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WO2025122077A1 - Compositions pharmaceutiques comprenant du bromhydrate de vortioxétine ayant un profil d'impureté de nitrosamine amélioré - Google Patents

Compositions pharmaceutiques comprenant du bromhydrate de vortioxétine ayant un profil d'impureté de nitrosamine amélioré Download PDF

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Publication number
WO2025122077A1
WO2025122077A1 PCT/TR2023/051451 TR2023051451W WO2025122077A1 WO 2025122077 A1 WO2025122077 A1 WO 2025122077A1 TR 2023051451 W TR2023051451 W TR 2023051451W WO 2025122077 A1 WO2025122077 A1 WO 2025122077A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
solid pharmaceutical
stable solid
composition according
cellulose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/TR2023/051451
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English (en)
Inventor
Erol KIRESEPI
Ersin Yildirim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Santa Farma Ilac Sanayi AS
Original Assignee
Santa Farma Ilac Sanayi AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Santa Farma Ilac Sanayi AS filed Critical Santa Farma Ilac Sanayi AS
Priority to PCT/TR2023/051451 priority Critical patent/WO2025122077A1/fr
Publication of WO2025122077A1 publication Critical patent/WO2025122077A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient

Definitions

  • the present invention relates to a stable pharmaceutical composition comprising vortioxetine hydrobromide or pharmaceutically acceptable salt/derivatives thereof with improved nitrosamine impurity profile wherein the composition comprising vortioxetine hydrobromide and at least one pharmaceutically acceptable excipient which was manufactured by using wet granulation method by employing water as the granulation solvent.
  • Vortioxetine is an antidepressant used for the treatment of major depressive disorder (MDD). It functions as an antagonist for 5-HT3, 5-HT7 and 5-HT1D receptors, a partial agonist for 5- HT1B receptors, an agonist for 5-HT1A receptors, and an inhibitor of the serotonin (5-HT) transporter (SERT). Moreover, it has demonstrated to enhance the levels of the neurotransmitters serotonin, noradrenalin, dopamine, acetylcholine and histamine in specific areas of the brain.
  • MDD major depressive disorder
  • SERT serotonin transporter
  • Vortioxetine is l-[2-(2, 4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and has an empirical formula of CisH22N2S.HBr and its relative molecular mass is 298.45 mg/mol as a free base and 379.36 mg/mol as the hydrobromide salt.
  • the chemical structure of Vortioxetine is shown in the Formula I.
  • Vortioxetine hydrobromide (Vortioxetine HBr) appears as a white to very slightly beige powder, non-hygroscopic, soluble in methanol and ethanol and slightly soluble in water and aqueous solutions at pH 2.0 to 8.3. Its pKa is 9.1 as the free base and 3.0 as the salt.
  • Vortioxetine HBr was first commercially authorized in FDA by the U.S. Food &Drug Administration in September 2013. The medicinal product of it available on the market at film- coated tablet comprising Vortioxetine as the HBr salt and as an oral drop solution comprising Vortioxetine as the DL lactate salt under the name of the BRINTELLIX " which are used for the treatment of major depressive disorder (MDD) in adults.
  • MDD major depressive disorder
  • Vortioxetine base and its pharmaceutically acceptable acid addition salts first have been described in EP 1436271 by H. Lundbeck A/S.
  • vortioxetine could pose a potential risk of nitrosamine formation due to containing a secondary amine group.
  • Nitrosamines are a class of organic compounds to which we are exposed at low levels in our daily lives, found in sources such as water, foods, even some drugs.
  • nitrosamines in the pharmaceutical formulation may increase the risk of the cancer if people are exposed to them above acceptable intake levels over a long period of time. Thus, these are classified as probable human carcinogens (substances that could cause cancer). Because of that, the presence of nitrosamines in pharmaceutical compositions is required to be mitigated as much as possible and to ensure that the levels of these impurities do not exceed strict limits.
  • Nitrosamines can be found naturally in the environment and could generate with a trigger such as oxidative environment, reagents, temperature and acidic conditions. Specifically, a nitrosamine impurity originates from the nitrosation of a reagent by a nitrosating agent. Nitrosatable compounds and nitrosating agents can be introduced at various points in the manufacturing process of the drug subdtance or drug product, such as in the chemicals and solvents utilized, or they may emerge as a result of the degradation of the drug substance during the shelf-life of the drug product. As a result, a carryover could be present from drug substance to the drug products.
  • the prevailing strategy for mitigating nitrosamine impurities in active pharmaceutical ingredients and/or the final dosage form is to modify the synthesis pathways to eliminate nitrosable compounds and nitrosating agents capable of generating nitrosamines, which could contaminate the final drug product.
  • the active pharmaceutical ingredient (API) is a secondary amine and is manufactured using a method such as wet granulation, the presence of water, which serves as the granulation solvent, can potentially dissolve trace nitrite. Then, the dissolved nitrite could be turned into the nitrosamine impurity during the removing the granulation solvent during or after due to the drying process.
  • the inventors of the present invention have surprisingly found that the amount of the nitrosamine already present in the drug product, vortioxetine hydrobromide, does not increase during the production of the final product; even when employing potentially triggering process steps for nitrosamine formation, such as granulation and drying processes during the wet granulation.
  • the present invention relates to a stable solid pharmaceutical composition
  • a stable solid pharmaceutical composition comprising vortioxetine hydrobromide or pharmaceutically acceptable salt/derivatives thereof and at least one pharmaceutically acceptable excipient, wherein the improved stability profiles with lower levels of nitrosamine impurities are achieved, even though the developed pharmaceutical composition is manufactured by using wet granulation method with water as the granulation solvent.
  • the object of this invention is to develop a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a therapeutically effective amount of vortioxetine hydrobromide or pharmaceutically acceptable salt/derivatives thereof and at least one pharmaceutically acceptable excipient wherein the nitrosamine impurity profile of the composition is remarkably improved.
