FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PHARMACEUTICAL ANTIRETROVIRAL COMPOSITIONS"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3.REAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

RELATED APPLICATIONS:
This application is Complete Cognate Application for the Provisional Patent Application No. 2962/MUM/2011 dated 20/10/2011 and Provisional Patent Application No. 2877/MUM/2012 dated 28/09/2012.
FIELD OF INVENTION, BACKGROUND AND PRIOR ART:
[0001] The present invention relates to pharmaceutical antiretroviral compositions comprising a combination of antiretroviral agents, the manufacturing process thereof and use of the said compositions for the prevention, treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
[0002] Demographically the second largest country in the world, India also has the third largest number of people living with HIV/AIDS. The total number of people living with HIV (PLHIV) in India is estimated at 2.4 million with uncertainty bounds of 1.93 to 3.04 million in 2009. Children under 15 years of age account for 4.4% of all infections, whilst people aged 15 to 49 years account for 82.4% of all infections. Thirty-nine percent of all HIV infections are estimated to be among women. This amounts to 0.93 million women with HIV in India.
[0003] Acquired Immune Deficiency Syndrome (AIDS) causes a gradual breakdown of the body's immune system as well as progressive deterioration of the central and peripheral nervous systems. Since its initial recognition in the early 1980's, AIDS has spread rapidly and has now reached epidemic proportions within a relatively limited segment of the population. Intensive research has led to the discovery of the responsible agent, human T-lymphotropic retrovirus 111 (HTLV-111), now more commonly referred to as the human immunodeficiency viruses or HIV.
[0004] Human immunodeficiency virus (HIV) is the etiological agent of Acquired Immune Deficiency Syndrome (AIDS) that has created a major health care problem not only in India but also globally.

[0005] HIV is a member of the class of viruses known as retroviruses. The retroviral genome is composed of RNA, which is converted to DNA by reverse transcription. This retroviral DNA is then stably integrated into a host cell's chromosome and, employing the replicative processes of the host cells, produces new retroviral particles and advances the infection to other cells. HTV appears to have a particular affinity for the human T- 4 lymphocyte cell which plays a vital role in the body's immune system. HIV infection of these white blood cells depletes this white cell population. Eventually, the immune system is rendered inoperative and ineffective against various opportunistic diseases.
[0006] The current strategy recommended for the treatment of HIV infection is Highly Active Antiretroviral Therapy (HAART). HAART normally consists of a combination of three or more antiretroviral drugs (ARV) taken together.
[0007] Currently available antiretroviral drugs for the treatment of HIV include nucleoside reverse transcriptase inhibitors (NRTI) or approved single pill combinations: zidovudine or AZT (Retrovir®), didanosine or DDI (Videx®), stavudine or D4T (Zenith®), lamivudine or 3TC (Epivir®), zalcitabine or DDC (Hivid®), abacavir sulphate (Ziagen®), tenofovir disoproxil fumarate salt (Viread®), emtricitabine (Emtriva®), Combivir® (contains 3TC and AZT), Trizivir (contains abacavir, 3TC and AZT); non-nucleoside reverse transcriptase inhibitors (NNRTI): nevirapine (Viramune®), delavirdine (Rescriptor®) and efavirenz (Sustiva ), peptidomimetic protease inhibitors or approved formulations: saquinavir (Invirase®, Fortovase®), indinavir (Crixivan®), ritonavir (Norvir ), nelfinavir (Viracept ), amprenavir (Agenerase ), atazanavir (Reyataz ), fosamprenavir (Lexiva®), Kaletra® (contains lopinavir and ritonavir), one fusion inhibitor enfuvirtide (T-20, Fuzeon®), Truvada® (contains Tenofovir and Emtricitabine) and Atripla® (contains fixed-dose triple combination of tenofovir, emtricitabine and efavirenz).
[0008] The goal of HAART therapy is to maximize viral suppression thus limiting and reversing damage to the immune system, leading to decline of opportunistic infections. The durability of response depends on various factors such as viral, drug and patient

related factors. However, the most'important patient related factor is adherence, to ensure the success of HA ART therapy.
[0009] The HIV therapy is a life-long therapy coupled with high levels of adherence to the same. This is rather a demanding task for HIV infected patients due to various reasons such as low morale, social stigma, low immunity attributed to the disease.
[00010] Further, the therapy may involve use of different drug combinations,
which are difficult to adhere, because of the different dosage forms for administering each such as antiretroviral drug separately. This is particularly of importance in case of elderly patients.
[00011] Further some studies have shown that adherence to prescribed drugs over
long treatment periods is generally poor. (Jintanat A. et al. Swiss HIV Cohort Study. Failures of 1 week on, 1 week off antiretroviral therapies in a randomized trial AIDS, 2003; 17:F33-F37).
[00012] Hence, such non-adherence to HAART can lead to rebound in viral
replication and, in presence of sub-optimal drug concentration may lead to rapid development of drug resistance. This development of drug resistance can be disastrous because of the complexity and cost associated with second line regimens and the potential for transmission of drug resistant virus in the community.
[00013] For most of the therapeutic agents, to produce systemic effects, the oral
route still represents the preferred way of administration, owing to its several advantages and high patient compliance as compared to any other routes of administration. Tablets and hard gelatin capsules still constitute a major portion of drug delivery systems that are currently available.
[00014] However, many patient groups such as the elderly, children, and patients
who are mentally retarded, uncooperative, nauseated, or on reduced liquid-intake/diets have difficulties swallowing the dosage forms such as tablets and hard gelatin capsules. Further, those who are traveling or have little access to water are similarly affected.

Also, the route of drug administration, appearance, color, taste, tablet size and dosing regimen are most important parameters that govern patient compliance.
[00015] Especially, the geriatric and pediatric patients experience difficulty in
swallowing larger sized tablets wherein large size tablet may result in esophageal damage due to its physical characteristics if it is not swallowed properly, which ultimately leads to poor patient compliance.
[000)6] Also, oral administration of bitter drugs with an acceptable degree of
palatability is a key issue for health care providers, especially for pediatric patients.
[00017] Further, there has been an enhanced demand for dosage forms that are
more patient-friendly and patient compliant. Since the development cost of a new drug molecule is very high, efforts are now being made to focus on the development of new drug dosage forms for existing drugs with improved safety and efficacy together with reduced dosing frequency as well as which are cost-effective.
[00018] Although, different treatment methods and dosage regimens have been
framed in order to increase the patient adherence for treatment of HIV, there still remains a critical need for developing improved dosage forms such as a kit composition or dosage form by which a patient is encouraged to adhere to his daily dosage regimen. In particular, the present invention attempts to overcome the problems of patient adherence for treatment of HIV.
OBJECTS OF THE INVENTION:
[00019] The object of the present invention is to provide a pharmaceutical
antiretroviral composition comprising at least one reverse transcriptase inhibitor and at least one protease inhibitor, preferably wherein said composition is in the form of a kit.
[00020] Another object of the present invention is to provide a pharmaceutical
antiretroviral composition comprising at least one reverse transcriptase inhibitor and at

least one protease inhibitor, optionally with one or more pharmaceutically acceptable excipients, preferably wherein said composition is in the form of a kit.
[00021] Yet another object of the present invention is to provide a pharmaceutical
antiretroviral composition for once a day administration comprising at least one reverse transcriptase inhibitor and at least one protease inhibitor, optionally with one or more pharmaceutically acceptable excipients, preferably wherein said composition is in the form of a kit.
[00022] Yet another object of the present invention is to provide a process for
manufacturing a pharmaceutical antiretroviral composition for once daily administration comprising at least one reverse transcriptase inhibitor and at least one protease inhibitor, optionally with one or more pharmaceutically acceptable excipients, preferably wherein said composition is in the form of a kit.
[00023] Another object of the present invention is to provide a method of
prevention, treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, which method comprises administering a pharmaceutical antiretroviral composition comprising at least one reverse transcriptase inhibitor and at least one protease inhibitor to a patient in need thereof, preferably wherein said composition is in the form of a kit.
[00024] Yet another object of the present invention is to provide the use of a
pharmaceutical antiretroviral composition comprising at least one reverse transcriptase inhibitor and at least one protease inhibitor for the treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, wherein said composition is for once a day administration and is preferably in the form of a kit.
SUMMARY OF THE INVENTION:
[00025] According to one aspect of the present invention, there is provided a
pharmaceutical antiretroviral composition comprising:

