DESC:FORM 2
THE PATENT ACT, 1970
(39 of 1970)
COMPELETE SPECIFICATION
(See section 10; rule 13)

“MONOLAYER TABLET OF DOLUTEGRAVIR AND LAMIVUDINE”

LAURUS LABS LIMITED, an Indian Company of Plot No. DS1, IKP Knowledge Park, Genome Valley, Turkapally, Shameerpet, Hyderabad-500 078, Telangana, INDIA

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION

The present invention relates to monolayer tablet formulation comprising integrase inhibitor and nucleoside reverse transcriptase translocation inhibitor. In particular present invention relates to monolayer tablet formulation comprising Dolutegravir and its pharmaceutically acceptable salts thereof and lamivudine. The present invention also relates to process for preparing monolayer tablet formulation.

BACKGROUND OF THE INVENTION

There have been remarkable advances in drug development for the treatment of HIV-1 infection. A more potent, effective and better tolerated treatment regimens have revolutionized the treatment of HIV and led to significant gains in life expectancy among people living with HIV.

Monotherapy is associated with the rapid development of resistance. To minimize the emergence of drug resistant mutations, drugs are administered in combination with one or more additional anti-HIV agents, most typically in the three-way combination and two-drug regimens. Combinations administered in a single dosage unit can result in increased patient compliance as the pill burden is reduced and dosing schedules are simplified.

Dolutegravir is an integrase inhibitor that exhibits subnanomolar potency and antiviral activity against a broad range of HIV-1 strains. Oral administration of dolutegravir has exhibited acceptable safety and tolerability profiles and few drug-drug interactions. Dolutegravir is known from WO2006/116764 as a compound possessing, an inhibitory activity against HIV integrase.

Lamivudine is an NRTI that works by interfering with the conversion of viral RNA into DNA which in turn stops the virus from multiplying. Lamivudine may be made by methods disclosed in U.S. Pat. Nos. 5047407, 7119202, 5905082, 569654, 5693787, 6051709 or 6329522.

Dolutegravir is currently marketed as immediate release tablets of 10mg, 25mg and 50mg under brand name of TIVICAY® by ViiV and also marketed as tablets for suspension of 5mg under the brand name of TIVICAY® PD by ViiV.

Dolutegravir is also marketed in combination with other drugs Abacavir/Dolutegravir/Lamivudine tablets under the brand name of TRIUMEQ®; Dolutegravir/Lamivudine tablets under the brand name of DOVATO® and Dolutegravir/Rilpivirine under the brand name of JULUCA®.

Dolutegravir with lamivudine is a promising maintenance therapy in HIV-1-infected patients with controlled virological suppression. It has favorable characteristics such as excellent tolerability (both drugs) and high resistance barrier (DTG).

As per the European Public Assessment Report (EPAR)of DOVATO®, the tablets of Dolutegravir/Lamivudine are bilayer tablets. The bilayer consists of Dolutegravir layer (layer 2) and Lamivudine layer (layer 1). In the EPAR, it discloses that initial development was started with monolayer tablets, but due to differences in pharmacokinetic performance of the monolayer tablet compared to the reference Dolutegravir and lamivudine single formulations a bilayer tablet was subsequently developed.

EPAR also discloses comparative pharmacokinetic (PK) data of tablets prepared by monolayer tablets and bilayer tablets. In fasted state, the monolayer tablets was bioequivalent for lamivudine, however, Dolutegravir showed higher AUC (0-8), AUC (0-t) and Cmax compared with the co-administered Dolutegravir and EPIVIR® (Lamivudine) tablets. In fasted state, the bilayer tablet was bioequivalent for Dolutegravir AUC (0-8), AUC (0-t) and Cmax, and for lamivudine AUC (0-8), AUC (0-t), Cmax 31.8% higher than with reference. The higher Cmax is not considered clinically relevant; PK of the bilayer tablet provide an acceptable bridge to the co-administration of Tivicay® (Dolutegravir) and Epivir® tablets used in Phase III trials. The bilayer tablet was selected for further development.

