conjugate acid of the monovalent base are provided in a ratio between 30:70 and 70:30, optionally between 35:65 and 65:35, optionally between 40:60 and 60:40, optionally between 45:55 and 55:45.

[0049] Optionally, the activated carbon is modified with an amine base to produce a derivative of the activated carbon. Optionally, the amine base is tris(hydroxymethyl)aminomethane ("tri-activated carbon").

[0050] Optionally, the activated carbon is modified with an amine base by partially oxidizing the activated carbon to provide carboxylic acid moieties; and coupling the amine base to the carboxylic acid moieties to form amides.

[0051] Also provided herein is a method for manufacturing a container comprising a scavenging material capable of removing N-nitroso compounds, nitrite, or nitrous acid from a headspace within the container.

[0052] The disclosed concepts also include a drug delivery system comprising a blister pack configured to house a plurality of drug dosage forms. The blister pack comprises a backing and a cover attached to the backing. The cover and the backing together form at least one enclosure. The at least one enclosure houses a single drug dosage form and forms a headspace within the volume of the at least one enclosure that is not occupied by the drug dosage form. Additionally, an active agent is positioned in the at least one enclosure. The active agent can be effective to reduce or control the formation and / or concentration of N-nitroso compounds and / or nitrosating agents (e.g., nitrite and / or nitrous acid) in the headspace and / or in the drug dosage form.

[0053] Optionally, the product susceptible to contamination by N-nitroso compounds is a food product. Optionally, the product susceptible to contamination by N-nitroso compounds is a pharmaceutical product.

[0054] Optionally, the shelf life is not less than 1 week, optionally not less than 2 weeks, optionally not less than 3 weeks, optionally not less than 6 weeks, optionally not less than 13 weeks, optionally not less than 26 weeks, optionally not less than 1 year, optionally from 26 weeks to 3 years, optionally from 1 year to 3 years, optionally from 1 year to 2 years, optionally from 2 years to 3 years, optionally about 2 years.

[0055] Optionally, the shelf life is not more than 1 year, optionally not more than 26 weeks, optionally not more than 13 weeks, optionally not more than 6 weeks, optionally not more than 3 weeks, optionally not more than 2 weeks, optionally not more than 1 week, optionally from 1 week to 1 year, optionally from 13 weeks to 1 year.

[0056] Optionally, the product itself contains the N-nitroso compound and / or the nitrosating agent, e.g., nitrite or nitrous acid, prior to packaging, e.g., formed during synthesis or formulation prior to being placed or stored in the container or package. Optionally, the product releases the nitrosating agent, e.g., nitrite or nitrous acid, in the package, i.e., while stored in the container or package, which reacts with the primary or secondary amine without any preventive measures, thereby forming the N-nitroso compound in the product and / or in the headspace of the container or package.

[0057] Optionally, the scavenging material has an initial uptake rate of the N-nitroso compound and / or the nitrosating agent, e.g., nitrite or nitrous acid, that is less than the formation rate of the N-nitroso compound and / or the nitrosating agent, e.g., nitrite or nitrous acid, in the container or package. Optionally, the scavenging material has an initial uptake rate of the N-nitroso compound and / or the nitrosating agent, e.g., nitrite or nitrous acid, that is greater than the formation rate of the N-nitroso compound and / or the nitrosating agent, e.g., nitrite or nitrous acid, in the container or package. Optionally, the N-nitroso compound and / or the nitrosating agent, e.g., nitrite or nitrous acid, is not substantially formed during storage.

[0058] The disclosed concepts also include a method for treating a patient having a medical condition with a pharmaceutical dosage form comprising or forming an N-nitroso compound and / or a nitrosating agent. The method is configured to mitigate potential adverse effects to the patient associated with the N-nitroso compound and / or the nitrosating agent. The method includes providing a package comprising a housing and one or more pharmaceutical dosage forms contained within the housing, wherein a headspace is formed within the volume of the housing that is not occupied by the one or more pharmaceutical dosage forms. The method further includes providing an amount of an active agent, such as a scavenging material, in the headspace that is effective to scavenge the N-nitroso compound and / or the nitrosating agent in the headspace and / or in the pharmaceutical dosage form within the container, or to reduce the rate of formation or inhibit the formation of the N-nitroso compound and / or the nitrosating agent (e.g., nitrite or nitrous acid). The amount of the active agent is separate and spaced apart from the one or more pharmaceutical dosage forms. The one or more pharmaceutical dosage forms are removed from the housing for administration of a therapeutically effective amount of the pharmaceutical to the patient to treat the medical condition with improved patient safety by mitigating the potential adverse effects associated with the pharmaceutical dosage form with the amount of the active agent to reduce the N-nitroso compound and / or the nitrosating agent.

[0059] Optionally, the N-nitroso compound has a formula weight of 300 g / mol or less, optionally 200 g / mol or less, optionally 160 g / mol or less, optionally 120 g / mol or less.

[0060] Optionally, the N-nitroso compound has a vapor pressure of 0.2 torr or more at 20 °C, optionally 0.5 torr or more, optionally 1 torr or more, optionally 2 torr or more, optionally 3 torr or more, optionally 4 torr or more, or optionally 5 torr or more.

[0061] Optionally, the N-nitroso compound has a boiling point of 250 °C or less at atmospheric pressure, optionally 225 °C or less, optionally 200 °C or less, optionally 190 °C or less, optionally 180 °C or less, optionally 170 °C or less, or optionally 160 °C or less.

[0062] Optionally, the N-nitroso compound is an N-nitroso derivative of an aliphatic secondary amine. Optionally, the aliphatic secondary amine is a cyclic amine. Optionally, the aliphatic secondary amine is an acyclic amine.

[0063] Optionally, the aliphatic secondary amine is composed of elements selected from C, H, N, and O.

[0064] Optionally, the aliphatic secondary amine is composed of elements selected from C, H, and N.

[0065] Optionally, the secondary aliphatic amine has 10 or fewer carbons, optionally 8 or fewer carbons, optionally 6 or fewer carbons, optionally 4 or fewer carbons. Optionally, the secondary aliphatic amine has 1, 2, or 3 nitrogens, optionally 1 or 2 nitrogens, optionally 1 nitrogen. Optionally, the secondary aliphatic amine has zero, 1, or 2 oxygens, optionally zero or 1 oxygen, optionally zero oxygen.

[0066] Optionally, the N-nitroso compound has the formula R 1 R 2 N–N=O, where R 1 and R 2 Independently selected from C 1-6 Alkyl, C 3-7 cycloalkyl and 4- to 7-membered heterocycloalkyl.

[0067] Optionally, the N-nitroso compound has the formula R 1 R 2 N–N=O, where R 1 and R 2 Combined to form optionally selected from C 1-6 Alkyl and C 3-7 R of cycloalkyl 3 substituted 4 to 7 membered heterocycloalkyl. Optionally, the 4 to 7 membered heterocycloalkyl is selected from pyrrolidine, piperidine and piperazine.

[0068] Optionally, the N-nitroso compound is selected from N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodi-1-propylamine (NDPA), N-nitrosodi-2-propylamine (NDIPA), N-nitrosodi-1-butylamine (NDBA), N-nitroso-N-ethyl-2-propylamine (NEIPA), N-nitroso-N'-methylpiperazine (NMP), N-nitroso-N'-cyclopentylpiperazine (CPNP) and N-nitrosopyrrolidine (NPYR). Optionally, the N-nitroso compound is N-nitrosodimethylamine. Optionally, the N-nitroso compound is neither 1-methyl-4-nitrosopiperazine, 1-cyclopentyl-4-nitrosopiperazine, nor N-nitroso-3-azabicyclo[3.3.0]octane.

[0069] Optionally, the pharmaceutical dosage form mitigated by the methods, materials, and systems disclosed herein can include one or more of the following or pharmaceutically acceptable salts thereof: metformin, ranitidine, amitriptyline, nortriptyline, betahistine, chloropyramine, citalopram, sumatriptan, lamisil, terbisil, zostavax, tripelennamine, desvenlafaxine, orphenadrine, terbinafine, ethyl isopropylamine, sitagliptin, losartan, valsartan, atomoxetine, lidocaine, azelastine, duloxetine, fluoxetine, chloropyramine, phenylephrine, rasagiline, reboxetine, aripiprazole, mitapivat, rifampicin, alogliptin, ranolazine, rotigotine, azacyclonol, quetiapine, cinacalcet, desloratadine, nintedanib, sildenafil, landiolol, mirabegron, mirtazapine, valaciclovir, pramipexole, ranolazine, ribociclib, tetracaine, trimetazidine, varenicline, vortioxetine, methylphenidate, paroxetine, piperidine, moxifloxacin, daridorexant, rotigotine,Ropivacaine, Ambroxol, Atenolol, Benazepril, Betaxolol, Bisoprolol, Bumetanide, Bupropion, Celiprolol, Cilazapril, Ciprofloxacin, Dabigatran Etexilate, Trimebutine, Diclofenac, Dorzolamide, Enalapril, Esmolol, Isosorbide mononitrate, Imatinib, Isosorbide mononitrate, Indapamide, Ketamine, Labetalol, Leniolisib, Levofloxacin, Lisinopril, Metoprolol, Moxifloxacin, Nebivolol, Perindopril, Arpraziquantel, Propranolol, Pseudoephedrine, Quetiapine, Ramipril, Rivaroxaban, Salbutamol, Sertraline, Sotalol, Tamsulosin, Ticagrelor, Urapidil, Vildagliptin, Gliclazide, Mefenamic acid, Azithromycin, Calcium folinate, Calcium levofolinate, Azithromycin, Hydrochlorothiazide, and Quinapril.

[0070] Optionally, the pharmaceutical dosage form mitigated by the methods, materials, and systems disclosed herein does not comprise any of rifampin, rifapentine, or gliclazide. Optionally, the pharmaceutical dosage form mitigated by the methods, materials, and systems disclosed herein does not comprise a compound having a hydrazone or a semicarbazide moiety. Optionally, the pharmaceutical dosage form mitigated by the methods, materials, and systems disclosed herein does not comprise a compound that can undergo hydrolysis to provide a primary hydrazine.

[0071] It will be appreciated that the materials and methods disclosed herein can be generally applicable to NOCs, including both N-nitrosamines and N-nitrosamides.

[0072] Without intending to be bound by a particular theory, it is believed that certain amines, particularly secondary amines R 1 R 2 NH, are susceptible to nitrosation by nitrous acid, nitrite salts, and other nitrosating agents, thereby forming N-nitrosamines that are often genotoxic and / or carcinogenic. Nitrosation can generally occur at any time during the synthesis, formulation, or storage of a pharmaceutical product.

[0073] In certain embodiments, the chemical formula is R 1 R 2 N-NO, is produced during the decomposition of a product or pharmaceutical product, where R 1 and R 2 are independently selected from alkyl, or R 1 , R 2 combines with the intervening nitrogen to form an optionally substituted heterocycloalkyl group. Optionally, the nitrosamine R 1 R 2 N-NO is formed from a secondary amine R 1 R 2 NH that is present in the product or pharmaceutical product, as a contaminant formed during synthesis or formulation in the product or pharmaceutical product, or as a decomposition product that reacts with nitrous acid and / or nitrite salts.

[0074] Without limitation, compounds having the partial chemical structure R 1 R 2 N-C(=X 1 )-X 2 -(where X 1 and X 2 are independently selected from NH, O, and S) can undergo cleavage to provide a secondary amine R 1 R 2 NH.

[0075] Without limitation, compounds having the partial chemical structure R 1 R 2 N-N=C- can undergo cleavage to provide a secondary amine R 1 R2 NH.

[0076] Non-limitingly, compounds having the partial chemical structure R 1 R 2 Compounds having the partial chemical structure R 1 R 2 NH.

[0077] Optionally, compounds having the partial chemical structure R 1 R 2 Compounds having the partial chemical structure R 1 R 2 N-NO. Optionally, compounds having the partial chemical structure R 1 R 2 Compounds having the partial chemical structure R 1 R 2 N-NO.

[0078] Optionally, excipients used in formulating a compound or drug product can comprise nitrous acid and / or a nitrous acid salt, which are capable of reacting with a secondary or tertiary amine in the compound or drug product to produce a nitrosamine R 1 R 2 N-NO. Optionally, the excipient is microcrystalline cellulose (MCC), colloidal silicon dioxide, hypromellose (HPMC), povidone, mannitol, talc, sodium lauryl sulfate, polyvinyl alcohol, sodium starch glycolate, hydroxypropyl cellulose, poloxamer, citric acid, sodium chloride, sucrose, magnesium stearate, lactose monohydrate, corn starch, starch, croscarmellose sodium, polyethylene glycol, or crospovidone.

[0079] In certain embodiments, nitrosamine impurities such as N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), and N-nitrosodiisopropylamine (NDIPA) are produced from compounds that are nitrosatable, such as a primary amine, a secondary amine (e.g., diethylamine), or a tertiary amine or quaternary ammonium salt, in reaction with a nitrosating agent such as nitrous acid, which is formed in situ from a nitrous acid salt such as sodium nitrite.

