New trimetazidine salts

Abstract

The present invention relates to novel trimetazidine salts that reduce the formation of trimetazidine nitrosamine in the presence of nitrite.

Description

[Technical field]

[0001] The present invention relates to novel trimetazidine salts, their hydrates, and their crystalline forms.

[0002] Trimetazidine, i.e. 1-(2,3,4-trimethoxybenzyl)piperazine (formula (I)), is a compound that prevents the decrease in intracellular levels of adenosine triphosphate (ATP) by maintaining the energy metabolism of cells exposed to hypoxic or ischemic conditions. Thus, trimetazidine ensures the function of ion pumps and transmembrane flux of sodium-potassium, maintaining cellular homeostasis.

[0003] [ka]

[0004] Trimetazidine dihydrochloride is currently used therapeutically for the prophylactic treatment of angina episodes, chorioretinal attacks, and the treatment of vertigo of vascular origin (Meniere's vertigo, tinnitus).

[0005] Trimetazidine nitrosamine of formula (II) is an impurity that can be formed in the presence of nitrites from water and / or excipients during the synthesis process of trimetazidine salts or during the formulation process of such salts.

[0006] [ka]

[0007] Applicants have now discovered that the trimetazidine salts of the present invention are capable of reducing the formation of trimetazidine nitrosamine in the presence of nitrite.

[0008] Patent applications CN110105307, CN110183398 and CN110054599 disclose the synthesis of trimetazidine hemi-oxalate, oxalate and dioxalate salts, respectively, to overcome the problems of flowability, poor tabletability and hygroscopicity of trimetazidine dihydrochloride. Summary of the Invention [Problem to be solved by the invention]

[0009] The invention particularly relates to the hemimalate, hemiadipate, hemitartrate, hemiphosphate, hemisulfate, hemisuccinate and hemifumarate salts of trimetazidine.

[0010] The present invention also provides a process for the synthesis of trimetazidine salts, comprising reacting trimetazidine with an organic acid in a solvent to lead to the corresponding salt having a trimetazidine / organic acid ratio of 2 / 1, The organic acid is selected from malic acid, adipic acid, tartaric acid, phosphoric acid, sulfuric acid, succinic acid and fumaric acid. [Brief description of the drawings]

[0011] [Figure 1a] 1H NMR spectrum of trimetazidine hemiadipic acid salt obtained in Example 1 [Figure 1b] XRPD pattern of trimetazidine hemiadipic acid salt obtained in Example 1 [Figure 2a] 1H NMR spectrum of trimetazidine hemisuccinate obtained in Example 2 [Figure 2b] XRPD pattern of trimetazidine hemisuccinate obtained in Example 2 [Figure 3a] 1H NMR spectrum of trimetazidine hemimalate obtained in Example 3 [Figure 3b] XRPD pattern of trimetazidine hemimalate obtained in Example 3 [Figure 4] XRPD pattern of trimetazidine hemisulfate obtained in Example 4 [Figure 5a]1H NMR spectrum of trimetazidine hemifumarate obtained in Example 5 [Figure 5b] XRPD pattern of trimetazidine hemifumarate obtained in Example 5 [Figure 6a] 1H NMR spectrum of trimetazidine hemitartrate obtained in Example 6 [Figure 6b] XRPD pattern of trimetazidine hemitartrate obtained in Example 6 [Figure 7] XRPD pattern of trimetazidine hemiphosphate obtained in Example 6 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] In one embodiment of the invention, trimetazidine is reacted with 0.5 equivalents of malic acid, adipic acid, tartaric acid, phosphoric acid, sulfuric acid, succinic acid or fumaric acid in a solvent to lead to the corresponding hemimalate, hemiadipate, hemitartrate, hemiphosphate, hemisulfate, hemisuccinate or hemifumarate salt of trimetazidine 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.

[0013] Among the solvents, mention may be made, inter alia, of 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.

[0014] The salification reaction is preferably carried out at a temperature of from 20°C to 70°C.

