Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to novel trimetazidine salts, their hydrates, and crystalline forms thereof.
• Trimetazidine or l-(2,3,4-trimethoxybenzyl)piperazine (formula (I))
• Trimetazidine or l-(2,3,4-trimethoxybenzyl)piperazine (formula (I))
• ATP adenosine triphosphate
• Trimetazidine dihydrochloride is currently used therapeutically for the prophylactic treatment of angina pectoris crisis, in chorioretinal attacks and for the treatment of vertigo of vascular origin (Meniere's vertigo, tinnitus).
• Trimetazidine nitrosamine of formula (II) is an impurity which may be formed during the process of synthesis of trimetazidine salts or during the formulation process of such salts, in presence of nitrites coming from water and/or excipients.
• trimetazidine salts of the present invention allow to reduce the formation of trimetazidine nitrosamine in presence of nitrites.
• the patent applications CN110105307, CN110183398 and CN110054599 respectively disclose the synthesis of the trimetazidine hemioxalate, oxalate and dioxalate salts, in order to overcome flowability, poor tableting property and hygroscopicity issues of the trimetazidine dihydrochloride salt.
• the present invention relates especially to trimetazidine hemimalate, hemiadipate, hemitartrate, hemiphosphate, hemisulfate, hemisuccinate and hemifumarate salts.
• the present invention also relates to a process of synthesis of trimetazidine salts, wherein trimetazidine is reacted with an organic acid in a solvent, leading to the corresponding salt having a trimetazidine/organic acid ratio of 2/1, wherein the organic acid is selected from malic acid, adipic acid, tartaric acid, phosphoric acid, sulfuric acid, succinic acid, and fumaric acid.
• trimetazidine is reacted with 0.5 eq. malic acid, adipic acid, tartaric acid, phosphoric acid, sulfuric acid, succinic acid or fumaric acid, in a solvent, leading to the corresponding trimetazidine hemimalate, hemiadipate, hemitartrate, hemiphosphate, hemisulfate, hemisuccinate or hemifumarate having a trimetazidine/ malic acid, trimetazidine/ adipic acid, trimetazidine/ tartaric acid, trimetazidine/ phosphoric acid, trimetazidine/ trimetazidine/ sulfuric acid, trimetazidine/ succinic acid or trimetazidine/ fumaric acid molar ratio of 2/1.
• solvents there may be mentioned more especially anisole, methyl isobutyl ketone, toluene, n-heptane, acetonitrile, methyl ethyl ketone, ethyl acetate, 1,3-dioxalane, tetrahydrofuran, acetone, methyl tert-butyl ether, water, alcohols such as methanol, ethanol, isopropanol, isobutanol or n-butanol, and mixtures thereof.
• the salification reaction is preferably performed at a temperature of 20°C to 70°C.
• trimetazidine salts of the present invention allow to reduce the formation of trimetazidine nitrosamine in presence of nitrites.
• the trimetazidine salts of the present invention form less than 1 ppm of trimetazidine nitrosamine in a solution containing nitrites, after 22h at 40°C.
• the present invention also relates to pharmaceutical compositions comprising a trimetazidine hemimalate, hemiadipate, hemitartrate, hemiphosphate, hemisulfate, hemisuccinate or hemifumarate salt in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
• the useful dosage varies according to the age and weight of the patient, the administration route, the nature and severity of the disorder and any associated treatments, and ranges from 15 mg to 200 mg per day in one or more administrations.
• compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragees, sublingual tablets, gelatin capsules, capsules, minigranules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, and eye or nasal drops.
• parenteral intravenous, intramuscular or subcutaneous
• nasal rectal
• perlingual, ocular or respiratory administration and especially tablets or dragees, sublingual tablets, gelatin capsules, capsules, minigranules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, and eye or nasal drops.
• compositions may be in the form of immediate release or prolonged release compositions.
• the pharmaceutical composition is a tablet for immediate release oral administration.
• the pharmaceutical composition is a matrix tablet for prolonged release oral administration.
• the pharmaceutical composition is in the form of coated minigranules in capsules, for oral, once-a-day administration.
• the tablets according to the invention comprise one or more excipients or carriers, such as diluents, retardants, lubricants, binders, disintegrators, absorbents, plasticizers, colourants and sweeteners.
• excipients or carriers such as diluents, retardants, lubricants, binders, disintegrators, absorbents, plasticizers, colourants and sweeteners.
• ⁇ for the diluents', lactose, dextrose, sucrose, mannitol, sorbitol, glycerol, calcium hydrogen phosphate dihydrate, calcium carbonate, cellulose, cellulose ethers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose or hydroxypropyl methylcellulose,
• ethylcellulose ethylcellulose derivatives such as cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate and/or polymethacrylates,
• ⁇ for the plasticizers acetyl tributyl citrate, glycerol triacetate, acetyl triethyl citrate, acetyl ethyl citrate, diethyl sebacate, dibutyl sebacate, ethyl phthalate, dibutyl phthalate, polyethylene glycol, glycerol and/or propylene glycol,
• ⁇ for the disintegrants' agar, alginic acid and its sodium salt, effervescent mixtures.
• the percentage of active ingredient of formula (I) in the tablet is preferably between 5% and 50% by weight.
• the trimetazidine salt according to the present invention is administered in association with one or more additional active ingredients.
• the administration in association may be in the form of a simultaneous or successive coadministration of two or more separate pharmaceutical compositions each containing one of the active ingredients (free association), or in the form of the administration of a fixed-dose combination including two or more active ingredients combined in a single dosage form.
• the trimetazidine salt of the present invention is administered in association with a betablocker in the form of a fixed-dose combination.
• the betablockers there may be mentioned more especially metoprolol and bisoprolol.
• the fixed-dose combination of the trimetazidine salt and bisoprolol is a capsule containing 80 mg trimetazidine salt minigranules and 5 or 10 mg bisoprolol hemifumarate pellets.
• the fixed-dose combination of the trimetazidine salt and metoprolol is a capsule containing 80 mg trimetazidine salt minigranules, and 47.5 or 95 mg metoprolol succinate pellets.
• the mixture was placed under mechanical stirring at 72°C for 30 minutes. This solution was cooled to 63°C with a rate of 0.3°C/min. After 60 minutes at 63°C and under stirring, the suspension was cooled to 5°C with a rate of 0.25°C/min. The suspension was filtered, and the powder was dried at 40°C overnight. The obtained powder corresponds to a crystalline powder. The yield is about 91%.
• the XRPD pattern is the same as with Process A.
• trimetazidine nitrosamine In order to model the formation of trimetazidine nitrosamine during the formulation process, an aqueous solution of sodium nitrite was added to the trimetazidine salt.
• the sodium nitrite mimics the presence of nitrites in water and/or excipients during a drug product manufacturing process.
• trimetazidine salt in an amount corresponding to 600 mg trimetazidine, was placed in 2 mL volumetric flask.
• 150 DL of sodium nitrite aqueous solution at 0.12mg/mL was placed in the 2mL volumetric flask and the volume was adjusted to 2mL with water to obtain a solution at 300 mg/mL in trimetazidine equivalent.
• the solution was stirred at 40°C for 22 hours.
• the trimetazidine nitrosamine dosage was performed by LC/MS.
• Trimetazidine salt 18.6 to 20.1 mg (see the table below)
• EXAMPLE 10 MR matrix tablet - corresponding to the matrix MR tablet containing 35 mg trimetazidine dihydrochloride
• Trimetazidine salt 32.5 to 35.2 mg (see the table below)
• EXAMPLE 11 OD formulation - corresponding to the OD formulation containing 80 mg trimetazidine dihydrochloride
• Trimetazidine salt 74.4 to 80.5 mg (see the table below)
• EXAMPLE 12 OD formulation- combination with bisoprolol hemifumarate The trimetazidine salt minigranules obtained in Example 11 and bisoprolol hemifumarate pellets containing 5 mg bisoprolol hemifumarate are mixed together and encapsulated.
• EXAMPLE 13 OD formulation- combination with metoprolol succinate
• trimetazidine salt minigranules obtained in Example 11 and metoprolol succinate pellets containing either 47.5 mg, or 95 mg metoprolol succinate are mixed together and encapsulated.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• Urology & Nephrology (AREA)
• Vascular Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Saccharide Compounds (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (18)