WO2010/068253 patent publication discloses various crystalline forms of dolutegravir sodium salt or its hydrate.

WO2019074826 patent publication discloses bilayer tablet formulation of Dolutegravir and lamivudine. It also discloses comparative dissolution profile of bilayer tablet, monolayer tablet and commercially available Dolutegravir tablets (TIVICAY®). The bilayer tablet advantageously gave similar dissolution profile to that of TIVICAY® tablet, whereas monolayer tablets did not gave similar dissolution profile.

Bilayer tablets need to be manufactured using specialized separate manufacturing equipment. Bilayer tablets compression machine is equipped with two feeders, wherein the compositions of two layers are filled in two different feeders. Compositions of the bilayer tablets, each layer composition need to be prepared separately. Manufacturing process of bilayer tablets is tedious. Due to use of specialized equipment, preparation of two separate compositions for each layer and tedious process, bilayer tablet manufacturing becomes costly when compared to normal monolayer tablets. The inventors of the present invention during their continuous effort in developing cost effective product, has developed monolayer tablet of dolutegravir and lamivudine tablet. The developed monolayer tablet is cost effective, easy to manufacture, no requirement of specialized equipment etc.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides an oral monolayer tablet composition comprising(a) Dolutegravir and its pharmaceutically acceptable salts thereof; (b) lamivudine and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a process for preparing an oral monolayer tablet composition comprising (a) Dolutegravir and its pharmaceutically acceptable salts thereof; (b) lamivudine and one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides an oral monolayer tablet composition comprising (a) Dolutegravir and its pharmaceutically acceptable salt; (b) Lamivudine and one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides process for preparing an oral monolayer tablet composition comprising (a) Dolutegravir and its pharmaceutically acceptable salt; (b) Lamivudine and one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable salts of Dolutegravir according to the present invention is selected from Sodium, Potassium, Magnesium, Hydrochloride, Hydrobromide, Fumarate, Monofumarate, Hemifumarate, Tartrate, Maleate, Succinate, Sulfate, Hemisulfate, Dicarboylic, Glutarate, Benzoate, Carbonate, Mesylate, Besylate or Salicylate.

One or more pharmaceutically acceptable excipients according to the present invention are selected from the group of filler, binder, disintegrant, glidant and lubricant.

Suitable fillers that may be used according to the present invention are selected from the group comprising of microcrystalline cellulose, mannitol, lactose, starch, maize starch, wheat starch, potato starch, pregelatinized starch, calcium hydrogen phosphate, calcium silicate, sorbitol, sucrose, dicalcium phosphate and combinations thereof.

Suitable binders that may be used according to the present invention are selected from the group comprising of povidone, microcrystalline cellulose, alginic acid, starch, potato starch, wheat starch, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof.

Suitable disintegrants that may be used according to the present invention are selected from the group comprising of sodium starch glycolate, Crospovidone, low substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose potassium, starch, silicified microcrystalline cellulose, polacrilin potassium and combinations thereof.

Suitable glidants that may be used according to the present invention are selected from the group consisting of calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, talc and combinations thereof.

Suitable lubricants that may be used according to the present invention are selected from the group comprising of stearic acid, magnesium stearate, sodium stearyl fumarate, calcium stearate, hydrogenated vegetable oil, glyceryl behenate and combinations thereof.

The monolayer tablet of the present invention may be film-coated using film coating polymers. Film-coating polymers used according to the present invention are selected from hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropyl cellulose and combination thereof.

In an another aspect, the present invention provides a process for preparing an oral monolayer tablet comprising (a) Dolutegravir and its pharmaceutically acceptable salt (b) Lamivudine and additionally one or more pharmaceutically acceptable excipients, wherein said tablet is prepared by one or more processes selected from Granulation or Direct compression.

