Materials and methods for mitigating the presence of nitrosamines in packaging using an active agent
Disclosed herein are materials, articles of manufacture, and methods for decreasing, mitigating, removing or precluding formation of an amount of a nitrosating agent and/or an N-nitroso compound, including an N-nitrosamine, in an enclosure of a pharmaceutical drug package to inhibit a potential adverse health effect on a patient associated with the nitrosating agent or N-nitroso compound. The package contains an active agent and a pharmaceutical dosage form in an enclosure of the package. The active agent, consisting essentially of sodium bicarbonate in a granular, particulate or powdered form, is effective to decrease, mitigate, remove or preclude the formation of an amount of the nitrosating agent and/or N-nitroso compound in the enclosure and/or in the pharmaceutical dosage form. Also provided are drug delivery systems including a blister pack configured to house multiple pharmaceutical dosage forms, the blister pack including an active agent as discussed above.
1 . A method for treating a patient having a medical condition with a pharmaceutical dosage form, the pharmaceutical dosage form comprising or forming an N-nitroso compound contaminant, the method being configured to mitigate a potential adverse effect on a patient associated with the N-nitroso compound contaminant, the method comprising:
a) providing a package comprising:
i. an enclosure;
ii. the pharmaceutical dosage form housed within the enclosure, wherein a headspace is formed within a volume of the enclosure that is not occupied by the pharmaceutical dosage form; and
iii. an entrained polymer comprising a blended form of a base polymer and an active agent, the active agent consisting essentially of sodium bicarbonate in a granular, particulate or powdered form, the entrained polymer being provided in an amount within the headspace that is effective in decreasing a rate of formation of, or decreasing an amount of, the N-nitroso compound contaminant;
b) opening the enclosure to dispense the pharmaceutical dosage form; and
c) administering the pharmaceutical dosage form to provide a therapeutically effective amount of drug to the patient for treating the medical condition with improved patient safety by reducing the potential adverse effect associated with the pharmaceutical dosage form on account of the entrained polymer decreasing the rate of formation of, or the amount of, the N-nitroso compound contaminant.
2 . The method of claim 1 , wherein the entrained polymer is effective in decreasing a rate of formation of, or an amount of, a nitrosating agent in the enclosure, thereby decreasing the rate of formation of, or decreasing the amount of, the N-nitroso compound contaminant.
3 . The method of claim 2 , wherein the nitrosating agent is nitrite or NO x .
4 . The method of claim 3 , wherein the N-nitroso compound contaminant is selected from the group consisting of NDMA, NMBA, NDEA, NMPA, NIPEA and NDIPA.
5 . The method of claim 4 , wherein the entrained polymer is effective such that the amount of N-nitroso compound contaminant ingested by the patient does not exceed 96 ng/day for NDMA or NMBA, or 26.5 ng/day for NDEA, NMPA, NIPEA or NDIPA.
6 . The method of claim 1 , wherein the base polymer is selected from one or more of the group consisting of: polypropylene, polyethylene, polyisoprene, polybutadiene, polybutene, polysiloxane, polycarbonate, polyamide, ethylene-vinyl acetate copolymer, ethylene-methacrylate copolymer, poly(vinylchloride), polystyrene, polyester, polyanhydride, polyacrylonitrile, polysulfone, polyacrylic ester, acrylic, polyurethane and polyacetal and copolymers thereof.
7 . The method of claim 6 , wherein:
the entrained polymer comprises a polymeric channeling agent that is present in a range of from 1% to 25% by weight with respect to total weight of the entrained polymer, and
the polymeric channeling agent forms interconnecting channels through the entrained polymer.
8 . The method of claim 1 , wherein the active agent is present in a range of 30% to 70% by weight with respect to the total weight of the entrained polymer.
9 . The method of claim 1 , wherein the package is a blister package.
10 . The method of claim 9 , wherein:
the entrained polymer is an extruded or cast film,
the blister package comprises a backing and a cover attached to the backing,
the cover and backing in combination form the enclosure in the form of a blister cavity, and
the film is chemically bonded to an inner wall of the enclosure by a heat seal, without a separate adhesive between the film and the inner wall.