(i) at least one reverse transcriptase inhibitor comprising zidovudine; didanosine;
stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine;
emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir;
elvucitabine; tenofovir; festinavir; racivir; lersivirine; rilpivirine; etravirine;
SP1093 V and stampidine, or a pharmaceutically acceptable salts, solvates,
hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives
thereof; and (ii) at least one protease inhibitor comprising saquinavir; ritonavir; nelfinavir;
amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir;;
fosamprenavir; darunavir; and tipranavir, or a pharmaceutically acceptable
salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs,
complexes, derivatives thereof; and optionally (iii) one or more pharmaceutically acceptable excipients;
Preferably, said composition is for once a day administration and may be in the form of a kit.
[00026] According to another aspect of the present invention, there is provided a
pharmaceutical antiretroviral composition comprising:
(i) at least one reverse transcriptase inhibitor comprising zidovudine, lamivudine, tenofovir and emtricitabine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and (ii) at least one protease inhibitor comprising atazanavir and ritonavir, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and (iii) optionally one or more pharmaceutically acceptable excipients; preferably, said composition is for once a day administration and may be in the form of a kit.
[00027] According to another aspect of the present invention, there is provided a
process of manufacturing a pharmaceutical antiretroviral composition comprising:
(i) at least one reverse transcriptase inhibitor comprising zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine;

emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir;
elvucitabine; tenofovir; festinavir; racivir; lersivirine; rilpivirine; etravirine;
SP1093V and stampidine, or a pharmaceutically acceptable salts, solvates,
hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives
thereof; and (ii) and at least one protease inhibitor comprising saquinavir; ritonavir; nelfinavir;
amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir;
fosamprenavir; darunavir; and tipranavir, or a pharmaceutically acceptable
salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs,
complexes, derivatives thereof; and optionally (iii)one or more pharmaceutically acceptable excipients; wherein said composition is for once a day administration and is preferably in the form of a kit.
[00028] According to another aspect of the present invention there is provided a
process of manufacturing a pharmaceutical antiretroviral composition comprising:
(i) at least one reverse transcriptase inhibitor comprising zidovudine, lamivudine, tenofovir and emtricitabine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and (ii) at least one protease inhibitor comprising atazanavir and ritonavir, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and optionally (iii) one or more pharmaceutically acceptable excipients; wherein said composition is for once a day administration and is preferably in the form of a kit.
[00029] According to yet another aspect of the present invention, there is provided
a method of preventing, treating or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, which method comprises administering to a patient in need thereof, a pharmaceutical antiretroviral composition comprising:

(i) at least one reverse transcriptase inhibitor comprising zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine; emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir; elvucitabine; tenofovir; festinavir; racivir; lersivirine; rilpivirine; etravirine; SP1093Vand stampidine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and
(ii) at least one protease inhibitor comprising saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir; fosamprenavir; darunavir; and tipranavir, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and optionally (iii) one or more pharmaceutically acceptable excipients;
wherein said composition is in the form of a kit.
[00030] According to yet another aspect of the present invention, there is provided
a method of preventing, treating or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, which method comprises administering to a patient in need thereof, a pharmaceutical antiretroviral composition comprising:
(i) at least one reverse transcriptase comprising zidovudine, lamivudine, tenofovir and emtricitabine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and (ii) at least one protease inhibitor comprising atazanavir and ritonavir, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and optionally (iii) one or more pharmaceutically acceptable excipients; wherein said composition is for once a day administration and is preferably in the form of a kit.

[00031] According to another aspect of the present invention, there is provided the
use of a pharmaceutical antiretroviral composition comprising:
(i) at least one reverse transcriptase inhibitor comprising zidovudine; didanosine;
stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine;
emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir;
elvucitabine; tenofovir; festinavir; racivir; lersivirine; rilpivirine; etravirine;
SP1093V and stampidine, or a pharmaceutically acceptable salts, solvates,
hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives
thereof; and (ii) and at least one protease inhibitor comprising saquinavir; ritonavir; nelfinavir;
amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir;
fosamprenavir; darunavir; and tipranavir, or a pharmaceutically acceptable
salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes,
derivatives thereof; and optionally (Hi) one or more pharmaceutically acceptable excipients;
for the treatment or prophylaxis of diseases caused by retroviruses, especially
acquired immune deficiency syndrome or an HIV infection, wherein said
composition is for once a day administration and is preferably in the form of a
kit.
[00032] According to another aspect of the present invention, there is provided the
use of a pharmaceutical antiretroviral composition comprising:
(i) at least one reverse transcriptase inhibitor comprising zidovudine, lamivudine,
tenofovir and emtricitabine, or a pharmaceutically acceptable salts, solvates, hydrates,
esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and
(ii) at least one protease inhibitor comprising atazanavir and ritonavir, or a
pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers,
polymorphs, prodrugs, complexes, derivatives thereof; and optionally
(iii) one or more pharmaceutically acceptable excipients;
for the treatment or prophylaxis of diseases caused by retroviruses, especially
acquired immune deficiency syndrome or an HIV infection, wherein said composition
is for once a day administration and is preferably in the form of a kit.

DETAILED DESCRIPTION OF THE INVENTION:
[00033] As discussed above, there is a need to develop and formulate a suitable
pharmaceutical antiretroviral composition, in the form of a once a day formulation, comprising at least one reverse transcriptase inhibitor and at least one protease inhibitor which would, not only, be convenient for patient administration but would also maintain patient adherence to the therapy.
[00034] In general, the therapy for the treatment of HIV infection comprises a
combination of nucleoside reverse transciptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NfRTIs), non-nucleoside reverse transciptase inhibitors (NNRTIs) and protease inhibitors (Pis). The dose regimen of these drugs is such that the patient needs to administer several drugs throughout the day and at different time intervals. Further, this dosage regimen has to be followed throughout the patient's lifetime. This long term therapy may generally cause great inconvenience to the patient. Hence, there is a precise need that the patient is provided with a kit or a single package that will allow the patient to eliminate the inconvenience caused to him such as to remember the administration of the medication as well as the time at which it is to be administered.
[00035]
Thus, the present invention provides a kit comprising a combination of NRTIs, NtRTIs and Pis that provides the patient with his daily regimen of drugs in a single package. This further facilitates the patient in getting the drug regimen of the entire day in a single package which also enables the patient to avoid carrying of numerous medications and also confirm if the same are administered. It will be appreciated that the kit of the present invention may comprise a single dosage form in which a plurality of antiretroviral agents have been co-formulated, or a plurality of dosage forms containing one or more antiretroviral agents.

