WO2008096369A2

WO2008096369A2 - Pharmaceutical formulation for use in hiv therapy

Info

Publication number: WO2008096369A2
Application number: PCT/IN2008/000068
Authority: WO
Inventors: Neha Shesh Wyawahare; Ramesh A; Mahesh Mohanrao Bhadgale; Abhijit Mukund Deshmukh; Sanjeev Meharchand Sethi; Kumar Shanmugham; Prakash Balakrishna Shetiya; Chetan Murthy Rajashekara
Original assignee: Matrix Laboratories Limited
Priority date: 2007-02-05
Filing date: 2008-02-04
Publication date: 2008-08-14
Also published as: WO2008096369A3

Abstract

A monolithic tablet formulation comprising: a) a nucleotide analog reverse transcriptase inhibitor (NtRTI); b) a non-nucleoside reverse transcriptase inhibitors (NNRTI); c) a nucleoside analog reverse transcriptase inhibitors (NRTI) and d) one or more pharmaceutically acceptable carriers or excipients. Also disclosed is another pharmaceutical formulation comprising: a) nucleotide analog reverse transcriptase inhibitors (NtRTIs); b) nucleoside analog reverse transcriptase inhibitors (NRTIs) and d) one or more pharmaceutically acceptable carriers or excipients.

Description

PHARMACEUTICAL FORMULATION FOR USE IN HIV THERAPY

FIELD OF INVENTION

The present invention relates to a pharmaceutical formulation and in particular to pharmaceutical formulations for use in HIV therapy. It also discloses the processes to make the same. The invention has been developed primarily for use as a formulation to be used for treatment in HIV therapy and will be described hereinafter with reference to this application.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.

Emtricitabine [EMTRIVA^®], Lamivudine [EPIVIR^®], Efavirenz [SUSTIVA^®] and Tenofovir disoproxil fumarate [VIREAD®] are drugs for use in HIV therapy.

Nucleoside analog reverse transcriptase inhibitors (NRTIs) compose the first class of antiretroviral drugs developed. In order to be incorporated into the viral DNA, NRTIs must be activated in the cell by the addition of three phosphate groups to their deoxyribose moiety, to form NRTI triphosphates. This phosphorylation step is carried out by cellular kinase enzymes. Nucleoside analogs are converted into nucleotide analogs by the body. Taking nucleotide analog reverse transcriptase inhibitors (NtRTIs) directly allows conversion steps to be skipped, causing less toxicity.

Presently marketed TRUV ADA® tablet formulation is two drug combination containing 200 mg of Emtricitabine and 300 mg of Tenofovir disoproxyl fumarate as the active constituents and croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinzed starch [gluten free]. The tablets are coated with Opadry II Blue Y-30- 10701, which contains FD&C Blue # 2 Aluminum Lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide and triacetin.

ATRIPLA® is a combination formulation approved for treatment in HIV-I infection in adults by the United States Food and Drug Administration. It is a once-a-day bilayered film coated tablet comprising Efavirenz 600 mg in one layer and Emtricitabine 200 mg and Tenofovir disoproxil fumarate 300 mg in second layer along with the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate, sodium lauryl sulfate. The film coating contains black iron oxide, polyethylene glycol, polyvinyl alcohol, red iron oxide, talc, and titanium dioxide. WO2004064845 [and related WO2004064846, both assigned to Gilead] disclose two drug formulations of Tenofovir disoproxil fumarate co-formulated with Emtricitabine. WO2004064846 is similar in disclosure as WO2004064845 [assigned to Gilead] except that the main change is disclosure and claiming of GS-7340 [pro-drug of Tenofovir] instead of Tenofovir per se.

The focus of both the above PCT applications is a pharmaceutical formulation containing Tenofovir disoproxil fumarate [or its pro-drug] and Emtricitabine in a sufficiently homogenized form by using glidants so as to reduce the segregation of active ingredients in the pharmaceutical compositions during pre-compression material handling. Alternatively a glidant is used to achieve acceptable measure of homogeneity.

