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:
"A KIT COMPRISING 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.PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

FIELD OF INVENTION:
The present invention relates to pharmaceutical antiretroviral compositions in the form of a kit comprising a combination of anti-retroviral agents, manufacturing process thereof and use of the said composition for the prevention, treatment and prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HTV
infection.
BACKGROUND AND PRIOR ART:
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.
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.
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.
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. HIV 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.
The current strategy recommended for the treatment of HIV infection is Highly Active Anti retroviral Therapy (HAART). HAART normally consists of a combination of three or more antiretroviral drugs (ARV) taken together.
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 j, 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).
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 HAART therapy.
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.

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.
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 antiretrovir al therapies in a randomized trial AIDS, 2003; 17:F33-F37).
Hence, such non-adherence to HA ART 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.
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.
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.
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.
Also, oral administration of bitter drugs with an acceptable degree of palatability is a key issue for health care providers, especially for pediatric patients.
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.
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.
OBJECT OF THE INVENTION:
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 in the form of a kit.
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 in the form of a kit.
Yet 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 in the form of a kit for once a day administration.

A further object of the present invention is to provide a process of manufacturing the pharmaceutical antiretroviral composition comprising at least one reverse transcriptase inhibitor and at least one protease inhibitor optionally with one or more pharmaceutically acceptable excipients in the form of a kit for once a day administration.
StiJ! 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 in the form of a kit for use in the prevention, treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
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 the pharmaceutical antiretroviral composition comprising at least one reverse transcriptase inhibitor and at least one protease inhibitor as a kit.
Yet another object of the present invention is to provide use of the pharmaceutical antiretroviral composition in the form of a kit for the manufacture of a medicament for the treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection for the above mentioned compositions.
SUMMARY OF THE INVENTION:
According to one aspect of the present invention, there is provided a pharmaceutical
antiretroviral composition comprising:
(i) at least one reverse transcriptase inhibitor comprising at least one reverse transcriptase inhibitor selected from tenofovir, lamivudine, abacavir, zidovudine, emtricitabine didanosine, stavudine, adefovir, lobucavir, entecavir, apricitabine, zalcitabine, dexelvucitabine, alovudine, amdoxovir, elvucitabine, festinavir, racivir, lersivirine, rilpivirine, etravirine, stampidine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and

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

fosamprenavir, darunavir, or 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.
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 tenofovir, lamivudine, abacavir, zidovudine and emtricitabine or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and
(ii) at least one protease inhibitor comprising lopinavir 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.
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 selected from tenofovir, lamivudine, abacavir, zidovudine, emtricitabine didanosine, stavudine, adefovir, lobucavir, entecavir, apricitabine, zalcitabine, dexelvucitabine, alovudine, amdoxovir, elvucitabine, festinavir, racivir, lersivirine, rilpivirine, etravirine, stampidine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and
(ii) at least one protease inhibitor comprising lopinavir, ritonavir, saquinavir, nelfinavir, amprenavir, indinavir, nelfinavir, atazanavir, lasinavir, palinavir, tirpranavir, fosamprenavir, darunavir, or tipranavir, 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.
According to another aspect of the present invention, there is provided the use of a
pharmaceutical anttretroviral composition comprising:
(i) at least one reverse transcriptase inhibitor comprising tenofovir, lamivudine, abacavir, zidovudine and emtricitabine or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and
(ii) at least one protease inhibitor comprising lopinavir 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:
As discussed above, there is a need to develop and formulate a suitable pharmaceutical antiretroviral composition in the form of a kit for once a day administration, comprising at least one reverse transcriptase inhibitor and at least one protease inhibitor in the form of a kit which would not only, be convenient for patient administration but would also enable and maintain patient adherence to the therapy.
In general, the therapy for the treatment of HIV infection comprises a combination of NRTIs, NtRTIs, NNRTIs and Pis or combination of NRTIs, NtRTIs, NNRTIs and INI. The dose regimen of these drugs is such that the patient needs to administer several drugs throughout the day and that too at different time intervals and further, this dosage regimen has to be followed for year's altogether. This long term therapy may generally cause great

