EVEROLIMUS”

FIELD OF THE INVENTION:

The present invention relates to novel sublingual pharmaceutical formulations of Everolimus and pharmaceutically acceptable salt thereof. This present invention discloses sublingual tablet compositions of Everolimus and pharmaceutically acceptable salt thereof using one or more pharmaceutically acceptable excipients. Further, the present invention relates to providing an economical, patient compliant and technically advanced dosage form over existing dosage forms. In addition, the present invention shows industrial applicability in present industry infrastructure because it involves manufacturing of a tablet dosage form, which requires routine machineries.

BACKGROUND OF THE INVENTION:

Everolimus (CAS: 159351 -69-6) is a macrocyclic lactone that is rapamycin in which the hydroxy group attached to the cyclohexyl moiety has been converted into the corresponding 2-hydroxyethyl ether.

Everolimus is chemically known as (1 R,9S,12S,15R,16E,18R,19R,21 R,23S,24E, 26E,28E,30S,32S,35R)-1 ,18-dihydroxy- 12-{(1 R)-2-[(1 S,3R,4R)-4-(2-hydroxy- ethoxy)-3-methoxycyclohexyl]-1 -methylethyl}-19,30-dimethoxy-15,17,21 ,23,29, 35-hexamethyl-11 ,36-dioxa-4-aza-tricyclo[30.3.1 .0]hexatriaconta-16,24,26,28- tetraene-2,3,10,14,20-pentaone and is represented structurally as below: EVEROLIMUS (I)

Everolimus, the 40-O-(2-hydroxyethyl) derivative of rapamycin (sirolimus), is a potent and selective inhibitor of mammalian target of rapamycin (mTOR). Everolimus is selective for the mTORCI protein complex. Everolimus exhibits potent immunosuppressive and anticancer activities. Everolimus is a white to beige colored powder with an empirical formula of C53FI83NO14 and the molecular weight is 958.2.

US5665772 discloses O-alkylated rapamycin derivatives which covers Everolimus for the first time. Everolimus is marketed as tablets (AFINITOR ^® and Zortress ^® ), and tablets for oral suspension (AFINITOR DISPERZ ^® ) by Novartis in USA. AFINITOR ^® tablets are approved by the United States Food and Drug Administration (USFDA) as anticancer agent in the treatment of advanced renal cell carcinoma (RCC) and subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS). Zortress ^® tablets are approved by USFDA as immunosuppressant agent in the treatment of Prophylaxis of organ rejection in adult patients. Both AFINITOR ^® and Zortress ^® tablets contain lactose monohydrate, crospovidone, butylated hydroxytoluene (BFIT), hypromellose, magnesium stearate, and anhydrous lactose as inactive ingredients. AFINITOR DISPERZ ^® tablets contain lactose monohydrate, crospovidone, butylated hydroxytoluene, hypromellose, magnesium stearate, colloidal silicon dioxide, mannitol, and microcrystalline cellulose as inactive ingredients.

Innovator Brands in US Formulation Strengths available

AFINITOR ^® Oral Tablet 2.5 mg, 5 mg, 7.5 mg, 10 mg

ZORTRESS ^® Oral Tablet 0.25 mg, 0.5 mg, 0.75 mg, 1 mg

AFINITOR DISPERZ ^® Dispersible Tablet 2 mg, 3 mg, 5 mg From prior-art search results and as reported in Clinical Pharmacology and Biopharmaceutics review submitted for NDA 22-334, the inventors of the present invention are aware that Everolimus is considered as BCS Class-Ill drug which have high solubility and low permeability. Several approaches are reported to overcome the problem of permeability and stability. Following are the nearest prior- arts to the present invention:

US5989591 claims a pharmaceutical composition of Everolimus which is a sugar- coated tablet comprising of sucrose and poloxamer. An inert core is coated with solid dispersion of above-mentioned ingredients. This prior-art relates to the conventional sugar-coated tablet and but not to the sublingual tablet. Further, this prior-art, wherein the drug is present in coating layer, has not disclosed any stability data as well as microbial data which indicate towards unsuccessful development of the stable dosage form which may be commercialized.