[0080] Optionally, the scavenging material binds to a portion of the N-nitroso compound, thereby removing the portion of the N-nitroso compound from the gas phase. Optionally, the scavenging material binds in a substantially reversible manner. Optionally, the scavenging material binds in a substantially irreversible manner. Optionally, the process of binding of the scavenging material to the N-nitroso compound involves formation of a covalent bond. Optionally, the scavenging material binds to the N-nitroso compound in a non-covalent manner.

[0081] Optionally, a portion of the N-nitroso compound chemically reacts in the presence of the scavenging material, thereby removing the portion of the N-nitroso compound from the gas phase. Optionally, the chemical reaction is oxidation. Optionally, the chemical reaction is reduction. Optionally, the chemical reaction is addition. Optionally, the chemical reaction is cycloaddition. Optionally, the chemical reaction is mediated by a free radical process.

[0082] Optionally, the scavenging material comprises an acid. Optionally, the acid increases the binding affinity of the scavenging material for the N-nitroso compound. Optionally, the acid facilitates the chemical reaction of a portion of the N-nitroso compound.

[0083] Optionally, the product or drug product contains an N-nitroso compound prior to packaging. Optionally, the container has sufficient scavenging capacity to reduce the amount of N-nitroso compound to below a hazardous level during a storage period of 52 weeks, optionally 26 weeks, optionally 13 weeks, optionally 8 weeks, optionally 4 weeks, optionally 2 weeks, optionally 1 week after packaging.

[0084] Optionally, the product or drug product contains an N-nitroso compound prior to packaging. Optionally, the N-nitroso compound forms during storage of the product or drug product without any preventative measures. Optionally, the container has sufficient scavenging capacity to prevent accumulation of the N-nitroso compound to a hazardous level during a storage period of 1 week, optionally 2 weeks, optionally 4 weeks, optionally 6 weeks, optionally 13 weeks, optionally 26 weeks, optionally 52 weeks after packaging.

[0085] Optionally, the product or drug product is stored within the container at substantially ambient temperature.

[0086] Optionally, the maximum temperature of the container during storage does not exceed 50 °C. In further embodiments, the maximum temperature is 45 °C or less, optionally 40 °C or less, optionally 35 °C or less, or optionally 30 °C or less.

[0087] Optionally, the minimum temperature of the container during storage is not less than -40 °C. In further embodiments, the minimum temperature is -35 °C or more, optionally -30 °C or more, optionally -25 °C or more, optionally -20 °C or more, optionally -15 °C or more, optionally -10 °C or more, optionally -5 °C or more, optionally 0 °C or more, optionally 5 °C or more, optionally 10 °C or more, or optionally 15 °C or more, optionally 20 °C or more.

[0088] In certain embodiments, the scavenging material is provided in at least one entraining polymer. In certain embodiments, the scavenging material meets the requirements for an "active agent" as defined herein.

[0089] In certain embodiments, the entraining polymer comprises a base polymer and optionally a channeling agent.

[0090] In certain embodiments, the base polymer comprises 10% to 70% by weight of the total composition, optionally 20% to 60% by weight, optionally 20% to 50% by weight, optionally 20% to 40% by weight, optionally 30% to 70% by weight, optionally 30% to 60% by weight, optionally 30% to 50% by weight, optionally 40% to 70% by weight, optionally 40% to 60% by weight, optionally 40% to 50% by weight.

[0091] In certain embodiments, the channeling agent ranges from 1% to 20% by weight, optionally 1% to 15% by weight, optionally 1% to 10% by weight, optionally 1% to 5% by weight, optionally 5% to 20% by weight, optionally 5% to 15% by weight, optionally 5% to 10% by weight, optionally 10% to 20% by weight, optionally 10% to 15% by weight, relative to the total weight of the entraining polymer.

[0092] Optionally, the container further comprises a desiccant. Optionally, the desiccant comprises silica or silica gel.

[0093] Optionally, the container blocks light and / or UV radiation.

[0094] Certain embodiments disclosed herein provide methods for obtaining a pharmaceutically active composition substantially free of N-nitroso compounds, including but not limited to nitrosamines. In some embodiments, the composition contains a total amount of N-nitroso compounds less than 1500 ppm, optionally less than 400 ppm, optionally less than 100 ppm, optionally less than 95 ppm, optionally less than 90 ppm, optionally less than 85 ppm, optionally less than 80 ppm, optionally less than 75 ppm, optionally less than 70 ppm, optionally less than 65 ppm, optionally less than 60 ppm, optionally less than 55 ppm, optionally less than 50 ppm, optionally less than 45 ppm, optionally less than 40 ppm, optionally less than 35 ppm, optionally less than 25 ppm, optionally less than 20 ppm, optionally less than 15 ppm, optionally less than 14 ppm, optionally less than 13 ppm, optionally less than 12 ppm, optionally less than 11 ppm, optionally less than 10 ppm, optionally less than 9 ppm, optionally less than 8 ppm, optionally less than 7 ppm, optionally less than 6 ppm, optionally less than 5 ppm, optionally less than 4 ppm, optionally less than 3 ppm, optionally less than 2 ppm, optionally less than 1 ppm, optionally less than 0.9 ppm, optionally less than 0.8 ppm, optionally less than 0.7 ppm, optionally less than 0.6 ppm, optionally less than 0.5 ppm, optionally less than 0.4 ppm, optionally less than 0.3 ppm, optionally less than 0.2 ppm, optionally less than 0.1 ppm. In some embodiments, the standard daily dose of the composition is less than 400 ng, optionally less than 200 ng, optionally less than 100 ng, optionally less than 50 ng, optionally less than 26.5 ng, optionally less than 25 ng, optionally less than 20 ng, optionally less than 10 ng, optionally less than 5 ng. In some embodiments, the dose of the composition contains less than 100%, optionally less than 90%, optionally less than 80%, optionally less than 70% of the content allowed by the FDA or EMA effective as of January 1, 2024.

[0095] Certain embodiments disclosed herein provide methods for reducing the amount of N-nitroso compounds, including but not limited to nitrosamines, in a pharmaceutically active composition. In some embodiments, the reduction in the amount of N-nitroso compounds is achieved by scavenging the N-nitroso compounds. In some embodiments, the reduction in the amount of N-nitroso compounds is achieved by reducing the amount of primary hydrazine in the composition. In some embodiments, the reduction in the amount of N-nitroso compounds is achieved without reducing the amount of primary hydrazine in the composition. In some embodiments, the reduction in the amount of N-nitroso compounds is achieved by hydrolyzing a hydrazone or semicarbazone in a compound comprising the pharmaceutically active composition. In some embodiments, the reduction in the amount of N-nitroso compounds is achieved without hydrolyzing a hydrazone or semicarbazone in a compound comprising the pharmaceutically active composition.

[0096] Also provided are embodiments wherein any of the above embodiments can be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.

[0097] As used herein, two embodiments are "mutually exclusive" when one embodiment is defined as being different from the other.

[0098] definition

[0099] As used herein, the following terms have the specified meanings.

[0100] List of Abbreviations

[0101] au = arbitrary units; GC = gas chromatography; GC-MS (or GC-MSD) = gas chromatography-mass spectrometry; h = hour(s); NDMA = N-nitrosodimethylamine; NDEA = N-nitrosodiethylamine; NDPA = N-nitrosodi-l- propanamine; NDIPA = N-nitrosodi-2-propanamine; NDBA = N-nitrosodi-l- butanamine; NEIPA = N-nitroso-N-ethyl-2-propanamine; NMP = N-nitroso-N'- methylpiperazine; CPNP = N-nitroso-N'-cyclopentylpiperazine; NPYR = N- nitrosopyrrolidine; TG-DTA = thermogravimetric / differential thermal analysis; TPSR = temperature programmed surface reaction.

[0102] As used herein, the term "selected material" is defined as a material that is acted upon or interacts or reacts with an active agent and is capable of being transported through a channel with an entraining polymer. The selected material of primary interest in this specification is an N-nitrosamine.

[0103] As used herein, the term "amine" means a compound R 1 R 2 R 3 N, wherein R 1, R 2 and R 3 are independently selected from H, alkyl, and aryl, and two of R 1 , R 2 and R 3 may combine to form a ring. The term “primary amine” refers to an amine in which two of R 1 , R 2 and R 3 are H. The term “secondary amine” refers to an amine in which one of R 1 , R 2 and R 3 is H. The term “tertiary amine” refers to an amine in which none of R 1 , R 2 and R 3 are H. The term “cyclic amine” refers to an amine in which two of R 1 , R 2 and R 3 combine to form a ring. The term “acyclic amine” refers to an amine in which none of R 1 , R 2 and R 3 combine to form a ring. The term “aliphatic amine” refers to an amine in which R 1 , R 2 and R 3 are independently selected from H and alkyl, and two of R 1 , R 2 and R 3 may combine to form a ring. The term “aryl amine” refers to an amine in which at least one of R 1 , R 2 and R 3 is aryl.

[0104] As used herein, the term “active agent” is defined as a material that (1) is preferably not miscible with the base polymer and will not melt upon mixing and heating with the base polymer and channel forming agent, i.e., it has a higher melting point than the base polymer or channel forming agent, and (2) acts on, interacts with, or reacts with the selected material. The term “active agent” can include, but is not limited to, a material that absorbs, adsorbs, or releases the selected material. The “active agent” can include a “scavenging material”. In the present disclosure, a preferred active agent is activated carbon or a derivative thereof.

[0105] As used herein, the term "base polymer" is a polymer that optionally has a gas transport rate of a selected material that is substantially lower than, lower than, or substantially comparable to the gas transport rate of the channel forming agent. For example, in embodiments where the selected material is an N-nitroso compound and the active agent is a scavenging material capable of removing the N-nitroso compound from the volume of gas in contact with the entrained polymer, such transport rate is a vapor transport rate. The primary function of the base polymer is to provide structure to the entrained polymer.

[0106] Base polymers suitable for use in the present disclosure include thermoplastic polymers, for example, polyolefins such as polypropylene and polyethylene, polyisoprene, polybutadiene, polybutene, polysiloxane, polycarbonate, polyamide, ethylene-vinyl acetate copolymer, ethylene-methacrylate copolymer, poly(vinyl chloride), polystyrene, polyester, polyacid anhydride, polyacrylonitrile, polysulfone, polyacrylate, acrylic, polyurethane, and polyacetal, or copolymers or mixtures thereof.

[0107] In certain embodiments, the vapor transport rate of the channel forming agent is at least two times the vapor transport rate of the base polymer. In other embodiments, the vapor transport rate of the channel forming agent is at least five times the vapor transport rate of the base polymer. In other embodiments, the vapor transport rate of the channel forming agent is at least ten times the vapor transport rate of the base polymer. In still other embodiments, the vapor transport rate of the channel forming agent is at least twenty times the vapor transport rate of the base polymer. In still another embodiment, the vapor transport rate of the channel forming agent is at least fifty times the vapor transport rate of the base polymer. In still other embodiments, the vapor transport rate of the channel forming agent is at least one hundred times the vapor transport rate of the base polymer.

[0108] As used herein, the term "a channel forming agent" or "channel forming agents" is defined as a material that is not miscible with the base polymer and has an affinity to transport fluid (liquid or gas phase) species at a faster rate than the base polymer. Optionally, the channel forming agent is capable of forming channels through the entrained polymer when formed by mixing the channel forming agent with the base polymer. Optionally, such channels are capable of transporting the selected material through the entrained polymer at a faster rate than in the base polymer alone.

[0109] As used herein, the term "channel" or "interconnected channels" is defined as a passageway that is formed by the channel forming agent that penetrates the base polymer and can be interconnected to one another.

[0110] As used herein, the term "entrained polymer" is defined as a monolithic material formed at least from a base polymer, an active agent, and optionally also an entrained or integrally distributed channel forming agent. Thus, the entrained polymer has at least two phases (without a channel forming agent) or at least three phases (with a channel forming agent).

[0111] As used herein, the term "headspace" is defined as the volume within a package that is not occupied by the goods or product stored therein. The singular term "headspace" generally, but not necessarily, refers to a contiguous volume. The use of the term "headspace" does not imply a lower limit on the volume. Optionally, the headspace can be filled with a gas or gas mixture, the composition of which is different from the atmosphere. Unless otherwise specified, the gas within the headspace does not exchange significantly with the external atmosphere.

[0112] Some packages can provide separate compartments for individual units of goods or product, including but not limited to individual tablets, or alternatively, groups of tablets, each tablet contained within a single compartment, and the headspace of each compartment isolated from the other compartments in the package. The package is described as having multiple headspaces, one for each compartment. The design of such a package allows for the extraction of a single unit of goods or product while leaving the remaining compartments in the package intact.

[0113] As used herein, the term "monolithic," "monolithic structure," or "monolithic composition" is defined as a composition or material that is not composed of two or more discrete macroscopic layers or portions. Thus, a "monolithic composition" does not include a multilayer composite (although a monolithic composition can be a layer of a multilayer composite).

