DESC:FIELD OF INVENTION
Present invention relates to a stable solid oral composition comprising (a) Ivabradine or pharmaceutically acceptable salt thereof, optionally one or more pharmaceutical excipient(s) and (b) inert granules comprising one or more diluent, one or more cellulosic binder and optionally one or more pharmaceutical excipient(s), wherein said inert granules are substantially free of Ivabradine or pharmaceutically acceptable salt thereof. The present invention also relates to a solid oral composition comprising inert granules obtainable by granulating one or more diluent, one or more cellulosic binder and optionally one or more pharmaceutically acceptable excipient(s) and mixing/adding Ivabradine or pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipient(s) with said inert granules.

BACKGROUND
Ivabradine hydrochloride is chemically, 2 3-(3-{[((7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7¬ yl)methyl] methyl amino} propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one hydrochloride, having following structure
. HCl

Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that reduces the spontaneous pacemaker activity of the cardiac sinus node by selectively inhibiting the If ¬ current (If), resulting in heart rate reduction. It is approved in USA and EU as Corlanor® and Procoralan® respectively.
It is reported in prior art that Ivabradine hydrochloride exists in various polymorphic form such as beta form (EP1695965), alpha form (EP1589005), gamma form (EP1707562), Form Z, X and K (EP2534135), zeta form (WO2012025940) etc, which are characterized by XRPD.
Alternate to crystalline forms, amorphous form of Ivabradine hydrochloride is disclosed in WO2008146308. WO2011098582, WO2011157722, WO2015078845 and WO2015091992 disclose to prepare solid dispersion or solid solution of Ivabradine hydrochloride with various excipients to stabilize amorphous form.
The polymorphs of the Ivabradine are not sufficiently stable under all conditions, which can lead to problems in the processing as well as the storage of the product. This may also lead to undesired reactions with the excipients employed in the preparation of the pharmaceutical composition which results in unacceptable amount of impurity in the drug product.
Prior art also suggests to prepare composition, for example, WO2015001569 discloses compositions of Ivabradine Hydrochloride with Form II prepared using direct compression, and WO 2013064307 discloses composition of Ivabradine Hydrochloride with Form IV prepared using wet granulation and direct compression. WO2009124940 discloses another approach of preparation of HBr salt of Ivabradine and preparing its composition.
WO2014030113 and EP2774606 disclose oxygen and/or water impermeable pack material to stabilize Ivabradine or its compositions.
Additionally, it was observed that Ivabradine polymorphs also have problem of sticking, which result in poor flow and weight variation.
Despite of various prior art availability to stabilize polymorphic form and to control impurity of Ivabradine hydrochloride, still there is a need for a formulation which can be prepared by considerably avoiding material handling of Ivabradine or its blend with excipients and processing challenge.
Present invention provides a stable solid oral composition which helps in resolving processing challenge such as poor flow of blend, sticking problem associated with it and reducing weight variation issues. Additionally, composition according to present invention overcomes issue of stability of polymorphic form of Ivabradine.

SUMMARY OF THE INVENTION
One aspect of the present invention is to provide a solid oral composition comprising (a) Ivabradine, optionally one or more pharmaceutical excipient(s) and (b) inert granules comprising one or more diluent, one or more cellulosic binder and optionally one or more pharmaceutical excipient(s), wherein said inert granules are substantially free of Ivabradine.
Another aspect of present invention is to provide a solid oral composition comprising inert granules obtainable by granulating one or more diluent, one or more cellulosic binder, and optionally one or more pharmaceutically acceptable excipient(s) and adding/mixing Ivabradine and optionally one or more pharmaceutically acceptable excipient(s) with said inert granules.
Another aspect of present invention is to provide a process of preparation of solid oral composition comprising of
(a) Granulating one or more diluent, one or more cellulosic binder, and optionally one or more pharmaceutically acceptable excipient(s) to prepare inert granules
(b) Mixing/adding Ivabradine and optionally one or more pharmaceutically acceptable excipient(s) with said inert granules prepared in step (a).