W02000/033878 discloses pharmaceutical compositions of Everolimus that contains 0.2% (based on the weight of Everolimus) of antioxidant, preferably BFIT. Further, this prior-art relates to a conventional tablet and not to the sublingual tablet. This patent application was originally intended to prepare stabilized formulations of Everolimus; however, lack of stability data reporting in the patent application proves the said prior-art as an unstable one.

W02003/028705 claims a pharmaceutical composition of Everolimus comprising a solid dispersion of Everolimus, a disintegrant and colloidal silicon dioxide, wherein the composition comprises 1 to 5% colloidal silicon dioxide by weight. The disintegration time reported in this prior-art for the above-mentioned composition is around 3 minutes, i.e. 90 seconds. Further, this prior-art relates to a dispersible tablet and not to the sublingual tablet. In addition, this patent application has not reported stability data which may indicate unsuccessful development of a stable dosage form.

Although the prior arts disclose different types of compositions which try to address the permeability and stability issues of Everolimus. Flowever, the inventors of the present invention could not find sufficient supported analytical data reported in these prior-arts that may prove Everolimus dosage form as stable one.

In addition, the inventors of the present invention also noted that presently marketed Everolimus formulations have very serious adverse effects including infection, asthenia, cough, fatigue, diarrhoea, anaemia, constipation, hypertension, hyperlipidaemia, nausea, mouth ulcer and mucositis. Hence, the inventors of the present invention felt that still, there is an unmet need to develop a dosage form of Everolimus, which overcome the drawbacks of prior available formulations, has good physical stability, is cost effective, can be produced by simple manufacturing techniques and can maximize the permeability of Everolimus from such dosage form and thereby improve its bioavailability with patient compliance.

OBJECTIVES OF THE INVENTION:

The principal object of the present invention is to provide novel sublingual pharmaceutical formulations of Everolimus and pharmaceutically acceptable salt thereof in the form of tablet which is to be placed under the tongue. The sublingual tablet provides better patient compliance; however, none of prior-arts teaches about sublingual formulations for Everolimus.

Another prime objective of the present invention is to provide dose reduction of Everolimus with the sublingual route through bypassing first pass metabolism and thereby reducing excessive metabolism of Everolimus.

Yet another object of the present invention is to provide synergistic formulations of Everolimus or pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipients which are essential for synergistic effect.

Another object of the present invention is to provide technically advanced patient- compliant dosage forms over existing dosage form and prior-arts.

The other object of the present invention is to provide reduced dose Everolimus formulations and thereby reducing the cost of final formulations by providing an economic significant dosage form over existing dosage form and prior-arts.

One more object of the present invention is to provide a process for preparation of sublingual formulations of Everolimus and pharmaceutically acceptable salt thereof using one or more pharmaceutically acceptable excipients in the form of a tablet which is to be placed under the tongue. Prior-arts fail to disclose about such tablets which are sublingual for Everolimus. Yet another objective of the present invention is to provide sublingual formulations of Everolimus and one or more pharmaceutically acceptable excipients with longer stability profile. SUMMARY OF THE INVENTION:

Despite of extensive research on Everolimus as reported in prior-art publications, there is an unmet need to develop a patient compliant oral sublingual composition for Everolimus with technical advancement which provide fast dissolution for immediate action as well as good stability for long-term storage. This dosage form also increases patient compliance because patient feels difficulty in taking conventional tablet or dispersible tablets when he or she is outdoor; whereas sublingual tablet does not require even water. Thus, the present invention has solved the problem that is present in the prior-arts as well as in the existing marketed formulations. Accordingly, the present invention provides an oral composition of Everolimus preferably as a sublingual tablet form with pharmaceutically acceptable excipients and method of preparation thereof.

The present invention establishes a very fast release of the pharmaceutical composition during initial dissolution owing to kind of excipients used in the formulation and thereby producing an immediate burst release which in turn immediate absorption of the drug into the blood stream. This action will help to increase bioavailability of Everolimus and pharmaceutically acceptable salt thereof in very short time.

In another general embodiment of the present invention, a pharmaceutical composition as per the present invention comprises Everolimus or pharmaceutically acceptable salt thereof. Preferably, Everolimus is present in the form of free base, a pharmaceutically acceptable salt thereof, amorphous Everolimus, crystalline Everolimus, any isomer, derivative, hydrate, solvate or prodrug or a combination thereof. In another embodiment of the present invention, a synergistic pharmaceutical composition as per the present invention comprises several advantages including dose reduction, reduction in dose dependent side-effects and bypassing first pass metabolism of Everolimus in the liver.