According to a generalized aspect, the granulation process according to the present invention involves intragranular phase and extragranular phase, wherein said intragranular phase comprises addition of intragranular components i.e., one or more active pharmaceutical ingredient and excipients selected from filler, disintegrant and binder in order to obtain granules. Said granules can be prepared by any known method of granulation such as wet granulation i.e. by rapid mixing under high shear or low shear or fluidized bed processing, melt granulation and the like or dry granulation. Dry granulation may be carried out by slugging/deslugging or by roller compaction. Further, the extra granular phase according to the present invention comprises addition of one or more excipients selected from filler, disintegrant, lubricant and glidant and optionally an active pharmaceutical ingredient to the intragranular phase.

The wet granulation process according to the present invention is prepared by using aqueous or Non aqueous solvents. The wet granulation process according to the present invention further comprises following steps:

I. Intragranular phase:
a) Blending Dolutegravir and its pharmaceutically acceptable salts and/or lamivudine with intragranular components selected from filler(s), disintegrant;
b) Granulating blend of step a) with intragranular binder solution;
c) Drying the granules of step b) and optionally milling;

II. Extragranular Phase:
d) Blending the granules of step c) with extragranular components selected from fillers, disintegrant, lubricant, and glidant and optionally Dolutegravir and/or Lamivudine.

The dry granulation process according to the present invention is prepared either by roller compaction or slugging and de-slugging process. The dry granulation process according to the present invention comprises following steps:

I. Intragranular phase:
a) Blending Dolutegravir and its pharmaceutically acceptable salts and/or lamivudine with intragranular components selected from filler(s), disintegrant, binder, glidant and lubricant;
b) Compacting the blend of step a) in roller compactor and optionally milling

II. Extragranular Phase:
c) Blending the granules of step b) with extragranular components selected from fillers, disintegrant, lubricants, glidant and optionally Dolutegravir and/or Lamivudine.

In one preferred aspect, the present invention provides an oral monolayer tablet composition comprising i) an intragranular component comprising Dolutegravir and its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients; ii) an extragranular component comprising Lamivudine and one or more pharmaceutically acceptable excipients.

In an another preferred aspect, the present invention provides an oral monolayer tablet composition comprising i) an intragranular component comprising Lamivudine and one or more pharmaceutically acceptable excipients; ii) an extragranular component comprising Dolutegravir and its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

In another preferred aspect, the present invention provides an oral monolayer tablet composition comprising i) an intragranular component comprising a) Dolutegravir and its pharmaceutically acceptable salt, b) Lamivudine and one or more pharmaceutically acceptable excipients; ii) an extragranular component comprising one or more pharmaceutically acceptable excipients.

In an aspect, the present invention provides a process for preparing an oral monolayer tablet composition comprises intragranular component and extragranular component, wherein the monolayer tablets can be prepared by mixing the granules obtained from intragranular components and extragranular components together and compressing the mixture into a monolayer tablet.

In a preferred aspect, the present invention provides a process for preparing an oral monolayer tablet compositions prepared by wet granulation or dry granulation process may have:
i) an intragranular phase, wherein said intragranular phase comprises addition of a) Dolutegravir and its pharmaceutically acceptable salt and/or b) Lamivudine and excipients selected from filler, disintegrant, and binder and
ii) an extragranular phase, wherein said extragranular phase comprises addition of excipients selected from filler, binder, disintegrant, lubricant and glidant and optionally add a) Dolutegravir and/or b) Lamivudine.

In one of the preferred aspect, the present invention provides a process for preparing an oral monolayer tablet composition comprises an intragranular phase comprising addition of Dolutegravir and its pharmaceutically acceptable salt, Lamivudine and one or more pharmaceutically acceptable excipients; ii) an extragranular phase comprising addition of one or more pharmaceutically acceptable excipients.

In another preferred aspect, the present invention provides a process for preparing an oral monolayer tablet composition comprises i) an intragranular phase comprising addition of Dolutegravir and its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients;ii) an extragranular phase comprising addition of Lamivudine and one or more pharmaceutically acceptable excipients.

