DESC:STABLE PHARMACEUTICAL COMPOSITION OF IBRUTINIB

FIELD OF INVENTION
Present invention relates to a stabilized composition of Ibrutinib in an amorphous form, comprising ibrutinib, a hydrophilic polymer selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone and hydroxypropylcellulose, and a carrier selected from silicon dioxide and magnesium aluminometasilicate and one or more pharmaceutically acceptable excipient. Invention also relates to process of preparation of said pharmaceutical composition and its use in the treatment of mantle cell lymphoma, B-cell proliferative disorders and other auto-immune/ heteroimmune diseases.

BACKGROUND OF INVENTION:
Ibrutinib, 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one, also known as PCI-32765, a specific B-cell tyrosine kinase inhibitor, is approved as 140 mg capsule for treatment of Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, Waldenstrom's Macroglobulinemia and related B-cell proliferative disorders and conditions.

Prior art discloses composition of Ibrutinib and its preparation, for example, in US20130338172 capsules of Ibrutinib are prepared by blending Ibrutinib and excipients. Patent application also discloses various crystalline form and amorphous form of Ibrutinib.

WO 2015071432 discloses capsule comprising ibrutinib with sugar or sugar alcohol and a hydrophilic polymeric excipient, prepared by filling either blend/mixture of Ibrutinib and excipients or granules of ibrutinib prepared by wet granulation process.

WO2016022942 discloses to prepare solid dispersion of Ibrutinib (amorphous form) with polymers, specifically HPMCAS, Soluplus and PVA-VA, to improve dissolution profile and 2-9 times higher drug exposure in pk studies as compared to capsule formulation of prior art, which is prepared by filling granules/blend of Ibrutinib and excipients. Solid dispersion is prepared by using equal or more amount of polymer vs amount of API.

It is known that amorphous form of any drug are generally more soluble and thus are expected to provide higher bioavailability, as shown in prior art WO2016022942 for Ibrutinib, but amorphous form is generally less stable and therefore, when formulated as solid dispersion or pre-mix with polymer, it improves its stability.

With aim of providing a composition of ibrutinib that provides enhanced solubility, rapid onset of action and an enhanced bioavailability, a recent publication WO2016088074 aims to provide a stable composition comprising amorphous Ibrutinib which is prepared by dissolving Ibrutinib with polymer such as PVP, HPMC or HPC in 1:1 ratio.

Thus, according to prior art, solid dispersion of Ibrutinib gives high exposure or high bioavailability but high exposure of drug generally tends to concentration dependent undesirable effects also.

Additionally, it was observed that, Ibrutinib has low bulk density and has tendency of agglomeration, thus creates problem in handling it during processing.

Therefore, there exists a challenge to prepare a composition of Ibrutinib comprising amorphous form which remains bioequivalent to marketed formulation.

Present invention thus provides a stable composition comprising ibrutinib in amorphous form, which not only helps in resolving processing challenge such as poor flow, agglomeration problem, but also provides drug exposure equivalent to the marketed product Imbruvica®.

SUMMARY OF THE INVENTION
One aspect of the present invention is to provide an amorphous solid dispersion comprising Ibrutinib, a hydrophilic polymer selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone and hydroxypropylcellulose, and a carrier selected from silicon dioxide and magnesium aluminometasilicate, wherein Ibrutinib and hydrophilic polymer are present in a ratio of 1:0.1 to 1:0.9.

Another aspect of the present invention is to provide a solid oral composition comprising an amorphous solid dispersion of Ibrutinib and one or more pharmaceutically acceptable excipient(s).

Another aspect of the present invention is to provide a process of preparation of amorphous solid dispersion of ibrutinib, comprising:
a) Providing a solution or suspension of ibrutinib a hydrophilic polymer selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone and hydroxypropylcellulose, and a carrier selected from silicon dioxide and magnesium aluminometasilicate in a suitable solvent, wherein Ibrutinib and hydrophilic polymer are present in a ratio of 1:0.1 to 1:0.9.
b) Removing solvent from solution or suspension of step (a).

Another aspect of the present invention is to provide a process of preparation of pharmaceutical composition comprising amorphous solid dispersion of ibrutinib, comprising:
a) Providing a solution or suspension of ibrutinib a hydrophilic polymer selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone and hydroxypropylcellulose, and a carrier selected from silicon dioxide and magnesium aluminometasilicate in a suitable solvent, wherein Ibrutinib and hydrophilic polymer are present in a ratio of 1:0.1 to 1:0.9.
b) Removing solvent from solution or suspension of step (a).
c) Optionally drying the mixture obtained in step (b)
d) Adding or mixing one or more pharmaceutically acceptable excipient(s) with mixture obtained in step (b) or (c) to prepare a blend
e) Optionally filling the blend of step (d) in a capsule or compressing to form tablet.

