DESC:F O R M 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10; rule 13)

“STABLE PHARMACEUTICAL COMPOSITIONS FOR INHIBITING FORMATION OF NITROSAMINES”

ALEMBIC PHARMACEUTICALS LIMITED
An Indian Company
Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India

The following specification particularly describes the invention and the manner in which it is to be performed:
TECHNICAL FIELD:
The present subject matter relates to a stable pharmaceutical composition comprising an active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient. The subject matter further relates to a process for preparing stable pharmaceutical compositions of active pharmaceutical ingredients or pharmaceutically acceptable salts thereof by utilizing antioxidants to reduce the presence of N-nitrosamine impurities.
BACKGROUND:
The term “N-nitrosamine” describes a class of compounds that has chemical structure R1N(-R2–N=O). N-nitrosamines can form by a nitrosating reaction between amines (such as secondary, tertiary or quaternary amines) and nitrous acid. Nitrosamines are common in water and foods, including cured and grilled meats, dairy products and vegetables. Everyone is exposed to at least some level of nitrosamines. These impurities may increase the risk of cancer if people are exposed to them above the acceptable levels over long periods of time. N-nitrosamine has the following structure:

FDA has identified seven nitrosamine impurities that theoretically could be present in drug products: N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosoisopropylethyl amine (NIPEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodibutylamine (NDBA), and N-nitrosomethylphenylamine (NMPA).
The discovery of nitrosamines in some types of drug products led FDA and other international regulators to conduct a detailed analysis of these impurities in affected APIs and drug products. Drug products in which nitrosamine impurities have been found to be above the acceptable levels; batches of those products have been recalled. Because these N-nitrosamine contaminants are possibly carcinogens, regulatory agencies have been deeming the drugs unsafe for people to take and recalling them from shelves. Since 2018, several drug products including ARBs, ranitidine, nizatidine, and metformin have been found to contain unacceptable levels of nitrosamines.
Valsartan was recalled in July 2018, followed that October by irbesartan and in November by losartan. In September 2019, FDA learned that some common heartburn products (ranitidine, commonly known as Zantac, and nizatidine, commonly known as Axid) contained unacceptable levels of NDMA. FDA recommended that manufacturers voluntarily recall ranitidine and nizatidine products with NDMA levels above what the Agency considered acceptable. Recently, preliminary findings from FDA stability testing raised concerns that NDMA levels in some ranitidine products stored at room temperature can increase with time to unacceptable levels. FDA’s preliminary results using accelerated stability testing demonstrated that elevated levels of NDMA were measured in all products after 2 weeks. FDA’s testing suggests that NDMA levels increase with storage time. On April 1, 2020, FDA requested that all ranitidine products be withdrawn from the U.S. market.
Similar situation is being encountered by the scientists in multiple pharmaceutical drug products such as dabigatran capsules, duloxetine capsules, bumetanide tablets, etc.; wherein the presence of nitrosamine impurity, such as N-nitroso-dabigatran or N-nitroso-duloxetine or N-nitroso-bumetanide, respectively, was found to be above the established Acceptable Daily Intake (ADI) level, over the time during shelf life storage.
N-nitroso-dabigatran, N-nitroso-duloxetine and N-nitroso-bumetanide have the following structure given below:

