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WO2024176162A1 - Composition pharmaceutique stable d'antagoniste du récepteur h2 de l'histamine - Google Patents

Composition pharmaceutique stable d'antagoniste du récepteur h2 de l'histamine Download PDF

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Publication number
WO2024176162A1
WO2024176162A1 PCT/IB2024/051717 IB2024051717W WO2024176162A1 WO 2024176162 A1 WO2024176162 A1 WO 2024176162A1 IB 2024051717 W IB2024051717 W IB 2024051717W WO 2024176162 A1 WO2024176162 A1 WO 2024176162A1
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Prior art keywords
composition
pharmaceutical composition
stable pharmaceutical
alkalizer
ppm
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PCT/IB2024/051717
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English (en)
Inventor
Abhishek Tyagi
Sant Singh
Abhishek Srivastava
Simrata Bedi
Romi Singh
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Sun Pharmaceutical Industries Ltd
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Sun Pharmaceutical Industries Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides

Definitions

  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a Histamine H2-receptor antagonist or a pharmaceutically acceptable salt thereof and a stabilizing amount of at least one alkalizer.
  • the composition shows an improved stability with controlled levels of potentially carcinogenic nitrosamine drug substance-related impurities (NDSRIs).
  • Histamine H2-receptor antagonist are a class of medications that block the action of histamine at the histamine H2 receptors of the parietal cells in the stomach. This decreases the production of stomach acid.
  • H2 antagonists can be used in the treatment of dyspepsia, peptic ulcers and gastroesophageal reflux disease.
  • Various H2 blockers are cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine.
  • ranitidine was found to have a much better tolerability profile (i.e. fewer adverse drug reactions), longer-lasting action, and ten times the activity of cimetidine.
  • Ranitidine is a competitive, reversible inhibitor of the action of histamine at the histamine H2 receptors found in gastric parietal cells. This results in decreased gastric acid secretion and gastric volume, and reduced hydrogen ion concentration. It is sold under the brand name Zantac* among others, is a medication used to decrease stomach acid production. It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger- Ellison syndrome. It can be given by mouth, injection into a muscle, or injection into a vein.
  • nitrosamine impurities which are probable human carcinogens, in drugs such as angiotensin II receptor blockers (ARBs), H2 blockers such as ranitidine, nizatidine, and biguanides such as metformin
  • FDA has been investigating the presence of nitrosamine impurities in certain drug products. Since 2018, several drug products including ARBs, ranitidine, nizatidine, and metformin have been found to contain unacceptable levels of nitrosamines.
  • NDMA N-nitrosodimethylamine
  • N-Nitrosodimethylamine is an organic compound with the formula (CHshNNO which is formed by the combination of dimethyl amine with nitrates. Whilst NDMA is a known common environmental contaminant, nitrosamine such as NDMA are known to be carcinogenic. Chronic ingestion of NDNMA is postulated to cause an increase in liver and other cancers.
  • OMCLs official medicinal control laboratories
  • NDSRIs Nitrosamine Drug Substance Related Impurities
  • the inventors in the present application have evaluated various formulation strategies to mitigate the risk associated by nitrosamine compounds in drug product, and surprisingly arrived at a stable formulation.
  • the present disclosure relates to a stable composition
  • a stable composition comprising Histamine H2-receptor antagonist or a pharmaceutically acceptable salt thereof, a stabilizing amount of at least one alkalizer and one or more pharmaceutically acceptable excipient.
  • the composition provides effective control of the level of nitrosamine drug substance-related impurities (NDSRIs) in the drug product during shelf life of the product.
  • NDSRIs nitrosamine drug substance-related impurities
  • the present invention relates to stable pharmaceutical composition of ranitidine hydrochloride comprising an alkali metal stabilizer and one or more pharmaceutically acceptable excipients.
  • the composition according to the present invention comprises of Histamine H2-receptor antagonist with an alkali stabilizer and has controlled level of impurities including the nitrosamine drug substance-related impurities (NDSRIs).
  • NDSRIs nitrosamine drug substance-related impurities
  • the nitrosamine drug substance-related impurity is N- nitrosodimethylamine (NDMA).
  • the stable pharmaceutical composition according to the present invention comprises a Histamine H2-receptor antagonist, a stabilizing amount of at least one alkalizer and one or more pharmaceutically acceptable excipient, wherein the alkalizer effectively control the formation of nitrosamine drug substance-related impurities (NDSRIs) in the composition, to a level below about 11 ppm, upon storage or acid exposure.