[00036] In one embodiment, the present invention thus provides a pharmaceutical
antiretroviral composition comprising at least one reverse transcriptase inhibitor and at least one protease inhibitor as a combined preparation in a kit form, for simultaneous or separate use in the treatment of an HIV infection.
[00037] It will be appreciated from the above, that the respective therapeutic agents
of the combined preparation can be administered simultaneously, either in the same or different pharmaceutical formulations or separately. If there is separate administration, it will also be appreciated that the subsequently administered therapeutic agents should be administered to a patient within a time-scale so as to achieve, or more particularly optimize, a synergistic therapeutic effect of such a combined preparation.
[00038] Preferred protease inhibitors (Pis) that may be employed in a
pharmaceutical antiretroviral composition of the present invention are atazanavir and ritonavir. In a particularly preferred embodiment, the pharmaceutical composition of the invention comprises atazanavir and ritonavir.
[00039] Preferred nucleoside reverse transcriptase inhibitors (NRTIs) that may be
employed in a pharmaceutical antiretroviral composition of the present invention are lamivudine emtricitabine and zidovudine. In one preferred embodiment, the NRTI is lamivudine and/or zidovudine. In an alternative preferred embodiment, the NRTI is lamivudine and/or emtricitabine.
[00040] A preferred nucleotide reverse transcriptase inhibitor (NtTRI) that may be
employed in a pharmaceutical antiretroviral composition of the present invention is tenofovir.
[00041] In one embodiment, the present invention provides a pharmaceutical
antiretroviral composition comprising lamivudine, zidovudine, atazanavir and ritonavir. Preferably, said composition is suitable for once a day administration. Said composition may be in the form of a kit.

[00042] In one embodiment, the present invention provides a pharmaceutical
antiretroviral composition comprising lamivudine, tenofovir, atazanavir and ritonavir. Preferably, said composition is suitable for once a day administration. Said composition may be in the form of a kit.
[00043] In another embodiment, the present invention provides a pharmaceutical
antiretroviral composition comprising tenofovir, emtricitabine, atazanavir and ritonavir. Preferably, said composition is suitable for once a day administration. Said composition may be in the form of a kit.
[00044] In the context of the present invention, any references herein to an
antiretroviral agent, for example, "Emtricitabine", "Tenofovir", "Atazanavir", "Ritonavir", "Zidovudine" and "Lamivudine" includes not only, "Emtricitabine", "Tenofovir", "Atazanavir", "Ritonavir", "Zidovudine" and "Lamivudine" per se but also, their i pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable complexes, pharmaceutically acceptable derivatives thereof.
[00045] Tenofovir disoproxil fumarate is also known as PMPA. Tenofovir DF is a
fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. Tenofovir disoproxil fumarate is 9-[(R)-2-[[bis[[(isopropoxycarbonyl) oxy] methoxy] phosphinyl] methoxy] propyl] adenine fumarate (1:1). Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HTV reverse transcriptase by competing with the natural substrate deoxyadenosine 5 '-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases alpha & beta and of mitochondrial DNA polymerase.
[00046] Tenofovir disoproxil fumarate is an analog of adefovir and is classified as
a nucleotide reverse transcriptase inhibitor (NtRTl). Tenofovir DF is a competitive

inhibitor of other naturally occurring nucleotides, and its ultimate biological activity is viral DNA chain termination. Tenofovir DF is a novel nucleotide analog with antiviral activity against both HIV and HBV. The mechanism of tenofovir DF is similar to that of nucleoside analogs, which interferes with reverse transcriptase and prevents translation of viral genetic material into viral DNA. Unlike the nucleoside analogs, the nucleotide reverse transcriptase inhibitors are chemically pre-activated with the presence of phosphate group. Since the phosphorylation step is not necessary, nucleotide analogs can incorporate into viral DNA chain more rapidly than nucleoside analogs. More importantly, this will bypass a viral mechanism of nucleoside resistance. A preferred dosage of tenofovir disoproxil for use in a pharmaceutical antiretroviral composition of the present invention is in an amount from about 75mg to 300 mg.
[00047] Emtricitabine, is chemically known as 4-amino-5-fluoro-l- [2-
(hydroxymethyl) - 1, 3-oxathiolan-5-yl] - pyrimidin-2-one, belongs to a category of nucleoside reverse transcriptase inhibitor (NRTI) which is used to treat infection by HIV-I. Specifically, emtricitabine inhibits HBV DNA polymerase and HIV-1 reverse transcriptase (RT) both in vivo and in vitro. Emtricitabine is anabolized to its triphosphate form which is the active moiety that inhibits the polymerase. A preferred dosage of emtricitabine for use in a pharmaceutical antiretroviral composition of the present invention is in an amount of about 200 mg.
[00048] Zidovudine, chemically known as 3'-azido-3'deoxythymidine, is a
pyrimidine nucleoside analogue, which is well established as an important and useful chemotherapeutic agent for the treatment and / or prophylaxis of HIV infections including related clinical conditions such as AIDS, AIDS-related complex (ARC), AIDS dementia complex (ADC) and also for the treatment of patients who have an asymptomatic HIV infection and who are anti-HIV antibody positive. In addition to lamivudine's proven antiviral activity against HIV as referred to above, lamivudine also exhibits antiviral activity against other viruses such as HBV. A preferred dosage of zidovudine for use in a pharmaceutical antiretroviral composition of the present invention is in an amount from about 60 mg to about 600 mg.

[00049] Lamivudine (also known as 3TC) is a synthetic nucleoside analogue,
chemically known as (2R, cis)-4-aminoT-(2-hydroxymethyl-l, 3-oxathioIan-5-yl)-(lH)-pyrimidin-2- one. lntracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). The principal mode of action of L-TP is the inhibition of HIV-I reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleoside analogue into viral DNA. L-TP is a weak inhibitor of mammalian DNA polymerases (alpha) and (beta), and mitochondrial DNA polymerase (gamma). Lamivudine has also been referred to as (-)-l-[(2R, 5S) 2-(Hydroxymethyi)-l,3-oxathiolan-5-yl] cystosine, (HydroxymethyI)-l,3-oxathiolan-5-yl] cystosine and it has proven antiviral activity against human immunodeficiency virus (HIV) and other viruses such as hepatitis B. A preferred dosage of lamivudine for use in a pharmaceutical antiretroviral composition of the present invention is in an amount from about 30 mg to about 300 mg.
[00050] Atazanavir sulfate is an azapeptide inhibitor of HIV-1 protease and is
hemically known as (3S,8S,9S,12S)-3,12-Bis(l,l-dimethylethyl)-8hydroxy- 4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Atazanavir selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. A preferred dosage of atazanavir for use in a pharmaceutical antiretroviral composition of the present invention is in an amount from about lOOmg to about 300 mg.
[00051] Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(l-
methylethyl)-l- [2-(l-methylethyl)-4thiazolyl]- 3,6-dioxo-8,l l-bis(phenylmethyl)-2,4,7,12- tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,1 1R*)]. Ritonavir is a peptidomimetic inhibitor of the HIV-1 protease. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to production of noninfectious immature HIV particles. A preferred dosage of ritonavir for use in a pharmaceutical antiretroviral composition of the present invention is in an amount from about 33 mg to about 100 mg.