Considerable work has been focused on controlling the content of nitrosamine impurities, particularly, during the drug product manufacturing process and shelf life storage period. Still, there is a need for a proficient system for pharmaceutical drug products that eliminates or minimizes the nitrosamine impurities in compliance with the stringent regulatory requirements. Moreover, there is a need for a stable pharmaceutical composition, wherin the nitrosamine impurities remain under the established Acceptable Daily Intake (ADI) level, especially during shelf life storage period.
It was surprisingly found that use of certain excipients could achieve a stable pharmaceutical composition of active pharmaceutical ingredient or its pharmaceutically acceptable salt thereof with reduced nitrosamine impurities. The rigorous experimentation of the present disclosure led to the development of stable pharmaceutical compositions with nitrosamine impurities under the established Acceptable Daily Intake (ADI) level during the manufacturing process and the storage period and which can be prepared by simple, non-tedious and cost-effective process.
SUMMARY OF THE SUBJECT MATTER:
While not wishing to be bound by theory, it is believed that one of the reasons for the build up of the nitrosamine impurities in the pharmaceutical drug products is due to the interaction between nitrites and certain secondary, tertiary or quaternary amines during the manufacturing process or shelf life storage period. Such formation of nitrosamine impurities can be minimized with the use of antioxidants in the pharmaceutical drug products, resulting in nitrosamine impurities to be under the established Acceptable Daily Intake (ADI) level. Further it has been found that the nitrosamine impurities can be significantly reduced and controlled in pharmaceutical drug products by introducing one or more antioxidants into the pharmaceutical compositions.
In an embodiment of the subject matter, the active pharmaceutical ingredient may be combined with other substances. In preferred embodiments, these other substances are preferably inert and/or do not interfere with the efficacy of the active pharmaceutical ingredient. In some embodiments, carriers, binders, film forming agents, diluents, disintegrants, lubricants, glidants, and/or other excipients may be used for controlling the rate of dissolution of the active pharmaceutical ingredient.
In an embodiment, the present subject matter provides a pharmaceutical composition comprising active pharmaceutical ingredient and at least one excipient and from about 0.01 to about 10 %, preferably from about 0.01 to about 5 %, typically from about 0.1 to about 8 %, for example from about 0.2 to about 5 %, of an antioxidant, per total weight of the composition.
In an embodiment, the present subject matter provides a method for preparing a pharmaceutical composition comprising an active pharmaceutical ingredient and at least one or more antioxidants, in an amount effective to reduce and control the formation of nitrosamines impurities in the composition.
In a preferred embodiment, active pharmaceutical ingredients may be used, for example, but not limited to, dabigatran, duloxetine, bumetanide, and/or any pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE SUBJECT MATTER:
As used herein, "a" or "an" means one or more unless otherwise specified.
The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
The term "stable" and "stability" as used herein refers to both the physical form and the chemical purity of the active pharmaceutical ingredient or the pharmaceutical active dosage form including non-limiting examples of tablet, capsules.
The term “nitrosamine”, as used herein, refers to an organic compound of the chemical structure R1N(-R2)-N=O, wherein R1 and R2 is an alkyl or a derivative of an alkyl group. Examples of “nitrosamine” include N-nitrosodimethylamine (NDMA), A-nitrosodiethylamine (NDEA), N-nitroso-N -methyl -4-aminobutyric acid (NMBA), N-nitrosoisopropylethyl amine (NIPEA) and N- nitrosomethylphenylamine (NMPA). There are multiple reasons why nitrosamines can be present in drugs. It has been found that the source of nitrosamines can be related to the drug's manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As foods and drugs are processed in the body, nitrosamines can also be formed. Nitrosamine impurities may increase the risk of cancer in people exposed to them above acceptable levels and over long periods.
In one embodiment, at least one pharmaceutically acceptable excipient is selected from but not limited to drug carriers, diluent/fillers, binders, disintegrants, antioxidants, adsorbents, film forming agent, antistatic agents, lubricants or glidants, coloring or flavoring agent or combination thereof.
In one embodiment, the process for preparation of stable pharmaceutical composition can be selected from, but not limited to, dry granulation or wet granulation or direct mixing with excipients, etc.
In one embodiment, the pharmaceutical composition may be in the form of capsules, tablets, syrups, lozenges. The pharmaceutical formulation includes tablets, coated tablets, layered tablets, granules, powders, microparticles, capsules which may be hard gelatin or soft gelatin, delayed-release capsules, gastro-resistant capsules, caplets, sachets, pellets, spheroids, mini-tablets, beads, microcapsules and pills.
In one embodiment, pharmaceutical composition may be in the form of, but not limited to, capsule such as dabigatran etexilate capsules, delayed-release capsule such as duloxetine delayed-release capsules or gastro-resistant capsules or tablet such as bumetanide tablets, which are suitable for oral administration to a human.
