Novel trimetazidine solid phase

Abstract

The present invention relates to a novel trimetazidine solid phase which results in a reduction in trimetazidine nitrosamine formation in the presence of nitrite.

Description

[0001] The present invention relates to a new trimetazidine solid phase.

[0002] Trimetazidine or 1-(2,3,4-trimethoxybenzyl)piperazine (formula (I)) is a compound which avoids the collapse of intracellular adenosine triphosphate (ATP) levels by maintaining the energy metabolism of cells exposed to hypoxia or ischemia. It thus ensures the functional role of ion pumps and sodium-potassium transmembrane fluxes and maintains cellular homeostasis.

[0003]

[0004] Trimetazidine (in the form of its free base) is a liquid at room temperature.

[0005] Trimetazidine dihydrochloride is disclosed in GB 929 252 and is currently used therapeutically for the preventive treatment of angina crisis, retinochoroidal attacks and for the treatment of vascular vertigo (Meniere's vertigo, tinnitus).

[0006] Patent applications CN 110 105 307, CN 110 183 398 and CN 110 054 599 respectively disclose the synthesis of trimetazidine hemi-oxalate, oxalate and di-oxalate in order to overcome the flowability, poor tabletting properties and hygroscopicity problems of trimetazidine dihydrochloride.

[0007] Trimetazidine nitrosamine of formula (II) is an impurity which can be formed during the synthesis of trimetazidine or a trimetazidine salt or during the formulation of such a salt in the presence of a nitrite derived from water and / or an excipient.

[0008]

[0009] The Applicant has now found that the new trimetazidine solid phase of the present invention is able to reduce the formation of trimetazidine nitrosamine in the presence of a nitrite.

[0010] In a first embodiment, the present invention relates to a trimetazidine solid dispersion.

[0011] As used herein, the term "trimetazidine solid dispersion" means a dispersion of trimetazidine free base, liquid form, in a non-acidic pharmaceutically acceptable solid matrix compound.

[0012] Among the non-acidic pharmaceutically acceptable matrix compounds, mention can be made more particularly of non-acidic pharmaceutically acceptable polymers, preferably cellulose derivatives, such as cellulose, pre-gelatinized starch, cellulose ethers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose or hydroxypropylmethylcellulose.

[0013] The preferred non-acidic pharmaceutically acceptable matrix compound is hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose and pregelatinized starch, more preferably hydroxypropyl methylcellulose (HPMC).

[0014] The weight ratio of trimetazidine to the non-acidic pharmaceutically acceptable matrix compound is preferably about 50 / 50 or less, more preferably about 50 / 50 to about 10 / 90, such as about 40 / 60 to about 20 / 80, more preferably about 20 / 80.

[0015] The trimetazidine solid dispersion can be prepared by adding trimetazidine to the matrix compound in solution, followed by lyophilization of the mixture thus obtained. The trimetazidine solid dispersion is obtained in the form of an amorphous powder.

[0016] In another embodiment, the present application relates to a complex of trimetazidine and theophylline.

[0017] As used herein, the term "complex" refers to a solid formed of two chemical entities linked by weak interactions, usually hydrogen bonds or other non-covalent and non-ionic interactions, in a defined stoichiometric ratio. In the present application, the two chemical entities are trimetazidine and theophylline.

[0018] The complex of trimetazidine and theophylline can be prepared by stirring trimetazidine and theophylline in a solvent, followed by a slow increase in temperature to a heating temperature, such as about 50°C, for 2 hours at said temperature, then a return to room temperature, stirring again, and finally filtering and drying the powder thus obtained.

[0019] Among the solvents that can be used to prepare the complex of trimetazidine and theophylline, mention can be made of acetonitrile, methanol, ethanol, toluene, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, water or n-heptane.

[0020] The present application also relates to a pharmaceutical composition comprising the complex of trimetazidine and theophylline or the trimetazidine solid dispersion of the present application, combined with one or more inert, non-toxic pharmaceutically acceptable excipients or carriers.

[0021] The doses that can be used vary according to the age and weight of the patient, the route of administration, the nature and severity of the disorder, and any associated treatment, and range from 15 mg to 200 mg per day in one or more administrations.