amount of 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 get rid of the inconvenience caused to him such as to remember the administration of the medication as well as the time at which it needs to be administered.
The present invention thus, provides a pharmaceutical antiretroviral composition comprising at least one nucleotide reverse transcriptase inhibitor and/or one nucleoside 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 HIV infection.
The present invention thus, provides a pharmaceutical antiretroviral composition comprising at least one nucleotide reverse transcriptase inhibitor and/or one nucleoside reverse transcriptase inhibitor and at least one integrase inhibitor as a combined preparation in a kit form, for simultaneous or separate use in the treatment of HIV infection.
It will be appreciated from the above, that the respective therapeutic agents of the combined preparations 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, synergistic therapeutic effect of such a combined preparation.
Suitable protease inhibitors (Pis) that may be employed in the pharmaceutical composition of the present invention may comprise saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir; tirpranavir; fosamprenavir; darunavir; and/or tipranavir or their pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs and derivatives thereof.
Suitable nucleoside reverse transcriptase inhibitors (NRTIs) that may be employed in the pharmaceutical composition of the present invention may comprise Zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine;

emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir; elvucitabine; BCH-189; phosphazid; tenofovir; festinavir; racivir; SP1093V; and/or stampidine or their pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs and derivatives thereof.
Suitable nucleotide reverse transcriptase inhibitors (NtRTIs) that may be employed in the pharmaceutical composition of the present invention may comprise tenofovir and/or adefovir or their pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs and derivatives thereof.
Suitable integrase inhibitors (INI) that may be employed in the pharmaceutical composition of the present invention may comprise dolutegravir; raltegravir and/or elvitagravir or their pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs and derivatives thereof.
In one embodiment, the present invention provides a pharmaceutical antiretroviral composition in the form of a kit comprising tenofovir , lamivudine and lopinavir, ritonavir or their pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs and derivatives thereof.
In one another embodiment, the present invention provides a pharmaceutical antiretroviral composition in the form of a kit comprising abacavir, lamivudine and lopinavir, ritonavir or their pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs and derivatives thereof.
In one another embodiment, the present invention provides a pharmaceutical antiretroviral composition in the form of a kit comprising tenofovir, emtricitabine and lopinavir, ritonavir or their pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs and derivatives thereof.
In one another embodiment, the present invention provides a pharmaceutical antiretroviral composition in the form of a. kit comprising lamivudine, zidovudine and

lopinavir, ritonavir or their pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs and derivatives thereof.
The terms "Tenofovir", "Lamivudine",, "Abacavir" ,"Emtricitabine", "Zidovudine", "Lopinavir" and "Ritonavir" are used in broad sense to include not only, "Tenofovir", "Lamivudine",, "Abacavir" ,"Emtricitabine", "Zidovudine", "Lopinavir" and "Ritonavir" per se but also, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.
Tenofovir disoproxil fumarate is an analog of adefovir and is classified as a nucleotide reverse transcriptase inhibitor (NAtRTI). 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 is from about 75mg to about 300 mg.
Abacavir is a synthetic carbocyclic nucleoside analog and reverse transcriptase inhibitor which is used typically in combination with other agents in the therapy of the human immunodeficiency virus (HIV) infection. In vivo, the activated triphosphate metabolite of abacavir is incorporated into the viral DNA instead of the natural substrate deoxyguanosine, thereby inhibiting human immunodeficiency virus (HTV) reverse transcriptase (RT) and the replication of the viral DNA and infectious viral particles. This agent decreases HIV viral loads, retards or prevents the damage to the immune system,

and reduces the risk of developing AIDS. A preferred dosage of abacavir is from about 60mg to about 600 mg.
Lamivudine (also known as 3TC) is a synthetic nucleoside analogue, chemically known as (2R, cis)-4-amino-l-(2-hydroxymethyl-I, 3-oxathiolan-5-yl)-(lH)-pyrimidin-2- one. Intracellularly, 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, (Hydroxymethyl)-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 is from about 30mg to about 300 mg.
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 is from about 60 mg to about 600 mg.
Ritonavir is chemically designated as ]0-Hydroxy-2-methyl-5-(1-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*,11R*)]. 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 is from about 10 mg to about 200 mg.