[00052] In one preferred embodiment, the pharmaceutical antiretroviral
composition of the composition of the present invention comprises atazanavir and ritonavir in a single unit dosage form.
[00053] In another preferred embodiment, the pharmaceutical antiretroviral
composition of the present invention comprises lamivudine and tenofovir in a single unit dosage form.
[00054] In a further preferred embodiment, the pharmaceutical antiretroviral
composition of the present invention comprises lamivudine and zidovudine in a single unit dosage form.
[00055] In a further preferred embodiment, the pharmaceutical antiretroviral
composition of the present invention comprises tenofovir and emtricitabine in a single unit dosage form.
[00056] When formulated as a single unit dose, the antiretroviral agents may be co-
formulated with one or more pharmaceutically acceptable excipients to provide a single uniform composition or they may be formulated as individual compositions. When formulated individually, the unit dosage form may comprise two or more layers, each layer comprising a composition of at least one antiretroviral agent. Preferably, the single unit dosage form is suitable for once daily administration. .
[00057] Suitably, the pharmaceutical antiretroviral composition according to the
present invention are presented in solid dosage form, conveniently in unit dosage form, and include dosage form suitable for oral and buccal administration. However, other dosage forms, such as liquid dosage forms, may be envisaged under the ambit of the present invention.
[00058] Unit dosage forms, according to the present invention, are preferably in the
form of a tablet (disintegrating tablet, dissolving tablet, dispersible tablets, mouth dissolving tablets, tablets for oral suspension immediate release tablets, extended release tablet, immediate and extended release tablets, matrix tablets), mini-tablet, granules,

sprinkles or capsules (filled with mini tablets or granules), liquids such as suspension, emulsions, solutions, syrups, elixirs but other conventional dosages such as powders, pellets, capsules and sachets may fall within the scope of this invention.
[00059] The pharmaceutical antiretroviral composition, according to the present
invention, may be administered orally through known solid unit dosage forms including capsule and sachets (filled with powders, pellets, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, effervescent granules and microspheres). The capsules may be hard gelatin capsules. Sachets may be filled with powders, pellets, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, effervescent granules, microspheres that are suitable for direct administration. Preferably, the present invention may be administered as mini-tablets or granules filled in hard gelatin capsules or sachets.
[00060] Preferably, the mini-tablets or granules filled in such hard gelatin capsules
or sachets are directly administered or by sprinkling the mini-tablet or granules on regular meals. Alternatively, the mini-tablets or granules filled in hard gelatin capsules or sachets may be administered with liquid or semi-solid beverages such as but not limited to, juices and water.
[00061] The mini-tablets or granules, according to the present invention, may also
optionally be coated. Preferably, mini-tablets or granules, according to the present invention, may be film coated. More preferably, the mini-tablets or granules may be seal coated and then film coated and further filled in hard gelatin capsules or sachets.
[00062] In another embodiment, the present invention provides a pharmaceutical
antiretroviral composition comprising lamivudine, zidovudine, atazanavir and ritonavir in a kit form. Preferably, said composition is for once a day administration.
[00063] The pharmaceutical antiretroviral composition in kit form may comprise a
separate unit dosage form of lamivudine, a separate unit dosage form of zidovudine, a separate unit dosage form of atazanavir and a separate unit dosage form of ritonavir.

[00064] In another embodiment, the present invention provides a pharmaceutical
antiretroviral composition comprising lamivudine, tenofovir, atazanavir and ritonavir in a kit form. Preferably, said composition is for once a day administration.
[00065] The pharmaceutical antiretroviral composition in kit form may comprise a
separate unit dosage form of lamivudine, a separate unit dosage form of tenofovir, a separate unit dosage form of atazanavir and a separate unit dosage form of ritonavir.
[00066] In another embodiment, the present invention provides a pharmaceutical
antiretroviral composition comprising emtricitabine, tenofovir, atazanavir and ritonavir in a kit form. Preferably, said composition is for once a day administration.
[00067] The pharmaceutical antiretroviral composition in kit form may comprise a
separate unit dosage form of emtricitabine, a separate unit dosage form of tenofovir, a separate unit dosage form of atazanavir and a separate unit dosage form of ritonavir.
[00068] Kit compositions of the type disclosed herein have an advantage over other
packaged dosage forms since the patient always has access to the set of instructions for administration contained in the kit. The inclusion of a set of instructions for administration has been shown to improve patient compliance.
[00069] It will be understood that the administration of the pharmaceutical
antiretroviral composition of the invention by means of a kit, with a set of instructions for administration diverting the patient to the correct use of the invention is a desirable additional feature of this invention.
[00070] It is further well known in the art that a tablet formulation is the preferred
solid dosage form due to its greater stability, less risk of chemical interaction between different medicaments, smaller bulk, accurate dosage, and ease of production.
[00071] Solid unit dosage forms, according to the present invention, are preferably
in the form of tablets but other conventional dosages such as powders, pellets, capsules and sachets may fall within the scope of this invention.

[00072] According to the preferred embodiment, the pharmaceutical antiretroviral
composition may be administered simultaneously, separately or sequentially in a single unit dosage form wherein the drugs and excipients are present in one or more single layer tablets (such as a tablet or mini tablet in a capsule or sprinkle).
[00073] According to another preferred embodiment, the pharmaceutical
antiretroviral composition may be in the form of one or more bilayered or multilayered unit dosage forms.
[00074] In a preferred embodiment, the pharmaceutical antiretroviral composition
in a kit form comprises a separate unit dosage form comprising lamivudine and zidovudine and a further separate unit dosage form comprising atazanavir and ritonavir.
[00075] In a further preferred embodiment, the pharmaceutical antiretroviral
composition in a kit form comprises a separate unit dosage form comprising lamivudine and tenofovir and a further separate unit dosage form comprising atazanavir and ritonavir.
[00076] In another preferred embodiment, the pharmaceutical antiretroviral
composition in a kit form comprises a separate unit dosage form comprising emtricitabine and tenofovir and a further separate unit dosage form comprising atazanavir and ritonavir.
[00077] Suitable excipients may be used for formulating the various dosage forms
according to the present invention.
[00078] According to the present invention, pharmaceutically acceptable carriers,
diluents or fillers for use in the pharmaceutical antiretroviral composition of the present invention may comprise one or more, but not limited to lactose (for example, spray-dried lactose, a-lactose, (3-lactose) lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose, hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers, hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethyl hydroxyethylcellulose and

other cellulose derivatives, starches or modified starches (including potato starch, corn starch, maize starch and rice starch) and mixtures thereof.
[00079] According to the present invention, glidants, anti-adherents and lubricants
may also be incorporated in the pharmaceutical antiretroviral composition of the present invention, which may comprise one or more, but not limited to stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, sodium stearyl fumarate or other metallic stearate), talc, waxes (for example, microcrystalline waxes), glycerides, light mineral oil, PEG, silica acid or a derivative or salt thereof (for example, silicates, silicon dioxide, colloidal silicon dioxide and polymers thereof, crospovidone, magnesium aluminosilicate and/ or magnesium alumino metasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil) and mixtures thereof.
[00080] According to the present invention, suitable binders may also be present in
the in the pharmaceutical antiretroviral composition of the present invention, which may comprise one or more, but not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene glycol(s), acacia, alginic acid, agar, calcium carragenan, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, anhydrous dibasic calcium phosphate and mixtures thereof or any other suitable hinder.
[00081] According to the present invention, suitable disintegrants may also be
present in the pharmaceutical antiretroviral composition of the present invention, which may comprise one or more, but not limited to hydroxylpropyl cellulose (HPC), low density HPC, carboxymethylcellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium; starches exemplified under examples of fillers and carboxymethyl starch, hydroxylpropyl starch, modified starch, pregelatinized starch, crystalline cellulose, sodium starch glycolate; alginic acid or a salt thereof, such as sodium alginate or their equivalents and mixtures thereof.

