Novel Trimetazidine Solid Phase

Abstract

This invention relates to a novel trimetazidin solid phase that reduces the formation of trimetazidin nitrosamines in the presence of nitrites.

Description

Technical Field

[0001] The present invention relates to a novel trimethadione solid phase.

Background Art

[0002] Trimethadione, that is, 1-(2,3,4-trimethoxybenzyl)piperazine (Formula (I)), is a compound that avoids a sharp decrease in the intracellular level of adenosine triphosphate (ATP) by maintaining the energy metabolism of cells exposed to hypoxia or ischemia. Thereby, the function of ion pumps and the sodium-potassium membrane permeation current are ensured, and the homeostasis of cells is maintained.

[0003]

Chemical

[0004] Trimethadione is liquid at room temperature in the form of its free base.

[0005] Trimethadione dihydrochloride is disclosed in GB929252 and is currently used therapeutically for the preventive treatment of acute onset of angina pectoris in retinal seizures and the treatment of vascular dizziness (Meniere's disease dizziness, tinnitus).

[0006] Patent applications CN110105307, CN110183398 and CN110054599 disclose the synthesis of trimethadione hemisuccinate, succinate and disuccinate, respectively, to overcome the problems of fluidity, insufficient tableting properties and hygroscopicity of trimethadione dihydrochloride.

[0007] Trimethadione nitrosoamine of Formula (II) is an impurity that may be generated during the synthesis process of trimethadione or trimethadione salts or during the formulation process of such salts in the presence of nitrite derived from water and / or excipients.

[0008]

Chemical

[0009] The applicant has now found that the novel trimetazidine solid phase of the present invention can reduce the formation of trimetazidine nitrosamines in the presence of nitrites.

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

[0011] As used herein, the term “trimetazidine solid dispersion” means a dispersion of liquid trimetazidine, which is its free base, in a non-acidic, pharmaceutically acceptable solid matrix compound.

[0012] Examples of non-acidic, pharmaceutically acceptable matrix compounds include particularly non-acidic, pharmaceutically acceptable polymers, preferably cellulose derivatives, such as cellulose, pregelatinized starch, and cellulose ethers, such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, or hydroxypropylmethylcellulose. Preferred non-acidic, pharmaceutically acceptable matrix compounds are hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, and pregelatinized starch, and more preferably hydroxypropylmethylcellulose (HPMC).

[0013] The weight ratio of trimetazidine to a non-acidic, pharmaceutically acceptable matrix compound is preferably about 50 / 50 or less, more preferably between about 50 / 50 and about 10 / 90, for example between about 40 / 60 and about 20 / 80, more preferably about 20 / 80.

[0014] A trimetazidine solid dispersion can be prepared by adding trimetazidine to a dissolved matrix compound and freeze-drying the resulting mixture. The trimetazidine solid dispersion is obtained in the form of an amorphous powder.

[0015] In another embodiment, the present invention relates to a trimetazidine complex with theophylline.

[0016] As used herein, the term “complex” refers to a solid composed of two chemical substances in a specified stoichiometric ratio, bound together by a weak interaction (typically hydrogen bonding or other noncovalent and nonionic interactions). In this invention, the two chemical substances are trimetazidine and theophylline.

[0017] The trimetazidine complex with theophylline can be prepared by stirring the trimetazidine and theophylline in a solvent, then slowly raising the temperature to, for example, about 50°C, holding it at that temperature for 2 hours, returning it to room temperature, stirring further, and finally filtering and drying the resulting powder.

[0018] Solvents that can be used to prepare the trimetazidine complex with theophylline include acetonitrile, methanol, ethanol, toluene, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, water, or n-heptane.

[0019] The present invention also relates to a pharmaceutical composition comprising a trimetazidine complex or trimetazidine solid dispersion with theophylline of the present invention, combined with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

[0020] The effective dose varies depending on the patient's age and weight, route of administration, nature and severity of the disease, and related treatments, and is in the range of 15 mg to 200 mg administered at least once a day.

[0021] The pharmaceutical compositions of the present invention are particularly suitable for oral, parenteral (intravenous, intramuscular, or subcutaneous), per- or trans-cutaneous, intranasal, intrarectal, translingual, intraocular, or respiratory administration, and include tablets or sugar-coated tablets, sublingual tablets, gelatin capsules, capsules, granules, suppositories, creams, ointments, skin gels, injections or oral preparations, aerosols, and eye drops or nasal drops.