Embodiments of the pharmaceutical composition may include Everolimus as an active ingredient with one or more selected from pharmaceutically acceptable excipients like diluents, disintegrants, binders, lubricants, vehicles / solubility enhancing agents, stabilizers / anti-oxidants, suspending agents, permeability enhancers, preservatives, glidants, active carriers, anti-caking agents, wetting agents, preservatives, buffering agents and the like.

In another embodiment of the present invention, pharmaceutical composition is in the form of sublingual tablets is prepared by wet granulation process comprising the steps of: (a) sifting one or more pharmaceutically acceptable excipients, (b) dissolving Everolimus and anti-oxidants in solvent and surfactant, (c) granulating the dry mix of step (a) with the drug solution of step (b) to obtain wet mass, (d) drying and sieving the wet mass to obtain granules, (e) blending the granules of step (d) with extra granular excipients if any, followed by lubrication and (f) compressing the lubricated blend of step (e) into tablets or filled into capsules.

The details of one or more embodiments of the invention are set forth in the description below. Other features of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION:

The following detailed description of the present subject matter the various embodiments. These embodiments are described in sufficient detail to enable those skilled in the art to practice the present subject matter. Other embodiments may be utilized and structural, logical, and electrical changes may be made without departing from the scope of the present subject matter.

References to “an”, “one”, or “various” embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope is defined only by the appended claims, along with the full scope of legal equivalents to which such claims are entitled.

Everolimus, the 40-O-(2-hydroxyethyl) derivative of rapamycin (sirolimus), is a potent and selective inhibitor of mechanistic target of rapamycin (mTOR). Everolimus is selective for the mTORCI protein complex. Everolimus exhibit potent immunosuppressive and anticancer activities. Everolimus is considered as BCS Class-Ill drug which have high solubility and low permeability.

In accordance with the present invention, a pharmaceutical composition of Everolimus comprising of Everolimus as an active ingredient with pharmaceutically acceptable excipients.

The term "drug" or “active ingredient” or “active pharmaceutical ingredient (API)” herein refers to Everolimus or a pharmaceutically acceptable salt thereof.

The term "Everolimus" as used herein according to the present invention includes, Everolimus in the form of free base, a pharmaceutically acceptable salt thereof, amorphous Everolimus, crystalline Everolimus, any isomer, derivative, hydrate, solvate or prodrug or a combination thereof.

The term "drug solution" as used herein according to the present invention includes solution obtained by dissolving Everolimus or its pharmaceutically acceptable salt thereof in solvent and (or) mixture of solvents.

The term "granulation" as used herein according to the present invention includes, wet-granulation, dry-granulation or direct compression.

The term "pharmaceutically acceptable excipients" as used herein, refers to excipients those are routinely used in pharmaceutical compositions. The pharmaceutically acceptable excipients may comprise of diluents, disintegrants, binders, lubricants, vehicles / solubility enhancing agents, stabilizers / anti oxidants, suspending agents, permeability enhancers, preservatives, glidants, active carriers, anti-caking agents, wetting agents, preservatives, buffering agents and combinations thereof. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the health of the patient.

In accordance with the present invention, it provides a wet granulation process for preparing stable sublingual compositions of Everolimus comprising the steps of: (a) sifting one or more pharmaceutically acceptable excipients, (b) dissolving Everolimus and anti-oxidants in solvent and surfactant, (c) granulating the dry mix of step (a) with the drug solution of step (b) to obtain wet mass, (d) drying and sieving the wet mass to obtain granules, (e) blending the granules of step (d) with extra granular excipients if any, followed by lubrication and (f) compressing the lubricated blend of step (e) into tablets or filled into capsules.

The inventors of the present invention have invented such type of synergistic Everolimus sublingual dosage (with low dose of 3 mg) form which produces similar therapeutic effect as 10 mg of dosage form and thereby improving therapeutic efficacy of the present invention.

