WO2014184553A1

WO2014184553A1 - Pharmaceutical antiretroviral compositions

Info

Publication number: WO2014184553A1
Application number: PCT/GB2014/051478
Authority: WO
Inventors: Shrinivas Madhukar Purandare; Geena Malhotra
Original assignee: Cipla Limited; Turner, Craig Robert
Priority date: 2013-05-15
Filing date: 2014-05-14
Publication date: 2014-11-20
Also published as: IN2013MU01749A

Abstract

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, specifically acquired immune deficiency syndrome or an HIV infection.

Description

PHARMACEUTICAL ANTIRETROVIRAL COMPOSITIONS

FIELD OF INVENTION

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 1 1 1 (HTLV-1 1 1), 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 Antiretroviral 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^®), 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 antiretroviral therapies in a randomized trial AIDS, 2003; 17:F33-F37).

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.

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. Keeping in mind the patient compliance and the urge to treat HIV to achieve the desired positive results avoiding repetition or change in the line of therapy due to non- adherence to the dosing regimen, the inventors of the present invention have been successful in designing kits comprising compositions of HIV drugs in line of the therapy or dosing regimens generally recommended. In particular, the present invention attempts to overcome the problems of patient adherence for the treatment of HIV.

OBJECTS OF THE INVENTION

The object of the present invention is to provide a pharmaceutical antiretroviral composition comprising at least one reverse transcriptase inhibitor or at least one integrase inhibitor and at least one protease inhibitor, preferably wherein said composition is 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 or at least one integrase 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 comprising a plurality of antiretroviral agents which have been co- formulated, or a plurality of dosage forms containing one or more antiretroviral agents.

Yet another object of the present invention is to provide a pharmaceutical antiretroviral composition for once or twice a day administration comprising at least one reverse transcriptase inhibitor or at least one integrase 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 comprising a plurality of antiretroviral agents which have been co-formulated, or a plurality of dosage forms containing one or more antiretroviral agents.

Yet another object of the present invention is to provide a process for manufacturing a pharmaceutical antiretroviral composition for once or twice daily administration comprising at least one reverse transcriptase inhibitor or at least one integrase 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.

Another object of the present invention is to provide a method of prevention, treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, which method comprises administering a pharmaceutical antiretroviral composition comprising at least one reverse transcriptase inhibitor or at least one integrase inhibitor and at least one protease inhibitor to a patient in need thereof, preferably wherein said composition is in the form of a kit.

Yet another object of the present invention is to provide the use of a pharmaceutical antiretroviral composition comprising at least one reverse transcriptase inhibitor or at least one integrase inhibitor and at least one protease inhibitor for the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, wherein said composition is for once or twice a day administration and is preferably in the form of a kit.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides 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/or stampidine, and/or

(ii) at least one integrase inhibitor comprising: raltegravir; dolutegravir and/or elvitegravir, and

(iii) at least one protease inhibitor comprising: saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir; fosamprenavir; darunavir; and/or tiprinavir,

wherein the pharmaceutical antiretroviral composition optionally further comprises one or more pharmaceutically acceptable excipients.

The zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine; emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir; elvucitabine; tenofovir; festinavir; racivir; lersivirine; rilpivirine; etravirine; SP 1093V; stampidine; raltegravir elvitegravir; dolutegravir; saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir; indinavir; nelfinavir; atazanavir; lasinavir; palinavir; fosamprenavir; darunavir; and/or tiprinavir may be in the form of a pharmaceutically acceptable derivative thereof. The pharmaceutically acceptable derivative may be a salt, solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, enantiomer, polymorph or prodrug. The reverse transcriptase inhibitor may comprise: lamivudine; zidovudine; tenofovir; emtricitabine and/or abacavir. The integrase inhibitor may comprise: raltegravir and/or dolutegravir. The protease inhibitor may comprise: ritonavir and/or darunavir. The pharmaceutical antiretroviral composition may comprise lamivudine, zidovudine, darunavir and ritonavir. The pharmaceutical antiretroviral composition may comprise lamivudine, tenofovir, darunavir and ritonavir. The pharmaceutical antiretroviral composition may comprise tenofovir, emtricitabine, darunavir and ritonavir. The pharmaceutical antiretroviral composition may comprise abacavir, lamivudine, darunavir and ritonavir. The pharmaceutical antiretroviral composition may comprise raltegravir or dolutegravir, darunavir and ritonavir. The pharmaceutical antiretroviral composition may comprise: at least two reverse transcriptase inhibitors, wherein the at least two reverse transcriptase inhibitors are provided in a separate single unit dosage form; at least two protease inhibitors, wherein the at least two protease inhibitors are provided in a separate single unit dosage form; and/or at least one integrase inhibitor, wherein the at least one integrase inhibitor is provided in a separate single unit dosage form. The pharmaceutical antiretroviral composition may comprise darunavir and ritonavir provided in a separate single unit dosage form. The pharmaceutical antiretroviral composition may comprise raltegravir or dolutegravir provided in a separate single unit dosage form. The pharmaceutical antiretroviral composition may comprise lamivudine and zidovudine provided in a separate single unit dosage form. The pharmaceutical antiretroviral composition may comprise tenofovir and emtricitabine provided in a separate single unit dosage form. The pharmaceutical antiretroviral composition may comprise abacavir and lamivudine provided in a separate single unit dosage form. The pharmaceutical antiretroviral composition may comprise lamivudine and tenofovir provided in a separate single unit dosage form. The composition may be provided as a kit comprising instructions for administration. The pharmaceutical antiretroviral composition may be for once or twice daily administration. The at least one reverse transcriptase inhibitor, the at least one integrase inhibitor and the at least one protease inhibitor may be provided in a dosage form selected from: a tablet, a mini-tablet, sprinkles comprising a plurality of particles, a capsule, or a liquid. The tablet may be a disintegrating tablet, a dissolving tablet, a dispersible tablet, a mouth-dissolving tablet, a tablet for oral suspension, an immediate release tablet, an extended release tablet, an immediate and extended release tablet, or a matrix tablet. The plurality of particles of the sprinkles may be provide in the form of granules, powders, powders for reconstitution, beads, pellets, mini-tablets, film-coated tablets, film coated tablets MUPS, orally disintegrating MUPS, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, effervescent granules, or microspheres. The sprinkles may be provided in a sachet, a packet or a capsule. The one or more pharmaceutically acceptable excipient may comprise: a diluent, filler, bulking agent, disintegrant, binder, glidant, anti-adherent, lubricant, water soluble polymer, water insoluble polymer, water swellable polymer, plasticizer, and any mixture thereof.

In a second aspect, the present invention provides a process for preparing the pharmaceutical antiretroviral composition according to any preceding claim, comprising: admixing the at least one reverse transcriptase inhibitor or the at least one integrase inhibitor and the at least one protease inhibitor, optionally with the one or more pharmaceutically acceptable excipient.

In a third aspect, the present invention provides a method of preventing, treating or prophylaxis of a disease caused by a retrovirus, specifically acquired immune deficiency syndrome or an HIV infection, which method comprises administering to a patient in need thereof a pharmaceutical antiretroviral composition of the present invention.

In a fourth aspect, the present invention provides a pharmaceutical composition of the invention for use in the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, in a patient in need thereof.

In a fifth aspect, the present invention provides a use of the pharmaceutical antiretroviral composition of the invention for the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection.

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; SP 1093V and stampidine, and/or

(ii) at least one integrase inhibitor comprising raltegravir; elvitegravir; and/or dolutegravir and

(iii) at least one protease inhibitor comprising saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir;; fosamprenavir; darunavir; and/or tipranavir, and optionally

one or more pharmaceutically acceptable excipients.

Preferably, said composition is for once or twice a day administration and may be in the form of a kit comprising a plurality of antiretroviral agents have been co-formulated, or a plurality of dosage forms containing one or more antiretroviral agents.

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, abacavir and emtricitabine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; or

at least one integrase inhibitor comprising raltegravir or dolutegravir or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof and

(ii) at least one protease inhibitor comprising darunavir 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;

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; SP 1093V and stampidine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; or

at least one integrase inhibitor comprising raltegravir; elvitegravir; dolutegravir 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 or twice 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:

(ii) at least one protease inhibitor comprising darunavir 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 or twice 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, specifically 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; SP 1093V and stampidine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; or

(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.