In one embodiment, active pharmaceutical ingredients may be used, for example, but not limited to, Acalabrutinib, Adapalene, Afatinib, Agomelatine, Alogliptin, Amantadine, Apixaban, Apremilast, Aripiprazole, Asenapine, Atomoxetine, Axitinib, Azacitidine, Azilsartan, Azithromycin, Bempedoic acid, Bimatoprost, Binimetinib, Bosentan, Bosutinib, Brexpiprazole, Brivaracetam, Bupivacaine, Bupropion, Cabozantinib, Canagliflozin, Candesartan, Carfilzomib, Celecoxib, Cilostazol, Clevidipine, Dabigatran etexilate, Dapagliflozin, Dapsone, Darifenacin, Darolutamide, Dasatinib, Deferasirox, Dexlansoprazole, Donepezil, Dorzolamide, Dronedarone, Duloxetine, Empagliflozin, Enzalutamide, Erlotinib, Erythromycin, Etoricoxib, Famotidine, Febuxostat, Felodipine, Fenofibrate, Fenofibric acid, Ferumoxytel, Fesoterodine, Fingolimod, Fluoxetine, Fluphenazine, Fulvestrant, Gefitinib, Hydrochlorothiazide, Ibrutinib, Iloperidone, Infigratinib, Irbesartan, Iron sucrose, Ivabradine, Ivacaftor , Ivosidenib, Ketorolac, Lacosamide, Lamotrigine, Larotrectinib, Leflunomide, Lenalidomide, Lercanidipine, Linagliptin, Linezolid, Losartan, Lurasidone, Macitentan, Memantine, Methomyl, Methotrexate, Metolazone, Metoprolol, Mexiletine, Minodronic acid, Modafinil, Nelarabine, Niraparib, Nisoldipine, Nisoxetine, Nitrofurantoin, Obeticholic acid, O-desmethyl venlafaxine, Olaparib, Olmesartan, Oseltamivir, Osimertinib, Palbociclib, Pinaverium bromide, Pirfenidone, Ponatinib, Pramipexole, Prasugrel, Pregabalin, Prucalopride, Quetiapine, Rabeprazol, Ribociclib, Rifaximin, Riociguat, Rivaroxaban, Rivastigmine, Roflumilast, Ropinirole, Roxithromycin, Ruxolitinib, Sacubitril, Selexipag, Sertraline, Silodosin, Solifenacin, Sorafenib, Suvorexant, Tadalafil, Tegaserod, Telmisartan, Temazepam, Tepotinib, Teriflunomide, Ticagrelor, Tivozanib, Topiramate, Trametinib, Valsartan, Vardenafil, Venetoclax, Venlafaxine, Vilazodone, Vildagliptin, Viloxazine, Vortioxetine, Warfarin, Zolmitriptan, 2-chlorophenylisocyanate, 2-isocyanate ethyl methacrylate, or pharmaceutically acceptable salt thereof.
In one embodiment, active pharmaceutical ingredients may be used, for example, but not limited to, Erythromycin, Pemetrexed, Triamcinolone acetonide, Abiraterone, Acetaminophen, Acetazolamide, Acitretin, Acyclovir, Albendazole, Alcaftadine, Ambrisentan, Amiodarone, Amitriptyline, Amlodipine, Anidulafungin, Aprepitant, Argatroban, Atorvastatin, Azathieoprine, Azelastine, Baclofen ,Benzoyl peroxide, Bepotastine, Betamethasone, Bexarotene, Bisoprolol ,Bivalirudin, Bortezomib, Brimonidine, Brinzolamide, Bromfenac, Bromocriptine, Budesonide, Bumetanide, Calcipotriene, Calcipotriol, Calcitriol, Carbamazepine, Carbidopa, Carvedilol, Chlordiazepoxide, Chlorpromazine, Chlorthalidone, Ciprofloxacin , Clarithromycin, Clidinium , Clindamycin, Clobazam, Clobetasol, Clofarabine, Clonazepam, Clopidogrel, Clozapine, Cobicistat, Cyclobenzaprine, Cyclophosphamide, Cyclosporin, Cytarabine, Dantrolene, Daptomycin, Desipramine, Desmopressin, Desonide, Dexamethasone, Dextromethorphan, Diclofenac, Difluprednate, Diltiazem, Dimethyl fumarate, Divalproex, Docetaxel, Docosanol, Doxepin, Doxercalciferol, Doxycycline, Doxylamine, Dronabinol, Droxidopa, Efinaconazole, Emtricitabine, Entacapone, Eslicarbazepine, Esomeprazole, Estradiol, Ethacrynate ,Ezetimibe, Fluorouracil, Fosaprepitant, Galanthamine, Ganciclovir, Gemcitabine, Glipizide, Glycopyrollate, Guanfacine, Hydrocortisone, Ibuprofen, Itraconazole, Ivermectin, Ketoconazole, Lamotrigine, Lansoprazole, Latanoprost, Ledipasvir, Levodopa, Levothyroxine, Lidocaine, Loteprednol, Medroxyprogesterone, Meloxicam, Mesalamine, Metaxalone, Metformin, Methyl phenidate, Methylprednisolone, Metronidazole, Micafungin, Midodrine, Minocyclin, Molindone, Moxifloxacin, Mupirocin calcium , Nadolol, Nifedipine, Nilotinib, Nimodipine, Nintedanib, Nizatidine, Nystatin, Olanzapine, Olmesartan medoxomil, Olopatadine, Omeprazole, Ospemifien, Oxaliplatin, Oxcarbazepine, Oxcarbazepine, Oxybutynin, Paclitaxel, Palanosetron, Paliperidone, Paliperidone palmitate, Pantoprazole, Paroxetine, Paroxetine, Pazopanib, Penciclovir, Perindopril, Perindropil, Pimecrolimus, Pioglitazone, Piorxicam, Plerixafor , Posaconazole, Prazosin, Prednisolone, Prednisone, Prilocaine, Prilocaine , Progesterone, Propafenone, Propofol, Regadanoson, Rizatriptan, Sildenafil, Simvastatin, Sitagliptin, Sumatriptan, Sunitinib, Tacrolimus, Tamsulosin, Tavaborole, Tazarotene, Tegicyclin, Teicoplanin, Temozolamide, Testosterone, Theophylline, Timolol, Tizanidine, Tobramycin, Tofacitinib, Topiramate, Travoprost, Tretinoin, Trientine, Valganciclovir, Vancomycin, Varenicline, Verapamil, Zileuton, Zoledronic acid.
In a preferred embodiment, active pharmaceutical ingredients used are, for example, but not limited to, dabigatran, duloxetine, bumetanide, and/or any pharmaceutically acceptable salt thereof.
Another aspect of the present subject matter provides a stable pharmaceutical composition comprising,
(a) inert core such as carrier/pellets/spheres,
(b) active pharmaceutical ingredient,
(c) one or more pharmaceutically acceptable antioxidant (s),
(d) one or more pharmaceutically acceptable excipients, for example, but not limited to, binder (s), film forming agent (s), anticaking agent (s), polymer (s), sugar (s), diluent (s), plasticizer (s), lubricant (s), etc.
Another aspect of the present subject matter provides a stable pharmaceutical composition comprising,
(a) pellets,
(b) one or more pharmaceutically acceptable film forming agent (s),
(c) one or more pharmaceutically acceptable anticaking agent (s),
(d) dabigatran etexilate mesylate as the active pharmaceutical ingredient,
(e) one or more pharmaceutically acceptable binder (s),
(f) one or more pharmaceutically acceptable antioxidant (s),
(g) one or more pharmaceutically acceptable lubricant (s).
Another aspect of the present subject matter provides a process to prepare a stable pharmaceutical composition comprising,