[0114] The term "nitrite," as used herein, alone or in combination, refers to a compound of the general formula R-O-N=O, wherein R is selected from H, M + and organic moieties. The term also includes salts M a (NO2) b and the anion NO2 - Thus, the term includes compounds such as HONO (nitrous acid), NaNO2 (sodium nitrite), Ca(NO2)2 (calcium nitrite), and (CH3)2CHCH2CH2ONO (isopentyl nitrite).

[0115] As used herein, the term "phase" is defined as a part or constituent of a monolithic structure or composition that is uniformly distributed throughout to provide an overall property of the structure or composition.

[0116] As used herein, the term "three-phase" is defined as an overall composition or structure that contains three or more phases. An example of a three-phase composition according to the present disclosure is an entrained polymer formed from a base polymer, an active agent, and a channel-forming agent. Optionally, the three-phase composition or structure can include additional phases, such as a colorant, but is still considered "three-phase" given the presence of the three primary functional components.

[0117] In addition, the terms "package," "packaging," and "container" are used interchangeably herein to refer to a vessel having an enclosure that holds or contains a commodity (e.g., a food product or foodstuff, a pharmaceutical product, or a diagnostic test). Optionally, a package can include a container in which a product is stored. Non-limiting examples of packages, packaging, and containers include trays, boxes, cartons, bottle containers, vessels, pouches, and flexible bags. Pouches or flexible bags can be made of, for example, polypropylene or polyethylene. Packages or containers can be closed, covered, and / or sealed using various mechanisms, including, for example, covers, lids, caps, lidding sealants, adhesives, and heat seals. Packages or containers are constructed or structured from various materials, such as plastic (e.g., polyethylene or polypropylene), paper, foamed polystyrene, glass, metal, and combinations thereof. In one optional embodiment, a package or container is constructed from a rigid or semi-rigid polymer, optionally polypropylene or polyethylene, and optionally has sufficient rigidity to maintain its shape under gravity.

[0118] The term "container" can refer to a single object capable of holding one or more individual commodities, including but not limited to pills, tablets, capsules, caplets, liquids, powders, or any other type of individual object. Optionally, a container has a single interior space. Optionally, a container is partitioned into interior compartments. Optionally, a container partitioned into interior compartments is a blister pack. Optionally, interior compartments allow for vapor exchange. Optionally, individual compartments are isolated from one another. Optionally, individual objects comprise a pharmaceutical, a nutritional supplement, a herbal supplement, or the like. Optionally, individual objects occupy individual compartments in a container. Optionally, each individual object can be packaged in an individual compartment in a container. Optionally, a top space of each individual compartment is isolated from all other compartments. Optionally, a combination of individual compartments and channels for vapor communication between individual compartments form a single continuous volume. Optionally, a top space of each individual compartment is isolated from all other compartments.

[0119] Optionally, the active pharmaceutical ingredient of the pharmaceutical dosage form mitigated by the methods and materials of the present disclosure is selected from the group consisting of angiotensin-II-receptor antagonists and histamine H2 receptor antagonists. Optionally, the active pharmaceutical ingredient is selected from the group consisting of Losartan, Valsartan, Irbesartan, Candesartan, Olmesartan, Eprosartan, Azilsartan, Telmisartan, Ranitidine, Metformin, Nizatidine, Pioglitazone, Rifampicin, and Rifapentine.

[0120] As used herein, the term "scavenging material" is defined as a material capable of removing a compound of interest from a volume of gas. Optionally, removal can be accomplished by non-covalent binding of the compound of interest to the scavenging material. Optionally, the scavenging material is capable of keeping the concentration of the compound of interest low when the compound of interest is introduced into the volume of gas. In certain embodiments, the scavenging material comprises an entraining polymer comprising an active agent, and the compound of interest is a nitrite and / or nitrous acid. The scavenging material includes, but is not limited to, activated carbon or derivatives thereof, such as tri-activated carbon. The scavenging material can be entrained in at least one base polymer having optional channels therethrough.

[0121] As used herein, alone or in combination, the term "hydrazine" refers to a compound comprising the moiety -N-NR 1 R 2 -N-NR 3 R 4 wherein R 1 and R 2 are independently selected from H and substituted or unsubstituted alkyl, cycloalkyl, and aryl. As used herein, alone or in combination, the term "primary hydrazine" refers to a hydrazine where at least one of R 1 and R 2 is H.

[0122] As used herein, alone or in combination, the term "hydrazone" refers to a compound comprising the moiety -C=N-NR 1 R 2 wherein R 1 and R 2 are independently selected from H and substituted or unsubstituted alkyl, cycloalkyl, and aryl.

[0123] As used herein, alone or in combination, the term "semicarbazone" refers to a compound comprising the moiety -C=0-NH-NR 1 R 2 wherein R 1 and R 2independently selected from H and substituted or unsubstituted alkyl, cycloalkyl, and aryl.

[0124] As used herein, alone or in combination, the term "activated carbon" refers to a carbonaceous material that has been treated to increase surface area and / or porosity. In some embodiments, the activated carbon is obtained from coal or charcoal. As used herein, alone or in combination, the term "activated carbon derivative" refers to activated carbon that has been physically or chemically modified to improve the adsorptive capacity of the activated carbon. In some embodiments, the activated carbon is modified by chemical oxidation or auto-oxidation. In some embodiments, oxidation of the activated carbon forms carboxyl (-COOH) groups. In some further embodiments, the carboxyl groups thus formed are coupled with primary or secondary amines (NHR 1 R 2 ) to introduce amide moieties (-CONR 1 R 2 ). In yet further embodiments, the carboxyl groups are coupled with tris(hydroxymethyl)aminomethane ("tris") NH2-C(CH2OH)3 to introduce the following amide moiety: -CONHC(CH2OH)3.

[0125] In some embodiments, the activated carbon is modified by nitration. In some embodiments, the oxidized activated carbon is further modified by coupling with a compound having an amine or an ammonia, respectively, to provide an amide. In some embodiments, the oxidized activated carbon is further modified by coupling with an alcohol to provide an ester. In some embodiments, the activated carbon derivative is obtained by reacting the activated carbon with an acid, including but not limited to HNO3, H2O2, HCIO, H2SO4, and CH3COOH. In some embodiments, the activated carbon derivative is obtained by reacting the activated carbon with a base, including but not limited to NaOH, KOH, and NH3. In some embodiments, the activated carbon derivative is obtained by reacting the activated carbon with a metal salt, including but not limited to salts containing transition metal ions, including but not limited to Fe 2+ , Fe 3+ , Cu 2+ , Zn 2+ , Ni 2+ , Co 3+ .

[0126] As used herein, alone or in combination, the term "N-nitroso" refers to a functional group of the general formula -N-N=O.

[0127] As used herein, alone or in combination, the term "N-nitroso compound scavenging" refers to the process of removing N-nitroso compounds (including, but not limited to, nitrosamines) from a volume of a solid, liquid, or gas. In some embodiments, the scavenging process includes a chemical modification step, thereby removing the N-nitroso molecule from the molecule. In some embodiments, the chemical modification is selected from the group consisting of reduction, oxidation, cleavage (including hydrolysis), and condensation. In some embodiments, the scavenging process includes an adsorption step, including, but not limited to, adsorption to a surface and adsorption into a volume, thereby reducing the amount of free N-nitroso compound in the solid, liquid, or gas.

[0128] Due to the large surface area within the structure of activated carbon, activated carbon or its derivatives (e.g., ternary activated carbon) have the function of absorbing or adsorbing N-nitroso compounds and / or nitrosating agents (e.g., nitrite salts and / or nitrous acid). Further chemical treatment can enhance the absorption or adsorption properties of activated carbon or its derivatives.

[0129] Without wishing to be bound by mechanism of action, the scavenging material has the function of removing, reducing, scavenging, controlling, or altering the level of N-nitroso compounds and / or nitrosating agents (e.g., nitrite salts and / or nitrous acid) in the environment.

[0130] Optionally, the scavenging material adsorbs or absorbs moisture. In further embodiments, the scavenging material is a desiccant.

[0131] Activated carbon or its derivatives (e.g., ternary activated carbon) can be provided in any form, such as: a powder form, a pulverized form, a particulate form, a pellet form, a spherical form, or a cylindrical form.

[0132] Optionally, the scavenging material is provided in one or more scavenging articles. Optionally, each of the one or more scavenging articles is integral to, attached to, or chemically bound to the interior of the container. Optionally, each of the one or more scavenging articles is incorporated with a wall, a lid, a cap, or a covering of the container. Optionally, each individual compartment in a partitioned container is equipped with at least one scavenging article.

[0133] Exemplary Entrained Polymers

[0134] Conventionally, desiccants, oxygen absorbers, and other active agents have been used in a raw form, e.g., as loose particulates contained in a sachet or canister, within a package to control the interior environment of the package. For many applications, it is undesirable to have such loose storage of active materials. Accordingly, the present application provides compacted components or active-entrained polymers comprising active agents, where such polymers can be extruded and / or molded into a variety of desired forms, e.g., container liners, plugs, film sheets, pellets, and other such materials.

[0135] Optionally, such active-entraining polymers can include a channeling agent, such as polyethylene glycol (PEG), that forms channels between the surface of the entraining polymer and its interior to transport selected materials (e.g., moisture) to the entraining active (e.g., a desiccant to absorb moisture). As explained above, the entraining polymer can be a two-phase formulation (i.e., comprising a base polymer and an active without a channeling agent) or a three-phase formulation (i.e., comprising a base polymer, an active, and a channeling agent). Entraining polymers are described, for example, in U.S. Patent Nos. 5,911,937; 6,080,350; 6,124,006; 6,130,263; 6,194,079; 6,214,255; 6,486,231; 7,005,459; and U.S. Patent Publication No. 2016 / 0039955, each of which is incorporated by reference as if complete.

[0136] Base polymers suitable for use in the present disclosure include thermoplastic polymers, for example, polyolefins such as polypropylene and polyethylene, polyisoprene, polybutadiene, polybutene, polysiloxane, polycarbonate, polyamide, ethylene-vinyl acetate copolymer, ethylene-methacrylate copolymer, poly(vinyl chloride), polystyrene, polyester, polyacid anhydride, polyacrylonitrile, polysulfone, polyacrylate, acrylic, polyurethane, and polyacetal, or copolymers or mixtures thereof.

[0137] Suitable channeling agents in the present disclosure include polyglycols such as polyethylene glycol (PEG), ethylene-vinyl alcohol (EVOH), polyvinyl alcohol (PVOH), glycerol polyamine, polyurethane, and polycarboxylic acids including polyacrylic acid or polymethacrylic acid. Alternatively, the channeling agent can be, for example, a water-insoluble polymer such as polypropylene oxide monobutyl ether commercially available under the trade name Polyglykol B01 / 240 produced by Clariant. In other embodiments, the channeling agent can be polypropylene oxide monobutyl ether commercially available under the trade name Polyglykol B01 / 20 produced by Clariant, polypropylene oxide commercially available under the trade name Polyglykol D01 / 240 produced by Clariant, ethylene vinyl acetate, nylon 6, nylon 66, or any combination of the foregoing.

[0138] drug

[0139] Certain materials, articles, and methods can be used to store pharmaceutical products susceptible to contamination by N-nitroso compounds. Optionally, the N-nitroso compounds are formed during synthesis or processing of the pharmaceutical product. Optionally, the N-nitroso compounds are formed during storage of the pharmaceutical product without any preventative measures.

[0140] Optionally, the drug product is provided in solid, liquid, cream, or gel form. Optionally, the drug product is provided in granular or powder form. Optionally, the drug product is provided in the form of a pill or tablet. Optionally, the pill or tablet provided is not externally coated. Optionally, the drug product is packaged in the container in a multi-dose supply. Optionally, a single dose corresponds to a single pill or tablet. Optionally, a single dose corresponds to a small number of pills or tablets, for example, 2, 3, or 4 pills or tablets. Optionally, the package comprises a plurality of compartments, each of which is isolated from the other compartments in the package by a headspace. Optionally, a single dose is packaged into each individual compartment in the package. Optionally, the package allows a dose to be extracted from a single compartment without affecting the remaining compartments which still contain a single dose.

[0141] Entrained polymers containing active agents

[0142] Optionally, the active agent is a component of an entrained polymer, the entrained polymer being at least two phases and comprising the active agent and a base polymer. Optionally, the entrained polymer is at least three phases and comprises the active agent, the base polymer, and a channeling agent. The form of the entrained polymer is not limited. Optionally, such an entrained polymer is in the form of a film, a sheet, a liner, or a plug.

[0143] Generally, it is believed that the higher the concentration of active agent in the mixture, the greater the absorption, adsorption, or release capacity (as the case can be) of the final composition. However, too high a concentration of active agent results in a more brittle entrained polymer and a more difficult to thermoform, extrude, or injection mold molten mixture of active agent, base polymer material, and channeling agent.