[0015] The trimetazidine salts of the present invention are capable of reducing the formation of trimetazidine nitrosamine in the presence of nitrite.

[0016] According to one embodiment of the invention, the trimetazidine salts of the invention form less than 1 ppm of trimetazidine nitrosamine after 22 hours at 40° C. in a solution containing a nitrite salt.

[0017] The present invention also relates to pharmaceutical compositions comprising trimetazidine hemimalate, hemiadipate, hemitartrate, hemiphosphate, hemisulfate, hemisuccinate or hemifumarate salts in combination with one or more inert, non-toxic pharmaceutically acceptable excipients or carriers.

[0018] The useful dosage varies according to the age and weight of the patient, the route of administration, 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.

[0019] Among the pharmaceutical compositions according to the invention, mention may be made in particular of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), percutaneous, nasal, rectal, sublingual, ocular or respiratory administration, in particular tablets or dragees, sublingual tablets, gelatine capsules, capsules, microgranules, suppositories, creams, ointments, skin gels, preparations suitable for injection or drinking, aerosols and eye or nasal drops.

[0020] The pharmaceutical compositions may be in the form of immediate release or sustained release compositions.

[0021] According to one aspect of the invention, the pharmaceutical composition is a tablet for immediate release oral administration.

[0022] According to another aspect of the invention, the pharmaceutical composition is a matrix tablet for sustained release oral administration.

[0023] According to another embodiment of the invention, the pharmaceutical composition is in the form of coated microgranules in a capsule for oral, once-daily administration.

[0024] In addition to the trimetazidine salt, the tablets of the present invention contain one or more excipients or carriers, such as diluents, retardants, lubricants, binders, disintegrants, absorbents, plasticizers, colorants and sweeteners.

[0025] Examples of excipients or carriers may include: As diluents: lactose, dextrose, sucrose, mannitol, sorbitol, glycerol, calcium hydrogen phosphate dihydrate, calcium carbonate, cellulose, cellulose ethers, such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose or hydroxypropylmethylcellulose, For controlled release agents: ethylcellulose, ethylcellulose derivatives, such as cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate and / or polymethacrylates, As lubricants: silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol, glycerol behenate or sodium benzoate, As binders: aluminum and magnesium silicates, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, As 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, Disintegrants: agar, alginic acid and its sodium salts, effervescent mixtures.

[0026] The percentage of the active ingredient of formula (I) in the tablet is preferably 5% to 50% (by weight).

[0027] According to one aspect of the invention, the trimetazidine salts according to the invention are administered in combination with one or more additional active ingredients.

[0028] Co-administration can be in the form of simultaneous or sequential co-administration of two or more separate pharmaceutical compositions each containing one of the active ingredients (independent co-administration), or in the form of a fixed dose combination containing two or more active ingredients combined in a single dosage form.

[0029] Among the additional active ingredients, there may be mentioned beta-blockers.

[0030] According to one aspect of the invention, a trimetazidine salt of the invention is administered conjointly with a beta-blocker in the form of a fixed dose combination.

[0031] Among the beta-blockers, mention may in particular be made of metoprolol and bisoprolol.

[0032] According to a preferred embodiment of the invention, the fixed dose combination of trimetazidine salt and bisoprolol is a capsule containing 80 mg of trimetazidine salt microgranules and 5 or 10 mg of bisoprolol hemifumarate pellets.

[0033] According to another preferred embodiment of the invention, the fixed dose combination of trimetazidine salt and metoprolol is a capsule containing 80 mg of trimetazidine salt microgranules and 47.5 or 95 mg of metoprolol succinate pellets.

[0034] A formulation of bisoprolol hemifumarate pellets has already been disclosed in Example 4a of WO2016 / 071631.