According to the present invention, solvents suitable for processing the pharmaceutical compositions include one or more of organic solvents such as organic solvents such as an alcohol, for example methanol, ethanol, or isopropanol; an ester, e.g. ethyl acetate; an ether, e.g. diethyl ether; a ketone, e.g. acetone; or a halogenated hydrocarbon, e.g. dichloroethane, dichloromethane (MDC) and the like. The solvents may also include purified water.

Suitable stabilizers or anti-oxidants may include but are not limited to one or more from butylated hydroxytoluene (BHT), Butylated hydroxy anisole (BHA), tocopherols (Vitamin E), scorbic acid (Vitamin C) or its derivatives, propyl gallate, sodium bisulphite, L-cysteine, magnesium bisulfite, sodium metabisulfite, ubiquinol, b-carotenes, uric acid, lipoic acid, thiourea, glutathione and fumaric acid and the like. The inventors of the present invention surprisingly found that BHT provided better stability than other anti-oxidants. The present invention comprises about 1 -5% w/w of anti-oxidants of the total composition, preferably in the range of 1 -3% w/w of anti-oxidants of the total composition.

Suitable diluents, fillers, or bulking agents may include but are not limited to one or more from lactose, microcrystalline cellulose, reduced sugars such as monosaccharides like galactose, glucose, giyceraldehyde, fructose, ribose, and xylose; sugar alcohol such as mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol and hydrogenated starch hydrolysates; dibasic calcium phosphate, calcium phosphate, powdered cellulose, calcium carbonate, magnesium carbonate, starch, pre gelatinized starch and the like.

The inventors of the present invention used different diluents like Mannitol (Pearlitol 25C), Mannitol (Pearlitol 100 SD), F-Melt Type M, Prosolv Easytab SP, Prosolv Easytab SP - LM, PROSOLV ODT G2, Pharmaburst 500 and Dexrates (Emdex - Non-GMO).

Among these, Prosolv Easytab SP contains mixture of Microcrystalline Cellulose (96%), Colloidal Silicon Dioxide (2%), Sodium Starch Glycolate (1.2%), Sodium Stearyl Fumarate (0.8%). Further, Prosolv Easytab SP - LM is low moisture grade lower moisture content (< 3 %). Prosolv Easytab SP - LM was found to be suitable over other. The present invention comprises about 50-90% w/w of Prosolv Easytab SP of the total composition, preferably in the range of 65-75% w/w of Prosolv Easytab SP of the total composition.

The inventors of the present invention surprisingly observed at the time of development of sub-lingual tablet that the diluent impacts disintegration (DT) time, tablet properties and impurity. The inventors of the present invention observed problems of Tablet DT and Tablet surface roughness and moisture uptake on storage.

Suitable binders may include but are not limited to one or more from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (povidone), gum arabic and sugars such as sucrose, glucose, dextrose, lactose, polyvinyl alcohol and the like.

Suitable disintegrants may include but are not limited to one or more from crospovidone, croscarmellose sodium, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and the like. The present invention comprises about 5-25% w/w of disintegrants of the total composition, preferably in the range of 10-20% w/w of disintegrants of the total composition. The inventors of the present invention observed that disintegration time of Sodium starch glycolate was not achieved at different levels. Surprisingly, disintegration time of crospovidone was achieved with different grades and levels but the tablet surface was very rough. In addition, tablets made with crospovidone absorbed moisture and swelled. The inventors of the present invention noted that roughness on the tablet surface was observed due to the moisture absorption by crospovidone.

Surprisingly, when the inventors of the present invention combined Prosolv Easytab SP - LM in optimum concentration in combination with croscarmellose sodium, the rough surface tablet problem was solved and optimum disintegration time was also achieved. Thus, synergistic effect was observed by the inventors of the present invention by combining these two inactive ingredients. In addition, this excipient combination also provided rapid dissolution which is prime requirement of sub-lingual route. Furthermore, this combination of excipients also improved mouthfeel than other excipients which is also the requirement for the sub-lingual route.

Suitable wetting agents or surfactants or solubilizers may include but are not limited to one or more from the group comprising anionic, cationic, nonionic, or zwitterionic surfactants, or combinations thereof. Suitable examples of wetting agents are sodium lauryl sulphate, cetrimide, polyethylene glycols, polyoxyethylene- polyoxypropylene block copolymers such as poloxamers, pluronic F68, polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate, polyethylene glycol fatty acid esters such as polyoxyethylene monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, sepitrap 80, polysorbate 80 and the like. The present invention comprises about 5-20% w/w of solubilizers of the total composition, preferably in the range of 1 -15% w/w of solubilizers of the total composition.