[0144] In one embodiment, the loading level or concentration of active agent can range from 20% to 80% by weight, optionally 30% to 70% by weight, optionally 30% to 60% by weight, optionally 30% to 50% by weight, optionally 35% to 70% by weight, optionally 35% to 60% by weight, optionally 35% to 55% by weight, optionally 35% to 50% by weight, optionally 40% to 70% by weight, optionally 40% to 60% by weight, optionally 40% to 50% by weight, optionally 45% to 60% by weight, optionally 50% to 60% by weight, relative to the total weight of the entrained polymer.

[0145] In one embodiment, the base polymer ranges from 10% to 70% by weight of the total composition, optionally 20% to 60% by weight, optionally 20% to 50% by weight, optionally 20% to 40% by weight, optionally 30% to 70% by weight, optionally 30% to 60% by weight, 30% to 50% by weight, optionally 40% to 70% by weight, optionally 40% to 60% by weight, optionally 40% to 50% by weight of the total composition.

[0146] In one embodiment, the channel forming agent ranges from 1% to 20% by weight, optionally 1% to 15% by weight, optionally 1% to 10% by weight, optionally 1% to 5% by weight, optionally 5% to 20% by weight, optionally 5% to 15% by weight, optionally 5% to 10% by weight, optionally 10% to 20% by weight, optionally 10% to 15% by weight, relative to the total weight of the entraining polymer.

[0147] In one embodiment, the entraining polymer can be a triphasic formulation comprising 50% by weight of the active agent, 38% by weight of ethyl vinyl acetate (EVA) as the base polymer, and 12% by weight of polyethylene glycol (PEG) as the channel forming agent.

[0148] According to the disclosed concept, the entraining polymer includes a base polymer and an active agent (in this case activated carbon or a derivative thereof) dispersed in the base polymer. Optionally, the entraining polymer can also include a channel forming agent, which is preferably polymeric. The channel forming agent can form interconnected channels through the entraining polymer. At least some of the active agent is contained within these channels, such that the channels communicate between the active agent and the exterior of the entraining polymer through channel openings formed at the exterior surface of the entraining polymer.

[0149] The entraining polymer can be formed in various ways. For example, the entraining polymer can be in the form of a plug or pellet configured to be deposited in a container. Alternatively, the entraining polymer can be in the form of an extruded or cast film. Alternatively, the entraining polymer is in the form of a blown film, as described herein. Alternatively, the entraining polymer can be in the form of a container insert, or integral with the inner wall of a container housing, such as a layer of a blown bottle. Optionally, the skilled person can utilize the teachings of U.S. Patent Publication No. 2021 / 0245413, which is incorporated by reference herein in its entirety, to manufacture a blown bottle incorporating activated carbon or a derivative thereof as the active agent in an active layer of the bottle.

[0150] The interconnected channels in the entraining polymer, such as those disclosed herein, can help facilitate the transport of a desired material, such as a volatilized nitrosamine, through the entraining polymer and to the activated carbon or derivative thereof dispersed in the base polymer. In other words, the base polymer itself acts as a barrier substance in which the active agent can be entrained. The interconnected channels formed by the channel forming agent provide a pathway for the desired material to move through the entraining polymer.

[0151] Optionally, the entraining polymer can be in the form of an active sheet or film that is used in combination with a barrier sheet to form a composite material. The barrier sheet can be a substrate, such as a foil and / or a polymer having low moisture or oxygen permeability. The barrier sheet is compatible with the entraining polymer structure and is thus configured to thermally bond with the active sheet or film when the active sheet or film is solidified after extrusion or casting. Optionally, the entraining polymer is an extruded film that is heat fixed to a substrate, such as disclosed in U.S. Patent No. 8,142,603, which is incorporated by reference herein in its entirety.

[0152] Optionally, the active sheet or film is combined with a barrier sheet to form a package that has active properties at the interior surface formed by the entraining polymer in the active sheet or film and vapor resistant properties at the exterior surface formed by the barrier sheet. In this embodiment, the active sheet or film occupies a portion of the barrier sheet.

[0153] Optionally, the multi-layer film is generated by various routes, including extrusion, injection molding, vapor deposition, solvent casting, 100% solid state cooling, water dispersion, and blown film. The morphology of the multi-layer film contains 2-70% activated carbon or derivative thereof. The reaction rate can be controlled by introducing various concentrations of channel forming agents and active agents.

[0154] Optionally, the entraining polymer is positioned in a container, and the interior facing portion of the container is substantially entirely comprised of the entraining polymer. Optionally, the container is manufactured such that the entraining polymer is located above the level of the product contained in the package, thereby avoiding direct contact of the active agent with the product.

[0155] Embodiments are also provided in which the scavenging material is not in the form of an entraining polymer. Optionally, the scavenging material is provided in a pouch or canister that is inserted into the package. Optionally, the pouch or canister contains one or more holes that are small enough to retain the scavenging material within the pouch or canister. Optionally, the pouch or canister is included in the package so as to be located above the level of the product contained in the package, thereby avoiding direct contact of the scavenging material (e.g., pouch or canister) with the product.

[0156] Blown film

[0157] In an aspect, provided herein is a blown film material comprising a base polymer and an active agent, and optionally a channel forming agent. The active agent includes scavenging material, which includes activated carbon, such as a ternary activated carbon.

[0158] Optionally, the base polymer is selected from polyolefins, polyamides, and polyesters. Optionally, the base polymer is selected from polyolefins and polyesters. Optionally, the base polymer is selected from polyethylene, polypropylene, polyethylene / polypropylene copolymer, and poly(lactic acid).

[0159] Optionally, the base polymer has the chemical formula (-CHR-X-) n where -X- is selected from -CH2-, -COO-, and -CONH-, and R is selected from H and n-C 1-10 alkyl.

[0160] Optionally, the base polymer comprises at least one block copolymer.

[0161] Optionally, the base polymer comprises a block copolymer comprising a block of ester monomer. In some further embodiments, the base polymer comprises a block copolymer comprising a block of poly(alkylene) terephthalate monomer. In some further embodiments, the alkylene is selected from ethylene, propylene, and butylene.

[0162] Optionally, the base polymer comprises a block copolymer comprising a block of polyether diol.

[0163] Optionally, the base polymer comprises a block copolymer comprising both a block of ester monomer and a block of polyether diol. Optionally, the base polymer comprises a block copolymer. Optionally, the base polymer comprises 7246.

[0164] Optionally, the base polymer comprises an ethylene / alpha-olefin copolymer. In some further embodiments, the alpha-olefin is selected from propylene, 1-butene, 1-pentene; 1-pentene with one or more methyl, ethyl, or propyl substituents; 1-hexene; 1-hexene with one or more methyl, ethyl, or propyl substituents; 1-heptene; 1-heptene with one or more methyl, ethyl, or propyl substituents; 1-octene; 1-octene with one or more methyl, ethyl, or propyl substituents; 1-nonene; 1-nonene with one or more methyl, ethyl, or propyl substituents; 1-decene with ethyl, methyl, or dimethyl substituents; 1-dodecene; and styrene. In some further embodiments, the alpha-olefin is selected from propylene, 1-butene, 1-pentene, 1-hexene, 1-heptene, 1-octene, 1-nonene, 1-decene, and 1-dodecene.

[0165] Optionally, the base polymer comprises two block copolymers. In some further embodiments, one of the two block copolymers is an ethylene / alpha-olefin copolymer as disclosed herein. In some further embodiments, the base polymer comprises EXACT TM 3040. In some further embodiments, one of the two block copolymers is a block copolymer containing both blocks of ester monomers as disclosed herein and blocks of polyether diols. In some further embodiments, the base polymer comprises 7246. In some further embodiments, the base polymer comprises EXACT TM 3040 and 7246. In some further embodiments, the base polymer comprises EXACT TM 3040 and 7246. In some further embodiments, the base polymer comprises EXACT

[0166] Optionally, the base polymer comprises both a polyolefin and a polyester. Optionally, the polyolefin comprises between 10 wt.% and 40 wt.% of the total composition, optionally between 15 wt.% and 30 wt.%. Optionally, the polyester comprises between 20 wt.% and 80 wt.% of the total composition, optionally between 25 wt.% and 70 wt.%, optionally between 30 wt.% and 60 wt.%. Optionally, the polyolefin has the chemical formula (-CH2CHR-) n , and R is selected from H and n-C 1-10 alkyl. Optionally, the polyester has the chemical formula ((-CH2) m COO-) n , and m is selected from 1, 2, 3, 4, and 5. Optionally, the polyester has the chemical formula (-CHRCOO-) n , and R is selected from H and n-C 1-10 alkyl.

[0167] Also provided is a method of manufacturing a blown film material as disclosed herein, the method comprising the steps of: extruding a suitable precursor material (e.g., a molten mixture of a polymer and a scavenger material) in a screw extruder and warming; passing the warmed material through a tubular die; expanding and stretching the warmed material under positive pressure; and allowing the expanded and stretched material to cool.

[0168] Optionally, the extruding is performed at a temperature between 140 °C and 190 °C, optionally between 145 °C and 175 °C, optionally between 150 °C and 170 °C, optionally between 150 °C and 165 °C. As used herein, the term “between” includes the endpoints of the numerical range.

[0169] Optionally, the extrusion is conducted at a rate of 5 rpm or more, optionally 10 rpm or more, optionally 15 rpm or more, optionally 25 rpm or more, optionally 35 rpm or more, optionally 45 rpm or more, optionally 55 rpm or more.

[0170] Optionally, the extrusion is conducted at a rate of 65 rpm or less, optionally 55 rpm or less, optionally 45 rpm or less, optionally 35 rpm or less, optionally 30 rpm or less, optionally 25 rpm or less, optionally 20 rpm or less.

[0171] Optionally, the extrusion is conducted at a rate of between 10 rpm and 75 rpm, optionally between 15 rpm and 65 rpm, optionally between 15 rpm and 60 rpm, optionally between 20 rpm and 50 rpm.

[0172] Optionally, the extrusion is conducted at a rate of between 5 rpm and 35 rpm, optionally between 10 rpm and 30 rpm, optionally between 10 rpm and 25 rpm, optionally between 10 rpm and 20 rpm.

[0173] Optionally, the blown film material has a significantly higher tensile strength than a comparable cast extruded film material.

[0174] Optionally, the blown film material has a significantly higher dart impact resistance than a comparable cast extruded film material.

[0175] Optionally, the blown film material has a significantly higher transparency than a comparable cast extruded film material.

[0176] Optionally, the blown film material has a significantly higher haze than a comparable cast extruded film material.

[0177] Optionally, the blown film material has a significantly lower brittleness than a comparable cast extruded film material.

[0178] Optionally, the blown film material has a significantly higher density than a comparable cast extruded film material. Optionally, the blown film material has a significantly lower density than a comparable cast extruded film material.

[0179] Optionally, the blown film material has a significantly higher tensile strength in the machine and / or direction than a comparable cast extruded film material.

[0180] Optionally, the blown film material has a significantly higher elongation in the machine and / or direction than a comparable cast extruded film material.

[0181] Optionally, the blown film material has a Young's modulus in the machine and / or direction that is significantly higher than the Young's modulus of a comparable cast extruded film material in the machine and / or direction.

[0182] Figure 1 A representative process for forming blown film material is depicted. Precursor resin in pellet form is fed into a hopper 105, where a screw 110 rotates and forces the material forward while heating, gradually forming a melt. The molten material 115 then flows through a die 120, forming a hollow tube of material. Air is introduced through a small hole in the center of the die, forming bubbles 125 in the material. The material is moved upward around the bubbles, cooled, and eventually collapsed under the action of a collapsing frame 130. Throughout this step, a press roll 135 pulls the material upward and maintains an appropriate tension. The collapsed material passes through a series of rollers, including a slitter 140, and is ultimately wound onto a winder 145.

[0183] Due to the nature of the blown film process, certain physical properties of the resulting film material can be quite different from films made using other techniques, such as cast film extrusion. For example, the cast film process can result in a film with low and / or non-uniform orientation of polymer chains in the material. In contrast, blown film materials can have a high degree of orientation, which can be uniform throughout the cylindrical bubble.

[0184] In turn, the orientation of polymer chains in the material can affect the degree of crystallinity, which can affect properties such as clarity / haze, tear strength and elongation, puncture resistance, and toughness.

[0185] Mechanical properties in blown film can be quite different from those in cast film. In the blown film process, the material is stretched in both the transverse and machine directions. In contrast, the strength of a thixotropic film can be non-uniform in both directions.

[0186] Optionally, in any embodiment, the above-described extrusion process includes co-extruding two or more layers, at least one such layer being an active layer (a mixture of polymer and active agent), and at least another such layer being a polymeric material without active agent incorporated therein. In such embodiments, a multi-layer composite material can be formed, with at least one layer being an active-entrained polymeric layer.