Lopinavir is chemically designated as 2S)-N-[(2S,4S, 5S)-5-[2(2,6dimethylphenoxy)acetamido]-4-hydroxy-l,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-l,3-diazinan-l-y])butanamide. Lopinavir is an antiretroviral of the protease inhibitor class. It is used as a fixed-dose combination with another protease inhibitor. A preferred dosage of Lopinavir is from about 40 mg to about 800 mg.
Ritonavir on co-administration with lopinavir causes an improvement in the pharmacokinetics (i.e., increases half-life, increases the time to peak plasma concentration, increases blood levels) of lopinavir.
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 H1V-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 form of emtricitabine is emtricitabine free base. A preferred dosage of emtricitabine is from about is from about 9 mg to about 200 mg.
According to a preferred embodiment, the present invention provides a pharmaceutical antiretroviral composition comprising lamivudine, zidovudine and lopinavir, ritonavir in the form of a kit for once day administration-According to another preferred embodiment, the present invention provides a pharmaceutical antiretroviral composition comprising tenofovir, lamivudine and lopinavir, ritonavir in the form of a kit for once day administration.
According to yet another preferred embodiment, the present invention provides a pharmaceutical antiretroviral composition comprising abacavir, lamivudine and lopinavir, ritonavir in the form of a kit for once day administration.

According to yet another preferred embodiment, the present invention provides a pharmaceutical antiretroviral composition comprising tenofovir, emtricitabine and Jopinavir, ritonavir in the form of a kit for once day administration.
As discussed above and hereinafter, the pharmaceutical antiretroviral composition of the present invention in the form of a kit comprises lamivudine, zidovudine along with one or more pharmaceutically acceptable excipients to form an admixture which are blended and/or layered to provide a single unit dosage form.
The pharmaceutical antiretroviral composition of the present invention in the form of a kit comprises tenofovir, lamivudine along with one or more pharmaceutically acceptable excipients to form an admixture which are blended and/or layered to provide a single unit dosage form.
The pharmaceutical antiretroviral composition of the present invention in the form of a kit comprises abacavir, lamivudine along with one or more pharmaceutically acceptable excipients to form an admixture which are blended and/or layered to provide a single unit dosage form.
The pharmaceutical antiretroviral composition of the present invention in the form of a kit comprises tenofovir, emtricitabine along with one or more pharmaceutically acceptable excipients to form an admixture which are blended and/or layered to provide a single unit dosage form.
The pharmaceutical antiretroviral composition of the present invention in the form of a kit comprises lopinavir, ritonavir along with one or more pharmaceutically acceptable excipients to form an admixture which are blended and/or layered to provide a single unit dosage form.
Suitably, the pharmaceutical antiretroviral composition in the form of a kit according to the present invention are presented in solid dosage form, conveniently in unit dosage form, and also include dosage form suitable for oral and buccal administration. However,

other dosage forms such as liquid dosage form may be envisaged under the ambit of the invention.
Unit dosage forms, according to the present invention, are preferably in the form of tablet, mini-tablet, granules or 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. The pharmaceutical antiretroviral composition in the form of a kit, 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, micropellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, 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, 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.
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, water.
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.
According to the preferred embodiment, the pharmaceutical antiretroviral composition in the form of a kit may be administered simultaneously, separately or sequentially in a single unit dosage form wherein the drugs and excipients are present in a single layer tablets (such as a tablet or mini tablet in a capsule or sprinkle).