(a) pellets of organic acid (s),
(b) pellets of organic acid of (a) coated with one or more pharmaceutically acceptable film forming agent (s) and one or more pharmaceutically acceptable anticaking agent (s), (c) coated pellets of (b) further coated with dabigatran etexilate mesylate, one or more pharmaceutically acceptable anticaking agent (s), one or more pharmaceutically acceptable binder (s) and one or more pharmaceutically acceptable antioxidant (s),
(d) drug coated pellets of (c) are further blended with one or more pharmaceutically acceptable lubricant (s).
(e) lubricated pellets of (d) filled into the capsules.
Another aspect of the present subject matter provides a stable pharmaceutical composition comprising,
(a) 25 - 50 % w/w of pellets of organic acid,
(b) 1 - 25 % w/w of film forming agent (s),
(c) 1 - 5 % w/w of anticaking agent(s),
(d) 10 - 50 % w/w of dabigatran etexilate mesylate
(e) 1 - 15 % w/w of binder (s),
(f) 0.01 - 10 % w/w of antioxidants (s),
(g) 0.5 - 5 % w/w of lubricant (s),
Another aspect of the present subject matter provides a stable pharmaceutical composition comprising,
(a) inert spheres,
(b) duloxetine hydrochloride as the active pharmaceutical ingredient,
(c) one or more pharmaceutically acceptable film forming agent (s),
(d) one or more pharmaceutically acceptable antioxidant (s),
(e) one or more pharmaceutically acceptable anticaking agent (s),
(f) one or more pharmaceutically acceptable sugar (s),
(g) one or more pharmaceutically acceptable plasticizer (s),
(h) one or more pharmaceutically acceptable lubricant (s).
Another aspect of the present subject matter provides a process to prepare a stable pharmaceutical composition comprising,
(a) inert spheres,
(b) spheres of (a) coated with duloxetine hydrochloride, one or more pharmaceutically acceptable film forming agent (s), one or more pharmaceutically acceptable antioxidant (s), and one or more pharmaceutically acceptable anticaking agent (s),
(c) drug coated spheres of (b) further coated with one or more pharmaceutically acceptable sugar (s), one or more pharmaceutically acceptable anticaking agent (s) and one or more pharmaceutically acceptable film forming agent (s).
(d) coated spheres of (c) are further enteric coated with one or more pharmaceutically acceptable anticaking agent (s), one or more pharmaceutically acceptable plasticizer (s) and one or more pharmaceutically acceptable film forming agent (s).
(e) coated spheres of (d) further blended with one or more pharmaceutically acceptable lubricant (s).
(f) lubricated spheres of (e) filled into the capsules.
Another aspect of the present subject matter provides a stable pharmaceutical composition comprising,
(a) 10 - 30 % w/w of inert spheres,
(b) 10 - 50 % w/w of duloxetine hydrochloride,
(c) 1 - 25 % w/w of film forming agent (s),
(d) 0.01 - 10 % w/w of antioxidants (s),
(e) 1 - 5 % w/w of anticaking agent (s),
(f) 10 - 20 % w/w of sugar (s),
(g) 1 - 5 % w/w of plasticizer (s),
(h) 0.5 - 5 % w/w of lubricant(s) .
Another aspect of the present subject matter provides a stable pharmaceutical compositions comprising,
(a) bumetanide as the active pharmaceutical ingredient,
(b) one or more pharmaceutically acceptable diluent (s),
(c) one or more pharmaceutically acceptable antioxidant (s),
(d) one or more pharmaceutically acceptable disintegrant (s),
(e) one or more pharmaceutically acceptable glidant (s),
(f) one or more pharmaceutically acceptable lubricant (s).
Another aspect of the present subject matter provides a process to prepare a stable pharmaceutical composition comprising,
(a) mixing bumetanide with one or more pharmaceutically acceptable diluent (s),
(b) mixing blend of (a) with one or more pharmaceutically acceptable antioxidant (s),
(c) mixing blend of (b) further with one or more pharmaceutically acceptable diluent (s),
(d) mixing blend of (c) with one or more pharmaceutically acceptable disintegrant (s),
(e) mixing blend of (d) further with one or more pharmaceutically acceptable glidant (s),
(f) mixing blend of (e) with one or more pharmaceutically acceptable lubricant (s),
(g) lubricated blend of (e) compressed into tablets.
Another aspect of the present subject matter provides a stable pharmaceutical composition comprising,
(a) 0.01 - 20 % w/w of bumetanide,
(b) 20 - 90 % w/w of diluent (s),
(c) 0.01 - 10 % w/w of antioxidant (s),
(d) 5 - 40 % w/w of disintegrants (s),
(e) 0.2 - 5 % w/w of glidant (s),
(f) 0.5 - 5 % w/w of lubricant (s).
In this specification, terms “antioxidant'' and “antioxidants'', as used herein, refers to a group of substances that are capable of inhibiting, preventing or reducing oxidative reactions. Preferred antioxidants are, examples of which include butylated hydroxy anisole (BHA), butylated hydroxy toulene (BHT), ascorbic acid, sodium ascorbate, acetyl cysteine, cysteine, thiourea, 1-thiosorbitol, sulphites (eg sodium sulphite), bisulphites (eg sodium bisulphite), metabisulphites (eg sodium metabisulphite), thiosulphates (eg sodium thiosulfate), citric acid, tartaric acid, phosphoric acid, malic acid, lactic acid, methanesulfonic acid, ethanesulfonic acid, ?-toluenesulfonic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, gluconic acid, glucuronic acid, glutamic acid, fumaric acid, maleic acid, and the like.
In this specification, the terms “film forming agent” and “film forming agents” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable film forming agent according to the present subject matter can be selected form the group of, but not limited to hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL (HPC-SSL), hydroxypropyl cellulose SL (HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, povidone, Kollidone K30 LP, Kollidone VA64, Plasdone, Copovidone, Plasdone S630, polyoxyethylene–polyoxypropylene copolymers (Poloxamer), poloxamer 188, polyvinylpyrrolidone vinyl acetate, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, , methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-EPO), and the like.
