DESC:“ORAL SOLID PHARMACEUTICAL COMPOSITION OF LENVATINIB MESYLATE AND METHOD OF MANUFACTURING THEREOF”

FIELD OF THE INVENTION:
The present invention relates to oral solid dosage pharmaceutical composition of Lenvatinib or a pharmaceutically acceptable salt thereof, preferably in a capsule dosage form wherein the composition comprises amino sugar preferably meglumine or calcium hydroxide with Lenvatinib to provide more stable composition. Further, the present invention discloses the process for preparation of the same. The present invention provides a stable, economical dosage form over existing dosage form.

BACKGROUND OF THE INVENTION:
Lenvatinib a multiple kinase inhibitor having mechanism of action as a receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). It is a nitrogenous aromatic-ring containing compound with potential antineoplastic activity that is used in treatment of advanced, metastatic medullary thyroid cancer and refractory renal cell carcinoma. Lenvatinib is also used in combination with Everolimus to treat adults with advanced renal cell carcinoma (RCC) type of kidney cancer.

Lenvatinib is chemically known as 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide and is structurally represented as below:

Lenvatinib mesylate is a methanesulfonate salt obtained by reaction of Lenvatinib with methanesulfonic acid. Lenvatinib mesylate is indicated for the patients with progressive, locally recurrent or metastatic differentiated thyroid cancer (DTC) that can no longer be treated with radioactive iodine and is progressing.
Structurally, Lenvatinib mesylate is represented as below:

Lenvatinib mesylate

According to the National Cancer Institute, there are over 56,000 new cases of thyroid cancer in the US each year. Females are more likely to have thyroid cancer at a ratio of 3:1. Approximately 1.2 percent of all men and women will be diagnosed with thyroid cancer during the course of their lifetime.

There are three main histologic types of thyroid carcinoma: differentiated, medullary and anaplastic. Differentiated thyroid cancer (DTC), a common thyroid cancer, arises from follicular epithelial cells and accounts around 90% to 95% of total thyroid cancer cases. Lenvatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

US7253286 first disclosed the Lenvatinib and its pharmaceutically acceptable salts and is marketed by EISAI INC. as oral ypromellose hard capsules containing Lenvatinib as mesylate (methanesulfonate) salt in polymorphic ‘Type C’ crystals. In 2015, Lenvatinib was approved by USFDA as LENVIMA® capsule 4 mg and 10 mg for the treatment of differentiated thyroid cancer that has spread to other parts of the body (metastasis) or is locally advanced in adults. LENVIMA® capsule is reported to contain excipients like calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose and talc. In May 2016, the USFDA approved it (in combination with Everolimus) for the treatment of advanced renal cell carcinoma following one prior anti-angiogenic therapy.
Lenvatinib is taken once daily with or without food in the form of a capsule. Lenvatinib is available in 10 and 4 mg capsules. The recommended dose in differentiated thyroid cancer is 14 mg orally once daily and for renal cell carcinoma 10 mg orally once daily.
Lenvatinib is manufactured as a mesylate salt, and has a very low solubility in aqueous solutions. It is very slightly soluble in 0.1M HCl and practically insoluble in pH 3, 5, 7, 9, and 11 solutions, thus it is challenging for formulation scientists to formulate various formulations of Lenvatinib. Further, Lenvatinib mesylate as active ingredient is sometime rendered unstable and degrades under certain conditions like humidity and warm storage conditions when formulated into a pharmaceutical composition. Further, delayed dissolution of the active ingredients may occur due to moisture absorption.
US8969379 mentioned the pharmaceutical composition of Lenvatinib or a pharmaceutically acceptable salt thereof wherein the composition comprises silicic acid or salt or solvate thereof as stabilizing agent with Lenvatinib.
WO2017/028660 discloses a pharmaceutical composition of Lenvatinib or a pharmaceutically acceptable salt thereof wherein the composition comprising of at least one compound of a basic amino sugar or meglumine or calcium hydroxide, and/or at least one selected from potassium carbonate or potassium bicarbonate. The composition lacks microcrystalline cellulose.
However, prior art compositions do not show high dissolution and due to that bioavailability of the drug affected. Further, there are certain side-effects shown of using potassium carbonate and potassium bicarbonate like confusion, uneven heartbeat, unusual tiredness, weakness, heavy feeling in your legs; severe stomach pain cramping.
To overcome such problems, the present invention discloses a novel pharmaceutical composition of Lenvatinib that exclude the excipients including potassium carbonate, potassium bicarbonate, silicic acid or salt or solvate thereof. It is technically advanced and economically improved over existing prior arts without any harmful side effects of such excipients. Further, toxicity or side effects associated with these excipients are avoided and solubility and stability of the active ingredient is increased. So, the present invention composition is having rapid dissolution and good stability, without harmful side-effects associated with certain excipients.

