CONTROLLED-RELEASE PHARMACEUTICAL COMPOSITIONS OF IVABRADINE

Field of the Invention

The present invention relates to controlled-release pharmaceutical compositions comprising ivabradine or a pharmaceutically acceptable salt, solvate or polymorph thereof and at least one controlled-release agent.

Background of the Invention

Ivabradine, (marketed under the trade name Corlanor) is a medication used for the symptomatic management of stable heart related chest pain and heart failure not fully managed by beta blockers.

The chemical name of ivabradine is 3-{3-[{[(7S)-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-2H-3- benzazepin-2-one and its chemical structure is shown in the Formula 1.

Formula 1

Ivabradine is a heart rate lowering agent. It acts by selective and specific inhibition of the cardiac pacemaker If current, an important ionic current that usually controls spontaneous diastolic depolarisation in the sinus node and thereby regulates heart rate.

Ivabradine molecule is disclosed in EP0534859. W02006092493 discloses polymorph b of ivabradine hydrochloride, its process of preparation and compositions comprising this polymorph. Polymorph b is present in the marketed product. Other polymorphic forms of ivabradine hydrochloride are disclosed in W020051 10993, W02006092491 ,

W02006092492, W02006092494, W02007042656, W02007042657 and

WO2013064307. It’s known from the prior art, ivabradine salts crystallize easily and and polymorphic transitions of ivabradine hydrochloride take place rather easily, especially in drug products.

It’s known that ivabradine salts exhibit polymorphic transitions easily. Different polymorphs can lead to differences in solubility, dissolution profiles, and therefore bioavailability and stability of the product. Stable products should not undergo polymorphic transformation during their production and shelf life.

Amorphous ivabradine hydrochloride and methods for its preparation are disclosed in W02008146308, CN101597261 and CN101463008.

EP1345594 describes thermoformable solid pharmaceutical compositions for controlled release of ivabradine by using polymethacrylates polymers.

It is a desired feature to obtain an active pharmaceutical agent in an extended release form in the treatment of a number of diseases. The term extended release may be defined as reaching desired plasma levels of an active agent of interest throughout a determined period of time, and providing the drug release at a uniform and constant rate. Thus, the drug administration frequency can be decreased.

There are various difficulties associated with developing an extended release formulation. One of the problems encountered is dose dumping, as a result of too rapid release of the drug. Obtaining intended solubility profiles is also difficult to control the release rate. For this reason, there may occur fluctuations in the plasma concentrations of active agents, which may lead to toxicity. In addition, daily alterations may be possible for the active agent in plasma.

To overcome all these problems and adjust the dissolution profile, during the developing of a drug formulation, a controlled-release agent should be used and extended release is achieved.

In addition, ivabradine is an active agent which has a stability problem. Therefore, it is necessary to avoid degradation and polymorphic transition of ivabradine over the shelf life of the product. Mechanical stress associated with process and using high amount of excipients lead to polymorphic transformation of ivabradine. Therefore, it is important to use excipients in a specific amount that decrease the degradation and sustain the stability.

Ivabradine has also content uniformity problem which is a pharmaceutical analysis parameter for the quality control of capsules or tablets. In this present invention, these problems are also solved by adjusting the ratio of excipients. Accordingly, there is a need for an improved extended release formulation of ivabradine or pharmaceutically acceptable salt to achieve desired dissolution profile and release kinetic while overcoming stability and content uniformity problems.

Detailed Description of the Invention

The main object of the present invention is to provide controlled-release pharmaceutical compositions comprising ivabradine or a pharmaceutically acceptable salt, solvate or polymorph thereof with high stability and bioavailability.

Another object of the present invention is achive good content uniformity.

In this invention, the pharmaceutical compositions comprise ivabradine or a pharmaceutically acceptable salt, solvate or polymorph thereof and at least one controlled-release agent which is selected from glyceryl behenate, cellulose acetate, polyvinylpyrrolidone, polyvinyl acetate, lauroyl polyoxyl glycerides, ethylene vinyl acetate copolymer or mixtures thereof.

