NEW IVABRADINE SALT AND ITS PREPARATION PROCESS

Abstract

The invention relates to ivabradine hemipamate of formula (i): and its hydrates. The invention also relates to medicinal products.

Description

[0001] The present invention relates to a new salt of ivabradine, its preparation process and the pharmaceutical compositions which contain it.

[0002] Ivabradine, or 3-{3-[{[(7 S )-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2 H-3-benzazepin-2-one, as well as its pharmaceutically acceptable acid addition salts, and more particularly its hydrochloride, have very interesting pharmacological and therapeutic properties, including bradycardic properties, which make these compounds useful in the treatment or prevention of various clinical situations of myocardial ischemia such as angina pectoris, myocardial infarction and associated rhythm disturbances, as well as in various pathologies involving rhythm disturbances, particularly supraventricular, and in heart failure, both systolic and diastolic.

[0003] The preparation and therapeutic use of ivabradine and its salts of addition to a pharmaceutically acceptable acid, and more particularly of its hydrochloride, have been described in European patent EP 0 534 859.

[0004] The present invention relates to ivabradine hemipamoate of formula (I): as well as its hydrates, a process for preparing said salt, and pharmaceutical compositions containing it, in particular those allowing controlled release over time of the active ingredient.

[0005] Pamoic acid is also known as 4,4'-methanediylbis(3-hydroxynaphthalene-2-carboxylic acid).

[0006] The compound of formula (I) has an ivabradine / pamoic acid ratio of 1 / 0.5.

[0007] The compound of formula (I) is obtained by action of the disodium salt of pamoic acid or sodium pamoate on ivabradine hydrochloride in aqueous medium.

[0008] Ivabradine hydrochloride and sodium pamoate are combined in a proportion of between 1 / 0.5 and 1 / 0.6.

[0009] The compound of formula (I) thus prepared is then extracted from the aqueous medium using an organic solvent, for example dichloromethane.

[0010] After its formation, the compound of formula (I) can advantageously be reconstituted in methanol in order to remove the residual organic solvent.

[0011] The present invention also relates to pharmaceutical compositions containing ivabradine hemipamoate as the active ingredient, in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or vehicles.

[0012] Among the pharmaceutical compositions according to the invention, particular mention will be made of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), percutaneous or transcutaneous, nasal, rectal, sublingual, ocular or respiratory administration, and in particular plain or coated tablets, sublingual tablets, capsules, caplets, suppositories, creams, ointments, dermal gels, injectable or oral preparations, aerosols, eye or nasal drops.

[0013] In addition to ivabradine hemipamoate, the pharmaceutical compositions according to the invention contain one or more excipients or vehicles such as diluents, lubricants, binders, disintegrating agents, absorbents, colorants, sweeteners.

[0014] Examples of excipients or vehicles include: ◆ for thinners: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerin, ◆ for lubricants : silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol, ◆ for binders : aluminum magnesium silicate, starch, maltodextrin, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, ◆ for disintegrants : agar, alginic acid and its sodium salt, effervescent mixtures.

[0015] The percentage of ivabradine hemipamoate in the pharmaceutical composition is preferably between 5% and 50% by weight.

[0016] The useful dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the condition and any associated treatments and ranges from 2.5 to 30 mg of ivabradine per 24 hours and more preferably from 5 to 15 mg per day and even more preferably from 10 to 15 mg per day.

[0017] The percentage of diluents in the pharmaceutical composition is preferably between 40% and 80% by weight.

[0018] The percentage of lubricants in the pharmaceutical composition is preferably between 0.2% and 10% by weight.

[0019] The percentage of binders in the pharmaceutical composition is preferably between 5% and 50% by weight.

[0020] The Applicant found that the use of ivabradine hemipamoate allowed the preparation of a controlled-release pharmaceutical composition of the active ingredient, avoiding the problems generated by conventional methods.

[0021] Numerous pharmaceutical compositions designed for the controlled release of active pharmaceutical ingredients have been proposed and developed for administration via oral, buccal, sublingual, ocular, rectal, vaginal, and / or parenteral routes. The primary objectives of these new compositions were to: to reduce the frequency of drug administration, to obtain relatively constant levels of active ingredient in the environment or at the targeted biological site, to obtain release profiles in correlation with the pharmacological activity of the drugs.

[0022] To control this release, the most commonly used principle is to incorporate the active ingredient(s) with excipients, most often of a polymeric nature, into matrices.

[0023] Regardless of the matrix compositions considered, their production encounters specific manufacturing problems such as: complex and multi-step manufacturing process, stability of the active ingredient during the manufacturing process and with respect to the excipients used, modulation of the release rate of the active ingredient(s), delicate, often variable over time and dependent for example on the particle size of the polymer batches with compression processes, manufacturing process allowing the obtaining of a pharmaceutical form essentially adapted to a single route of administration, reproducibility of batches due to the multiplication of steps.

[0024] The use of ivabradine hemipamoate allows for a controlled release profile of the active ingredient without implementing the complex pharmaceutical formulation techniques described in the prior art.