OBJECT OF THE INVENTION:
The primary object of the present invention is to provide an oral pharmaceutical composition of Lenvatinib or a pharmaceutically acceptable salt thereof for oral solid dosage form.
Another object of the present invention is to provide the pharmaceutical composition of Lenvatinib or a pharmaceutically acceptable salt thereof for oral solid dosage form, preferably a capsule dosage form.
Another object of the present invention is to provide the pharmaceutical composition of Lenvatinib or a pharmaceutically acceptable salt thereof wherein amino sugar preferably meglumine or calcium hydroxide is used as stability agent along with Lenvatinib to enhance the stability of the composition.
Another object of the present invention is to provide the pharmaceutical composition of Lenvatinib or a pharmaceutically acceptable salt thereof wherein calcium hydroxide is used as stability agent along with Lenvatinib to enhance the stability of the composition.
Yet another object of the present invention is to provide a pharmaceutical composition of Lenvatinib that provides higher stability of the active ingredient in humidity and warm storage conditions.
Another object of the present invention is to provide an economical and advanced dosage form over existing dosage form with the use of minimal amount of excipients that leads to less side-effects.
Yet another object of the present invention is to provide a pharmaceutical composition of Lenvatinib without the use of stabilizers including potassium carbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, magnesium oxide, calcium oxide, disodium hydrogen phosphate, disodium potassium phosphate, sodium acetate and silicic acid and derivative thereof.
Another object of the present invention is to provide a pharmaceutical composition of Lenvatinib that provides or a pharmaceutically acceptable salt thereof having good dissolution profile with high bio-availability.
Yet another object of the present invention is to provide a novel, easy process for preparation of oral solid dosage pharmaceutical composition of Lenvatinib or a pharmaceutically acceptable salt thereof.
Still another object of the present invention is to provide a pharmaceutical composition comprising Lenvatinib for the use in the treatment of advanced, metastatic medullary thyroid cancer and refractory renal cell carcinoma.
Another object of the present invention is to provide process for the preparation of pharmaceutical composition comprising Lenvatinib with low substituted hydroxypropyl cellulose (L-HPC) and other suitable excipients, which then encapsulated in hard gelatin capsule of size “4” and “1” wherein faster dissolution of the Lenvatinib is obtained in recommended dissolution media.

SUMMARY OF THE INVENTION:
The present invention discloses an oral pharmaceutical composition of Lenvatinib or a pharmaceutically acceptable salt thereof preferably oral solid dosage form of a capsule with pharmaceutically acceptable excipients and method of preparation thereof. The pharmaceutical composition of present invention comprises Lenvatinib mesylate with one or more pharmaceutically acceptable excipients selected from the group comprising of at least one amino sugar or calcium hydroxide, at least one diluent, at least one disintegrant, at least one binder, at least one lubricant, wherein the composition does not comprise of stabilizer like potassium carbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, magnesium oxide, calcium oxide, disodium hydrogen phosphate, disodium potassium phosphate, sodium acetate and silicic acid and derivative thereof.
One preferred embodiment of the present invention comprises Lenvatinib mesylate in amorphous form as an active ingredient along with pharmaceutically acceptable excipients selected from amino sugar meglumine or calcium hydroxide, microcrystalline cellulose, hydroxy propyl cellulose, low substituted HPC and purified talc.
The pharmaceutical composition of the present invention comprises amino sugar preferably meglumine or calcium hydroxide as stability enhancing agent along with the active ingredient Lenvatinib that enhances the stability of the composition.
The pharmaceutical composition of the present invention is devoid of stabilizers including potassium carbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, magnesium oxide, calcium oxide, disodium hydrogen phosphate, disodium potassium phosphate, sodium acetate and silicic acid and derivative thereof.
More preferably, the pharmaceutical composition comprising Lenvatinib according to the present invention may be administered in a solid oral dosage form of a capsule. There are two types of capsules of 4 mg and 10 mg of the present invention pharmaceutical composition.
The pharmaceutical composition according to the present invention is economical and advanced dosage form over existing dosage form. It uses minimal amount of excipients that leads to less side-effects effects.
The present invention also discloses very simple process of preparation of pharmaceutical composition that is time efficient, especially for large-scale production, wherein the pharmaceutical composition shows a desired dissolution profile and higher stability.