Applications Claiming Priority (2)

Publications (1)

Family

ID=78592764

Family Applications (1)

Country Status (20)

Cited By (1)

Citations (5)

Family Cites Families (2)

• 2022
  • 2022-10-19 RS RS20251183A patent/RS67449B1/sr unknown
  • 2022-10-19 MX MX2024004714A patent/MX2024004714A/es unknown
  • 2022-10-19 CR CR20240157A patent/CR20240157A/es unknown
  • 2022-10-19 LT LTEPPCT/EP2022/079054T patent/LT4419510T/lt unknown
  • 2022-10-19 US US18/702,363 patent/US20250250245A1/en active Pending
  • 2022-10-19 AR ARP220102840A patent/AR127403A1/es unknown
  • 2022-10-19 EP EP22808665.8A patent/EP4419510B1/en active Active
  • 2022-10-19 IL IL311916A patent/IL311916A/en unknown
  • 2022-10-19 PL PL22808665.8T patent/PL4419510T3/pl unknown
  • 2022-10-19 AU AU2022369026A patent/AU2022369026A1/en active Pending
  • 2022-10-19 ES ES22808665T patent/ES3057370T3/es active Active
  • 2022-10-19 SI SI202230206T patent/SI4419510T1/sl unknown
  • 2022-10-19 PT PT228086658T patent/PT4419510T/pt unknown
  • 2022-10-19 DK DK22808665.8T patent/DK4419510T3/da active
  • 2022-10-19 HR HRP20251413TT patent/HRP20251413T1/hr unknown
  • 2022-10-19 WO PCT/EP2022/079054 patent/WO2023066971A1/en not_active Ceased
  • 2022-10-19 MA MA66951A patent/MA66951B1/fr unknown
  • 2022-10-19 JP JP2024523404A patent/JP2024539090A/ja active Pending
  • 2022-10-19 CN CN202280068113.8A patent/CN118076591A/zh active Pending
  • 2022-10-19 KR KR1020247015968A patent/KR20240093576A/ko active Pending

Patent Citations (5)

Also Published As

Similar Documents

Legal Events