Field of the invention
The present invention relates to stable pharmaceutical dosage forms of combination of antiretroviral agents. More particularly, the present invention relates to stable dosage forms comprising lamivudine, tenofovir disoproxil fumarate and efavirenz.
The present invention further relates to a process for the preparation of pharmaceutical dosage form comprising lamivudine, tenofovir disoproxil fumarate and efavirenz.
Background of the invention
The human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). This disease is characterized by the destruction of the immune system, particularly of the CD4 and T-cell making the host susceptible to opportunistic infections. HIV is also associated with a precursor AIDS-related complex (ARC), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
Anti-retroviral drugs, such as reverse transcriptase inhibitors and viral protease inhibitors, have been used to treat HIV infection. These treatments can effectively suppress viral production when used in combinations known as HAART (Highly Active Anti-Retroviral Therapy).
Tenofovir disoproxil fumarate (a prod rug of tenofovir) is a numeric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. Chemically, tenofovir disoproxil fumarate is 9-[()-2-[[bis[[(isopropoxycarbonyl)oxy] methoxy]phosphinyl]methoxy]propyl]adenine fumarate and is commercially available in tablet dosage form under the trade name Vireo®. Tenofovir disoproxil fumarate, for treating HIV was first disclosed in US patent No. 5,922,695.
Chemically, Lamivudine is (2R,cis)-4-amino-l-(2-hydroxymethyl-l,3-oxathiolan-5-yl)-(lH)-pyrimidin-2-one and is commercially available in tablets

and oral solution under the trade name Epivir®. Lamivudine and method of treating HIV using lamivudine was first disclosed in US 5,047,407.
Chemically, Efavirenz is (S)-6-chloro-4-(cyclopropylethynyl)-l,4-dihydro-4-(trifluoromethyl)-2H-3,l-benzoxazin- 2-one and is commercially available in tablets and capsules under the trade name Costive®. Efavirenz and method of treating HIV using efavirenz was first disclosed in US 5,519,021.
One substantial and persistent problem in the treatment of AIDS has been the ability of the HIV virus to develop resistance to the individual therapeutic agents employed to treat the disease. Thus, a need remains for an efficacious and long lasting therapy for AIDS which lowers HIV viral levels of patients to undetectable levels and raises CD4 cell counts for prolonged periods of time without the development of resistance. Hence, there is a need to develop combination of drugs to treat AIDS called as fixed dose combinations (FDC).
The various advantages of FDCs when compared to the separate ARV regimens are ease of use, better adherences to the dosage schedules, reduced risk of drug resistance and increased affordability. Combination therapy reduces the daily dosages to be taken by patients and simplifies dosing schedule thereby increases patient compliance.
Following are few patents/publications, which disclose combinations of antiretrovirals.
US 5,627,186 discloses combination of lamivudine and zidovudine for treating HIV.
US 6,417,191 discloses combination of abacavir and lamivudine; abacavir, lamivudine and zidovudine for treating HIV.
US 2004/0224917 discloses therapeutic combinations of emtricitabine and tenofovir DF useful for treatment of HIV infections.
US 2007/0077295 discloses composition of tenofovir DF and emtricitabine prepared by dry granulation for treating HIV.

us 2007/099902 discloses a multi component unitary dosage form comprising tenofovir DF and emtricitabine in first component and efavirenz in second component useful for treatment of HIV infections.
ZA 2001/10500 discloses pharmaceutical composition of lamivudine, zidovudine and nevirapine and process, which comprises wet granulating lamivudine, zidovudine, nevirapine and diluent with water; drying, sizing and blending the granules with disintegrant; lubricating the granules; and compressing the lubricated granules into tablets.
WO 2004/089382 discloses combination of lamivudine, zidovudine and efavirenz for treating HIV.
WO 2004/089383 discloses combination of lamivudine, stevedore and efavirenz for treating HIV.
WO 2006/001029 discloses composition of lamivudine, zidovudine and nevirapine and process which comprises granulating lamivudine, zidovudine, nevirapine, microcrystalline cellulose, starch, croscarmellose sodium with a solution of polyvinylpyrrolidone k-30 and drying the granules, blending the dried granules with magnesium stearate, croscarmellose sodium, colloidal anhydrous silica, crospovidone and compressing the blend into tablets.
WO 2006/086865 discloses a composition comprising lamivudine, zidovudine and nevirapine in a single coated tablet prepared by dry granulation.
WO 2006/114709 discloses a composition comprising lamivudine, zidovudine and nevirapine prepared by a granulation process comprising the steps of preparing granules of lamivudine plus zidovudine and granules of nevirapine separately, blending the obtained granules with percipients and finally compressing the granules into tablets.
WO 2007/026156 discloses a composition comprising lamivudine, stevedore and nevirapine for pediatric treatment of viral infections.
WO 2007/068934 discloses a bilayered formulation comprising lamivudine and tenofovir in order to avoid the discoloration tablet when lamivudine and

