WO2016198154A1

WO2016198154A1 - Pharmaceutical composition comprising ivabradine hydrochloride and method for preparation thereof

Info

Publication number: WO2016198154A1
Application number: PCT/EP2016/000928
Authority: WO
Inventors: Evangelos Karavas; Efthymios Koutris; Vasiliki SAMARA; Ioanna Koutri; Anastasia Kalaskani; Christina KIZIRIDI; Morfis Abatzis
Original assignee: Pharmathen SA
Current assignee: Pharmathen SA
Priority date: 2015-06-11
Filing date: 2016-06-06
Publication date: 2016-12-15
Anticipated expiration: 2017-12-11
Also published as: EP3307249A1; GR1008821B

Abstract

The present invention relates to a stable pharmaceutical formulation of solid dosage forms for oral administration containing a therapeutically effective amount of Ivabradine HCl polymorph IV or δ in combination with moisture protective excipients and/or low or non- hygroscopic anhydrous excipients in order to avoid polymorphic transformation of the active ingredient. It also relates to a process for the preparation thereof.

Description

PHARMACEUTICAL COMPOSITION COMPRISING IVABRADINE HYCROCHLORIDE AND METHOD FOR PREPARATION THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a stable pharmaceutical formulation for oral administration containing a therapeutically effective quantity of Ivabradine HQ polymorph IV or δ and a method for the preparation thereof. BACKGROUND OF THE INVENTION

Lowering heart rate is one of the most important therapeutic approaches in the treatment of stable angina pectoris. To date, beta blockers and some calcium-channel antagonists reduce heart rate, but their use may be limited by adverse reactions or contraindications. Ivabradine is a novel medication used for the treatment of stable angina pectoris and chronic heart failure. It acts by reducing the heart rate via specific inhibition of the funny channel, a mechanism different from beta blockers and calcium channel blockers.

Ivabradine acts on the If (f is for "funny" so called because it had unusual properties compared with other current systems known at the time of its discovery) ion current, which is highly expressed in the sinoatrial node. If is a mixed Na⁺-fC⁺ inward current activated by hyperpolarization and modulated by the autonomic nervous system. It is one of the most important ionic currents for regulating pacemaker activity in the sinoatrial (SA) node. Ivabradine selectively inhibits the pacemaker If current in a dose-dependent manner. Blocking this channel reduces cardiac pacemaker activity, slowing the heart rate and allowing more time for blood to flow to the myocardium.

The chemical name of Ivabradine HQ is 3-(3-{[((7S)-3,4-dimethoxybicyclo[4.2.0]octa-l,3,5- trien-7-yl)methyl]methylamino}propyl)-l,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-ben2azepin- 2-one hydrochloride and its molecular formula is C₂₇H₃₇CIN₂0₅ corresponding to a molecular weight of 505.05. It is a white to slightly yellow powder. It is freely soluble in water, dimethylsulfoxide, methanol and methylene chloride, soluble in ethanol and slightly soluble in acetone. Ivabradine hydrochloride is optically active and corresponds to the S isomer. Ivabradine hydrochloride shows polymorphism. It may be present in a variety of crystalline forms, some of them being hydrates or solvates. The most stable form is the tetrahydrate form (form β) and all other forms have a tendency of converting to this form under high moisture.

EP 1695965 B discloses the crystalline form β, a tetrahydrate form of Ivabradine HQ, characterized by PXRD and a process for its preparation.

EP 1775288 A discloses the crystalline form δ, a hydrated form of Ivabradine HC1, characterized by PXRD and a process for its preparation.

WO 2013/064307 A discloses Ivabradine HC1 form IV, which is a hemihydrate.

EP 1474152 B discloses an orodispersible solid pharmaceutical composition comprising Ivabradine which is characterised in that it contains Ivabradine or one of the pharmaceutically acceptable salts thereof and granules consisting of co-dried lactose and starch.

EP-2579859 A2 discloses a pharmaceutical composition with modified release comprising Ivabradine adipate and a combination of a water-insoluble and a water-soluble excipient.

Although each of the patents above represents an attempt to provide stable Ivabradine compositions for oral administration, there still remains the need in the art for an oral, robust and stable immediate release composition with enhanced dissolution and stability of drug substance.

SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide an improved stable solid dosage formulation for oral administration containing Ivabradine HQ as an active ingredient, which overcomes the deficiencies of the prior art and avoids polymorphic transformation of the active pharmaceutical ingredient. Further object of the present invention is to provide a film-coated tablet comprising Ivabradine HQ as an active ingredient, which is bioavailable and with sufficient self-life.

A major object of the present invention is the selection of the optimal combination of pharmaceutical acceptable excipients and method of preparation in order to achieve the appropriate dissolution profile and stability for the finished dosage form. Said dosage form affords predictable and reproducible drug release rates in order to achieve better treatment to a patient. A further approach of the present invention is to provide a tablet composition for oral administration comprising Ivabradine which is manufactured through a fast, simple and cost-effective process.

