FIELD OF THE INVENTION
The invention relates to tablet compositions of etravirine comprising hydroxypropyl methyl cellulose having a methoxy content of 25.0 - 32.0% (w/w), a hydroxypropoxy content of 22.0 - 27.0% (w/w) and a viscosity of 10.0 - 20.0 cps and process for preparing such tablet compositions.
BACKGROUND OF THE INVENTION
Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) known from U.S Patent No. 6,878,717. It is chemically 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile having structure as below:
Tablets of etravirine for oral administration are currently being marketed in United States under the name INTELENCE® by Janssen Research and Development LLC approved to use in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents, and are available in three dosage strengths i.e., 25 mg, 100 mg and 200 mg.
U.S. Patent No. 7,887,845 claims solid dispersion comprising etravirine and one or more pharmaceutically acceptable water-soluble polymers.

U.S. Patent No. 9,603,803 claims process for preparing spray dried formulations comprising microcrystalline cellulose, hydroxypropyl methyl cellulose and etravirine in the ratio of 0.5:3:1.
Etravirine is classified as a BCS Class IV compound (i.e., a low aqueous solubility irrespective of pH, and low to intermediate permeability). It suffers from the disadvantage of being poorly soluble in aqueous media, and, as a result, having an undesirable dissolution profile and, consequently, poor bioavailability within the organism following oral administration. Thus, there exists a need to develop compositions without compromising on the formulation properties as well as dissolution profile.
SUMMARY OF THE INVENTION
In one general aspect, there is provided tablet compositions of etravirine comprising hydroxypropyl methyl cellulose having a methoxy content of 25.0 - 32.0% (w/w), a hydroxypropoxy content of 22.0 - 27.0% (w/w) and a viscosity of 10.0 - 20.0 cps.
In another general aspect, there is provided tablet compositions of etravirine comprising hydroxypropyl methyl cellulose having a methoxy content of 25.0 - 32.0% (w/w), a hydroxypropoxy content of 22.0 - 27.0% (w/w) and a viscosity of 10.0 - 20.0, wherein at least 85 wt % of etravirine dissolves within 10 minutes and at least 90 wt % of etravirine dissolves within 15 minutes.
In another embodiment, the present invention relates to use of composition of the present invention for use in combination with other antiretroviral agents for the treatment of HIV infection.
The tablet composition may further include one or more pharmaceutically acceptable excipients selected from the group of fillers/diluents, binders, disintegrants, surfactants, lubricants, glidants.
The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates tablet compositions of etravirine comprising hydroxypropyl methyl cellulose having a methoxy content of 25.0 - 32.0% (w/w), a hydroxypropoxy content of 22.0 - 27.0% (w/w) and a viscosity of 10.0 - 20.0 cps.
Etravirine suffers from the disadvantage of being poorly soluble in aqueous media, and, as a result, having an undesirable dissolution profile and, consequently, poor bioavailability within the organism following oral administration.
Inventors of the present invention has developed tablet compositions of etravirine comprising hydroxypropyl methyl cellulose having a methoxy content of 25.0 - 32.0% (w/w), a hydroxypropoxy content of 22.0 - 27.0% (w/w) and a viscosity of 10.0 - 20.0 cps.
The tablet compositions of etravirine comprising hydroxypropyl methyl cellulose having a methoxy content of 25.0 - 32.0% (w/w), a hydroxypropoxy content of 22.0 - 27.0% (w/w) and a viscosity of 10.0 - 20.0, wherein at least 85 wt % of etravirine dissolves within 10 minutes and at least 90 wt % of etravirine dissolves within 15 minutes.
The term "composition" as used herein refers to a dosage form suitable for oral administration, such as powder, granules, spheroids, pellets, pills, capsule, solution, suspension, emulsion and the like.
The term "pharmaceutically acceptable" as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.
The term "excipients" as used herein means a component of a pharmaceutical product that is not an active ingredient such as, for example, basic agents, sweeteners, flavors, diluents, carriers and the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
The term "premix" as used herein means the solid dispersion of etravirine, hydroxypropyl methyl cellulose and optionally, one or more pharmaceutically acceptable excipient.