DETAILED DESCRIPTION OF THE INVENTION:
The nature of the invention is clearly described in the specification. The invention has various components and they are clearly described in the following pages of the provisional specification. The present invention will now be disclosed by describing certain preferred and optional embodiments, to facilitate various aspects thereof.
The present invention discloses an oral pharmaceutical composition of Lenvatinib or a pharmaceutically acceptable salt thereof preferably oral solid dosage form of a capsule. The pharmaceutical composition of the present invention comprises Lenvatinib preferably mesylate salt with one or more pharmaceutically acceptable excipients selected from the group consisting of at least one diluent, at least one disintegrant, at least one binder, at least one lubricant, and at least one stability enhancing agent wherein the composition lacks excipients potassium carbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, magnesium oxide, calcium oxide, disodium hydrogen phosphate, disodium potassium phosphate, sodium acetate and silicic acid and derivative thereof..
In accordance with the present invention, a novel pharmaceutical composition comprising Lenvatinib as an active ingredient and one or more pharmaceutically acceptable excipients including diluents/filler, disintegrants, binders, lubricants, stability enhancing agents but not limited thereof.

In one aspect of the present invention, the pharmaceutical composition of Lenvatinib comprises amino sugar preferably meglumine or calcium hydroxide as stability enhancing agent along with the active ingredient Lenvatinib to enhance the stability of the composition. The present invention is to provide a pharmaceutical composition of Lenvatinib that provides higher stability of the active ingredient in humidity and warm storage conditions. Further, present invention shows a desired dissolution profile with minimum use of excipients.

In one preferred embodiment of the present invention comprises Lenvatinib mesylate in amorphous form as an active ingredient along with pharmaceutically acceptable excipients selected from amino sugar meglumine or calcium hydroxide, microcrystalline cellulose, hydroxy propyl cellulose, low substituted HPC, purified talc.

Table:1 General composition of the present invention is as under:
Sr. No. Ingredients for oral solid dosage of Lenvatinib Range (%w/w)
Stage: A Dry mixing
1. Lenvatinib mesylate 4.90 %
2. Meglumine 2-6 %
3. Microcrystalline cellulose 40-50 %
4. Hydroxy Propyl cellulose
(Klucel-LF) 1-5 %
5. Low substituted HPC (L-HPC) 5-15 %
Stage: B Lubrication
6. Purified Talc 1-5 %
Stage: C Capsule filling
7. Hard gelatin capsule of Size “4” and Size “1”