[0187] Blister Packaging

[0188] According to optional embodiments of the disclosed concept, the structure of the blister pack or blister pack can be similar to any of the structures described in U.S. Patent No. 6,279,736 (Hekal), International Publication No. WO 2020 / 146556 (Hollinger), and International Publication No. WO 2022 / 236313 (Hollinger), each of which is incorporated herein by reference. The blister packs described in the above disclosures can include a backing and a cover affixed thereto to form one or more blister cavities. These blister packs also include an active member, for example, in the form of an active entrained polymer film provided within each blister cavity. Such active films in the prior art can include a desiccant, for example, a molecular sieve. Blister packs in the prior art and according to the disclosed concept can include a single blister or multiple blisters, for example, with more or less than four blisters per blister card.

[0189] In optional aspects of the disclosed concept, the container is a blister pack. Optionally, the blister pack contains an active agent in the form of activated carbon or a derivative thereof. The active agent is capable of reducing, mitigating, or eliminating the formation and / or amount of a nitroso-forming agent and / or an N-nitroso compound in the headspace and / or in the pharmaceutical dosage form within the respective blister cavity. Additionally or as an alternative, the active agent is capable of scavenging the N-nitroso compound in the headspace and / or in the pharmaceutical dosage form.

[0190] Figure 2 A cross-sectional view of a single blister of a non-limiting example blister pack 210 (which optionally has multiple blisters) is shown in FIG. 2. The blister pack 210 includes a backing 212 and a cover 214 attached to the backing 212. Further, the cover 214 is attached to the backing 212 such that at least one cavity or enclosure is formed between the cover and the backing, or multiple spaced apart cavities / enclosures are formed by the combination of the cover 214 and the backing 212. Thus, the cover 214 and the backing 212 form at least one enclosure configured and / or arranged to store at least one product 217. Optionally, the cover 214 can have any of a variety of shapes and / or arrangements, as disclosed in WO 2020 / 146556.

[0191] The backing 212 can have a first side or surface 212a and an opposing second side or surface 212b. Optionally, at least the first side 212a of the backing 212 can be flat or planar. In one embodiment, each of the first side 212a and the second side 212b of the backing 212 is flat or planar, such that each of the first side 212a and the second side 212b extends in at least a slightly spaced apart plane.

[0192] The cover 214 can have a first side or surface 214a and an opposite second side or surface 214b. Optionally, at least a portion of the first side 214a and the second side 214b of the cover 214 is flat or planar. At least a portion of the second side 214b of the cover 214 can be attached or adhered to the first side 212a of the backing 212, such as by heat setting, thermoforming, or cold forming, to form a sealed package for containing a product. The thickness of the cover 214 can be the same or different than the thickness of the backing 212 (as measured in the direction of D2). In one embodiment, the cover 214 is made or formed from a formable web. In one embodiment, the formable web is made from a thermoplastic material, such as a thermoform film.

[0193] The cover 214 includes or is formed to have at least one blister, generally indicated as 218. For example, the cover 214 can include two or more spaced-apart blisters 218. The cover 214 can have more or fewer blisters, as desired, and one or more of the blisters can have a different size and / or shape than another one of the blisters 218 of the blister pack 210. Optionally, each blister 218 can have at least a partial egg or spherical shape. Alternatively, in one embodiment, each blister 218 can have at least a partial platform shape (e.g., when viewed from the side) or a cylindrical shape. When the cover 214 is attached to the backing 212, a sealed cavity or enclosure is formed within or by each blister 218.

[0194] The blister pack 210 can enclose one or more products 217 (shown schematically in Figure 2 ), such as oral solid pharmaceutical dosage forms, vitamins or other nutritional supplements, food items, small consumer goods, probiotics, and the like. Such products can be in the form of pills, such as tablets, capsules, and the like.

[0195] Activated carbon or a derivative thereof is provided in the enclosure formed by each blister 218. For example, the activated carbon or derivative thereof can be provided as an active agent in an entrained polymer film 216 (e.g., an extruded film) deposited within the enclosure. Optionally, the entrained polymer film adheres to a portion of the interior wall of the enclosure, such as to the first face 212a of the backing 212. With this configuration, the activated carbon or derivative thereof can be effective to reduce, mitigate, or exclude the formation and / or amount of nitroso-forming agents and / or N-nitroso compounds in at least one of the enclosures and / or in the pharmaceutical dosage forms.

[0196] Inert atmosphere packaging

[0197] Certain methods disclosed herein provide containers for packaging dosage forms, including blister packs, and related methods. In some embodiments, an inert gas is introduced into the container, thereby partially or completely replacing ambient air within the headspace with the inert gas. The inert gas can be nitrogen or an inert gas such as argon. The introduction of the inert gas can occur before, during, or after the introduction of the dosage forms within the package. It will be appreciated that the partial or complete replacement of ambient air can have the effect of reducing the amount of moisture and / or oxygen within the headspace, thereby reducing the likelihood or extent of hydrolysis or oxidation reactions, respectively. It will also be appreciated that the partial or complete replacement of ambient air during or after the introduction of the dosage forms can have the effect of reducing the amount of volatile nitrosamines released from the dosage forms into the headspace.

[0198] Examples

[0199] The application is further illustrated by the following examples.

[0200] Example 1 : Materials

[0201] Membrane

[0202] Membranes were manufactured using a single screw extruder to achieve an optimal thickness between 0.3 mm and 1.2 mm. Formulations for the ternary activated carbon ("T-AC") and activated carbon ("AC") consisted of 70% resin-3040 and 30% activated material. The T-AC material was Chemsorb 1505-60G5 20 x 50 mesh activated carbon, and the activated carbon material was Chemsorb 1000-60-G5 activated carbon. The 4A molecular sieve ("4A") and 3A molecular sieve ("3A") were extruded in a formulation comprising 17% Visparent E100, 3% activator CC10200143WE, 24% resin 3040, 3% pvp va64, 30% active, and 24% resin-9074.

[0203] Standard Nitrosamine Solution

[0204] The NDMA, NDEA, and NDIPA solutions were prepared using techniques known in the art and were calibrated by analyzing an aliquot of the solution using GC-MSD analysis.

[0205] Example 2: Nitrosamine Absorption Protocol

[0206] The following protocol was employed to detect the absorption of nitrosamines by potential absorbers.

[0207] Samples were prepared in duplicate. The potential absorber was added to a 20 mL gas chromatography vial. 50 mg of the absorber in its original (non-membrane) form was used. A DMSO standard solution of mixed nitrosamines was then added. The use of DMSO as a diluent for nitrosamines is recommended by the FDA in order to have a meaningful analysis of these compounds. The samples were then left with the control solution at room temperature for 1 day and 3 days. The samples were measured on a headspace GC-MSD.

[0208] Example 3: Absorption of nitrosamines by absorbers

[0209] Four samples were analyzed using the protocol of Example 2: (a) 3A molecular sieves ("3A"), (b) 4A molecular sieves ("4A"), (c) activated carbon ("AC"), and (d) tri-activated carbon ("T-AC"). The results of the measurements are provided in Tables 1-3 below. The numbers in the tables reflect the percentage of nitrosamines absorbed.

[0210] Table 1. Absorption of NDMA

[0211] absorber 1 day 3 days (a) 3A 3％ 3％ (b) 4A 7％ 7％ (c) AC 14％ 13％ (d) T-AC 20％ 21％

[0212] Table 2. Absorption of NDEA

[0213] absorber 1 day 3 days (a) 3A 3％ 4％ (b) 4A 7％ 6％ (c) AC 10％ 13％ (d) T-AC 16％ 16％

[0214] Table 3. Absorption of NDIPA

[0215] absorber 1 day 3 days (a) 3A 35％ -11％ (b) 4A 8％ 6％ (c) AC 27％ -25％ (d) T-AC 21％ -14％

[0216] Example 4: Protocol for absorption of nitrosamines from aspirin soaked

[0217] Small pieces of "Infant" aspirin (81 mg, Bayer) were soaked with a standard nitrosamine solution in a GC tube. The potential absorber was combined with the material in the GC tube. The samples were left with the control solution at 60 °C for 48 hours. The samples were measured on a headspace GC-MSD. All experiments described in the example using small pieces of "Infant" aspirin used tablets from the same batch from Bayer.

[0218] Example 5: Absorption of nitrosamines by absorbers from aspirin soaked

[0219] Four samples were analyzed using the protocol of Example 4: (a) 3A molecular sieves ("3A"), (b) 4A molecular sieves ("4A"), (c) activated carbon ("AC"), and (d) tri-activated carbon ("T-AC"). The results of the measurements are provided in Tables 4-6 below.

[0220] Table 4. Absorption of NDMA in impregnated aspirin

[0221] absorber 48 hours (a) 3A 2.49％ (b) 4A 4.40％ (c) AC 8.86％ (d) T-AC 10.26％

[0222] Table 5. Absorption of NDEA impregnated in aspirin

[0223]

[0224]

[0225] Table 6. Absorption of NDIPA impregnated in aspirin

[0226] absorber 48 hours (a) 3A 8.96％ (b) 4A 9.83％ (c) AC 12.23％ (d) T-AC 15.73％

[0227] Example 6: Absorption of nitrosamines impregnated in aspirin by ternary activated carbon and 4A

[0228] Small tablets of "baby" aspirin (81 mg, Bayer) were combined with 4 mL of DMSO and 1 mL of a standard NDMA (0.5 pg / ml) solution was added to the GC tube. A 1 cm piece of the potential absorber (4A or TAC membrane) was combined with the material in the GC tube. The samples were placed at 60 °C for 48 hours along with a control sample. The samples were measured on headspace GC-MSD. The absorbers tested were ternary activated carbon and 4A in triplicate. The results are shown in Table 7 below. 2 Potential absorbers (4A or TAC membranes) were combined with the material in the GC tube. The samples were placed at 60 °C for 48 hours along with a control sample. The samples were measured on headspace GC-MSD. The absorbers tested were ternary activated carbon and 4A in triplicate. The results are shown in Table 7 below.

[0229] Table 7. Absorption of NDMA in impregnated aspirin

[0230]

[0231] Example 7: Absorption of nitrosamines impregnated in aspirin by absorbers in blister packs

[0232] Small tablets of "baby" aspirin (81 mg, Bayer) were stored in blister packs made with a ternary activated carbon membrane. The ternary activated carbon in the modified blister pack ("sample") on average absorbed 7% of NDMA and 35% of NDEA in the NDMA and NDEA impregnated tablets compared to the control lacking the ternary activated carbon membrane. The samples were measured on headspace using GC-MSD.

[0233] Example 8: Lined bottles

[0234] Blow molded bottles lined completely with a membrane containing a potential absorber were used. 4.25 mL of a sulfuric acid solution and 4.25 mL of a potassium nitrite solution were placed into a 20 mL scintillation vial. The vial was placed into a blow molded bottle and sealed. GC was performed on headspace using a derivatization method. The method is based on a chemical derivatization method that reacts all available nitrite directly into a measurable compound (cyclohexene). The reaction is shown below:

[0235]

[0236] The general method is outlined in the following publication: “A high-throughput headspace gas chromatographic technique for the determination of nitrite content in water samples”, Shu-Xin Zhang, Rong Peng, Ran Jiang, Xin-Sheng Chai, Donald G. Barnes; Journal of Chromatography A, 1538 (2018) 104-107.

[0237] The results of the assay are provided in Table 8.

[0238] Table 8 Absorption of nitrous acid in lined bottles

[0239]

[0240]

[0241] The results shown in Table 8 indicate that after 10 days, the nitrite in the AC and T-AC lined bottles was reduced by 91.68% and 64.73%, respectively.

[0242] Example 9: Excipient tablets without API

[0243] AC was tested using excipient tablets without API. The tablets contained 80% microcrystalline cellulose (MCC), which is a source of nitrite. The MCC and lactose were mixed in a 2:1 ratio and a small amount of lubricant was added as needed for manufacturing.

[0244] Three tablets of MCC with or without a membrane (2 x 2 inches) were added to a 2.5 x 2.5 inch foil pouch. The samples with or without a membrane were placed at 60°C for 6 days. GC was performed on the headspace using derivatization. The results of the assay are provided in Table 9 below.

[0245] Table 9. Absorption of released nitrite from excipient tablets without API

[0246] Tested membrane response Average PPM reduce% PPM Standard Deviation Standard Deviation (%) count comparison 3867357 53.5 33.23 10 AC 659594 8.9 83.4 6.35 11.88 14

[0247] The results shown in Table 9 indicate that the activated carbon membrane resulted in an 83.4% reduction in nitrite.

[0248] Example 10: Metformin formation of NDMA and / or nitrite

[0249] To determine if the film absorbs NDMA, 1 cm 2 The film was immersed in a mixture of 2 mL metformin and 0.1 mL nitrous acid. The sample was left at room temperature for 24 hours. GC-MSD was performed on the headspace with unknown analysis for NDMA and nitrous acid. The results are provided in Table 10 below.

[0250] Table 10. NDMA concentration

[0251]

[0252]

[0253] The results shown in Table 10 indicate that the ternary activated carbon film reduced the concentration of NDMA by 29.6%.

