FIELD OF INVENTION

The present invention relates to novel combinations of anti-retroviral agents.
More particularly, the present invention relates to pharmaceutical compositions comprising novel combinations of efavirenz, tenofovir, emtricitabine with HIV integrase inhibitor which exhibits antiretroviral activity.

BAC KGROUND OF THE INVENTION AND RELATED PRIOR ART

Human immunodeficiency virus (HIV) infection is a major worldwide medical problem. The number of new cases of HIV and AIDS (acquired immunodeficiency syndrome) continues to rise rapidly. Currently approved drugs for the treatment of HIV infection, include:

i. nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine;

ii. nucleotide reverse transcriptase inhibitor (NtRTI) such as tenofovir disoproxil fumarate;

iii. non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine, delavirdine and efavirenz;

iv. protease inhibitors (Pis) such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir (combined with ritonavir at 4/1 ratio) and atazanavir;

v. fusion inhibitors such as enfuvirtide;

vi. entry inhibitors such as maraviroc;

vii. integrase inhibitors (IIs), such as raltegravir (MK-0518).

Integrase inhibitors are designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Integrase inhibitors were initially developed for the treatment of HIV infection, but they could be applied to other retroviruses.

Raltegravir (RTG) potassium is a first-in-class integrase inhibitor. Chemically, it is N-[(4-Fluorophenyl) methyl]-1, 6-dihydro5-hydroxy-l-methyl-2-[1 -methyl- l-[[(5-methyl-l, 3, 4-oxadiazol-2-yl) carbonyl] amino] ethyl]-6-oxo-4-pyrimidine carboxamide mono potassium salt.

It is marketed singly as ISENTRESS® as tablets for oral administration. Raltegravir is disclosed in U.S. Patent No. 7,169,780.
Elvitegravir (EVG) is an investigational HIV integrase inhibitor. Chemically, it is 6-[(3-Chloro-2-fluorophenyl) methyl]-1-[(25)-l-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxoquinoline-3-carboxylic acid.3

Efavirenz is a NNRTI antiretroviral drug. Chemically, it is 8-chloro-5-(2-cyclopropyl-ethynyl)-5-(trifluoromethyl)-4-oxa-2-azabicyclo [4.4.0] deca-7, 9, ll-trien-3-one.

It is marketed singly as SUSTIVA® and in combination with tenofovir and emtricitabine, under the brand name ATRIPLA®. Efavirenz is disclosed in U.S. Patent Nos. 5,519,021, and 6,939,964.

Emtricitabine is a cytidine analog NRTI drug. Chemically, it is (4-amino-5-fluoro-l-[2-(hydroxylrnethyl)-l, 3-oxathiolan-5-yl]-pyrimidin-2-one. It is disclosed in U.S. Patent Nos. 5,814,639 and 5,914,331. (-) enantiomer of cis emtricitabine is disclosed in U.S. Patent No. 6,703,396.

Tenofovir is an NtRTIs drug. Chemically, it is l-(6-aminopurin-9-yl) propan-2-yloxymethylphosphonic acid. Commercially it is marketed as tenofovir disoproxil fumarate (a prodrug of tenofovir); which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. Tenofovir is disclosed in
U.S. Patent Nos. 5,977,089 and 5,922,695.

U.S. Application No. 2007/0077295 and 2007/0099902 disclose stable dry granulated preparations of emtricitabine/tenofovir disoproxil fumarate.

WO2004064845 discloses therapeutic combinations of tenofovir disoproxil fumarate, emtricitabine, efavirenz and treatment of HIV infections including infections with HIV mutants bearing resistance to nucleoside and/or non- nucleoside inhibitors.

WO2008096369 discloses monolithic tablet formulation comprising tenofovir, efavirenz, emtricitabine and one or more pharmaceutically acceptable carriers or excipients.

US20100285122 discloses combination compositions of elvitegravir, emtricitabine, tenofovir disoproxil fumarate and cobicistat and the process for preparing the said compositions.

The use of combinations of compounds can yield an equivalent anti-retroviral effect with reduced toxicity, or an increase in drug efficacy. Lower overall drug doses can reduce the frequency of occurrence of drug-resistant variants of HIV. Lower doses predict better patient compliance when pill burden decreases, dosing schedules are simplified and, optionally, if synergy between compounds occurs [Loveday, C. "Nucleoside reverse transcriptase inhibitor resistance" (2001): Journal of Acquired Immune Deficiency Syndromes 26:S10-S24].