In this specification the terms “diluent” and “diluents” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable diluent according to the present subject matter can be selected form the group of, but not limited to sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, erythritol, maltose, polydextrose, sucrose, trehalose and xylitol; calcium carbonate; dicalcium phosphate; pregelatinized starch; corn starch; calcium sulfate; cellulose acetate; ethylcellulose; inulin; magnesium carbonate; magnesium oxide; maltodextrin; sodium bicarbonate; sodium carbonate; sodium chloride, microcrystalline cellulose, and the like.
In this specification, the terms “binder” and “binders” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable binder according to the present subject matter can be selected form the group of, but not limited to povidone, copovidone, pregelatinized starch, cellulose, methyl cellulose, ethyl cellulose, cellulose derivatives (e.g., Hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC)), polyethylene glycol, and the like.
In this specification the terms “disintegrant” and “disintegrants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable disintegrants according to the present subject matter can be selected form but not limited to pregelatinized starch, corn starch, croscarmellose sodium, alginic acid, sodium alginate, carboxymethylcellulose calcium, chitosan, crospovidone, glycine, pregelatinized starch, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium carboxymethylcellulose, sodium starch glycolate, and the like.
In this specification, the terms “sugar” and “sugars” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable sugar according to the present subject matter can be selected form the group of, but not limited to sucrose, glucose, fructose, lactose, maltose, dextrose, and the like.
In this specification, the terms “lubricant”, “lubricants”, anticaking agent” and “anticaking agents” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical lubricant or anticaking agent according to the present subject matter can be selected from, but not limited to, magnesium, aluminium, zinc or calcium stearate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of benenate esters of glycerine (e.g. a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate), magnesium stearate, myristic acid, palmitic acid, stearic acid, talc, tribehenin, sodium stearyl fumarate (SSF), and the like.
In another embodiment, the present subject matter relates to a process for the preparation of a stable pharmaceutical composition, comprising the steps of:
a) dissolving a film forming agent in a solution and mixing with an anticaking agent to form a dispersion,
b) spraying dispersion of step a) onto pellets to form a seal coating on the pellets,
c) preparing a binder solution and mixing the solution with one or more antioxidants, an active ingredient and an anticaking agent to form a dispersion,
d) spraying the dispersion of step c) onto the seal coated pellets, followed by drying the pellets,
e) mixing the drug loaded pellets of d) with a lubricant,
f) filling the mixture of step e) into capsules,
In another embodiment, the present subject matter relates to a process for the preparation of a stable pharmaceutical composition, comprising the steps of:
a) preparing a dispersion containing an active agent, a film forming agent, an antioxidant, anticaking agent in a solvent,
b) spraying the dispersion of a) onto the sugar spheres to form drug coated spheres,
c) further coating spheres of b) with an enteric coating dispersion containing film forming agent, plasticizer, anticaking agent and solvent,
d) mixing the spheres of c) with a lubricant,
e) filling the lubricated spheres of d) into capsules.
In another embodiment, the present subject matter relates to process for the preparation of a stable pharmaceutical composition, comprising the steps of:
a) co-sifting active pharmaceutical ingredient with part of 1st diluent,
b) mixing one or more antioxidants with step a) blend,
c) co-sifting material of step b) with remaining quantity of 1st diluent,
d) mixing 2nd diluent with material of step b) & c),
e) mixing a disintegrant with material of step d)
f) mixing a glidant & lubricant with material of step e),
j) compressing the lubricated blend of step f) into tablets.
In one embodiment, the pharmaceutical composition is a stable pharmaceutical composition suitable for oral administration.
Accordingly, the stable pharmaceutical composition prepared by the method given according to the subject matter and stored under the conditions, such as, but not limited to, room temperature, accelerated condition, with or without using nitrogen purging, at high temperature, etc.; complies the regulatory requirement with respect to genotoxic impurities as prescribed by various regulatory bodies like USFDA, PMDA, EMCA, TGA etc. throughout their stability period.
In one embodiment, the nitrosamine impurities are measured by a validated Liquid chromatography mass spectrometer (LCMS) method.
Stability testing is carried out to provide evidence of how the quality of the manufactured tablets (especially nitrosamine impurities) may change with time under the influence of environmental factors such as temperature and humidity coupled with presence and absence of antioxidants.
Embodiments provided herein may be more fully understood by reference to the following examples. These examples are meant to be illustrative of pharmaceutical composition and dosage form provided herein, but is not in any way limiting.
Example 1:
Table 1: Dabigatran etexilate mesylate capsule compositions with and without antioxidant (s):