tenofovir are prepared as conventional single layer tablet. This patent publication further discloses a kit comprising bilayered tablet of lamivudine and tenofovir as first formulation and efavirenz tablet as second formulation. This publication does not disclose lamivudine, tenofovir and efavirenz in a single dosage form.
WO 2008/043829 discloses combination of emtricitabine, tenofovir and nevirapine for once a day administration.
WO 2008/096369 discloses monolithic tablets comprising emtricitabine/lamivudine, tenofovir DF and efavirenz prepared by separately granulating tenofovir DF plus emtricitabine/lamivudine and efavirenz, blending the two granules or separately granulating tenofovir DF and efavirenz, blending the two granules with extra granular lamivudine and finally compressing into tablets.
The above prior art disclose compositions of various combinations of antiretroviral agents prepared as single and/or double layered tablets. However, still there is a need to develop stable dosage form comprising lamivudine, tenofovir and efavirenz.
Objective of the invention
Accordingly, the main objective of the present invention is to provide a stable dosage form comprising lamivudine, tenofovir disoproxil fumarate and efavirenz and process for preparing the dosage form.
Yet another objective of the present invention is to provide stable dosage form of lamivudine, tenofovir disoproxil fumarate and efavirenz in such a way that it will comply with the reference products of each of these approved individual drugs in terms of in vitro parameters like dissolution, disintegration etc. and in vivo parameters like bioequivalence.
Summary of the invention
Accordingly, the present invention provides a stable dosage form comprising lamivudine, tenofovir disoproxil fumarate and efavirenz.

Detailed description of the invention
In another embodiment, the dosage form further comprises one or more recipients selected from diluents, binders, disintegrants, surfactants, glidants and lubricants.
Suitable diluents of the present invention are selected from manifold, lactose, microcrystalline cellulose, multifold, malt dextrin, maltose, starch, calcium carbonate, calcium phosphate dibasic, calcium sulfate, and dexterities or a combination thereof The diluent may be used in the range of 10-50% by weight of the composition.
Suitable binders of the present invention are selected from hydroxy propyl cellulose, hydroxypropyl methylcellulose, gelatin, hydroxy ethyl cellulose, povidone, starch and methylcellulose or a combination thereof. The binder may be used in the range of 1 -20%) by weight of the composition.
Suitable disintegrants of the present invention are selected from sodium starch glycolate, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, magnesium aluminum silicate, pregelatinized starch, cornstarch, sodium carboxymethyl cellulose or a combination thereof. The disintegrant may be used in the range of 1-10% by weight of the composition.
Suitable surfactants of the present invention are selected from sodium laurels sulphate, polysorbate, Sorbian monolaurate, polyoxyethylene-polyoxypropylene block copolymer (poloxamer), polyethylene glycol derivatives, acetyl alcohol or a combination thereof. The surfactant may be used in the range of 0.01-1% by weight of the composition.
Suitable glidants of the present invention are selected from magnesium trisilicate, talc, Triassic calcium phosphate, glyceryl monostearate, glyceryl stearate and silica dioxide or a combination thereof. The glidants may be used in the range of 0.1 -2% by weight of the composition.
Suitable lubricants of the present invention are selected from calcium stearate, magnesium stearate, hydrogenated vegetable oil, satiric acid, magnesium

aluminum silicate, sodium steady fumarate or a combination thereof The lubricant may be used in the range of 0.1-5% by weight of the composition.
In another embodiment, the stable dosage form comprising lamivudine, tenofovir DF and efavirenz may be in the form of tablets, bilayered tablets, capsules or tablet in capsule.
In another embodiment, the stable dosage form comprising lamivudine, tenofovir DF and efavirenz may be prepared by wet granulation or dry granulation.
In another embodiment, the granulation process involves preparation of lamivudine plus tenofovir disoproxil fumarate and efavirenz granules separately and then formulating into a stable dosage form.
In another embodiment, the granulation process involves preparation of lamivudine plus tenofovir disoproxil fumarate and efavirenz granules separately and then formulating into a stable bilayered dosage form.
In another embodiment, the granulation process involves preparation of lamivudine, efavirenz and tenofovir disoproxil fumarate granules in a single granulation process and then formulating into a stable dosage form.
In another embodiment, the granulation process involves preparation of lamivudine plus efavirenz and tenofovir disoproxil fumarate granules separately and then formulating into a stable bilayered dosage form.
In a preferred embodiment of the present invention, the stable bilayered dosage form comprises lamivudine, tenofovir disoproxil fumarate, 10-50% w/w of diluent selected from microcrystalline cellulose, lactose and mannitol, 1-10% w/w of disintegrant selected from croscarmellose sodium, crospovidone and sodium starch glycolate in the first layer and efavirenz, 10-50% w/w of diluent selected from microcrystalline cellulose, lactose and mannitol, 1-10% w/w of disintegrant selected from croscarmellose sodium, crospovidone and sodium starch glycolate in the second layer.