(i) at least one reverse transcriptase comprising zidovudine, lamivudine, tenofovir, abacavir and emtricitabine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; or

at least one integrase inhibitor comprising raltegravir dolutegravir or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof and

According to another aspect of the present invention, there is provided the use of a pharmaceutical antiretroviral composition comprising:

(iii) one or more pharmaceutically acceptable excipients;

for the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, wherein said composition is for once or twice 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:

(iii) optionally one or more pharmaceutically acceptable excipients;

for the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, wherein said composition is for once or twice a day administration and is preferably in the form of a kit.

DETAILED DESCRIPTION OF THE INVENTION

Many forms of dispensing containers and other holders for pharmaceutical compositions have been proposed and commercially introduced, especially those in the dosage form of tablets, pills, and capsules, are generally dispensed in vials, bottles, or blister packs. One deficiency with such packaging is that the user is responsible for maintaining an independent record by human memory or other means as to whether or not the proper dosage has actually been administered. This deficiency is particularly problematic for users who suffer from impaired memory performance or who may be taking multiple medications. Some patients may find it difficult to continuously maintain such records, especially over the long term, such that some dosages are missed and thus leading to reduced patient compliance. The lack of patient compliance with adhering to a drug administration program is a problem. Aside from the fact that the patient may not be receiving the intended therapeutic benefit from noncompliance, there are potentially more serious issues that can arise from noncompliance. Studies documenting patient noncompliance have shown rates ranging from about 15% to about 93%, depending upon the population studied and the medical regimen involved ["Overview of Patient Compliance with Medication Dosing: A Literature Review", Clinical Therapeutics, Vol. 6, No. 5, pp. 592-599 (1984)].

Evidently, there is a continuing unmet need to make patient compliance in the administration of pharmaceutical compositions easier. Many forms of dispensing kits, containers, and other holders for pharmaceutical compositions have been proposed and commercially introduced. Many of these containers are intended for dispensing dosages of the pharmaceutical product on a daily basis.

Even though such once-daily therapies represent a significant advantage, it would be highly desirable to foster the ease of administration and help ensure patient compliance with such once daily therapies in the form of a kit.

Therefore, there is a need to develop and formulate a suitable pharmaceutical antiretroviral composition, in the form of a once or twice a day composition, comprising at least one reverse transcriptase inhibitor or at least one integrase inhibitor and at least one protease inhibitor which would not only be convenient for patient administration, but would also maintain or improve patient adherence to the therapy.

In general, the therapy for the treatment of HIV infection comprises a combination of actives such as nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors 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 the means that allows the patient to eliminate the inconvenience caused to him, such as remembering the administration of the medication, as well as the time at which it is to be administered.

Thus, the present invention provides a kit comprising a combination of NRTIs, NtRTIs, integrase inhibitors 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 confirms 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.

In an aspect, the present invention thus provides a pharmaceutical antiretroviral composition comprising at least one reverse transcriptase inhibitor or at least one integrase 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.

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 composition or dosage form, 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.

Preferred protease inhibitors (Pis) that may be employed in a pharmaceutical antiretroviral composition of the present invention are darunavir and ritonavir.

Preferred nucleoside reverse transcriptase inhibitors (NRTIs) that may be employed in a pharmaceutical antiretroviral composition of the present invention include lamivudine, emtricitabine and/or zidovudine. In a preferred aspect, the NRTI may be lamivudine and/or zidovudine. In an alternative preferred aspect the NRTI may be lamivudine and/or emtricitabine. A preferred nucleotide reverse transcriptase inhibitor (NtRTI) that may be employed in a pharmaceutical antiretroviral composition of the present invention is tenofovir.

A preferred integrase inhibitor that may be employed in a pharmaceutical antiretroviral composition of the present invention is raltegravir or dolutegravir.

A preferred reverse transcriptase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is lamivudine.

A preferred reverse transcriptase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is zidovudine.

A preferred reverse transcriptase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is emtricitabine.

A preferred reverse transcriptase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is tenofovir.

A preferred reverse transcriptase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is abacavir.

A preferred integrase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is raltegravir.

A preferred integrase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is dolutegravir.

A preferred protease inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is ritonavir. In an aspect, the present invention may provide a pharmaceutical antiretroviral composition comprising lamivudine, zidovudine, darunavir and ritonavir. Preferably, said composition is formulated for, or suitable for, once or twice a day administration. Said composition may be in the form of a kit.

In an aspect, the present invention may provide a pharmaceutical antiretroviral composition comprising lamivudine, tenofovir, darunavir and ritonavir. Preferably, said composition is formulated for, or suitable for, once or twice a day administration. Said composition may be in the form of a kit.

In an aspect, the present invention may provide a pharmaceutical antiretroviral composition comprising tenofovir, emtricitabine, darunavir and ritonavir. Preferably, said composition is formulated for, or is suitable for, once or twice a day administration. Said composition may be in the form of a kit.

In another aspect, the present invention may provide a pharmaceutical antiretroviral composition comprising raltegravir or dolutegravir, darunavir and ritonavir. Preferably, said composition is formulated for, or is suitable for once or twice a day administration. Said composition may be in the form of a kit.

In another aspect, the pharmaceutical antiretroviral composition in accordance with the present invention may be provided for use in the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, in a patient in need thereof.

In the context of the present invention, any references herein to an antiretroviral agent, for example, "zidovudine"; "didanosine"; "stavudine"; "lamivudine"; "abacavir"; "adefovir"; "lobucavir"; "entecavir"; "apricitabine"; "emtricitabine"; "zalcitabine"; "dexelvucitabine"; "alovudine"; "amdoxovir"; "elvucitabine"; "tenofovir"; "festinavir"; "racivir"; "lersivinne"; "nlpivirine"; "etravinne"; "SP 1093V", "stampidine", "raltegravir", "elvitegravir", "dolutegravir", "saquinavir"; "ritonavir"; "nelfinavir"; "amprenavir"; "lopinavir", "indinavir"; "nelfinavir"; "atazanavir"; "lasinavir"; "palinavir"; "fosamprenavir"; "darunavir"; "tiprinavir" includes by definition not only "zidovudine"; "didanosine"; "stavudine"; "lamivudine"; "abacavir"; "adefovir"; "lobucavir"; "entecavir"; "apricitabine"; "emtricitabine"; "zalcitabine"; "dexelvucitabine"; "alovudine"; "amdoxovir"; "elvucitabine"; "tenofovir"; "festinavir"; "racivir"; "lersivinne"; "nlpivirine"; "etravinne"; "SP 1093V", "stampidine", "raltegravir", "elvitegravir", "dolutegravir". "saquinavir"; "ritonavir"; "nelfinavir"; "amprenavir"; "lopinavir", "indinavir"; "nelfinavir"; "atazanavir"; "lasinavir"; "palinavir"; "fosamprenavir"; "darunavir"; "tiprinavir" per se, but also its pharmaceutically acceptable derivatives thereof. Suitable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes, and the like.

For instance, "tenofovir" as used herein by definition includes not only the phosphonic acid form, but also its prodrug form tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate. The term "darunavir" as used herein by edition includes not darunavir per se, but also its solvates, such as darunavir ethanolate, and its hydrates, such as darunavir hydrate.

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. Tenofovir disoproxil fumarate is an analog of adefovir and is classified as a nucleotide reverse transcriptase inhibitor (NtRTI). 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.

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 form 9 mg to 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 for use in a pharmaceutical antiretroviral composition of the present invention is in an amount from about 60 mg to about 600 mg.

Lamivudine (also known as 3TC) is a synthetic nucleoside analogue, chemically known as (2R, cis)-4-amino-l-(2-hydroxymethyl-l, 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-(Hy droxym ethyl)- 1,3- oxathiolan-5-yl] cytosine, (Hydroxymethyl)-l,3-oxathiolan-5-yl] cytosine 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.