DETAILED DESCRIPTION OF THE INVENTION
A specific B-cell tyrosine kinase inhibitor, Ibrutinib targets B-cell proliferative disorders and is indicated in treatment of Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, Waldenstrom's Macroglobulinemia and other auto-immune/ heteroimmune diseases.

Present invention provides a stable solid oral composition, specifically in the form of capsule comprises solid dispersion of Ibrutinib and one or more pharmaceutically acceptable excipient(s), having desired dissolution profile and content uniformity, wherein said formulation provides a bioequivalent composition to marketed capsule form.

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.

Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have” and "include" and variations such as "comprises", "comprising", “having”, "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

The term “Ibrutinib” herein is used in context of a specific B-cell tyrosine kinase inhibitor, including its pharmaceutically acceptable salts, pharmacologically active metabolites and its polymorphs. Preferably, “Ibrutinib” is in an amorphous form.

The term “solid dispersion” as used herein means dispersion of Ibrutinib in a matrix of a pharmaceutically acceptable excipient. Solid dispersion can be alternatively referred as “premix”.

One embodiment of present invention provides an amorphous solid dispersion comprising Ibrutinib, a hydrophilic polymer selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone and hydroxypropylcellulose and a carrier selected from silicon dioxide and magnesium aluminometasilicate, wherein Ibrutinib and hydrophilic polymer are present in a ratio of 1:0.1 to 1:0.9.

Preferably, ratio of Ibrutinib to hydrophilic polymer according to present invention is 1: 0.9, most preferably ratio is 1:0.5.

Hydrophilic polymer according to present invention is about 20 to 30% by weight of total weight of solid dispersion. Preferably, hydroxypropylmethylcellulose is about 20-30% by weight of total weight of solid dispersion.

Silicon dioxide used according to present invention include colloidal silicon dioxide, light anhydrous silicic acid or fumed silica. Silicon dioxide or magnesium aluminometasilicate, according to present invention is about 10- 25% of total weight of solid dispersion. Preferably, colloidal silicon dioxide is about 15-18% by weight of solid dispersion. Ratio of Ibrutinib to silicon dioxide/ magnesium aluminometasilicate according to present invention is from 1: 0.1 to 1: 0.5, preferably ratio is 1: 0.3.

Another embodiment of the present invention provides a process of preparation of amorphous solid dispersion of ibrutinib, comprising:
a) Providing a solution or suspension of ibrutinib, a hydrophilic polymer selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone and hydroxypropylcellulose, and a carrier selected from silicon dioxide and magnesium aluminometasilicate in a suitable solvent, wherein Ibrutinib and hydrophilic polymer are present in a ratio of 1:0.1 to 1:0.9.
b) Removing solvent from solution or suspension of step (a).

Solution or suspension of ibrutinib, a hydrophilic polymer and a carrier selected from silicon dioxide and magnesium aluminometasilicate can be prepared in any suitable solvent selected from water, alcohols such as methanol, ethanol, butanol, isopropanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, ?,?-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide; sulfoxides, such as dimethylsulfoxide; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, or chlorobenzene; or any mixtures of two or more solvents thereof. Preferably alcohol, most preferably methanol, is used for preparation of solution or suspension of step a). Term “suspension” as used herein include mixture of solvent and at least one hydrophilic polymer and/or a carrier according to present invention, wherein said polymer or carrier is not completely dissolved in solvent, and remain suspended or dispersed.

Any suitable process can be used for removal of solvent of step b) such as solvent evaporation, spray drying, freeze drying, thin film drying etc, providing a dried or semi-dried mixture/dispersion. Preferably, rotatory solvent evaporation or spray drying technique is employed for removal of solvent. Alternatively, solution or suspension of step (a) can be sprayed on pharmaceutical excipient(s), and thus after removal of solvent, may result in adsorbate. Optionally, obtained material of step b) can be further dried.

Another aspect of the present invention is to provide a solid oral composition comprising an amorphous solid dispersion of Ibrutinib and one or more pharmaceutically acceptable excipient.

Amount of solid dispersion present in solid oral composition of present invention ranges from 60%-85%, preferably 70%-80% of total composition.

A pharmaceutically acceptable excipient according to present invention comprises at least one excipient selected from diluent, surfactant, disintegrant and lubricant. Said composition can be prepared by either mixing or blending solid dispersion and one or more said excipients and filling it in capsule or alternatively, solid dispersion composition can be granulated with one or more excipients to prepare a blend to fill in a capsule.