11 . The method of claim 1 , wherein the pharmaceutical dosage form comprises an active pharmaceutical ingredient or a pharmaceutically acceptable salt and/or enantiomer thereof selected from the group consisting of: Almotriptan, Metformin, Ranitidine, Amitriptyline, Nortriptyline, Betahistine, Chloropyramine, Citalopram, Sumatriptan, Lamisil, Terbisil, Zostavax, Bedaquiline, Brompheniramine, Cabergoline, Carbinoxamine, Chlophedianol, Chlorpheniramine, Chlorpromazine, Clarithromycin, Clomipramine, Clozapine, Cyclobenzaprine, Demeclocycline, Dexbrompheniramine, Dexchlorpheniramine, Diltiazem, Diphenhydramine, Doxepin, Doxycycline, Doxylamine, Eravacycline, Erythromycin, Escitalopram, Imipramine, Maralixibat, Masitinib, Methadone, Methylene Blue, Mifepristone, Minocycline, Olopatadine, Omadacycline, Padimate O, Pheniramine, Phenyltoloxamine, Promethazine, Propoxyphene, Pyrilamine, Quinupristin, Rivastigmine, Rizatriptan, Sarecycline, Sildenafil, Spinosad, Tamoxifen, Tapentadol, Telithromycin, Tetracycline, Thonzylamine, Tigecycline, Tramadol, Trimethobenzamide, Trimipramine, Ulipristal Acetate, Venlafaxine, Zolmitriptan, Tripelennamine, Desvenlafaxine, Orphenadrine, Terbinafine, Ethylisopropylamine, 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, Hydrochlorothiazide, Quinapril and Ritonavir.
12 . A method of decreasing a rate of formation of, or decreasing an amount of, an N-nitroso compound contaminant in an enclosure of a pharmaceutical drug package to inhibit a potential adverse health effect on a patient associated with the N-nitroso compound contaminant, the method comprising:
(a) providing at least one pharmaceutical dosage form unit in the enclosure of the pharmaceutical drug package, thereby forming a headspace in the enclosure in a portion of the enclosure not occupied by the at least one pharmaceutical dosage form unit, the at least one pharmaceutical dosage form unit comprising or forming the N-nitroso compound contaminant; and
(b) providing an entrained polymer within the headspace, the entrained polymer comprising a blended form of a base polymer and an active agent, the active agent consisting essentially of sodium bicarbonate in a granular, particulate, or powdered form;
wherein the entrained polymer is provided in an amount that is effective in decreasing the rate of formation of, or decreasing the amount of, the N-nitroso compound contaminant, thereby inhibiting the potential adverse health effect on the patient associated with the N-nitroso compound contaminant.
13 . The method of claim 12 , wherein the entrained polymer is effective in decreasing a rate of formation of, or an amount of, a nitrosating agent in the enclosure, thereby decreasing the rate of formation of, or decreasing the amount of, the N-nitroso compound contaminant.
14 . The method of claim 13 , wherein the nitrosating agent is nitrite or NO x .
15 . The method of claim 12 , wherein the N-nitroso compound contaminant is selected from the group consisting of NDMA, NMBA, NDEA, NMPA, NIPEA, and NDIPA.
16 . The method of claim 15 , wherein the entrained polymer is effective such that the amount of N-nitroso compound contaminant ingested by the patient does not exceed 96 ng/day for NDMA or NMBA, or 26.5 ng/day for NDEA, NMPA, NIPEA or NDIPA.
17 . The method of claim 12 , wherein the base polymer is selected from one or more of the group consisting of: polypropylene, polyethylene, polyisoprene, polybutadiene, polybutene, polysiloxane, polycarbonate, polyamide, ethylene-vinyl acetate copolymer, ethylene-methacrylate copolymer, poly(vinylchloride), polystyrene, polyester, polyanhydride, polyacrylonitrile, polysulfone, polyacrylic ester, acrylic, polyurethane and polyacetal and copolymers thereof.
18 . The method of claim 17 , wherein:
the entrained polymer comprises a polymeric channeling agent that is present in a range of from 1% to 25% by weight with respect to total weight of the entrained polymer, and
the polymeric channeling agent forms interconnecting channels through the entrained polymer.
19 . The method of claim 12 , wherein the active agent is present in a range of 30% to 70% by weight with respect to the total weight of the entrained polymer.
20 . The method of claim 12 , wherein the package is a blister package.
21 . The method of claim 20 , wherein:
the entrained polymer is an extruded or cast film,
the blister package comprises a backing and a cover attached to the backing,
the cover and backing in combination form the enclosure in the form of a blister cavity, and
the film is chemically bonded to an inner wall of the enclosure by a heat seal, without a separate adhesive between the film and the inner wall.
22 . The method of claim 12 , wherein the at least one pharmaceutical dosage form unit comprises an active pharmaceutical ingredient or a pharmaceutically acceptable salt and/or enantiomer thereof selected from the group consisting of: Almotriptan, Metformin, Ranitidine, Amitriptyline, Nortriptyline, Betahistine, Chloropyramine, Citalopram, Sumatriptan, Lamisil, Terbisil, Zostavax, Bedaquiline, Brompheniramine, Cabergoline, Carbinoxamine, Chlophedianol, Chlorpheniramine, Chlorpromazine, Clarithromycin, Clomipramine, Clozapine, Cyclobenzaprine, Demeclocycline, Dexbrompheniramine, Dexchlorpheniramine, Diltiazem, Diphenhydramine, Doxepin, Doxycycline, Doxylamine, Eravacycline, Erythromycin, Escitalopram, Imipramine, Maralixibat, Masitinib, Methadone, Methylene Blue, Mifepristone, Minocycline, Olopatadine, Omadacycline, Padimate O, Pheniramine, Phenyltoloxamine, Promethazine, Propoxyphene, Pyrilamine, Quinupristin, Rivastigmine, Rizatriptan, Sarecycline, Sildenafil, Spinosad, Tamoxifen, Tapentadol, Telithromycin, Tetracycline, Thonzylamine, Tigecycline, Tramadol, Trimethobenzamide, Trimipramine, Ulipristal Acetate, Venlafaxine, Zolmitriptan, Tripelennamine, Desvenlafaxine, Orphenadrine, Terbinafine, Ethylisopropylamine, 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, Hydrochlorothiazide, Quinapril and Ritonavir.