According to another preferred embodiment, the pharmaceutical antiretroviral composition in the form of a kit may be administered as a bilayer/multi layer tablet wherein each layer separately contains drug/drugs and pharmaceutically acceptable excipients which are then compressed to give a bilayer/multi layer tablet.
In one embodiment, the present invention provides a pharmaceutical antiretroviral composition comprising lamivudine, zidovudine and lopinavir, ritonavir in the form of a kit.
In another embodiment, the present invention provides a pharmaceutical antiretroviral composition comprising tenofovir, lamivudine and lopinavir, ritonavir in the form of a kit.
In yet another embodiment, the present invention provides a pharmaceutical antiretroviral composition comprising abacavir, lamivudine and lopinavir, ritonavir in the form of a kit. In another embodiment, the present invention provides a pharmaceutical antiretroviral composition comprising tenofovir, emtricitabine and lopinavir, ritonavir in the form of a kit.
As discussed above and hereinafter, the pharmaceutical antiretroviral composition in the form of a kit may comprise a separate unit dosage form of lamivudine, zidovudine and a separate unit dosage form of lopinavir, ritonavir.
The pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form of tenofovir and lamivudine and a separate unit dosage form of lopinavir, ritonavir.
The pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form of abacavir, lamivudine and a separate unit dosage form of lopinavir, ritonavir.

The pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form of tenofovir, emtricitabine and a separate unit dosage form of lopinavir, ritonavir.
As discussed above and hereinafter, the pharmaceutical antiretroviral composition in the form of a kit and may comprise a separate unit dosage form of lamivudine, a separate unit dosage form of zidovudine and a separate unit dosage form of lopinavir, a separate unit dosage form of ritonavir.
The pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form of tenofovir and separate unit dosage form of lamivudine and a separate unit dosage form of lopinavir, separate unit dosage form of ritonavir.
The pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form of abacavir, a separate unit dosage form of lamivudine and a separate unit dosage form of lopinavir, a separate unit dosage form of ritonavir.
The pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form of tenofovir, a separate unit dosage form of emtricitabine and a separate unit dosage form of lopinavir, a separate unit dosage form of ritonavir.
Kit composition has an advantage over the other packaged dosage forms such as; the patient always has an access to the set of instructions for administration of the pharmaceutical antireteroviral composition contained in the kit. The inclusion of such a set of instructions for administration has been shown to improve patient compliance.
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.
Suitable excipients may be used for formulating the various dosage forms according to the present invention.

According to the present invention, pharmaceutically acceptable carriers, diluents or fillers for use in the pharmaceutical antiretroviral composition in the form of a kit may comprise one or more, but not limited to, lactose (for example, spray-dried lactose, a-lactose, β-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.
According to the present invention, glidants, anti-adherents and lubricants may also be incorporated in the pharmaceutical antiretroviral composition in the form of a kit, 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.
According to the present invention, suitable binders may also present in the in the pharmaceutical antiretroviral composition in the form of a kit, 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 binder.
According to the present invention, suitable disintegrants may also be present in the pharmaceutical antiretroviral composition in the form of a kit in the form of a kit, 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.
The present invention also provides a hot melt extruded pharmaceutical formulation comprising ritonavir and at least one or more water soluble and/or one or more insoluble polymer and optionally one or more pharmaceutically acceptable excipients.
Water soluble polymers which may be used, in the pharmaceutical antiretroviral composition in the form of a kit 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.
Water insoluble polymers, which may be used in the pharmaceutical antiretroviral composition in the form of a kit 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 ; polyvinylacetate, for example, Kollicoat SR 30D; cellulose derivatives such as ethylcellulose, cellulose acetate e.g. Surelease , Aquacoat ECD and Aquacoat CPD and mixtures thereof.
One or more optional pharmaceutically acceptable excipients may include plasticizer.
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.

Plasticizers which may be used, in the pharmaceutical antiretroviral composition in the form of a kit 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.
According to an embodiment of the present invention, pharmaceutical antiretroviral composition in the form of a kit 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.
According to an another embodiment of the present invention, pharmaceutical antiretroviral composition in the form of a kit may be seal coated comprises film forming polymeric materials, such as but not limited to, anionic copolymers based on methacrylic acic and methyl methacrylate, 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 compr i ses h ydroxypropy lmethylce 1 lulose.
According to an another embodiment of the present invention, pharmaceutical antiretroviral composition in the form of a kit may be seal coated followed by film coated whereas seal coated comprises film forming polymeric materials, such as but not limited to anionic copolymers based, on methacrylic acic and methyl methacrylate, 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.