Batch Control 1 2 3 4 5 6
Ingredients %w/w
Seal coating stage
Tartaric acid pellets 41.44 41.01 40.60 40.39 40.60 40.60 40.80
Hypromellose phthalate 2.58 2.58 2.56 2.54 2.56 2.56 2.57
Talc 0.29 - 0.28 0.28 0.28 0.28 0.29
Silica - 0.29 - - - - -
Dichloromethane: Ethanol q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Drug coating stage
Seal coated Tartaric acid pellets 43.88 43.88 43.44 43.22 43.44 43.45 43.66
HPC 8.47 8.47 8.38 8.34 8.38 8.38 8.42
Dabigatran etexilate mesylate 45.75 45.75 45.30 45.07 45.30 45.31 45.53
Talc 0.85 - 0.84 0.83 0.84 0.84 0.84
Silica - 0.85 - - - - -
BHA - - - 1.00 0.98 - -
Ascorbic acid - - - 0.50 - 0.98 0.50
Sodium ascorbate - - 1.00 - - - -
IPA q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Pellets weight 98.94 98.94 98.95 98.96 98.95 98.95 98.95
Talc 1.06 1.06 1.05 1.04 1.05 1.05 1.05
Total filled weight 100 100 100 100 100 100 100
The control batch is absent of any antioxidant. In batch 1, the talc as anticaking agent is replaced with silica, as silica was found to have low nitrite content. Batches 2 to 6 contain one or more antioxidants.
Example 2:
Table 2: N-nitroso-dabigatran impurity data (in ppm):
Batch N-nitroso-dabigatran (in ppm)
Initial 60°C, 7 days
API 0.005 -
Control 0.058 0.9569
1 0.0562 0.6671
2 0.0387 0.2563
3 0.0375 0.0359
4 0.034 0.1565
5 0.0387 0.0139
6 0.0515 0.0567
Based on above data, it is evidenced that antioxidants have the potential to reduce the nitrosamine impurities. All the tested antioxidants reduced the levels of impurity compared to control formulation. Ascorbic acid and BHA were found to be the most promising both individually and in combination.
Example 3:
Table 3: Stable compositions of dabigatran capsule with antioxidant (s):
Ingredients % w/w
Batches A B C D E
Seal coating stage
Tartaric acid pellets 39.48 38.97 39.228 40.495 40.495
Hypromellose phthalate 2.58 2.58 2.583 2.551 2.551
Talc 0.29 0.29 0.287 0.283 0.283
Dichloromethane: Ethanol q.s. q.s. q.s. q.s. q.s.
Drug coating stage
Coated Tartaric acid pellets 42.35 41.84 42.098 43.330 43.330
Hydroxy propyl cellulose 8.47 8.47 8.466 8.360 8.360
Dabigatran etexilate mesylate 45.75 45.75 45.754 45.185 45.185
Talc 0.85 0.85 0.847 0.836 0.836
Butylated hydroxy anisole 1.02 1.02 1.016 0.993 -
Ascorbic acid 0.51 1.02 0.762 0.251 0.977
IPA q.s. q.s. q.s. q.s. q.s.
Pellets weight 98.94 98.94 98.942 98.955 98.688
Talc 1.06 1.06 1.058 1.045 1.045
Total filled weight 100.00 100.00 100.000 100.000 99.734
Example 4:
Table 4: Compositions of duloxetine delayed-release capsule with and without antioxidant (s):
Batch Control 1 2 3 4 5 6 7 8
Ingredients %w/w
Drug layering
Sugar spheres 19.49 18.49 18.49 18.49 18.53 18.99 19.24 18.99 18.49
Duloxetine hydrochloride 21.50 21.50 21.50 21.50 21.50 21.50 21.50 21.50 21.50
HPMC 4.15 4.15 4.15 4.15 4.15 4.15 4.15 4.15 4.15
Ascorbic acid - 1.00 - - - 0.50 0.25 0.50 1.00
Vitamin E TPGS - - - 1.00 - - - -
Sodium ascorbate - - 1.00 - - - - - -
Talc 3.19 3.19 3.19 3.19 3.19 3.19 3.19 3.19 3.19
BHA - - - - 0.64 - - - -
BHT - - - - 0.32 - - - -
Acetone (50%) - - - - q.s. - - - -
Purified Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Sub coating
Sucrose 15.02 15.02 15.02 15.02 15.02 15.02 15.02 9.27 9.27
HPMC 15.02 15.02 15.02 15.02 15.02 15.02 15.02 22.77 22.77
Talc 7.51 7.51 7.51 7.51 7.51 7.51 7.51 7.51 7.51
Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s q.s
Enteric coating
HPMC Phthalate 11.57 11.57 11.57 11.57 11.57 11.57 11.57 11.57 11.57
Triethyl Citrate 1.16 1.16 1.16 1.16 1.16 1.16 1.16 1.16 1.16
Talc 1.18 1.18 1.18 1.18 1.18 1.18 1.18 1.18 1.18
Isopropyl Alcohol q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Dichloromethane q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Lubrication
Talc 0.22 0.22 0.22 0.22 0.22 0.22 0.22 0.22 0.22
Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0
The control batch is absent of any antioxidant. Batches 1 to 8 contain one or more antioxidants.
Example 5:
Table 5: N-nitroso-duloxetine impurity data (in ppm)
Control 1 2 3 4 5 6 7
Drug loading 0.655 0.08 3.804 0.964 1.226 0.127 0.131 0.130
Sub coating 1.035 0.126 4.834 1.004 1.479 0.184 0.171 -
Enteric coating 0.659 0.153 - 0.667 1.126 0.117 0.118 0.134
Based on above data, it is evidenced that antioxidants have the potential to reduce the nitrosamine impurities. Ascorbic acid was found to be the most promising.
Example 6:
Table 6: N-nitroso impurity data (in ppm) of duloxetine compositions in HDPE bottle
Condition/Batch no Initial 1M Accelerated condition
(without nitrogen purge) 1M Accelerated condition
(with nitrogen purge)
Control 0.659 2.117 1.928
5 0.117 0.15 0.141
6 0.118 0.188 0.168
Example 7:
Table 7: N-nitroso impurity data (in ppm) of duloxetine compositions in Alu-Alu blister
Condition/Batch no Initial 1M Accelerated condition
Control 0.659 3.326
5 0.117 0.224
6 0.118 0.415
Example 8:
Table 8: Compositions of bumetanide tablet with and without antioxidants:
Batch Control 1 2 3 4
Ingredients %w/w
Bumenatide 0.56 0.56 0.56 0.56 0.56
Ascorbic Acid - 1.00 - 1.00 1.00
BHA - 1.00 1.00 0.50 0.25
Lactose Anhydrous 38.22 38.22 38.22 38.22 38.22
Microcrystalline Cellulose 35.67 34.67 35.67 35.17 35.42
Corn starch 5% 11.67 11.67 11.67 11.67 11.67
Pregelatinized starch 11.11 11.11 11.11 11.11 11.11
Talc 0.83 0.83 0.83 0.83 0.83
Magnesium Stearate 0.94 0.94 0.94 0.94 0.94
Total filled weight 99.00 100 100 100 100
The control batch is absent of any antioxidant. Batches 1 to 4 contain one or more antioxidants.
Example 9:
Table 9: N-nitroso-bumetanide impurity data (in ppm)
Batch N-nitroso-bumetanide (in ppm)
Control 38.625
1 Not detected
2 0.480
3 Not detected
4 0.430
Based on above data, it is evidenced that the antioxidants have the potential to reduce the nitrosamine impurities. All the tested antioxidants reduced the levels of impurity compared to control formulation.