[0022] The pharmaceutical composition may be in the form of an immediate-release composition or a sustained-release composition. According to one aspect of the present invention, the pharmaceutical composition is an immediate-release oral tablet. According to another aspect of the present invention, the pharmaceutical composition is a sustained-release oral matrix tablet. According to yet another aspect of the present invention, the pharmaceutical composition is in the form of coated granules in a capsule for once-daily oral administration.

[0023] In addition to the trimetazidine solid phase of the present invention, the tablets of the present invention contain one or more excipients or carriers, such as diluents, retarders, lubricants, binders, disintegrants, absorbents, plasticizers, colorants, and sweeteners. Examples of excipients or carriers include the following: Diluents include: lactose, dextrose, sucrose, mannitol, sorbitol, glycerol, calcium hydrogen phosphate dihydrate, calcium carbonate, cellulose, cellulose ethers (such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, or hydroxypropylmethylcellulose), Release control agents include: ethylcellulose, ethylcellulose derivatives (cellulose acetate, cellulose butyrate acetate, cellulose propionate acetate, cellulose phthalate acetate, hydroxypropyl methylcellulose succinate acetate, etc.) and / or polymethacrylic acids. Lubricants include: silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol, glycerol behenate, or sodium benzoate. Binders include: aluminum silicate and magnesium silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, Plasticizers include: tributyl acetyl citrate, triacetin, triethyl acetyl citrate, ethyl acetyl citrate, diethyl sebacate, dibutyl sebacate, ethyl phthalate, dibutyl phthalate, polyethylene glycol, glycerol and / or propylene glycol, Disintegrants include: agar, alginic acid and its sodium salt, foaming mixture.

[0024] The proportion of the active ingredient of formula (I) in the tablets is preferably between 5% and 50% by weight.

[0025] According to one aspect of the present invention, the trimethazidine solid phase of the present invention is administered in combination with one or more additional active ingredients. The combined administration may be in the form of simultaneous or sequential combined administration (free combination) of two or more separate pharmaceutical compositions each containing one active ingredient, or in the form of administration of a fixed-dose combination containing two or more active ingredients formulated in a single dosage form.

[0026] Particularly mentioned as additional active ingredients are beta-blockers. According to one aspect of the present invention, the trimethazidine solid phase of the present invention is administered in combination with a beta-blocker in the form of a fixed-dose combination. Particularly mentioned as beta-blockers are metoprolol and bisoprolol. According to a preferred aspect of the present invention, the fixed-dose combination of trimethazidine solid phase and bisoprolol is a capsule containing an amount of trimethazidine solid phase granules corresponding to 80 mg of trimethazidine dihydrochloride fine granules and 5 mg or 10 mg of bisoprolol hemifumarate pellets.

[0027] According to another preferred aspect of the present invention, the fixed-dose combination of trimethazidine solid phase and metoprolol is a capsule containing an amount of trimethazidine solid phase granules corresponding to 80 mg of trimethazidine dihydrochloride fine granules and 47.5 mg or 95 mg of metoprolol succinate pellets.

[0028] A formulation of bisoprolol hemifumarate pellets has already been disclosed in Example 4a of WO2016 / 071631. [Brief explanation of the drawing]

[0029] [Figure 1] Figure 1 shows the 1H NMR spectrum of the trimetazidine-theophylline 1 / 2 complex obtained in Example 1. [Figure 2] Figure 2 shows the XRPD pattern of the trimetazidine-theophylline 1 / 2 complex obtained in Example 1. [Figure 3] Figure 3 shows the DSC and TG graphs of the trimetazidine-theophylline 1 / 2 complex obtained in Example 1.

[0030] Abbreviation DSC: Differential Scanning Calorimetry eq.: Molar equivalent HPMC: Hydroxypropylmethylcellulose NMR: Nuclear magnetic resonance method TG: Thermogravimetry TMZ: Trimetazidine XRPD: X-ray powder diffraction method

[0031] Experiment Section Using an X-ray diffractometer operating in transmission mode with a 45kV and 40mA CuKα line (λ=1.5418Å), XRPD patterns were recorded for 10 minutes with a step size of 0.013°2θ from 3.5°2θ to 35°2θ. The XRPD table only lists peaks with a relative intensity exceeding 10%. Relative intensity may change in the case of preferred orientation.

[0032] The chemical shift (in ppm) is given relative to tetramethylsilane (TMS) using partially deuterated dimethyl sulfoxide or partially deuterated methanol as an internal standard. In a partially deuterated dimethyl sulfoxide solution, 1D 1The 2.5 ppm resonance in the 1H NMR spectrum is attributed to partially deuterated dimethyl sulfoxide.