The inventors of the present invention surprisingly found that Sodium Lauryl Sulfate [SLS] (brand: Kolliphor SLS Fine, Kolliphor P188) improved dissolution in different dissolution media. Flence, it shows that the final formulation is showing the same dissolution nature in any pH of the dissolution media and hence, is more stable in releasing profile.

SEPITRAP 80 is a micro-encapsulated solubilizer in powder form designed to simplify the manufacturing of solid oral form drugs. It is manufactured by adsorption of the solubilizer in liquid form on a porous support. It contains Polysorbate 80 (45- 65%) adsorbed on Magnesium Alumino metasilicate (35-55%). The inventors of the present invention found Sepitrap 80 as beneficial because it helped to provide a better dissolution profile.

Suitable lubricants may include but are not limited to one or more from fatty acids, fatty acid salts, and fatty acid esters such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, colloidal silicon dioxide and mixtures thereof. The present invention comprises about 1 -15% w/w of lubricants of the total composition, preferably in the range of 1 -7% w/w of lubricants of the total composition.

The inventors of the present invention surprisingly found that being water-soluble lubricant, Sodium stearyl fumarate provided better dissolution profile than water insoluble lubricants like Magnesium stearate. In addition, the inventors of the present invention observed that colloidal silicon dioxide improved wet granulation process. Hence, the combination of these inactive ingredients provided a synergistic effect.

Suitable permeability enhancers may include but are not limited to one or more from the group comprising alcohols, Polyols, short-chain glycerides, amines, amides, cyclodextrins, fatty acids, pyrrolidines, azones, sulfoxides, surfactants, terpenes and the like.

Suitable chelating or complexing agents may include but are not limited to one or more from the group comprising cyclodextrin, ethylenediamine tetra acetic acid or derivatives/salts thereof, e.g. disodium edetate, dihydroxyethyl glycine, glucamine, citric acid, tartaric acid, gluconic acid, phosphoric acid and the like.

Suitable coloring and flavoring agents may include but are not limited to one or more from sucralose, maltose, orange flavor, vanilla flavor and the like. Being zero- calorie artificial flavoring agent, Sucralose was used in the formulation. Hence, the patients with diabetes can also take this medicine and thus, the present invention provided better patient compliance. The present invention comprises about less than 3% w/w of flavoring agents of the total composition, preferably less than 1% w/w of flavoring agents of the total composition. The inventors of the present invention also optimized the hardness of the tablet and disintegration time of the tablet by the selection of suitable punch tolling.

The prime aspect of the present invention is that the pharmaceutical composition establishes a fast release pattern owing to the kind of excipients used in the formulation and thereby producing an immediate release that will in turn increase in bioavailability at initial release.

In another aspect of the present invention, a synergistic pharmaceutical composition as per the present invention comprises several advantages including dose reduction, reduction in dose dependent side-effects and bypassing first pass metabolism of Everolimus in the liver. One aspect of the present invention may include a pharmaceutical composition comprising about 0.1 mg to 20 mg of Everolimus with pharmaceutically acceptable excipients.

In yet another aspect of the present invention, wherein the pharmaceutical composition manufactured is sublingual tablet, which results in to enhanced in-vitro dissolution profile.

Another aspect according to the present invention, wherein the formulated product manufactured is homogenous dispersions, which results in to enhanced in-vitro dissolution profile about 80% to 95% within initial 10 minutes of release.

In yet another aspect of the present invention, wherein the pharmaceutical composition manufactured by number of stages in manufacturing process including mixing, wet-granulation and compression.

