FIELD OF INVENTION

The invention relates to oral taste-masked pharmaceutical compositions comprising an integrase inhibitor. More particularly, the invention relates to novel oral taste-masked chewable tablet compositions comprising raltegravir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s).

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Raltegravir is chemically known as N[(4-Fluorophenyl)methyl]-l,6-dihydro5-hydroxy-l-methyl-2-[l-methyl-l-[[(5-methyl-l,3,4-oxadiazol-2-yl) carbonyl]amino]ethyl]-6-oxo-4pyrimidinecarboxamide and is disclosed in U.S. Patent No. 7,169,780. It is marketed as the mono-potassium salt. It is mainly used for the treatment of human-immunodeficiency virus (HIV-1) infection.

Raltegravir potassium is marketed by Merck under the trade name Isentress® in the form of tablet and chewable tablet in the U.S. and Europe, in strengths of either 400mg (for tablet) or lOOmg & 25mg (for chewable tablet).

Raltegravir, being a hydroxy pyrimidinecarboxamide derivative, has an unpleasant, bitter and disagreeable taste, so it is mostly administered in the form of either capsule or coated tablet that dissolves or disintegrates in the stomach after being swallowed. But some patient populations like children or geriatric patients have difficulty in swallowing such formulations. Therefore, other dosage forms such as orally disintegrating tablets, chewable tablets and/or liquid suspensions are recommended, due to their ease in swallowing.

Amongst all the above, chewable tablets are often used in the administration of pharmaceuticals in children or geriatric patients, since the act of chewing helps to break up the tablet into particles, which can be easily swallowed. Further act of chewing, hasten the disintegration and dissolution of tablet and ultimately helps in increasing the rate of absorption in the digestive tract.

Prior arts, as discussed below, disclose pharmaceutical compositions comprising raltegravir and process to prepare those.

U.S. Patent Application No. 2012/0270888 discloses composition comprising raltegravir, non-gelling polymer selected from polymethacrylates or polyethylene oxide and one or more pharmaceutically acceptable excipient(s), wherein said composition is free of anti-nucleating agent.

U.S. Patent Application No. 2012/0213851 discloses compressed tablet comprising: (A) an intragranular component comprising: (i) an effective amount of an alkali metal salt of raltegravir; (ii) optionally a first superdisintegrant; and (iii) a binder; and (B) an extragranular component comprising: (i) a second superdisintegrant; (ii) a filler; and (iii) a lubricant; with the proviso that the tablet is free of atazanavir or a pharmaceutically acceptable salt thereof.

U.S. Patent Application No. 2009/0136570 discloses taste-masked oral dosage forms comprising raltegravir or a pharmaceutically acceptable salt thereof, a taste-masking polymer and a superdisintegrant, wherein the process involves dry granulation followed by coating.

U.S. Patent Application No. 20080/118559 discloses a composition for oral administration comprising a drug compound in the form of a salt, wherein the salt is characterized by conversion of the drug compound to a less soluble form at a gastrointestinal-relevant pH and an anti-nucleating agent.

U.S. Patent Application No. 2007/0292504 discloses a pharmaceutical composition comprises raltegravir potassium and a release rate controlling agent comprising a solubilizing agent, a gelling agent and optionally water soluble filler.

PCT Application No. 2012/0163893 discloses a composition comprising raltegravir and V-methyglucamine.

PCT Application No. 2012/0145446 discloses a composition for oral administration which comprises a plurality of taste-masked granules, each of which comprises: (i) a core granule comprising raltegravir and a binder; and (ii) a taste-masking polymer composition that forms a coating on the core granule; wherein the process involves Wurster granulation process.

Above prior arts disclose various taste-masked pharmaceutical compositions comprising raltegravir, however still there is a need to develop a novel and alternate taste-masked pharmaceutical compositions comprising raltegravir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s).

The present inventors have successfully developed a novel and an alternate oral taste-masked chewable tablet comprising raltegravir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s), having comparable in-vitro dissolution profile with that of the marketed Isentress® chewable tablet.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to oral taste-masked pharmaceutical compositions comprising raltegravir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s).

An objective of the invention is to prepare novel oral taste-masked pharmaceutical compositions comprising raltegravir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s).

Another objective of the invention is to prepare novel oral taste-masked chewable tablet comprising raltegravir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s).