In an another preferred aspect, the present invention provides a process for preparing an oral monolayer tablet composition comprises i) an intragranular phase comprising addition of lamivudine and one or more pharmaceutically acceptable excipients; ii) an extragranular phase comprising addition of Dolutegravir and its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

In another aspect the present invention provides use of monolayer tablet Dolutegravir, or a pharmaceutically acceptable salt thereof and Lamivudine in the manufacture of a medicament for the treatment of an HIV infection.

The invention is further illustrated by following non-limiting examples:

Example 1:

Sr No Ingredients 1A 1B 1C
INTRAGRANULAR PART % w/w % w/w % w/w
01 Dolutegravir Sodium 6.19 6.19 6.19
02 Mannitol 17.10 11.81 11.81
03 Microcrystalline cellulose 7.06 7.06 7.06
04 Sodium Starch Glycolate 0.35 0.35 1.18
05 Polyvinylpyrrolidone 2.94 2.94 2.35
06 Purified water Qs Qs Qs
EXTRA GRANULAR PART
07 Lamivudine 35.29 35.29 35.29
08 Microcrystalline cellulose 25.39 30.68 25.94
09 Sodium Starch Glycolate 3.00 3.00 7.50
10 Colloidal silicon dioxide 1.18 1.18 1.18
11 Magnesium stearate 1.50 1.50 1.50
Film coating
12 Opadry II Pink 3.00 3.00 3.00
13 Purified water Qs Qs Qs

Brief manufacturing process steps:

I. Intragranular phase

1. Sift Microcrystalline Cellulose, Mannitol, Sodium starch glycolate and Dolutegravir sodium,
Charge and mix them in the bowl of high shear granulator;
2.The mixture of step 1) is granulated with polyvinyl pyrrolidone solution;
3. The wet granules obtained in step 2) are dried in fluid bed dryer;
4. The dried granules of step 3) are then milled using Quadracomil;
II. Extragranular Phase

5. The Dolutegravir granules of step 4) are blended with Lamivudine, Microcrystalline Cellulose,
Sodium starch glycolate and colloidal silicon dioxide in a bin blender;
6. The prelubricated mixture of step 5) is blended with sifted Magnesium stearate in bin blender;
III Compression & Coating
7. The final lubricated blend of step 6)is compressed into monolithic tablet using single rotary tablet compression machine.
8. The tablets of step 7) are film coated.

Example 2:

Sr No Ingredients
INTRAGRANULAR PART % w/w
01 Dolutegravir Sodium 6.19
02 Mannitol 6.21
03 Microcrystalline cellulose 14.48
04 Sodium Starch Glycolate 2.47
05 Polyvinylpyrrolidone 1.06
06 Colloidal Silicon Dioxide 1.41
07 Sodium stearyl fumarate 1.00
EXTRA GRANULAR PART
08 Lamivudine 35.29
09 Microcrystalline cellulose 29.21
10 Sodium Starch Glycolate 1.18
11 Magnesium stearate 1.50
Film coating
12 Opadry II Pink 3.00
13 Purified water --
Brief manufacturing process steps:

I. Intragranular phase
1. Sift Mannitol, Microcrystalline Cellulose, Colloidal Silicon Dioxide, sodium starch glycolate, polyvinyl pyrrolidone and Dolutegravir sodium and then blend in bin blender. The blend is then lubricated with sifted Sodium stearyl fumarate in the same blender;
2. Blend of step 1) is then roller compacted;
3. The ribbons of step 2) are subsequently milled into granules using the rotary fine granulator;

II Extragranular Phase

4. Granules of step 3) are blended with Lamivudine, Microcrystalline Cellulose, and sodium starch glycolate in a bin blender;
5. Blend of step 4) is lubricated with sifted Magnesium stearate;

III Compression & Coating

6. Lubricated blend of step 5) is then compressed into monolithic tablet using single rotary tablet compression machine.
7. The tablets of step 6) are film coated.