[0254] To investigate the effect of reducing the amount of nitrous acid on the concentration of NDMA, the samples were prepared as described above, but the amount of nitrous acid was varied, as shown in Table 11 below.

[0255] Table 11. NDMA concentrations at different nitrous acid dosages

[0256] Tested membrane Nitrous acid NDMA concentration (ppm) T-AC 0mL 0.000ppm T-AC 0.1mL 0.018ppm T-AC 0.05mL 0.018ppm

[0257] The results shown in Table 11 indicate that reducing the amount of nitrous acid from 0.1 mL to 0.05 mL did not reduce the NDMA formed. This indicates that 0.05 mL of nitrous acid can be used for the test.

[0258] To investigate the effect of the film on the concentration of nitrous acid, the same sample conditions as in Table 10 were used. The results are provided in Table 12.

[0259] Table 12. Nitrite concentration

[0260] Tested membrane Nitrite concentration (ppm) reduce% comparison 0.76 4A 0.52 31.6 T-AC 0.15 80.3

[0261] The results shown in Table 12 indicate that the ternary activated carbon film reduced the concentration of nitrite by 80.3%.

[0262] To investigate the effect of reducing the amount of nitrous acid on the concentration of nitrite, the samples were prepared as described above, but the amount of nitrous acid was varied, as shown in Table 13 below.

[0263] Table 13. Nitrite concentrations at different nitrite dosages

[0264] Tested membrane Nitrous acid Nitrite concentration (ppm) T-AC 0mL 0.000ppm T-AC 0.1mL 0.08ppm T-AC 0.05mL 0.05ppm

[0265] The results shown in Table 13 indicate that reducing the amount of nitrous acid from 0.1 mL to 0.05 mL still resulted in the formation of nitrite. This indicates that 0.05 mL of nitrous acid can be used for the test.

[0266] Exemplary Embodiments

[0267] The following exemplary embodiments further describe optional aspects of the technology of the present disclosure and are part of the detailed description. These exemplary embodiments are shown in a format substantially similar to the claims (each claim followed by a number name in capital letters), but are not technically the claims of the present application. The following exemplary embodiments refer to each other as “embodiments” rather than “claims” in a dependency relationship.

[0268] Blown film

[0269] 1A. A blown film entraining polymer comprising:

[0270] a base polymer; and

[0271] activated carbon or a derivative thereof dispersed within the base polymer, optionally wherein the activated carbon or derivative thereof is in the form of a granule, a particulate, or a powder.

[0272] 2A. The blown film entraining polymer of embodiment 1A, wherein the base polymer is selected from the group consisting of a polyolefin and a polyester.

[0273] 3A. The blown film entraining polymer of embodiment 2A, wherein the base polymer is a polyolefin of the chemical formula (-CH2CHR-) n wherein R is selected from the group consisting of H and C 1-10 alkyl.

[0274] 4A. The blown film entraining polymer of embodiment 2A, wherein the base polymer is a polyester.

[0275] 5A. The blown film entraining polymer of embodiment 4A, wherein the polyester is of the chemical formula (OOC-Y-COO-Z) n wherein:

[0276] Y is 1,4-phenylene, and

[0277] Z is selected from the group consisting of ethylene, butylene, hexylene, and 1,4- cyclohexene dimethylene.

[0278] 6A. The blown film entraining polymer of embodiment 4A, wherein the polyester is of the chemical formula ((CH2) m COO) n wherein m is selected from the group consisting of 1, 2, 3, 4, and 5.

[0279] 7A. The blown film entraining polymer of embodiment 4A, wherein the polyester is of the chemical formula (-CHRCOO-) n wherein R is selected from the group consisting of H and C1-10 alkyl.

[0280] 8A. The blown film entrained polymer of any one of embodiments 3A and 7A, wherein R is selected from the group consisting of H, CH3, (CH2)CH3, (CH2)3CH3, (CH2)5CH3, and (CH2)7CH3.

[0281] 9A. The blown film entrained polymer of embodiment 3A, wherein R is selected from the group consisting of C2H5, C4H9, and C6H 13 .

[0282] 10A. The blown film entrained polymer of embodiment 7A, wherein R is CH3.

[0283] 11A. The blown film entrained polymer of any one of embodiments 1A to 7A, wherein the polymer composition is a monolithic material.

[0284] 12A. The blown film entrained polymer of any one of embodiments 1A to 9A, wherein the base polymer comprises from 10 wt% to 80 wt%, optionally 20 wt% to 70 wt%, optionally 30 wt% to 60 wt%, optionally 40 wt% to 50 wt%, optionally 45 wt% to 65 wt%, optionally 45 wt% to 60 wt%, optionally 45 wt% to 55 wt%, optionally 50 wt% to 70 wt%, optionally 50 wt% to 60 wt%, optionally 55 wt% to 65 wt%, optionally 55 wt% to 60 wt%, of the entrained polymer material.

[0285] 13A. The blown film entrained polymer of any one of embodiments 1A to 3A, 8A, and 10A to 12A, wherein the base polymer is selected from the group consisting of polyethylene, polypropylene, and polyethylene / polypropylene copolymer.

[0286] 14A. The blown film entrained polymer of embodiment 1A, wherein the base polymer is a block copolymer.

[0287] 15A. The blown film entrained polymer of embodiment 14A, wherein the block copolymer comprises a polyester segment and a polyether segment.

[0288] 16A. The blown film entrained polymer of embodiment 14A, wherein the polyester segment is a poly(alkylene terephthalate).

[0289] 17A. The blown film entrained polymer of embodiment 16A, wherein the polyester segment is poly(butylene terephthalate).

[0290] 18A. The blown film entraining polymer of any one of embodiments 14A to 17A, wherein the polyether segment is a poly(alkylene glycol).

[0291] 19A. The blown film entraining polymer of embodiment 18A, wherein the polyether segment is selected from the group consisting of polyethylene glycol, polypropylene glycol, and polytetramethylene glycol.

[0292] 20A. The blown film entraining polymer of embodiment 14A, wherein the block copolymer is optionally is 7246.

[0293] 21A. The blown film entraining polymer of any one of embodiments 1A to 20A, wherein the activated carbon or derivative thereof comprises 1 wt% to 70 wt%, optionally 10 wt% to 80 wt%, optionally 20 wt% to 70 wt%, optionally 35 wt% to 65 wt%, optionally 40 wt% to 60 wt%, optionally 45 wt% to 55 wt%, relative to the total weight of the material.

[0294] 22A. The blown film entraining polymer of any one of embodiments 1A to 21A, wherein the activated carbon derivative is a ternary modified activated carbon.

[0295] 23A. The blown film entraining polymer of any one of embodiments 1A to 22A, further comprising a channel forming agent, optionally wherein the channel forming agent is present in a range of 1 wt% to 25 wt%, optionally 2 wt% to 15 wt%, optionally 2 wt% to 6 wt%, optionally 3 wt% to 12 wt%, optionally 5 wt% to 20 wt%, optionally 8 wt% to 15 wt%, optionally 10 wt% to 20 wt%, optionally 10 wt% to 15 wt%, or optionally 10 wt% to 12 wt%, relative to the total weight of the blown film entraining polymer.

[0296] 24A. The blown film entraining polymer of embodiment 23A, wherein the channel forming agent is selected from the group consisting of a polydiol, a glycerol polyamine, a polyurethane, and a polycarboxylic acid, or any combination of the foregoing.

[0297] 25A. The blown film entraining polymer of embodiment 23A, wherein the channel forming agent is selected from the group consisting of a propylene oxide polymerization product, a propylene oxide polymerization product-monobutyl ether, an ethylene vinyl acetate (EVA), a nylon, or any combination of the foregoing.

[0298] 26A. The blown film entraining polymer of embodiment 23A, wherein the channel forming agent is a polyethylene glycol (PEG).

[0299] 27A. A method for manufacturing a blown film entrained polymer according to any one of embodiments 1A to 26A, the method comprising the steps of:

[0300] extruding and warming a suitable precursor material in a screw extruder to form a warmed extruded material, the precursor material being a molten mixture of a base polymer and activated carbon or a derivative thereof;

[0301] passing the warmed extruded material through a die;

[0302] expanding and stretching the warmed extruded material under positive pressure to form an expanded and stretched material; and

[0303] cooling the expanded and stretched material, thereby forming a blown film entrained polymer.

[0304] 28A. The method according to embodiment 27A, wherein extruding is carried out at a rotational speed of 5 rpm to 35 rpm, optionally 10 rpm to 30 rpm, optionally 10 rpm to 25 rpm, optionally 10 rpm to 20 rpm.

[0305] 29A. The method according to any one of embodiments 27A or 28A, wherein extruding is carried out at a temperature of 140 °C to 180 °C, optionally 145 °C to 175 °C, optionally 150 °C to 170 °C, optionally 150 °C to 165 °C.

[0306] 30A. The method according to any one of embodiments 27A to 29A, wherein the method comprises co-extruding at least two layers to form the expanded and stretched material.

[0307] 31A. The method according to embodiment 30A, wherein a first layer comprises the blown film entrained polymer and a second layer comprises a polymer material free of active agents such as activated carbon or a derivative thereof.

[0308] 32A. A container comprising a blown film entrained polymer according to any one of embodiments 1A to 26A or made according to the method of any one of embodiments 27A to 31A, and an interior space suitable for storing a pharmaceutical product.

[0309] 33A. The container according to embodiment 32A, wherein the container is one of a vial, a bottle, a pouch and a blister pack.

[0310] 34A. The container according to embodiment 32A or 33A, wherein the blown film entrained polymer is integral with or attached to an inner wall of the container.

[0311] 35A. A method for reducing contamination of a pharmaceutical product with formaldehyde, the method comprising storing the pharmaceutical product in a container according to any one of embodiments 32A to 34A and allowing the blow molded film to entrain a polymer scavenger or otherwise mitigate the formaldehyde.

[0312] 36A. A method for reducing contamination of a pharmaceutical product with N-nitroso compounds (e.g., nitrosamines), the method comprising storing the pharmaceutical product in a container according to any one of embodiments 32A to 34A and allowing the blow molded film to entrain a polymer scavenger of the N-nitroso compounds (e.g., nitrosamines), inhibit formation of the N-nitroso compounds, or otherwise mitigate the N-nitroso compounds.

[0313] Methods and systems for controlling / inhibiting N-nitroso compounds

[0314] 1B. A method of reducing, mitigating, or excluding the formation and / or amount of nitrosating agents and / or N-nitroso compounds in a pharmaceutical package, the method comprising:

[0315] providing a housing;

[0316] positioning at least one pharmaceutical dosage form in the housing;

[0317] forming a headspace in the housing that is not occupied by the at least one pharmaceutical dosage form; and

[0318] positioning activated carbon and / or derivatives thereof within the headspace,

[0319] wherein the activated carbon and / or derivatives thereof are effective to reduce, mitigate, or exclude the formation and / or amount of nitrosating agents and / or N-nitroso compounds in the headspace and / or in the pharmaceutical dosage form.

[0320] 2B. The method of embodiment 1B, wherein one or more of the headspace and the at least one pharmaceutical dosage form comprises nitrosating agents and / or N-nitroso compounds.

[0321] 1C. A system for mitigating the presence of nitrosamine impurities in a pharmaceutical product and their potential adverse effects on patients, the system comprising:

[0322] a package comprising a housing and one or more drug dosage forms contained within the housing, each of the one or more drug dosage forms having or tending to form or release a nitrosating agent and / or N-nitroso compound as a source of the potential adverse effect, wherein a headspace is formed within the volume of the housing that is unoccupied by the one or more drug dosage forms, the headspace having disposed therein an effective amount of activated carbon or derivative thereof to inhibit the formation and / or reduce the presence of the nitrosating agent and / or N-nitroso compound in or on the one or more drug dosage forms and / or in the headspace to reduce the potential adverse effect associated with the drug product by the effective amount of activated carbon and / or derivative thereof to reduce the nitrosating agent and / or N-nitroso compound to improve patient safety.

[0323] 1D. A method for reducing, mitigating, or excluding the formation and / or amount of a nitrosamine in a drug dosage form, the method comprising:

[0324] providing a housing;

[0325] positioning the drug dosage form in the housing;

[0326] forming a headspace in the housing that is unoccupied by the drug dosage form, and

[0327] positioning activated carbon and / or derivative thereof within the headspace,

[0328] wherein the activated carbon and / or derivative thereof is effective to reduce the amount of the nitrosamine in the drug dosage form.

[0329] 2D. The method of embodiment 1D, wherein the nitrosamine has a molecular weight of 300 g / mol or less, optionally 200 g / mol or less, optionally 160 g / mol or less, optionally 120 g / mol or less.

[0330] 3D. The method of embodiment 1D or 2D, wherein the nitrosamine has a vapor pressure at 20 °C of 0.2 torr or more, optionally 0.5 torr or more, optionally 1 torr or more, optionally 2 torr or more, optionally 3 torr or more, optionally 4 torr or more, or optionally 5 torr or more.