Yet another objective of the invention is to prepare novel oral taste-masked chewable tablet comprising raltegravir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s), having comparable in-vitro dissolution profile when compared with the commercially available Isentress® chewable tablet.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to oral taste-masked pharmaceutical compositions comprising raltegravir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s).

Particularly, the invention relates to novel oral taste-masked pharmaceutical compositions comprising raltegravir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s), and process to prepare such compositions.

More particularly, the invention relates to novel oral taste-masked chewable tablet comprising raltegravir or its pharmaceutically acceptable salts an one or more pharmaceutically acceptable excipient(s), and process to prepare such tablets.

In context of the invention, terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for raltegravir or its pharmaceutically acceptable salts or esters or derivatives thereof.

The term "taste-masked pharmaceutical compositions" as used herein refers to dosage form for oral administration in the form of granules, tablets, chewable tablets, pellets, beads, capsules, pills or mini-tablets. More preferably, the present composition relates to chewable tablets.

The term "pharmaceutically acceptable excipient(s)" as used herein refers to any ingredients that may be added to the formulation besides the active ingredient.

In context of the invention, terms like "fluid bed granulator" or "fluid bed processor" or "fluid bed coater" or "fluid bed dryer" may be used interchangeably and synonymously for fluid bed equipment for carrying out granulation/ drying/ coating process.

According to an embodiment of the invention, oral taste-masked chewable tablet comprises:
a) raltegravir granules comprising silicified microcrystalline cellulose (sMCC), copovidone and one or more other pharmaceutically acceptable excipient(s);
b) a coating of taste-masking polymer over the raltegravir granules; and
c) atleast one pharmaceutically acceptable excipient(s) added extra granularly.
According to another embodiment of the invention, oral taste-masked chewable tablet comprises:
a) raltegravir pellets comprising sugar sphere, copovidone and one or more other pharmaceutically acceptable excipient(s);
b) a coating of taste-masking polymer over the raltegravir granules; and
c) atleast one pharmaceutically acceptable excipient(s) added extra granularly.
According to an embodiment of the invention, the process for preparing oral taste-masked pharmaceutical compositions comprising raltegravir or its

pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s) involves the following steps:
a) dissolving raltegravir potassium and copovidone in a suitable solvent to get a binder solution;
b) granulating sMCC using binder solution of step (a) in a fluid bed granulator followed by drying to get dry granules;
c) milling/ sizing the dry granules of step (b) to get appropriate sized granules;
d) mixing the sized granules of step (c) with one or more pharmaceutically acceptable excipient(s);
e) lubricating the granules of step (d); and
f) processing said granules of step (e), into suitable composition.
According to another embodiment of the invention, the process for preparing taste-masked chewable tablets comprising raltegravir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s) involves the following steps:
a) dissolving raltegravir potassium and copovidone in a suitable solvent to get a binder solution;
b) granulating sMCC using binder solution of step (a) in a fluid bed granulator followed by drying to get dry granules;
c) milling/ sizing the dry granules of step (b) to get appropriate sized granules;
d) dissolving a combination of hydrophilic and hydrophobic polymer(s) in a suitable solvent to get a coating polymer solution;
e) coating the granules of step (c) using the polymer solution of step (d) in a fluid bed processor;
f) mixing the coated granules of step (e) with one or more pharmaceutically acceptable excipient(s);
g) lubricating the granules of step (f); and

h) compressing the lubricated granules of step (g) into chewable tablets.
According to another embodiment of the invention, the process for preparing oral taste-masked chewable tablets comprising raltegravir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s) involves the following steps:
a) dissolving raltegravir potassium and copovidone in a suitable solvent to get a drug coating solution;
b) spraying the solution of step (a) onto sugar sphere/ pellets in a fluid bed processor to get drug loaded/ coated pellets;
c) dissolving a combination of hydrophilic and hydrophobic polymer(s) in a suitable solvent to get a coating polymer solution;
d) coating the drug loaded/ coated pellets of step (b) using the polymer solution of step (c) in a fluid bed processor;
e) mixing the coated pellets of step (d) with one or more pharmaceutically acceptable excipient(s);
f) lubricating the coated pellets of step (e); and
g) compressing the lubricated coated pellets of step (f) into chewable tablets.
A taste masking polymer coating is prepared by dissolving one or more taste masking polymer in suitable solvents with or without plasticizer.
Suitable taste masking polymers include either hydrophilic or hydrophobic polymers or combination thereof. Suitable hydrophilic polymers of includes polyvinylpyrrolidone (PVP), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxyethylcellulose (HEC), copolymer of N-vinyl-2-pyrrolidone and vinyl acetate (i.e. Plasdone™, Plasdone™ S-630), vinyl acetate copolymers and the like or combinations thereof. Suitable hydrophobic polymers includes ethyl cellulose, cellulose acetate, polymethacrylic acid esters copolymer such as Eudragit™

NE30D and Eudragit™ NE40D, copolymers of polyvinyl alcohol and high molecular weight polyvinyl alcohols, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate and glyceryl distearate and the like or combinations thereof. More preferably, combinations of hydroxypropylmethylcellulose and ethyl cellulose as suitable polymers are used for taste masking polymer coating.