[00082] The present invention also provides a hot melt extruded pharmaceutical
formulation comprising antiretroviral drug/drugs and at least one water soluble and/or water swellable and/or water insoluble polymer or combination thereof and one or more optional pharmaceutically acceptable excipients.
[00083] Water soluble polymers which may be used in the pharmaceutical
antiretroviral composition of the present invention, include, but are not limited to, homopolymers and co-polymers of N-vinyl lactams, especially homopolymers and copolymers of N- vinyl pyrrolidone e.g. polyvinylpyrrolidone (PVP), co-polymers of PVP and vinyl acetate, co-polymers of N-vinyl pyrrolidone and vinyl acetate (Copovidone) or vinyl propionate, dextrins such as grades of maltodextrin, cellulose esters and cellulose ethers, high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and co-polymers of ethylene oxide, propylene oxide and mixtures thereof.
[00084] Water insoluble polymers which may be used in the pharmaceutical
antiretroviral composition of the present invention, include, but are not limited to, acrylic copolymers e.g. Eudragit El00 or Eudragit EPO; Eudragit L30D-55, Eudragit FS30D, Eudragit RL30D, Eudragit RS30D, Eudragit NE30D, Acryl-Eze (Colorcon Co.); polyvinylacetate, for example, Kollicoat SR 30D (BASF Co.); cellulose derivatives such as ethylcellulose, cellulose acetate e.g. Surelease (Colorcon Co.), Aquacoat ECD and Aquacoat CPD (FMC Co.) and mixtures thereof.
[00085] Water swellable polymers that may be used, according to the present
invention include, but are not limited to polyethylene oxide; poly (hydroxy alkyl methacrylate); poly (vinyl) alcohol, having a low acetal residue, which is cross-linked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of from 200 to 30,000; a mixture of methyl cellulose, cross- linked agar and carboxymethyl cellulose; Carbopol® carbomer which is an acidic carboxy polymer; Cyanamer® polyaerylam ides; cross-linked water swellable indene- maleic anhydride polymers; Goodrich® polyacrylic acid; starch graft copolymers; Aqua Keeps® acrylate polymer polysaccharides composed of condensed glucose units such as diester cross-linked polyglucan, and the like; Amberlite® ion exchange resins; Explotab® sodium starch glycolate; Ac-Di-Sol® croscarmellose sodium or mixtures thereof.

[00086] One or more optional pharmaceutically acceptable excipients may include
plasticizer.
i
[00087] Plasticizers reduce the viscosity of the polymer melt and thereby allow for
lower processing temperature and extruder torque during hot melt extrusion. They further
decrease the glass transition temperature of the polymer.
[00088] Plasticizers which may be used in the pharmaceutical antiretroviral
composition of the present invention, include, but are not limited to, polysorbates such as sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate; citrate ester type plasticizers like triethyl citrate, citrate phthalate; propylene glycol; glycerin; polyethylene glycol (low & high molecular weight); triacetin; dibutyl sebacate, tributyl sebacate; dibutyltartrate, dibutyl phthalate, glycerol palmitosterate and mixtures thereof.
[00089] The pharmaceutical antiretroviral composition, according to the present
invention, may be prepared through various techniques or 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.
[00090] It will be appreciated that the above mentioned techniques may be used
either singly or in combination with other above mentioned techniques to provide unit dosage form according to the present invention in the form of single layered, bilayered or multilayered tablets, mini tablets or sprinkles.
[00091] Suitable processes may be used for formulating the various dosage forms
according to the present invention.
[00092] In one embodiment, the dosage form of the present invention is prepared
by hot melt extrusion. The process of hot melt extrusion is carried out in the conventional extruders as known to a person having a skill in the art.

[00093] Typically, the melt-extrusion process comprises the steps of preparing a
homogeneous melt of one or more drugs, the polymer and the excipients, and cooling the melt until it solidifies.
[00094] Melting usually involves heating above the softening point of the polymer.
The preparation of the melt can take place in a variety of ways. The mixing of the components can take place before, during or after the formation of the melt.
[00095] Usually, the melt temperature is in the range of about 50° C to about 200°
C.
[00096] Suitable extruders include single screw extruders, intermeshing screw
extruders or else multiscrew extruders, preferably twin screw extruders, which can be co -rotating or counter - rotating and, optionally, be equipped with kneading disks.
[00097] The extrudates can be in the form of beads, granulates, tube, strand or
cylinder and this can be further processed into any desired shape.
[00098] , In an alternative process, the present invention may further be allowed to form granules which may be compressed to form tablets, or the granules may be filled into capsules, sachets, pellets in capsules or in a similar dosage form.
[00099] This process involves heating the polymer(s) to soften it, without melting
it, and mixing the active ingredient(s) with polymer(s), to form granules.
[000100] The process can be carried out in the same type of extrusion apparatus as
the hot melt extrusion process, except that the product is not extruded through the extrusion nozzle of the apparatus.
[000101] The extrudates/granules so obtained according to the present invention may then be admixed with other suitable one or more pharmaceutically acceptable excipients.

[000102] According to a preferred embodiment, the pharmaceutical antiretroviral
composition of the present invention is processed by wet granulation of lamivudine and zidovudine wherein the diluent, the disintegrant along with the actives lamivudine and zidovudine are treated with the binder solution to form granules. Granules are lubricated and compressed to provide a single layered tablet or compressed separately to provide a bilayered tablet which may optionally be coated. Alternatively, the granules so obtained are filled into hard gelatin capsules or sachets or by compressing the granules to form mini-tablets which may also be filled into capsules or sachets and can be sprinkled onto food.
[000103] According to yet another preferred embodiment, the pharmaceutical
antiretroviral composition of the present invention is processed by mixing atazanavir with intragranular excipients such as diluents, disintegrants to form granules. Ritonavir, polymers (i.e. either water soluble and/or water swellable or/and water insoluble or mixture thereof), one or more plasticizer, one or more disintegrants, one or more lubricants and glidants are extruded through hot melt extrusion technique wherein extrudates are obtained which can be molded into granules. Granules are lubricated and compressed to provide a single layered tablet or compressed separately to provide a bilayered tablet which may optionally be coated. Alternatively, the granules so obtained are filled into hard gelatin capsules or sachets or by compressing the granules to form mini-tablets which may also be filled into capsules or sachets and can be sprinkled onto food.
[000104] Further, the granules comprising atazanavir and ritonavir as obtained
above may be further mixed, sieved, sifted and compressed into a single tablet. Alternatively, the tablet may be seal coated and finally film coated.
[000105] Alternatively, the granules comprising atazanavir and ritonavir as obtained
above may be individually compressed into two tablets and finally compacted and compressed into a bilayer tablet. Alternatively, the tablet may be seal coated and finally film coated.