23 . A drug delivery system for mitigating a potential adverse effect on a patient that is associated with an N-nitroso compound contaminant, the system comprising:
a package comprising:
i. an enclosure;
ii. at least one pharmaceutical dosage form unit housed within the enclosure, wherein a headspace is formed within a volume of the enclosure that is not occupied by the at least one pharmaceutical dosage form unit; and
iii. an entrained polymer comprising a blended form of a base polymer and an active agent, the active agent consisting essentially of sodium bicarbonate in a granular, particulate, or powdered form, the entrained polymer being provided in an amount within the headspace that is effective in decreasing a rate of formation of, or an amount of, the N-nitroso compound contaminant in the headspace and/or in the at least one pharmaceutical dosage form unit, thereby mitigating the potential adverse effect on the patient associated with the N-nitroso compound contaminant.
24 . The system of claim 23 , wherein the entrained polymer is effective in decreasing a rate of formation of, or an amount of, a nitrosating agent in the enclosure, thereby decreasing the rate of formation of, or decreasing the amount of, the N-nitroso compound contaminant.
25 . The system of claim 24 , wherein the nitrosating agent is chosen from nitrite and NO x .
26 . The system of claim 23 , wherein the base polymer is selected from one or more of the group consisting of: polypropylene, polyethylene, polyisoprene, polybutadiene, polybutene, polysiloxane, polycarbonate, polyamide, ethylene-vinyl acetate copolymer, ethylene-methacrylate copolymer, poly(vinylchloride), polystyrene, polyester, polyanhydride, polyacrylonitrile, polysulfone, polyacrylic ester, acrylic, polyurethane and polyacetal and copolymers thereof.
27 . The system of claim 23 , wherein:
the entrained polymer comprises a polymeric channeling agent that is present in a range of from 1% to 25% by weight with respect to total weight of the entrained polymer, and
the polymeric channeling agent forms interconnecting channels through the entrained polymer.
28 . The system of claim 23 , wherein the active agent is present in a range of 30% to 70% by weight with respect to the total weight of the entrained polymer.
29 . The system of claim 23 , wherein:
the package is a blister package,
the entrained polymer is an extruded or cast film,
the blister package comprises a backing and a cover attached to the backing,
the cover and backing in combination form the enclosure in the form of a blister cavity, and
the film is chemically bonded to an inner wall of the enclosure by a heat seal, without a separate adhesive between the film and the inner wall.
30 . The system of claim 23 , wherein the at least one pharmaceutical dosage form unit comprises an active pharmaceutical ingredient or a pharmaceutically acceptable salt and/or enantiomer thereof selected from the group consisting of: Almotriptan, Metformin, Ranitidine, Amitriptyline, Nortriptyline, Betahistine, Chloropyramine, Citalopram, Sumatriptan, Lamisil, Terbisil, Zostavax, Bedaquiline, Brompheniramine, Cabergoline, Carbinoxamine, Chlophedianol, Chlorpheniramine, Chlorpromazine, Clarithromycin, Clomipramine, Clozapine, Cyclobenzaprine, Demeclocycline, Dexbrompheniramine, Dexchlorpheniramine, Diltiazem, Diphenhydramine, Doxepin, Doxycycline, Doxylamine, Eravacycline, Erythromycin, Escitalopram, Imipramine, Maralixibat, Masitinib, Methadone, Methylene Blue, Mifepristone, Minocycline, Olopatadine, Omadacycline, Padimate O, Pheniramine, Phenyltoloxamine, Promethazine, Propoxyphene, Pyrilamine, Quinupristin, Rivastigmine, Rizatriptan, Sarecycline, Sildenafil, Spinosad, Tamoxifen, Tapentadol, Telithromycin, Tetracycline, Thonzylamine, Tigecycline, Tramadol, Trimethobenzamide, Trimipramine, Ulipristal Acetate, Venlafaxine, Zolmitriptan, Tripelennamine, Desvenlafaxine, Orphenadrine, Terbinafine, Ethylisopropylamine, 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, Hydrochlorothiazide, Quinapril and Ritonavir.