,CLAIMS:We claim:

1. A stable pharmaceutical composition comprising an active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable antioxidants and one or more pharmaceutically acceptable excipients and wherein the amount of nitrosamine impurity is controlled in the pharmaceutical composition.

2. The stable pharmaceutical composition as claimed in claim 1, wherein the amount of nitrosamine impurity in the pharmaceutical composition during manufacturing process and storage period is less than the FDA acceptable limit of the nitrosamine impurity based on maximum daily dose of the active pharmaceutical ingredient.

3. The stable pharmaceutical composition as claimed in claim 1, wherein the active pharmaceutical ingredient include but are not limited to dabigatran, duloxetine, bumetanide, valsartan, sacubitril, ticagrelor, trametinib, doxycycline, viloxazine and/or any pharmaceutically acceptable salt thereof.

4. The stable pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable antioxidants are selected from butylated hydroxy anisole (BHA), butylated hydroxy toulene (BHT), ascorbic acid, sodium ascorbate, acetyl cysteine, cysteine, thiourea, 1-thiosorbitol, sulphites (eg sodium sulphite), bisulphites (eg sodium bisulphite), metabisulphites (eg sodium metabisulphite), thiosulphates (eg sodium thiosulfate), citric acid, tartaric acid, phosphoric acid, malic acid, lactic acid, methanesulfonic acid, ethanesulfonic acid, ?-toluenesulfonic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, gluconic acid, glucuronic acid, glutamic acid, fumaric acid, maleic acid, or a combination thereof; and wherein the pharmaceutically acceptable excipient is selected from carriers, diluents, fillers, binders, disintegrants, adsorbents, film forming agents, anticaking agents, plasticizers, sugars, lubricants, glidants, coloring or flavoring agents or combinations thereof.