Both these documents do not disclose any working formulation or actual process to make a three drug combination formulation embodied in Atripla i.e. Tenofovir, Emtricitabine and Efavirenz. The foregoing discussion clearly indicates that the above two applications relate to the two drug combination of Truvada rather than the triple drug combination tablet formulation of Atripla. We have not come across any patent/ pending application that specifically and directly discloses a working process/ method of making a tablet containing the triple drug bilayered tablet formulation of Emtricitabine, Tenofovir disoproxyl fumarate and Efavirenz.

Bristol Myers Squibb [proprietors of Sustiva] originally conceived the concept behind

Atripla and roped in Gilead [proprietors of Viread and Emtriva] to jointly develop this triple combination. [Wall Street Journal, July 10 2006, page B8]. Atripla has had a difficult, though interesting development cycle. Some unique points from Atripla' s development are: a) Each of the three drugs had already proven to be successful in establishing virologic control as a stand alone formulation. b) Getting the three drugs in a single formulation to give acceptable pharmacokinetic profile and equivalent bio-availability as the stand alone formulations was the key challenge.

c) When Emtricitabine, Tenofovir disoproxil fumarate and Efavirenz were simply mixed together by Gilead scientists, the mixture was a glue-like mass that had a lowering of the levels of drug circulating in the bloodstream. [New York Times, July 09 2006]

d) Gilead tried multiple approaches and finally got a formulation that allowed each drug to dissolve at its own pace. [From Wall Street Journal, July 10 2006, page

B8]. 'The eventual solution was to keep Emtricitabine, Tenofovir disoproxil fumarate and Efavirenz in separate layers. [New York Times, July 09 2006] i.e. Emtricitabine and Tenofovir disoproxil fumarate in one layer and Efavirenz in another layer. '

As will be obvious to a person skilled in the art, a bilayered tablet has more negative factors as compared to a normal single layer tablet:

a) A bi-layered tablet requires use of special machinery while a single layer tablet can be made in the simplest of tableting machines;

b) Use of bi-layer tableting results in a loss of approx. 10% in production, thereby reducing the final yield and thus adds to the cost.

c) A bi-layered tablet has more processing steps, needs increased human supervision as well as processing time, thus increasing to the overall cost. A single layer tablet has less complexity, reduced processing time and hence can be at a more economical cost compared to a bi-layered tablet. HIV therapy formulations need to be made in the most economical manner thereby reducing the final prices for AIDS patients across the world, especially in third world and developing countries.

In our research, we have now surprisingly found that the earlier mentioned solution of creating two separate layers for the triple drug combination is not required.

We have come up with a simple process to make a single layered formulation covering the three drugs without using complex bilayering technique and still have managed to get a dissolution profile similar to that of Atripla.

OBJECTS QF THE INVENTION

It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

It is an object of the invention in its preferred form to provide an economical formulation for administration of three anti-retro viral drugs in a single formulation.

It is an object of the invention in its preferred form to provide an economical formulation for administration of three anti-retro viral drugs in a single formulation without using complex formulation techniques like bilayering and related processing equipment.

It is an object of the invention in its preferred form to provide an economical single layered formulation for administration of at least one NRTI and at least one NtRTI.

It is an object of the invention in its preferred form to provide an economical formulation for administration of Emtricitabine and Tenofovir disoproxil fumarate in a single formulation. It is an object of the invention in its preferred form to provide an economical single layered formulation for administration of at least one NRTI, at least one NtRTI and at least one NNRTI.

It is an object of the invention in its preferred form to provide an economical single layered formulation for administration of Emtricitabine, Tenofovir disoproxil fumarate and Efavirenz in a single formulation.

It is an object of the invention in its preferred form to provide an economical single layered formulation for administration of Emtricitabine, Tenofovir disoproxil fumarate and Efavirenz in a single formulation, having a pharmacokinetic profile, dissolution profile similar to Atripla.

It is an object of the invention in its preferred form to provide an economical single layered formulation for administration of two NRTI[s] Lamivudine, Tenofovir disoproxil fumarate and one NNRTI Efavirenz in a single formulation.