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.
The pharmaceutical antiretroviral composition in the form of a kit, 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, spheronization spray drying, solution evaporation or combinations thereof.
It will be acknowledged to a person skilled in the art, 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.
Suitable processes may be used for formulating the various dosage forms according to the present invention.
According to the present invention the process of hot melt extrusion is carried out in the conventional extruders as known to a person having a skill in the art.
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.
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. Usually, the melt temperature is in the range of about 50° C to about 200° C.
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. The extrudates can be

in the form of beads, granulates, tube, strand or cylinder and this can be further processed into any desired shape.
In an alternative process, the present invention may further be allowed to form granules which may be compressed to form tablets, minitablets, pellets or granules/sprinkle that may be filled into sprinkles, capsules, and sachet or in a similar dosage form.
The process involves heating the polymer(s) to soften it, without melting it, and mixing the active ingredient(s) with polymer(s), to form-granules.
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.
The extrudates/granules so obtained according to the present invention may then be admixed with other suitable one or more pharmaceutically acceptable excipients.
According to preferred embodiment, the present invention may comprise one or more antiretroviral drug(s) and at least one or more water soluble polymers which are melt extruded by the process as described herein, where a powder blend of two antiretroviral drugs most preferably one or more protease inhibitor drugs i.e. lopinavir & ritonavir with one or more water soluble polymer and/or at least one or more water insoluble polymer, or a combination of atleast one or more water soluble and water insoluble polymer, and other excipients which may comprise suitable bulking agents and flavourants. The process comprises: (a) melt granulating one or more solubility enhancers and one or more pharmaceutically acceptable excipients with the/or each drugs in water or other suitable solvent to form a granulated material; (b) sieving the granulated material; (c) drying the sieved granulated material to form dried granules; (d) lubricating the dried granules with one or more lubricants and one or more second pharmaceutically acceptable excipients; and (e) optionally further processing the lubricated dried granules.
According to preferred embodiment, the pharmaceutical antiretroviral composition in the form of a kit of the present invention is processed by wet granulation of tenofovir and

lamivudine wherein the diluent, the disintegrant along with the actives lamivudine and tenofovir are treated with the binder solution to form granules. Granules are lubricated and final obtained granules are 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 to ease administration.
According to preferred embodiment, the pharmaceutical antiretroviral composition in the form of a kit 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 final obtained granules are 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.
According to preferred embodiment, the pharmaceutical antiretroviral composition in the form of a kit 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 treated with the binder solution to form granules. Granules are lubricated and final obtained granules are 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.
According to another preferred embodiment, the pharmaceutical antiretroviral composition in the form of a kit of the present invention is processed by wet granulation of lamivudine and abacavir wherein the diluent, the disintegrant along with the actives lamivudine and abacavir are treated with the binder solution to form granules. Granules are lubricated and final obtained granules are 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.
The present invention, further provides a process to manufacture the pharmaceutical antiretroviral composition in the form of a kit, which process comprises (1) Coating one or more antiretroviral drugs with at least one or more water soluble polymers, at least one or more water insoluble polymers or a combination of at least one or more water soluble and water insoluble polymers to form coated granules containing the active ingredient or ingredients, (2) Mixing the coated granules obtained in step (1) with one or more pharmaceutically acceptable excipients, (3) Finally (i) filling the mixture formed in step (2) into hard gelatin capsules or sachets which can be opened by a patient and its contents sprinkled onto food to ease administration; or (ii) compressing the mixture formed in step (2) to form mini-tablets which may alternatively be filled into capsules or sachets which can be sprinkled onto food to ease administration.
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 or, with at least one or more water soluble polymers or a combination of at least one or more water soluble polymers with one or more water insoluble polymer, the resulting product acquires taste masking property wherein the ratio of drug:polymer is 1 :1 to 1 :6.
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.
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 in the form of a kit 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.
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.
Alternatively, the pharmaceutical antiretroviral composition in the form of a kit according to the present invention may also comprise the actives in nano size form. Preferably, the active pharmaceutical ingredients have average particle size less than about 2000 nm, preferably less than about 1000 nm.
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 al., 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].
Nano-sizing leads to increase in the exposure of surface area of particles leading to an increase in the rate of dissolution.
The nanoparticles of the present invention can be obtained by any of the process such as but not limited to milling, precipitation and homogenization.
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.