There is a need for new compositions of orally-active anti-retroviral drug combination for the treatment of patients infected with HIV that provide enhanced therapeutic safety and efficacy, impart lower resistance, and assist in higher patient compliance. Further there is also need for anti-retroviral drug products having combination of drugs in a unit dose, which helps in treating AIDS effectively and improves patient compliance, which avoids consuming multiple drugs at different intervals of time.

SUMMARY AND OBJECTIVES OF THE INVENTION

The present invention relates to novel combinations of anti-retroviral agents. More particularly, the present invention relates to novel pharmaceutical compositions of efavirenz, tenofovir, emtricitabine with HIV integrase inhibitors which exhibits anti-retroviral activity.

In one embodiment, the invention provides pharmaceutical compositions comprising an effective novel combination of efavirenz, tenofovir, emtricitabine with raltegravir/ elvitegravir.

In another embodiment, the invention provides processes for various pharmaceutical compositions comprising the novel combination of efavirenz, tenofovir, emtricitabine with raltegravir/ elvitegravir.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel combinations of anti-retroviral agents. More particularly, the present invention relates to novel pharmaceutical compositions of efavirenz, tenofovir, emtricitabine with HIV integrase inhibitors which exhibits anti-retroviral activity.

The term "Novel combination" includes any new combination, mixture, aggregation, addition of two or more antiretroviral drugs

The term "efavirenz" is meant to include the free base form, pharmaceutically acceptable salt forms, solvates of either the free base or salt forms, hydrates of either the free base or salt forms, crystalline forms, amorphous forms, and isotopically enriched or labeled forms of the compound 8-chloro-5-(2-cyclopropylethynyl)-5-(trifluoromethyl)-4-oxa-2-azabicyclo[4.4.0]deca-7,9,11 -trien-3-one.

The term "emtricitabine" is meant to include the free base form, pharmaceutically acceptable salt forms, solvates of either the free base or salt forms, hydrates of either the free base or salt forms, crystalline forms, amorphous forms, and isotopically enriched or labeled forms of the compound (4-amino-5-fluoro-1 -[2-(hydroxylmethyl)-1,3-oxathiolan-5-yl]-pyrimidin-2-one.

The term "tenofovir" is meant to include the free base form, alternative pharmaceutically acceptable salt forms, solvates of either the free base or salt forms, hydrates of either the free base or salt forms, crystalline forms , amorphous forms, and isotopically enriched or labeled forms of the compound l-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid. It also includes the prodrug of tenofovir. Preferably tenofovir selected include tenofovir disoproxil fumarate.

The term "raltegravir" is meant to include the free base form, pharmaceutically acceptable salt forms, solvates of either the free base or salt forms, hydrates of either the free base or salt forms, crystalline forms , amorphous forms, and isotopically enriched or labeled forms of the compound N-[(4-Fluorophenyl) methyl]-l, 6-dihydro5-hydroxy-1 -methyl-2-[ 1 -methyl-1 -[[(5-methyl-l,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide mono potassium salt.

The term "elvitegravir" is meant to include the free base form,pharmaceutically acceptable salt forms, solvates of either the free base or salt
forms, hydrates of the free base or salt forms, crystalline forms, amorphous forms,and isotopically enriched or labeled forms of the compound 6-[(3-Chloro-2-fluorophenyl)methyl]-l-[(2S)-l-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-
oxoquinoline-3-carboxylic acid.

The present invention also includes compositions comprising pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

The compositions of the invention can be administered in the form of single pharmaceutical compositions in novel combination with one or more pharmaceutically acceptable excipients.

Accordingly, the invention also includes pharmaceutical compositions which contain the active ingredients, i.e., (A) emtricitabine; (B) tenofovir disoproxil fumarate; (C) efavirenz; and (D) raltegravir; or (A) emtricitabine; (B) tenofovir disoproxil fumarate; (C) efavirenz; and (D) elvitegravir, in combination with one or more pharmaceutically acceptable excipients.