[0331] 4D. The method of any one of embodiments 1D to 3D, wherein the nitrosamine has a boiling point at atmospheric pressure of 250 °C or less, optionally 225 °C or less, optionally 200 °C or less, optionally 190 °C or less, optionally 180 °C or less, optionally 170 °C or less, or optionally 160 °C or less.

[0332] 5D. The method of any one of embodiments 1D to 4D, wherein the nitrosamine is not 1 -methyl-4-nitrosopiperazine, 1 -cyclopentyl-4-nitrosopiperazine, or N-nitroso-3- azabicyclo[3.3.0]octane.

[0333] 6D. The method of any one of embodiments 1D to 5D, wherein the pharmaceutical dosage form does not comprise any of rifampicin, rifapentine, or gliclazide.

[0334] 7D. The method of any one of embodiments 1D to 6D, wherein the pharmaceutical dosage form does not comprise a hydrazone or a semicarbazide moiety.

[0335] 8D. The method of any one of embodiments 1D to 7D, wherein the pharmaceutical dosage does not comprise a functional group capable of undergoing hydrolysis to provide a primary hydrazine.

[0336] 9D. The method of any one of embodiments 1D to 8D, wherein the nitrosamine is selected from the group consisting of NDMA, NDEA, and NDIPA.

[0337] Blister Packs / Drug Delivery Systems

[0338] 1E. A drug delivery system, comprising:

[0339] a blister pack configured to house a plurality of pharmaceutical dosage forms, the blister pack comprising:

[0340] a backing;

[0341] a cover attached to the backing, the cover and the backing in combination forming at least one enclosure configured to contain a single pharmaceutical dosage form;

[0342] a single pharmaceutical dosage form housed within the at least one enclosure;

[0343] a headspace formed within the volume of the at least one enclosure, unoccupied by the single pharmaceutical dosage form; and

[0344] an active agent comprising activated carbon or a derivative thereof and positioned in the at least one enclosure,

[0345] wherein the active agent is effective to reduce, mitigate, or exclude the formation and / or amount of a nitroso agent and / or an N-nitroso compound in the headspace and / or in the pharmaceutical dosage form.

[0346] 1F. A drug delivery system for mitigating potential adverse effects associated with a drug, the system comprising:

[0347] a package comprising an enclosure and one or more pharmaceutical dosage forms contained within the enclosure, wherein a headspace is formed within the volume of the enclosure that is not occupied by the one or more pharmaceutical dosage forms; and

[0348] a material capable of reducing or inhibiting the rate of formation of a nitroso- forming agent and / or an N-nitroso compound in the headspace within the package and / or in the pharmaceutical dosage forms,

[0349] wherein the material is separate from and spaced apart from the pharmaceutical dosage forms stored within the blister pack.

[0350] 1G. A pharmaceutical delivery system for mitigating potential adverse effects associated with a pharmaceutical, the system comprising:

[0351] (e) a blister pack configured to contain one or more pharmaceutical dosage forms, the blister pack comprising:

[0352] (iii) a backing;

[0353] (iv) a cover attached to the backing, the cover and the backing in combination forming at least one enclosure configured to contain a single pharmaceutical dosage form;

[0354] (f) a single pharmaceutical dosage form contained within the at least one enclosure;

[0355] (g) a headspace formed within the volume of the enclosure that is not occupied by the one or more pharmaceutical dosage forms; and

[0356] (h) a material capable of reducing or inhibiting the rate of formation of a nitroso- forming agent and / or an N-nitroso compound in the headspace within the package and / or in the pharmaceutical dosage forms,

[0357] wherein the material is separate from and spaced apart from the pharmaceutical dosage forms stored within the blister pack.

[0358] Package

[0359] 1H. A package comprising:

[0360] an enclosure;

[0361] at least one pharmaceutical dosage form within the enclosure;

[0362] a headspace within the enclosure that is not occupied by the at least one pharmaceutical dosage form;

[0363] a nitrosating agent and / or an N-nitroso compound located in one or more of the headspace and the at least one pharmaceutical dosage form; and

[0364] activated carbon and / or a derivative thereof located within the headspace,

[0365] wherein the activated carbon is effective to reduce, mitigate, or preclude formation and / or amount of a nitrosating agent and / or an N-nitroso compound in the enclosure and / or the at least one pharmaceutical dosage form.

[0366] Treatment

[0367] 1I. A method for treating a patient having a medical condition with a pharmaceutical dosage form that contains or is capable of forming a nitrosating agent and / or an N-nitroso compound, the method configured to mitigate potential adverse effects on the patient associated with the nitrosating agent and / or the N-nitroso compound, the method comprising:

[0368] (e) providing a package comprising an enclosure and one or more pharmaceutical dosage forms contained within the enclosure, wherein a headspace is formed within the volume of the enclosure that is not occupied by the one or more pharmaceutical dosage forms;

[0369] (f) providing an amount of activated carbon and / or a derivative thereof in the headspace, the amount of activated carbon and / or a derivative thereof effective to reduce a rate of formation or inhibit formation of a nitrosating agent and / or an N-nitroso compound in the headspace and / or in the pharmaceutical dosage forms within the package, the amount of activated carbon and / or a derivative thereof being separate and spaced apart from the one or more pharmaceutical dosage forms;

[0370] (g) opening the enclosure to dispense the one or more pharmaceutical dosage forms; and

[0371] (h) administering the one or more pharmaceutical dosage forms to provide a therapeutically effective amount of a drug to the patient to treat the medical condition with improved patient safety by mitigating the potential adverse effects associated with the pharmaceutical dosage forms with the amount of activated carbon or a derivative thereof to reduce the nitrosating agent and / or the N-nitroso compound.

[0372] Drug dosage form

[0373] 1J. A pharmaceutical dosage form that is predisposed to form or release a nitrosating agent and / or an N-nitroso compound that is a source of potential adverse effects to a patient to whom the pharmaceutical dosage form is administered, the pharmaceutical dosage form being substantially free of the N-nitroso compound when housed within a packaging enclosure, the formation of and / or depletion of the N-nitroso compound being inhibited by an effective amount of activated carbon and / or a derivative thereof provided in the headspace of the enclosure, the effective amount of activated carbon and / or a derivative thereof being separate and spaced apart from the pharmaceutical dosage form.

[0374] 2J. The pharmaceutical dosage form of embodiment 1J, wherein the pharmaceutical dosage form is substantially free of the N-nitroso compound, such that the pharmaceutical dosage form comprises less than 100%, optionally less than 90%, optionally less than 80%, optionally less than 70% of the FDA or EMA allowable N-nitroso compound content effective as of January 1, 2024.

[0375] 3J. The pharmaceutical dosage form of embodiment 1J or 2J, wherein the pharmaceutical dosage form is substantially free of the N-nitroso compound, such that the pharmaceutical dosage form comprises a total amount of N-nitroso compound that is less than 1500 ppm, optionally less than 400 ppm, optionally less than 100 ppm, optionally less than 95 ppm, optionally less than 90 ppm, optionally less than 85 ppm, optionally less than 80 ppm, optionally less than 75 ppm, optionally less than 70 ppm, optionally less than 65 ppm, optionally less than 60 ppm, optionally less than 55 ppm, optionally less than 50 ppm, optionally less than 45 ppm, optionally less than 40 ppm, optionally less than 35 ppm, optionally less than 25 ppm, optionally less than 20 ppm, optionally less than 15 ppm, optionally less than 14 ppm, optionally less than 13 ppm, optionally less than 12 ppm, optionally less than 11 ppm, optionally less than 10 ppm, optionally less than 9 ppm, optionally less than 8 ppm, optionally less than 7 ppm, optionally less than 6 ppm, optionally less than 5 ppm, optionally less than 4 ppm, optionally less than 3 ppm, optionally less than 2 ppm, optionally less than 1 ppm, optionally less than 0.9 ppm, optionally less than 0.8 ppm, optionally less than 0.7 ppm, optionally less than 0.6 ppm, optionally less than 0.5 ppm, optionally less than 0.4 ppm, optionally less than 0.3 ppm, optionally less than 0.2 ppm, optionally less than 0.1 ppm.

[0376] Dependent embodiments

[0377] 1K. According to any one of embodiments 1B to 3J, wherein the housing comprises an inner wall, and the activated carbon or derivative thereof is integral with or attached to the inner wall.

[0378] 2K. According to any one of embodiments 1B to 1K, wherein the pharmaceutical dosage form is an oral dosage form selected from the group consisting of a tablet, a sublingual tablet, a chewable tablet, a capsule, and a liquid-filled capsule.

[0379] 3K. According to any one of embodiments 1B to 2K, wherein the N-nitroso compound is a nitrosable compound selected from a primary amine, a secondary amine, a tertiary amine, and a quaternary ammonium salt.

[0380] 4K. According to any one of embodiments 1B to 3K, wherein the N-nitroso compound is a nitrosable compound selected from a primary amine, a secondary amine, a tertiary amine, and a quaternary ammonium salt.

[0381] 5K. According to any one of embodiments 1B to 4K, wherein the N-nitroso compound is a reaction product of a nitrosable compound and a nitrite salt or a nitrosating agent.

[0382] 6K. According to embodiment 5K, wherein the nitrosating agent is nitrous acid.

[0383] 7K. According to embodiment 5K, wherein the nitrite salt is sodium nitrite.

[0384] 8K. According to any one of embodiments 1B to 7K, wherein the N-nitroso compound is selected from the group consisting of N-nitrosodimethylamine, N-nitrosodiethylamine, R 1 R 2 N-N=O and volatile low molecular weight nitrosamines.

[0385] 9K. According to any one of embodiments 1B to 8K, wherein the nitrosamine is selected from the group consisting of NDMA, NDEA, and NDIPA.

[0386] 10K. According to any one of embodiments 1C, 1F, 1G, 1I, 1J, or 1K to 9K, wherein the potentially adverse effect is carcinogenicity.

[0387] 11K. According to any one of embodiments 1B to 10K, wherein the activated carbon derivative is a ternary activated carbon.

[0388] 12K. According to any one of embodiments 1B to 11K, wherein the activated carbon and derivative thereof are provided in a pouch or a jar.

[0389] 13K. According to any of embodiments 1B to 11K, wherein the activated carbon and / or derivatives thereof are combined with a binder and compressed into a component that is optionally attached to or chemically bound to an inner wall of the housing.

[0390] 14K. According to any of embodiments 1B to 11K, wherein the package is a bottle or vial and the activated carbon and / or derivatives thereof are within a component that is attached to, chemically bound to (optionally by multi-pin injection molding) or dispersed within a cap of the package and / or an inner wall of the package.

[0391] 15K. According to any of embodiments 1B to 11K, wherein the activated carbon and / or derivatives thereof are provided in a granular, particulate or powder form and dispersed within a base polymer to form an entrained polymer, the entrained polymer optionally further comprising a channel forming agent (optionally a polymeric channel forming agent) within the entrained polymer that forms channels.

[0392] 16K. According to embodiment 15K, the entrained polymer comprises the channel forming agent in a range of 1 wt% to 25 wt%, optionally 2 wt% to 15 wt%, optionally 2 wt% to 6 wt%, optionally 3 wt% to 12 wt%, optionally 5 wt% to 20 wt%, optionally 8 wt% to 15 wt%, optionally 10 wt% to 20 wt%, optionally 10 wt% to 15 wt%, or optionally 10 wt% to 12 wt%, relative to the total weight of the blown film entrained polymer.

[0393] 17K. According to embodiment 16K, wherein the channel forming agent is selected from one or more of the group consisting of polyglycols, polyethylene glycol (PEG), ethylene-vinyl alcohol (EVOH), polyvinyl alcohol (PVOH), glycerol polyamine, polyurethane, polycarboxylic acid, propylene oxide polymerization product-monobutyl ether, propylene oxide polymerization product monobutyl ether, propylene oxide polymerization product, ethylene vinyl acetate, nylon 6, nylon 66, and vinylpyrrolidone-vinyl acetate copolymer 60 / 40 (PVPVA 64).

[0394] 18K. According to any of embodiments 15K-17K, wherein the activated carbon and / or derivatives thereof are present in 10 wt% to 80 wt%, optionally 20 wt% to 70 wt%, optionally 30 wt% to 70 wt%, optionally 30 wt% to 60 wt%, optionally 30 wt% to 50 wt%, optionally 35 wt% to 70 wt%, optionally 35 wt% to 60 wt%, optionally 35 wt% to 55 wt%, optionally 35 wt% to 50 wt%, optionally 40 wt% to 70 wt%, optionally 40 wt% to 60 wt%, optionally 40 wt% to 50 wt%, optionally 45 wt% to 60 wt%, optionally 50 wt% to 60 wt%, relative to the total weight of the entrained polymer.

[0395] 19K. According to any of embodiments 15K-18K, wherein the base polymer is present in a range of 10 wt% to 70 wt%, optionally 20 wt% to 60 wt%, optionally 20 wt% to 50 wt%, optionally 20 wt% to 40 wt%, optionally 30 wt% to 70 wt%, optionally 30 wt% to 60 wt%, 30 wt% to 50 wt%, optionally 40 wt% to 70 wt%, optionally 40 wt% to 60 wt%, optionally 40 wt% to 50 wt%, of the total weight of the entrained polymer.