[0033] The DSC profile was obtained by an equilibration process at 0°C, followed by heating to 130°C at 10°C / min. The TG profile was obtained by heating from 25°C to 130°C at 10°C / min. [Example 1]

[0034] Trimetazidine / theophylline 1 / 2 complex 10.16 g of trimetazidine was added to 200 mL of n-heptane, and then 6.98 g of theophylline was added to the solution. The mixture was stirred at ambient temperature for 25 minutes, heated to 50°C at 1°C / min, then kept isothermal at 50°C for 2 hours, and finally cooled to 20°C at 0.1°C / min, followed by isothermal holding for 12 hours. This suspension was filtered, and the powder was dried overnight under vacuum at 40°C. The resulting powder corresponds to an anhydrous crystalline powder of 1 / 2 stoichiometric (trimetazidine / theophylline) with a melting point of approximately 95°C. 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); b=broad, s=singlet, t=triplet handle 1 The 1H NMR spectrum is shown in Figure 1.

[0035] [Table 1]

[0036] The corresponding XRPD patterns are shown in Figure 2. The DSC / TG graph is shown in Figure 3. [Example 2]

[0037] Trimetazidine solid dispersion

[0038] [Example 2a] Trimetazidine / non-acid polymer 20 / 80 solid dispersion TMZ / HPMC 20 / 80: 2.4 g of HPMC was slowly added to 350 mL of water, and after complete dissolution, 0.64 g of trimetazidine was added to the solution. The mixture was freeze-dried under a vacuum of 0.05 mbar to obtain an amorphous powder. Other examples of TMZ / non-acid polymer 20 / 80 solid dispersions, including TMZ / hydroxyethylcellulose 20 / 80, TMZ / methylcellulose 20 / 80, and TMZ / pregelatinized starch 20 / 80 solid dispersions, are prepared under the same operating conditions as above, by substituting HPMC with hydroxyethylcellulose, methylcellulose, or pregelatinized starch, respectively.

[0039] [Example 2b] Trimetazidine / non-acidic polymer solid dispersions in other ratios TMZ / HPMC 50 / 50: 2.0 g of 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 freeze-dried under a vacuum of 0.05 mbar to obtain an amorphous powder. Other examples of trimetazidine solid dispersions, including TMZ / HPMC 40 / 60 and TMZ / HPMC 30 / 70 solid dispersions, are prepared under the same operating conditions as above, by adapting the amounts of trimetazidine and HPMC. [Example 3]

[0040] Comparative experiment: Formation of trimetazidine nitrosamine To model 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 mimics the presence of nitrites in pharmaceuticals.

[0041] Preparation of excipients with high nitrite content: The first step consists of preparing 100 mL of a 1 mg / mL sodium nitrite solution. a) Pregelatinized starch with a high nitrite content: 4 g of pregelatinized starch was dissolved in 500 mL of water, and after complete dissolution, 3 mL of sodium nitrite solution was added. The solution was frozen at -40°C, and then freeze-dried to obtain a powder. b) Hydroxyethylcellulose with a high nitrite content: 2.8 g of hydroxyethylcellulose was dissolved in 500 mL of water, and after complete dissolution, 2.1 mL of sodium nitrite solution was added. The solution was frozen at -40°C, and then freeze-dried to obtain a powder. c) HPMC with high nitrite content: 4.8 g of HPMC was dissolved in 500 mL of water, and after complete dissolution, 3.6 mL of sodium nitrite solution was added. The solution was frozen at -40°C, and then freeze-dried to obtain a powder.

[0042] Preparation of physical mixtures of trimetazidine salt or cocrystal and high nitrite excipient: A physical mixture of the salt or cocrystal and the high nitrite excipient was prepared in a 25 mL glass vial by mixing the two powders with a spatula.

[0043] [Table 2]

[0044] Preparation of a trimetazidine solid dispersion with a high nitrite content: a) TMZ / pregelatinized starch 20 / 80 solid dispersion with high nitrite content: 400 mg of pregelatinized starch was dissolved in 500 mL of water, and 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 freeze-dried to obtain a powder. b) TMZ / hydroxyethylcellulose 20 / 80 solid dispersion with high nitrite content: 400 mg of hydroxyethylcellulose was dissolved in 500 mL of water, and 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 freeze-dried to obtain a powder. c) TMZ / HPMC 20 / 80 solid dispersion with high nitrite content: 400 mg of HPMC was dissolved in 500 mL of water, and 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 freeze-dried to obtain a powder.

[0045] [Table 3]

[0046] A solid dispersion of trimetazidine with a high nitrite content, and a physical mixture of trimetazidine salt or cocrystal with a high nitrite excipient, were left in open glass vials at 40°C / 75% RH for two weeks.