Darunavir (TMC-1 14, UIC-94017) is chemically known as [(3R,3aS,6aR)-2,3,3a,4,5,6a- Hexahydrofuro[5,4-b]furan-3-yl]N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2- methylpropyl) amino]-3-hydroxy-l-phenylbutan-2 yljcarbamate A preferred dosage of darunavir for use in a pharmaceutical antiretroviral composition of the present invention is in an amount from about 350 mg to about 1200 mg.

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. 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 (HIV) 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 60 mg to about 600 mg.

Raltegravir is a human immunodeficiency virus integrase strand transfer inhibitor. Raltegravir inhibits the catalytic activity of HIV- 1 integrase, an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryltransferases including DNA polymerases α, β, and γ. A preferred dosage of raltegravir is from about 40 mg to about 1200 mg.

Dolutegravir is an orally active integrase inhibitor, and has been approved for the treatment of HIV infections. It is a HIV-1 integrase strand transfer inhibitor which inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid integration which is essential for the HIV replication cycle. A preferred dosage of dolutegravir is from about 1 mg to about 100 mg.

In another aspect, the present invention provide a pharmaceutical antiretroviral composition comprising lamivudine, zidovudine, darunavir and ritonavir in a kit form. Preferably, said composition is for once or twice a day administration. 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 darunavir and a separate unit dosage form of ritonavir.

In another aspect, the present invention may provide a pharmaceutical antiretroviral composition comprising lamivudine, tenofovir, darunavir and ritonavir in a kit form. Preferably, said composition is for once or twice a day administration.

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 darunavir and a separate unit dosage form of ritonavir.

In another aspect, the present invention may provide a pharmaceutical antiretroviral composition comprising emtricitabine, tenofovir, darunavir and ritonavir in a kit form. Preferably, said composition is for once or twice a day administration.

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 darunavir and a separate unit dosage form of ritonavir.

In another aspect, the present invention may provide a pharmaceutical antiretroviral composition comprising abacavir, lamivudine, darunavir and ritonavir in a kit form. Preferably, said composition is for once or twice a day administration.

The pharmaceutical antiretroviral composition in kit form may comprise a separate unit dosage form of abacavir, a separate unit dosage form of lamivudine, a separate unit dosage form of darunavir and a separate unit dosage form of ritonavir.

In another aspect, the present invention may provide a pharmaceutical antiretroviral composition comprising raltegravir or dolutegravir, darunavir and ritonavir in a kit form. Preferably, said composition is for once or twice a day administration. The pharmaceutical antiretroviral composition in kit form may comprise a separate unit dosage form of raltegravir a separate unit dosage form of darunavir and a separate unit dosage form of ritonavir.

The pharmaceutical antiretroviral composition in kit form may comprise a separate unit dosage form of dolutegravir a separate unit dosage form of darunavir and a separate unit dosage form of ritonavir.

In any of the above compositions the pharmaceutical antiretroviral composition of the composition of the present invention may comprise darunavir and ritonavir in a single unit dosage form.

In any of the above compositions, where appropriate, the pharmaceutical antiretroviral composition of the present invention may comprise lamivudine and tenofovir in a single unit dosage form.

In any of the above compositions, where appropriate, the pharmaceutical antiretroviral composition of the present invention may comprise lamivudine and zidovudine in a single unit dosage form.

In any of the above compositions, where appropriate, the pharmaceutical antiretroviral composition of the present invention comprises tenofovir and emtricitabine in a single unit dosage form.

In any of the above compositions, where appropriate, the pharmaceutical antiretroviral composition of the present invention comprises abacavir and lamivudine in a single unit dosage form.

In any of the above compositions, where appropriate, the pharmaceutical antiretroviral composition of the present invention comprises raltegravir in a single unit dosage form. In any of the above compositions, where appropriate, the pharmaceutical antiretroviral composition of the present invention comprises dolutegravir in a single unit dosage form.

In any of the above compositions, where appropriate, the pharmaceutical antiretroviral composition of the present invention comprises darunavir and ritonavir, raltegravir dolutegravir, lamivudine and tenofovir, lamivudine and zidovudine, tenofovir and emtricitabine, abacavir and lamivudine are each provided in a separate single unit dosage forms.

In any of the above compositions, where appropriate, any two of the at least one reverse transcriptase inhibitor, the at least one integrase inhibitor and the at least one protease inhibitor may be provided in a single unit dosage form.

In any of the above compositions, where appropriate, any three of the at least one reverse transcriptase inhibitor, the at least one integrase inhibitor and the at least one protease inhibitor are provided in a single unit dosage form.

In any of the above compositions, where appropriate, all of the at least one reverse transcriptase inhibitor, the at least one integrase inhibitor and the at least one protease inhibitor are provided in a single unit dosage form.

When formulated as a single unit dose, the antiretroviral agents may initially be co- formulated with one or more pharmaceutically acceptable excipients to provide a single uniform composition or they may initially be formulated as individual compositions. When formulated individually, the individual compositions may subsequently be co- formulated as a single unit dosage form, where the unit dosage form may comprise two or more layers, each layer comprising a composition of at least one antiretroviral agent (i.e. the individually formulated compositions). Preferably, the single unit dosage form is suitable for once or twice daily administration.

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 and the like, may be envisaged under the ambit of the present invention.

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 (filled with powders, powders for reconstitution; beads; pellets; mini-tablets; film coated tablets; film coated tablets MUPS (multiple unit pellet system); orally disintegrating MUPS; pills; micro-pellets; small tablet units; MUPS; disintegrating tablets; dispersible tablets; granules; effervescent granules; microspheres) or capsules filled with (powders, powders for reconstitution; beads; pellets; mini-tablets; film coated tablets; film coated tablets MUPS; orally disintegrating MUPS; pills; micro-pellets; small tablet units; MUPS; disintegrating tablets; dispersible tablets; granules; effervescent granules; microspheres), liquids such as suspension, emulsions, solutions, syrups, elixirs but other dosage forms may also fall within the scope of this invention.

Preferably, the pharmaceutical antiretroviral composition, according to the present invention, may be administered orally through known solid unit dosage forms including capsule and sachets or packets (filled with powders, powders for reconstitution; beads; pellets; mini-tablets; film coated tablets; film coated tablets MUPS; orally disintegrating MUPS; pills; micro-pellets; small tablet units; MUPS; disintegrating tablets; dispersible tablets; granules; effervescent granules; microspheres). The capsules may be hard gelatin capsules. Sachets or packets may be filled with powders, powders for reconstitution; beads; pellets; mini-tablets; film coated tablets; film coated tablets MUPS; orally disintegrating MUPS; pills; micro-pellets; small tablet units; MUPS; disintegrating tablets; dispersible tablets; granules; effervescent granules; microsphere that are suitable for direct administration. Preferably, the present invention may be administered as mini- tablets or granules filled in hard gelatin capsules, sachets or packets. Preferably, the mini-tablets or granules filled in such hard gelatin capsules, sachets or packets 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, sachets or packets may be administered with liquid or semi-solid beverages such as but not limited to, fruit juices, water, milk, baby formulas, soft foods, apple sauce or yogurt and the like.

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, sachets or packets.

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.

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, sachets or packets may fall within the scope of this invention.

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.

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.

According to a preferred aspect, 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).

According to another preferred aspect, the pharmaceutical antiretroviral composition may be in the form of one or more bilayered or multilayered unit dosage forms.

In a preferred aspect, the pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form comprising lamivudine and zidovudine and a further separate unit dosage form comprising darunavir and ritonavir.

In a further preferred aspect, the pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form comprising lamivudine and tenofovir and a further separate unit dosage form comprising darunavir and ritonavir.

In another preferred aspect, the pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form comprising emtricitabine and tenofovir and a further separate unit dosage form comprising darunavir and ritonavir.

In another preferred aspect, the pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form comprising abacavir and lamivudine and a further separate unit dosage form comprising darunavir and ritonavir.

In another preferred aspect, the pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form comprising raltegravir and a further separate unit dosage form comprising darunavir and ritonavir.

In another preferred aspect, the pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form comprising dolutegravir and a further separate unit dosage form comprising darunavir and ritonavir.