[0035] Abbreviation eq. Molar equivalent NMR nuclear magnetic resonance XRPD X-ray powder diffraction EXAMPLES

[0036] Experimental section For the compounds of Examples 1, 3, 4, 5 and 7, XRPD patterns were recorded from 3.5°2θ to 35°2θ over 10 minutes using an X-ray diffractometer operating in transmission mode, with CuKα radiation (λ=1.5418 Å) at 45 kV and 40 mA and a step size of 0.013°2θ.

[0037] For the compounds of Examples 2 and 6, XRPD patterns were recorded from 3.5°2θ to 55°2θ over 30 minutes using an X-ray diffractometer operating in transmission mode, with CuKα radiation (λ=1.5418 Å) at 45 kV and 40 mA and a step size of 0.013°2θ.

[0038] Only peaks with a relative intensity higher than 10% are listed in the XRPD tables.

[0039] Chemical shifts (in ppm) are given relative to tetramethylsilane (TMS) using partially deuterated dimethylsulfoxide or partially deuterated methanol as internal standard.

[0040] In a solution of partially deuterated dimethylsulfoxide, the resonance at 2.5 ppm on the 1D 1H NMR spectrum is due to the partially deuterated dimethylsulfoxide and the resonance at 3.30 ppm is due to the presence of water.

[0041] In a solution of partially deuterated methanol, the resonance at 3.3 ppm on the 1D 1H NMR spectrum is due to the partially deuterated methanol and the resonance at 4.83 ppm is due to the presence of water.

[0042] Example 1: Trimetazidine Hemiadipic Acid Salt 1.0 g of trimetazidine and 0.28 g (0.5 eq) of adipic acid were placed in 4 mL of isopropanol. The mixture was left under stirring at ambient temperature for 22 hours. The suspension was filtered and the powder was dried overnight under vacuum at 40° C. The powder obtained corresponds to a crystalline powder. 1H NMR: 6,95 ppm, 6.75 ppm, 3.77ppm, 3.76 ppm, 3.73 ppm, 3.33 ppm, 2.67 ppm, 2.29ppm, 2.18 ppm, 1.49 ppm.

[0043] handle 1 The H NMR spectrum is shown in Figure 1a.

[0044] XRPD table: [Table 1]

[0045] The corresponding XRPD pattern is shown in FIG.

[0046] Example 2: Trimetazidine hemisuccinate Process A 5.0 g of trimetazidine and 1.11 g of succinic acid were placed in 75 mL of ethanol. The mixture was left under stirring at 70° C. for 2 hours and then at ambient temperature for 60 hours. The suspension was filtered and the powder was dried overnight under vacuum at 40° C. The powder obtained corresponds to a crystalline powder. 1 H NMR: 6.96 ppm, 6.75 ppm, 3.77 ppm, 3.77 ppm, 3.73 ppm, 3.37 ppm, 2.80 ppm, 2.37 ppm, 2.26 ppm.

[0047] handle 1 The H NMR spectrum is shown in Figure 2a.

[0048] XRPD table: [Table 2]

[0049] The corresponding XRPD pattern is shown in Figure 2b.

[0050] Process B 64 kg of trimetazidine, 14 kg of succinic acid, 4.9 kg of water and 569 kg of isopropyl alcohol were charged to the reactor.

[0051] The mixture was placed under mechanical stirring at 72° C. for 30 min. The solution was cooled to 63° C. at a rate of 0.3° C. / min. After 60 min at 63° C. and under stirring, the suspension was cooled to 5° C. at a rate of 0.25° C. / min. The suspension was filtered and the powder was dried overnight at 40° C. The powder obtained corresponds to a crystalline powder. The yield is about 91%.

[0052] The XRPD pattern is the same as for Process A.

[0053] Example 3: Trimetazidine hemimalate 1.0 g of trimetazidine and 0.25 g of malic acid were placed in 4 mL of isopropanol. The mixture was stirred at ambient temperature for 22 hours. The suspension was filtered and the powder was dried overnight under vacuum at 40° C. The powder obtained corresponds to a crystalline powder. 1 H NMR: 6.96 ppm, 6.76 ppm, 3.77 ppm, 3.77 ppm, 3.73 ppm, 3.39 ppm, 2.85 ppm, 2.45 ppm, 2.40 ppm, 2.30 ppm.