[0047] Result: Amount of trimetazidine nitrosamine. The sodium nitrite added to the excipient can theoretically produce approximately 10,000 ppm of trimetazidine nitrosamine if the entire amount of trimetazidine nitrosamine is generated. The amount of trimetazidine nitrosamine was measured by LC / MS. This method allows for accurate quantification of trimetazidine nitrosamine up to 300 ppm. Values ​​exceeding this amount deviate from the linearity of this method and represent trends, not quantitatively determine the production rate of trimetazidine nitrosamine. The results were classified as follows: - A: Trimetazidine nitrosamine content 300-500 ppm - B: Trimetazidine nitrosamine content 500-1000 ppm - C: Trimetazidine nitrosamine content 1000-2000 ppm - D: Trimetazidine nitrosamine content 2000-3000 ppm - E: Trimetazidine nitrosamine content > 3000 ppm

[0048] a) Products containing high nitrite pregelatinized starch:

[0049] [Table 4]

[0050] b) Products containing high nitrite hydroxyethylcellulose:

[0051] [Table 5]

[0052] c) Products containing high nitrite (HPMC):

[0053] [Table 6]

[0054] The above results demonstrate that the trimetazidine solid phase of the present invention can reduce the formation of trimetazidine nitrosamines in the presence of nitrites compared to the trimetazidine salts of the prior art. [Example 4]

[0055] Immediate-release formulation (equivalent to a formulation containing 20 mg of trimetazidine dihydrochloride) Trimetazidine solid phase 36.94 mg or 78.50 mg (see table below) Corn starch 26mg Mannitol 34mg Polyvidone 4mg Magnesium stearate 1 mg Talc 5mg

[0056] [Table 7]

[0057] Other immediate-release formulations containing TMZ / non-acidic matrix compound solid dispersions in other ratios are prepared by adjusting the amount of trimetazidine solid dispersion. [Example 5]

[0058] MR Matrix Tablets (equivalent to Matrix MR Tablets containing 35 mg of trimetazidine dihydrochloride) Trimetazidine solid phase 64.65 mg or 137.40 mg (see table below) Hydroxypropyl methylcellulose 74.0 mg Povidone 8.7mg Calcium hydrogen phosphate dihydrate 80.9 mg Magnesium stearate 1.0 mg Anhydrous colloidal silica 0.4 mg

[0059] [Table 8]

[0060] Other MR matrix tablets containing TMZ / non-acidic matrix compound solid dispersions in different ratios are prepared by adjusting the amount of trimetazidine solid dispersion. [Example 6]

[0061] Oral disintegration preparation (equivalent to an oral disintegration preparation containing 80 mg of trimetazidine dihydrochloride) Trimetazidine solid phase 147.77 mg or 266.85 mg (see table below) Neutral sucrose / corn starch granules 36.67 mg Hydroxypropyl methylcellulose 6.40 mg Tributyl acetyl citrate 1.20 mg Ethylcellulose 8.00 mg Talc 12.00 mg Magnesium stearate 0.43 mg

[0062] [Table 9]

[0063] Other OD formulations containing TMZ / non-acidic matrix compound solid dispersions in other proportions are prepared by adjusting the amount of trimetazidine solid dispersion. [Example 7]

[0064] OD formulation (combined with bisoprolol hemifumarate) The trimetazidine solid-phase granules obtained in Example 6 and bisoprolol hemifumarate pellets containing 5 mg of bisoprolol hemifumarate were mixed together and encapsulated. [Example 8]

[0065] OD formulation (combined with metoprolol succinate) The trimetazidine solid-phase granules obtained in Example 6 are mixed with metoprolol succinate pellets containing either 47.5 mg or 95 mg of metoprolol succinate, and then encapsulated.

Claims

1. A 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 liquid trimetazidine, which is its 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 hydroxyethylcellulose.

3. A trimetazidine solid dispersion according to any one of claims 1 or 2, wherein the weight ratio of trimetazidine to a non-acidic, pharmaceutically acceptable matrix compound is preferably about 50 / 50 or less, more preferably between about 50 / 50 and about 10 / 90, for example between about 40 / 60 and about 20 / 80, and more preferably about 20 / 80.

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

5. The pharmaceutical composition according to claim 4, which is in the form of an immediate-release oral tablet, a sustained-release oral matrix tablet, or coated granules contained in a capsule for once-daily oral administration.

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. A trimetazidine solid phase according to any one of claims 1 to 3, or a 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 disease, or for the treatment of vascular vertigo.

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