Suitable excipients may be used for formulating the various dosage forms according to the present invention. According to the present invention, pharmaceutically acceptable 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, β- lactose) lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers, hydroxy ethyl cellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethyl hydroxyethylcellulose and other cellulose derivatives, starches or modified starches (including potato starch, corn starch, maize starch and rice starch) and combinations thereof.

The amount of diluents or fillers that may be present in the pharmaceutical antiretroviral composition can range from about 20% to about 70%.

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, magnesium aluminosilicate and/ or magnesium alumino metasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil) and combinations thereof.

The amount of glidants, anti-adherents and lubricants that may be present in the pharmaceutical antiretroviral composition can range from about 0.3% to about 2%.

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 combinations thereof or any other suitable binder.

The amount of binders that may be present in the pharmaceutical antiretroviral composition can range from about 1% to about 7%.

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), crospovidone, 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 combinations thereof.

The amount of disintegrants that may be present in the pharmaceutical antiretroviral composition can range from about 0.7% to about 5%.

The present invention also provides a hot melt extruded pharmaceutical antiretroviral composition 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.

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 co-polymers of N- vinyl pyrrolidone e.g. polyvinylpyrrolidone (PVP), co-polymers of PVP and vinyl acetate, copolymers 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 combinations thereof.

The amount of water soluble polymers that may be present in the pharmaceutical antiretroviral composition can range from about 10% to about 50%.

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 El 00 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 combinations thereof.

The amount of water insoluble polymers that may be present in the pharmaceutical antiretroviral composition can range from about 3% to about 15%).

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^® polyacrylamides; 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 combinations thereof.

The amount of water swellable polymers that may be present in the pharmaceutical antiretroviral composition can range from about 1%> to about 10%). 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 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 combinations thereof.

The amount of plasticizers that may be present in the pharmaceutical antiretroviral composition can range from about 0.4% to about 3%.

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.

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.

Suitable processes may be used for formulating the various dosage forms according to the present invention. In one aspect, the dosage form of the present invention may be 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.

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 multi screw 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, or the granules may be filled into capsules, sachets, pellets in capsules or in a similar dosage form.

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.

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 a preferred aspect, the pharmaceutical antiretroviral composition of the present invention may 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.

According to yet another preferred aspect, the pharmaceutical antiretroviral composition of the present invention may be processed by mixing darunavir 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.

Further, the granules comprising darunavir 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 or the tablet may be film coated and then seal coated.

Alternatively, the granules comprising darunavir 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 or the tablet may be film coated and then seal coated. According to a further preferred aspect, the pharmaceutical antiretroviral composition of the present invention may be 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.

According to another preferred aspect, the pharmaceutical antiretroviral composition of the present invention may be 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.

Alternatively, after compression into tablets, they can be further seal coated and then sprayed with a coating suspension.

Additional excipients such as film forming polymers, solvents, plasticizers, anti- adherents, opacifiers, colorants, pigments, antifoaming agents, and polishing agents can be used in coatings.

Suitable seal forming material may comprise: hydroxypropylmethylcellulose (optionally HPMC 6 CPS, or HPMC 6 CPS to HPMC 15CPS grade); hydroxypropylcellulose; polyvinylpyrrolidone; methylcellulose; carboxymethylcellulose; hypromellose; acacia; gelatin; or any combination thereof, to increase adherence and coherence of the seal coat. Preferably the seal coat comprises hydroxypropylmethylcellulose.

The amount of seal forming materials that may be present in the pharmaceutical antiretroviral composition can range from about 0.2% to about 10%.

The HPMC component of the seal coating, if present, may be mixed with a solvent, wherein said solvent may comprise: acetone; methylene chloride; isopropyl alcohol; or any combination thereof. The seal coating may also comprise talc.

Suitable film-forming agents include, but are not limited to, cellulose derivatives, such as, soluble alkyl- or hydroalkyl-cellulose derivatives such as methylcelluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethylethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, insoluble cellulose derivatives such as ethylcelluloses and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acids, polyvinyl alcohols, polyvinyl acetates, polyvinylpyrrolidones, polymethacrylates and derivatives thereof, chitosan and derivatives thereof, shellac and derivatives thereof, waxes, fat substances and any combinations or combinations thereof.

The amount of film forming agents that may be present in the pharmaceutical antiretroviral composition can range from about 0.2% to about 10%).

Suitable enteric coating materials, include, but are not limited to, cellulosic polymers like cellulose acetate phthalates, cellulose acetate trimellitates, hydroxypropyl methylcellulose phthalates, polyvinyl acetate phthalates, methacrylic acid polymers, any copolymer thereof, any mixture thereof, or combination thereof.

The amount of enteric coating materials that may be present in the pharmaceutical antiretroviral composition can range from about 1%> to about 15%). Some of the excipients are used as adjuvant to the coating process, including excipients such as plasticizers, opacifiers, antiadhesives, polishing agents, and the like.

Suitable plasticizers include, but are not limited to, stearic acid, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycols, triacetin, triethyl citrate, or combinations thereof.

Suitable opacifiers include, but are not limited to, titanium dioxide.

Suitable anti-adhesives include, but are not limited to, talc.

Suitable polishing agents include, but are not limited to, polyethylene glycols of various molecular weights or combinations thereof, talc, surfactants (glycerol monostearate and poloxamers), fatty alcohols (stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (carnauba wax, candelilla wax and white wax), or combinations thereof.

The amount of polishing agents that may be present in the pharmaceutical antiretro viral composition can range from about 0.2% to about 1%.

Suitable solvents used in the processes of preparing the pharmaceutical solid oral composition of the present invention, include, but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, N,N- dimethylformamide, tetrahydrofuran, or combinations thereof.

Further, the 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.

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 aspect, 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.

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 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.

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, homogenization, high pressure homogenization, spray-freeze drying, supercritical fluid technology, emulsion/solvent evaporation, PRINT, thermal condensation, ultrasonication and spray drying.

The present invention provides method of prevention, treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, which method comprises administering a pharmaceutical antiretroviral composition of the type hereinbefore described.

In preferred aspects, the pharmaceutical antiretroviral composition of the present invention may comprise: (i) lamivudine, zidovudine, darunavir and ritonavir; (ii) lamivudine, tenofovir, darunavir and ritonavir; (iii) emtricitabine, tenofovir, darunavir and ritonavir (iv) lamivudine, abacavir, darunavir and ritonavir; (v) raltegravir, darunavir and ritonavir or (vi) dolutegravir, darunavir and ritonavir.

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, specifically acquired immune deficiency syndrome or an HIV infection. In preferred aspects, the pharmaceutical antiretroviral composition of the present invention may comprise: (i) lamivudine, zidovudine, darunavir and ritonavir; (ii) lamivudine, tenofovir, darunavir and ritonavir; (iii) emtricitabine, tenofovir, darunavir and ritonavir; (iv) lamivudine, abacavir, darunavir and ritonavir; (v) raltegravir, darunavir and ritonavir or (vi) dolutegravir, darunavir and ritonavir.

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, specifically acquired immune deficiency syndrome or an HIV infection. In, preferred aspects, the pharmaceutical antiretroviral composition may comprise: (i) lamivudine, zidovudine, darunavir and ritonavir; (ii) lamivudine, tenofovir, darunavir and ritonavir; (iii) emtricitabine, tenofovir, darunavir and ritonavir; (iv) lamivudine, abacavir, darunavir and ritonavir; (v) raltegravir, darunavir and ritonavir or (vi) dolutegravir, darunavir and ritonavir.

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

Emtricitabine & Tenofovir Disoproxil Bilayered Tablets:

Process:

Preparation of Layer I

A) Granulation 1) Tenofovir, lactose, croscarmellose, corn starch were sifted.

2) The sifted ingredients were dry mixed.

3) Binder solution was prepared using corn starch, polysorbate 80 and purified water.

4) Binder solution obtained in step (3) was sprayed on the mixture obtained in step (2) to form granules.

5) Granules obtained in step (4) were dried, sized and lubricated.

Preparation of Layer II

1) Emtricitabine, microcrystalline cellulose, crospovidone were sifted.

2) The sifted ingredients were dry mixed.