Additional aspect according to the present invention is that the formulated product is a stabilized sublingual tablet. In one aspect process for preparation of an oral pharmaceutical composition as per the present invention comprising following steps:

1. Co-milling of Mannitol, crospovidone and colloidal silicon dioxide through #30 sieve; Binder solution preparation:

2. Mixing of ethanol and water were followed by addition of BFIT, Poloxamer 188 and orange flavour;

3. Dissolving Everolimus in to the solution obtained in step-2 to prepare the binder solution; Granulation:

4. Geometrically mixing of dry mix blend obtained in step-1 in slow manner to the binder solution obtained in step-3;

5. Drying and sifting of wet-granules obtained in stape-4;

Lubrication: 6. Adding and mixing of Crospovidone, sucralose, Sepitrap 80 to the dried and sized granules obtained in step-5;

7. Lubricating the blend obtained in step-6 with magnesium stearate;

Compression:

8. Compressing the lubricated blend obtained in step-7 to form tablets.

The invention will be further described with respect to the following examples; however, the scope of the invention is not limited thereby. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES:

Following section now will describe various formulation example as well as test examples by which the formulation example were evaluated. Further, results of the present invention were compared with the marketed formulation as well as nearest prior-arts.

EXAMPLE-1 : Solvents do not remain in the finished product except in traces and are lost during processing.

Process for preparation:

1 . Mannitol, crospovidone and colloidal silicon dioxide were co-sifted through #30 sieve; Binder solution preparation:

2. Ethanol and water were mixed followed by addition of BHT, Poloxamer 188 and orange flavour;

3. Everolimus was dissolved in to the solution obtained in step-2 to prepare the binder solution; Granulation: 4. Dry mix blend obtained in step-1 was geometrically mixed in slow manner to the binder solution obtained in step-3;

5. Wet-granules obtained in stape-4 were dried and sifted through #30 sieve;

Lubrication: 6. Crospovidone, sucralose, Sepitrap 80 were added to the dried and sized granules obtained in step-5 and mixed;

7. Magnesium stearate was added to the blend obtained in step-6 for the lubrication;

Compression: 8. Lubricated blend obtained in step-7 was compressed to form tablets.

EXAMPLE-2: Solvents do not remain in the finished product except in traces and are lost during processing. Similar manufacturing procedure was followed as per example-1 and results are reported in Test Example-2.

EXAMPLE-3: Solvents do not remain in the finished product except in traces and are lost during processing.

Process for preparation:

1. Prosolv easy Tab SP- LM, SLS (Kolliphor SLS Fine), and colloidal silicon dioxide were shifted through 40# Sieve. 2. Binder Solution:

Ethanol and Dichloromethane (MDC) in 1 :1 ratio was taken and BHT was dissolved followed by addition of Poloxamer 188, Orange flavor and Everolimus.

3. Granulation: The granules were prepared using binder solution prepared in step-2 and blend of step-1. These granules were dried at 42 - 45°C until loss on drying (LOD) of granules at 105°C were attained less than 2.5%. Dried granules were sifted through 40# sieve. 4. Blending:

Croscarmellose sodium, Sucralose and Sepitrap 80 were passed through 40# sieve and blended with dried-sized granules obtained in step-3.

5. Lubrication:

Sodium Stearyl Fumarate was sifted through 60 # sieve for 5 minutes and added to the blend of step-4.

6. Compression:

The lubricated blend obtained in step-5 was compressed sing 6 mm size punch tooling. TEST EXAMPLE-1 : Dissolution Profile comparison

Comparison of the dissolution profile study was incorporated to evaluate the comparative dissolution profile of the composition prepared in Example-1.

For this comparative study, dissolution profile in two different dissolution media was performed. One Media taken was Water with 0.4% Sodium dodecyl sulfate (SDS) and the other was pH 6.8 Phosphate buffer with 0.4% SDS. Both having 900 ml volume of in USP apparatus type II (paddle) at 50 RPM at 37°C. The obtained dissolution profile results are reported in the table-2.

TEST EXAMPLE-2: ANALYTICAL EVALUATION FOR EXAMPLE-2

Following are the analytical evaluation data for example-2 with stability study which includes assay, water content and related substance.

The inventors of the present invention observed that related impurities at 40°C / 75 % RH storage condition was higher. Hence, the inventors of the present invention checked related impurities at 30°C / 75 % RH storage condition and surprisingly found that impurities were drastically reduced. The inventors of the present invention hence now undergoing for studies at storage condition of 2-8°C.

TEST EXAMPLE-3: ANALYTICAL EVALUATION FOR EXAMPLE-3

Following are the analytical evaluation data for example-3 with stability study which includes assay, related substance and dissolution studies.

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.

The above-mentioned examples are provided for illustrative purpose only and these examples are in no way limitative on the present invention.