Example 3:

Sr No Ingredients
INTRAGRANULAR PART % w/w
01 Dolutegravir Sodium 6.19
02 Mannitol 17.11
03 Microcrystalline cellulose 7.06
04 Sodium Starch Glycolate 1.76
05 Polyvinylpyrrolidone 1.76
06 Purified water Qs
EXTRA GRANULAR PART
07 Lamivudine 35.29
08 Microcrystalline cellulose 17.44
09 Croscarmellose sodium 5.31
10 Colloidal silicon dioxide 1.25
11 Sodium stearyl fumarate 2.50
Film coating
12 Opadry II Pink 3.00
13 Purified water Qs

Brief manufacturing process steps:

1. Sift Microcrystalline Cellulose, Mannitol, Sodium starch glycolate and Dolutegravir sodium,
Charge and mix them in the bowl of high shear granulator;
2. The mixture of step 1) is granulated with Polyvinyl pyrrolidone solution;
3. The wet granules obtained in step 2) are dried in fluid bed dryer;
4. The dried granules of step 3) are then milled using Quadracomil;
5. The Dolutegravir granules of step 4) are blended with Lamivudine, Microcrystalline Cellulose,
Croscarmellose sodium and colloidal silicon dioxide in a bin blender;
6. The prelubricated mixture of step 5) is blended with sifted Sodium stearyl fumarate in bin
blender;
7. The final lubricated blend of step 6) is compressed into monolithic tablet using single rotary tablet compression machine.
8. The tablets of step 7) are film coated.

Example 4:

Sr No Ingredients
INTRAGRANULAR PART % w/w
01 Dolutegravir Sodium 6.58
02 Lamivudine 37.50
03 Mannitol 6.60
04 Microcrystalline cellulose 17.95
05 Sodium Starch Glycolate 2.63
06 Polyvinylpyrrolidone 4.38
Purified water Qs
EXTRA GRANULAR PART
08 Microcrystalline cellulose 16.25
09 Croscarmellose sodium 5.00
10 Colloidal silicon dioxide 0.63
11 Sodium stearyl fumarate 2.50
Film coating
12 Opadry II Pink 3.00
13 Purified water Qs

Brief manufacturing process steps:

1. Sift Microcrystalline Cellulose, Mannitol, Sodium starch glycolate, Lamivudine and
Dolutegravir sodium, Charge them in the Fluid bed granulator bowl;
2. The mixture of step 1) is granulated with spraying polyvinyl pyrrolidone solution;
3. The dried granules of step 2) are then milled using Quadracomil;
4. The Dolutegravir and Lamivudine granules of step 3) are blended with Microcrystalline Cellulose, Croscarmellose sodium and colloidal silicon dioxide in a bin blender;
5. The prelubricated mixture of step 5) is blended with sifted Sodium stearyl fumarate in bin blender;
6. The final lubricated blend of step 6) is compressed into monolithic tablet using single rotary tablet compression machine.
7. The tablets of step 6) are film coated.

Example 5:

Sr No Ingredients
INTRAGRANULAR PART % w/w
01 Lamivudine 35.29
02 Mannitol 16.50
03 Microcrystalline cellulose 7.36
04 Sodium Starch Glycolate 1.76
05 Polyvinylpyrrolidone 1.76
06 Purified water Qs
EXTRA GRANULAR PART
07 Dolutegravir sodium 6.19
08 Microcrystalline cellulose 17.44
09 Croscarmellose sodium 5.61
10 Colloidal silicon dioxide 1.25
11 Sodium stearyl fumarate 2.50
Film coating
12 Opadry II Pink 3.00
13 Purified water Qs

Brief manufacturing process steps:

1. Sift Microcrystalline Cellulose, Mannitol, Sodium starch glycolate and Lamivudine, Charge them in the Fluid bed granulator bowl;
2. The mixture of step 1) is granulated with spraying polyvinyl pyrrolidone solution;
3. The dried granules of step 2) are then milled using Quadracomil;
4. The Lamivudine granules of step 3) are blended with sifted Dolutegravir sodium, Microcrystalline Cellulose, Croscarmellose sodium and colloidal silicon dioxide in a bin blender;
5. The prelubricated mixture of step 5) is blended with sifted Sodium stearyl fumarate in bin blender;
6. The final lubricated blend of step 6) is compressed into monolithic tablet using single rotary tablet compression machine.
7. The tablets of step 6) are film coated.
Comparison of Dissolution profiles of test tablets vs Reference product
Monolayer tablets according to the present invention of Examples 1 and 2 were analysed for dissolution test using following conditions:

Dissolution parameters Value
Apparatus USP<711>Apparatus II
Dissolution medium Simulated Gastric Fluid (SgF) pH 1.6
Volume 500 mL
Sampling times 5,10,15,30,60 minutes
Paddle speed 65 rpm

Dissolution profile of Examples 1 & 2 and Reference Product (Dovato®) is given below:
Dovato® Example 1A Example 1B Example 1C Example 2
Time (min) % of Dolutegravir release
5 17 11 14 27 20
10 41 35 35 36 47
15 48 46 41 38 55
30 47 50 45 43 57
60 50 51 48 45 57
% of Lamivudine release
5 84 31 43 85 46
10 89 75 87 98 78
15 92 92 93 99 85
30 95 96 96 99 88
60 98 98 98 100 93

It can be seen from the above dissolution data that monolayer tablets of the present invention shows similar dissolution profile as that of Reference Product bilayer tablets of Dovato® for both Dolutegravir and Lamivudine drug substances.
,CLAIMS:We claim:

1. An oral monolayer tablet composition comprising, a) Dolutegravir and its pharmaceutically acceptable salt thereof; b) Lamivudine and one or more pharmaceutically acceptable excipients.

2. An oral monolayer tablet composition as claimed in claim 1, wherein the composition comprises i) intragranular components comprising Dolutegravir and its pharmaceutically acceptable salt thereofand one or more pharmaceutically acceptable excipients; ii) extragranular components comprising Lamivudine and one or more pharmaceutically acceptable excipients.

3. An oral monolayer tablet composition as claimed in claim 1, wherein the composition comprises i) intragranular components comprising Lamivudine and one or more pharmaceutically acceptable excipients; ii) extragranular components comprising Dolutegravir and its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

4. An oral monolayer tablet composition as claimed in claim 1, wherein the composition comprises i) intragranular components comprising a) Dolutegravir and its pharmaceutically acceptable salt thereof; b) Lamivudine and one or more pharmaceutically acceptable excipients; ii) extragranular components comprising one or more pharmaceutically acceptable excipients.

5. A process for preparing an oral monolayer tablet composition comprising a) dolutegravir and its pharmaceutically acceptable salt thereof and b) lamivudine, wherein the process is by granulation or direct compression.

6. The granulation process for preparing an oral monolayer tablet as claimed in claim 5,wherein the process comprises i) an intragranular phase comprising addition of Dolutegravir and its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients; ii) an extragranular phase comprising addition of Lamivudine and one or more pharmaceutically acceptable excipient.

7. The granulation process for preparing an oral monolayer tablet as claimed in claim 5,wherein the process comprises i) an intragranular phase comprising addition of Lamivudine and one or more pharmaceutically acceptable excipients; ii) an extragranular phase comprising addition of Dolutegravir and its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient.

8. The granulation process for preparing an oral monolayer tablet as claimed in claim 5,wherein the process comprises i) an intragranular phase comprising addition of a) Dolutegravir and its pharmaceutically acceptable salt thereof, b) Lamivudine and one or more pharmaceutically acceptable excipients;(ii) an extragranular phase comprising addition of one or more pharmaceutically acceptable excipient.

9. The oral monolayer tablet as claimed in any of the preceding claims, wherein pharmaceutically acceptable salts are selected from sodium, potassium, magnesium, and calcium, hydrochloride, hydro bromide, sulphate, fumarate, strontium and phosphate.

10. The oral monolayer tablet as claimed in any of the preceding claims, wherein one or more pharmaceutically acceptable excipients are selected from filler, binder, disintegrant, glidant and lubricant.