FIGURES
Fig 1a: Morphology of tablet prepared according to Example 1
Fig 1b: Morphology of tablet prepared according to Comparative example

DETAIL DESCRIPTION OF THE INVENTION
The following paragraphs detail various embodiments of the invention. For the avoidance of doubt, it is specifically intended that any particular feature(s) described individually in any one of these paragraphs (or part thereof) may be combined with one or more other features described in one or more of the remaining paragraphs (or part thereof). In other words, it is explicitly intended that the features described below individually in each paragraph (or part thereof) represent important aspects of the invention that may be taken in isolation and combined with other important aspects of the invention described elsewhere within this specification as a whole, and including the examples and figures. The skilled person will appreciate that the invention extends to such combinations of features and that these have not been recited in detail here in the interests of brevity.
The use of the terms “a” and "an” and "the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
The term “Ivabradine” as used herein includes Ivabradine free base, its pharmaceutically acceptable salt, its polymorphs or its hydrate. Preferably, Ivabradine is Ivabradine hydrochloride(HCl). Ivabradine HCl can be crystalline form with polymorphic characterization as beta form (EP1695965), alpha form (EP1589005), gamma form (EP1707562), Form Z, X and K (EP2534135), zeta form (WO2012025940), Form IV (WO 2013064307), Form II (WO2013102919), or amorphous form; all documents are cited herein as reference. Average particle size (D50) of Ivabradine or its pharmaceutical acceptable salt used according to present invention ranges from 1 micron to 100 microns as measured by Malvern Mastersizer® 2000.
The term “inert granule” as used herein means granules, beads or pellets wherein Ivabradine or any other active pharmaceutical ingredient is not added during processing. The term excludes the active pharmaceutical ingredient which is adsorbed or absorbed inside the said first inert component after its preparation.
The term “substantially free” as used herein means less than 30% of Ivabradine is present in the inert granules. Preferably, less than 10%, most preferably less than 1% of Ivabradine is present in the inert granules.
The term “w/w” as used herein means weight of component by total weight of composition, unless specified otherwise.
The term “about” when used in reference to a particular recited numerical value, means variation in value up to ±10%.
The term “adding” “added” “mixing” or “mixed” as used herein are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply mixing, adding one or more excipient with each other or with inert granules or with Ivabradine to form mixture or blend.
The first embodiment of the present invention provides a solid oral composition comprising (a) Ivabradine, optionally one or more pharmaceutical excipient(s) and (b) inert granules comprising one or more diluent, one or more cellulosic binder and optionally one or more pharmaceutical excipient(s), wherein said inert granules are substantially free of Ivabradine.
Another embodiment of the present invention provides a solid oral composition comprising (a) Ivabradine, one or more disintegrant, one or more glidant and/or one or more lubricant and (b) inert granules comprising one or more diluent, one or more binder and one or more disintegrant, wherein said inert granules are substantially free of Ivabradine.
While preparing composition according to prior art, for example using direct compression method, poor flow and sticking was observed. However, surprisingly it was noticed that compositions prepared according to present invention solved these issues and less weight variation was observed in the compositions. Additionally, compositions prepared according to present invention resulted in stable product with less impurity.
A preferred embodiment of present invention provides a solid oral composition comprising (a) Ivabradine, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate (b) inert granules comprising one or more diluent, one or more cellulosic binder and one or more disintegrant, wherein said inert granules are substantially free of Ivabradine.
Another preferred embodiment of present invention provides a solid oral composition comprising (a) about 6.5% w/w of Ivabradine HCl, about 0.80% w/w of colloidal silicon dioxide, about 2.80% w/w of croscarmellose sodium and about 0.8% w/w of magnesium stearate (b) inert granules comprising about 81.00% w/w of lactose monohydrate, about 1.50% w/w of hydroxyl propyl cellulose and about 2.80% w/w of croscarmellose sodium, wherein said inert granules are substantially free of Ivabradine.
The solid oral composition prepared according to any of the embodiment as described herein has average particle size of inert granules of less than 400 microns. This particle size is measured by sieving method. It was observed that the particle size of inert granules of less than 400 microns results in improved flow properties and provides homogenous mixing. Preferably, composition comprises mixture of different size of inert granules. Such mixture comprises mixture of inert granules (A) of size more than 250 microns and inert granules (B) of size less than 250 microns. Such size is measured by sieving method, preferably using 60# size sieve. Granules (A) and (B) are present in the ratio of 50:50, 40:60, 30:70, 20:80, preferably ratio is 10:90.
Inert granules according to present invention are prepared by granulating mixture of one or more diluents preferably lactose monohydrate; and one or more disintegrant preferably croscarmellose sodium with aqueous or non-aqueous solution or suspension of cellulosic binder, preferably aqueous solution of hydroxypropyl cellulose. This component is mixed/added with Ivabradine containing component.
Ivabradine containing component is prepared by mixing Ivabradine, preferably its hydrochloride salt with one or more glidant, preferably colloidal silicon dioxide. Obtained blend is optionally mixed/added with mixture of one or more disintegrant, preferably croscarmellose sodium and one or more glidant, preferably colloidal silicon dioxide.
Composition may suitably comprise one or more lubricant, preferably magnesium stearate.
Present invention also provides process of preparation of composition according to present invention, preferably using direct compression method.
Another embodiment of present invention provides a process of preparation of a composition comprising of:
(a) Granulating one or more diluent, one or more cellulosic binder, and optionally one or more pharmaceutically acceptable excipient(s) to prepare inert granules
(b) Mixing/adding Ivabradine and optionally one or more pharmaceutically acceptable excipient(s) with said inert granules prepared in step (a).
A preferred embodiment of present invention provides a process of preparation of a composition comprising of:
(a) Granulating one or more diluent, one or more cellulosic binder, and one or more disintegrant to prepare inert granules
(b) Mixing/adding Ivabradine and one or more disintegrant, one or more glidant, one or more lubricant with said inert granules prepared in step (a).
(c) Compressing the blend/mixture obtained in step (b).
(d) Optionally, coating the compressed tablet of step (c).

