FIELD OF INVENTION

The invention relates to the pharmaceutical field. More specifically, it relates to solid oral pharmaceutical compositions comprising rilpivirine and one or more pharmaceutically acceptable excipient(s).

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) and used in combination with other antiretroviral agents, which is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naive adult patients.

Rilpivirine hydrochloride is described chemically as, 4-[[4-[[4-[(E)-2-cyanoethenyl]-2, 6-dimethylphenyl] amino] 2-pyrimidinyl] amino] benzonitrile monohydrochloride. Its molecular formula is C22H18N6 • HC1 and its molecular weight is 402.88. Rilpivirine hydrochloride is a white to almost white powder and is practically insoluble in water over a wide pH range.

In the U.S., Rilpivirine hydrochloride is marketed under the brand name of Edurant® by Janssen, as an oral tablet containing 25mg of rilpivirine hydrochloride and the following inactive ingredients: croscarmellose sodium, magnesium stearate, lactose monohydrate, povidone K30, polysorbate 20 and
silicified microcrystalline cellulose. The tablet coating contains hypromellose 29106 mPa.s, lactose monohydrate, PEG 3000, titanium dioxide and triacetin.

U.S. Patent No. 7,638,522 discloses that rilpivirine free base as well as the hydrochloride salt have poor solubility in water as well as in 0.01 N HC1 and free base and hydrochloride salt may be classified as BCS class II compounds. It was also found that the solubility of the free base is significantly increased in polyethylene glycol 400. Therefore, there was a need to incorporate a wetting agent or surfactant in solid oral pharmaceutical composition to improve the solubility of rilpivirine free base and hydrochloride salt in water and as well as in 0.01 N HC1, the media present in the stomach. The preferred wetting agents according to said patent belongs to the group of sodium lauryl sulfate, sodium dioctyl sulfosuccinate or PEG sorbitan fatty acid esters, such as Tween, e.g. Tween 20™, Tween 60™, Tween 80™, most preferably Tween 20™. According to said patent, pharmaceutical composition comprises rilpivirine and from 0.01 to 5% w/w of a wetting agent; from 40 to 92% w/w of a diluent; from 0 to 10% w/w of a polymer; from 2 to 10% w/w of a disintegrant; from 0.1 to 5% w/w of a glidant; and from 0.1 to 1.5% w/w of a lubricant.

From the above prior art, it is clear that rilpivirine base and its hydrochloride salt is practically insoluble in water and therefore the use of wetting agent is essential or mandatory for improving the dissolution properties of rilpivirine base or hydrochloride salt present in a tablet.

There is no art or literature till date, which teaches that pharmaceutical compositions comprising rilpivirine could be made without the use of such a surfactant or a wetting agent that meets the dissolution standards as set out by the various International Agencies.

The present inventors surprisingly found that solid oral pharmaceutical compositions or tablets comprising rilpivirine or its acceptable salts can be prepared without the use of any wetting agent or a surfactant and said composition/ tablet being comparable with the brand Edurant® in terms of in-vitro dissolution, which contains a wetting agent or as surfactant.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to solid oral pharmaceutical compositions comprising rilpivirine and one or more pharmaceutically acceptable excipient(s). More specifically, it relates to solid oral tablet comprising rilpivirine and one or more pharmaceutically acceptable excipient(s), where in the tablet is free of a wetting agent(s).

One of the objectives of the invention is to prepare solid oral pharmaceutical compositions comprising rilpivirine and one or more pharmaceutically acceptable excipient(s), wherein the composition is free of a wetting agent(s).

Another objective of the invention is to prepare solid oral tablet comprising rilpivirine and one or more pharmaceutically acceptable excipient(s), wherein the tablet is free of a wetting agent(s).

Another objective of the invention relates to a process for preparing solid oral pharmaceutical compositions comprising rilpivirine and one or more pharmaceutically acceptable excipient(s), wherein the composition is free of a wetting agent(s).

Another objective of the invention relates to a process for preparing tablet comprising rilpivirine and one or more pharmaceutically acceptable excipient(s), wherein the tablet is free of a wetting agent(s).

An another objective of the invention relates to a wet granulation process for preparing oral tablet comprising rilpivirine and one or more pharmaceutically acceptable excipient(s), wherein the tablet is free of a wetting agent(s).

Yet another objective of the invention is to prepare solid oral tablet comprising rilpivirine and one or more pharmaceutically acceptable excipient(s) having comparable in-vitro dissolution profile with that of the marketed Edurant® tablet, wherein the tablet is free of a wetting agent(s).