[0396] 20K. According to embodiment 15K, the activated carbon and / or derivatives thereof are provided in a blown film entrained polymer according to any of embodiments 1A-26A, or made according to the method of any of embodiments 27A-31A.

[0397] 21K. According to embodiment 20K, the blown film entrained polymer has a thickness of 0.01 mm to 0.25 mm, optionally 0.01 mm to 0.15 mm, optionally 0.01 mm to 0.12 mm, optionally 0.01 mm to 1.0 mm, optionally 0.02 mm to 0.8 mm, optionally 0.05 mm to 0.5 mm, optionally 0.1 mm to 0.5 mm.

[0398] 22K. According to any of embodiments 15K-19K, the entrained polymer is provided in the form of an extruded film or a cast film.

[0399] 23K. According to embodiment 22K, the film has a thickness of 0.1 mm to 1.2 mm, optionally 0.2 mm to 1.0 mm, optionally 0.2 mm to 0.6 mm.

[0400] 24K. According to any one of embodiments 1B to 23K, wherein the drug dosage form comprises an active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof selected from the group consisting of metformin, ranitidine, amitriptyline, nortriptyline, betahistine, chloropyramine, citalopram, sumatriptan, riluzole, terbinafine, zolmitriptan, chlorpheniramine, nortriptyline, orphenadrine, terbinafine, ethylisopropylamine, sitagliptin, losartan, valsartan, tomoxetine, lidocaine, azelastine, duloxetine, fluoxetine, chloropyramine, phenylephrine, rasagiline, reboxetine, aripiprazole, mitapivat, rifampin, alogliptin, ranolazine, rotigotine, azetidine, quetiapine, cinalukast, desloratadine, nintedanib, sildenafil, landiolol, mirabegron, mirtazapine, valacyclovir, pramipexole, ranolazine, ribociclib, tetracaine, trimebutine, varenicline, vortioxetine, atomoxetine, paroxetine, piperidine, moxifloxacin, dalireborn, rotigotine, ropivacaine, ambroxol, atenolol, benazepril, betaxolol, bisoprolol, bumetanide, bupropion, celiprolol, cilazapril, ciprofloxacin, dabigatran, trimebutine, diclofenac, doxazosin, enalapril, esmolol, isosorbide mononitrate, imatinib, isosorbide mononitrate, indapamide, ketamine, labetalol, lenilixibat, levofloxacin, lisinopril, metoprolol, moxifloxacin, nebivolol, perindopril, apramycin, propranolol, pseudoephedrine, quetiapine, ramipril, rivaroxaban, salbutamol, sertraline, sotalol, tamsulosin, ticagrelor, urapidil, vildagliptin, gliclazide, mefenamic acid, azithromycin, leucovorin calcium, leucovorin calcium, azithromycin, hydrochlorothiazide, and quinapril.

[0401] All U.S. or foreign references, patents, or applications cited in this application are incorporated by reference as if fully set forth herein. In the event of inconsistencies, the material disclosed in the text of this document takes precedence.

[0402] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this application, and without departing from the spirit and scope thereof, can make various changes and modifications of the application to adapt it to various uses and conditions.

Claims

1. A method for treating a patient suffering from a medical condition with a pharmaceutical dosage form comprising or capable of forming a nitrosating agent and / or an N-nitroso compound, the method being configured to mitigate potential adverse effects on the patient associated with the nitrosating agent and / or the N-nitroso compound, the method comprising: (a) providing a package comprising a shell and one or more pharmaceutical dosage forms contained within the shell, wherein a headspace is formed within the volume of the shell that is not occupied by the one or more pharmaceutical dosage forms; (b) providing an amount of activated carbon and / or a derivative thereof in the headspace, said amount of activated carbon and / or a derivative thereof being effective to reduce the rate of formation of or inhibit the formation of a nitrosating agent and / or N-nitroso compound in the headspace and / or in the pharmaceutical dosage form within the package, said amount of activated carbon and / or a derivative thereof being separate and spaced apart from said one or more pharmaceutical dosage forms; (c) opening the housing to dispense the one or more pharmaceutical dosage forms; and (d) administering the one or more pharmaceutical dosage forms to provide a therapeutically effective amount of a drug to the patient to treat the medical condition with improved patient safety by mitigating the nitrosating agent and / or N-nitroso compound with the amount of activated carbon or derivative thereof to reduce the potential adverse effects associated with the pharmaceutical dosage form.

2. The method for treating a patient according to claim 1, wherein the housing comprises an inner wall, and the activated carbon or derivative thereof is integral with or attached to the inner wall.

3. The method for treating a patient according to claim 1 or 2, wherein the N-nitroso compound is selected from the group consisting of NDMA, NDEA and NDIPA.

4. A method for treating a patient according to any one of the preceding claims, wherein the potential adverse effect is carcinogenicity.

5. A method for treating a patient according to any one of the preceding claims, wherein step (b) of the method comprises providing the amount of activated carbon derivative in the headspace, wherein the activated carbon derivative is ternary activated carbon.

6. A method for treating a patient according to any one of the preceding claims, wherein the packaging is a bottle or vial and the activated carbon and / or derivatives thereof are provided in a component that is attached to, chemically bonded to, or dispersed within the cap and / or inner wall of the bottle or vial.

7. A method for treating a patient according to any one of the preceding claims, wherein the activated carbon and / or derivatives thereof are provided in granular, particulate or powdered form and dispersed within a base polymer to form an entrained polymer.

8. Method for treating a patient according to claim 7, wherein the activated carbon and / or its derivatives are present in an amount of 20% to 70% by weight relative to the total weight of the entrained polymer.

9. A method for treating a patient according to claim 7 or 8, wherein the entrained polymer is a blown film, wherein the base polymer is selected from polyolefins and polyesters, the blown film optionally having a thickness of 0.01 mm to 0.15 mm.

10. A method for treating a patient according to claim 7 or 8, wherein the entrained polymer is provided in the form of an extruded film having a thickness of 0.1 mm to 1.2 mm, optionally 0.2 mm to 1.0 mm, optionally 0.2 mm to 0.6 mm.

11. A method for treating a patient according to any one of claims 7 to 10, wherein the one or more pharmaceutical dosage forms are in the form of a liquid in which the entraining membrane is immersed.

12. The method for treating a patient according to claim 10, wherein the package is a blister pack and the housing is one or more blister cavities of the blister pack.

13. The method for treating a patient according to claim 12, wherein the extruded film is heat sealed to the inner wall of the housing.

14. The method for treating a patient according to any one of the preceding claims, wherein the pharmaceutical dosage form comprises an active pharmaceutical ingredient selected from the group consisting of metformin, ranitidine, amitriptyline, nortriptyline, betahistine, chlorpyramine, citalopram, sumatriptan, lamisil, terbisil, zostavax, desmin, or a pharmaceutically acceptable salt thereof. Tripelennamine, Desvenlafaxine, Orphenadrine, Terbinafine, Ethylisopropylamine, Sitagliptin, Losartan, Valsartan, Atomoxetine, Lidocaine, Azelastine, Duloxetine, Fluoxetine, Clopyrilamine, Phenylephrine, Rasagiline asagiline, reboxetine, aripiprazole, mitapivat, rifampicin, alogliptin, ranolazine, rotigotine, azacyclonol, quetiapine, cinacalcet, desloratadine, nintedanib, sildenafil, landiol ol), Mirabegron, Mirtazapine, Valacicclovir, Pramipexole, Ranolazine, Ribociclib, Tetracaine, Trimetazidine, Varenicline, Vortioxetine, Methylphenidate, Paroxetine, Piperidine, Moxifloxacin, Daridorexant,Rotigotine, Ropivacaine, Ambroxol, Atenolol, Benazepril, Betaxolol, Bisoprolol, Bumetanide, Bupropion, Celiprolol, Cilazapril, Ciprofloxacin, Dabigatran Etexilate, Trimebutine, Diclofenac, Dorzolamide, Enalapril, Esmolol, Isosorbide Mononitrate mononitrate), Imatinib, Isosorbide mononitrate, Indapamide, Ketamine, Labetalol, Leniolisib, Levofloxacin, Lisinopril, Metoprolol, Moxifloxacin, Nebivolol, Perindopril, Arpraziquantel, Propranolol, Pseudoephedrine, Quetiapine, Ramipril , Rivaroxaban, Salbutamol, Sertraline, Sotalol, Tamsulosin, Ticagrelor, Urapidil, Vildagliptin, Gliclazide, Mefenamic acid, Azithromycin, Calciumfolinate, Calciumlevofolinate, Azithromycin, Hydrochlorothiazide, and Quinapril.

15. A drug delivery system for mitigating potential adverse effects associated with a drug, the system comprising: (i) a blister pack configured to contain one or more pharmaceutical dosage forms, the blister pack comprising: (v) backing; (vi) a cover attached to the backing, the cover and the backing combining to form at least one shell configured to contain a single pharmaceutical dosage form; (j) a single pharmaceutical dosage form contained within at least one housing; (k) a headspace formed within the volume of the housing that is not occupied by the one or more pharmaceutical dosage forms; as well as (1) activated carbon or a derivative thereof, said activated carbon or a derivative thereof being dispersed in a base polymer to form an entrained polymer film, said entrained polymer film being capable of reducing the rate of formation of or inhibiting the formation of nitrosating agents and / or N-nitroso compounds in the head space within the package and / or in the pharmaceutical dosage form, wherein the entrained polymeric film is separate and spaced apart from the single drug dosage form.

16. The drug delivery system of claim 15, wherein the entrained polymer film is heat sealed to the inner wall of the at least one housing.

17. The drug delivery system according to claim 16, wherein the activated carbon and / or its derivatives are present in an amount of 20 to 70 wt% relative to the total weight of the entrained polymer film.

18. The drug delivery system according to any one of claims 15 to 17, wherein the entrained polymer film comprises the activated carbon derivative, and the activated carbon derivative is a ternary activated carbon.

19. The drug delivery system according to any one of claims 15 to 18, wherein the drug dosage form comprises an active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof selected from the group consisting of metformin, ranitidine, amitriptyline, nortriptyline, betahistine, clopyramine, citalopram, sumatriptan, lanamisil, terbisil, zostavax, desenzyme, desvenlafaxine, orphenadrine, terbinafine, ethylisopropylamine, ciglide losartan, valsartan, atomoxetine, lidocaine, azelastine, duloxetine, fluoxetine, clopyramine, phenylephrine, rasagiline, reboxetine, aripiprazole, mitapival, rifampin, alogliptin, ranolazine, rotigotine, azacycline, quetiapine, cinacalcet, desloratadine, nintedanib, sildenafil, landiolol, mirabegron, mirtazapine, valacyclovir, pramipexole, ranolazine, ribociclib, tetracaine, trimethoprim-sulfamethoxazole methamphetamine, varenicline, vortioxetine, methylphenidate, paroxetine, piperidine, moxifloxacin, darilexan, rotigotine, ropivacaine, ambroxol, atenolol, benazepril, betaxolol, bisoprolol, bumetanide, bupropion, celiprolol, cilazapril, ciprofloxacin, dabigatran etexilate, trimebutine, diclofenac, dorzolamide, enalapril, esmolol, isosorbide mononitrate, imatinib, isosorbide mononitrate, indapamide, Ketamine, labetalol, lenilixib, levofloxacin, lisinopril, metoprolol, moxifloxacin, nebivolol, perindopril, apraqualone, propranolol, pseudoephedrine, quetiapine, ramipril, rivaroxaban, albuterol, sertraline, sotalol, tamsulosin, ticagrelor, urapidil, vildagliptin, gliclazide, mefenamic acid, azithromycin, folinate, leucovorin, azithromycin, hydrochlorothiazide, and quinapril.

20. A method for reducing, mitigating or eliminating the formation and / or amount of nitrosamines in a pharmaceutical dosage form, the method comprising: Provide housing; positioning the pharmaceutical dosage form within the housing; forming a headspace in the housing that is not occupied by the pharmaceutical dosage form, and positioning activated carbon and / or derivatives thereof within said headspace, wherein the activated carbon and / or its derivatives can effectively reduce the amount of the nitrosamine in the pharmaceutical dosage form, wherein the nitrosamine is selected from the group consisting of NDMA, NDEA and NDIPA.

21. The method of claim 20, wherein the activated carbon and / or its derivatives are provided in granular, particulate or powdered form and dispersed within a base polymer to form an entrained polymer.

22. The method of claim 20 or 21, comprising positioning the activated carbon derivative in the headspace, wherein the activated carbon derivative is ternary activated carbon.

23. A method according to claim 21 or 22, wherein the entrained polymer is in the form of an extruded film having a thickness of from 0.1 mm to 1.2 mm.

24. The method according to any one of claims 20 to 23, wherein the pharmaceutical dosage form does not comprise a hydrazone or semicarbazide moiety.

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