  • Another object of the present invention is to provide a preparation method of a pharmaceutical composition of vortioxetine hydrobromide wherein the pharmaceutical composition herein disclosed can be manufactured into solid dosage forms, such as tablets.
  • Wet granulation is one of the manufacturing methods that commences by adding the granulating solution or solvent to the mixed powders under shear to obtain granules with the strongest form of adhesion between particles, which is achieved when the granulation solvent, such as water, is eventually evaporated.
  • nitrosamines in drug products during drying step could be attributed to the interaction of drug substances containing nitrates/nitrites with water, which serves as a source of oxygen in a strongly possible oxidation reaction.
  • Another object of the present invention is to provide a stable solid pharmaceutical composition manufactured by using wet granulation method, including the steps of: a) obtaining the powder blend comprising vortioxetine hydrobromide and at least one pharmaceutical acceptable excipient; b) obtaining granulation solution comprising proper amount of binder and granulation solvent; c) obtaining granule by adding the granulation solution on to the powder blend; d) removing the solvent by heating to obtain the dried granule.
  • Another object of the present invention is to provide a stable pharmaceutical composition comprising vortioxetine hydrobromide or pharmaceutically acceptable salt/derivatives thereof and at least one pharmaceutically acceptable excipient manufactured using wet granulation process with a low amount of nitrosamine impurity, wherein the step of evaporating of granulation solvent occurs at a specified product temperature range 22°C - 28°C.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprises vortioxetine hydrobromide or pharmaceutically acceptable salt/derivatives thereof as active substance and pharmaceutically acceptable excipient manufactured by using wet granulation method.
  • Vortioxetine hydrobromide is classified as BCS (Biopharmaceutics Classification System) class I or III compound which means that it exhibits high solubility and high permeability.
  • Vortioxetine as a base form has a high potency of nitrosamine impurity risk due to its chemical structure.
  • the structure itself includes a secondary amine group.
  • a secondary amine group two of the hydrogens in an ammonia molecule have been replaced by hydrocarbon groups. At this level, you are only likely to come across simple ones where both of the hydrocarbon groups are alkyl groups and both are the same.
  • the secondary amine groups are strongly likely to nitrosating by nitrosating agents.
  • the nitrosating agents are nitrites and nitrates.
  • the nitrosamine impurities are explored and identified.
  • the names of the impurities are N-nitroso piperazine monomer, N-nitroso piperazine dimer and N-nitroso vortioxetine.
  • the manufacturing method of the present invention is designed as wet granulation in which the water is the granulation solvent.
  • the preferred embodiment of the present invention provides pharmaceutical compositions such as powders, granules, tablets and capsules thereof. Moreover, the pharmaceutical composition is also provided for the immediate release solid dosage form containing the active ingredient, diluent, disintegrant, binder, lubricant and solvent.
  • the pharmaceutical composition comprising at least one diluent which can be selected from dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, lactose monohydrate, mannitol, primarily calcium salts and the like and mixtures thereof.
  • diluent is mannitol and microcrystalline cellulose.
  • the pharmaceutical composition comprising at least one disintegrant which can be selected from croscarmellose sodium, sodium starch glycolate, crospovidone, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose.
  • the disintegrant is sodium starch glycolate.
  • the pharmaceutical composition comprises at least a binder which can be selected from hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof.
  • the binder is hydroxypropyl methylcellulose.
  • the pharmaceutical composition comprising at least one lubricant which can be selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof.
  • the lubricant is magnesium stearate.
  • a. Binder is dissolved in water.
  • b. Vortioxetine hydrobromide, diluent(s) is weighed, sifted, transferred to High Shear Mixer (HSM) device and mixed.
  • HSM High Shear Mixer
  • c. The powder blend in step b is mixed with the binder solution at step a, to carry out the granulation process.
  • d. The granule in step c is sieved, dried with fluid-bed dryer till the product temperature is between 30°C - 32°C to get maximum 1% humidity level and sifted.
  • Disintegrant is added to the sifted granules and mixed.
  • Lubricant is weighed and added to the powder blend in step e, mixed.
  • Tablet compression is performed with the powder in step f.
  • Example-1 was analysed to investigate whether there is any possibility of nitrosamine impurity at high levels regarding possibilities due to excipient, active substance and manufacturing process.
  • the nitrosamine impurities that were examined are N-nitroso piperazine monomer, N- nitroso piperazine dimer and N-nitroso vortioxetine.
  • N.D. is abbreviation for the phrase of “Not detected”. Based on the results, it was observed that N-nitroso vortioxetine is at remarkably high levels in Example-1. Thus, active substance and the excipients were analysed to find out the root-cause.
  • Table-2 The result of nitrosamine impurity analysis of Vortioxetine hydrobromide active substance
  • Table-3 The result of nitrosamine impurity analysis of excipients
  • Vortioxetine hydrobromide as active substance was literally declared to be degraded under high oxidative conditions.
  • the storage temperature of the active substance is between 2°C-8°C.
  • the storage temperature of the drug product is room temperature.
  • Example-1 Only process that should be improved is the drying process.
  • the product temperature in drying process during the manufacturing process of Example-1 was between 30°C-32°C. However, regarding it is not industrially applicable to decrease the temperature till to 2°C-8°C to remove water and get low level of nitrosamine impurity, the first choice would be changing the manufacturing process completely to avoid any oxidation source.
  • the inventors surprisingly achieved to obtain a stable solid pharmaceutical composition manufactured by using wet granulation process which presents improved nitrosamine impurity profile, by gradually decreasing the relevant product temperature during drying process even though not removing the oxidation source, water, form the composition.
  • Table-5 Examples manufactured with different drying temperature ranges and the results of nitrosamine impurity analysis