[0022] Among the pharmaceutical compositions of the present application, mention can more particularly be made of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal or transcutaneous, nasal, rectal, sublingual, ocular or respiratory administration, and in particular tablets or caplets, sublingual tablets, gelatin capsules, capsules, small granules, suppositories, creams, ointments, dermal gels, injection or drinkable formulations, aerosols and eye or nose drops.

[0023] The pharmaceutical composition can be in the form of an immediate release or extended release composition.

[0024] According to one aspect of the application, the pharmaceutical composition is a tablet for immediate release oral administration.

[0025] According to another aspect of the application, the pharmaceutical composition is a matrix tablet for extended release oral administration.

[0026] According to another aspect of the application, the pharmaceutical composition is in the form of coated small particles in capsules for oral administration once a day.

[0027] The tablet of the application comprises, in addition to the trimetazidine solid phase of the application, one or more excipients or carriers, such as diluents, retardants, lubricants, binders, disintegrants, adsorbents, plasticizers, colorants and sweeteners.

[0028] The following excipients or carriers can be mentioned as examples:

[0029] For diluents: lactose, dextrose, sucrose, mannitol, sorbitol, glycerol, calcium hydrogen phosphate dihydrate, calcium carbonate, cellulose, cellulose ethers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose or hydroxypropylmethylcellulose,

[0030] 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,

[0031] For lubricants: silicon dioxide, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol, glyceryl behenate or sodium benzoate,

[0032] For binders: aluminum and magnesium silicates, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone,

[0033] For plasticizers: acetyltributyl citrate, triacetin, acetyltriethyl citrate, acetyl ethyl citrate, diethyl sebacate, dibutyl sebacate, ethyl phthalate, dibutyl phthalate, polyethylene glycol, glycerol and / or propylene glycol,

[0034] For disintegrants: agar agar, alginic acid and its sodium salt, effervescent mixtures.

[0035] The percentage of active ingredient of formula (I) in the tablet is preferably between 5% and 50% by weight.

[0036] According to one aspect of the present application, the trimetazidine solid form of the present application is administered in combination with one or more additional active ingredients.

[0037] The combination administration can be in the form of simultaneous or sequential coadministration of two or more separate pharmaceutical compositions each containing one of the active ingredients (free combination), or in the form of a fixed dose combination comprising two or more active ingredients combined in a single dosage form.

[0038] Among the additional active ingredients, beta blockers can be mentioned more particularly.

[0039] According to one aspect of the present application, the trimetazidine solid form of the present application is administered in combination with a beta blocker in the form of a fixed dose combination.

[0040] Among the beta blockers, metoprolol and bisoprolol can be mentioned more particularly.

[0041] According to one preferred aspect of the present application, the fixed dose combination of trimetazidine solid form and bisoprolol is a capsule comprising trimetazidine solid form granules in an amount equivalent to 80 mg of trimetazidine dihydrochloride granules, and 5 or 10 mg of bisoprolol hemifumarate granules.

[0042] According to another preferred aspect of the present application, the fixed dose combination of trimetazidine solid form and metoprolol is a capsule comprising trimetazidine solid form granules in an amount equivalent to 80 mg of trimetazidine dihydrochloride granules, and 47.5 or 95 mg of metoprolol succinate granules.

[0043] The formulation of bisoprolol hemifumarate granules has been disclosed in Example 4a of WO2016 / 071631.

[0044] Figure 1 The H NMR spectrum of the trimetazidine theophylline 1 / 2 complex obtained in Example 1. 1 H NMR spectrum.

[0045] Figure 2 The XRPD pattern of the trimetazidine theophylline 1 / 2 complex obtained in Example 1.

[0046] Figure 3 The DSC and TG patterns of the trimetazidine theophylline 1 / 2 complex obtained in Example 1 are depicted.

[0047] Abbreviations

[0048] DSC: differential scanning calorimetry

[0049] eq.: molar equivalent

[0050] HPMC: hydroxypropylmethylcellulose

[0051] NMR: nuclear magnetic resonance

[0052] TG: thermogravimetric analysis

[0053] TMZ: temozolomide

[0054] XRPD: X-ray powder diffraction

[0055] Test section

[0056] XRPD patterns were recorded using an X-ray diffractometer operating in transmission mode at 3.5° 2Q - 35° 2Q, Cu Ka radiation (l = 1.5418 A) at 45 kV and 40 mA, and a step of 0.013° 2Q for 10 minutes.