As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, reference to "a method" includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure so forth.
The present invention relates tablet compositions of etravirine comprising hydroxypropyl methyl cellulose having a methoxy content of 25.0 - 32.0% (w/w), a hydroxypropoxy content of 22.0 - 27.0% (w/w) and a viscosity of 10.0 - 20.0 cps.
Preferred viscosity of hydroxypropyl methyl cellulose is 15 cps.
Hydroxypropyl methyl cellulose having a methoxy content of 25.0 - 32.0% (w/w), a hydroxypropoxy content of 22.0 - 27.0% (w/w) and a viscosity of 15 cps is available under the trade name as AFFINISOL™ HPMC HME from Dow Pharma & Food Solutions.
Etravirine and hydroxypropyl methyl cellulose (HPMC) is in the form of solid dispersion.
The amount of etravirine in the tablet composition is about 5% w/w to about 50% w/w, preferably, about 10% w/w to about 25% w/w.
The ratio of etravirine to hydroxypropyl methyl cellulose is 1:2 to 1:4.
A process for preparing tablet composition comprising:
a) preparing a solution comprising etravirine and hydroxypropyl methyl cellulose having a methoxy content of 25.0 - 32.0% (w/w), a hydroxypropoxy content of 22.0 - 27.0% (w/w) and a viscosity of 10.0 - 20.0 cps in a solvent, b) spray drying the solution of step (a),
c) granulating the spray dried powder of step (b) with one or more pharmaceutically
acceptable excipients,
d) blending the granules with one or more pharmaceutically acceptable excipients, and
e) compressing the blend into tablet dosage form.

The tablet composition is prepared by direct compression, dry granulation or wet granulation, preferably, dry granulation.
Etravirine in the tablet composition is in amorphous form.
Tablet compositions of etravirine of the present invention can be used in combination with other antiretroviral agents for the treatment of HIV infection.
The tablet composition further comprises at least one pharmaceutically acceptable excipient selected from diluents, binders, disintegrants, lubricants, glidants and the like.
Suitable fillers include, but are not limited to, micro crystal line cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol, erythritol and the like. The filler may be present in an amount of 5 to 80% by weight of the composition.
Suitable binders include, but are not limited to, carbomers, dextrin, ethyl cellulose, shellac, zein, gelatin, polymethacrylates (e.g., Eudragit), pregelatinized starch, sodium alginate, gums, synthetic resins, silicic acid and the like.
Suitable disintegrants include, but are not limited to, agar, alginic acid, bentonite, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylcellulose, cellulose, a cation exchange resin, cellulose, gums, citrus pulp, colloidal silicon dioxide, corn starch, croscarmellose sodium (e.g., Ac-DiSol®), crospovidone, guar gum, hydrous aluminum silicate, an ion exchange resin (e.g., polyacrin potassium), magnesium aluminum silicate, methyl cellulose, modified cellulose gum, modified corn starch, montmorillonite clay, natural sponge, polyacrilin potassium, potato starch, powdered cellulose, povidone, pregelatinized starch, sodium alginate, sodium bicarbonate in admixture with an acidulant such as tartaric acid or citric acid, sodium starch glycolate, starch, silicates (e.g., Veegum.RTM. HV), and combinations thereof.

Suitable lubricants include, but are not limited to, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, and combinations thereof.
Suitable glidants include, but are not limited to colloidal silicon dioxide, talc, starch, starch derivatives, and combinations thereof.
The solvent used in the solid dispersion of the present invention is selected from water, acetone, dichloromethane, ethanol, methanol, dimethyl sulfoxide or mixtures thereof, preferably, dichloromethane, ethanol and acetone, more preferably, mixture of ethanol, acetone and dichloromethane.