The pharmaceutical composition of the present invention comprises Lenvatinib as active ingredient in the dosage form in amount of 4.90 % w/w.
The novel pharmaceutical composition of Lenvatinib oral dosage form of comprises a Lenvatinib, more preferably Lenvatinib mesylate as an active ingredient along with pharmaceutically acceptable excipients selected from meglumine or calcium hydroxide, microcrystalline cellulose, hydroxy propyl cellulose, low substituted HPC (L-HPC), purified talc, mannitol.
The pharmaceutically acceptable salt of the present invention selected from hydrochloride, hydrobromide, p-toluenesulfonate, sulfate, methanesulfonate or ethanesulfonate. It is preferably methanesulfonate or mesylate salt.
In one embodiment of present invention, active ingredient is Lenvatinib mesylate in amorphous form in the dosage form.
Inventors of the present invention have developed the formulation of Lenvatinib which is more stable with high dissolution profile that comprises Lenvatinib, preferably mesylate, more preferably in its amorphous form with one or more pharmaceutically acceptable excipients selected from at least one diluent, at least one disintegrant, at least one binder, at least one lubricant; at least one stability enhancing agent; wherein diluent is preferably selected from microcrystalline cellulose, lactose, mannitol, Soluplus®; binder is preferably selected from low substituted HPC (L-HPC), povidone, disintegrant is preferably selected from hydroxy propyl cellulose and lubricant is preferably selected from purified talc.
The composition of the present invention lacks excipients including calcium carbonate, potassium carbonate and silicic acid or salt or solvate thereof. In the composition of the present invention amino sugar meglumine or calcium hydroxide is used. Use of meglumine or calcium hydroxide in the composition enhanced the solubility and bioavailability of the composition of the present invention. Further, it increased the stability of the composition in harsh conditions of storage of the composition. Therefore, solubility and stability of the active ingredient is increased. Thus, the present invention composition leads to achieve good dissolution profile with minimum use of excipients. Therefore, stability of solid dosage forms of the present invention is quite higher. Further, toxicity or side effects associated with excipients are also avoided in the present invention, wherein the composition devoid of calcium carbonate, potassium carbonate and silicic acid or salt or solvate thereof.
The excipients used in the present composition are as listed above; however, it is not limited to the said excipients only.
In further aspect of the present invention, diluents may be selected from the group consisting of dextrates, dextrin, dextrose, fructose, 1-O-a-D-glucopyranosyl-D-mannitol, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, lactose monohydrate, maltitol, mannitol, maltodextrin, maltose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), pregelatinized starch, sodium chloride, sorbitol, starches, sucrose, talc and xylitol or a mixture of one or more of said diluents.
In one aspect, Lenvatinib may be used in amorphous for crystalline form. In another embodiments, Lenvatinib may be in crystalline form DRC-1 and DRC-2 as reported in Indian patent application no. 202021005373.
In another aspect of the present invention, amino sugars may be selected from the group consisting of meglumine, calcium hydroxide, N-acetylglucosamine, galactosamine, glucosamine, L-daunosamine.
Disintegrants used for the preparation of solid oral dosage form are selected from the group consisting of carboxymethyl cellulose, low substituted hydroxypropyl cellulose, powdered cellulose, croscarmellose sodium, Polyplasdone® XL (crospovidone), methylcellulose, polacrilin potassium, sodium alginate or a mixture of one or more of said disintegrants.
Lubricants may be selected from the group consisting of calcium stearate, glyceryl palmitostearate, sodium benzoate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and magnesium stearate or a mixture of one or more of said lubricants.
The binders may be selected from the group consisting of hydroxyl propyl methyl cellulose (HPMC or hypromellose), polyvinyl pyrrolidone (povidone), hydroxyl propyl cellulose, polyvinyl alcohol, methyl cellulose, ethyl cellulose, gum arabic, alginic acid, polyethylene glycol (PEG), pregelatinized starch (PGS) and the like.
The solvent used for binding of the granules of Lenvatinib mesylate may include water, isopropyl alcohol and dichloromethane or mixture thereof, but not limited to thereof.
In the present invention, the term “Lenvatinib” is not only limited to “Lenvatinib” per se but also includes in broader way its pharmaceutically acceptable derivatives thereof. These derivatives include pharmaceutically acceptable salts, solvates, hydrates, anhydrates, isomers, prodrugs, enantiomers, polymorphs, esters, tautomers, etc. Preferably, lapatinib is present in the form of lapatinib ditosylate monohydrate in the present invention. In the present invention, Lenvatinib used is in amorphous form preferably.
The pharmaceutical composition comprising Lenvatinib according to the present invention is administered orally through the solid dosage forms such as capsules, granules, fine granules, tablets and so on. It is preferably capsule or capsule filled with fine granules.
More preferably, the pharmaceutical composition comprising Lenvatinib according to the present invention may be administered in a solid oral dosage form of a capsule. There are two types of capsules of 4 mg and 10 mg of the present invention pharmaceutical composition.