[0057] In the XRPD table, only peaks with relative intensities higher than 10% are mentioned.

[0058] In the case of preferential orientation, the relative intensities can be different.

[0059] Chemical shifts (ppm) are given relative to tetramethylsilane (TMS) using partially deuterated dimethyl sulfoxide or partially deuterated methanol as internal standard.

[0060] In partially deuterated dimethyl sulfoxide solution, the resonance at 2.5 ppm on the 1D 1H NMR spectrum is attributed to partially deuterated dimethyl sulfoxide.

[0061] DSC curves were obtained after an equilibration step at 0°C, followed by a heating step at 10°C / min up to 130°C. TG curves were obtained by heating at 10°C / min from 25°C to 130°C.

[0062] Example 1 : temozolomide theophylline 1 / 2 complex

[0063] Temozolomide (10.16 g) was placed in 200 mL of n-heptane, then theophylline (6.98 g) was added to the solution. The mixture was left under stirring at ambient temperature for 25 minutes, heated at 1°C / min up to 50°C, then an isothermic step at 50°C for 2 hours, finally cooled at 0.1°C / min up to 20°C, followed by an isothermic step for 12 hours. The suspension was filtered and the powder was vacuum dried at 40°C overnight. The obtained powder corresponds to an anhydrous crystalline powder with 1 / 2 stoichiometry (temozolomide / theophylline) and a melting point of about 95°C.

[0064] 1H NMR: 9.61 ppm (1H, b), 7.97 ppm (2H, s); 6.95 and 6.75 ppm (2H, d, J 12-13= 8,50 Hz); 3.77 and 3.73 ppm (9H, s); 3.44 ppm (6H, s); 3.34 ppm (2H, s); 3.24 ppm (6H, s); 2.71 ppm (4H, bt); 2.30 ppm (4H, bt)

[0065] b = broad singlet, s = singlet, t = triplet

[0066] The corresponding1H NMR spectrum is shown in Figure 1 .

[0067] The XRPD pattern is shown in

[0068]

[0069] The corresponding XRPD pattern is shown in Figure 2

[0070] The DSC / TG pattern is shown in Figure 3

[0071] Example 2 : Trimetazidine solid dispersion

[0072] Example 2a : Trimetazidine / non-acidic polymer 20 / 80 solid dispersion

[0073] TMZ / HPMC 20 / 80:

[0074] HPMC was slowly added to 350 mL of water and, after complete dissolution, 2.0 g of trimetazidine was added to the solution. The mixture was vacuum freeze-dried at 0.05 mbar to obtain an amorphous powder.

[0075] Other examples of TMZ / non-acidic polymer 20 / 80 solid dispersions, including TMZ / hydroxyethylcellulose 20 / 80, TMZ / methylcellulose 20 / 80 and TMZ / pre-gelatinized starch 20 / 80 solid dispersions, were prepared by replacing HPMC with hydroxyethylcellulose, methylcellulose or pre-gelatinized starch, respectively, under the same operating conditions as described above.

[0076] Example 2b : Trimetazidine / non-acidic polymer solid dispersions with other ratios

[0077] TMZ / HPMC 50 / 50:

[0078] HPMC was slowly added to 350 mL of water and, after complete dissolution, 2.0 g of trimetazidine was added to the solution. The mixture was vacuum freeze-dried at 0.05 mbar to obtain an amorphous powder.​​

[0079] Other examples of trimetazidine solid dispersions, including TMZ / HPMC 40 / 60 and TMZ / HPMC 30 / 70 solid dispersions, were prepared using the same operating conditions as above by adjusting the amount of trimetazidine and HPMC.

[0080] Example 3 Comparative test: trimetazidine nitrosamine formation

[0081] To simulate the formation of trimetazidine nitrosamines in the solid state, trimetazidine solid phase (salt, complex, solid dispersion) products containing excipients with high nitrite content were prepared. Sodium nitrite was used to simulate the presence of nitrite in the pharmaceutical product.