A solid oral composition according to present invention surprisingly provides dissolution profile same as marketed formulation of Imbruvica®. Additionally, present invention also resolved the problem of agglomeration of Ibrutinib and improves stability of the composition.

Another embodiment of the present invention provides a process of preparation of pharmaceutical composition comprising amorphous solid dispersion of ibrutinib, comprising:
a) Providing a solution or suspension of ibrutinib, a hydrophilic polymer selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone and hydroxypropylcellulose, and a carrier selected from silicon dioxide and magnesium aluminometasilicate in a suitable solvent, wherein Ibrutinib and hydrophilic polymer are present in a ratio of 1:0.1 to 1:0.9.
b) Removing solvent from solution or suspension of step (a).
c) Optionally drying the mixture obtained in step (b)
d) Adding or mixing one or more pharmaceutically acceptable excipient(s) with mixture obtained in step (b) or (c) to prepare a blend
e) Optionally filling the blend of step (d) in a capsule or compressing to form tablet.

Compositions according to present invention may optionally further comprises one or more glidant, coloring agent, flavoring agent, preservatives, antioxidants and the like. Example and suitable amount of said optional excipient is known to a skilled person or as given in Handbook of pharmaceutical excipients (sixth edition, 2009).

Diluent according to present invention includes powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, dibasic calcium phosphate, tribasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, calcium carbonate, magnesium carbonate, calcium bicarbonate, magnesium bicarbonate magnesium oxide, calcium sulfate; sugars such as dextrose, lactose, fructose or sucrose, maltose maltodextrin; sugar alcohols such as mannitol, sorbitol, xylitol, lactitol, maltitol or erythritol; dextrin, kaolin and mixtures thereof. The diluent may be present in an amount ranging from 2 % to 30 % by weight of the composition. Preferably microcrystalline cellulose or silicified microcrystalline cellulose is present in an amount ranging from 2 % to 15 % by weight of the composition.

Disintegrant according to present invention 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, microcrystalline or microfine or powdered cellulose, silicified microcrystalline cellulose, sodium alginate; starch derivatives such as maize starch, rice starch, pregelatinized starch; cross-linked N-vinyl-2-pyrrolidone ("CLPVP") (marketed under the trade names Polyplasdone® XL and Polyplasdone® XL-10), sodium starch glycollate, low substituted hydroxypropyl cellulose and mixtures thereof. Pharmaceutical composition comprises disintegrant in the amount of 1 % to 10.0 % by weight of the total composition. Preferably cross-linked carboxymethyl cellulose sodium is present in an amount ranging from 4 % to 8 % by weight of the composition.

Surfactant according to present invention 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®; various oils, such as castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, almond oil; various polyols, such as glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol and pentaerythritol; 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; d-[alpha]- tocopheryl polyethylene glycol 1000 succinate and d-[alpha]-tocopherol acid salts such as succinate, acetate; dioctyl sodium sulfosuccinate, etc; or mixtures thereof. The surfactant may be present in an amount ranging from 0.5% to 10% by weight of the composition. Preferably, sodium lauryl sulfate is present in an amount ranging from 2% to 6% by weight of the composition.

Lubricant according to present invention include metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, sodium stearyl fumerate hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc and mixture thereof. The lubricant may be present in an amount ranging from about 0.1 % to about 2% by weight of the composition. Preferably, magnesium stearate is present in an amount ranging from 0.2% to 1% by weight of the composition.

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 capsule.

Another embodiment of present invention provides use of the composition prepared according to present invention for treatment of Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, Waldenstrom's Macroglobulinemia.

The invention will be further illustrated by the following examples, however, without restricting its scope to these embodiments.

Example 1
Solid dispersion

S. No. Ingredients % W/W
1 Ibrutinib 43.12
2 Hydroxypropyl methylcellulose 3 cps 21.56
3 Colloidal silicon dioxide 12.87
Total 77.55

Ibrutinib was dissolved in the methanol under stirring, followed by addition of HPMC. Colloidal silicon dioxide was added slowly under stirring into the solution to prepare dispersion which was transferred in a round bottom flask and dried under vacuum at temperature 45 °C in rotary evaporator.

Composition
S. No. Ingredients % W/W
1 Solid dispersion 77.55
2 Silicified Microcrystalline cellulose SMCC 90HD 10.71
3 Sodium Lauryl Sulphate 4.29
4 Croscarmellose Sodium 6.97
5 Mg Stearate 0.48
Total 100.00

Solid dispersion, microcrystalline cellulose and croscarmellose sodium were mixed to form a blend which was lubricated with Magnesium stearate and final blend was filled in capsule.