In another preferred embodiment of the invention, the stable bilayered dosage form comprises lamivudine, efavirenz, 10-50%o w/w of diluent selected from microcrystalline cellulose, lactose and mannitol, 1-10% w/w of disintegrant selected from croscarmellose sodium, crospovidone and sodium starch glycolate in the first layer and tenofovir disoproxil fumarate, 10-50%o w/w of diluent selected from microcrystalline cellulose, lactose and marmite, 1-10% w/w of disintegrant selected from croscarmellose sodium, crospovidone and sodium starch glycolate in the second layer.
In another embodiment of the present invention, the stable dosage form comprising lamivudine, tenofovir disoproxil fumarate and efavirenz is prepared by granulation process comprising the steps of:
a) preparing granules comprising lamivudine, tenofovir disoproxil fumarate and pharmaceutically acceptable excipients,
b) preparing granules of efavirenz by granulating with pharmaceutically acceptable excipients,
c) blending the granules of step (a) and (b), with pharmaceutically acceptable excipients,
d) lubricating the blended granules and finally compressing the granules into tablets or filling into capsules.
According to another embodiment of the present invention, there is provided an alternative process for the preparation of stable dosage form comprising lamivudine, tenofovir disoproxil fumarate and efavirenz by granulation process, which comprises the steps of:
a) preparing granules comprising lamivudine, tenofovir disoproxil fumarate and pharmaceutically acceptable excipients,
b) preparing granules of efavirenz by granulating with pharmaceutically acceptable excipients,
c) separately blending the granules of step (a) and (b), with pharmaceutically acceptable excipients.

d) separately lubricating the blended granules of step (c) and finally compressing the granules into bi-layer tablets.
According to another embodiment of the present invention, the stable dosage form comprising lamivudine, tenofovir disoproxil fumarate and efavirenz may also be prepared by granulation process comprising the steps of:
a) preparing granules comprising lamivudine, efavirenz and tenofovir disoproxil fumarate and pharmaceutically acceptable excipients,
b) blending the granules of step (a) with pharmaceutically acceptable excipients,
c) lubricating the blended granules and finally compressing the granules into tablets or filling into capsules.
According to another embodiment of the present invention, the stable dosage form comprising lamivudine, tenofovir disoproxil fumarate and efavirenz may also be prepared by granulation process comprising the steps of:
a) preparing granules comprising lamivudine, efavirenz and pharmaceutically acceptable excipients,
b) lubricating the granules of step (a) with magnesium stearate,
c) preparing granules of tenofovir disoproxil fumarate by granulating with pharmaceutically acceptable excipients,
d) lubricating the granules of step (c) with magnesium stearate,
e) compressing the lubricated granules of step (b) and step (d) into bi-layer tablets.
In another embodiment, the solvents used for granulation process may be selected from water, isopropyl alcohol, acetone or combination thereof
In another embodiment of the present invention, the tablets of the present invention may optionally be coated to prevent the degradation of lamivudine from light with coating polymers.

Suitable film forming polymers used according to the present invention are selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose, xanthan gum and the like or a combination there of.
In another embodiment, the stable dosage form of the present invention is used for the treatment or prevention of symptoms of HIV infection in an infected individual.
The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.



The processing steps involved in manufacturing stable dosage form of lamivudine, tenofovir and efavirenz are given below:
a) preparation of granules of lamivudine plus tenofovir DF:
i) sifted and blended lamivudine, tenofovir DF, microcrystalline cellulose and
croscarmellose sodium,
ii) granulated the blend using water,
iii) dried and sized the wet mass,
b) preparation of granules of efavirenz:
i) sifted and blended efavirenz, microcrystalline cellulose, croscarmellose sodium
and sodium lauryl sulfate,
ii) granulated the blend using binder solution of hydroxypropyl cellulose,
iii) dried and sized the wet mass,
c) blending and lubrication of granules:
i) blended granules of lamivudine and tenofovir with efavirenz granules,
ii) lubricated the blend of step (i) with magnesium stearate and compressed into
tablets or filled into capsules, and
iii) coated the tablets of step (ii) with Paddy white.