Suitable solvents for preparing taste masking polymer coating solution includes ethanol, cyclohexane, mixtures of cyclohexane and n-hexane, isopropyl alcohol, dichloromethane and the like or combinations thereof. More preferably, mixture of isopropyl alcohol and dichloromethane is used.

Sugar spheres are used as an inert core or bead or pellets or base made of sucrose and starch.

According to an embodiment of the invention chewable tablet contains raltegravir and one or more other pharmaceutically acceptable excipient(s) selected from a group comprising of but are not limited to diluents, binders, disintegrants, taste masking polymers, sequestering agents, lubricants, coloring agents, flavoring agents, sweetening agents, taste modifier, stabilizer and the like.

Suitable diluents include, but not limited to microcrystalline cellulose (MCC), silicified MCC, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like.

Suitable binders include, but are not limited to copovidone, acacia, alginic acid, carbomer copolymer, carbomer interpolymer, copovidone, copolymer of N-vinyl-2-pyrrolidone and vinyl acetate (i.e. Plasdone™, Plasdone™ S-630), microcrystalline cellulose, dextrin, ethyl cellulose, gelatin, glucose (liquid), guar gum, hydroxypropyl cellulose, maltose, methylcellulose, polyethylene oxide, polyvinylpyrrolidone, povidone, starch, or sodium carboxymethylcellulose and the like or combinations thereof.

Suitable disintegrants include, but not limited to alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polyacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate and starch and the like or combinations thereof.

Suitable sequestering agent include, but not limited to starch, pregelatinized starch, sodium citrate, hydrous monosodium citrate, anhydrous monosodium citrate, magnesium sulfate, calcium chloride, silica gel, kaolin and the like or combinations thereof.

Suitable lubricants include, but not limited to colloidal silicon dioxide, talc, stearic acid and its salts such as magnesium stearate, calcium stearate, sodium stearyl fumarate or calcium stearyl fumarate and the like or combinations thereof.

Suitable coloring agents include, but not limited to iron oxide yellow, iron oxide red, Aluminum stearate, Sunset yellow, Carmine, Erythrosine, FD & C blue, orange, green etc. and the like or combinations thereof.

Suitable flavoring agents include, but not limited to natural flavors include mint (such as peppermint or spearmint), menthol, cinnamon, vanilla, artificial vanilla, orange, chocolate, artificial chocolate or bubblegum and the like or combinations thereof.

Suitable sweetening agents include, but not limited to sodium saccharine, sucrose, sorbitol, sucralose, cyclamate, aspartame, acesulfame potassium and the like or combinations thereof.

Suitable taste modifiers include, but not limited to monoammonium glycyrrhizinate, sorbitol, maltose, maltodextrin, dextrose, fructose and the like or combinations thereof.

Suitable stabilizer include, but not limited to citric acid, sodium citrate, monosodium citrate anhydrous and the like.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Brief Manufacturing Process:
a) dissolve raltegravir potassium in purified water under stirring to get clear solution and then add Plasdone™ S-630 under stirring till it gets clear solution;
b) sift silicified MCC through #30 ASTM and load in fluid bed granulator;
c) granulate the step (b) material by using step (a) solution;

d) after drying sift the material though # 25 ASTM and retained material were milled through suitable screen in Quadro® Comil®;
e) sift mannitol, fructose, crospovidone, saccharin sodium through #30 ASTM;
f) sift orange flavor, iron oxide yellow, iron oxide red and mono sodium citrate anhydrous through # 60 ASTM;
g) blend the material of step (d) with step (e) and step (f) material in blender for suitable time;
h) sift sodium stearyl fumarate through # 40 ASTM and lubricate with the material of step (g) blend for suitable time;
i) compress the lubricated blend of step (h) into tablets by using suitable tooling.