It is an object of the invention in its preferred form to provide an economical single layered formulation for administration of Lamivudine, Tenofovir disoproxil fumarate and Efavirenz in a single formulation.

It is an object of the invention in its preferred form to provide an economical single layered formulation for administration of Lamivudine, Abacavir and Efavirenz in a single formulation.

SUMMARY OF THE INVENTION

According to the invention there is provided a single layered pharmaceutical formulation for use in HIV therapy having a plurality of anti-retro viral drugs in a single formulation. According to one aspect of the invention there is also provided a process to make a single layered formulation comprising at least two anti-retro viral drugs in a single formulation, for example one NRTI and one NtRTI.

According to one aspect of the invention there is also provided a process to make a single layered formulation comprising at least three anti-retro viral drugs in a single formulation, for example one NRTI, one NtRTI and one NNRTI or alternatively two NRTI[S] and a NNRTI.

Another aspect of the invention provides a process for making a pharmaceutical formulation disclosed above.

DETAILED DESCRIPTION INCLUDING PREFERRED EMBODIMENTS OF THE INVENTION:

The bioavailability of drugs is directly related to their dissolution in the gastro-intestinal fluids. The commercially available bilayered formulation [Atripla] having three drugs viz., tenofovir disoproxil fumarate, emtricitabine and efavirenz needs specialized equipment and additional processing resources. The present invention avoids factors such as use of a bilayered tableting machine. Thus, using conventional machinery a novel, stable and economical formulation for delivering a plurality of anti-retro viral drugs is disclosed.

The present invention is a "monolithic tablet" formulation where the formulation contains combination of drugs and is devoid of separate/ discrete layers in the formulation. Although the invention has been described with reference to specific examples, it will be appreciated by those skilled in the art that the invention may be embodied in other forms.

The formulation of the present invention uses a glidant cum channeling agent alone or in combination with disintegrant. The glidant cum channeling agent is selected form talc, colloidal silicon dioxide, starch etc. The disintegrant is selected from Sodium starch glycolate, crospovidone, Croscarmellose, Microcrystalline cellulose, starch, starch, Pregelatinised starch, polacrillin potassium, Poloxamer etc.

In its primary form the present invention, the invention discloses a formulation having three anti-retro viral drugs in a single layered formulation. The three drugs can be selected from one NRTI, one NtRTI & one NNRTI along with acceptable pharmaceutical excipients or alternatively, two NRTI[s] and one NNRTI.

Another form of the invention discloses a formulation having two anti-retro viral drugs in a single formulation. The two drugs can be selected from one NRTI and one NtRTI along with acceptable pharmaceutical excipients.

The invention also encompasses a process to make an oral pharmaceutical formulation having a plurality of anti retro viral drugs.

Embodiment 1:

LAMIVUDINE + TENOFOVIR DISOPROXIL FUMARATE + EFAVIRENZ:

Efavirenz granules and Tenofovir granules are prepared individually. These granules can be prepared by various methods such as dry / wet granulation etc. Lamivudine is blended to the above two drug granules and the mixture is then compressed and coated.

EMBODIMENT 1 EMBODIMENT IA

Sr. Ingredients % w/w Sr. Ingredients % w/w

No. No.