  • the Histamine H2-receptor antagonist is ranitidine hydrochloride
  • the stable pharmaceutical composition according to the present invention comprises the ratio of a Histamine H2-receptor antagonist and an alkalizer in the composition in the range of 100:0.1 to 100:5.
  • the stable pharmaceutical composition according to the present invention the nitrosamine drug substance-related impurity is N- nitrosodimethylamine (NDMA) impurity.
  • NDMA N- nitrosodimethylamine
  • the alkalizer is selected from alkali metal oxide, pH modifier, nitrite quencher.
  • the alkalizer is alkali metal oxide. More preferably, the alkali metal oxide is magnesium oxide
  • the level of nitrosamine drug substance related impurities (NDSRIs) level is below about 11 ppm upon storage under controlled room temperature condition of 25°C/60% RH for at least 12 months.
  • the stable pharmaceutical composition according to the present invention comprises ranitidine hydrochloride and magnesium oxide, wherein the magnesium oxide is present in the composition in an amount present in an amount ranging from about 0.1% w/w to about 10% w/w of the composition, wherein the composition is characterized by a level of N- Nitrosodimethylamine (NDMA) impurity below 11 ppm, upon storage at 25°C/60% RH for a period of at least 12 months. More preferably, the amount of magnesium oxide ranges from about 0.1% w/w to about 2% w/w of the composition.
  • NDMA N- Nitrosodimethylamine
  • the stable pharmaceutical composition according to the present invention is characterized by a level of nitrosamine drug substance related impurity below 3 ppm, upon storage at 25°C/60% RH for a period of 12 months.
  • the composition is a stable oral dosage form of ranitidine Hydrochloride with controlled levels of N- nitrosodimethylamine (NDMA) impurity.
  • NDMA N- nitrosodimethylamine
  • the present invention also provides method for controlling nitrosamine drug substance-related impurities (NDSRIs) in amine containing drug products.
  • the present invention provides a method for preparing a stable pharmaceutical composition comprising a Histamine H2-receptor antagonist or a pharmaceutically acceptable salt and at least one alkali metal stabilizer, wherein the alkali metal stabilizer is placed in the composition in a way to effectively control the formation of nitrosamine drug substance-related impurities (NDSRIs) in the composition.
  • NDSRIs nitrosamine drug substance-related impurities
  • coating as used herein the description, can be used interchangeably with the term “coat” or “layer” around the core.
  • Histamine H2-receptor antagonist can be used interchangeably to "HR2as” or "H2 blockers".
  • the most commonly used Histamine H2-receptor antagonist that can be used according to the present invention including but not limited to cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine.
  • the disclosure according to present invention can also be used with other amine drugs such as sartans, antidiabetic drugs, antihistamines, and antibiotics; for e.g.
  • the drugs include Amoxicillin, Bendroflumethiazide, Betahistine, Bisoprolol, Bromazepam, Carvedilol, Cetirizine, Desloratadine, Diclofenac, Doxylamine, Duloxetine, Enalapril, Ergometrine, Felodipine, Flecainide, Fluoxetine, Hydrochlorothiazide (HCT), Levofloxacin, Metoprolol, Metformin, Mirabegron, Mirtazapine, Moxifloxacin, Nebivolol, Opipramol, Pergolide, Propranolol, Quetiapine, Ramipril, Roxithromycin, Sertraline, Sotalol, Sumatriptan, Sitagliptin, Valsartan, Varenicline, Metformin, ranitidine, Gliclazide, Sitagliptin, Prucalopride, Clarithromycin, Oxcarbazepin
  • shelf life means the shelf life of the drug product, in its form as a product sold for use by consumers, during which period the product is suitable for use by a patient.
  • the shelf life of the drug product can be greater than 3, 6, 12, 18, or preferably 24 months.
  • the shelf life may be achieved when the product is stored at room temperature at about 25° C, protected from light and moisture.
  • composition as used herein the description, can be used interchangeably with the term 'pharmaceutical composition' or 'pharmaceutical formulation' or 'pharmaceutical preparation' or 'drug product', wherein the drug product is defined as a composition of H2 blocker drug and one or more pharmaceutical excipients.
  • alkalizer represents the chemical entity responsible for increasing the pH of the composition, and comprises alkali metal stabilizers such as alkali metal oxides, alkali metal salts; pH modifiers; and Nitrite quenchers.