Example 2
Solid dispersion

S. No. Ingredients % W/W
1 Ibrutinib 43.12
2 Hydroxypropyl methylcellulose 3 cps 21.56
3 Magnesium aluminometasilicate 12.87
Total 77.55

Ibrutinib was dissolved in the methanol under stirring, followed by addition of HPMC. Magnesium aluminometasilicate was added slowly under stirring into the solution to prepare dispersion which was transferred in a round bottom flask and dried under vacuum at temperature 45 °C in rotary evaporator.

Example 3
Solid dispersion

S. No. Ingredients % W/W
1 Ibrutinib 42.42
2 Hydroxypropyl methylcellulose 3 cps 21.21
3 Colloidal silicon dioxide 12.72
Total 76.35

Composition
S. No. Ingredients % W/W
1 Solid dispersion 76.35
2 Silicified Microcrystalline cellulose SMCC 90HD 11.89
3 Sodium Lauryl Sulphate 4.29
4 Croscarmellose Sodium 6.97
5 Mg Stearate 0.48
Total 100.00

Solid dispersion and composition of Example 3 were prepared according to the process described in example 1.
Dissolution test was performed for marketed formulation and composition prepared in example 3.
Dissolution test was performed using USP Type-II apparatus at 75 RPM.
Dissolution media used was 900 mL of Polysorbate 20 in 50mM phosphate buffer, pH 6.8.

% Drug Release
Time (Min) Imbruvica|®
L0501370A1 Example 3
0 0 0
5 56.2 45.5
10 77.3 75.2
15 84.3 83.1
20 88.5 87.9
30 93 90.7
45 96.2 91.7

Observation:
Dissolution profile of example 3 composition prepared according to the present invention was found to be comparable to the marketed formulation.
,CLAIMS:We Claim:
1. An amorphous solid dispersion comprising Ibrutinib, a hydrophilic polymer selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone and hydroxypropylcellulose, and a carrier selected from silicon dioxide and magnesium aluminometasilicate, wherein Ibrutinib and hydrophilic polymer are present in a ratio of 1:0.1 to 1:0.9.
2. The amorphous solid dispersion according to claim 1, where Ibrutinib and hydrophilic polymer are present in a ratio of 1:0.5.
3. The amorphous solid dispersion according to claim 1, where Ibrutinib and silicon dioxide and/or magnesium aluminometasilicate are present in a ratio of 1:0.1 to 1:0.5, preferably 1:0.3.
4. The amorphous solid dispersion according to claim 1 or 3, wherein silicon dioxide or magnesium aluminometasilicate is about 10- 25% of total weight of solid dispersion.
5. The amorphous solid dispersion according to claim 1 or 2, wherein hydrophilic polymer is about 20 to 30% by weight of total weight of solid dispersion.
6. A solid oral composition comprising an amorphous solid dispersion of Ibrutinib according to any of the preceding claims and one or more pharmaceutically acceptable excipient(s).
7. The solid oral composition of claim 6, wherein pharmaceutically acceptable excipient is selected from diluent, surfactant, disintegrant and lubricant.
8. The solid oral composition according to claim 6, wherein solid dispersion of ibrutinib is present in an amount ranging from 60-85 % w/w, preferably 70-80 % w/w of total composition.
9. A process for preparation of amorphous solid dispersion of ibrutinib, comprising:
a) Providing a solution or suspension of ibrutinib a hydrophilic polymer selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone and hydroxypropylcellulose, and a carrier selected from silicon dioxide and magnesium aluminometasilicate in a suitable solvent, wherein Ibrutinib and hydrophilic polymer are present in a ratio of 1:0.1 to 1:0.9.
b) Removing solvent from solution or suspension of step (a).
10. A process for preparation of pharmaceutical composition comprising amorphous solid dispersion of ibrutinib, comprising:
a) Providing a solution or suspension of ibrutinib a hydrophilic polymer selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone and hydroxypropylcellulose, and a carrier selected from silicon dioxide and magnesium aluminometasilicate in a suitable solvent, wherein Ibrutinib and hydrophilic polymer are present in a ratio of 1:0.1 to 1:0.9.
b) Removing solvent from solution or suspension of step (a)
c) Optionally drying the mixture obtained in step (b)
d) Adding or mixing one or more pharmaceutically acceptable excipient(s) with mixture obtained in step (b) or (c) to prepare a blend
e) Optionally filling the blend of step (d) in a capsule or compressing to form tablet.