Efavirenz granules Efavirenz granules

1 Efavirenz 37.50 1 Efavirenz 37.50

2 Microcrystalline 5.69 2 Microcrystalline 5.69 cellulose cellulose

3 Croscarmellose sodium 3.00 3 Croscarmellose sodium 3.00

4 Hydroxy propyl 2.50 4 Hydroxy propyl 2.50 cellulose cellulose

5 Sodium lauryl sulphate 0.38 5 Sodium lauryl sulphate 0.38

Tenofovir DF granules Tenofovir DF granules

6 Tenofovir disoproxil 18.75 6 Tenofovir disoproxil 18.75 fumarate fumarate

Lactose monohydrate 4.69 7 Lactose monohydrate 3.81

Magnesium stearate 0.06 8 Croscarmellose sodium 0.88

Lamivudine + Extragranular ingredients 9 Magnesium stearate 0.06

7 Lamivudine 18.75 Lamivudine + Extragranular ingredients

8 Croscarmellose sodium 1.25 7 Lamivudine 18.75

9 Lactose monohydrate 5.00 8 Croscarmellose sodium 1.25

10 Magnesium stearate 0.94 9 Lactose monohydrate 5.00

11 Opadry white 1.49 10 Magnesium stearate 0.94

Total 100.00 11 Opadry 1.49

Total 100.00

Brief manufacturing Process [Embodiment I]:

Step 1: Preparation of Efavirenz granules (Process: Wet granulation) a) Sift Efavirenz, Microcrystalline cellulose, Croscarmellose sodium and Sodium lauryl sulphate through suitable screen;

b) Prepare binding solution of Hydroxy propyl cellulose in Purified water by ^' soaking or dispersing; c) Granulate Step [a] ingredients using suitable shear granulator; d) Dry the granules and mill to size the granules using suitable mill and screen.

Alternatively, Efavirenz granules can also be made by dry granulation/ Slugging approach in the following manner [Embodiment IA]: a) Sift Efavirenz , Microcrystalline cellulose, Croscarmellose sodium and Sodium lauryl sulphate and Hydroxy propyl cellulose through suitable screen; b) Blend step 1 ingredients using suitable blender; c) Compact/ slug the above blended ingredients; d) Mill to size the compacts/ slugs using suitable mill and screen.

Step 2: Preparation of Tenofovir disoproxil fumarate granules (Process: Dry granulation) a) Sift Tenofovir disoproxil fumarate, Lactose monohydrate and Magnesium stearate (Part quantity) through suitable screen and blend using suitable blender; b) Compact the step [a] blended ingredients using suitable compactor; c) Mill to size the granules using suitable mill and screen; d) Blend the milled -screened granules with Magnesium stearate (Part quantity) using suitable blender.

Alternatively, Tenofovir disoproxil fumarate granules can also be made [Embodiment IA] by using direct compression process in the following manner: a) Sift Tenofovir disoproxil fumarate, Lactose monohydrate, Croscarmellose sodium and Magnesium stearate (Part quantity) through suitable screen and blend using suitable blender;

b) Sift Magnesium stearate through suitable screen using sifter and add to mix from step a and continue blending using suitable blender. Step 3: Final blending (Lamivudine + Extragranular materials) a) Sift Lamivudine, Croscarmellose sodium, Lactose monohydrate through suitable screen;

b) Blend efavirenz granules, tenofovir granules and Lamivudine mix using suitable blender; c) Sift Magnesium stearate through suitable screen and add to above mixture to continue blending for suitable duration.

Step 4: Compress the blend using suitable tooling.

Step 5: Coat the core tablets with Opadry dispersion using suitable coating machine.

Dissolution study analysis [Embodiment I]:

The above combination of Lamivudine, Tenofovir and Efavirenz is not available as a single formulation. Hence dissolution studies were done for the present formulation with samples from the innovator companies. Below is the dissolution data: Dissolution performed as recommended by Office of Generic Drugs (OGD) and U.S. Food Drug and Administration (US FDA)

% Tenofovir Disoproxil fumarate and Lamivudine dissolved

* Results tabulated based on ISOmg strength , 300mg under analysis

% Efavirenz dissolved

It is worth while to note that the above combination in single formulation matches the independent dissolution profiles of the innovator products.

Embodiment 2:

EMTRICITABINE + TENOFOVIR DISOPROXIL FUMARATE + EFAVIRENZ

Efavirenz granules are prepared individually; while Tenofovir and Emtricitabine are mixed to prepare granules. The two granules are then mixed and the mixture is then compressed and coated. These granules can be prepared by various methods such as dry/ wet granulation etc.