The processing steps involved in manufacturing stable dosage form of lamivudine, tenofovir and efavirenz are given below:
a) preparation of granules of lamivudine plus tenofovir DF:
i) sifted and blended lamivudine, tenofovir DF, microcrystalline cellulose and
croscarmellose sodium,
ii) granulated the blend using water,
iii) dried and sized the wet mass,
b) preparation of granules of efavirenz:
i) sifted and blended efavirenz, microcrystalline cellulose, croscarmellose sodium,
sodium lauryl sulfate,
ii) granulated the blend using binder solution of hydroxypropyl cellulose.

iii) dried and sized the wet mass,
c) blending and lubrication of granules:
i) blended granules of lamivudine and tenofovir,
ii) lubricated the blend of step (i) with magnesium stearate,
iii) blended granules of efavirenz,
iv) lubricated the blend of step (iii) with magnesium stearate,
iv) compressed the blends of step (ii) and (iv) on bilayered compression machine,
and
v) coated the tablets with Opadry white.


The processing steps involved in manufacturing stable dosage form of lamivudine, tenofovir and efavirenz are given below:
a) preparation of granules of lamivudine, tenofovir DF plus efavirenz:
i) sifted and blended lamivudine, tenofovir DF, efavirenz which intragranular portions of microcrystalline cellulose and croscarmellose sodium, ii) granulated the blend of step (i) using water, iii) dried and sized the wet mass,
b) blending and lubrication of granules:
i) blended granules of lamivudine, tenofovir and efavirenz with extra granular
croscarmellose sodium,
ii) lubricated the blend of step (i) with magnesium stearate and compressed into
tablets or filled into capsules, and
iv) coated the tablets with Opadry white and then again coated with Opadry white
containing sodium lauryl sulfate.



The processing steps involved in manufacturing stable dosage form of lamivudine, tenofovir and efavirenz are given below:
a) preparation of granules of lamivudine plus efavirenz:
i) sifted and blended lamivudine, efavirenz, microcrystalline cellulose,
croscarmellose sodium and sodium lauryl sulphate,
ii) granulated the blend using binder solution of hydroxypropyl cellulose,
iii) dried and sized the wet mass and lubricated with magnesium stearate,
b) preparation of granules of tenofovir disoproxil fumarate:
i) sifted and blended tenofovir disoproxil fumarate, microcrystalline cellulose and
croscarmellose sodium,
ii) granulated the blend of step (i) using water,
iii) dried and sized the wet mass and lubricated with magnesium stearate,
c) preparation of tablets:
i) compressed the lubricated granules of step (a) and (b) on bilayered compression machine with lamivudine and efavirenz granules into one layer and tenofovir disoproxil fumarate granules into second layer, and ii) coated the tablets with coating agent.

We claim:
1. A stable bilayered dosage form comprising lamivudine, tenofovir disoproxil fumarate and efavirenz.
2. The dosage form as claimed in claim 1, further comprises one or more excipients selected from diluents, binders, disintegrants, surfactants, glidants and lubricants.
3. The dosage form as claimed in claim 2, wherein the diluent is selected from mannitol, lactose, microcrystalline cellulose, maltitol, maltodextrin, maltose, starch, calcium carbonate, calcium phosphate dibasic, calcium sulfate, and dextrates or a combination thereof
4. The dosage form as claimed in claim 2, wherein the binder is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, gelatin, hydroxy ethyl cellulose, povidone, starch and methylcellulose or a combination thereof
5. The dosage form as claimed in claim 2, wherein the disintegrant is selected from sodium starch glycolate, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, magnesium aluminum silicate, pregelatinized starch, cornstarch, sodium carboxymethyl cellulose or a combination thereof.
6. The dosage form as claimed in claim 2, wherein the surfactant is selected from sodium lauryl sulphate, polysorbate, sorbitan monolaurate, polyoxyethylene-polyoxypropylene block copolymer (poloxamer), polyethylene glycol derivatives, cetyl alcohol or a combination thereof
7. The dosage form as claimed in claim 2, wherein the lubricant is selected from calcium stearate, magnesium stearate, hydrogenated vegetable oil, stearic acid, magnesium aluminum silicate, sodium stearyl fumarate or a combination thereof
8. A stable bilayered dosage form comprising lamivudine, tenofovir disoproxil fumarate, 10-50% w/w of diluent selected from microcrystalline cellulose, lactose and mannitol, 1-10% w/w of disintegrant selected from

croscarmellose sodium, crospovidone and sodium starch glycolate in the first layer and efavirenz, 10-50% w/w of diluent selected from microcrystalline cellulose, lactose and mannitol, 1-10% w/w of disintegrant selected from croscarmellose sodium, crospovidone and sodium starch glycolate in the second layer. 9. A stable bilayered dosage form comprising lamivudine, efavirenz, 10-50% w/w of diluent selected from microcrystalline cellulose, lactose and mannitol, 1-10% w/w of disintegrant selected from croscarmellose sodium, crospovidone and sodium starch glycolate in the first layer and tenofovir disoproxil fumarate, 10-50% w/w of diluent selected from microcrystalline cellulose, lactose and mannitol, 1-10% w/w of disintegrant selected from croscarmellose sodium, crospovidone and sodium starch glycolate in the second layer.