In accordance with the above aspects of the present invention, a pharmaceutical composition for oral administration is provided comprising Ivabradine as an active ingredient in combination with moisture protection excipients and/or low or non- hygroscopic excipients in order to avoid polymorphic transformation.

According to another embodiment of the present invention, a process for the preparation of a stable, solid dosage form for oral administration, containing Ivabradine HQ as an active ingredient in combination with moisture protection excipients and/or low or non- hygroscopic anhydrous excipients is provided, which comprises the following steps:

-Blending active ingredient with excipients of internal phase;

-Adding magnesium stearate;

-Compressing the mixture into a tablet dosage form;

-Applying a film-coating on the core.

Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, a pharmaceutical composition comprising an active ingredient is considered to be "stable" if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions. As already mentioned the main object of the present invention is to provide a stable pharmaceutical composition of Ivabradine HQ for oral administration that avoids polymorphic transformation of the active pharmaceutical ingredient, is simple to manufacture, bioavailable, cost effective and possesses good pharmacotechnical properties.

Two different forms have been studied during development: form IV which is a hemihydrate and form δ with 2.8% water content.

The X-ray diffractogram of polymorph IV comprises characteristic peaks at the following 2 theta (+/- 0.2) angles: 8.8°, 15.6°, 17.1°, 19.9°, 24.2° and 24.5°. The most characteristic peak ofform lVis at 15.5°.

The X-ray diffractogram of polymorph δ comprises characteristic peaks at the following 2 theta (+/- 0.2) angles: 8.1°, 14.7°, 15.1° and 21.9°.

Ivabradine HC1 used in the compositions of the present invention is 2 to 10 weight % of the total weight of the composition. Most preferably is 7 weight % of the total weight of the composition. The excipients were selected with the perspective to enhance dissolution, physicochemical properties and stability of drug substances in the finished dosage form and thus were subjected to compatibility study with the API.

Water can be associated with the drug or the excipients. It can be incorporated during manufacture of the dosage form or acquired from the environment during processing, packaging or storage. Excipients with affinity for moisture might be expected to mitigate moisture sensitivity. Thus, formulations with a substance having a greater affinity for water compared with the drug could mean that moisture in the product is sequestrated by the excipient.

It has been surprisingly found that Ivabradine polymorphic forms do not undergo transformation to the most stable tetrahydrate form in solid compositions comprising moisture protection excipients and/or low or non-hygroscopic anhydrous excipients. Moisture protection excipients have the property of either adsorbing or repelling water in order to protect the active ingredient from moisture and prevent any conversion of Ivabradine polymorphic forms to another polymorfic form. Dimethicone, attapulgite and a specific type of colloidal silicon dioxide (Syloid® FP) were used in the present invention for moisture protection.

Syloid® AL-l/FP is a highly porous with the smallest particle size silica powder. When added to a formulation, the high porosity of Syloid® FP silica is capable of adsorbing a considerable amount of moisture, keeping the product dry and improving the stability. It is effective in amounts up to 20% in a two- step mixing process in which in first mixing it is blended with the active ingredient protecting it from moisture and then mixing with the rest of the excipients. Syloid 244/FP is also highly porous with bigger particle size and is used as glidant. The higher density of Syloid FP silicas, when compared to many fumed colloidal silicas, makes it easier to handle, results in less dust for a cleaner production environment and eliminates the need for sieving prior to usage.

Moisture protection excipients are comprised in the compositions of the present invention in an amount of from 1 to 25 weight % of the total weight of the composition.

Low or non-hygroscopic excipients do not absorb or attract moisture from the surrounding environment. The incorporation of such excipients, for example maltodextrin, copovidone, mannitol spray-dried in Ivabradine solid compositions eliminates the problem of polymorphic transformation over a period of time.

Common diluents, for example lactose anhydrous, mannitol, starlac, microcrystalline cellulose, dextrose and fructose were used in formulation trials in order to enhance flowability and compaction properties of the powder blend.

Disintegrants provide the necessary force to rapture and eventually disintegrate the tablets. Common disintegrants include crospovidone, primojel, sodium starch glycolate, alginic acid, carboxymethylcellulose sodium. Preferably, crospovidone and primojel were used in the present invention. Due to their large swelling capacity in aqueous solution they enhance the force needed to push particles apart within tablet pores exerted by the water, resulting in rapid tablet disintegration.

Binders promote cohesiveness to the powders and improve their processability. Common binders include carbomer, ethyl cellulose, gelatin, guar gum, hydroxyethyl cellulose, maltodextrin, copovidone. Preferably, maltodextrin and copovidone were used in the present invention.