[000106] According to a further preferred embodiment, the pharmaceutical
antiretroviral composition of the present invention is processed by wet granulation of tenofovir and emtricitabine wherein the diluent, the disintegrant along with the actives tenofovir and emtricitabine are sifted and dried. Then, binder solution is prepared by first dissolving the binder in purified water. Granulation is carried out by spraying of the binder solution to the above dry mixture of the ingredients, after which the formed granules are dried, sifted through the specified mesh. After unloading, the granules of tenofovir, emtricitabine were lubricated. The granules as obtained above are compressed to provide a single layered tablet or compressed separately to provide a bilayered tablet. The tablets thus obtained via the process are then sprayed with a coating suspension made of ready colour mix system.
[000107] According to another preferred embodiment, the pharmaceutical
antiretroviral composition of the present invention is processed by wet granulation of tenofovir and lamivudine wherein the diluent, the disintegrant along with the actives tenofovir and lamivudine are sifted and dried. Then, binder solution is prepared by first dissolving the binder in purified water. Granulation is carried out by spraying of the binder solution to the above dry mixture of the ingredients, after which the formed granules are dried, sifted through the specified mesh. After unloading, the granules of tenofovir, lamivudine were lubricated. The granules as obtained above are compressed to provide a single layered tablet or compressed separately to provide a bilayered tablet. The tablets thus obtained via the process are then sprayed with a coating suspension made of ready colour mix system.
[000108] Alternatively, after compression into tablets, they can be further seal
coated and then sprayed with a coating suspension made of ready colour mix system.
[000109] The formulation can be coated with ready colour mix systems.
[000110] According to an embodiment of the present invention, pharmaceutical
antiretroviral composition may be film coated, with, but not limited to Ready colour mix systems (such as Opadry colour mix systems) and polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol.

[000H1] According to an another embodiment of the present invention,
pharmaceutical antiretroviral composition may be seal coated comprises film forming polymeric materials, such as but not limited to, hydroxypropylmethylcellulose (HPMC 6 CPS, or HPMC 6 CPS to HPMC 15CPS grade), hydroxypropylcellulose, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, hypromellose, acacia, gelatin, or combinations thereof to increase adherence and coherence of the seal coat. Preferably the seal coat comprises hydroxypropylmethylcellulose.
[000112] According to an another embodiment of the present invention,
pharmaceutical antiretroviral composition may be seal coated followed by film coated
whereas seal coated comprises film forming polymeric materials, such as but not limited
to hydroxypropylmethylcellulose (HPMC 6 CPS, or HPMC 6 CPS to HPMC 15CPS
grade), hydroxypropylcellulose, polyvinylpyrrolidone, methylcellulose,
carboxymethylcellulose, hypromellose, acacia, gelatin, or combinations thereof and film coated, with, but not limited to Ready colour mix systems (such as Opadry colour mix systems) and polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol.
[000113] The HPMC component of the seal coating may be mixed with solvents such as, but not limited to, acetone, methylene chloride and isopropyl alcohol or combinations thereof. The seal coating may also comprise talc.
[000114] Accordingly, the present inventors have surprisingly found that when, by a process comprising hot melt extrusion of one or more drugs with at least one or more water insoluble polymers, with at least one or more water soluble polymers, with at least one or more water swellable polymers or a combination of at least one or more water soluble polymers and/or water swellable and/or water insoluble polymer, the resulting product acquires taste masking property wherein the ratio of drug: polymer is 1:1 to 1: 6.
[000115] It was surprisingly found that while carrying out the melt extrusion process an in-situ reaction occurred between the drug and polymer. This in-situ reaction led to ionic interaction between the drug and polymer eventually leading to taste masked

product.
[000116] According to a preferred embodiment, the present invention may be
formulated for pediatric patients and from the point of view of pediatric patient acceptability suitable bulking agents may be incorporated, in the pharmaceutical antiretroviral composition comprising saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols but not limited to arabinose, lactose, dextrose, sucrose, fructose, maltose, mannitol, erythritol, sorbitol, xylitol, lactitol, powdered cellulose, microcrystalline cellulose, purified sugar and their derivatives and combination thereof.
[000117] Accordingly, the present invention may further incorporate suitable
pharmaceutically acceptable flavourants, such as but not limited to citric acid, tartaric acid, lactic acid, orange permaseal, strawberry cream flavour or other natural flavourants and sweeteners such as but not limited to aspartame or combination thereof.
[000118] Alternatively, the pharmaceutical antiretroviral composition according to
the present invention may also comprise the actives in nano size form. Preferably, the active pharmaceutical ingredients have an average particle size less than about 2000 nm, preferably less than about 1000 nm.
[000119] Nanonization of hydrophobic or poorly water-soluble drugs generally
involves the production of drug nanocrystals through either chemical precipitation (bottom-up technology) or disintegration (top-down technology). Different methods may be utilized to reduce the particle size of the hydrophobic or poorly water soluble drugs. [Huabing Chen et ah, discusses the various methods to develop nano-formulations in "Nanonization strategies for poorly water-soluble drugs," Drug Discovery Today, Volume 00, Number 00, March 2010].
[000120] Nano-sizing leads to increase in the exposure of surface area of particles
leading to an increase in the rate of dissolution.

[000121] The nanoparticles of the present invention can be obtained by any of the
process such as but not limited to milling, precipitation and homogenization.
[000122] Accordingly, the process of milling comprises dispersing drug particles in
a liquid dispersion medium in which the drug is poorly soluble, followed by applying mechanical means in the presence of grinding media to reduce the particle size of drug to the desired effective average particle size.
[000123] Accordingly, the process of precipitation involves the formation of
crystallineor semi-crystalline drug nanoparticles by nucleation and thegrowth of drug crystals. In a typical procedure, drug molecules arefirst dissolved in an appropriate organic solvent such as acetone, tetrahydrofuran or N-methyl-2-pyrrolidone at a supersaturation concentration to allow for the nucleation of drug seeds. Drug nanocrystals are then formed by adding the organic mixture to an antisolvent like water in the presence of stabilizers such surfactants. The choice of solvents and stabilizers and the mixing process are key factors to control the size and stability of the drug nanocrystals.
[000124] Accordingly, the process of homogenization involves passing a suspension of crystalline drug and stabilizers through the narrow gap of a homogenizer at high pressure (500-2000 bar). The pressure creates powerful disruptive forces such as cavitation, collision and shearing, which disintegrate coarse particles to nanoparticles.
[000125] Accordingly, the process of high pressure homogenization comprises drug
pre-suspension (containing drug in the micrometer range) by subjecting the drug to air jet milling in the presence of an aqueous surfactant solution. The pre-suspension is then subjected to high-pressure homogenization in which it passes through a very small homogenizer gap of ~25 um which leads to a high streaming velocity. High-pressure homogenization is based on the principle of cavitations (i.e., the formation, growth, and implosive collapse of vapor bubbles in a liquid).
[000126] Accordingly, the process of spray-freeze drying involves the atomization
of an aqueous drug solution into a spray chamber filled with a cryogenic liquid {liquid

nitrogen)or halocarbon refrigerant such as chlorofluorocarbon orfluorocarbon. The water is removed by sublimation after the liquid droplets solidify.
[000127] Accordingly, the process of supercritical fluid technology involves controlled crystallization of drug from dispersion in super critical fluids, carbon dioxide.
Accordingly, the process of double emulsion/solvent evaporation technique involves preparation of oil/water (o/w) emulsions with subsequent removal of the oil phase through evaporation. The emulsions are prepared by emulsifying the organic phase containing drug, polymer and organic solvent in an aqueous solution containing emulsifier. The organic solvent diffuses out of the polymer phase and into the aqueous phase, and is then evaporated, forming drug-loaded polymeric nanoparticles.
[000128] Accordingly, the process of PRINT (Particle replication in non-wetting
templates) involves utilization of a low surface energy fluoro polymeric mold that enables high-resolution imprint lithography, to fabricate a variety of organic particles. PRINT can precisely manipulate particle size of drug ranging from 20 nm to more than 100 nm.
[000129] Accordingly, the process of thermal condensation involves use of capillary aerosol generator (CAG) to produce high concentration condensation submicron to micron sized aerosols from drug solutions.
[000130] Accordingly, the process of ultrasonication involves application of
ultrasound during particle synthesis or precipitation, which leads to smaller particles of drug and increased size uniformity.
[000131] Accordingly, the process of spray drying involves supplying the feed
solution at room temperature and pumping it through the nozzle where it is atomized by the nozzle gas. The atomized solution is then dried by preheated drying gas in a special chamber to remove water moisture from the system, thus forming dry particles of drug.