Method of Manufacturing:
The present invention also discloses a method of manufacturing the oral solid dosage pharmaceutical composition of Lenvatinib or a pharmaceutically acceptable salt thereof that is divided in different steps as following:
(a) Sifting
Lenvatinib API and other excipients are co-sifted using appropriate size sieve;
(b) Dry mixing
All the ingredients are mixed together except purified talc;
(c) Blending
Previously dry mixed all the ingredients except purified talc are co-sifted into conta blender and blend for 45 minutes at 18 RPM;
(d) Lubrication
Purified talc is added in the blend prepared in step (c) and lubrication is carried out for 5 minutes in conta blender at 18 RPM;
(e) Encapsulation
Prepared lubricated blend in step (e) is filled in appropriate size capsule using capsule filling machine of targeted weight.
(f) Packaging
Packaging of the capsule is done.
The present invention can be described by way of example or strategy only. It is to be recognized that modifications falling within the scope and spirit of the description or claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this disclosure.

EXAMPLES:

Example: 1
Table:2 Lenvatinib formulation preparation 1 [4 mg Capsule]
Ingredients for oral solid dosage of Lenvatinib mg/Capsule
Dry mixing
Lenvatinib mesylate 4.90
Meglumine 4.00
Microcrystalline cellulose 76.10
Hydroxy Propyl cellulose
(Klucel-LF) 3.00
Low substituted HPC (L-HPC) 10.00
Lubrication
Purified Talc 2.00
Total weight 100.00

Manufacturing process for Lenvatinib formulation (Example: 1)
1) Sifting
Lenvatinib mesylate API, meglumine, microcrystalline cellulose, hydroxy propyl cellulose (Klucel-LF) and low substituted HPC (L-HPC) were co-sifted through size 30# sieve. Purified talc was sifted through size 60# sieve.
2) Dry mixing
All the ingredients were dry mixed together except purified talc.
3) Blending
Previously dry mixed all the ingredients except purified talc were co-sifted into conta blender and blended for 45 minutes at 18 RPM.
4) Lubrication
Purified talc was added in the blend prepared in step (3) and lubrication was carried out for 5 minutes in conta blender at 18 RPM.
5) Encapsulation
100 mg of the prepared lubricated blend in step (4) was filled in size “4” hard gelatin capsule using capsule filling machine of targeted weight.
6) Packaging
Packaging of the capsule was done.
Example: 2
Table:3 Lenvatinib formulation preparation 2 [10 mg Capsule]
Ingredients for oral solid dosage of Lenvatinib mg/Capsule
Dry mixing
Lenvatinib mesylate 12.25
Meglumine 10.00
Microcrystalline cellulose 190.25
Hydroxy Propyl cellulose
(Klucel-LF) 7.50
Low substituted HPC (L-HPC) 25.00
Lubrication
Purified Talc 5.00
Total weight 250.00

Manufacturing process for Lenvatinib formulation (Example: 2)
1) Sifting
Lenvatinib mesylate API, meglumine, microcrystalline cellulose, hydroxy propyl cellulose (Klucel-LF) and low substituted HPC (L-HPC) were co-sifted through size 30# sieve. Purified talc was sifted through size 60# sieve.
2) Dry mixing
All the ingredients were dry mixed together except purified talc.
3) Blending
Previously dry mixed all the ingredients except purified talc were co-sifted into conta blender and blended for 45 minutes at 18 RPM.
4) Lubrication
Purified talc was added in the blend prepared in step (3) and lubrication was carried out for 5 minutes in conta blender at 18 RPM.
5) Encapsulation
250 mg of the prepared lubricated blend in step (4) was filled in hard gelatin capsule using capsule filling machine of targeted weight.
6) Packaging
Packaging of the capsule was done.

Example: 3
Table:4 Lenvatinib formulation preparation 3 [10 mg Capsule]
Ingredients for oral solid dosage of Lenvatinib mg/Capsule
Dry mixing
Lenvatinib mesylate 12.25
Meglumine 5.00
Mannitol 75.00
Microcrystalline cellulose 120.25
Hydroxy Propyl cellulose
(Klucel-LF) 7.50
Low substituted HPC (L-HPC) 25.00
Lubrication
Purified Talc 5.00
Total weight 250.00

Manufacturing process for Lenvatinib formulation (Example: 3)
1) Sifting
Lenvatinib mesylate API, meglumine, mannitol, microcrystalline cellulose, hydroxy propyl cellulose (Klucel-LF) and low substituted HPC (L-HPC) were co-sifted through size 30# sieve. Purified talc was sifted through size 60# sieve.
2) Dry mixing
All the ingredients were transferred in one polybag and dry mixed together except purified talc.
3) Lubrication
Previously sifted purified talc was added in the blend prepared in step (2) and mixed all the ingredients well.
4) Encapsulation
250 mg of prepared lubricated blend in step (3) was filled in size “1” of hard gelatin capsule.
5) Packaging
Packaging of the capsule was done.

