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

FIELD OF INVENTION:
The present invention relates to an antiretroviral composition comprising immunomodulators and anti-retro viral agents, the manufacturing process thereof and use of the said composition for the prevention, treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
BACKGROUND AND PRIOR ART:
Demographically the second largest country in the world, India also has the third largest number of people living with HIV/AIDS. As per the provisional HIV estimate of 2008-09, by NACO (National AIDS Control Organization) there are an estimated 22.7 lakh people living with HIV/AIDS in India. The HIV prevalence rate in the country is 0.29 percent.
Acquired Immune Deficiency Syndrome (AIDS) causes a gradual breakdown of the body's immune system as well as progressive deterioration of the central and peripheral nervous systems. Since its initial recognition in the early 1980's, AIDS has spread rapidly and has now reached epidemic proportions within a relatively limited segment of the population. Intensive research has led to the discovery of the responsible agent, human T-lymphotropic retrovirus 111 (HTLV-111), now more commonly referred to as the human immunodeficiency virus 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 for the treatment of HIV infection is Highly Active Antiretroviral Therapy (HAART), which is based on the combination of inhibitors of reverse transcriptase and protease.
Currently available antiretroviral drugs for the treatment of HIV include nucleoside reverse transcriptase (RT) inhibitors or approved single pill combinations: zidovudine or AZT (or Retrovir®), didanosine or DDI (or Videx®), stavudine or D4T (or Zenith®), Iamivudine or 3TC (or Epivir®), zalcitabine or DDC (or Hivid®), abacavir sulphate (or Ziagen®), tenofovir disoproxil fumarate salt (or Viread ), emtricitabine (or Emtriva®), Combivir® (contains 3TC and AZT), Trizivir® (contains abacavir, 3TC and AZT); non-nucleoside reverse transcriptase inhibitors: nevirapine (or Viramune®), delavirdine (or Rescriptor®) and efavirenz (or Sustiva®), peptidomimetlc protease inhibitors or approved formulations: saquinavir (or Invirase® or Fortovase®), indinavir (or Crixivan®), ritonavir (or Norvir®), nelfinavir (or Viracept®), amprenavir (or Agenerase®). atazanavir (Reyataz®), fosamprenavir (or Lexiva®), Kaletra® (contains lopinavir and ritonavir), and one fusion inhibitor enfuvirtide (or T-20 or Fuzeon®).
Although Highly Active Antiretroviral Therapy (HAART) has succeeded in reducing the virus count to a bare minimum, it has helped to improve the immune system and has reduced death from AIDS-related diseases, it is still an expensive regime, often not well tolerated, induces numerous side effects on long term use and may also lead to drug resistance.
Resistance usually occurs when the drugs being used are not potent enough to completely stop virus replication. If the virus can reproduce at all in the presence of drugs, it has the opportunity to make changes in its structure, called mutations, until it finds one that allows it to reproduce in spite of the presence of the drugs. Once a mutation occurs, it then grows unchecked and soon is the dominant strain of the virus in the individual. The drug becomes progressively weaker against the new strain. There is also increasing concern about cross-resistance. Cross-resistance occurs when mutations-causing

resistances to one drug also cause resistance to another.. Several studies have proven that combining two drugs delays the development of resistance to one or both drugs compared to when either drug is used alone. Other studies suggest that three-drug combinations extend this benefit even farther. As a result, it is commonly believed that the best way of preventing, or at least delaying resistance is to use multi-drug combination therapies. The risk of drug interactions and toxicity to the patient may also increase as the number of drugs increases.
In the efforts to develop a vaccine for the treatment of HIV, certain approaches are showing early promise in monkeys. However, the persistence of HIV infection coupled with its high rate of spontaneous mutation raises concems about the effect of this vaccine on the modified structure of this virus.
One of the further strategies for the treatment of HIV involves identification of anti-HIV compounds from natural sources, particularly from plants. While traditional medicine has served as a source of alternative system of medicine and also a source of new pharmaceuticals as well as health care products. Considerable research on pharmacognosy, phytochemistry, pharmacology and clinical therapeutics has been carried out on potential Ayurvedic medicinal plants.
But, in case of the herbal therapy or alternative system of medicine, it has always been observed that till date many compositions have been tried but majorities of them are just polyherbal formulation containing large number of herbs combined together.
In a study conducted by Rege et al, it has been concluded that in vitro testing of O.sanctum, T. cordifolia, A. officinals and R. mucronata exhibited potential anti-HIV activity by inhibiting the virus by two different mechanisms viz interference with the gp1120/CD4 interaction and inhibition of viral Reverse Transcriptase (RT) (Anuya Rege, Ramkrishna Ambaye and Ranjana Deshmukh, Indian Journal of natural Products and Resources, Vol 1(2), June 2010, pp. 193-199).
A polyherbal formulation consisting of extracts of Ocimum sanctum, Withania somnfera, Emblica officinalis and Tinospora cordfolia has been reported to protect nonspecific host