Brief Manufacturing Process:

a) raltegravir potassium was dissolved in purified water under stirring to get a clear solution and further Plasdone™ S-630 was added to it and mixed well to get a clear solution;
b) silicifled MCC was loaded in fluid bed granulator;
c) material of step (b) was granulated using a solution of step (a) followed by drying and milling;
d) dissolve ethyl cellulose in isopropyl alcohol under stirring and further disperse HPMC and dichloromethane to it with constant stirring to get a clear solution;
e) solution of step (d) was coated over granules of step (c) in a fluid bed processor to get coated granules;
f) other ingredients including mannitol, fructose, crospovidone, saccharin sodium, orange flavor, iron oxide yellow, iron oxide red and mono sodium citrate anhydrous was passed through suitable sieve;
g) coated granules of step (e) were blended with step (f) to get the desired blends;
h) blend of step (g) was lubricated using sodium stearyl fumarate;
i) lubricated blend of step (h) was compressed using suitable tooling to get the chewable tablets.

Brief Manufacturing Process:
a) raltegravir potassium was dissolved in purified water under stirring to get a clear solution and further Plasdone™ S-630 was added to it and mixed well to get a clear solution;
b) sugar spheres were loaded in fluid bed processor;
c) spray the solution of step (a) on the sugar sphere of step (b) till a complete drug loaded over the sphere to get drug loaded pellets;
d) dissolve ethyl cellulose in isopropyl alcohol under stirring and further disperse HPMC and dichloromethane to it with constant stirring to get a clear solution;

e) solution of step (d) was coated over pellets of step (c) in a fluid bed processor to get coated pellets;
f) other ingredients including mannitol, fructose, crospovidone, saccharin sodium, orange flavor, iron oxide yellow, iron oxide red and mono sodium citrate anhydrous was passed through suitable sieve;
g) coated pellets of step (e) were blended with step (f) to get the desired blends;
h) blend of step (g) was lubricated using sodium stearyl fumarate;
i) lubricated blend of step (h) was compressed using suitable tooling to get the chewable tablets.

The composition given in Example-4 was prepared by using similar procedure as described in Example-3.
Brief Manufacturing Process:
a) dissolve raltegravir potassium in purified water under stirring to get clear solution and add Plasdone™ S-630 under stirring till it gets clear solution;
b) sift silicified MCC through #30 ASTM and load in fluid bed granulator;
c) granulate the step (b) material by using step (a) solution;
d) after drying, sift the material though # 25 ASTM and retained material were milled through suitable screen in Quadro® Comil®;
e) dissolve ethyl cellulose in isopropyl alcohol under stirring (solution 1) and disperse hypromellose in isopropyl alcohol under stirring and add
15

dichloromethane to the above solution with constant stirring to get clear solution and add solution 1 under stirring.
f) coat step (e) solution on step (d) material by using fluid bed processor till a desirable weight gain is achieved.
g) sift mannitol, fructose, crospovidone, saccharin sodium through #30 ASTM.
h) sift orange flavor, iron oxide yellow, iron oxide red and mono sodium citrate anhydrous through # 60 ASTM.
i) blend the material of step (f) step (g) and step (h) material in blender for suitable time.
j) sift sodium stearyl fumarate through # 40 ASTM and lubricate with the material of step (i) blend for suitable time.
k) compress the lubricated blend of step (j) into tablets by using suitable tooling.

Brief Manufacturing Process:
a) dissolve raltegravir potassium in purified water under stirring and add Plasdone™ S-630 under stirring to get clear solution and add talc under stirring;
b) spray the solution of step (a) onto the sugar spheres till there is complete drug loading on the sugar spheres;
c) dissolve ethyl cellulose in isopropyl alcohol under stirring (solution 1) and disperse the required quantity of hypromellose in isopropyl alcohol and add dichloromethane to the above solution with constant stirring to get clear solution and add solution 1 under stirring, add talc in final resulted solution and filter the solution through a suitable mesh or screen.
d) coat drug loaded pellets of step (b) with the solution of step (c) till a desirable weight gain is achieved, dry the coated pellets for suitable time to get coated particles;
e) sift microcrystalline cellulose, mannitol, fructose, crospovidone, saccharin sodium through # 30 ASTM;
f) sift orange flavor, iron oxide yellow, iron oxide red and mono sodium citrate anhydrous through # 60 ASTM;
g) blend the material of step (d), step (e) and step (f) material in blender for suitable time;
h) sift sodium stearyl fumarate through # 40 ASTM and lubricate with the material of step (g) blend for suitable time;
i) compress the lubricated blend into tablets by using suitable tooling.