Choice of the controlled-release agents is essential for providing an efficient and desired release kinetic. In this invention, the controlled-release agents are limited to glyceryl behenate, cellulose acetate, polyvinylpyrrolidone with polyvinyl acetate, lauroyl polyoxyl glycerides, ethylene vinyl acetate copolymer or mixtures thereof.

In one embodiment, the amount of the controlled-release agents is between 0.50% and 60.00% by weight of the total composition. Preferably this ratio is between 0.50% and 40.00% by weight of the total composition. In one embodiment, the amount of ivabradine or a pharmaceutically acceptable salt, solvate or polymorph thereof is between 0.01% and 10.00% by weight of the total composition.

According to these embodiments, the weight ratio of the amount of the controlled-release agents to amount of ivabradine or a pharmaceutically acceptable salt, solvate or polymorph thereof is between 1.00 and 100.0, preferably 1 .00 and 80.0.

These specific selections of the weight ratio of the amount of the controlled-release agents to amount of ivabradine or a pharmaceutically acceptable salt, solvate or polymorph thereof help to ensure the desired release kinetic of ivabradine-containing pharmaceutical compositions.

In a preferred embodiment, the controlled-release agents are polyvinylpyrrolidone, polyvinyl acetate and glyceryl behenate.

According to this preferred embodiment, the amount of glyceryl behenate is between 5.00% and 30.00% by weight of the total composition.

According to these embodiments, the amount of polyvinylpyrrolidone and polyvinyl acetate is between 1 .00% and 30.00% by weight of the total composition.

In a preferred embodiment, the controlled-release agent is lauroyl polyoxylglycerides.

According to this preferred embodiment, the amount of lauroyl polyoxylglycerides is between 0.50% and 40.00% by weight of the total composition.

In a preferred embodiment, the controlled-release agents are glyceryl behenate and ethylene vinyl acetate copolymer.

According to this preferred embodiment, the amount of glyceryl behenate is between 5.00% and 30.00%, and the amount of ethylene vinyl acetate copolymer is between 0.50% and 20.00% by weight of the total composition.

In one preferred embodiment, the controlled-release agent is cellulose acetate. According to this preferred embodiment, the amount of cellulose acetate is 0.50% and 20.00% by weight of the total composition.

In one embodiment, the composition is in the form of coated tablet, trilayer tablet, bilayer tablet, multilayer tablet, mini tablet, pellet, sugar pellet, modified release tablet, film-coated tablet, gastric disintegrating tablet, pill, capsule, oral granule, powder, coated bead system, microsphere, tablet in tablet, inlay tablet or orally administrable film.

In one preferred embodiment, the composition is in the form of a tablet or a film-coated tablet.

Film-coating layer may also be used for the protection from the moisiture, light and oxygen since ivabradine has a stability problem.

Suitable film-coating layer can be selected from the group comprising polyvinyl alcohol- polyethylene glycol copolymers (Kollicoat IR); polyvinyl alcohol or copolymers or mixtures thereof (Opadry AMB II); polyvinylpyrrolidone-vinyl acetate copolymers (Kollidon VA 64); ethylcellulose dispersions (Surelease); polyethylene glycol; polyvinyl alcohol and lecithin (Sheffcoat PVA+); polyvinylprolidone and all kinds of OpadryTM, as well as pigments, dyes, titanium dioxide, iron oxide, talc or polymethylmetacrylate copolymers (Eudragit).

In one embodiment, the composition further comprises at least one pharmaceutically acceptable excipient which is selected from a group comprising fillers, binders, glidants, lubricants, plasticizers or mixtures thereof.

Suitable fillers are selected from a group comprising microcrystalline cellulose, dibasic calcium phosphate dihydrate, heavy magnesium carbonate, lactose, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate, polyols, dextrose, maltitol or mixtures thereof.

In one preferred embodiment, the filler is selected from a group comprising microcrystalline cellulose, dibasic calcium phosphate dihydrate, heavy magnesium carbonate or mixtures thereof. It’s known that obtaining stable formulations comprising ivabradine is difficult due to physicochemical properties of ivabradine. In this invention, the amount of excipients which are used in specific amounts, is very important for providing good stability and long shelf- life. Especially, the amount of filler is a major parameter for stability.