defense mechanisms (S Chatterjee and SN Das. Ani Sci Life, 16. 200-205, 1997: Ani Sci Life, 15 (4): 250-253, 1996). Chatterjee et al. also have shown that in immunodeficient and immunocompromised host, this polyherbal preparation restored and improved the immune status.
Epigallocatechin gallate (EGCG), a major component of tea catechin, has an inhibitory effect on HIV-1 infection. EGCG efficiently inhibited binding of anti-CD4 antibody to its corresponding antigen. This effect was mediated by the direct binding of EGCG to the CD4 molecule, with consequent inhibition of antibody binding, as well as gpl 20 binding. (Kawai et al, Epigallocatechin gallate, the main component of tea polyphenol, binds to CD4 and interferes with gpl20 binding, J Allergy Clin Immunol 2003; 112:951-7.)
Anti-HIV viral activity of EGCg (Epigallocatechin gallate) is due to the result of interaction with several steps in the HIV-1 life cycle as disclosed by Koushi et al (Inhibitory effects of (-)-epigallocatechin gallate on the life cycle of human immunodeficiency virus type 1 (HIV-1), Antiviral Research 53 (2002) 19-34).
The extract of Tinospora cordifolia significantly affects the symptoms of HIV as validated by clinical evaluation is disclosed by Kaliker et al in Immunomodulatory effect of Tinospora cordifolia extract in human immuno-deficiency virus positive patients, Indian Journal of Pharmacology, Jun 2008, Vol 40. Issue 3, 107-110.
Traditional Indian medicine and homeopathy has commonly been used by most practitioners and that these practitioners have outnumbered the allopathic practitioners, this has been mentioned in the review article (M Fritts, CC Crawford, D Quibell, A Gupta, WB Jonas, I Coulter and SA Andrade, Traditional Indian medicine and homeopathy for HIV/AIDS: a review of the literature, AIDS Research and Therapy 2008, 5:25).
US5529778 has described a composition consisting of eight different plant extracts which have beneficial effects against AIDS, flu, tuberculsis, hepatitis, cirrhosis and immunodeficiency conditions. This patent also describes the use of a very high dose

(Igx2/day) to the patients. Plant extracts are not standardized against their bioactive principles. Hence, consistency of results is expected to be compromised and questionable.
WO2010029562 discloses a bioactive composition for the treatment of HIV comprising curcumin, cyprenone, ursolic acid optionally combined with vinflunine and berberine sulphate particularly by the removal of HIV antigen glycoprotein.
US20070122495 discloses novel herbal formulation comprising Bacopa monniera, Convolvulus pluricaulis, Nardostachys jatamansi, Valerian wallichi, Myristica fragrans Centella asiatica, Withania somnifera, Ocimum sanctum, Acorus calamus, Boerhavia diffusa and Tinospora cordifolia that has been found to be effective for a range of psychological, pathological, and physiological conditions involving many systems in the human body.
US5980903 discloses a composition comprising thymol from Bishop's Weed, Chebulic myroblan and Holy Basil for the treatment of viral infections including HIV.
WO2006008761 discloses anti retroviral herbal formulation comprising synergistic
combination of medicinal herbs such as Gycyrrihza glabra, Allium sativum, Azadirachta
indica, Piper betel, Pichcorhiza kurroa, Annona
Squamosa, Withania Somnifera and Tinospora Cordifolia.
WO2004012655 discloses an anti-microbial composition comprising a first ingredient obtainable from ginger, a second ingredient obtainable from green tea wherein the infecting microbe is a HIV virus, AIDS virus.
WO2006065889 discloses a method to inhibit the transmissivity of a virus such as HIV and AIDS virus by administering a composition comprising a first ingredient obtainable from ginger, a second ingredient obtainable from green tea.
EP2179722 discloses a topical formulation such as ointment, cream, gel, suppository, liquid for vaginal irrigation, intravaginal ring or concentrate for preventing sexual transmission of viral infection, in particular HIV infection wherein the composition

comprises at least one compound from the class of catechins, such as epigallo-catechin-gallate(EGCG).
However, from the discussion above it may be noted that anti-retroviral drugs and alternative system of medicine such as herbal drugs have always been administered separately and not as a combination. Also, none of the prior art discloses the anti-retroviral with herbal drugs as a combination therapy.
Further, in view of the magnitude of AIDS pandemic, absence of protective vaccine, paucity of non-toxic therapy and resistance developed by the virus to different anti-HIV therapeutic drugs, there is an urgent need for the development of new, specific and nontoxic anti-retroviral therapy.
Accordingly, there exists a need for an alternative efficacious therapy for HJV infection by reducing the mean viral load and simultaneously improve the immune system of the immunocompromised AIDS patient.
Hence, there still remains a need to formulate a suitable novel pharmaceutical composition which is acceptable, have reduced side effects, as well as effective for the treating of HIV infection.
OBJECT OF THE INVENTION:
The object of the present invention is to provide a pharmaceutical composition suitable for administration.
Another object of the present invention is to provide a pharmaceutical composition optionally with pharmaceutically acceptable excipients.
One more object of the present invention is to provide a novel pharmaceutical composition comprising antiretroviral drugs which is easy to manufacture.