Brief manufacturing procedure:
Step 1: Dissolve Etravirine and Hypromellose 5 cps / Affinisol HME 15 cps in solvent blend
of Dehydrated Alcohol, and Methylene dichloride and evaporate solvent in spray dryer and
collect amorphous material (etravirine premix),
Step 2: sift etravirine premix, microcrystalline cellulose, croscarmellose sodium, colloidal
anhydrous silica through # 20 mesh and blend it for 15 min,
Step 3: sift magnesium stearate through #40 mesh,
Step 4: transfer material of step 3 into step 2 and blend it for 5 min,
Step 5: compact the material of step 4 using roller compactor,
Step 6: sift extra granular Silicified microcrystalline cellulose, croscarmellose sodium
through # 20 mesh,
Step 7: sift extra granular magnesium stearate through #40 mesh,
Step 8: blend material of step 5 and step 6 for 15 min in a suitable blender,
Step 9: lubricate blend of step 8 with step 7 and compress in to tablets with suitable tooling
set.

Brief manufacturing procedure:
Step 1: Dissolve Etravirine and Hypromellose 5 cps / Affinisol HME 15 cps in solvent blend
of Dehydrated Alcohol, and Methylene dichloride and evaporate solvent in spray dryer and
collect amorphous material (etravirine premix),
Step 2: sift etravirine premix, microcrystalline cellulose, croscarmellose sodium, colloidal
anhydrous silica through # 20 mesh and blend it for 15 min,
Step 3: sift magnesium stearate through #40 mesh,
Step 4: transfer material of step 3 into step 2 and blend it for 5 min,
Step 5: compact the material of step 4 using roller compactor,

Step 6: sift extra granular Silicified microcrystalline cellulose, croscarmellose sodium
through # 20 mesh,
Step 7: sift extra granular magnesium stearate through #40 mesh,
Step 8: blend material of step 5 and step 6 for 15 min in a suitable blender,
Step 9: lubricate blend of step 8 with step 7 and compress in to tablets with suitable tooling
set.
Dissolution Profile:
The tablets obtained by the above examples were subjected to dissolution test according to
United States Pharmacopoeia, Dissolution apparatus II, under following conditions:
Dissolution Medium: 1.0 % Sodium lauryl sulfate (SLS) in 0.01 M HC1 in two phases: Phase
1: 1000 mL of degassed 0.01 M HC1 for 10 minutes. Phase 2: Add 800 mL of 2.25% SLS in
0.01 MHC1.
Paddle rotation: 70 rpm
Volume of the medium (mL): 1000 (phase 1): 1800 (phase 2)

WE CLAIM:
1. A tablet composition comprising etravirine and hydroxypropyl methyl cellulose (HPMC) having a methoxy content of 25.0 - 32.0% (w/w), a hydroxypropoxy content of 22.0 - 27.0% (w/w) and a viscosity of 10.0 - 20.0 cps.
2. The tablet composition of claim 1, wherein at least 85 wt % of etravirine dissolves within 10 minutes and at least 90 wt % of etravirine dissolves within 15 minutes in 1.0 % Sodium lauryl sulfate (SLS) in 0.01 M HC1.
3. The tablet composition of claim 1, wherein the viscosity of hydroxypropyl methyl cellulose is 15 cps.
4. The tablet composition of claim 1, wherein the etravirine and hydroxypropyl methyl cellulose (HPMC) is in the form of solid dispersion.
5. The tablet of claim 1, wherein the amount of etravirine in the tablet composition is about 10% w/w to about 25% w/w.
6. The tablet composition of claim 1, wherein the etravirine and hydroxypropyl methyl cellulose is in the ratio of 1:2 to 1:4.
7. The tablet composition of claim 1, wherein the tablet further comprises at least one pharmaceutically acceptable excipient selected from diluents, binders, disintegrants, surfactants, lubricants, glidants and the like.
8. A process for preparing tablet composition comprising:

a) preparing a solution comprising etravirine and hydroxypropyl methyl cellulose having a methoxy content of 25.0 - 32.0% (w/w), a hydroxypropoxy content of 22.0 - 27.0% (w/w) and a viscosity of 10.0 - 20.0 cps in a solvent,
b) spray drying the solution of step (a),

c) granulating the spray dried powder of step (b) with one or more pharmaceutically acceptable excipients,
d) blending the granules with one or more pharmaceutically acceptable excipients, and
e) compressing the blend into tablet dosage form.
9. The solvent according to claim 8, is selected from water, acetone, dichloromethane,
ethanol, methanol, dimethyl sulfoxide or mixtures thereof.
10. The process of claim 8, wherein the tablet composition is prepared by dry
granulation.