  • the present invention provides a stable pharmaceutical composition of an H2 blocker or a pharmaceutically acceptable salt thereof, and at least one alkali metal stabilizer in the composition, wherein the alkali metal stabilizer effectively controls the level of the nitrosamine drug substance-related impurities (NDSRIs) in the composition.
  • NDSRIs nitrosamine drug substance-related impurities
  • the nitrosamine drug substance-related impurities (NDSRIs) in the composition is /V-nitrosodimethylamine (NDMA) impurity.
  • the pharmaceutical composition is a stable composition comprising an H2 blocker or a pharmaceutically acceptable salt thereof, with stabilizing amount of one or more alkali metal stabilizer in an amount effective for controlling the level of nitrosamine related impurities in the drug product during shelf life of the product.
  • the alkali metal stabilizer is an alkali metal oxide present in the composition in such a way that it effectively controls the level of nitrosamine drug substance-related impurities (NDSRIs) in the drug product.
  • NDSRIs nitrosamine drug substance-related impurities
  • the alkali metal oxide is present in the core of the composition for effective control of the level of nitrosamine drug substance-related impurity in the drug product. In another aspect of the above embodiment, the alkali metal oxide is present in the composition within a coating for effective control of the level of nitrosamine drug substance-related impurity in the drug product.
  • the nitrosamine drug substance-related impurities (NDSRIs) in the composition may be formed due to nitrosating reaction between amines (primary, secondary, tertiary, or quaternary amines) of drug and/or excipients present in the drug product, and the applicant surprisingly found that the alkali metal stabilizer in claimed concentration ranges and arrangement play crucial role in controlling nitrosamine drug substance-related impurities (NDSRIs) as well as other impurities simultaneously in the composition below acceptable levels.
  • the composition comprises of an amine containing drug and stabilizing amount of at least one alkalizer.
  • the alkalizer characteristically controls or prevents formation of nitrosamine drug substance- related impurity in the drug product upon storage or acid exposure.
  • stable refers to a chemical stability of the composition which means that the level of nitrosamine drug substance related impurity (NDSRIs) in the composition remains below about 11 ppm, preferably below about 10 ppm, below about 9 ppm, below about 8 ppm, below about 7 ppm, below about 6 ppm, below about 5 ppm, below about 4 ppm, below about 3 ppm, below about 2 ppm, or below about 1 ppm, upon storage under the temperature and humidity conditions of 40°C/75% RH for at least 3 months and at controlled room temperature condition of 25°C/60% RH for at least 12 months, 18 months or 24 months.
  • NDSRIs nitrosamine drug substance related impurity
  • stable also refers to physical stability which means that the composition retain its structural integrity and does not rupture in a significant way after exposure to storage conditions which means the composition is stable when stored under the temperature and humidity conditions of 40°C./75% RH and 30°C./75% RH for at least 3 months or at controlled room temperature condition of 25°C/60% RH for at least 12 months, 18 months or 24 months
  • the disclosed composition comprises of an H2-blocker drug or a pharmaceutically acceptable salt thereof, with one or more alkalizer in an amount effective for controlling the level of nitrosamine drug substance-related impurities (NDSRIs) in the drug product, the drug product is coated with a suitable coating.
  • the coating is a film coating.
  • the coating is an aqueous film coating.
  • the coating is a non-aqueous film coating.
  • the disclosed stable composition comprises amine drug or a pharmaceutically acceptable salt thereof, with one or more alkalizer in an amount effective for controlling the level of nitrosamine drug substance-related impurities (NDSRIs) in the drug product and the drug product is coated with an aqueous film coating.
  • NDSRIs nitrosamine drug substance-related impurities
  • the amine drug is ranitidine or a pharmaceutical acceptable salt thereof.
  • the disclosed stable composition comprises amine drug or a pharmaceutically acceptable salt thereof, with one or more alkalizer in an amount effective for controlling the level of nitrosamine drug substance-related impurities (NDSRIs) in the drug product and the drug product is coated with a non-aqueous film coating.
  • NDSRIs nitrosamine drug substance-related impurities
  • the amine drug is ranitidine or a pharmaceutical acceptable salt thereof.
  • the disclosed stable dosage form comprises ranitidine or a pharmaceutically acceptable salt thereof with one or more alkalizer for controlling the level of nitrosamine drug substance related impurities (NDSRIs) to a level below about 11 ppm.