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to solid oral pharmaceutical compositions comprising rilpivirine and one or more pharmaceutically acceptable excipient(s). More specifically, it relates to solid oral tablet comprising rilpivirine and one or more pharmaceutically acceptable excipient(s), wherein the tablet is free of a wetting agent(s). The present inventors surprisingly found that oral pharmaceutical tablet comprising rilpivirine and free of a wetting agent(s) can be prepared successfully, wherein said tablet exhibits comparable in-vitro dissolution profile to that of marketed Edurant®.

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 rilpivirine or its pharmaceutically acceptable salts or esters or derivatives thereof.

More specifically, the term "rilpivirine" is intended to include the base itself, as well as its pharmaceutically acceptable salts or derivatives thereof. It may also include solvates, hydrates, enantiomers etc. Pharmaceutically acceptable salts include but are not limited to hydrochloride, hydro bromide, sulphate, acetate, tartrate, citrate, fumarate, tosylate, malate, phosphate, besylate, succinate, mesylate, and the likes. More specifically, the hydrochloride salt is preferred.

According to the invention, rilpivirine may be present in amorphous or crystalline form or other solvated forms or hydrated or mixed forms. More specifically, rilpivirine hydrochloride may be in pure crystalline form or in pure amorphous state or in a mixed crystalline and amorphous form.

In the context of the invention, the solid oral composition of rilpivirine preferably includes granules, pellets, mini-tablets, tablets, modified release tablets and capsules filled with granules or pellets.

According to the invention, the process of preparing solid oral pharmaceutical composition comprising rilpivirine and one or more pharmaceutically acceptable excipient(s), involves the process of either wet granulation or dry granulation or direct compression.

As used herein, the term "wet granulation" relates to a process by which powder particles are made to adhere to each other to form agglomeration of particles called as agglomerates or granules by the addition of a granulation fluid onto a bed of powder or powder blend. The wet granulation could be carried out using an aqueous or non-aqueous or mixture of aqueous and non-aqueous granulation fluid.

As used herein, the term, "direct compression" relates to the process by which tablets are compressed directly from the powder blend of active ingredient and suitable pharmaceutically acceptable excipient(s).
As used herein, the term, "dry granulation" relates to the process of dry granulating the powder blend of active ingredients and suitable pharmaceutically acceptable excipient(s) without the use of granulating solvent/liquid.

As used herein, the term "wetting agent" relates to a chemical substance which lowers the surface tension at a water-solid interface, and thereby improves the solubility/ dissolution of said solid in water, wherein the solid is preferably a drug substance, which according to the invention is rilpivirine.

According to the invention, the solid oral pharmaceutical composition comprising rilpivirine and one or more pharmaceutically acceptable excipient(s), is free of a wetting agent(s)/ surfactant(s) such as anionic, cationic, zwitterionic or non-ionic having a HLB value greater than about 10, which are generally considered as being hydrophilic wetting agents. The preferred wetting agent(s)/ surfactant(s) which according to the invention is not present or contained in the oral pharmaceutical composition or solid oral tablet belongs to a group consisting of sodium lauryl sulfate, sodium dioctyl sulfosuccinate or PEG sorbitan fatty acid esters, such as Tween, e.g. Tween 20™, Tween 60™, Tween 80™, most preferably Tween 20™.

According to an embodiment of the invention, wet granulation process for preparing solid oral composition of rilpivirine involves the use of either aqueous or non-aqueous or hydro-alcoholic solvent as a granulating liquid or solvent, most preferably an aqueous solvent. Such an aqueous solvent is selected among purified water or mixture of alcoholic solvents and purified water.

According to an embodiment of the invention, non-aqueous solvents for use in granulation process steps include, but are not limited to methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, ethyl acetate, dimethylsulfoxide or their combinations thereof.

According to an embodiment of the invention, hydro-alcoholic solvents are mixtures of one or more alcohols and purified water, in various volume ratios.

According to an embodiment of the invention, the solid oral tablet comprising rilpivirine and one or more pharmaceutically acceptable excipient(s) is most preferably prepared by employing aqueous wet granulation process.

According to an embodiment of the invention, a fluid bed processor (FBP) is used for aqueous wet granulation process. Alternatively rapid mixer granulator (RMG) and fluid bed dryer (FBD) can also be used for wet granulation process and drying the wet granules (drying process) respectively.

The tablet dosage form of the invention may be prepared by using one or more pharmaceutically acceptable excipient(s) which may be selected from the group comprising of diluents, binder, disintegrants/super-disintegrants, glidants, and/ or lubricants.

Suitable diluent(s) according to the invention include, but are not limited to, mannitol, xylitol, sorbitol, lactose, sucrose, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, starch, calcium trisilicate, magnesium trisilicate, cellulose acetate, dextrose, or combinations thereof.