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.
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.
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 \\m 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).
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.
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 oiI/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.
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.
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.
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.
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.
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.
According to one aspect of the present invention, the pharmaceutical antiretroviral composition in the form of a kit comprising lamivudine, zidovudine and lopinavir, ritonavir is used for prevention, treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
The present invention also provides a pharmaceutical antiretroviral composition in the form of a kit comprising tenofovir, lamivudine and lopinavir, ritonavir is used for

prevention, treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
The present invention also provides a pharmaceutical antiretroviral composition in the form of a kit comprising abacavir, lamivudine and lopinavir, ritonavir is used for prevention, treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrpme or an HIV infection.
The present invention also provides a pharmaceutical antiretroviral composition in the form of a kit comprising tenofovir, emtricitabine and lopinavir, ritonavir is used for prevention, treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
According to one another aspect of the pharmaceutical antiretroviral composition in the form of a kit of the present invention comprising lamivudine, zidovudine and lopinavir, ritonavir is for simultaneous, separate or sequential administration.
The present invention further also provides pharmaceutical antiretroviral composition in the form of a kit comprising tenofovir, lamivudine and lopinavir, ritonavir is for simultaneous, separate or sequential administration.
The present invention further also provides pharmaceutical antiretroviral composition in the form of a kit comprising lamivudine, abacavir and lopinavir, ritonavir is for simultaneous, separate or sequential administration.
The present invention further provides pharmaceutical antiretroviral composition in the form of a kit comprising tenofovir, emtricitabine and lopinavir, ritonavir is for simultaneous, separate or sequential administration.
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.

Example 1
Lopinavir and Ritonavir Sprinkle:

Sr. No. Ingredients Qty /Capsule (mg)
I. Dry Mix
1. Lopinavir 40.00
2. Ritonavir 10.00
3. Colloidal Silicon Dioxide 2.00
4. Cros povidone 140.7
5. Sorbitan Monolaurate 14.00
II. Blending & Lubrication
6. Colloidal Silicon Dioxide 2.00
7. Sodium Stearyl Fumarate 2.00
III Coating
8. Hydroxy Propyl Methyl Cellulose 12.642
9. Polyethylene Glycol 6000 0.129
10. Talc 0.129
11. Acetone q.s.
12. Water q.s
IV. Total 223.6
Process:
(1) Dry mix of lopinavir, ritonavir, and colloidal silicon dioxide, was prepared.
(2) Sorbitan monolaurate was mixed with Copovidone in a suitable granulator separately to form the polymer premix.
(3) The dry mix obtained in step (1) and step (2) was mixed in a suitable granulator.
(4) The mixture obtained in step (3) was subjected to melt extrusion (hot).
(5) Colloidal silicon dioxide was blended with the dried granules and lubricated by using sodium stearyl fumarate.
(6) The lubricated granules were compressed into mini-tablets.
(7) The compressed mini-tablets were coated with seal coating solution.
(8) The mini-tablets obtained in step (6) were filled into hard gelatin capsules.

Eample 2
Lopinavir and Ritonavir Sprinkle:

Sr.No. Ingredients Qty/Sachet (mg)
I. Dry Mix for Hot melt Extrusion
1. Lopinavir 40.00
2. Ritonavir 10.00
3. Eudragit 25 - 250
4. Colloidal silicon dioxide q.S
II. Blending
5. Sugar (Pulverized) 25 - 250
6. Flavour q.s
7. Colloidal silicon dioxide q.s
ffl. Total (Range) 100-500
Process:
1. Dry mix of lopinavir, ritonavir, eudragit and colloidal silicon dioxide was prepared.
2. Dry mix obtained in step (1) was subjected to melt extrusion (hot).
3. Extrudes obtained in step (2) were sized and sifted to form granules.
4. Granules obtained in step (3) were blended with colloidal silicon dioxide, sugar and flavor was added.
Example 3
Lopinavir and Ritonavir Sprinkle:

Sr.No. Ingredients Qty/Sachet (mg)
I. Dry Mix for Hot melt Extrusion
1. Lopinavir 40.00
2. Ritonavir 10.00
3. Eudragit 25 -250
4. Sugar (Pulvarised) 25 - 250
5. Colloidal silicon dioxide q.s
Blending

II.
6. Flavour q.s
7. Colloidal silicon dioxide q.s
III. Total (Range) 100-500
Process:
1. Dry mix of lopinavir, ritonavir, eudragit, sugar and colloidal silicon dioxide was prepared.
2. Dry mix obtained in step (1) was subject to melt extrusion (hot).
3. Extrudes obtained in step (2) were sized and sifted to form granules.
4. Granules obtained in step (3) were blended with colloidal silicon dioxide and flavor was added.
Eample 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.
Eample 5
Abacavir Sulfate and Lamivudine Tablets

Sr.
No. Ingredients Qty J tabiet (mg)
I. Abacavir Sulfate granulates
1. Abacavir Sulfate 70.28
2. Microcrystalline Cellulose 37.43
3. Sodium Starch Glycolate 15.00
II. Binder for Abacavir Sulfate granulation
4. Hypromellose 5.00
5. Purified water q.s.
III. Lamivudine granulates
6. Lamivudine 30.00
7. Sodium Starch Glycolate 5.00
8. Microcrystalline Cellulose 70.57
IV. Binder for Lamivudine granulation
9. Starch 2.00
10. Purified water q.s.
V. Lubricants
11. Sodium Starch Glycolate 10.00
12. Microcrystalline Cellulose 42.72

13.
Flavour 3.00
14. Aspartame 6.00
15. Colloidal Silicon dioxide 2.50
16. Magnesium Stearate 2.50
VI. Total (Uncoated tablet) 300.00
Process:
A. Preparation of Abacavir Sulfate granulates:
1) Dry mix of abacavir sulfate, macrocrystalline cellulose and sodium starch glycolate, hydroxy propyl was prepared.
2) Binder solution was prepared using hypromellose in purified water.
3) Prepared binder solution from step (2) was sprayed over the dry mix obtained from step (1) to form granules.
4) Granules obtained in step (3) were dried.
B. Preparation of Lamivudine granulates:
1) Dry mix of iamivudine, microcrystalline cellulose and sodium starch glycolate was prepared.
2) Binder solution was prepared using corn starch in purified water.
3) Prepared binder solution obtained from step (2) was sprayed over the dry mixture obtained from step (1) to form granules.
4) Granules obtained from step (3) were dried.
C. Blending &Lubrication:
Granules obtained from step (A) and (B) was mixed, blended & lubricated.
D. Compression:
Lubricated granules obtained from step (C) were compressed into single layer tablet.

Example 6
Emtricitabine & Tenofovir Disoproxil Tablets:

Sr. No. Ingredients Qty / tablet (mg)
I. Dry Mix
1. Tenofovir Disoproxil Fumarate 300.00
2. Emtricitabine 200.00
3. Lactose Monohydrate 80.00
4. Croscarmellose sodium 30.00
5. Microcrystalline Cellulose 300.00
6. Pregelatinized Starch NF 25.00
n. Binder preparation
7. Pregelatinized Starch NF 25.00
8. Purified Water USP q.s.
III Lubrication
9. Croscarmellose sodium 30.00
10. Magnesium Stearate NF 10.00
Total 1000.00
IV. Film Coating
11. Opadry Blue 1132K-80963 INH 15.00
12. Purified Water USP q.s
Process:
1) Dry mix of tenofovir and emtricitabine with lactose monohydrate, crosscarmellose sodium and starch was prepared.
2) Binder solution was prepared using pregelatinized starch in purified water.
3) Prepared binder solution obtained from step (2) was sprayed over the dry mixture obtained from step (1) to form granules.
4) Granules obtained from step (3) were dried, mixed, blended & lubricated.
5) Lubricated granules obtained from step (4) were compressed into single layer tablet and coated.