[0082] Preparation of excipients with high nitrite content:

[0083] The first step consisted in preparing a 100 mL solution of sodium nitrite at 1 mg / mL.

[0084] a) Pre-gelatinized starch with high nitrite content:

[0085] 4 g of pre-gelatinized starch were placed in 500 mL of water, after complete dissolution, 3 mL of sodium nitrite solution were added. The solution was frozen at -40°C and then subjected to a freeze-drying process, obtaining a powder.

[0086] b) Hydroxyethylcellulose with high nitrite content:

[0087] 2.8 g of hydroxyethylcellulose were placed in 500 mL of water, after complete dissolution, 2.1 mL of sodium nitrite solution were added. The solution was frozen at -40°C and then subjected to a freeze-drying process, obtaining a powder.

[0088] c) HPMC with high nitrite content:

[0089] 4.8 g of HPMC were placed in 500 mL of water, after complete dissolution, 3.6 mL of sodium nitrite solution were added. The solution was frozen at -40°C and then subjected to a freeze-drying process, obtaining a powder.

[0090] Preparation of physical mixtures between trimetazidine salt or co-crystal and excipients with high nitrite content:

[0091] The physical mixtures between salt or co-crystal and excipients with high nitrite content were prepared in 25 mL glass vials by mixing the two powders with a spatula.

[0092]

[0093] Preparation of trimetazidine solid dispersions with high nitrite content:

[0094] a) TMZ / pregelatinized starch 20 / 80 solid dispersions with high nitrite content:

[0095] 400 mg of pregelatinized starch were placed in 500 mL of water, after complete dissolution, 100 mg of trimetazidine base and 0.3 mL of sodium nitrite solution were added. The solution was frozen at -40°C and then subjected to a freeze-drying process, obtaining a powder.

[0096] b) TMZ / hydroxyethylcellulose 20 / 80 solid dispersions with high nitrite content:

[0097] 400 mg of hydroxyethylcellulose were placed in 500 mL of water, after complete dissolution, 100 mg of trimetazidine base and 0.3 mL of sodium nitrite solution were added. The solution was frozen at -40°C and then subjected to a freeze-drying process, obtaining a powder.

[0098] c) TMZ / HPMC 20 / 80 solid dispersions with high nitrite content:

[0099] 400 mg of HPMC were placed in 500 mL of water, after complete dissolution, 100 mg of trimetazidine base and 0.3 mL of sodium nitrite solution were added. The solution was frozen at -40°C and then subjected to a freeze-drying process, obtaining a powder.

[0100]

[0101] Trimetazidine solid dispersions with high nitrite content and physical mixtures of trimetazidine salts or co-crystals with high nitrite content excipients were placed in open glass vials at 40°C / 75% RH for 2 weeks.

[0102] Results: Trimehtazine nitrosamine doses

[0103] The sodium nitrite added in the excipient can theoretically form about 10000 ppm of trimetazidine nitrosamine, provided that the formation is complete.

[0104] Dose determination of trimetazidine nitrosamines was performed by LC / MS. This method allows to quantify trimetazidine nitrosamines up to 300 ppm with accuracy. The above values are out of the linear range of the method and these values can only be used for trends and not to quantify the percentage of trimetazidine nitrosamine formation. They are classified as follows:

[0105] - A: trimetazidine nitrosamine content 300-500 ppm

[0106] - B: trimetazidine nitrosamine content 500-1000 ppm

[0107] - C: trimetazidine nitrosamine content 1000-2000 ppm

[0108] - D: trimetazidine nitrosamine content 2000-3000 ppm

[0109] - E: trimetazidine nitrosamine content > 3000 ppm

[0110] a) Products containing pregelatinized starch with high nitrite content:

[0111]

[0112] b) Products containing hydroxyethylcellulose with high nitrite content:

[0113]

[0114] c) Products containing HPMC with high nitrite content:

[0115]

[0116] The above results show that the trimetazidine solid phase of the present application is able to reduce the formation of trimetazidine nitrosamine in the presence of nitrite compared to trimetazidine salts of the prior art.