3) Binder solution was prepared using povidone and purified water.

5) Granules obtained in step (4) were dried, sized and lubricated.

B) Compression

1) Lubricated granules of Layer I and Layer II was compressed to produce a bilayer tablets.

C) Coating

1) Tablets so obtained were coated with Opadry solution.

EXAMPLE 2

Emtricitabine & Tenofovir Disoproxil Single layer Tablets:

Film Coating

1. Opadry Blue 15.00

2. Purified Water q.s

Final Tablet Weight 1115.00

Process:

Preparation of Layer I

A) Granulation

1) Tenofovir, emtricitabine, lactose, croscarmellose, microcrystalline cellulose and pregelatinized starch were sifted.

2) The sifted ingredients were dry mixed.

3) Binder solution was prepared using pregelatinized starch and purified water.

5) Granules obtained in step (4) were dried, sized and lubricated.

B) Compression

1) Lubricated granules was compressed to produce a single layer tablets.

C) Coating

1) Tablets so obtained were coated with Opadry solution.

EXAMPLE 3

Ritonavir and Darunavir Bilayered Tablet

9 Darunavir 325.24

10 Crospovidone 10.00

Binder

1 1 PVP 15.00

12 Purified water q.s.

Blending & Lubrication

13 Crospovidone 10.00

14 Yellow iron oxide 0.50

15 Microcrystalline Cellulose 254.50

16 Colliodal Silicon Dioxide 4.00

17 Magnesium Stearate 6.00

Total 625.24

Seal Coating

19 Opadry 5.00

20 Purified water q.s.

Film Coating

21 Opadry 04F 52201 Yellow 15.00

22 Purified water q.s.

Total 1305.24

Process:

(1) Darunavir was mixed with pre-sieved and pre-sifted amounts of crospovidone, yellow iron oxide, polyvinyl pyrrolidone, microcrystalline cellulose and colloidal silicon dioxide.

(2) The blend obtained in step (1) was granulated with purified water.

(3) Ritonavir with small amount of colloidal silicon dioxide was sifted and mixed with Kollidon and Span 20 in a mixer.

(4) The blend obtained in (3) was mixed and subjected to hot melt extrusion (HME) and the molten mass thus obtained was collected on a conveyor where it was cooled to form extrudates and these extrudates on further milling were converted into granules.

(5) Crospovidone, colloidal silicon dioxide and microcrystalline cellulose were added to the granules obtained in step (4) and further lubricated with sodium stearyl monostearate and magnesium stearate.

(6) The granules obtained in (2) and (5) were compressed together to form a bilayer tablet which was then seal coated and finally film coated.

EXAMPLE 4

Ritonavir and Darunavir Bilayered Tablet

Sr. No. Ingredients Quantity/Unit (mg) Darunavir Part

1 Darunavir ethanolate 325.24

2 Microcrystalline cellulose 145.00

3 Crospovidone 10.00

4 Binder

5 Povidone (PVP) 15.00

6 Purified water q. s.

Extragranular

7 Microcrystalline cellulose 1 10.00

8 Crospovidone 10.00

Lubrication

9 Colliodal Silicon dioxide 4.00

10 Magnesium stearate 6.00

Total 625.24

Ritonavir Part

1 1 Ritonavir 50.00

12 Colloidal silicon dioxide 3.45

Polymer Part

13 Kollidon 246.50

14 Polyoxyl hydrogenated castor oil 33.35

Blending & Lubrication

15 Colloidal silicon dioxide 6.95

16 Dibasic calcium phosphate (anhydrous) 84.70

Total 1050.19

Process:

(1) Darunavir Ethanolate was mixed with pre-sieved and presifted quantities of crospovidone and microcrystalline cellulose.

(2) The mixture obtained in step (1) was granulated with PVP followed by mixing and lubrication with crospovidone, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate.

(3) Ritonavir with small amount of colloidal silicon dioxide was sifted and mixed together with Kollidon and polyoxyl 40 hydrogenated castor oil in a mixer.

(5) Colloidal silicon dioxide and anhydrous dibasic calcium phosphate was added to the granules obtained in step (4).

(6) The granules obtained in (2) and (5) were compressed together to form a bilayer tablet which was then finally film coated. EXAMPLE 5

Ritonavir and Darunavir Bilayered Tablet

Darunavir Layer:

Process

Manufacturing Process for Darunavir Layer:

1. Darunavir, silicified microcrystalline cellulose, crospovidone and colloidal dioxide and were sifted and mixed to form granules.

2. The granules obtained in step (1) were lubricated with magnesium stearate. Manufacturing Process for Ritonavir Layer: 1. Ritonavir, colloidal silicon dioxide & dibasic calcium phosphate were sifted and granulated with copovidone and sorbitan monolaureate to form granules

2. The granules obtained in step (1) were extruded and lubricated with sodium stearyl fumarate

3. The lubricated granules obtained in step (2) of the darunavir layer and step (2) of the ritonavir layer were compressed to produce a bilayer tablet and coated with opadry orange.

EXAMPLE 6

Darunavir and Ritonavir Bilayered Tablet

Darunavir Layer:

Process

Manufacturing Process for Darunavir Layer:

1. Darunavir, silicified microcrystalline cellulose, crospovidone and colloidal silicon dioxide and were sifted and mixed to form granules.

2. The granules obtained in step (1) were lubricated with magnesium stearate.

Manufacturing Process for Ritonavir Layer:

1. Ritonavir, colloidal silicon dioxide & dibasic calcium phosphate were sifted and granulated with copovidone and sorbitan monolaureate to form granules

EXAMPLE 7

Darunavir and Ritonavir Bilayered Tablet

III Blending and lubrication

6 Colloidal silicon dioxide 5.00

7 Dibasic calcium phosphate anhydrous 22.20

8 Sodium stearyl fumarate 1.95

Total weight of Layer II 385.00

Total weight of core tablet 967.87

Film Coating

9 Opadry Red 37.00

10 Purified water -

Total weight of film coated tablet 1004.87

Process

Manufacturing Process for Darunavir Layer:

1. Darunavir, HPMC, silicified microcrystalline cellulose, colloidal silicon dioxide and crospovidone were sifted and granulated to form granules.

2. The granules obtained in step (1) were lubricated with magnesium stearate.

Manufacturing Process for Ritonavir Layer:

1. Ritonavir, colloidal silicon dioxide and dibasic calcium phosphate were sifted and granulated with copovidone, sorbitan monolaureate.

2. The granules obtained in step (1) were extruded and lubricated by sodium stearyl fumarate.

3. The lubricated granules obtained in step (2) of the darunavir layer and step (2) of the ritonavir layer were compressed to produce a bilayer tablet and coated with opadry red.

EXAMPLE 8

Darunavir and Ritonavir Bilayered Tablet

Total weight of Layer I 582.87

Ritonavir Part

I Drug premix

1 Ritonavir 100.000

2 Colloidal silicon dioxide 6.900

3 Dibasic calcium phosphate anhydrous 45.000

II Polymer premix

4 Copovidone 493.100

Sorbitan monolaurate

5

66.700

III Blending and lubrication

6 Colloidal silicon dioxide 10.000

7 Dibasic calcium phosphate anhydrous 44.400

8 Sodium stearyl fumarate 3.900

Total weight of Layer II 770.00

Total weight of core tablet 1352.87

Film Coating

9 Opadry Red 40.00

10 Purified water -

Total weight of film coated tablet 1392.87

Process

Manufacturing Process for Darunavir Layer:

2. The granules obtained in step (1) were lubricated with magnesium stearate.

Manufacturing Process for Ritonavir Layer:

2. The granules obtained in step (1) were extruded and lubricated with sodium stearyl fumarate.

3. The lubricated granules obtained in step (2) of the darunavir layer and step (2) of the ritonavir layer were compressed to produce a bilayer tablet and coated with opadry

EXAMPLE 9

Darunavir Ritonavir and Dolutegravir Bilayered Tablet

Darunavir Layer: Sr. No. Ingredients Quantity/Unit (mg)

I Dry Mix for Compaction

1 Darunavir Ethanolate 325.24

2 Dolutegravir 50.00

3 Silicified Microcrystalline Cellulose 275.36

4 Crospovidone 12.48

Colloidal Silicon Dioxide 6.24

II Lubrication

5 Magnesium Stearate 4.680

Total of Layer I 674.000 onavir Layer:

Sr. No. Ingredients Quantity/Unit (mg)

I Drug Premix

1 Ritonavir 50.00

2 Colloidal Silicon Dioxide 3.450

3 Dibasic Calcium Phosphate 22.50

II Polymer Premix

4 Copovidone 246.55

5 Sorbitan Monolaureate 33.35

III Blending

6 Colloidal Silicon Dioxide 5.00

7 Dibasic Calcium Phosphate 22.20

IV Lubricant

8 Sodium Stearyl Fumarate 1.95

Total of Layer II 385.00

Total (Layer I + Layer II) 1059.00

Film Coating

9 Opadry Orange 31.00

10 Purified Water q. s.

Total 1090.00

Process

Manufacturing Process for Darunavir Layer:

1. Darunavir, dolutegravir, silicified microcrystalline cellulose, crospovidone and colloidal silicon dioxide were sifted and granulated to form granules.