EMBODIMENT 2 EMBODIMENT 2A

Sr. Ingredients Mg/ Sr. Ingredients Mg/

No Tablets No Tablets

1 Efavirenz 600 1 Efavirenz 600

2 Emtricitabine 200 2 Emtricitabine 200

3 Tenofovir Disoproxil 300 3 Tenofovir Disoproxil 300

Fumarate Fumarate

4 Microcrystalline cellulose 240 - 4 Microcrystalline cellulose 240

5 Hydroxy propyl cellulose 38 5 Hydroxy propyl cellulose 38

6 Croscarmellose sodium 48 6 Croscarmellose sodium 48

7 Sodium lauryl sulphate 6 7 Sodium lauryl sulphate 6

8 Cross Povidone 58 8 Magnesium stearate 5

9 Colloidal silicon dioxide 10 9 Colloidal silicon dioxide 10

10 Microcrystalline cellulose 60 10 Microcrystalline cellulose 60

11 Croscarmellose sodium 24 11 Crospovidone 24

12 Magnesium stearate 6 12 Magnesium stearate 6

13 Colloidal silicon dioxide 6 13 Colloidal silicon dioxide 6

14 Magnesium stearate 16 14 Cross Povidone 41

Total 1600 15 Magnesium stearate 16

15 Opadry II pink 64 Total 1600

16 Opadry II pink 64

Brief manufacturing process [Embodiment 2]: a) Weigh Efavirenz, micro crystalline cellulose, hydroxyl propyl cellulose, croscarmellose sodium and sodium lauryl sulphate and dry mix them; b) Granulate above dry mix with water to suitable consistency; c) Dry the above granulated wet mass and then size the product using screens or sieves; d) Mix the dried/ sized granules with crospovidone and colloidal silicon dioxide in a blender; e) Mix Emtricitabine, Tenofovir disoproxil fumarate, micro crystalline cellulose, and croscarmellose sodium followed by lubrication with magnesium stearate and compact;

f) Mill the above compacted material followed by milling and sizing; g) Mix colloidal silicon dioxide with the milled/ sized material;

h) Mix Efavirenz granules and the Emtricitabine + Tenofovir disoproxil fumarate granules followed by lubrication with magnesium stearate; i) Compress the above blended/ lubricated granules; j) Prepare an aqueous dispersion of Opadry and coat the earlier prepared tablets.

Brief manufacturing Process [Embodiment 2A]: a) Weigh Efavirenz, micro crystalline cellulose, hydroxyl propyl cellulose, croscarmellose sodium and sodium lauryl sulphate and mix them; b) Add Magnesium stearate to the above blend; c) Mix Colloidal silicon dioxide with the above granules; d) Mix Emtricitabine, Tenofovir disoproxil fumarate, micro crystalline cellulose, and crospovidone followed by lubrication with magnesium stearate and compact; ^• e) Mill the above compacted material and size it; f) Compact the above blend followed by milling and sizing till desired ratio of granules and fines are obtained; g) Granulate above dry mix with water to suitable consistency;

h) Dry the above granulated wet mass and then size the product using screens or sieves; i) Mix the dried/ sized granules with crospovidone and colloidal silicon dioxide; j) Mix colloidal silicon dioxide with above granules;

k) Mix the Efavirenz granules with the Emtricitabine + Tenofovir granules and lubricate them with magnesium stearate; 1) Compress the above blended/ lubricated granules; m) Prepare an aqueous dispersion of Opadry and coat the earlier prepared tablets.

Dissolution study analysis [Embodiment 2]:

The above combination of Emtricitabine, Tenofovir and Efavirenz has the same as active drugs as Atripla formulation. Dissolution testing was performed as recommended by Office of Generic Drugs (OGD) and U.S. Food Drug and Administration (US FDA). OGD specifies that dissolution testing for generic formulation vis-a-vis Atripla must be done in the following method:

Apparatus: USP Apparatus II [paddle]

Speed: 100 rpm

Medium: 2% Sodium lauryl sulfate [SLS] in water

Volume: 100O mL

The Efavirenz dissolution of single layered tablet of example 1 was compared with

Atripla.