  • NDSRIs nitrosamine drug substance related impurities
  • the level of nitrosamine drug substance related impurity (NDSRIs) in the composition remains below about 11 ppm, preferably below about 10 ppm, below about 9 ppm, below about 8 ppm, below about 7 ppm, below about 6 ppm, below about 5 ppm, below about 4 ppm, below about 3 ppm, below about 2 ppm or below about 1 ppm upon storage under the temperature and humidity conditions of 40°C./75% RH or 30°C./75% RH for at least 3 months and at controlled room temperature condition of 25°C/60% RH for at least 12 months, 18 months or 24 months.
  • the nitrosamine drug substance related impurities (NDSRIs) is N- Nitrosodimethylamine (NDMA).
  • the level of N- nitrosodimethylamine (NDMA) is below about 11 ppm, preferably below 5 ppm, more preferably below 3 ppm for shelf life period.
  • N- nitrosodimethylamine refers to the nitrosamine drug substance related impurities (NDSRIs) associated with ranitidine or its pharmaceutical acceptable salts. Such impurities may be present in active pharmaceutical ingredients or can be formed in the drug product up on storage.
  • the disclosed stable dosage form comprises an H2 blocker drug or a pharmaceutically acceptable salt thereof and at least one alkalizer.
  • the alkalizer is selected from alkali metal oxide, pH modifier, nitrite quencher.
  • the alkali metal oxide is magnesium oxide.
  • the alkalizer is sodium metabisulfite.
  • the pH modifier is selected from meglumine.
  • the disclosed stable dosage form comprises an H2 blocker drug or a pharmaceutically acceptable salt thereof and a combination of two or more alkalizer, in an amount and ratio effective for controlling the Nitrosamine drug substance related impurities (NDSRIs).
  • NDSRIs Nitrosamine drug substance related impurities
  • the H2 blocker drug is ranitidine or a pharmaceutical acceptable salt thereof and the alkalizer is a combination of alkali metal oxide and pH modifier.
  • the composition further comprises alkalizer as alkali metal oxide and an additional antioxidant component.
  • the composition comprises alkalizer as a pH modifier and an additional antioxidant component.
  • the alkalizer is a combination of alkali metal oxide and pH modifier, with an additional antioxidant component.
  • the disclosed stable dosage form comprises a ranitidine or a pharmaceutically acceptable salt thereof and one or more alkalizer, in an amount and ratio effective for controlling the nitrosamine drug substance related impurities (NDSRIs).
  • the composition comprises ranitidine hydrochloride and magnesium oxide, wherein the magnesium oxide is present in the composition in an amount effective for controlling the nitrosamine drug substance related impurities (NDSRIs) of ranitidine.
  • NDSRIs nitrosamine drug substance related impurities
  • nitrosamine drug substance related impurities (NDSRIs) of ranitidine is N- Nitrosodimethylamine (NDMA).
  • the alkalizer is magnesium oxide and is present in an amount ranging from about 0.1% w/w to about 10% w/w, preferably about 0.1% w/w to about 2% w/w.
  • the present invention provides a stable pharmaceutical composition
  • a Histamine H2-receptor antagonist drug or a pharmaceutically acceptable salt thereof and an alkalizer wherein the composition is characterized by a level of nitrosamine drug substance related impurity below 11 ppm, preferably below 5 ppm, more preferably below 3 ppm.
  • the alkalizer is selected from an alkali metal stabilizer such as alkali metal oxides, alkali metal salts, pH modifiers and nitrite quencher, or mixture thereof.
  • the alkalizer is an alkali metal stabilizer selected from magnesium oxide, sodium oxide and potassium oxide or mixture thereof.
  • the alkali metal stabilizer is magnesium oxide.
  • the alkalizer can be selected from sodium sulfites, sodium metabisulfite, sodium bisulfite, or combination thereof.
  • the alkalizer can be used in combination with an antioxidant selected from ascorbic acid, tocopherol, sodium ascorbate, butylated hydroxy anisole, butylated hydroxyl toluene, and propyl gallate or mixture thereof.
  • the alkalizer is a nitrite quencher selected from ascorbic acid or salt thereof.
  • the nitrite quencher is sodium ascorbate.
  • the alkalizer is a pH modifier selected from meglumine or salt thereof.
  • the alkalizer is present in the composition in a concentration range of about 0.1% w/w to about 10% w/w of the composition, preferably about 0.1% w/w to about 5% w/w, more preferably about 0.1 to about 3% w/w of the composition.