In one preferred embodiment, the fillers are microcrystalline cellulose and dibasic calcium phosphate dihydrate.

According to this embodiment, the amount of microcrystalline cellulose is between 5.00% and 90.00% by weight of the total composition and the amount of dibasic calcium phosphate dihydrate is between 5.00% and 50.00% by weight of the total composition.

In one preferred embodiment, the fillers are dibasic calcium phosphate dihydrate and heavy magnesium carbonate.

According to this embodiment, the amount of dibasic calcium phosphate dihydrate is between 5.00% and 50.00% by weight of the total composition, the amount of heavy magnesium carbonate is between 5.00% and 30.00% by weight of the total composition.

Suitable binders are selected from a group comprising carboxymethyl cellulose sodium, polyvinylpyrrolidone, carnauba wax, pullulan, glyceryl behenate, polycarbophil, polyvinyl acetate and its copolymers, cellulose acetate phthalate, hydroxypropyl starch, sugars, tragacanth gum, cetostearyl alcohol, acacia mucilage, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, cellulose derivatives such as hydroxyethyl cellulose, carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, carrageenan, guar gum, polymethacrylates, methacrylate polymers, collagens, proteins like gelatin, agar, alginate, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminium hydroxide, laponite, bentonite, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.

In one preferred embodiment, the binder is carboxymethyl cellulose sodium.

According to this preferred embodiment, the amount of binder is 0.50% and 20.00% by weight of the total composition. Suitable lubricants are selected from a group comprising magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyceryl palmitostearate, sodium lauryl sulphate or mixtures thereof.

In one embodiment, the amount of the lubricant is between 0.10% and 10.00% by weight of the total composition.

In one preferred embodiment, the lubricant is magnesium stearate.

According to this preferred embodiment, the amount of magnesium stearate is between 0.10% and 10.00% by weight of the total composition.

This specific amount of the lubricant is effective for achieving good tablet content uniformity. Additionally, content uniformity problem of ivabradine could also be overcome when magnesium stearate has been used as the lubricant.

Suitable plasticizers are selected from a group comprising diethyl phthalate, polyethylene glycol, medium chain glycerides, triacetin, triethyl citrate, acetyltributyl citrate, acetyltriethyl citrate, alpha tocopherol, chlorobutanol, dibutyl sebacate, tributyl citrate or mixtures thereof.

In one preferred embodiment, the plasticizer is diethyl phthalate.

In one embodiment, the amount of the plasticizer is between 1.00% and 20.00% by weight of the total composition.

Suitable glidants are selected from a group comprising colloidal silicon dioxide, talc, aluminium silicate or mixtures thereof.

In one preferred embodiment, the glidant is colloidal silicon dioxide.

In one embodiment, the amount of glidant is between 0.10% and 10.00% by weight of the total composition. It has been found that, when the lubricant and the glidant are used in specific amounts, the content uniformity problem of ivabradine is solved. In this invention, wherein the weight ratio of the glidant to the lubricant is between 0.02 and 10.0, preferably this ratio is between 0.02 and 4.0.

Another important parameter for content uniformity is particle size values of the glidants and the lubricants.

In this invention, these specific selections of particle size distribution values, especially the D90 value ranges of the glidant and the lubricant ensure the uniformity of the content of active substance of the pharmaceutical compositions.

Particle size distribution of the filler play a significant role for the qualification of the composition subjected to the invention. As used herein,‘particle size distribution’ means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (Malvern analysis).

Laser diffraction measures particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles, as illustrated below. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering. The particle size is reported as a volume equivalent sphere diameter.

According to this measuring method, the term D10 means, the size at which 10% by volume of the particles are finer and D50 means the size at which 50% by volume of the particles are finer and D90 means the size at which %90 by volume of the particles are finer.

The D90 value of the glidant is ranging between 1 to 100 pm. Preferably, this value is ranging between 10 to 80 pm. More preferably this value is ranging between 10 to 50 pm.