Colloidal silicon dioxide was used as glidant in order to improve flow properties of the powder blend and magnesium stearate was used in formulations as lubricant to prevent any sticking during compression.

The tablets of the present invention may be optionally film-coated with an immediate release coating preparation which has no effect on the release of the active ingredient. Such coating may have no functionality such as Opadry® Π or it may confer moisture protection to the composition such as Opadry® AMB.

Both direct compression and wet granulation method were tested in manufacturing process.

Wet granulation using substantial amounts of wetting agent is the method which is most commonly used in pharmaceutical industry, as it provides better prospects in terms of ease of processing and presumably less problems associated with physical characteristics of various ingredients in the formulation.

Direct compression is more economic over wet granulation since it requires fewer unit operations. This means less equipment, lower power consumption, less space, less time and less labor leading to reduced production cost of tablets. The tablets prepared by direct compression disintegrate into API particles instead of granules that directly come into contact with dissolution fluid and exhibits comparatively faster dissolution.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention. Composition 1 2 3 4 5 6 7 8

% w/w

Internal phase

Ivabradine HC1 6.74 6.74 6.74 6.74 6.74 6.74 6.74 6.74

Lactose anhydrous - - 77.77 - 81.26 77.26 85.26 64.26

Maltodextrin 5.00 5.00 8.00 5.00 5.00 5.00 - -

Copovidone - - - - - - 2.00 2.00

Crospovidone - 5.00 5.00 5.00 5.00 5.00 5.00 5.00

Starlac 81.26 81.26 - - - - - -

Primojel 5.00 - - - - - - -

Mannitol spray-dried - - - 81.26 - - - -

Dimethicone - - - - 1.00 - - -

Attapulgite - - - - - 5.00 - -

Syloid AL-l/FP - - - - - - - 20.00

Syloid 244/FP - - - - - - - 1.00

Colloidal silicon dioxide 1.00 1.00 1.00 1.00 - - - -

External phase

Magnesium stearate 1.00 1.00 1.5 1.00 1.00 1.00 1.00 1.00

Total 100.00

Compositions 1 to 8 were prepared with two different polymorphic forms of Ivabradine, form IV and form δ.

Composition 1 was prepared with dry and wet granulation using starlac as diluent which is a co-dried mixture of lactose monohydrate with starch. Also, maltodextrin and primojel were used as binder and disintegrant respectively.

Composition 1 was prepared through dry granulation process according to the following steps:

-Mixing Ivabradine HC1 with starlac;

-Addition of the rest of internal phase excipients and mixing;

-Addition of magnesium stearate and mixing for 3 min; -Compression in tablets;

-Film-coating of the tablets.

Composition 1 was also prepared through wet granulation process according to the following steps:

-Mixing Ivabradine HQ with starlac;

-Addition of the rest of internal phase excipients and mixing;

-Kneading with water and then drying at 40°C;

-Addition of magnesium stearate to the granules and mixing for 3 min;

-Compression in tablets;

-Film-coating of the tablets.

The physical characteristics (hardness, disintegration) and the dissolution profile of Composition 1 obtained through both dry and wet granulation were not the desirable.

In Composition 2 crospovidone was used as disintegrant instead of primojel and the physical properties were tested again for both dry and wet granulation.

Composition 2 was prepared with the same processes as Composition 1.

Comparing physical characteristics of Compositions 1 and 2 (with both processes), it was decided to proceed with crospovidone since it provides better physical properties.

Tablets of Composition 1 and 2 with both polymorphs were packed in several blister types like Aluminum, PVC and triplex (PVC/PE/PVDQ as well as HDPE bottles with mounted desiccant and closed under nitrogen and the stability of the active ingredient's solid state was studied under normal (25°C/ 60% RH) and accelerated conditions (40°C/ 75% RH) through XRD analysis. According to the results, when wet granulation process was applied both polymorphs were converted to some extent to the most stable form β (tetrahydrate) at zero time since water is incorporated in the manufacturing process. Dry formulations were stable in all packages under normal conditions but under accelerated conditions they converted to some extent to form β after 3 months in Aluminum blister and bottle and completely convert to form β in FVC and triplex blister. In order to stabilize the polymorph several compositions have been prepared using dry mixing process with anhydrous excipients that are not hygroscopic and/or have very low moisture content.

In Composition 3 starlac was replaced by lactose anhydrous which has very low moisture content and is used with moisture sensitive drug substances. Also, it has very good flow properties and can be used in direct compression processes.

Composition 3 was prepared according to the following manufacturing process:

-Mixing Ivabradine HC1 with lactose anhydrous;

-Addition of the rest of internal phase excipients and mixing;

-Addition of magnesium stearate and mixing for 3 min;

-Compression in tablets;

-Film-coating of the tablets. Composition 4 was prepared with mannitol spray-dried as diluent which is non-hygroscopic and is commonly used with moisture sensitive drugs.