Pharmaceutical excipients used according to present invention may comprises one or more diluent, binder, disintegrant, lubricant, surfactant, glidant and the like.
A diluent according to present invention may include powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate; sugars such as dextrose, lactose (monohydrate or anhydrous) or sucrose; sugar alcohols such as mannitol, sorbitol, xylitol or erythritol; or mixtures thereof. Preferably, diluent is lactose monohydrate or starch. Composition comprises diluent in the amount of 50-98% w/w of the total composition. Preferably, composition comprises about 80-82% w/w of lactose monohydrate.
A binder according to present invention may include polyvinyl pyrrolidone, polyvinyl alcohol, pregelatinised starch; cellulose derivatives such as cellulose powder, microcrystalline cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose; gelatin, zein, polymethacrylates, sodium alginate, gums, synthetic resins or mixtures thereof. Composition comprises binder in the amount of 0.5-20% w/w of the total composition.
A cellulosic binder according to present invention may include cellulose derivatives such as cellulose powder, microcrystalline cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or mixtures thereof. Preferably, composition comprises about 1-2% w/w of hydroxypropyl cellulose as cellulosic binder.
A disintegrant according to present invention may include carboxymethyl cellulose and its salt including sodium or calcium salt, cross-linked carboxymethyl cellulose sodium (Croscarmellose sodium), cross-linked carboxymethyl cellulose calcium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, pregelatinized starch, low substituted hydroxypropyl cellulose, and mixtures thereof. Preferably, disintegrant is croscarmellose sodium. Composition comprises disintegrant in the amount of 0.6 - 8.0% w/w of the total composition. Preferably, composition comprises about 5-6% w/w of croscarmellose sodium. More preferably, inert granules comprise croscarmellose sodium in amount of about 2-4% w/w of total composition.
A surfactant according to present invention may include one or more non-ionic or ionic (i. e., cationic, anionic and Zwitterionic) surfactants suitable for use in pharmaceutical compositions. Suitable surfactants include mono fatty acid esters of polyoxyethylene sorbitan such as those sold under the brand name Tween®; sodium lauryl sulfate, polyoxyethylene castor oil derivatives such as those sold under the brand name Cremophor®, polyethoxylated fatty acids and their derivatives, propylene glycol fatty acid esters, sterol and sterol derivatives; sorbitan fatty acid esters and their derivatives, sugar esters, polyoxyethylene-polyoxypropylene block copolymers such as those sold under the brand name Poloxamer®, soy lecithin, or mixtures thereof. Composition comprises surfactant in the amount of 0.01-7 % w/w of the total composition.
A lubricant according to present invention may include talc, metallic stearate such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, magnesium trisilicate or mixtures thereof. Preferably, lubricant is magnesium stearate. Composition comprises lubricant in the amount of 0.2-2% w/w of the total composition. Preferably, composition comprises about 0.5- 1% w/w of magnesium stearate.
A glidant according to present invention may include talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch and tribasic calcium phosphate or mixture thereof. Preferably, glidant is colloidal silicon dioxide. Composition comprises glidant in the amount of 0.2-2% w/w of the total composition. Preferably, composition comprises about 0.5-1% w/w of colloidal silicon dioxide.