Example: 4
Table:5 Lenvatinib formulation preparation 4 [10 mg Capsule]
Ingredients for oral solid dosage of Lenvatinib mg/Capsule
Dry mixing
Lenvatinib mesylate +HPMC E6 complex 25.00
Meglumine 8.00
Mannitol 75.00
Microcrystalline cellulose PH 102 104.50
Hydroxy Propyl cellulose
(Klucel-LF) 7.50
Low substituted HPC (L-HPC) 25.00
Lubrication
Purified Talc 5.00
Total weight 250.00

Manufacturing process for Lenvatinib formulation (Example: 4)
1) Complex preparation
Lenvatinib mesylate API and HPMC E6 complex was prepared using ethanol and purified water 1:1 mixture using solvent evaporation technique.
2) Sifting
Lenvatinib mesylate + HPMC E6 complex, meglumine, mannitol, microcrystalline cellulose, hydroxy propyl cellulose (Klucel-LF) and low substituted HPC (L-HPC) were co-sifted through size 30# sieve. Purified talc was sifted through size 60# sieve.
3) Dry mixing
All the ingredients were transferred in one polybag and dry mixed together except purified talc.
4) Lubrication
Previously sifted purified talc was added in the blend prepared in step (3) and mixed all the ingredients well.
5) Encapsulation
250 mg of prepared lubricated blend in step (3) was filled in size “1” of hard gelatin capsule.
6) Packaging
Packaging of the capsule was done.
Example: 5
Table:6 Lenvatinib formulation preparation 5 [10 mg Capsule]
Ingredients for oral solid dosage of Lenvatinib mg/Capsule
Dry mixing
Lenvatinib mesylate 12.25
Meglumine 14.00
Mannitol 75.00
Microcrystalline cellulose PH 102 111.25
Hydroxy Propyl cellulose
(Klucel-LF) 7.50
Low substituted HPC (L-HPC) 25.00
Lubrication
Purified Talc 5.00
Total weight 250.00

Manufacturing process for Lenvatinib formulation (Example: 5)
1) Sifting
Lenvatinib mesylate API, meglumine, mannitol, microcrystalline cellulose, hydroxy propyl cellulose (Klucel-LF) and low substituted HPC (L-HPC) were co-sifted through size 30# sieve. Purified talc was sifted through size 60# sieve.
2) Dry mixing
All the ingredients were transferred in one polybag and dry mixed together except purified talc.
3) Lubrication
Previously sifted purified talc was added in the blend prepared in step (2) and mixed all the ingredients well.
4) Encapsulation
250 mg of prepared lubricated blend in step (3) was filled in size “1” of hard gelatin capsule.
5) Packaging
Packaging of the capsule was done.

Example: 6
Table:7 Lenvatinib formulation preparations [4 and 10 mg Capsule]
Sr. No. Ingredients Qty./Cap
(mg) for 4 mg Qty./Cap
(mg) for 10 mg
Stage: A – Binder solution
1. Lenvatinib Mesylate eq. Lenvatinib base 4.90 12.25
2. HPMC E5 LV 4.90 12.25
3. Isopropyl alcohol 20.58 51.45
4. Dichloromethane 82.32 205.8
Stage: B – Intragranular ingredients
5. Calcium hydroxide 4.00 10.00
6. Microcrystalline cellulose PH 112 (FLOCEL 112*) 71.20 178.00
7. Hydroxy Propyl cellulose (Klucel-LF) 3.00 7.50
8. Low substituted HPC (L-HPC LH-11) 10.00 25.00
Stage: B - Lubrication
9. Purified Talc 2.00 5.00
Total 100.00 250.00