  • the alkalizer is alkali metal oxide.
  • the alkali metal oxide is magnesium oxide.
  • the Histamine H2-receptor antagonist drug in the pharmaceutical composition is selected from cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine or a pharmaceutically acceptable salt thereof.
  • the Histamine H2-receptor antagonist drug is ranitidine or a pharmaceutically acceptable salt thereof.
  • the Histamine H2-receptor antagonist drug is Nizatidine or a pharmaceutically acceptable salt thereof.
  • the nitrosamine drug substance related impurity is N- nitrosodimethylamine (NDMA) impurity.
  • the present invention provides a stable pharmaceutical composition of ranitidine comprising ranitidine or a pharmaceutically acceptable salt thereof, at least one alkali metal stabilizer, and one or more pharmaceutically acceptable excipient, wherein the composition is characterized by nitrosamine drug substance-related impurities (NDSRIs) in the composition below 11 ppm, preferably below 5 ppm, more preferably below 3 ppm upon storage at 25°C./60% RH for a period of 24 months.
  • NDSRIs nitrosamine drug substance-related impurities
  • the present invention provides a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising of ranitidine hydrochloride and magnesium oxide with one or more pharmaceutically acceptable excipients, wherein the composition is characterized by nitrosamine drug substance related impurity as N- Nitrosodimethylamine (NDMA) below 11 ppm, preferably below 5 ppm, more preferably below 3 ppm upon storage at 25°C/60% RH for a period of 24 months.
  • NDMA N- Nitrosodimethylamine
  • the pharmaceutical composition is further coated with a film coating.
  • the film coating is an aqueous film coating.
  • the film coating is a non-aqueous film coating.
  • the pharmaceutical composition according to present invention comprises Histamine H2-receptor antagonist or a pharmaceutically acceptable salt thereof and an alkalizer, wherein a ratio of a Histamine H2-receptor antagonist drug or a pharmaceutically acceptable salt thereof and an alkalizer in the composition is 100:0.1 to 100:10, preferably 100:0.1 to 100:5.
  • the presence of Histamine H2-receptor antagonist or a pharmaceutically acceptable salt thereof and an alkalizer in a ratio of 100:0.1 to 100:10 is effective for controlling the level of N- Nitrosodimethylamine (NDMA) impurity below 11 ppm, preferably below 5 ppm, more preferably below 3 ppm upon storage at 25°C/60% RH for a period of 24 months.
  • NDMA N- Nitrosodimethylamine
  • the present invention provides a process for preparing a stable pharmaceutical composition of Histamine H2-receptor antagonist comprising a Histamine H2-receptor antagonist or a pharmaceutically acceptable salt and at least one alkali metal stabilizer, wherein the alkali metal stabilizer is placed in the composition for effective control of the formation of nitrosamine drug substance-related impurities (NDSRIs) in the composition below 11 ppm, preferably below 5 ppm, more preferably below 3 ppm upon storage at 25°C./60% RH for a period of 24 months.
  • NDSRIs nitrosamine drug substance- related impurities
  • the process comprises of: a) blending Histamine H2-receptor antagonist and alkali metal stabilizer and sifting with one or more pharmaceutically acceptable excipient to form the core blend; b) lubricating the core blended, followed by compressing into tablets; c) coating the tablet and packing.
  • the Histamine H2-receptor antagonist and alkali metal stabilizer are mixed prior to co-sifting with other excipients.
  • the process according to present invention is carried out under sodium light with low relative humidity condition.
  • the present invention provides a method for controlling N-nitrosodimethylamine in a pharmaceutical composition of an amine drug, wherein the method comprises mixing an amine drug with an alkali metal oxide during preparation of the pharmaceutical composition followed by sifting the mixture with pharmaceutical acceptable excipient.
  • the method characteristically controls the level of the N- Nitrosodimethylamine below 11 ppm, preferably below 5 ppm, more preferably below 3 ppm upon storage at 25°C/60% RH for a period of 24 months.
  • the stable dosage form comprising ranitidine or a pharmaceutically acceptable salt thereof with at least one or more alkalizer
  • alkalizer is selected from magnesium oxide, meglumine, aluminum oxide, ammonium hydroxide, magaldrate, an alkali metal salt or alkaline earth metal salt, such as sodium bicarbonate, calcium carbonate or sodium citrate, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide.
  • the preferred alkalizer according to the present invention is magnesium oxide.