5. The stable pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable antioxidants are in the range of about 0.01 to about 10 %, preferably in the range of about 0.01 to about 5 %, by weight with respect to the total weight of the composition.

6. The stable pharmaceutical composition as claimed in claim 1, comprising:
(a) 25 - 50 % w/w of pellets or spheres,
(b) 1 - 25 % w/w of film forming agent (s),
(c) 1 - 5 % w/w of anticaking agent (s),
(d) 10 - 50 % w/w of active pharmaceutical ingredient (s),
(e) 1 - 15 % w/w of binder (s),
(f) 0.01 - 10 % w/w of antioxidant (s),
(g) 0.5 - 5 % w/w of lubricant (s),
(h) 10 - 20 % w/w of sugar (s), and
(i) 1 - 5 % w/w of plasticizer (s); based on the total weight of the composition.

7. The stable pharmaceutical composition as claimed in claim 1, comprising:
(a) 0.01 - 20 % w/w of active pharmaceutical ingredient (s),
(b) 20 - 90 % w/w of diluent (s),
(c) 0.01 - 10 % w/w of antioxidant (s),
(d) 5 - 40 % w/w of disintegrant (s),
(e) 0.2 - 5 % w/w of glidant (s), and
(g) 0.5 - 5 % w/w of lubricant (s); based on the total weight of the composition.

8. The stable pharmaceutical composition as claims in claim 1 or 6, wherein the process for preparation of said composition comprises,
(a) carriers, pellets of organic acid (s) or inert spheres (s),
(b) pellets or spheres of (a), optionally coated with one or more pharmaceutically acceptable film forming agent (s), one or more pharmaceutically acceptable anticaking agent (s),
(c) pellets or spheres of (a) or (b) coated with active pharmaceutical ingredient (s), one or more pharmaceutically acceptable anticaking agent (s), one or more pharmaceutically acceptable antioxidant (s), one or more pharmaceutically acceptable binder (s), one or more pharmaceutically acceptable film forming agent (s), or combinations thereof,
(d) drug coated pellets or spheres of (c), further optionally coated with one or more pharmaceutically acceptable sugar (s), one or more pharmaceutically acceptable anticaking agent (s) and one or more pharmaceutically acceptable film forming agent (s),
(e) coated pellets or spheres of (d), further optionally enteric coated with one or more pharmaceutically acceptable anticaking agent (s), one or more pharmaceutically acceptable plasticizer (s) and one or more pharmaceutically acceptable film forming agent (s),
(f) coated pellets or spheres of (c) or (e) are further blended with one or more pharmaceutically acceptable lubricant (s).
(g) lubricated pellets or spheres of (f) filled into the capsules.

9. The stable pharmaceutical composition according to any precedent claim, wherein the process for the preparation of said composition comprises dry granulation, wet granulation or direct mixing with excipients.

10. The stable pharmaceutical composition according to any precedent claim, wherein said composition is in the form of tablets, coated tablets, layered tablets, granules, powders, microparticles, capsules, caplets, sachets, pellets, spheroids, mini-tablets, beads, microcapsules, pills or a combination thereof.

Dated this 5th July, 2024

(Signature):

_______________
(Sonal Ben Parimal Patel)
For Alembic Pharmaceuticals Limited