Manufacturing process for Lenvatinib formulation (Example: 6)
1) Dry Blend:
Calcium hydroxide, microcrystalline cellulose, hydroxy propyl cellulose (Klucel-LF) and low substituted HPC (L-HPC) were co-sifted through size 30# sieve to obtain dry blend;
2) Binding Solution:
HPMC E5 LV was dissolved in Isopropyl alcohol (IPA) and dichloromethane (DCM) followed by dissolving Lenvatinib mesylate to obtain binding solution;
3) Granulation & Drying:
Binding solution added in step-2 was added to the dry blend obtained in step-1 to prepare granules followed by drying of the same;
4) Lubrication:
Talc was added to the dried granules to obtain the final blend useful for capsule filling;
5) Capsule Filling:
Lubricated blend obtained in step-4 was then filled in the capsules to obtain final formulation.

Example: 7
Table:8 Lenvatinib formulation preparations [4 and 10 mg Capsule]
Sr. No. Ingredients Qty./Cap
(mg) for 4 mg Qty./Cap
(mg) for 10 mg
Stage: A – Binder solution
1. Lenvatinib Mesylate eq. Lenvatinib base 4.90 12.25
2. HPMC E5 LV 4.90 12.25
3. Isopropyl alcohol 20.58 51.45
4. Dichloromethane 82.32 205.8
Stage: B – Intragranular ingredients
5. Meglumine 4.00 10.00
6. Microcrystalline cellulose PH 112 (FLOCEL 112*) 71.20 178.00
7. Hydroxy Propyl cellulose (Klucel-LF) 3.00 7.50
8. Low substituted HPC (L-HPC LH-11) 10.00 25.00
Stage: B - Lubrication
9. Purified Talc 2.00 5.00
Total 100.00 250.00

Manufacturing process for Lenvatinib formulation (Example: 7)
1) Dry Blend:
Meglumine, microcrystalline cellulose, hydroxy propyl cellulose (Klucel-LF) and low substituted HPC (L-HPC) were co-sifted through size 30# sieve to obtain dry blend;
2) Binding Solution:
HPMC E5 LV was dissolved in Isopropyl alcohol (IPA) and dichloromethane (DCM) followed by dissolving Lenvatinib mesylate to obtain binding solution;
3) Granulation & Drying:
Binding solution added in step-2 was added to the dry blend obtained in step-1 to prepare granules followed by drying of the same;
4) Lubrication:
Talc was added to the dried granules to obtain the final blend useful for capsule filling;
5) Capsule Filling:
Lubricated blend obtained in step-4 was then filled in the capsules to obtain final formulation.
The inventors of the present invention have surprisingly developed a new manufacturing method in above example-6 and example-7, wherein Lenvatinib is complexed using HPMC during preparation of binding solution. Due to this complexing activity, the final product yields better dissolution when compared with without doing above activity. Based on this surprising effect, it may be concluded that the present invention is not just a mere admixture.
In addition to above, the inventors of the present invention have also observed surprisingly that when pH of the final composition is less than 9 at that time, the stability of the product reduces. Hence, due to above important observation, the inventors of the present invention have developed pharmaceutical formulation wherein pH of the final product is not less than 9. The inventors of the present invention have observed pH in example-6 was as 11.8 and in example-7, it was 9.6.

TEST EXAMPLE-1:
Example-6 and 7 were tested for stability study testing. The products as per the present invention were placed under accelerated stability testing at conditions of 60°C in open and closed containers for 15 days.
Various parameters including % assay and % total impurities were measured at least for 15 days which are reported as followed:

Parameters Initial Open Container for 15 days at 60°C Closed Container for 15 days at 60°C
Example-6
% Assay 100.00 99.75 101.00
% Total Impurities 0.132 0.130 0.127
Example-7
% Assay 99.25 98.75 100.50
% Total Impurities 0.129 0.129 0.129

From above data, the inventors of the present invention surprisingly found that Lenvatinib formulations prepared as per the preset invention are stable even after 15 days of open container study in accelerated stability testing.
The inventors of the present invention surprisingly found from the above data that % assay of the Lenvatinib capsules as per the present invention shown consistency proving it a stable dosage form in long term storage as well. Similar results were obtained with all the examples described in the present invention. Thus, the final product of the present invention is found as stable due to its unique composition which is not just a mere admixture but provides synergistic effect.
The invention described herein comprises in various objects as mentioned above and their description in relation to characteristics, compositions and process adopted. While these aspects are emphasised in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.