Brief Manufacturing Process:
a) dissolve raltegravir potassium in purified water under stirring and add Plasdone™ S-630 under stirring to get clear solution and then add talc under stirring;
b) spray the solution of step (a) onto the sugar spheres till there is complete drug loading on the sugar spheres;
c) dissolve ethyl cellulose in Isopropyl alcohol under stirring (solution 1) and disperse the required quantity of hypromellose in Isopropyl alcohol and add dichloromethane to the above solution with constant stirring to get clear

solution and add solution 1 under stirring, then add talc in final resulted solution and filter the solution through a suitable mesh or screen;
d) coat drag loaded pellets of step (b) with the solution of step (c) till a desirable weight gain is achieved, dry the coated pellets for suitable time to get coated particles;
e) sift microcrystalline cellulose, mannitol, fructose, crospovidone, saccharin sodium through # 30 ASTM;
f) sift orange flavor, iron oxide yellow, iron oxide red and mono sodium citrate anhydrous through # 60 ASTM;
g) blend the material of step (d), step (e) and step (f) material in blender for suitable time;
h) sift sodium stearyl fumarate through # 40 ASTM and lubricate with the material of step (g) blend for suitable time;
i) compress the lubricated blend into tablets by using suitable tooling.
In-Process Quality Control Tests:
Tablets prepared according to Example 1, 5, 6 & 7 were subjected to in-process quality control tests and the resultant data are compiled in Table 1.

Dissolution Data:
Tablets prepared according to Example 1, 5, 6 & 7 and marketed Isentress® lOOmg were subjected to in-vitro dissolution test in 900ml of purified water, using USP Type II (with sinker) at 100 rpm and the resultant data is compiled in Table 2.
Above in-vitro dissolution data also shows that the tablets prepared according to Example 1, 6 and 7 has similar in-vitro dissolution profile as that of marketed Isentress® lOOmg tablets.
Stability Data:
Raltegravir tablets prepared according to Example 5 and 6 were packed in HDPE containers with 2gm desiccant and subjected to stability study for 3 months at 40 °C ± 2 °C/75% RH ± 5% RH and the resultant data is compiled in Table 3.

Above stability data shows that the tablets prepared according to Example 5 and 6 are stable at the end of 3 months at 40°C ± 2°C / 75% RH ± 5% RH.

WE CLAIM:

1. A chewable tablet formulation comprising raltegravir, silicified MCC, Plasdone™ and one or more pharmaceutically acceptable excipient(s), wherein said chewable tablet formulation is prepared by wet granulation process using fluid bed granulator.

2. A chewable tablet formulation comprising raltegravir and one or more pharmaceutically acceptable excipient(s), wherein said taste masked formulation comprises of:

a) a core particles comprising raltegravir, silicified MCC, Plasdone™ and one or more pharmaceutically acceptable excipient(s);
b) a taste masking coating layer over said core particles, comprising ethyl cellulose, HPMC and one or more pharmaceutically acceptable excipient(s);
wherein said step (a) and (b) are conducted in a fluid bed processor.

3. A chewable tablet formulation comprising raltegravir and one or more pharmaceutically acceptable excipient(s), wherein said taste masked formulation comprises of:
a) sugar spheres;
b) drug layer over the sugar spheres comprising raltegravir, Plasdone™ and one or more pharmaceutically acceptable excipient(s);
c) a taste masking coating layer over said drug layer coated sugar spheres, comprising ethyl cellulose, HPMC and one or more pharmaceutically acceptable excipient(s);
wherein said step (b) and (c) are conducted in a fluid bed processor.

4. A chewable tablet formulation comprising raltegravir and one or more pharmaceutically acceptable excipient(s) having following unit composition:

5. A chewable tablet formulation comprising raltegravir and one or more pharmaceutically acceptable excipient(s) having following unit composition:

6. A chewable tablet formulation according to any of the preceding claims, wherein said pharmaceutically acceptable excipient is selected from a group comprising of diluents, binders, disintegrants, taste masking polymers, sequestering agents, lubricants, coloring agents, flavoring agents, sweetening agents, taste modifier and stabilizer.

7. A chewable tablet formulation comprising raltegravir and one or more pharmaceutically acceptable excipient(s) as herein described and exemplified.