Composition 4 was prepared according to the following manufacturing process:

-Mixing Ivabradine HQ with mannitol spray-dried;

-Addition of the rest of internal phase excipients and mixing;

-Addition of magnesium stearate and mixing for 3 min;

-Compression in tablets;

-Film-coating of the tablets. Both Compositions 3 and 4 provided rapid dissolution profiles and good physical characteristics of the tablets. Physical and chemical stability of Compositions 3 and 4 was tested after 6 months storage under normal (25°C/60% RH) and accelerated conditions (40°C/75%RH). The X-ray diffractograms indicated that Compositions 3 and 4 with both crystal forms were stable after 6 months storage under accelerated conditions in Aluminum blister and HDPE bottle. In the other blister types (PVC and triplex) the characteristic peaks of each form were not detected thus concluding that conversion to another polymorph took place. In particular, the most characteristic peak of form IV is at 15.5° which was detected in Compositions 3 and 4 only in Aluminum blister and HDPE bottle. In form δ the characteristic peaks are at 8.1°, 14.7°, 15.1° and 21.9° and were also present in Compositions 3 and 4 only in Aluminum blister and HDPE bottle.

Further compositions were prepared with moisture protection excipients that prevent any conversion of the polymorphic forms to the tetrahydrate form.

Composition 5 was prepared using lactose anhydrous as diluent and dimethicone as water repellent in an amount of 1%. In Composition 6 attapulgite was used as water adsorbent in an amount of 5% and again lactose anhydrous as diluent.

Compositions 5 and 6 were prepared with the same process as Composition 3.

As physical characteristics, hardness and disintegration, of Compositions 5 and 6 were not the desirable, it was decided to use in Composition 7 copovidone as binder instead of maltodextrin since it is less hygroscopic.

Composition 7 was prepared with the same process as Composition 3.

Finally, in Composition 8 a specific type of colloidal silicon dioxide, Syloid® FP was used for moisture protection.

Composition 8 was prepared according to the following manufacturing process:

-Mixing Ivabradine HQ with Syloid AM /FP;

-Addition of lactose anhydrous, copovidone, crospovidone and Syloid 244/FP and mixing; -Addition of magnesium stearate and mixing for 3 min;

-Compression in tablets;

-Film-coating of the tablets. Tablets of Composition 5 to 8 have been also tested for their physical and chemical stability under normal (25°C/60%RH) and accelerated conditions (40°C/75%RH).

The polymorphic forms were stable in Aluminum blister and HDPE bottle. In the other blister types (PVC and triplex) the characteristic peaks of each form were not detected thus concluding that conversion to another polymorph took place.

While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and scope thereof, as defined in the appended claims.

Claims

1. A pharmaceutical composition for oral administration comprising Ivabradine HC1 polymorph IV or δ in combination with moisture protective excipients and/or low or non- hygroscopic anhydrous excipients in order to avoid polymorphic transformation of the active ingredient.

2. The pharmaceutical composition according to claim 1, wherein the active ingredient is Ivabradine HQ polymorph IV or δ.

3. The pharmaceutical composition according to any preceding claim, wherein Ivabradine HQ is 2 to 10 weight % of the total weight of the composition.

4. The pharmaceutical composition according to any preceding claim, wherein the moisture protective excipients are selected from dimethicone, attapulgite, high density silica.

5. The pharmaceutical composition according to claim 4, comprising moisture protective excipients in an amount of from 1 to 25 weight % of the total weight of the composition.

6. The pharmaceutical composition according to any preceding claim, wherein the low or non-hygroscopic anhydrous excipients are selected from lactose anhydrous, maltodextrin, copovidone, crospovidone.

7. The pharmaceutical composition according to any preceding claim, wherein it further comprises other optional pharmaceutical acceptable excipients such as lubricants and/or glidants.

8. The pharmaceutical composition according to any preceding claim, wherein it is in the form of immediate release tablets.

9. The pharmaceutical composition according to claim 8, wherein tablets are packed in aluminum blister or HOPE bottle s .

10. A process for the preparation of a pharmaceutical composition for oral administration comprising Ivabradine HQ polymorph IV or δ as the active ingredient in combination with moisture protective excipients and/or low or non-hygroscopic anhydrous excipients to avoid polymorphic transformation of the active ingredient is provided, which comprises the following steps:

-Blending API with excipients of internal phase; -Adding magnesium stearate; -Compressing the mixture into a tablet dosage form; -Applying a film-coating on the core.

11. The process according to claim 10, wherein the active ingredient is Ivabradine HQ polymorph IV or δ.

12. The process according to claim 10, wherein Ivabradine HQ is 2 to 10 weight % of the total weight of the composition.

13. The process according to claim 10, wherein the moisture protective excipients are 1 to 25 weight % of the total weight of the composition.