Composition according to present invention may optionally comprise coloring agent, flavoring agent, preservatives, antioxidants and the like. Example and suitable amount of said excipient is known to a skilled person or as given in Handbook of pharmaceutical excipients (sixth edition, 2009).
Compositions prepared according to present invention, comprises Ivabradine, preferably Ivabradine hydrochloride in the amount of 1-10%, preferably about 6-7% w/w of the total composition.
Composition according to present invention may optionally comprise a coating. Coating according to present invention may be functional or non-functional coating, preferably coating is non-functional coating. Non-functional coating comprises a film forming polymer and one or more excipients suitable for said coating such as film former, plasticizer, glidant, opacifier or colorant. Example and suitable amount of said excipient is known to a skilled person or as given in Handbook of pharmaceutical excipients (sixth edition, 2009). Preferably coating comprises hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, magnesium stearate, glycerin and iron oxide (yellow or red).
Solid oral composition according to present invention can be in the form of tablet, capsule, powder or sachet. Preferably solid oral composition according to present invention is film coted tablet.
Another embodiment of present invention provides use of the composition prepared according to present invention for treatment of angina pectoris or heart failure.
The invention will be further illustrated by the following examples, however, without restricting its scope to these embodiments.

Example 1
Name of Ingredient % W/W
Inert granules
Lactose Monohydrate 81.50
Croscarmellose Sodium 2.82
Hydroxy Propyl Cellulose (Klucel-LF) 1.50
Purified Water q.s

Ivabradine Hydrochloride 6.52
Colloidal Silicone Dioxide 0.80
Croscarmellose Sodium 2.82
Magnesium Stearate 0.80
Opadry Beige® 03G570005 3.23
Methylene Chloride q.s
Isopropyl Alcohol q.s
Total 100.00

Lactose monohydrate and 2.82% of croscarmellose sodium were sifted through 40#, and blended in Conta blender for 5 minutes. Obtained blend was loaded in fluidized bed processor (FBP) and granulated using aqueous solution of hydroxypropyl cellulose (Klucel® LF) at the inlet temperature of 60-65°C to prepare inert granules. Obtained inert granules were dried in FBP at inlet temperature of 60-65°C for 30 minutes. Obtained granules were sized using Quadro mill with 457 screen, followed by sifting the granules using 60# sieve (250 microns). Obtained granules (A) having size of more than 250 microns and granules (B) having size of less than 250 microns were mixed in ratio of 10:90.
Separately sifted crystalline Ivabradine hydrochloride and 0.40% of colloidal silicon dioxide (aerosil) through 40# was mixed with mixture of obtained granules (A+ B) and blended for 30 minutes in Conta blender followed by blending with 0.40% colloidal silicon dioxide and croscarmellose sodium mixture for 10 minutes. Magnesium stearate was added to resulted mixture followed by compression. Obtained tablet was coated with Opadry Beige® 03G570005 comprising 72.5 % hydroxypropylmethyl cellulose (Hypromellose), 11.04% of titanium dioxide, 8.5% of polyethylene glycol (MacrogolTM), 5% of magnesium stearate, 2% of glycerin, and 0.78% of iron oxide yellow and 0.18% of iron oxide red, using methylene dichloride and isopropyl alcohol. (All coating weights are % w/w of total coating weight)
Impurity profile of the tablet of Example 1 was checked using HPLC method. The HPLC method included separation using gradient-reverse phase HPLC (Shimadzu - HT2010) with UV detection.
Results are summarized in table 1.

Table 1
Parameters Initial 3 Month
40°C/75% RH
Total impurity 0.07 0.13
Polymorphic Evaluation - Matches with initial; No extra peak observed

Observation: Smooth and even surface of tablet was observed as shown in Fig 1. Moreover, better flow of blend before compression lead to comparatively less weight variation as shown in Table 2.

Comparative Example:
Sr. No Name of Ingredient % W/W
1 Ivabradine Hydrochloride 7.77
2 Lactose Monohydrate 82.13
3 Croscarmellose Sodium 4.81
4 Colloidal Silicone Dioxide 0.48
5 Magnesium Stearate 0.96
Total 96.15
Coating
6 Opadry Beige 03G570005 3.85
7 Methylene Chloride --
8 Isopropyl Alcohol --
Total 100.00

Ivabradine hydrochloride and lactose monohydrate were sifted, and blended in Conta blender for 5 minutes, which was then blended with sifted croscarmellose sodium and colloidal silicon dioxide. Obtained mixture was lubricated using magnesium stearate followed by compression and coating analogous to example 1.
Observation: Tablet morphology is shown in Fig 1b, which shows that because of sticking of blend to the punch, uneven surface of the tablet was observed. Moreover, poor flow of blend lead to comparatively more weight variation as shown in Table 2.