The D90 value of the lubricant is ranging between 1 to 100 pm. Preferably, this value is ranging between 10 to 80 pm. More preferably this value is ranging between 10 to 50 pm. The ratio of the D90 value of the lubricant to D90 value of the glidant is between 0.1 and 10.0. Preferably this ratio is between 0.2 and 5.0. More preferably this ratio is between 0.50 and 2.0. Accoridng to one embodiment, suitable salts of ivabradine are selected from a group comprising hydrochloride, the hydrobromide, the oxalate, the sulfate, the phosphate, the acetate, the propionate, however also salts of the ivabradine with propionic acid, maleic acid, fumaric acid, tartaric acid, nitric acid, benzoic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, citric acid, toluenesulfonic acid, trifluoroacetic acid, and camphoric acid and also the lactate, pyruvate, malonate, succinate, glutarate, and ascorbate of the ivabradine. Further, the following salts can be employed: Laspartate, glutamate, sorbate, acinotate, gluconate, hippurate, and salts of the ivabradine with ethanesulfonic acid, mandelic acid, adipic acid, or sulfamic acid. Example 1 : Tablet

The pharmaceutical compositions mentioned above are prepared by following these steps: a. Mixing ivabradine or a pharmaceutically acceptable salt, solvate or polymorph thereof and the half of polyvinyl pyrrolidone/polyvinyl acetate (Kollidon SR) in water to form a homogen mixture b. Adding dibasic calcium phosphate dihydrate, microcrystalline cellulose and glyceryl behenate to the homogen mixture to form granules and drying the granules and sieving

c. Adding the other half of polyvinyl pyrrolidone/polyvinyl acetate (Kollidon SR) and colloidal silicon dioxide to the granules and mixing

d. Adding magnesium stearate to the granules and mixing

e. Compressing the mixture to form tablets

f. Coating these tablets with Opadry AMB II or Kollicoat IR. (Optionally)

Example 2: Tablet

The pharmaceutical compositions mentioned above are prepared by following these steps: a. Melting gelucire

b. Mixing melted gelucire and ivabradine or a pharmaceutically acceptable salt, solvate or polymorph thereof

c. Cooling the mixture and sieving

d. Adding heavy magnesium carbonate, dibasic calcium phosphate dihydrate, colloidal silicon dioxide to the mixture and mixing

e. Adding magnesium stearate to this mixture

f. Compressing the mixture to form tablets

g. Coating these tablets with Opadry AMB II or Kollicoat IR. (Optionally) Example 3: Tablet

The pharmaceutical compositions mentioned above are prepared by following these steps: a. Solving ivabradine or a pharmaceutically acceptable salt, solvate or polymorph thereof and ethylene vinyl acetate copolymer in a suitable solvent

b. Encapsulating by using spray drying process to form encapsulated granules c. Adding microcrystalline cellulose, glyceryl behenate, dibasic calcium phosphate dihydrate, colloidal silicon dioxide to these encapsulated granules to form a homogen mixture

d. Adding magnesium stearate to this mixture and mixing

e. Compressing the mixture to form tablets

f. Coating these tablets with Opadry AMB II or Kollicoat IR. (Optionally)

Example 4: Tablet

The pharmaceutical compositions mentioned above are prepared by following these steps:

a. Preparing an alcoholic or hydroalcoholic solution of the active agent with ivabradine or a pharmaceutically acceptable salt, solvate or polymorph thereof and the half of carboxymethy cellulose sodium

b. Coating the sugar pellets with this solution to form sugar pellets which contains active agent

c. Preparing an alcoholic or hydroalcoholic solution of the other half of carboxymethy cellulose sodium, cellulose acetate and diethyl phthalate

d. Coating the pellets with this solution to form coated pellets

e. Mixing microcrystalline cellulose, dibasic calcium phosphate dihydrate, colloidal silicon dioxide and the coated pellets to form a homogen mixture

f. Adding magnesium stearate to this homogen mixture

g. Compressing the mixture to form tablets

h. Coating these tablets with Opadry AMB II or Kollicoat IR. (Optionally)