Example 7
Lamivudine & Tenofovir Disoproxil Tablets:
Layer I- Tenofovir

Sr. No. Ingredients Qty / tablet (mg)
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. Macrocrystalline Cellulose 100
9. Croscarmellose sodium 20.00
10. Magnesium Stearate 12.50
Total 660.00
Layer II-Lamivudine

Sr. No. Ingredients Qty / tablet (rag)
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. Ingredients Qry / tablet (mg)
1. Opadry 18
2. Purified water q.s.
Process:
Preparation of Layer I
1) Dry mix of tenofovir, lactose, croscarmellose and corn starch was prepared.
2) Binder solution was prepared using corn starch, polysorbate 80 and purified water.
3) Binder solution so obtained from step (2) was sprayed over the dry mix obtained
from step (1).
4) Granules so obtained were dried, sized and lubricated.
Preparation of Layer II
1) Dry mix of Lamivudine, microcrystalline cellulose and sodium starch glycolate was prepared.
2) Binder solution was prepared using corn starch and purified water.
3) The binder solution so obtained in step (2) was sprayed on the dry mix obtained in step (1).
4) Granules obtained were dried, sized and lubricated.
B) Compression
Lubricated granules of Layer I and Layer II was compressed into a bilayer tablets.
C) Coating
1) Tablets so obtained were coated with Opadry solution.
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.
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.
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 "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) a reverse transcriptase inhibitor selected from tenofovir, lamivudine, abacavir,
zidovudine and emtricitabine or pharmaceutically acceptable salts, solvates,
hydrates, esters, complexes and derivatives thereof; and (ii) a protease inhibitor selected from lopinavir and ritonavir or pharmaceutically
acceptable salts, solvates, hydrates, esters, complexes and derivatives thereof
and (iii)one or more pharmaceutically acceptable excipients.
2. A pharmaceutical antiretroviral composition according to claim 1, further comprising:
(i) at least one reverse transcriptase inhibitor selected from didanosine, stavudine, adefovir, lobucavir, entecavir, apricitabine, zalcitabine, dexelvucitabine, alovudine, amdoxovir, elvucitabine, festinavir, racivir, lersivirine, rilpivirine, etravirine, stampidine, or pharmaceutically acceptable salts, solvates, hydrates, esters, complexes and derivatives thereof; and
(ii) at least one protease inhibitor selected from saquinavir, nelfinavir, amprenavir, indinavir, nelfinavir, atazanavir, lasinavir, palinavir, tirpranavir, fosamprenavir, darunavir, or tipranavir or pharmaceutically acceptable salts, solvates, hydrates, esters, complexes and derivatives thereof
3. A pharmaceutical antiretroviral composition according to any preceding claim, wherein tenofovir is present in an amount from about 75 mg to 300 mg, abacavir is present in an amount from about 60 mg to 600 mg, lamivudine is present in an amount from about 30 mg to 300 mg, zidovudine is present in an amount from about 60 mg to 600 mg, emtricitabine is present in an amount from about 9 mg to 200 mg, ritonavir is present in an amount from about 10 mg to 200 mg and lopinavir is present in amount from about 40 mg to 800 mg.
4. A pharmaceutical antiretroviral composition according to any preceding claim for once a day oral administration.

5. A pharmaceutical antiretroviral composition according to any preceding claim in the form of a kit.
6. A pharmaceutical antiretroviral composition according to any preceding claim, wherein the dosage form is a tablet, mini-tablet, granule, sprinkle, capsule, suspension, emulsion, solution, syrup, elixir, sachet, powders, pellets, pills, micropellets, disintegrating tablets, dispersible tablets, small tablet units, MUPS, effervescent granules and microspheres.
7. 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.
8. A process for preparing a pharmaceutical antiretroviral composition according to claim 7, 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.
9. A pharmaceutical antiretroviral composition according to any preceding claim as a combined preparation for simultaneous, sequential or separate use in the treatment of an HIV infection.
10. A pharmaceutical antiretroviral composition substantially as herein described with reference to the examples.