Pharmaceutical composition comprising novel combination of efavirenz, emtricitabine, tenofovir with raltegravir/ elvitegravir can be formulated as pharmaceutical compositions for administration in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, monolayer tablets, multilayer tablets or mini-tablets. Preferably the composition is in the form of tablets or granules in capsules. Multilayer tablets according to the invention are the tablets with more than one layer.

Pharmaceutically acceptable excipients which can be used in the preparation of the composition according to the invention may include, but are not limited to diluents such as 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; binders such as acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, maltodextrin, methylcellulose,polymethacrylates, povidone,pregelatinized starch,sodium alginate, and starch.; disintegrants such as 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 ; surfactants such as anionic and cationic surfactants, such as sodium lauryl sulfate, docusate sodium (dioctyl sulfosuccinate sodium salt), benzalkonium chloride, benzethonium chloride, and cetrimide; suitable glidants and lubricants such as colloidal silicon dioxide, talc, stearic acid and its salts and the like. Other pharmaceutically acceptable excipients include but not limited to film former, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

The manufacturing process is directed to one embodiment of the invention. This embodiment entails the preparation of an oral pharmaceutical composition comprising combination of efavirenz, emtricitabine, tenofovir with raltegravir/ elvitegravir.

Processing techniques employed prior to compressing into a tablet involve but not limited to direct compression or granulation techniques such as dry granulation or wet granulation. In dry granulation, the ingredients are blended in dry form, made denser by slugging or compaction and reduced to granules by grinding or milling, using suitable equipment.

The ground particles or granules can be compressed into tablet form or either filled into empty capsule shells in conventional manner using lubricants, glidants, etc., which can take any of the conventional shapes, e.g., round, elongated, oval, etc. A tablet press fitted with suitably sized punches and dies can be used to form the tablet core.

The wet granulation technique can also be used. According to this procedure, the active ingredient, other diluents are blended, for example, in a planetary mixer or a rapid mixer granulator. The powders are wetted with a granulating liquid like water, isopropyl alcohol or acetone or dichloromethane and other hydro-alcoholic solvents such as isopropyl alcohol-water mixture. Binders may be included in the granulating liquid. The moist mass is granulated, e.g., by forcing through a screen of suitable mesh size, dried, and, if desired, the particles further reduced in size. Granulates are then either filled into empty capsule shells or compressed into tablets in conventional manner, using lubricants, glidants, etc., as required.

The tablet core can optionally be coated with a film coat, which provides an aesthetic appeal or can also provide some functional role such as moisture protection, taste masking etc. The film coat may comprise polymers such as cellulose derivatives such as but not limited to Opadry™.

Conventional coating machines, for example, pan coaters, rotary drum-type coaters, Wurster-type fluidizing coaters and fluidizing coaters may be employed in the method of the invention.

One embodiment of the manufacturing method for the oral pharmaceutical composition of combination tablet employs separate granulation steps. The efavirenz blend (efavirenz and excipients) is produced by a wet granulation process whereas emtricitabine, tenofovir, and raltegravir/ elvitegravir and suitable excipients are blended and dry granulated by a roller compaction process. The final blends can be compressed into a monolayer or bilayer tablet or trilayer or inlay tablet which in turn can be film-coated.

The compositions prepared according to the invention are studied for invitro drug release profile. The invitro release profile studies can be done by using any method and apparatus known at the time of invention

The following examples illustrate specific aspects and some 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.

Example: 1

A. Tenofovir + Emtricitabine+ Efavirenz + Raltegravir
Efavirenz Granules- A:

S. No. Ingredients mg/unit dosage
1. Efavirenz 600.0
2. Microcrystalline Cellulose 140.0
3. Croscarmellose sodium 24.0
4. Hydroxy propyl cellulose 46.0
5. Sodium lauryl sulfate 6.0
6. Purified water q.s.
7. Croscarmellose sodium 8.0
8. Magnesium stearate 6.0
Total Efavirenz granules weight 700.0

Emtricitabine-Tenofovir Granules- B:

S. No. Ingredients mg/unit dosage
1. Emtricitabine 200.0
2. Tenofovir disoproxil fumarate 300.0
3. Microcrystalline Cellulose 90.0
4. Croscarmellose sodium 40.0
5. Lactose monohydrate 120.0
6. Magnesium stearate 14.0
7. Croscarmellose sodium 8.0
8. | Magnesium stearate 8.0
Total Emtricitabine-tenofovir granules 780.0
weight I

Raltegravir Granules- C:

S. No. Ingredients mg/unit dosage
1. Raltegravir 400.0
2. Microcrystalline Cellulose 240.0
3. Crosprovidone 25.0
4. Croscarmellose sodium 40.0
5. Lactose monohydrate 160.0
6. Magnesium stearate qs
7. Croscarmellose sodium 8.0
8. Magnesium stearate 7.0
Total Raltegravir granules
Weigh 660.0
9. OpadryTM 60.0
10. Purified water Qs
Total Tablet weight 2200.0

Brief Manufacturing Process for Preparation of Granules:

A. Efavirenz Granules:

1. Sift Efavirenz, Microcrystalline cellulose, Croscarmellose sodium Part 1, Hydroxypropyl cellulose and Sodium Lauryl Sulfate together through a suitable sieve.

2. Sift Croscarmellose sodium Part 2 through a suitable sieve.

3. Sift Magnesium stearate through a suitable sieve.

4. Load the material of step no. 1 into rapid mixer granulator and mix for suitable time period.

5. Granulate the material of step no 4 with required quantity of water.

6. Dry the wet mass of step no. 5 in fluid bed drier, till desirable LOD is obtained.

7. Pass the dried granules through a suitable screen / sieve and load into the blender.

8. Add the sifted material of step no. 2 to the material of step no. 7 and blend for suitable time period.

9. Add magnesium stearate of step no. 3 to step no. 8 and continue blending for suitable time period.

B. Emtricitabine-Tenofovir disoproxil fumarate granules:

1. Sift Tenofovir disoproxil fumarate and Lactose monohydrate together through a suitable sieve.

2. Sift Emtricitabine, Microcrystalline cellulose, Croscarmellose sodium through a suitable sieve.

3. Sift Magnesium stearate (Part 1) through a suitable sieve.

4. Sift Magnesium stearate (Part 2) through a suitable sieve.

5. Load the material of step no. 1 and 2 into bin-blender and mix for suitable time period.

6. Add the sifted material of step no. 3 to the blend of step no. 5 and mix for suitable period.

7. Compact the material of step no. 6 and mill the compacts through a suitable screen followed by sifting using suitable sieve to separate granules and fines.

8. Repeat the step no. 7 using fines obtained till desired ratio of fines and granules is obtained.

9. Load the granules of step no. 7 and 8 and fines of step no 8 into the blender and blend for suitable period of time.

10. Add the material of step no. 4 to the material of step no 9 and continue blending for suitable period.

C. Raltegravir Granules:

1. Sift Raltegravir, MCC, Lactose, Crospovidone and Croscarmellose sodium through suitable screen/seive

2. Compact Step 1 materials using Roller compactor.

3. Mill the granules using suitable screen to collect fines and granules, repeat until desired granules are obtained.

4. Sift Magnesium stearate through suitable screen/sieve.

5. Blend step 2 fines and granules for specified time and continue blending with sifted magnesium stearate for specified time.

Brief Manufacturing Process for Preparation of Tablets:

1. Monolayer Tablet Dosage form
2. Bilayer Tablet Dosage form
3. Trilayer Tablet Dosage form
4. Inlay Tablet (Tablet in Tablet)

1. Monolayer Tablet Dosage form:

1. Blend Efavirenz granules, Tenofovir-Emtricitabine granules and Raltegravir granules.

2. Compress the granules of Step 1 using tablet compressing machine with tablet tool.

3. Coat the tablets using Opadry™ coating suspension.

2. Bilayer Tablet dosage form:

1. Blend Efavirenz granules separately.

2. Blend Tenofovir-Emtricitabine granules and Raltegravir granules seperately

3. Compress the granules of Step 1 and Step
2 using bilayer tablet compression machine.

4. Coat the tablets using Opadry™ coating.

3. Trilayer Tablet Dosage form
1. Blend Efavirenz granules separately.
2. Blend Tenofovir-Emtricitabine granules separately
3. Blend Raltegravir granules separately
4. Compress the granules of Step 1, Step 2 and Step 3 using trilayer tablet compression machine with tablet tool having Efavirenz in one layer and Tenofovir-Emtricitabine in second layer and Raltegravir in third layer.
5. Coat the tablets using Opadry™ coating.

4. Inlay Tablet Dosage form (Tablet in Tablet)

1. Blend Efavirenz granules separately.
2. Blend Tenofovir- Emtricitabine granules and Raltegravir separately
3. Compress the granules of Step 1 to produce tablets.
4. Compress the blend of Step 2 blend having Efavirenz tablet inlayed with Tenofovir-Emtricitabine granules and Raltegravir blend using tablet in tablet compression machine
5. Coat the tablets using Opadry™ coating.

Example: 2
B. Tenofovir + Emtricitabine + Efavirenz + Elvitegravir

Efavirenz Granules- A:

S. No. Ingredients mg/unit dosage
1. Efavirenz 600.0
2. Microcrystalline Cellulose 140.0
3. Croscarmellose sodium 24.0
4. Hydroxy propyl cellulose 46.0
5. Sodium lauryl sulfate 6.0
6. Purified water qs
7. Croscarmellose sodium 8.0)
8. Magnesium stearate 6.0
Total weight of Efavirenz granules 700.0

Emtricitabine-Tenofovir Granules- B:

S. No. Ingredients mg/ unit dosage
1. Emtricitabine 200.0
2. Tenofovir disoproxil fumarate 300.0
3. Microcrystalline Cellulose 90.0
4. Croscarmellose sodium 40.0
5. Lactose monohydrate 120.0
6. Magnesium stearate 14.0
7. Croscarmellose sodium 8.0
8. Magnesium stearate 8.0
Total Emtricitabine-Tenofovir
granules weight 780.0

Elvitegravir Granules- C:

S. No. Ingredients mg/ unit dosage
1. Elvitegravir 150.0
2. Microcrystalline Cellulose 230.0
3. Crosprovidone 25.0
4. Croscarmellose sodium 40.0
5. Lactose monohydrate 160.0
6. Magnesium stearate qs
7. Croscarmellose sodium 8.0
8. Magnesium stearate 7.0
Total Elvitagrayir granules weight 400.0
9. Opadry™ 60.0
10. Purified water Qs
Total Tablet weight 1940.0

Brief Manufacturing Process for Preparation of Granules:

A. Efavirenz Granules:

1. Sift Efavirenz, Microcrystalline cellulose Croscarmellose sodium Part 1, Hydroxypropyl cellulose and Sodium Lauryl Sulfate together through a suitable sieve.

2. Sift Croscarmellose sodium Part 2 through a suitable sieve.

3. Sift Magnesium stearate through a suitable sieve.

4. Load the material of step no. 1 into rapid mixer granulator and mix for suitable time period.

5. Granulate the material of step no 4 with required quantity of water.

6. Dry the wet mass of step no. 5 in fluid bed drier, till desirable LOD is obtained.

7. Pass the dried granules through a suitable screen / sieve and load into the blender.

8. Add the sifted material of step no. 2 to the material of step no. 7 and blend for suitable time period.

9. Add magnesium stearate of step no. 3 to step no. 8 and continue blending for suitable time period.

B. Emtricitabine-Tenofovir disoproxil fumarate granules:

1. Sift Tenofovir disoproxil fumarate and Lactose monohydrate together through a suitable sieve.

2. Sift Emtricitabine, Microcrystalline cellulose, Croscarmellose sodium through a suitable sieve.

3. Sift Magnesium stearate (Part 1) through a suitable sieve.

4. Sift Magnesium stearate (Part 2) through a suitable sieve.

5. Load the material of step no. 1 and 2 into bin-blender and mix for suitable time period.

6. Add the sifted material of step no. 3 to the blend of step no. 5 and mix for suitable period.

7. Compact the material of step no. 6 and mill the compacts through a suitable screen followed by sifting using suitable sieve to separate granules and fines.

8. Repeat the step no. 7 using fines obtained till desired ratio of fines and granules is obtained.

9. Load the granules of step no. 7 and 8 and fines of step no 8 into the blender and blend for suitable period of time.

10. Add the material of step no. 4 to the material of step no 9 and continue blending for suitable period.

C. Elvitegravir Granules:

1. Sift Elvitegravir , MCC, Lactose, Crospovidone and Croscarmellose sodium through suitable screen/seive

2. Compact Stepl materials using Roller compactor.

3. Mill the granules using suitable screen to collect fines and granules, repeat until desired granules are obtained.

4. Sift Magnesium stearate through suitable screen/sieve.

5. Blend step3 fines and granules for specified time and continue blending with sifted magnesium stearate for specified time.

Brief Manufacturing Process for Preparation of Tablet:

1. Monolayer Tablet Dosage form
2. Bilayer Tablet Dosage form
3. Trilayer Tablet Dosage form
4. Inlay Tablet (Tablet in Tablet)
1. Monolayer Tablet Dosage form:

1. Blend Efavirenz granules, Tenofovir-Emtricitabine granules and Elvitegravir granules.

2. Compress the granules of Step 1 using tablet compressing machine with tablet tool.

3. Coat the tablets using Opadry™ coating suspension.

2. Bilayer Tablet dosage form:

1. Blend Efavirenz granules separately.

2. Blend Tenofovir-Emtricitabine granules and Elvitegravir granules separately
3. Compress the granules of Step 1 and Step
2 using bilayer tablet compression machine.
4. Coat the tablets using Opadry™ coating.

3. Trilayer Tablet Dosage form

1. Blend Efavirenz granules separately.
2. Blend Tenofovir-Emtricitabine granules separately
3. Blend Elvitegravir granules separately
4. Compress the granules of Step 1, Step 2 and Step 3 using trilayer tablet compression machine with tablet tool having Efavirenz in one layer and Tenofovir-Emtricitabine in second layer and Elvitegravir in third layer
5. Coat the tablets using Opadry™ coating.

4. Inlay Tablet Dosage form (Tablet in Tablet)

1. Blend Efavirenz granules separately.
2. Blend Tenofovir-Emtricitabine granules and Elvitegravir separately
3. Compress the granules of Step 1 to produce tablets.
4. Compress the blend of Step 2 blend having Efavirenz tablet inlayed with Tenofovir-Emtricitabine granules and Elvitegravir blend using tablet in tablet compression machine
5. Coat the tablets using Opadry™ coating.

Dissolution Study:

The compositions prepared according to example 1 are studied for drug release profile under following conditions.

Dissolution study for the prepared tablets was carried out in 1000 ml of 2% sodium lauryl sulphate in purified water at 50 rpm and the results are given below.

Dissolution study results:

Time in % Drug release
minutes Tenofovir Emtricitabine Efavirenz Raltegravir
10 69 76 42 60
15 86 89 65 72
30 94 92 78 85
45 99 96 82 90
60 99 98 95 93

WE CLAIM:

1. A pharmaceutical composition comprising a combination of tenofovir, emtricitabine, efavirenz and HIV integrase inhibitor with one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition according to claim 1, wherein said HIV integrase inhibitor is selected from raltegravir, elvitegravir used alone or in combinations thereof

3. The pharmaceutical composition according to claim 1, wherein said pharmaceutically acceptable excipient is selected from a group comprising a filler, disintegrant, binder, surfactant, glidant, lubricant, film former and mixtures thereof.

4. The pharmaceutical composition according to claim 1, wherein said composition is in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads or minitablets.

5. The pharmaceutical composition according to claim 1, wherein said composition is in the form of a monolayer, bilayer, trilayer or an inlay tablet.

6. The pharmaceutical trilayer tablet composition according to claim5, wherein said composition comprises a tenofovir, emtricitabine, efavirenz and HIV integrase inhibitor, one or more pharmaceutically acceptable excipients,

7. The pharmaceutical composition according to claim 2 is prepared by the process wherein, said process comprises the steps of i) preparing efavirenz granules by wet granulation process ii)preparing tenofovir and emtricitabine granules by dry granulation iii) preparing raltegravir granules by dry granulation iv) compressing the granules into layered tablets.

8. The pharmaceutical composition according to claim 2 is prepared by the process wherein, said process comprises the steps of i) preparing efavirenz granules by wet granulation process ii) preparing tenofovir and emtricitabine granules by dry granulation iii) preparing elvitegravir granules by dry granulation iv) compressing the granules into layered tablets.