  • the dosage form is characterized by controlled level of the N-Nitrosodimethylamine below 11 ppm, preferably below 5, more preferably below 3 ppm upon storage at 25°C/60% RH for a period of 24 months.
  • the dosage form according to present invention may be present in the form of solid oral dosage form such as tablet, pellet, granule, capsules.
  • the dosage form according to present invention comprises one or more pharmaceutically acceptable excipients selected from one or more of fillers, disintegrants, lubricants, glidants, anti-adherents, coating agents, and mixtures thereof.
  • Suitable diluents are selected from the group consisting of lactose, microcrystalline cellulose, starch, pregelatinized starch, calcium sulphate, calcium carbonate, powdered cellulose, mannitol, sorbitol, xylitol, lactitol, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, calcium sulphate, and mixtures thereof.
  • Suitable binders are selected from the group consisting of cellulose derivatives (for example methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC / Hypromellose), ethylcellulose, hydroxyl ethyl cellulose, L-hydroxy propyl cellulose); polyvinylpyrrolidone (for example povidone, copovidone); starch (for example corn starch, pre-gelatinized starch and hydroxypropyl starch), polymethacrylates (for example Eudragit RS, RL), and mixtures thereof.
  • cellulose derivatives for example methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC / Hypromellose), ethylcellulose, hydroxyl ethyl cellulose, L-hydroxy propyl cellulose
  • polyvinylpyrrolidone for example povidone, copovidone
  • starch for example corn starch, pre-gelatinized starch and hydroxypropyl star
  • Suitable disintegrants are selected from the group consisting of low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, starch derivatives, and mixtures thereof.
  • Suitable lubricants are selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and mixtures thereof.
  • Suitable glidants or antiadherents are selected from the group consisting of talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate, and mixtures thereof.
  • Non-limiting examples of suitable coating gents selected from the group comprising of aqueous and non-aqueous coating agents selected from Hypromellose, polyvinyl acetate, cellulose acetate, ethyl cellulose or combination thereof.
  • Additional excipients present in the coating include one or more of film forming polymers, plasticizers, anti-adherents, opacifiers, colorants, pigments, antifoaming agents, and polishing agents.
  • Suitable film-forming polymers are selected from the group consisting of hydroxypropylmethyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, and methacrylic acid copolymers, e.g., Eudragit*, polyvinylpyrrolidone, polyvinylalcohol, polyethylene glycol, and mixtures thereof.
  • Other suitable film-forming polymers which are known in the art may also be used.
  • Many suitable film coating products which are commercially available, e.g., Opadry*, Colorezy and Opagios* may be used.
  • Suitable plasticizers are selected from the group consisting of propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, acetyl tributyl citrate, glyceryl monostearate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, diacetylated monoglycerides, cetyl alcohol, and mixtures thereof.
  • Suitable opacifiers are selected from the group consisting of titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and mixtures thereof.
  • Suitable coloring agents are selected from FDA approved colorants such as iron oxide, lake of tartrazine, allura red, titanium dioxide, and mixtures thereof.
  • Suitable polishing agents are selected from the group consisting of polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (glycerol monostearate and poloxamers), fatty alcohols (stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol), waxes (carnauba wax, candelilla wax and white wax), and mixtures thereof.
  • Various solvents that may be employed during the preparation of the dosage form of the present invention are selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, and mixtures thereof.
  • the coating may be carried out by using any conventional coating techniques known in the art, such as spray coating in a conventional coating pan or fluidized bed processor, or dip coating.
  • Raw material including excipient and active pharmaceutical ingredient were weighed and dispensed for manufacturing the tablet;
  • Example 3 Formulation with aqueous and non-aqueous coating using different alkalizer:
  • Ranitidine Hydrochloride is taken in a weight equivalent to 300 mg of ranitidine base for example A to G and 150 mg of ranitidine base for example H and I respectively.
  • step-3 ingredients were blended in blender for 30 minutes at suitable speed.
  • Magnesium Stearate and Talc were sifted through suitable sieve.
  • Step-4 material were lubricated with the material of step-5 in a blender for suitable time at suitable speed.
  • the lubricated blend was unloaded in double polyethylene lined HDPE container.
  • step 10 Then the core tablets of step 10 were coated with dispersion of step 10 respectively to achieve a target weight buildup of 4.5 ⁇ 0.5% w/w.