[000132] According to a preferred embodiment of the present invention, the nano-
milled drugs may be obtained by nano-milling of drugs with at least one surface stabilizer, at least one viscosity building agent and at least one polymer.
[000133] The present invention provides method of prevention, treatment or
prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, which method comprises administering a pharmaceutical antiretroviral composition of the type hereinbefore described. In preferred embodiments, the pharmaceutical antiretroviral composition comprises: (i) lamivudine, zidovudine, atazanavir and ritonavir; (ii) lamivudine, tenofovir, atazanavir and ritonavir; or (iii) emtricitabine, tenofovir, atazanavir and ritonavir.
[000134] The present invention also provides use of the pharmaceutical antiretroviral composition of the type hereinbefore described for the treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection. In preferred embodiments, the pharmaceutical antiretroviral composition comprises: (i) lamivudine, zidovudine, atazanavir and ritonavir; (ii) lamivudine, tenofovir, atazanavir and ritonavir; or (iii) emtricitabine, tenofovir, atazanavir and ritonavir.
[000135] The present invention further provides pharmaceutical antiretroviral
composition of the type hereinbefore described for simultaneous, separate or sequential use in the prevention, treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection. In preferred embodiments, the pharmaceutical antiretroviral composition comprises: (i) lamivudine, zidovudine, atazanavir and ritonavir; (ii) lamivudine, tenofovir, atazanavir and ritonavir; or (iii) emtricitabine, tenofovir, atazanavir and ritonavir.
[000136] The following examples are for the purpose of illustration of the invention
only and are not intended in any way to limit the scope of the present invention.
[000137] Example 1
Emtricitabine & Tenofovir Disoproxil Tablets:

Sr.No
Name of Ingredients Qty/tab (mg)
Tenofovir Layer
I Dry Mix
1. Tenofovir Disoproxil Fumarate 300.0
2. Lactose Monohydrate 159.0
3. Croscarmellose sodium 20.00
4. Corn Starch 30.00
II Binder Preparation
5. Corn Starch 15.00
6. Polysorbate 80 3.00
7. Purified Water q.s.
III. Lubrication
8. Microcrystalline Cellulose 100
9. Croscarmellose sodium 20.00
10. Magnesium Stearate 12.50
Total 660.00

Sr.No Name of Ingredients Qty/tab (mg)
Emtricitabine Layer
I Dry Mix
1. Emtricitabine 200.0
2. Microcrystalline cellulose 106.0
3. Crospovidone 20.0
II Binder Preparation
4. Povidone 10.0
5. Purified water q.s.
III. Lubrication
6. Microcrystalline Cellulose 86.0
7. Colloidal silicon dioxide 15.0
8. Crospovidone 4.0
9. Magnesium Stearate 4.0
Total 445.00

Film Coating:

Sr.No Name of Ingredients Qty/tab (mg)
1. Opadry AMB OY-B-29000 Translucent 18
2. Purified water q.s.
Process:
Preparation of Layer I
A) Granulation
1) Tenofovir, lactose, croscarmellose, corn starch were sifted through mesh of required
pore size.
2) The sifted ingredients were loaded in a Fluid bed processor and dry mixed.
3) Binder solution was prepared using corn starch, polysorbate 80 and purified water.
4) Binder solution so obtained was sprayed on the mixture obtained in step 2.
5) Granules so obtained were dried, sized and lubricated. Preparation of Layer II

1) Emtricitabine, microcrystalline cellulose, crospovidone were sifted through mesh of required pore size.
2) The sifted ingredients were loaded in a Fluid bed processor and dry mixed.
3) Binder solution was prepared using povidone and purified water.
4) Binder solution so obtained was sprayed on the mixture obtained in step 2.
5) Granules so obtained were dried, sized and lubricated.
B) Compression
1) Lubricated blend of Layer I and Layer II was compressed to produce a bilayer tablets.
C) Coating
1) Tablets so obtained were coated with Opadry solution.
[000138] Example 2
Lamivudine & Tenofovir Disoproxil Tablets:

Sr.No Name of Ingredients Qty/tab (mg)
Tenofovir Layer
I Dry Mix

1.
Tenofovir Disoproxil Fumarate 300.0
2. Lactose Monohydrate 159.0
3. Croscarmellose sodium 20.00
4. Corn Starch 30.00
II Binder Preparation
5. Corn Starch 15.00
6. Polysorbate 80 3.00
7. Purified Water q.s.
III. Lubrication
8. Microcrystalline Cellulose 100
9. Croscarmellose sodium 20.00
10. Magnesium Stearate 12.50
Total 660.00

Sr.No Name of Ingredients Qty/tab (mg)
Lamivud ine Layer
I Dry Mix
1. Lamivudine 300.0
2. Microcrystalline cellulose 103.20
3. Sodium starch glycolate 30.0
II Binder Preparation
4. Corn starch 10.20
5. Purified water q.s.
III. Lubrication
6. Sodium starch glycolate 20.0
7. Magnesium Stearate 6.0
Total 470.00
Film Coating:

Sr.No Name of Ingredients Qty/tab (mg)
1. Opadry AMB OY-B-29000 Translucent 18
2. Purified water q.s.

Process:
Preparation of Layer I
A) Granulation
1) Tenofovir, lactose, croscarmellose, corn starch were sifted through mesh of required
pore size.
2) The sifted ingredients were loaded in a Fluid bed processor and dry mixed.
3) Binder solution was prepared using corn starch, polysorbate 80 and purified water.
4) Binder solution so obtained was sprayed on the mixture obtained in step 2.
5) Granules so obtained were dried, sized and lubricated. Preparation of Layer II

1) Lamivudine, microcrystalline cellulose, sodium starch glycolate were sifted through mesh of required pore size.
2) The sifted ingredients were loaded in a Fluid bed processor and dry mixed.
3) Binder solution was prepared using corn starch and purified water.
4) Binder solution so obtained was sprayed on the mixture obtained in step 2.
5) Granules so obtained were dried, sized and lubricated.
B) Compression
1) Lubricated blend of Layer I and Layer II was compressed to produce a bilayer tablets.
C) Coating
1) Tablets so obtained were coated with Opadry solution.
[000139] Example 3
Atazanavir & Ritonavir Tablets:

Sr.No Name of Ingredients Qty/tab (mg)
Atazanavir Layer
I Dry Mix
1. Atazanavir 341.70
2. Lactose monohydrate. 120.29
3. Crospovidone 16.0
4. Yellow Iron Oxide 0.50
II Binder Preparation

5.
Purified water q.S.
III. Blending & Lubrication
6. Crospovidone 16.0
7. Magnesium Stearate 5.50
Total 500.00
Ritonavir Layer
I Dry Mix
1. Ritonavir 100.00
2. Colloidal Silicon dioxide 6.90
II Polymer Premix
3. Crospovidone 493.10
4. Sorbitan Mono laureate 66.70
Ill Blending & Lubrication
5. Colloidal Silicon dioxide 10.00
6. Anhydrous Dibasic Calcium Phosphate 89.40
7. Sodium Stearyl Fumarate 3.90
Total 770.0
Total tablet weight 1270
Coating:

Sr.No Name of Ingredients Qty/tab (mg)
Seal Coating
1. Hypromellose 8.00
2. Talc 2.0
3. Isopropyl alcohol q.s.
4. Methylene Chloride q.s.
Film Coating
1. Opadry II Yellow 15.00
2. Purified water q.s.
Process:

1) Atazanavir sulphate was mixed with pre-sieved and pre-sifted amounts of lactose monohydrate, crospovidone, yellow iron oxide, and granulated with purified water.
2) Ritonavir with small amount of colloidal silicon dioxide was sifted & mixed together with crosspovidone and sorbitan monolaureate in a mixer.
3) The contents obtained in step (2) were mixed and finally subjected to hot melt extrusion (HME) with the molten mass thus obtained being collected on a conveyor where it was cooled to form extrudates and these extrudates on further milling were converted into granules which was followed by addition of crospovidone, colloidal silicon dioxide and microcrystalline cellulose and further lubricated with sodium stearyl fumarate.
4) The granules obtained in (1) and (3) were compressed together to form a bilayer tablet which was then seal coated and finally film coated.
[000140] Example 4
Lamivudine and Zidovudine Tablet for Oral Suspension:

Sr. No. Ingredients Qty ! tablet (mg)
1. Lamivudine 30.00
2. Zidovudine 60.00
3. Microcrystalline Cellulose 52.38
4. Sodium starch glycolate 6.00
5. Starch 4.00
6. Purified water q.s.
7. Colloidal silicon dioxide 0.50
8. Aspartame 3.00
9. Flavour 3.00
10. Magnesium Stearate 1.12
Total 160.0

Process:
(1) Dry mix of lamivudine, zidovudine with microcrystalline cellulose, sodium starch glycolate, starch and colloidal silicon dioxide was prepared.
(2) Binder solution was prepared and dry mix obtained from step (1) was granulated.
(3) Granules obtained from step (2) were blended and lubricated and were compressed to form tablet.
[000141] It will be readily apparent to one skilled in the art that varying
substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
[000142] It is to be understood that the phraseology and terminology used herein is
for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
[000143] It must be noted that, 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 propellant" includes a single propellant as well as two or more different propellants; reference to a "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like.

We Claim,
1. A pharmaceutical antiretroviral composition comprising:
(i) at least one reverse transcriptase inhibitor comprising lamivudine, zidovudine,
tenofovir, emtricitabine, or a pharmaceutically acceptable salts, solvates,
hydrates, esters and other derivatives thereof; and (ii) at least one protease inhibitor comprising atazanavir, ritonavir, or a
pharmaceutically acceptable salts, solvates, hydrates, esters, and other
derivatives thereof and (iii) one or more pharmaceutically acceptable excipients.
2. A pharmaceutical antiretroviral composition according to claim 1, further
comprising:
(i) a reverse transcriptase inhibitor comprising didanosine; stavudine; abacavir;
adefovir; lobucavir; entecavir; apricitabine; zalcitabine; dexelvucitabine;
alovudine; amdoxovir; elvucitabine; festinavir; racivir; lersivirine; rilpivirine;
etravirine; stampidine, or a pharmaceutically acceptable salts, solvates,
hydrates, esters, and other derivatives thereof; and/or (ii) a protease inhibitor comprising saquinavir; nelfinavir; amprenavir; lopinavir,
indinavir; nelfinavir; lasinavir; palinavir; tipranavir; fosamprenavir; darunavir;
or a pharmaceutically acceptable salts, solvates, hydrates, esters, and other
derivatives thereof
3. A pharmaceutical antiretroviral composition according to claim 1, comprising lamivudine, zidovudine, atazanavir, ritonavir, and/or one or more pharmaceutically acceptable salts, solvates, hydrates, esters and other derivatives thereof.
4. A pharmaceutical antiretroviral composition according to claim 1, comprising lamivudine, tenofovir, atazanavir, ritonavir, and/or one or more pharmaceutically acceptable salts, solvates, hydrates, esters and other derivatives thereof.
5. A pharmaceutical antiretroviral composition according to claim 1, comprising tenofovir, emtricitabine, atazanavir, ritonavir, and/or one or more pharmaceutically acceptable salts, solvates, hydrates, esters and other derivatives thereof.

6. A pharmaceutical antiretroviral composition according to claim 1 to 5, wherein, lamivudine, zidovudine, tenofovir, emtricitabine are present in a single unit dosage form.
7. A pharmaceutical antiretroviral composition according to claim 1 to 5, wherein, atazanavir and ritonavir are present in a single unit dosage form.
8. A pharmaceutical antiretroviral composition according to any preceding claim, wherein emtricitabine is present in an amount of about 200 mg.
9. A pharmaceutical antiretroviral composition according to any preceding claim, wherein tenofovir is present in an amount from about 75 mg to 300 mg.
10. A pharmaceutical antiretroviral composition according to any preceding claim, wherein zidovudine is present in an amount from about 60 mg to 600 mg.
11. A pharmaceutical antiretroviral composition according to any preceding claim, wherein lamivudine is present in an amount from about 30 mg to 300 mg.
12. A pharmaceutical antiretroviral composition according to any preceding claim, wherein atazanavir is present in an amount from about 100 mg to 300 mg.
13. A pharmaceutical antiretroviral composition according to any preceding claim, wherein ritonavir is present in an amount from 33 mg to 100 mg.
14. A pharmaceutical antiretroviral composition comprising:
(i) at least one reverse transcriptase inhibitor comprising lamivudine, zidovudine,
tenofovir and emtricitabine, or a pharmaceutically acceptable salts, solvates,
hydrates, esters, and other derivatives thereof; and (ii) at least one protease inhibitor comprising atazanavir and ritonavir, or a
pharmaceutically acceptable salts, solvates, hydrates, esters and other
derivatives thereof and (iii) one or more pharmaceutically acceptable excipients

in the form of a kit comprising instructions for administration.
15. A pharmaceutical antiretroviral composition according to claim 14, wherein the dosage form is a tablet, mini-tablet, granule, sprinkle, capsule, suspension, emulsion, solution, syrup, elixir, sachet, powders, pellets, pills, micro-pellets, small tablet units, MUPS, effervescent granules and microspheres.
16. A pharmaceutical antiretroviral composition according to any preceding claim for once a day administration.
17. A pharmaceutical antiretroviral composition according to any preceding claim for oral administration.
18. A pharmaceutical antiretroviral composition according to any preceding claim, wherein the at least one reverse transcriptase inhibitor and at least protease inhibitor are in nanosize form.
19. A pharmaceutical antiretroviral composition according to any preceding claim, wherein the pharmaceutically acceptable excipients are selected from the group comprising at least one of diluent, filler, bulking agent, disintegrant, binder, lubricant, water soluble polymer, water insoluble polymer, water swellable polymer, plasticizer and mixtures thereof.
20. A process for preparing a pharmaceutical antiretroviral composition comprising admixing at least one reverse transcriptase inhibitor and at least one protease inhibitor according to any preceding claim with one or more pharmaceutically acceptable excipients.
21. A method for the prevention, treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, which method comprises administering a pharmaceutical antiretroviral composition according to any one of claims 1 to 20.

22. Use of the pharmaceutical antiretroviral composition according to any one of claims 1 to 20 for the treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
23. A pharmaceutical antiretroviral composition according to any one of claims 1 to 20 for simultaneous, separate or sequential use in the prevention, treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
24. A pharmaceutical antiretroviral composition substantially as herein described with reference to the examples.
26. A process for making a pharmaceutical antiretroviral composition substantially as herein described with reference to the examples.