[0054] handle 1 The H NMR spectrum is shown in Figure 3a.

[0055] XRPD table: [Table 3]

[0056] The corresponding XRPD pattern is shown in Figure 3b.

[0057] Example 4: Trimetazidine hemisulfate 550.0 g of trimetazidine and 211 g of a 96% sulfuric acid solution were charged into 2.2 L of toluene. The mixture was stirred for 24 hours at 20° C. The suspension was filtered and the powder was dried overnight under vacuum at 40° C. The powder obtained corresponds to a crystalline powder.

[0058] XRPD table: [Table 4]

[0059] The corresponding X-ray spectrum is shown in FIG.

[0060] Example 5: Trimetazidine hemifumarate 1.0 g of trimetazidine and 0.23 g of fumaric acid were placed in 4 mL of isopropanol. The mixture was stirred at ambient temperature for 22 hours. The suspension was filtered and the powder was dried overnight under vacuum at 40° C. The powder obtained corresponds to a crystalline powder. 1 H NMR: 7.01 ppm, 6.76 ppm, 6.66 ppm, 3.87 ppm, 3.84 ppm, 3.82 ppm, 3.56 ppm, 3.12 ppm, 2.66 ppm.

[0061] handle 1 The H NMR spectrum is shown in Figure 5a.

[0062] XRPD table: [Table 5]

[0063] The corresponding XRPD pattern is shown in Figure 5b.

[0064] Example 6: Trimetazidine hemitartrate 5.0 g of trimetazidine and 1.42 g of L-tartaric acid were placed in 75 mL of anisole. The mixture was left under stirring at 70° C. for 2 hours and then at ambient temperature for 60 hours. The suspension was filtered and the powder was dried overnight under vacuum at 40° C. The powder obtained corresponds to a crystalline powder. 1 H NMR: 6.96 ppm, 6.76 ppm, 3.77 ppm, 3.73 ppm, 3.39 ppm, 2.86 ppm, 2.41 ppm.

[0065] handle 1 The H NMR spectrum is shown in Figure 6a.

[0066] XRPD table: [Table 6]

[0067] The corresponding XRPD pattern is shown in Figure 6b.

[0068] Example 7: Trimetazidine hemiphosphate 1.0 g of trimetazidine and 0.18 g of phosphoric acid were placed in 4 mL of isopropanol. The mixture was stirred at ambient temperature for 22 hours. The suspension was filtered and the powder was dried overnight under vacuum at 40° C. The powder obtained corresponds to a crystalline powder.

[0069] XRPD table: [Table 7]

[0070] The corresponding XRPD pattern is shown in FIG.

[0071] Example 8: Comparative experiment: Trimetazidine nitrosamine formation 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 nitrite in water and / or excipients during the drug manufacturing process.

[0072] A trimetazidine salt equivalent to 600 mg of trimetazidine was placed in a 2 mL volumetric flask. 150 L of a 0.12 mg / mL aqueous sodium nitrite solution was placed in a 2 mL volumetric flask and the volume was adjusted to 2 mL with water to obtain a 300 mg / mL solution in terms of trimetazidine.

[0073] The solution was stirred for 22 h at 40° C. Trimetazidine nitrosamine was determined by LC / MS.

[0074] Due to the low solubility of trimetazidine dioxalate and oxalate, experiments with these two salts were carried out at 6 mg / mL and 30 mg / mL trimetazidine, respectively, instead of 300 mg / mL.

[0075] result [Table 8]

[0076] The above results show that the trimetazidine salts of the present invention have superior performance to the trimetazidine salts of the prior art.