Dissolution comparison for Efavirenz, Emtricitabine and Tenofovir for Matrix tablet as compared to Atripla tablets showing percentage of drug released at specific time points:

Embodiment 3:

TENOFOVIR DISOPROXIL FUMARATE + LAMIVUDINE

Brief manufacturing Process [Embodiment 3]:

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

2. Sift Magnesium Stearate (Intragranular) and Magnesium Stearate (Extragranular) separately through suitable screen.

3. Sift Lamivudine through suitable screen.

4. Sift Microcrystalline Cellulose and Croscarmellose Sodium together through suitable screen.

5. Charge the sifted material of the Step 1 into low shear bin blender and blend.

6. Add Magnesium Stearate (Intragranular) of Step 2 to Step 5 and blend.

7. Compact the above blend using Roll compactor.

8. Mill compacts through suitable screen using Quadra co mill. 5 9. Collect the milled material of Step 8 and sift through ASTM 60 mesh (250 microns) and collect retains and passings separately.

_^ 10. Recompact the ASTM 60 mesh (250 microns) passings of Step 9 using Roll compactor and mill the compacts through suitable screen using Quadra co mill. 0 11. If necessary repeat the compaction, milling and sifting steps to obtain 65% -

75% granules (above ASTM 60 mesh (250 microns).

12. Load the granules and fines of step 11, sifted material of step 3 and 4 (Lamivudine, Microcrystalline Cellulose, Croscarmellose Sodium) into low 5 shear bin blender and blend.

13. Add sifted Magnesium Stearate (Extragranular) of Step 2 to the blended material of Step 12 and blend. 0 14. Compress the blend.

15. Prepare the coating dispersion of Opadry in Purified Water and film coat the tablets in perforated coating pan.

Claims

We Claim

1. A monolithic tablet formulation comprising: a) a nucleotide analog reverse transcriptase inhibitor (NtRTI); b) a non-nucleoside reverse transcriptase inhibitors (NNRTI); c) a nucleoside analog reverse transcriptase inhibitors (NRTI) and d) one or more pharmaceutically acceptable carriers or excipients.

2. The pharmaceutical formulation according to claim 1 where a) Nucleotide analog reverse transcriptase inhibitors (NtRTI) selected is Tenofovir or a physiologically functional derivative or salt thereof. b) A non-nucleoside reverse transcriptase inhibitors (NNRTI) selected is Efavirenz or a physiologically functional derivative or salt thereof. c) Nucleoside analog reverse transcriptase inhibitors (NRTI) are selected from

Emtricitabine and Lamivudine or a physiologically functional derivative or salt thereof.

3. The pharmaceutical formulation according to claim 2 further comprising one or more pharmaceutically acceptable carriers or excipients.

4. A pharmaceutical formulation according to claim 3 wherein Tenofovir disoproxil fumarate, Efavirenz and Emtricitabine are each present in an amount from about 100 mg to about 600 mg per unit dosage forms.

5. The pharmaceutical formulation according to claim 4 where the combination comprises about 300 mg of tenofovir disoproxil fumarate, about 600 mg of Efavirenz and about 200 mg of Emtricitabine.

6. The pharmaceutical formulation according to claim 1 wherein the pharmaceutically acceptable carriers or excipients are selected from pregelatinized starch, starch, sodium starch glycolate, croscarmellose sodium, crosspovidone, povidone, microcrystalline cellulose, polacrillin potassium, poloxamer, talc, colloidal silicon dioxide and magnesium stearate; and combinations thereof.

7. A process for preparation of a monolithic tablet comprising a combination of Tenofovir disoproxil fumarate, Efavirenz and Emtricitabine/ Lamivudine or their pharmaceutical acceptable salts, said process comprising the steps of: a) blending Tenofovir disoproxil fumarate and Emtricitabine/ Lamivudine with pharmaceutically acceptable excipients, granulating said blend, milling and optionally screening to obtain granules, b) blending Efavirenz with pharmaceutically acceptable excipients, granulating said blend, milling and optionally screening to obtain granules,

c) blending said granules from step [a] and [b], d) compressing said blended granules to form tablets.