[0025] Thus, the Applicant has demonstrated that the use of ivabradine hemipamoate in the pharmaceutical composition of the invention allows a controlled release of ivabradine, even though the galenic formulation used corresponds to that implemented with ivabradine hydrochloride for the immediate release of the active ingredient.

[0026] While all of the ivabradine hydrochloride is released within 15 minutes in vitro, the dissolution test in vitro described in this application showed that only 80% of ivabradine hemipamoate was released after approximately 6 hours.

[0027] The following examples illustrate the invention. EXAMPLE 1 Preparation of ivabradine hemipamoate

[0028] Elemental analysis was performed on a Carlo Erba 1108 instrument.

[0029] The results are corrected by the water content of the product which is 1.82% (measured by coulometry).

[0030] 4.1 g of ivabradine hydrochloride (8.12 mmol) are solubilized in 200 mL of water and 2.0 g of sodium pamoate (4.63 mmol) are solubilized in 200 mL of water.

[0031] Sodium pamoate solution is added to ivabradine hydrochloride solution with vigorous stirring. Hemipamoate salt is formed instantly by precipitation.

[0032] Agitation is maintained for approximately 30 minutes, then ivabradine hemipamoate is extracted first with 200 mL of dichloromethane, and then a second time with 100 mL of dichloromethane. The organic fractions are combined and rinsed with 100 mL of water. The organic phase is dried with magnesium sulfate, yielding a clear, yellow solution.

[0033] The organic phase is evaporated to dryness at 40°C under vacuum in a rotary evaporator. A yellow powder is obtained.

[0034] The yellow powder is dried at 40°C under vacuum (10 mbar) for 16 hours and then rehydrated in 200 mL of methanol.

[0035] The solution is evaporated to dryness at 40°C under vacuum in a rotary evaporator. A yellow powder is obtained again.

[0036] The yellow powder is dried at 40°C under vacuum (10 mbar) for 20 hours.

[0037] The 1< H NMR spectrum indicates a residual methanol content of 0.8%.

[0038] Subsequent drying of the powder at 80°C under vacuum (10 mbar) for 24 hours yields 3.53 g of a product with a residual methanol content of less than 0.1%. Yield = 66.5% Elementary Analysis : Element %theoretical % corrected average C 69.77 69.40 H 6.69 6.60 N 4.23 4.25 O 19.31 Method for correcting results: Example for C 69.14*100 / (100-1.82) = 69.40% Example for H : 6.68*100 / (100-1.82) - 2*1.82 / 18 = 6.60% because (the hydrogen atoms of water (2 / 18) must be taken into account) EXAMPLE 2 Pharmaceutical composition

[0039] Preparation formula for tablets containing 5 mg of ivabradine in 100 mg Ivabradine hemipamoate 7.07 mg Lactose monohydrate 62.23 mg Corn starch 20 mg Maltodextrin (Lycatab® DSH) 10 mg Magnesium Stearate 0.5 mg Anhydrous colloidal silica (Aerosil 200) 0.2 mg EXAMPLE 3 : Dissolution test Operating conditions for dissolution

[0040] Paddle-type dissolving apparatus described in the European Pharmacopoeia (2.9.3) Dissolving medium: 0.01 N hydrochloric acid (pH ∼ 2.1) degassed. Medium temperature: 37 °C ± 0.5 °C. Medium volume: 500 mL ± 5 mL. Blade rotation speed: 50 rpm ± 2 rpm. Standard sampling times: 0, 15, 30, and 45 min. Added sampling times: 1, 2, 4, 6, 8, 12, and 16 h. Sample volume: 1 mL. Sample volume replacement: no. Number of units tested: 6. Number of units per flask: 1. Table 1 - Dissolution Results % of active ingredient released Time (hour) B1 B2 B3 B4 B5 B6 Average Standard deviation Derivative 0 0 0 0 0 0 0 0 0 0 0.25 12 11 12 13 12 11 12 0.84 0.79 0.5 18 17 18 20 17 16 18 1.15 0.4 0.75 21 22 22 24 21 20 22 1.5 0.26 1 24 25 26 28 23 23 25 1.8 0.2 2 38 40 40 43 38 34 39 2.87 0.23 4 64 70 71 70 72 66 69 3 0.25 6 81 89 88 85 91 84 86 3.58 0.15 8 89 99 96 94 101 93 95 4.34 0.07 12 96 109 102 103 110 101 104 5.16 0.03 16 98 114 104 106 114 105 107 6.27 0.01

[0041] There figure 1 provides a graphical illustration of the data presented in the table above.

Claims

1. Ivabradine hemipamoate of formula (I): and its hydrates.

2. Process for the preparation of ivabradine hemipamoate, characterised in that ivabradine hydrochloride is brought together with sodium pamoate in an aqueous medium in a proportion ivabradine hydrochloride / sodium pamoate of from 1 / 0.5 to 1 / 0.6.

3. Pharmaceutical composition comprising as active ingredient ivabradine hemipamoate, in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

4. Pharmaceutical composition according to claim 3 for use in the treatment or prevention of the various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarction and the associated rhythm disturbances, as well as in the various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in systolic or diastolic heart failure.