Suitable binder(s) according to the invention include, but are not limited to povidone, copovidone, pregelatinized starch, polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), starch, hydroxyethyl cellulose (HEC), chitosan, gelatin, guar gum, methyl cellulose (MC), Carbomer™, or combinations thereof. The binder may be present in the composition in the weight percentage of 2 to 25% w/w. More preferably said binder may be present in the weight percentage between 5-20% w/w.

Suitable disintegrant(s) according to the invention include, but are not limited to crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), pregelatinised starch, starch, microcrystalline cellulose, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, polacrilin potassium or combinations thereof.

Suitable glidant(s) and lubricant(s) according to the invention include, but are not limited to, colloidal silicon dioxide, talc, magnesium stearate, sodium stearyl fumarate, calcium stearate or combinations thereof.

According to the invention, film coating excipient(s) may be selected from a group comprising of film polymers, plasticizers, opacifiers, and coloring agents, etc.

Suitable film polymer(s) according to the invention include, but are not limited to, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), methyl cellulose (MC) and ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methacrylic acid copolymer, cellulose acetate phthalate, cellulose phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, and natural gums and resins such as zein, gelatin, shellac and acacia or combinations thereof.

Suitable plasticizer(s) according to the invention include, but are not limited to castor oil, polyethylene glycol, propylene glycol, glycerin, triacetin, polysorbates, phthalate esters, dibutyl sebacate, citrate esters, and monoglycerides or combinations thereof.

Suitable opacifier(s) according to the invention include, but are not limited to titanium dioxide and talc or combinations thereof.

Suitable coloring agent(s) according to the invention include, but are not limited to FDA approved dyes and lakes such as sunset yellow, tartrazine, erythrosine, iron oxide yellow and natural colors such as carmine or combinations thereof.

According to the invention ready-to-use / ready mix film coating systems such as Opadry® and Instacoat™ may also be used for film coating of tablets.

According to an embodiment of the invention, the solid oral tablet consists of rilpivirine hydrochloride, lactose, croscarmellose sodium, copovidone, silicified microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate, wherein the process for preparing said tablet involves aqueous wet granulation.

According to an embodiment of the invention, the process for preparing solid oral tablet comprising rilpivirine and one or more pharmaceutically acceptable excipient(s) includes the steps of:

1. Dissolving a binder in purified water to get binder solution;

2. Sifting and mixing rilpivirine and one or more pharmaceutically acceptable excipient(s) to get uniform blend;

3. Spray granulating the blend of step (2) in a fluid bed processor (FBP) using binder solution obtained in step (1) to get granules;

4. Sifting the dried granules of step (3) through suitable seize sieve to get dry granules of suitable size;

5. Blending the sifted granules of step (4) with extragranular excipient(s);

6. Lubricating the blend of step (5) and compressing in to tablets; and

7. Film coating the tablets obtained in step (6).

According to an embodiment of the invention, another process for preparing solid oral tablet comprising rilpivirine and one or more pharmaceutically acceptable excipient(s) includes the steps of:

1. Dissolving a binder in purified water to get a binder solution;

2. Sifting and mixing rilpivirine and one or more pharmaceutically acceptable excipient(s) to get a uniform blend;

3. Granulating the blend of step (2) in a rapid mixer granulator (RMG) using binder solution obtained in step (1) to get wet granules;

4. Drying the wet granules of step (3) in a fluid bed dryer (FBD) to get dried granules;

5. Sifting the dried granules of step (4) through suitable seize sieve to get dry granules of suitable size;

6. Blending the sifted granules of step (5) with extra-granular excipient(s);

7. Lubricating the blend of step (6) and compressing in to tablets; and

8. Film-coating the tablets obtained in step (7).

EXAMPLES:

Following example are illustrative only and do not limit the scope of this invention.

Brief manufacturing process:

1. Dissolve copovidone in water.

2. Sift lactose, croscarmellose sodium and rilpivirine hydrochloride using suitable size sieve and mix well to get uniform blend.

3. Granulate the blend obtained in step (2) in a rapid mixer granulator (RMG) with copovidone solution obtained in step (1) to get wet granules.

4. Dry the wet granules obtained in step (3) using fluid bed dryer (FBD) and sift through suitable seize sieve.

5. Blend the sifted dried granules obtained in step (4) with silicified microcrystalline cellulose,
croscarmellose sodium and colloidal silicon dioxide.

6. Lubricate the blend obtained in step (5) with magnesium stearate.

7. Compress the lubricated blend of step (6) into tablet.

8. Film-coat the compressed tablets of step (7) using aqueous dispersion of Opadry® white.

Brief manufacturing process:

1. Dissolve copovidone in water.

2. Sift lactose, croscarmellose sodium and rilpivirine hydrochloride using suitable size sieve and mix well to get uniform blend.