,CLAIMS:1. An oral pharmaceutical composition of Lenvatinib and pharmaceutical acceptable salt thereof comprising:
a. Lenvatinib mesylate complexed with HPMC (hydroxypropyl methyl cellulose);
b. at least one pharmaceutical excipient selected from calcium hydroxide or meglumine, wherein in the concentration of calcium hydroxide or meglumine is not greater than 5% w/w of the total composition;
wherein the composition is devoid of potassium carbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, magnesium oxide, calcium oxide, disodium hydrogen phosphate, disodium potassium phosphate, sodium acetate and silicic acid and derivative thereof.

2. The oral pharmaceutical composition of Lenvatinib and pharmaceutical acceptable salt thereof as claimed in claim 1, wherein pH of the final composition is greater than 9.

3. The oral pharmaceutical composition of Lenvatinib and pharmaceutical acceptable salt thereof as claimed in claim 1, wherein the concentration of Lenvatinib mesylate is not greater than 5% w/w of the total composition.

4. The oral pharmaceutical composition of Lenvatinib and pharmaceutical acceptable salt thereof as claimed in claim 1, wherein the concentration of HPMC is not greater than 5% w/w of the total composition.

5. The oral pharmaceutical composition of Lenvatinib and pharmaceutical acceptable salt thereof as claimed in claim 1, further comprising other cellulosic derivative like hydroxypropyl cellulose and derivative thereof along with microcrystalline cellulose.

6. The oral pharmaceutical composition of Lenvatinib and pharmaceutical acceptable salt thereof as claimed in claim 1, wherein the concentration of hydroxypropyl cellulose is not less than 10% w/w and microcrystalline cellulose not less than 70% w/w of the total composition.

7. Oral pharmaceutical compositions of Lenvatinib mesylate comprising following formula:
Ingredients Qty. per Capsule (mg)
4 mg 10 mg
Lenvatinib Mesylate eq. Lenvatinib base 4.90 12.25
HPMC E5 LV 4.90 12.25
Calcium hydroxide 4.00 10.00
Microcrystalline cellulose PH 112 (FLOCEL 112*) 71.20 178.00
Hydroxy Propyl cellulose (Klucel-LF) 3.00 7.50
Low substituted HPC (L-HPC LH-11) 10.00 25.00
Purified Talc 2.00 5.00

8. Oral pharmaceutical compositions of Lenvatinib mesylate comprising following formula:
Ingredients Qty. per Capsule (mg)
4 mg 10 mg
Lenvatinib Mesylate eq. Lenvatinib base 4.90 12.25
HPMC E5 LV 4.90 12.25
Meglumine 4.00 10.00
Microcrystalline cellulose PH 112 (FLOCEL 112*) 71.20 178.00
Hydroxy Propyl cellulose (Klucel-LF) 3.00 7.50
Low substituted HPC (L-HPC LH-11) 10.00 25.00
Purified Talc 2.00 5.00

9. Process for preparation of an oral pharmaceutical composition of Lenvatinib mesylate comprising following steps:
a. dry mixing of Meglumine or calcium hydroxide, microcrystalline cellulose, hydroxy propyl cellulose (Klucel-LF) and low substituted HPC (L-HPC) to obtain dry blend;
b. dissolving HPMC in suitable solvent followed by dissolving Lenvatinib mesylate to obtain binding solution as Lenvatinib-HPMC complex;
c. granulating Lenvatinib-HPMC complex obtained in step-b to the dry blend of step-a followed by drying of the granules;
d. lubricating dried granules obtained in step-c using talc to obtain final blend;
e. filling final blend obtained in step-d in appropriate size of capsules.

10. The process for preparation of an oral pharmaceutical composition of Lenvatinib mesylate as claimed in claim 9, wherein suitable solvent is selected from water, Isopropyl alcohol and Dichloromethane or mixture thereof.