2. The granules obtained in step (1) were lubricated with magnesium stearate.

Manufacturing Process for Ritonavir Layer:

1. Ritonavir, colloidal silicon dioxide and dibasic calcium phosphate were sifted and granulated with copovidone, sorbitan monolaureate and water to form granules. 2. The granules obtained in step (1) were extruded and lubricated with sodium stearyl fumarate.

EXAMPLE 10

Darunavir Ritonavir and Dolutegravir Bilayered Tablet

Darunavir Layer:

Process

Manufacturing Process for Darunavir Layer:

2. The granules obtained in step (1) were lubricated with magnesium stearate.

Manufacturing Process for Ritonavir Layer:

1. Ritonavir, colloidal silicon dioxide and dibasic calcium phosphate were sifted and granulated with copovidone, sorbitan monolaureate and water to form granules.

3. The lubricated granules obtained in step (2) of the darunavir layer and step (2) of the ritonavir layer were compressed to produce a bilayer tablet and coated with opadry orange_^

EXAMPLE 11

Darunavir Ritonavir and Dolutegravir Bilayered Tablet

6 Colloidal silicon dioxide 5.00

7 Dibasic calcium phosphate anhydrous 22.20

8 Sodium stearyl fumarate 1.95

Total weight of Layer II 385.00

Total weight of core tablet 1017.87

Film Coating

9 Opadry Red 37.00

10 Purified water -

Total weight of film coated tablet 1054.87

Process

Manufacturing Process for Darunavir Layer:

1. Hypromellose was sprayed onto darunavir to produce granules.

2. The granulates obtained in step (1) were dried, sized and mixed with dolutegravir, microcrystalline cellulose, colloidal Silicon Dioxide and crospovidone to produce a mixed blend.

3. The mixed blend obtained in step (2) was lubricated with magnesium stearate. Manufacturing Process for Ritonavir Layer:

1. Ritonavir, colloidal silicon dioxide and dibasic calcium phosphate were sifted, dry mixed and granulated with copovidone, sorbitan monolaureate and water to produce granules.

3. The lubricated granules obtained in step (3) of the darunavir layer and step (2) of the ritonavir layer were compress to form a bilayer tablet and coated with opadry red.

EXAMPLE 12

Darunavir Ritonavir and Dolutegravir Bilayered Tablet

6 Colloidal silicon dioxide 1.65

7 Crospovidone 16.50

8 Magnesium Stearate 2.75

Total weight of Layer I 632.87

Ritonavir Part

I Drug premix

1 Ritonavir 100.000

2 Colloidal silicon dioxide 6.900

3 Dibasic calcium phosphate anhydrous 45.000

II Polymer premix

4 Copovidone 493.100

5 Sorbitan monolaurate 66.700

III Blending and lubrication

6 Colloidal silicon dioxide 10.000

7 Dibasic calcium phosphate anhydrous 44.400

8 Sodium stearyl fumarate 3.900

Total weight of Layer II 770.00

Total weight of core tablet 1402.87

Film Coating

9 Opadry Red 40.00

10 Purified water -

Total weight of film coated tablet 1442.87

Process

Manufacturing Process for Darunavir Layer:

1. Hypromellose was sprayed onto darunavir to produce granules.

3. The lubricated granules obtained in step (3) of the darunavir layer and step (2) of the ritonavir layer were compress to form a bilayer tablet and coated with opadry red. EXAMPLE 13

Darunavir Ritonavir and Dolutegravir Trilayered Tablet

Dolutegravir layer

Darunavir Layer

Ritonavir Layer:

Total (Layer I + Layer II + Layer III) 1309.00

Film Coating

9 Opadry Orange 41.00

10 Purified Water q. s.

Total 1350.00

Process

Manufacturing Process for Dolutegravir Layer:

1. Dolutegravir, mannitol, microcrystalline cellulose and polyvinyl pyrollidone were sifted, granulated, dried and sized to form granules

2. The granules obtained in step (1) were lubricated with sodium starch glycolate and sodium stearyl fumarate.

Manufacturing Process for Darunavir Layer:

1. Darunavir, silicified microcrystalline cellulose, crospovidone and colloidal silicon dioxide were sifted, mixed and granulated.

2. The granules obtained in step (1) were lubricated with magnesium stearate.

Manufacturing Process for Ritonavir Layer:

1. Ritonavir, colloidal silicon dioxide and dibasic calcium phosphate were sifted, dry mixed and granulated with copovidone, sorbitan monolaureate and water to form granules.

2. The granules were extruded and colloidal silicon dioxide, dibasic calcium phosphate were further added to the granules which were then lubricated with sodium stearyl fumarate.

3. The lubricated granules obtained in step (2) of the dolutegravir layer and the step (2) of the darunavir layer and the step (2) of the ritonavir layer were compressed to form a trilayer tablet and coated with opadry orange.

EXAMPLE 14

Darunavir Ritonavir and Dolutegravir Trilayered Tablet

Dolutegravir layer

3. Microcrystalline Cellulose 162.853

4. Sodium Starch Glycolate 6.00

5. Polyvinyl Pyrollidone 5.00

Binder

6. Purified Water q.s

Lubrication

7. Sodium Starch Glycolate 15.00

8. Sodium Stearyl Fumarate 0.75

Total of Layer I 300.00

Darunavir Layer

Sr. No. Ingredients Quantity/Unit (mg)

I Dry Mix for Compaction

1 Darunavir Ethanolate 325.236

2 Silicified Microcrystalline Cellulose 275.364

3 Crospovidone 12.480

Colloidal Silicon Dioxide 6.240

II Lubrication

4 Magnesium Stearate 4.680

Total of Layer II 624.000

Ritonavir Layer:

Sr. No. Ingredients Quantity/Unit (mg)

I Drug Premix

1 Ritonavir 100.000

2 Colloidal Silicon Dioxide 6.900

3 Dibasic Calcium Phosphate 45.000

II Polymer Premix

4 Copovidone 493.100

5 Sorbitan Monolaureate 66.700

III Blending

6 Colloidal Silicon Dioxide 10.000

7 Dibasic Calcium Phosphate 44.400

IV Lubricant

8 Sodium Stearyl Fumarate 3.900

Total of Layer III 770.00

Total (Layer I + Layer II + Layer III) 1694.00

Film Coating

9 Opadry Orange 41.000

10 Purified Water q. s.

Total 1735.00 Process

Manufacturing Process for Dolutegravir Layer:

2. The granules obtained in step (2) were lubricated with sodium starch glycolate and sodium stearyl fumarate.

Manufacturing Process for Darunavir Layer:

2. The granules obtained in step (1) were lubricated with magnesium stearate.

Manufacturing Process for Ritonavir Layer:

2. The granules were extruded and lubricated with sodium stearyl fumarate.

EXAMPLE 15

Darunavir Ritonavir and Dolutegravir Trilayered Tablet

Dolutegravir Layer

Darunavir Layer

Process

Manufacturing Process for Dolutegravir Layer:

2. The granules obtained in step (2) were lubricated with sodium starch glycolate and sodium stearyl fumarate. Manufacturing Process for Darunavir Layer:

1. Darunavir, HPMC, silicified microcrystalline cellulose, crospovidone and colloidal silicon dioxide were sifted, mixed and granulated.