  • Example 4 Stability data of Sample F & G with different percentage of
  • Example 5 Stability data of Sample A-D and H-H # with different percentage of Alkalizer:
  • Bottle pack is comparatively better than strip pack to control NDMA using at least one alkalizer as shown in above table.
  • Alu strip samples are having higher percentage of impurities in samples A and B, however the impurity levels were significant controlled in case of sample C & D under accelerate stability condition i.e. 40°C/75%RH conditions, which depicts that magnesium oxide and sodium ascorbate provides a comparatively better NDMA control in case of HDPE over Alu strip packings.
  • Batch J Prepared with modified milled API using similar process as in example 3, with a granulation step including Isopropyl alcohol granulation without alkalizer.
  • Batch K Prepared with modified coarse API using similar process as in example 3, with 10% ascorbic acid.
  • Batch L Prepared with modified coarse API using similar process as in example 3, with alkalizer as 10% sodium metabisulphite.
  • Batch M Prepared with modified coarse API using similar process as in example 3, with alkalizer as 5% Sodium Carbonate.
  • Batch N Prepared with modified coarse API using similar process as in example 3, without alkalizer.
  • Batch P Prepared with modified milled API using similar process as in example 3, with 1.2% Vitamin E.
  • samples which were loaded for stability were unstable and have higher NDMA levels within IM at 40°C/75%RH and 14 days at 60°C.
  • Example 7 Stability data of composition of Example 3C with aqueous coating and non-aqueous coating stored in 25x30's Strips
  • compositions are stable with an NDMA amount of less than llppm when stored for 12 months at 30°C/75%RH and at 40°C/75%RH for 6 months.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique stable comprenant un antagoniste du récepteur H2 de l'histamine ou un sel pharmaceutiquement acceptable de celui-ci et une quantité stabilisante d'au moins un alcaliseur. La composition permet une régulation efficace du niveau d'impuretés associées à une substance médicamenteuse à base de nitrosamine (NDSRI) telles que la NDMA dans le produit médicamenteux pendant la durée de conservation du produit.
PCT/IB2024/051717 2023-02-22 2024-02-22 Composition pharmaceutique stable d'antagoniste du récepteur h2 de l'histamine Ceased WO2024176162A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090099154A1 (en) * 2005-06-29 2009-04-16 Panacea Biotec Ltd. Pharmaceutical Sustained Release Compositions and Processes Thereof
KR101567937B1 (ko) * 2013-09-17 2015-11-10 셀티스팜 주식회사 안정성이 개선된 다층 고형 제제
WO2022079287A1 (fr) * 2020-10-16 2022-04-21 Zentiva K.S. Compositions pharmaceutiques à faibles teneurs en impuretés nitrosamine et leurs procédés de production

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090099154A1 (en) * 2005-06-29 2009-04-16 Panacea Biotec Ltd. Pharmaceutical Sustained Release Compositions and Processes Thereof
KR101567937B1 (ko) * 2013-09-17 2015-11-10 셀티스팜 주식회사 안정성이 개선된 다층 고형 제제
WO2022079287A1 (fr) * 2020-10-16 2022-04-21 Zentiva K.S. Compositions pharmaceutiques à faibles teneurs en impuretés nitrosamine et leurs procédés de production

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FDA: "Updates on possible mitigation strategies to reduce the risk of nitrosamine drug substance-related impurities in drug products | FDA", 18 November 2021 (2021-11-18), FDA Government Website, pages 1 - 4, XP093157924, Retrieved from the Internet <URL:https://www.fda.gov/drugs/drug-safety-and-availability/updates-possible-mitigation-strategies-reduce-risk-nitrosamine-drug-substance-related-impurities?utm_medium=email&utm_source=govdelivery> [retrieved on 20240503] *
NANDA KAUSIK K. ET AL: "Inhibition of N-Nitrosamine Formation in Drug Products: A Model Study", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 110, no. 12, 14 August 2021 (2021-08-14), US, pages 3773 - 3775, XP093146433, ISSN: 0022-3549, [retrieved on 20240503], DOI: 10.1016/j.xphs.2021.08.010 *
ZACHARY BRENNEN: "FDA seeks witdrawal of eartbur drugs due to new carcinogen concerns", 1 April 2020 (2020-04-01), XP093158498, Retrieved from the Internet <URL:https://www.raps.org/News-and-Articles/News-Articles/2020/4/FDA-Seeks-Withdrawal-of-Heartburn-Drugs-Due-to-New> [retrieved on 20240503] *

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