[0077] Example 9: Immediate release formulation - equivalent to a formulation containing 20 mg of trimetazidine dihydrochloride Trimetazidine salt 18.6-20.1mg (see table below) Corn starch 26mg Mannitol 34mg Polyvidone 4mg Magnesium stearate 1mg Talc 5mg

[0078] equivalence table [Table 9]

[0079] Example 10: MR matrix tablets - corresponding to matrix MR tablets containing 35 mg of trimetazidine dihydrochloride Trimetazidine salt 32.5-35.2mg (see table below) Hydroxypropyl methylcellulose 74.0mg Povidone 8.7mg Calcium hydrogen phosphate dihydrate 80.9mg Magnesium stearate 1.0mg Anhydrous colloidal silica 0.4mg

[0080] equivalence table [Table 10]

[0081] Example 11: OD formulation - corresponds to an OD formulation containing 80 mg of trimetazidine dihydrochloride Trimetazidine salt 74.4-80.5mg (see table below) Neutral sucrose / corn starch microgranules 36.67mg Hydroxypropyl methylcellulose 6.40mg Acetyltributyl citrate 1.20mg Ethyl cellulose 8.00mg Talc 12.00mg Magnesium stearate 0.43mg

[0082] equivalence table [Table 11]

[0083] Example 12: OD formulation - combination with bisoprolol hemifumarate The trimetazidine salt microgranules obtained in Example 11 are mixed with bisoprolol hemifumarate pellets containing 5 mg of bisoprolol hemifumarate and encapsulated.

[0084] Example 13: OD formulation - combination with metoprolol succinate The trimetazidine salt microgranules obtained in Example 11 are mixed with metoprolol succinate pellets containing either 47.5 mg or 95 mg of metoprolol succinate and encapsulated.

Claims

1. A trimetazidine salt selected from trimetazidine hemimalate, trimetazidine hemidipic acid salt, trimetazidine hemitartrate, trimetazidine hemiphosphate, trimetazidine hemisulfate, trimetazidine hemisuccinate, and trimetazidine hemifumarate, a hydrate thereof, and a crystal thereof.

2. 2. A method for synthesizing the trimetazidine salt of claim 1, comprising reacting trimetazidine with an organic acid selected from malic acid, adipic acid, tartaric acid, phosphoric acid, sulfuric acid, succinic acid and fumaric acid in a solvent to lead to the corresponding salt having a trimetazidine / organic acid ratio of 2 / 1.

3. 3. The process of claim 2, comprising reacting trimetazidine with 0.5 equivalents of malic acid, adipic acid, tartaric acid, phosphoric acid, sulfuric acid, succinic acid or fumaric acid in a solvent to lead to the corresponding hemimalate, hemiadipate, hemitartrate, hemiphosphate, hemisulfate, hemisuccinate or hemifumarate salt of trimetazidine having a trimetazidine / malic acid, trimetazidine / adipic acid, trimetazidine / tartaric acid, trimetazidine / phosphoric acid, trimetazidine / sulfuric acid, trimetazidine / succinic acid or trimetazidine / fumaric acid molar ratio of 2 / 1.

4. 4. The method of claim 2 or 3, wherein the solvent is selected from the group consisting of anisole, methyl isobutyl ketone, toluene, n-heptane, acetonitrile, methyl ethyl ketone, ethyl acetate, 1,3-dioxolane, tetrahydrofuran, acetone, methyl tert-butyl ether, water, methanol, ethanol, isopropanol, isobutanol, n-butanol, and mixtures thereof.

5. A pharmaceutical composition comprising the trimetazidine salt of claim 1.

6. 6. The pharmaceutical composition of claim 5, in the form of an immediate release oral tablet, an extended release oral matrix tablet, or coated microgranules in a capsule for oral once-daily administration.

7. 6. The pharmaceutical composition of claim 5, further comprising a beta-blocker.

8. 8. The pharmaceutical composition of claim 7, wherein the beta-blocker is metoprolol or bisoprolol.

9. A pharmaceutical composition according to any one of claims 5 to 8 for use in the preventive treatment of angina pectoris, in the course of chorioretinal disorders or in the treatment of vertigo of vascular origin.

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