2. The granules obtained in step (1) were lubricated with magnesium stearate.

Manufacturing Process for Ritonavir Layer:

1. Ritonavir, colloidal silicon dioxide and dibasic calcium phosphate were sifted, dry mixed and granulated with copovidone and sorbitan monolaureate water to form granules.

2. The granules were extruded and lubricated with sodium stearyl fumarate.

3. The lubricated granules obtained in step (2) of the dolutegravir layer and the step (2) of the darunavir layer and the step (2) of the ritonavir layer were compressed to form a trilayer tablet and coated with opadry red.

EXAMPLE 16

Darunavir Ritonavir and Dolutegravir Trilayered Tablet

Dolutegravir Layer

Darunavir Layer

5 Colloidal silicon dioxide 1.65

6 Crospovidone 16.50

7 Magnesium Stearate 2.75

Total weight of Layer II 582.87

Ritonavir Part

I Drug premix

1 Ritonavir 100.000

2 Colloidal silicon dioxide 6.900

3 Dibasic calcium phosphate anhydrous 45.000

II Polymer premix

4 Copovidone 493.100

Sorbitan monolaurate

J

66.700

III Blending and lubrication

6 Colloidal silicon dioxide 10.000

7 Dibasic calcium phosphate anhydrous 44.400

8 Sodium stearyl fumarate 3.900

Total weight of Layer III 770.00

Total weight of core tablet (Layer I +

Layer II + Layer III) 1652.87

Film Coating

9 Opadry Red 40.00

10 Purified water -

Total weight of film coated tablet 1692.87

Process

Manufacturing Process for Dolutegravir Layer:

Manufacturing Process for Darunavir Layer:

2. The granules obtained in step (1) were lubricated with magnesium stearate.

Manufacturing Process for Ritonavir Layer:

2. The granules were extruded and lubricated with sodium stearyl fumarate. 3. The lubricated granules obtained in step (2) of the dolutegravir layer and the step (2) of the darunavir layer and the step (2) of the ritonavir layer were compressed to form a trilayer tablet and coated with opadry red.

EXAMPLE 17

Darunavir Ritonavir Raltegravir trilayer tablets

Raltegravir Layer

4 Copovidone 293.10

5 Sorbitan monolaurate 66.70

III Blending and lubrication

6 Colloidal silicon dioxide 10.00

7 Dibasic calcium phosphate anhydrous 44.40

8 Sodium stearyl fumarate 3.90

Total weight of Layer III 570.00

Total weight of core tablet (Layer I +

Layer II + Layer III) 1800.00

Film Coating

9 Opadry Red 36.00

10 Purified water -

Total weight of film coated tablet 1836.00

Process

Manufacturing Process for Raltegravir Layer:

1. Raltegravir, lactose, calcium phosphate, polaxamer, hypromellose, and microcrystalline cellulose were sifted, granulated, dried and sized to form granules

2. The granules obtained in step (2) were lubricated with magnesium stearate and sodium stearyl fumarate.

Manufacturing Process for Darunavir Layer:

2. The granules obtained in step (1) were lubricated with magnesium stearate.

Manufacturing Process for Ritonavir Layer:

2. The granules were extruded and lubricated with sodium stearyl fumarate.

3. The lubricated granules obtained in step (2) of the dolutegravir layer and the step (2) of the darunavir layer and the step (2) of the ritonavir layer were compressed to form a bilayer tablet and coated with opadry red.

EXAMPLE 18

Darunavir Ritonavir Raltegravir bilayer tablets

Raltegravir Layer

Sr. No. I Ingredients Quantity / Unit (mg) Dry Mixing

1 Raltegravir Potassium 434.40

2 Lactose Monohydrate 26.06

3 Calcium Phosphate 69.50

4 Magnesium Stearate 13.03

Binder

5. Polaxamer 104.48

6. Hypromellose 43.44

7. Purified Water q.s

Blending and Lubrication

8. Microcrystalline Cellulose 50.40

9. Sodium Stearyl Fumarate 8.69

Total Weight of Layer I 750.00

Darunavir Layer

10 Purified water -

Total weight of film coated tablet 1836.00

Process

Manufacturing Process for Raltegravir Layer:

Manufacturing Process for Darunavir Layer:

2. The granules obtained in step (1) were lubricated with magnesium stearate.

Manufacturing Process for Ritonavir Layer:

1. Ritonavir, colloidal silicon dioxide and dibasic calcium phosphate were sifted, dry mixed and granulated with copovidone and sorbitan monolaureate to form granules.

2. The granules were extruded and lubricated with sodium stearyl fumarate.

EXAMPLE 19

Lamivudine and Tenofovir Disoproxil Bilayer Tablets:

Film Coating:

Sr. No Name of Ingredients Quantity/tab (mg)

1. Opadry 18.00

2. Purified water q.s.

Process:

Preparation of Layer I

A) Granulation

1) Tenofovir, lactose, croscarmellose, corn starch were sifted.

2) The sifted ingredients were dry mixed.

5) Granules obtained in step (4) were dried, sized and lubricated.

Preparation of Layer II

1) Lamivudine, microcrystalline cellulose, sodium starch glycolate were sifted.

2) The sifted ingredients were dry mixed.

3) Binder solution was prepared using corn starch and purified water.

5) Granules obtained in step (4) were dried, sized and lubricated.

B) Compression 1) Lubricated granules of Layer I and Layer II was compressed to produce a bilayer tablets.

C) Coating

1) Tablets so obtained were coated with Opadry solution.

EXAMPLE 20

Lamivudine and Zidovudine Monolayer Tablet for Oral Suspension:

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.

EXAMPLE 21

Lamivudine and Zidovudine Monolayer Tablets

Total 750.00

Film Coating

7. Hypromellose 8.83

8. Titanium Dioxide 2.94

9. Talc 1.77

10. Propylene Glycol 1.46

1 1. Isopropyl Alcohol q.s.

12. Purified Water q.s.

Total 765.00

Process

(1) Lamivudine, zidovudine, microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide were mixed in a blender.

(2) Magnesium stearate was added to the mixture obtained in step (1) and the mixture was compressed into tablets.

(3) The tablets obtained in step (2) were film coated.

EXAMPLE 22

Tenofovir Disoproxil Fumarate & Lamivudine Bilayer Tablets

14. FD& C Yellow No.6 INH 0.60

II. Binder Preparation

15. Corn Starch 10.20

16. Purified water q.s.

III. Lubrication

17. Sodium Starch Glycolate 20.00

18. Magnesium Staerate 6.00

Total 470.00

Film Coating

19 Opadry AMB OY-B 29000 Translucent 18.00

20. Purified Water q.s.

Total 1148.00

Process:

Tenofovir Disoproxil Fumarate Layer:

(1) Tenofovir Disoproxil Fumarate, lactose monohydrate, croscarmellose sodium and corn starch were mixed to produce a dry mix.

(2) Corn starch and polysorabte 80 were mixed to form a binder solution.

(3) The binder solution obtained in step (2) was sprayed onto the dry mix obtained in step (1) to form granules.

(4) The granules obtained in step (3) were dried and sized and mixed with microcrystalline cellulose and croscarmellose sodium and lubricated with magnesium stearate.

Lamivudine Layer:

(1) Lamivudine, microcrystalline cellulose, sodium starch glycolate were mixed to form a dry mix.

(2) Corn starch and purified water were mixed to form a binder solution.

(4) The granules obtained in step (3) were dried and sized and mixed with sodium starch glycolate and lubricated with magnesium stearate.

Compression and Coating:

(1) Tenofovir Disoproxil Fumarate granules and Lamivudine granules were compressed into a bilayer tablet and coated with Opadry solution.

EXAMPLE 23 Abacavir Sulfate & Lamivudine Monolayer Tablets

Formula

Process:

Abacavir granules

(1) Abacavir Sulfate, microcrystalline cellulose, sodium starch glycolate were mixed to form a dry mix.