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique solide stable comprenant du bromhydrate de vortioxétine ou un sel/dérivé pharmaceutiquement acceptable de celui-ci avec un profil d'impureté de nitrosamine amélioré, la composition comprenant du bromhydrate de vortioxétine et son sel pharmaceutiquement acceptable et fabriqué à l'aide d'un procédé de granulation par voie humide en utilisant de l'eau en tant que solvant de granulation.
PCT/TR2023/051451 2023-12-04 2023-12-04 Compositions pharmaceutiques comprenant du bromhydrate de vortioxétine ayant un profil d'impureté de nitrosamine amélioré Pending WO2025122077A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/TR2023/051451 WO2025122077A1 (fr) 2023-12-04 2023-12-04 Compositions pharmaceutiques comprenant du bromhydrate de vortioxétine ayant un profil d'impureté de nitrosamine amélioré

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2023/051451 WO2025122077A1 (fr) 2023-12-04 2023-12-04 Compositions pharmaceutiques comprenant du bromhydrate de vortioxétine ayant un profil d'impureté de nitrosamine amélioré

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WO2025122077A1 true WO2025122077A1 (fr) 2025-06-12

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180193334A1 (en) * 2015-09-07 2018-07-12 Changzhou Fangnan Pharmaceuticals, Ltd. Pharmaceutical composition of vortioxetine or salt thereof, and preparation method therefor
WO2018150344A1 (fr) * 2017-02-17 2018-08-23 Unichem Laboratories Ltd Composition pharmaceutique bioéquivalente de bromhydrate de vortioxétine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180193334A1 (en) * 2015-09-07 2018-07-12 Changzhou Fangnan Pharmaceuticals, Ltd. Pharmaceutical composition of vortioxetine or salt thereof, and preparation method therefor
WO2018150344A1 (fr) * 2017-02-17 2018-08-23 Unichem Laboratories Ltd Composition pharmaceutique bioéquivalente de bromhydrate de vortioxétine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CIOC, R. C. ET AL.: "Formation of N-nitrosamine drug substance related impurities in medicines: a regulatory perspective on risk factors and mitigation strategies.", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 27, no. 10, 2023, pages 1736 - 1750, XP093171119, DOI: 10.1021/acs.oprd.3c00153 *

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