3. Spray-granulate the blend obtained in step (2) in a fluid bed processor (FBP) with copovidone solution obtained in step (1) to get granules.

4. Sift the dried granules obtained in step (3) through suitable seize sieve.

5. Blend the sifted granules obtained in step (4) with silicified microcrystalline cellulose, croscarmellose sodium and colloidal silicon dioxide.

6. Lubricate the blend obtained in step (5) with magnesium stearate.

7. Compress the lubricated blend of step (6) into tablet.

8. Film-coat the compressed tablets of step (7) using aqueous dispersion of Opadry® white.

Comparative in-vitro dissolution data:

Rilpivirine hydrochloride tablets prepared according to Example-1 and the marketed Edurant® tablets were subjected to in-vitro dissolution test in 900ml of 0.01 N HC1 containing 0.5% of polysorbate 20, using USP type II dissolution apparatus at 50 rpm and the resultant data is compiled in Table-1.

Also, the rilpivirine hydrochloride tablets prepared according to Example-1 and the marketed Edurant® tablets were subjected to in-vitro dissolution test in 900ml of 0.01 N HC1 without containing 0.5% of polysorbate 20, using USP type II dissolution apparatus at 50 rpm and the resultant data is compiled in Table-2, to check whether 0.5% of polysorbate 20 present in the dissolution medium had any effect in the drug dissolution profile. However, to our surprise we found that polysorbate 20 had no effect on the drug dissolution and release profile for either Edurant® or the tablets of Example 1 according to the invention.

Above dissolution data (Table 1 & Table 2) shows that the tablets prepared according to Example-1 has comparative in-vitro dissolution profile as that of marketed Edurant®.

Stability Data:
Rilpivirine hydrochloride tablets prepared according to Example-1 were packed in HDPE bottles and were subjected to accelerated stability study at 40°C/75%RH and the resultant data are compiled in Table-3.

Table-3
Rilpivirine hydrochloride tablets prepared according to Example-1 were found stable at the end of 8 weeks at 40°C/ 75% RH.

WE CLAIM:

1. A solid oral pharmaceutical composition comprising rilpivirine and one or more pharmaceutically acceptable excipient(s), wherein said composition is free of a wetting agent(s).

2. A solid oral pharmaceutical composition in the form of tablet comprising rilpivirine and one or more pharmaceutically acceptable excipient(s), wherein said tablet is free of a wetting agent(s).

3. A wet-granulation process for preparing a solid oral tablet comprising rilpivirine and one or more pharmaceutically acceptable excipient(s); wherein said tablet is free of a wetting agent (s).

4. The wet-granulation process according to claim 3, wherein said process involves the steps of:

a. dissolving a binder in a solvent to get binder solution;

b. sifting and mixing rilpivirine and one or more pharmaceutically acceptable excipient(s) to get uniform blend;

c. spray granulating the blend of step (b) in a fluid bed processor using binder solution obtained in step (a) to get granules;

d. sifting the dried granules of step (c) through suitable seize sieve to get dry granules of suitable size;

e. blending the sifted granules of step (d) with extra-granular excipient(s);

f. lubricating the blend of step (e) and compressing in to tablets; and

g. film-coating the tablets obtained in step (f).

5. The wet-granulation process according to claim 3, wherein said process involves the steps of:

a. dissolving a binder in a solvent to get a binder solution;

b. sifting and mixing rilpivirine and one or more pharmaceutically acceptable excipient(s) to get a uniform blend;

c. granulating the blend of step (b) in a rapid mixer granulator using binder solution obtained in step (a) to get wet granules;

d. drying the wet granules of step (c) in a fluid bed dryer to get dried granules;

e. sifting the dried granules of step (d) through suitable seize sieve to get dry granules of suitable size;

f. blending the sifted granules of step (e) with extra-granular excipient(s);

g. lubricating the blend of step (f) and compressing in to tablets; and

h. film-coating the tablets obtained in step (g).

6. The solid oral pharmaceutical composition or tablet according to any of the preceding claim(s), wherein said rilpivirine is selected from rilpivirine hydrochloride.

7. The solid oral pharmaceutical composition or tablet according to any of the preceding claim(s), wherein said pharmaceutically acceptable excipient is selected from a group comprising of diluent(s), binder(s), disintegrant(s), glidant(s), lubricant(s) or combinations thereof.

8. The binder according to any of the preceding claim(s) is selected from a group consisting of povidone, copovidone, pregelatinized starch, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, starch, gelatin, hydroxyethyl cellulose, chitosan, guar gum, methyl cellulose, Carbomer ™, or combinations thereof.

9. The process according to claims 4 or 5 wherein said solvent is selected from a group consisting of purified water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, dimethylsulfoxide or their combinations thereof.

10. A solid oral tablet comprising rilpivirine having following unit composition: