Anti-retroviral compositions

Abstract

The present invention relates to pharmaceutical antiretroviral compositions comprising a combination of antiretroviral agents (darunavir, dolutegravir and ritonavir), the manufacturing process thereof and use of the said compositions for the prevention, treatment or prophylaxis of HIV infection.

Claims

1. A bilayer tablet composition comprising (a) a first layer comprising a combination of 300 to 800 mg of darunavir base equivalent, 50 mg of dolutegravir base equivalent, and first layer pharmaceutically acceptable excipients, wherein a total weight of the first layer ranges from 1050 mg-1250 mg, and the first layer is characterized by a bulk density of 0.45-0.7 gm/cm.sup.3, and (b) a second layer comprising 100 mg of ritonavir, and second layer pharmaceutically acceptable excipients, wherein a total weight of the second layer ranges from 600 mg-750 mg, and the second layer is characterized by bulk density of 0.5-0.7 gm/cm.sup.3, wherein a total weight of the bilayer tablet ranges from 1650 mg-2000 mg.

2. The bilayer tablet composition of claim 1, wherein the first layer and second layer are in the form of granules.

3. The bilayer tablet composition of claim 1, wherein the darunavir is darunavir ethanolate, and the dolutegravir is dolutegravir sodium.

4. The bilayer tablet of claim 1, in the form of a bilayer caplet comprising 800 mg of darunavir base equivalent, and 50 mg of dolutegravir base wherein the caplet has an 8.0 to 9.5 mm thickness.

5. The bilayer tablet of claim 4, having a length of 15 to 22 mm and a width of 7 to 11 mm.

6. The bilayer tablet composition of claim 1, wherein the darunavir is present in an amount of 800 mg darunavir base equivalent, the dolutegravir is present in an amount of 50 mg dolutegravir base equivalent, and the ritonavir is present in an amount of 100 mg.

7. The bilayer tablet composition of claim 1, in the form of an immediate release bilayered tablet.

8. The bilayer tablet composition of claim 1, wherein the first layer is prepared by wet granulation, dry granulation or direct compression, and the second layer is prepared by hot melt extrusion.

9. A method of treating HIV comprising administering a therapeutically effective amount of the tablet composition as defined in claim 1.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The present invention relates to tablet composition comprising combination of anti-retro virals particularly, darunavir, dolutegravir and ritonavir and process of manufacturing the same.

(2) One embodiment of the present invention relates to pharmaceutical tablet comprising darunavir, dolutegravir and ritonavir with one or more pharmaceutically acceptable excipients thereof.

(3) The term “active agent” as used herein according to the present invention refers to “darunavir”, “dolutegravir” and “ritonavir”.

(4) The term “darunavir” as used herein according to the present invention includes darunavir in the form of free base or a pharmaceutically acceptable solvates or salts or its hydrates, preferably darunavir ethanolate.

(5) The term “dolutegravir” as used herein according to the present invention includes dolutegravir in the form of free base or a pharmaceutically acceptable salt or solvate thereof. Preferably, dolutegravir sodium.

(6) The term “bulk density” as used herein according to the present invention is bulk density of a powder or granules and is the ratio of the mass of an untapped powder or granules sample and its volume including the contribution of the interparticulate void volume. Hence, the bulk density depends on both the density of powder or granules and the spatial arrangement of particles in the powder or granular bed. The bulk density is expressed in grams per milliliter (g/ml) although the international unit is kilogram per cubic metre (1 g/ml=1000 kg/m.sup.3) because the measurements are made using cylinders. It may also be expressed in grams per cubic centimeter (g/cm.sup.3).

(7) The bulk density of a powder is determined by measuring the volume of a known mass of powder sample, that may have been passed through a sieve, into a graduated cylinder (Method A), or by measuring the mass of a known volume of powder that has been passed through a volumeter into a cup (Method B) or a measuring vessel (Method C).

(8) Important physicochemical characteristics of powders are the density properties such as bulk and tapped density, weight variation and flow properties such as angle of repose. Bulk density is the undisturbed packing density of that substance and tapped density relates to the packing density after tapping a bed of substance until no change in the packing density is seen. Bulk density and tapped density, can be determined using compendial bulk density apparatus, such as the method given in Test 616 “Bulk Density and Tapped Density,” United States Pharmacopeia 39, United States Pharmacopeial Convention, Inc., Rockville, Md., 2005 (“USP”). The bulk density is measured in a graduated cylinder according to the European Pharmacopeia.

(9) Bulk density determination: For the determination of bulk density of granules, the method suggested by Butler, Ransey and Martin was used. A sample of about 500 cc of the sized granules carefully introduced into a 100 cc graduated cylinder. The cylinder was then dropped onto a hard wood surface (table top) three times from a height of about one inch approximately two second intervals. Bulk density was then determined by dividing the weight of the sample of granules in grams by the final volume in cc. of the sample contained in the cylinder.

(10) As used in this 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.

(11) The term “excipient” means a pharmacologically inactive component such as a diluent, a binder, a disintegrant, a glidant, a lubricant, etc of a pharmaceutical product. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human pharmaceutical use. Reference to an excipient includes both one and more than one such excipients.

(12) The term “solid dosage form” or “dosage form” or “unitary composition” or “unit dosage form” or “composition” or “formulation” or “tablet” or “caplet” as used herein refers to a solid dosage form suitable for oral administration, such as tablets including layered tablets, capsules, mini-tablets, spheroids, pellets, granules, pills and the like meant for oral administration.

(13) The term “part” also used herein synonymously as “compartment” or “layer”.

(14) By the term “core” is meant the granulate phase including the active agents and excipients.

(15) By “total weight of the tablet” is meant the weight of a tablet including the first and the second parts without coating.

(16) The term “immediate release” as used herein refers to a dosage form that disintegrates and dissolves rapidly to release the actives.

(17) Suitably, the pharmaceutical antiretroviral composition according to the present invention is presented in the solid dosage form suitable for oral administration. However, other dosage forms, such as liquid dosage forms and the like, may be envisaged under the ambit of the present invention.

(18) Unit dosage form, according to the present invention, are preferably in the form of a tablet (disintegrating tablet, dissolving tablet, dispersible tablet, mouth dissolving tablets, tablet for oral suspension, immediate release tablets, extended release tablet, immediate and extended release tablets, matrix tablets), mini-tablet, granules, sprinkles (filled with powders, powders for reconstitution; beads; pellets; mini-tablets; film coated tablets; film coated tablets MUPS (multiple unit pellet system); orally disintegrating MUPS; pills; micro-pellets; small tablet units; MUPS; granules; effervescent granules; microspheres) or capsule (filled with powders, powder for reconstitution; beads; pellets; mini-tablets; film coated tablets; film coated tablets MUPS; orally disintegrating MUPS; pills; micro-pellets; small tablet units; MUPS; disintegrating tablets; dispersible tablets; granules; effervescent granules; microspheres), liquids such as suspension, emulsion, solution, syrup, elixir however, other dosage forms may also fall within the scope of this invention.

(19) Preferably, the pharmaceutical antiretroviral composition, according to the present invention, is in the form of solid unit dosage forms including tablets and capsules, preferably in the form of immediate release tablets.

(20) Another embodiment of the present invention relates to a tablet composition comprising darunavir or a pharmaceutically acceptable solvate thereof and dolutegravir or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients.

(21) The composition of the present invention includes a high dose of darunavir, dolutegravir, ritonavir and excipients having a specific bulk density. The composition is dimensioned to form a caplet. The caplets may be prepared such that the length should not exceed 22 mm, width should not exceed 11 mm and thickness should not exceed 9 mm.

(22) The said caplet is having different shapes like oblong shape, oval shape, modified capsule shape etc.

(23) One embodiment of the present invention relates to pharmaceutical tablet composition comprising darunavir, dolutegravir and ritonavir with one or more pharmaceutically acceptable excipients in the form of tablet, wherein, darunavir and dolutegravir is present in first part and ritonavir is present in the second part.

(24) One other embodiment of the present invention relates to pharmaceutical tablet composition comprising darunavir, dolutegravir and ritonavir with one or more pharmaceutically acceptable excipients in the form of bilayered tablet, wherein, darunavir and dolutegravir is present in first part and ritonavir is present in the second part, wherein weight of the first part ranges from 1050 mg-1250 mg, characterized by bulk density of 0.45-0.7 gm/cm.sup.3 and weight of the second part ranges from 600 mg-750 mg, characterized by bulk density of 0.5-0.7 gm/cm.sup.3, wherein total weight of the tablet ranges from 1650 mg-2000 mg.

(25) One other embodiment of the present invention relates to a tablet composition comprising first part and second part, wherein first part and second part are in the form of powder or granules.

(26) One other embodiment of the present invention relates to a caplet dosage form comprising darunavir, dolutegravir, ritonavir and one or more excipients, wherein caplet having a length of 15 to 22 mm, width of 7 to 11 mm and thickness of 8.0 to 9.5 mm.

(27) One other embodiment of the present invention relates to a caplet dosage form comprising darunavir, dolutegravir, ritonavir and one or more excipients, wherein caplet is having a length of 18 to 22 mm, width of 8 to 11 mm and thickness 8.0 to 9.5 mm.

(28) One other embodiment of the present invention relates to a caplet comprising 800 mg of darunavir, 50 mg of dolutegravir and 100 mg of ritonavir with one or more pharmaceutically acceptable excipients, wherein caplet is having 8.0 to 9.5 mm in thickness.

(29) Further embodiment of the present invention relates to pharmaceutical tablet composition comprising a) 300 mg to 800 mg of darunavir, b) 50 mg of dolutegravir, c) 100 mg of ritonavir and d) one or more pharmaceutically acceptable excipients.

(30) One or more pharmaceutically acceptable excipients of the present invention include diluents, binders, disintegrants, glidants, lubricants and the like.

(31) Diluents include but are not limited to microcrystalline cellulose, powdered cellulose, lactose anhydrous, lactose monohydrate, dibasic calcium phosphate, tribasic calcium phosphate, starch, pregelatinized starch, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, sucrose, dextrates, dextrin, dextrose, maltodextrin, mannitol, xylitol and sorbitol, and the like and combinations thereof.

(32) Binders include but are not limited to hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, pregelatinized starch, powdered acacia, gelatin, guar gum, carbomers and the like and combinations thereof.

(33) Disintegrants include but are not limited to croscarmellose sodium, sodium starch glycolate, crospovidone, polacrillin potassium, carboxymethyl cellulose calcium, starches such as corn starch, potato starch, pregelatinized starch and modified starches, clays, bentonite and the like or combinations thereof.

(34) Glidants include but are not limited to colloidal silicon dioxide, other forms of silicon dioxide, such as aggregated silicates and hydrated silica, magnesium silicate, magnesium trisilicate, talc, and the like and combinations thereof.

(35) Lubricants include but are not limited to talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, palmitic acid, sodium stearyl fumarate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols, and the like and combinations thereof.

(36) The pharmaceutical antiretroviral composition, according to the present invention, may be prepared through various processes known in the art which includes, but are not limited to direct compression, wet granulation, dry granulation, melt granulation, melt extrusion, spray drying, solution evaporation or combinations thereof.

(37) Pharmaceutical compositions of the present invention are prepared by either granulation techniques or direct compression. Preferably, first layer is prepared by granulation process and second layer is prepared by melt extrusion process.

(38) Another aspect of the present invention relates to the tablet composition comprising darunavir, dolutegravir and ritonavir and one or more pharmaceutically acceptable excipients for once daily administration.

(39) Even though such once-daily therapies represent a significant advantage, it would be highly desirable to faster the ease of administration, reduce dosing frequency and help ensure patient compliance with such once daily therapies in the form of a tablet dosage form.

(40) In yet another embodiment, the present invention relates to method of treating HIV or AIDS comprising administering a therapeutically effective amount of the composition of the present invention.

(41) Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which are provided only for the purpose of illustration and are not intended to limit the scope of the invention in any manner.

EXAMPLES

Example 1: Darunavir, Dolutegravir and Ritonavir Bilayered Tablet

(42) TABLE-US-00001 Ingredients mg/tab DARUNAVIR + DOLUTEGRAVIR LAYER Darunavir Ethanolate 867.296 Dolutegravir sodium 52.622 Mannitol 54.982 Sodium starch glycolate 32.000 Povidone 42.500 Purified Water Qs Lubrication Sodium stearyl fumarate 10.600 Layer Weight 1060.000 RITONAVIR LAYER Ritonavir 100.000 Copovidone 350.000 Colloidal silicon dioxide 1.000 Sorbitan monolaurate 45.000 Prelubrication Dibasic calcium phosphate anhydrous 15.500 Colloidal silicon dioxide 1.000 Lubrication Sodium stearyl fumarate 5.500 Layer Weight 518.000 Core Tablet weight 1578.000 Film coated tablet weight 1625.340
Brief Manufacturing Process:
Preparation of Darunavir+Dolutegravir Layer: a) Sifting darunavir, dolutegravir, mannitol and sodium starch glycolate and then loading into rapid mixer granulator and mixing for 10 minutes, b) dissolving povidone in purified water and adding to the blend of step a) and kneading the wet mass, followed by drying, sifting to get the desired size granules, c) sifting sodium stearyl fumarate, d) mixing granules of step b) with sodium stearyl fumarate of step c) in blender;
Preparation of Ritonavir Layer: a) Sifting ritonavir, copovidone and colloidal silicon dioxide and b) adding sorbitan monolaurate to step a) and passing the material through hot melt extruder and collect the extrudes, c) sifting dibasic calcium phosphate anhydrous and colloidal silicon dioxide and adding the material to step b) and blending for 10 minutes, d) sifting sodium stearyl fumarate and adding to material of step c) and blending for 5 minutes;
Compression of Bilayered Tablets:

(43) Compressing the above blends of darunavir+dolutegravir in one layer and ritonavir in another layer into bilayered tablets, followed by film-coating.

(44) Bulk Density:

(45) TABLE-US-00002 Bulk Darunavir + Dolutegravir layer: 0.51 gm/cm.sup.3 density Ritonavir layer: 0.53 gm/cm.sup.3
Thickness: 7.5±0.1 (of tablet)
Dissolution Profile:

(46) TABLE-US-00003 Time in % of drug released minutes Darunavir Dolutegravir Ritonavir 30 66 83 26 60 89 92 39 90 94 95 45 120 96 95 48

Example 2: Darunavir, Dolutegravir and Ritonavir Bilayered Tablet

(47) TABLE-US-00004 Ingredients mg/tab DARUNAVIR + DOLUTEGRAVIR LAYER Darunavir Ethanolate 867.296 Dolutegravir sodium 52.622 Mannitol 54.982 Sodium starch glycolate 32.000 Povidone 42.500 Purified Water Qs Lubrication Sodium stearyl fumarate 10.600 Layer Weight 1060.000 RITONAVIR LAYER Ritonavir 100.000 Copovidone 458.810 Colloidal silicon dioxide 0.540 Sorbitan monolaurate 42.000 Prelubrication Dibasic calcium phosphate anhydrous 74.750 Colloidal silicon dioxide 0.750 Lubrication Sodium stearyl fumarate 6.150 Layer Weight 683.000 Core Tablet weight 1743.000 Film coated tablet weight 1795.290
Brief Manufacturing Process:
Preparation of Darunavir+Dolutegravir Layer: a) Sifting darunavir, dolutegravir, mannitol and sodium starch glycolate and then loading into rapid mixer granulator and mixing for 10 minutes, b) dissolving povidone in purified water and adding to the blend of step a) and kneading the wet mass, followed by drying, sifting to get the desired size granules, c) sifting sodium stearyl fumarate, d) mixing granules of step b) with sodium stearyl fumarate of step c) in blender
Preparation of Ritonavir Layer: a) Sifting ritonavir, copovidone and colloidal silicon dioxide and b) adding sorbitan monolaurate to step a) and passing the material through hot melt extruder and collect the extrudes, c) sifting dibasic calcium phosphate anhydrous and colloidal silicon dioxide and adding the material to step b) and blending for 10 minutes, d) sifting sodium stearyl fumarate and adding to material of step c) and blending for 5 minutes;
Compression of Bilayered Tablets:

(48) Compress the above blends of darunavir+dolutegravir in one layer and ritonavir in another layer into bilayered tablets, followed by film-coating.

(49) Bulk Density:

(50) TABLE-US-00005 Bulk Darunavir + Dolutegravir layer: 0.52 gm/cm.sup.3 density Ritonavir layer: 0.60 gm/cm.sup.3
Thickness: 9.2±0.1 (of tablet)
Dissolution Profile:

(51) TABLE-US-00006 Time in % of drug released minutes Darunavir Dolutegravir Ritonavir 30 63 82 59 60 91 89 90 90 97 89 96 120 99 89 98

Example 3: Darunavir, Dolutegravir and Ritonavir Bilayered Tablet

(52) TABLE-US-00007 Ingredients mg/tab DARUNAVIR + DOLUTEGRAVIR LAYER Darunavir Ethanolate 867.296 Dolutegravir sodium 52.622 Microcrystalline cellulose 54.982 Sodium starch glycolate 32.000 Hydroxypropyl cellulose 42.500 Purified Water Qs Lubrication Sodium stearyl fumarate 10.600 Layer Weight 1060.000 RITONAVIR LAYER Ritonavir 100.000 Copovidone 430.000 Colloidal silicon dioxide 1.000 Sorbitan monolaurate 36.000 Prelubrication Dibasic calcium phosphate anhydrous 40.000 Colloidal silicon dioxide 3.000 Lubrication Sodium stearyl fumarate 5.500 Layer Weight 615.500 Core Tab weight 1675.500 Film Coated tablet weight 1725.765
Brief Manufacturing Process:
Preparation of Darunavir+Dolutegravir Layer: a) Sifting darunavir, dolutegravir, microcrystalline cellulose, sodium starch glycolate and then loading into rapid mixer granulator and mixing for 10 minutes, b) dissolving hydroxypropyl cellulose in purified water and adding to the blend of step a) and kneading the wet mass, followed by drying, sifting to get the desired size granules, c) sifting sodium stearyl fumarate, d) mixing granules of step b) with sodium stearyl fumarate of step c) in blender
Preparation of Ritonavir Layer: a) Sifting ritonavir, copovidone and colloidal silicon dioxide and b) adding sorbitan monolaurate to step a) and passing the material through hot melt extruder and collect the extrudes, c) sifting dibasic calcium phosphate anhydrous and colloidal silicon dioxide and adding the material to step b) and blending for 10 minutes, d) sifting sodium stearyl fumarate and adding to material of step c) and blending for 5 minutes;
Compression of Bilayered Tablets:

(53) Compress the above blends of darunavir+dolutegravir in one layer and ritonavir in another layer into bilayered tablets, followed by film-coating.

(54) Bulk Density:

(55) TABLE-US-00008 Bulk Darunavir + Dolutegravir layer: 0.50 gm/cm.sup.3 density Ritonavir layer: 0.56 gm/cm.sup.3
Thickness: 8.2±0.1 (of tablet)

Example 4

(56) Darunavir, Dolutegravir and Ritonavir Bilayered Tablet:

(57) TABLE-US-00009 Ingredients mg/tab DARUNAVIR + DOLUTEGRAVIR LAYER Darunavir Ethanolate 867.296 Dolutegravir sodium 52.622 Mannitol 55.082 Pregelatinized starch 77.000 Povidone 43.000 Purified Water Qs Lubrication Sodium stearyl fumarate 11.000 Layer Weight 1106.000 RITONAVIR LAYER Ritonavir 100.000 Copovidone 400.100 Colloidal silicon dioxide 1.000 Sorbitan monolaurate 42.000 Pre-lubrication Dibasic calcium phosphate anhydrous 50.000 Colloidal silicon dioxide 0.700 Lubrication Sodium stearyl fumarate 6.150 Layer Weight 600.000 Core Tab weight 1706.000 Film Coated tablet weight 1757.180
Brief Manufacturing Process:
Preparation of Darunavir+Dolutegravir Layer: a) Sifting darunavir, dolutegravir, mannitol and pregelatinized starch and then loading into rapid mixer granulator and mix for 10 minutes, b) dissolving povidone in purified water and adding to the blend of step a) kneading the wet mass, followed by drying, sifting to get the desired size granules, c) sifting sodium stearyl fumarate, d) mixing granules of step b) with sodium stearyl fumarate of step c) into blender and compressing into tablets;
Preparation of Ritonavir Layer: a) Sifting ritonavir, copovidone and colloidal silicon dioxide through mesh, b) adding sorbitan monolaurate to step a) and pass the material through hot melt extruder and collect the extrudes, c) sifting dibasic calcium phosphate anhydrous and colloidal silicon dioxide together through mesh, add the material to step b) blending for 10 minutes, d) adding sodium stearyl fumarate to material of step c) and blend for 5 minutes;
Compression of Bilayered Tablets:

(58) Compress the above blends of darunavir+dolutegravir in one layer and ritonavir in another layer into bilayered tablets, followed by film-coating.

(59) Bulk Density:

(60) TABLE-US-00010 Bulk Darunavir + Dolutegravir layer: 0.53 gm/cm.sup.3 density Ritonavir layer: 0.60 gm/cm.sup.3
Thickness: 8.5±0.1 (of tablet)

Example 5: Darunavir, Dolutegravir and Ritonavir Bilayered Tablet

(61) TABLE-US-00011 Ingredients mg/tab DARUNAVIR + DOLUTEGRAVIR LAYER Darunavir Ethanolate 867.296 Dolutegravir sodium 52.622 Mannitol 55.082 Microcrystalline cellulose 44.982 Sodium starch glycolate 57.000 Povidone 43.000 Purified Water Qs Lubrication Sodium stearyl fumarate 12.000 Layer Weight 1131.982 RITONAVIR LAYER Ritonavir 100.000 Copovidone 508.810 Colloidal silicon dioxide 1.000 Sorbitan monolaurate 52.000 Prelubrication Dibasic calcium phosphate anhydrous 94.750 Colloidal silicon dioxide 0.750 Lubrication Sodium stearyl fumarate 6.150 Layer Weight 763.460 Core Tab weight 1895.442 Film Coated tablet weight 1952.305
Brief Manufacturing Process:
Preparation of Darunavir+Dolutegravir Layer: a) Sifting darunavir, dolutegravir, mannitol, microcrystalline cellulose and sodium starch glycolate and then load into rapid mixer granulator and mix for 10 minutes, b) dissolving povidone in purified water and add to the blend of step a) knead the wet mass, followed by drying, sifting to get the desired size granules, c) sifting sodium stearyl fumarate, d) mixing granules of step b) with sodium stearyl fumarate of step c) into blender and compressing into tablets;
Preparation of Ritonavir Layer: a) Sifting ritonavir, copovidone and colloidal silicon dioxide through mesh, b) adding sorbitan monolaurate to step a) and pass the material through hot melt extruder and collect the extrudes, c) sifting dibasic calcium phosphate anhydrous and colloidal silicon dioxide together through mesh, add the material to step b) blending for 10 minutes, d) adding sodium stearyl fumarate to material of step c) and blend for 5 minutes;
Compression of Bilayered Tablets:

(62) Compression of above ritonavir extrudes with darunavir+dolutegravir layered tablets to obtain bilayered tablets and film-coating the obtained bilayered tablets.

(63) Bulk Density:

(64) TABLE-US-00012 Bulk Darunavir + Dolutegravir layer: 0.54 gm/cm.sup.3 density Ritonavir layer: 0.60 gm/cm.sup.3
Thickness: 10.0±0.1 (of tablet), which is not suitable for swallowing thereby, invites patient compliance problems.
Test Results:
Physical Parameters:

(65) TABLE-US-00013 Bulk density First Second Total wt. of Darunavir + Ritonavir Example layer wt. layer wt. core tablet Thickness Dolutegravir Layer Layer 1 1060 518 1578 7.5 ± 0.1 mm 0.51 0.53 2 1060 683 1743 9.2 ± 0.1 mm 0.52 0.62 3 1060 615.500 1675.5 8.2 ± 0.1 mm 0.50 0.56 4 1106 600 1706 8.5 ± 0.1 mm 0.53 0.69 5 1131.982 763.460 1895.442 10.0 ± 0.1 mm  0.54 0.61

(66) Above results indicate that thickness of 8.0±0.1 mm to 9.2±0.1 mm shows improved dissolution profile over tablets having thickness of less than 8.0 mm.

(67) Further, it was observed that tablets having thickness of 10.0±0.1 mm and above will pose problems of patient compliance, feeling difficulty in swallowing.

(68) Dissolution Profile:

(69) TABLE-US-00014 TABLE A (Test results): % of drug released Time in Example 1 Example 2 minutes Darunavir Dolutegravir Ritonavir Darunavir Dolutegravir Ritonavir 30 66 83 26 63 82 59 60 89 92 39 91 89 90 90 94 95 45 97 89 96 120 96 95 48 99 89 98

(70) TABLE-US-00015 TABLE B (Innovator dissolution profiles for plain marketed tablets): % of drug released Time in Darunavir Dolutegravir Ritonavir minutes (Prezista ®) (Tivicay ®) (Norvir ®) 30 94 97 42 60 98 97 75 90 99 95 90 120 100 94 96

(71) From the results shown in Table A, it was observed that tablets (Example 2) with specific physical parameters of the present invention could produce better dissolution without any delay as compared to example 1.

(72) Drug release for the tablets of the present invention (Example 2) for three active agents found to be comparable with Innovator product drug release.