Table 2
Sr. No Wt of tablet – Example 1 Wt of tablet- Comparative Example
1 121.6 116.1
2 120.4 119.5
3 120.3 120.4
4 120.2 122.8
5 120.6 124.6
6 119.8 119.1
7 121.0 118.7
8 119.9 117.6
9 120.9 121.9
10 120.9 123.5
Average 120.56 120.42
Minimum 119.8 116.1
Maximum 121.6 124.6
RSD 0.46 2.27

Example 2
Name of Ingredient % W/W
Inert granules
Lactose Monohydrate 80.84
Croscarmellose Sodium 2.80
Hydroxy Propyl Cellulose (Klucel-LF) 1.49
Purified Water q.s

Ivabradine Hydrochloride 6.47
Colloidal Silicone Dioxide 0.80
Croscarmellose Sodium 2.80
Magnesium Stearate 0.80
Opadry Beige® 03G570005 4.00
Methylene Chloride q.s
Isopropyl Alcohol q.s
Total 100.00

Lactose monohydrate and 2.80% of croscarmellose sodium were sifted through 40#. Obtained blend was loaded in fluidized bed processor (FBP) and granulated using aqueous solution of hydroxypropyl cellulose (Klucel® LF) to prepare inert granules. Obtained inert granules were dried in FBP followed by sifting the granules using 60# sieve (250 microns). Granules (A) having size of more than 250 microns and granules (B) having size of less than 250 microns were separated. Granules (A) were sized using quadro co-mill and mixed with Granules (B) in Conta blender for 5 minutes. Obtained granules were again sifted using 60# sieve (250 microns) and granules (A) having size of more than 250 microns and granules (B) having size of less than 250 microns were separated. Granules (A) were sifted through 30# on vibratory sifter and Granules (B) were divided in 4 equal parts, one part of which was sifted through 40# on Vibratory Sifter.
Second part of granules (B), Crystalline Ivabradine hydrochloride and 0.40% of colloidal silicon dioxide (aerosil) were sifted through 40#. 3rd part of Granules (B) was also sifted through same sieve and added to obtained blend of Ivabradine hydrochloride which was added to the Conta blender having 4th part of Granules (B). Granules (A) were mixed to obtained mixture and sifted for 10 minutes, followed by blending with 0.40% colloidal silicon dioxide and croscarmellose sodium mixture for 10 minutes. Magnesium stearate was added to resulted blend for 5 minutes followed by compression. Coating was done similar to example 1.
,CLAIMS:1. A solid oral composition comprising (a) Ivabradine or pharmaceutically acceptable salt thereof, optionally one or more pharmaceutical excipient(s) and (b) inert granules comprising one or more diluent, one or more cellulosic binder and optionally one or more pharmaceutical excipient(s), wherein said inert granules are substantially free of Ivabradine.

2. The solid oral composition according to claims 1, wherein one or more pharmaceutical excipient of (a) is selected from disintegrant, glidant and lubricant.

3. The solid oral composition according to claims 2, wherein disintegrant is croscarmellose sodium, glidant is colloidal silicon dioxide and lubricant is magnesium stearate.

4. The solid oral composition according to claims 1, wherein one or more pharmaceutical excipient of (b) is selected from disintegrant and diluent.

5. The solid oral composition according to claim 1, wherein average particle size of inert granules is less than 400 microns.

6. The solid oral composition according to claim 1, wherein cellulosic binder is hydroxypropyl cellulose.

7. A solid oral composition comprising (a) about 6.5% w/w of Ivabradine HCl, about 0.80% w/w of colloidal silicon dioxide, about 2.80% w/w of croscarmellose sodium and about 0.8% w/w of magnesium stearate (b) inert granules comprising about 81.00% w/w of lactose monohydrate, about 1.50% w/w of hydroxyl propyl cellulose and about 2.80% w/w of croscarmellose sodium, wherein said inert granules are substantially free of Ivabradine.

8. A process of preparation of a solid oral composition comprising of:
(c) Granulating one or more diluent, one or more cellulosic binder, and optionally one or more pharmaceutically acceptable excipient(s) to prepare inert granules;
(d) Mixing/adding Ivabradine and optionally one or more pharmaceutically acceptable excipient(s) with said inert granules prepared in step (a).

9. A solid oral composition of Ivabradine as substantially described and exemplified herein.