[0117] Example 4 : immediate release formulation - equivalent to a formulation containing 20 mg of trimetazidine dihydrochloride

[0118] Trimetazidine solid phase: 36.94 or 78.50 mg (see table below)

[0119] Corn starch: 26 mg

[0120] Mannitol: 34 mg

[0121] Povidone: 4 mg

[0122] Magnesium stearate: 1 mg

[0123] Talc: 5 mg

[0124] Table of equivalence

[0125]

[0126] Other immediate release formulations were prepared by adjusting the amount of trimetazidine solid dispersion containing TMZ / non-acidic matrix compound solid dispersion with other proportions.

[0127] Example 5: MR skeleton tablet - equivalent to a skeleton MR tablet containing 35 mg of trimetazidine dihydrochloride

[0128] Trimetazidine solid phase: 64.65 or 137.40 mg (see table below)

[0129] Hydroxypropyl methylcellulose: 74.0 mg

[0130] Polyvidone: 8.7 mg

[0131] Calcium hydrogen phosphate dihydrate: 80.9 mg

[0132] Magnesium stearate: 1.0 mg

[0133] Colloidal anhydrous silica: 0.4 mg

[0134] Equivalent table

[0135]

[0136] Other MR skeleton tablets are prepared by adjusting the amount of trimetazidine solid dispersion, containing solid dispersions with other proportions of TMZ / non-acidic matrix compound.

[0137] Example 6 : OD formulation - equivalent to an OD formulation containing 80 mg of trimetazidine dihydrochloride

[0138] Trimetazidine solid phase: 147.77 or 266.85 mg (see table below)

[0139] Neutral sucrose / corn starch small granules: 36.67 mg

[0140] Hydroxypropyl methylcellulose: 6.40 mg

[0141] Acetyltri-butyl citrate: 1.20 mg

[0142] Ethylcellulose: 8.00 mg

[0143] Talc: 12.00 mg

[0144] Magnesium stearate: 0.43 mg

[0145] Equivalent table

[0146]

[0147] Other OD formulations are prepared by adjusting the amount of trimetazidine solid dispersion, containing solid dispersions with other proportions of TMZ / non-acidic matrix compound.

[0148] Example 7: OD formulation - in combination with bisoprolol hemifumarate

[0149] The trimetazidine solid phase small granules obtained in Example 6 were mixed together with the bisoprolol hemifumarate granules containing 5 mg of bisoprolol hemifumarate and encapsulated.

[0150] Example 8 : OD formulation - in combination with metoprolol succinate

[0151] The trimetazidine solid phase small granules obtained in Example 6 were mixed together with the metoprolol succinate granules containing 47.5 mg or 95 mg of metoprolol succinate and encapsulated.

Claims

1. Trimetazidine solid phase selected from a trimetazidine solid dispersion in a non-acidic pharmaceutically acceptable matrix compound and a trimetazidine complex with theophylline, wherein the trimetazidine solid dispersion is a dispersion of trimetazidine in liquid form of the free base in a non-acidic pharmaceutically acceptable solid matrix compound.

2. The trimetazidine solid dispersion according to claim 1, wherein the non-acidic pharmaceutically acceptable matrix compound is a polymer, preferably pregelatinized starch or a cellulose derivative, more preferably hydroxypropyl methylcellulose or hydroxyethyl cellulose.

3. The trimetazidine solid dispersion according to any one of claims 1 or 2, wherein the weight ratio of trimetazidine to non-acidic pharmaceutically acceptable matrix compound is preferably about 50 / 50 or below, more preferably about 50 / 50 to about 10 / 90, such as about 40 / 60 to about 20 / 80, more preferably about 20 / 80.

4. A pharmaceutical composition comprising a trimetazidine solid phase according to any one of claims 1 to 3 in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

5. The pharmaceutical composition according to claim 4 in the form of an immediate release oral tablet, an extended release oral matrix tablet or coated small granules in a capsule for oral administration, administered once a day.

6. The pharmaceutical composition according to any one of claims 4 or 5, further comprising a beta blocker.

7. The pharmaceutical composition according to claim 6, wherein the beta blocker is metoprolol or bisoprolol.

8. The trimetazidine solid phase according to any one of claims 1 to 3 or the pharmaceutical composition according to any one of claims 4 to 7 for use in the prophylactic treatment of angina pectoris, in the course of chorioretinal disorders or for the treatment of vasogenic dizziness.

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