(2) Hypromellose and purified water were mixed to form a binder solution.

(4) The granules obtained in step (3) were dried and sized

Lamivudine Granules

(1) Lamivudine, sodium starch glycolate microcrystalline cellulose were mixed to form a dry mix.

(2) Corn Starch and purified water were mixed to form a binder solution. (3) The binder solution obtained in step (2) was sprayed onto the dry mix obtained in step (1) to form granules.

(4) The granules obtained in step (3) were dried and sized

Blending and Lubrication

(1) Abacavir granules and lamivudine granules were blended with colloidal silicon dioxide and sodium starch glycolate and lubricated with magnesium stearate.

Compression and coating

(1) The granules were compressed into the monolayer tablet and coated with Opadry.

EXAMPLE 24

Darunavir Ritonavir Raltegravir bilayer tablets

Darunavir Layer

Film Coating

9 Opadry Red 36.00

10 Purified water -

Total weight of film coated tablet 1553.27

Process

Manufacturing Process for Darunavir Layer:

1. Darunavir, Raltegravir, HPMC, silicified microcrystalline cellulose, crospovidone and colloidal silicon dioxide were sifted, mixed and granulated.

2. The granules obtained in step (1) were lubricated with magnesium stearate.

Manufacturing Process for Ritonavir Layer:

2. The granules were extruded and lubricated with sodium stearyl fumarate.

EXAMPLE 25

Darunavir Ritonavir Raltegravir bilayer tablets

Darunavir Layer

3 Dibasic calcium phosphate 45.00

II Polymer premix

4 Copovidone 293.10

5 Sorbitan monolaurate 66.70

III Blending and lubrication

6 Colloidal silicon dioxide 10.00

7 Dibasic calcium phosphate anhydrous 94.40

8 Sodium stearyl fumarate 3.90

Total weight of Layer II 570.00

Total weight of core tablet (Layer I +

Layer II) 1517.27

Film Coating

9 Opadry Red 36.00

10 Purified water -

Total weight of film coated tablet 1553.27

Process

Manufacturing Process for Darunavir Layer:

2. The granules obtained in step (1) were lubricated with magnesium stearate.

Manufacturing Process for Ritonavir Layer:

2. The granules were extruded and lubricated with sodium stearyl fumarate.

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 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.

It will be appreciated that the invention may be modified within the scope of the appended claims.

Claims

CLAIMS:

1. A pharmaceutical antiretroviral composition comprising:

(iii) at least one protease inhibitor comprising: saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir; fosamprenavir; darunavir and/or tiprinavir,

2. The pharmaceutical antiretroviral composition according claim 1, wherein the zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine; emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir; elvucitabine; tenofovir; festinavir; racivir; lersivirine; rilpivirine; etravirine; SP 1093V; stampidine; raltegravir elvitegravir; dolutegravir; saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir; indinavir; nelfinavir; atazanavir; lasinavir; palinavir; fosamprenavir; darunavir; and/or tiprinavir is in the form of a pharmaceutically acceptable derivative thereof.

3. The pharmaceutical antiretroviral composition according to claim 2, wherein the pharmaceutically acceptable derivative is a salt, solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, enantiomer, polymorph or prodrug.

4. The pharmaceutical antiretroviral composition according to any preceding claim wherein the reverse transcriptase inhibitor comprises: lamivudine; zidovudine; tenofovir; emtricitabine and/or abacavir.

5. The pharmaceutical antiretroviral composition according to any preceding claim wherein the integrase inhibitor comprises: raltegravir and/or dolutegravir.

6. The pharmaceutical antiretroviral composition according to any preceding claim wherein the protease inhibitor comprises: ritonavir and/or darunavir.

7. The pharmaceutical antiretroviral composition according to any preceding claim comprising lamivudine, zidovudine, darunavir and ritonavir.

8. The pharmaceutical antiretroviral composition according to any preceding claim comprising lamivudine, tenofovir, darunavir and ritonavir.

9. The pharmaceutical antiretroviral composition according to any preceding claim comprising tenofovir, emtricitabine, darunavir and ritonavir.

10. The pharmaceutical antiretroviral composition according to any preceding claim comprising abacavir, lamivudine, darunavir and ritonavir.

1 1. The pharmaceutical antiretroviral composition according to any preceding claim comprising raltegravir or dolutegravir, darunavir and ritonavir.

12. The pharmaceutical antiretroviral composition according to any preceding claim, comprising:

at least two reverse transcriptase inhibitors, wherein the at least two reverse transcriptase inhibitors are provided in a separate single unit dosage form;

at least two protease inhibitors, wherein the at least two protease inhibitors are provided in a separate single unit dosage form; and/or

at least one integrase inhibitor, wherein the at least one integrase inhibitor is provided in a separate single unit dosage form.

13. The pharmaceutical antiretroviral composition according to any preceding claim comprising darunavir and ritonavir provided in a separate single unit dosage form.

14. The pharmaceutical antiretroviral composition according to any preceding claim comprising raltegravir or dolutegravir provided in a separate single unit dosage form.

15. The pharmaceutical antiretroviral composition according to any preceding claim comprising lamivudine and zidovudine provided in a separate single unit dosage form.

16. The pharmaceutical antiretroviral composition according to any preceding claim comprising tenofovir and emtricitabine provided in a separate single unit dosage form.

17. The pharmaceutical antiretroviral composition according to any preceding claim comprising abacavir and lamivudine provided in a separate single unit dosage form.

18. The pharmaceutical antiretroviral composition according to any preceding claim comprising lamivudine and tenofovir provided in a separate single unit dosage form.

19. The pharmaceutical antiretroviral composition according to any preceding claim, wherein the composition is provided as a kit comprising instructions for administration.

20. The pharmaceutical antiretroviral composition according to any preceding claim for once or twice daily administration.

21. The pharmaceutical antiretroviral composition according to any preceding claim, wherein the at least one reverse transcriptase inhibitor, the at least one integrase inhibitor and the at least one protease inhibitor are provided in a dosage form selected from: a tablet, a mini-tablet, sprinkles comprising a plurality of particles, a capsule, or a liquid.

22. The pharmaceutical antiretroviral composition according to claim 21, wherein the tablet is a disintegrating tablet, a dissolving tablet, a dispersible tablet, a mouth-dissolving tablet, a tablet for oral suspension, an immediate release tablet, an extended release tablet, an immediate and extended release tablet, or a matrix tablet.

23. The pharmaceutical antiretroviral composition according to claim 21, wherein the plurality of particles of the sprinkles are provide in the form of granules, powders, powders for reconstitution, beads, pellets, mini-tablets, film-coated tablets, film coated tablets MUPS, orally disintegrating MUPS, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, effervescent granules, or microspheres.

24. The pharmaceutical antiretroviral composition according to claim 21 or 23, wherein the sprinkles are provided in a sachet, a packet or a capsule.

25. The pharmaceutical antiretroviral composition according to any preceding claim, wherein the one or more pharmaceutically acceptable excipient comprises: a diluent, filler, bulking agent, disintegrant, binder, glidant, anti-adherent, lubricant, water soluble polymer, water insoluble polymer, water swellable polymer, plasticizer, and any mixture thereof.

26. A process for preparing the pharmaceutical antiretroviral composition according to any preceding claim, comprising: admixing the at least one reverse transcriptase inhibitor or the at least one integrase inhibitor and the at least one protease inhibitor, optionally with the one or more pharmaceutically acceptable excipient.

27. A method of preventing, treating or prophylaxis of a disease caused by a retrovirus, specifically acquired immune deficiency syndrome or an HIV infection, which method comprises administering to a patient in need thereof a pharmaceutical antiretroviral composition according to any one of claims 1 to 25.

28. A pharmaceutical composition according to any one of claims 1 to 25 for use in the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, in a patient in need thereof.

29. A use of the pharmaceutical antiretroviral composition according to any one of claims 1 to 25 for the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection.

30. The pharmaceutical antiretroviral composition as substantially described herein with reference to the examples.

31. The process of manufacturing a pharmaceutical antiretroviral composition as substantially described herein with reference to the examples.