8. The process as claimed in claim 7 where granulation is done utilizing wet granulation technique.

9. The process as claimed in claim 7 where granulation is done utilizing dry granulation/ slugging technique.

10. A monolithic tablet comprising a combination of Tenofovir disoproxil fumarate, Efavirenz and Emtricitabine, wherein the percentage of drugs released form the dosage during in- vitro dissolution is comparable to that of ATRIPLA.

11. The pharmaceutical formulation according to claim 10 that exhibits the following dissolution profile for Efavirenz, when tested in a USP Type II apparatus at 100 rpm and 37° C. in a 2% sodium lauryl sulphate in water 90-95% of the efavirenz is released within 30 min; 95-99% of the efavirenz is released within 45 min; 99-100% of the efavirenz is released within 60 min;

12. The pharmaceutical formulation according to claim 10 that exhibits the following dissolution profile for Tenofovir disoproxil fumarate, when tested in a USP Type II apparatus at 100 rpm and 37° C. in a 2% sodium lauryl sulphate in water, 95-99% of the Tenofovir disoproxil fumarate is released within 30 min; 99-100% of the Tenofovir disoproxil fumarate is released within 45 min;

13. The pharmaceutical formulation according to claim 10 that exhibits the following dissolution profile for Emtricitabine, when tested in a USP Type II apparatus at 100 rpm and 37° C. in a 2% sodium lauryl sulphate in water, 98-100% of the Emtricitabine is released within 30 min;

14. A method for treating or preventing of AIDS which comprises administering a monolithic tablet comprising a combination of Tenofovir disoproxil fumarate, Efavirenz and Emtricitabine/ Lamivudine or their pharmaceutical acceptable salt thereof, to a patient in need thereof.

15. The pharmaceutical formulation according to claim 3 where the combination comprises about 300 mg of tenofovir disoproxil fumarate, about 600 mg of Efavirenz and about 300 mg of Lamivudine.

16. A pharmaceutical formulation comprising: a) nucleotide analog reverse transcriptase inhibitors (NtRTIs); b) nucleoside analog reverse transcriptase inhibitors (NRTIs) and d) one or more pharmaceutically acceptable carriers or excipients.

17. The pharmaceutical formulation according to claim 16 where a) Nucleotide analog reverse transcriptase inhibitors (NtRTIs) selected is Tenofovir or a physiologically functional derivative or salt thereof. b) Nucleoside analog reverse transcriptase inhibitor (NRTIs) is Lamivudine or a physiologically functional derivative or salt thereof.

18. The pharmaceutical formulation according to claim 17 further comprising one or more pharmaceutically acceptable carriers or excipients.

19. A pharmaceutical formulation according to claim 18 where the combination comprises about 300 mg of tenofovir disoproxil fumarate, about 300 mg of Lamivudine.

20. A process for preparation of monolithic tablet comprising a combination of Tenofovir disoproxil fumarate and Lamivudine or their pharmaceutical acceptable salts, said process comprising the steps of: a) Sifting Tenofovir disoproxil fumarate with a pharmaceutically acceptable diluent or filler, b) Sifting Lamivudine through a suitable screen, c) Sifting MCC and croscarmellose sodium through a suitable screen, d) blending materials of step a) with other excipients in a low shear bin blender, e) compacting blend of step d) using roll compactor, f) milling compacts using a Quadra co mill, g) sifting milled material of step f) through ASTM 60 mesh, h) recompacting sifted material of step g) using roll compactor, milling said compacts using Quadra co mill, i) Loading material of step h), step b) and step c) into a low shear bin blender and blending, j) Lubricating blend of step i) and compressing to form tablets.

21. A method for treating or preventing of AIDS which comprises administering a monolithic tablet, to a patient in need thereof comprising a combination of Tenofovir disoproxil fumarate, and Lamivudine or their pharmaceutical acceptable salt thereof.