Another object of the present invention is to provide a formulation that effectively inactivates or reduces the human retrovirus load.
Yet another object of the present invention is to boost immune system of the patient.
Another object of the present invention is to increase the count of CD 4 cells and CD 8 cells.
Another object of the present invention is to provide a formulation which stimulates the cell mediated immunity in human.
A further object of the present invention is to provide a pharmaceutical composition for use in the prevention, treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
SUMMARY OF THE INVENTION:
According to one aspect of the present invention there is provided a pharmaceutical composition comprising Ocimum sanctum, Tinospora cordifolia, Camellia sinensis with at least one anti-retroviral agent.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising Ocimum sanctum, Tinospora cordifolia, Camellia sinensis with at least one anti-retroviral agent optionally with one or more pharmaceuticaily acceptable excipients.
According to a yet another aspect of the present invention there is provided a process of manufacturing the pharmaceutical composition comprising Ocimum sanctum, Tinospora cordifolia, Camellia sinensis with at least one anti-retroviral agent optionally with one or more pharmaceuticaily acceptable excipients.
According to a further aspect of the present invention there is provided a method of boosting the immune system, reducing the retroviral load and increasing the CD 4 cell

and CD 8 cell count which method comprises administering to a patient in need thereof a pharmaceutical composition comprising Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and at least one anti-retroviral agent.
According to a still further aspect of the present invention there is provided a method of preventing, treating or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, which method comprises administering to a patient in need thereof the pharmaceutical composition comprising Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and at least one anti-retroviral agent.
DETAILED DESCRIPTION OF THE INVENTION:
As discussed above, there is a need to develop and formulate a composition which is in an acceptable form, provides reduced side effects, as well as is effective for the treating HIV infection by reducing the viral load and also improves the immune system of the immunocompromised patients affected by AIDS.
Further, there is also a need to develop an alternative efficacious therapy for HIV infection by reduces the mean viral load and simultaneously improves the immune system of the immunocompromised AIDS patient.
In particular, the inventors of the present invention have surprisingly found that, administering a combination therapy of Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and an antiretroviral drug in a fixed dose proportion may reduce the viral load, increase the CD4 and CD8 cell count and may thus boost the immunity of the patients.
Thus, the present invention provides a composition comprising Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and one or more antiretroviral agents.
In particular, the present invention provides a pharmaceutical composition comprising Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and at least one anti-retroviral agent optionally with one or more pharmaceutically acceptable excipients.

The term "pharmaceutically acceptable" mentioned throughout the specification would be applied to a carrier, diluent or any other excipient which is compatible with Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and one or more antiretroviral drugs as employed.
The term "Ocimum sanctum" is used throughout the description in broad sense to include not only Ocimum sanctum per se but also the extract prepared using plant leaves or any parts of the plant such as roots, stem, flower, fruit may be used. Any suitable commercially available Ocimum sanctum extract may also be used provided that the said extract possesses immune stimulating activity.
The term "Tinospora cordifolia" is used throughout the description in broad sense to include not only Tinospora cordifolia per se but also the extract prepared using stem or any parts of the plant such as roots, leaves, flower, fruit may be used. Any suitable commercially available Tinospora cordifolia extract may also be used provided that the said extract possesses immune stimulating activity.
The term "Camellia sinensis" is used throughout the description in broad sense to include not only Camellia sinensis per se but also the extract prepared using leaves or any parts of the plant such as roots, stem, flower, fruit may be used. Any suitable commercially available Camellia sinensis extract may also be used provided that the said extract possesses immune stimulating activity.
For the purpose of the present invention, any parts of the plant of Ocimun sanctum, Tinospora cordifolia, Camellia sinensis may be used to obtain the extract.
For the purpose of the present invention, suitable extract of Ocimum sanctum, Tinospora cordifolia, Camellia sinensis can be prepared using various extraction methods known in the art such as maceration, remaceration, digestion, agitation, agitation maceration, filtration, vortex extraction, centrifugation, ultrasonic extraction, countercurrent extraction, percolation, repermolation, evacolation (extraction under reduced pressure), diacolation and solid liquid extraction under continuous reflux in a Soxhlet extractor.

Ocimum sanctum commonly known as holy basil is an herbaceous sacred plant found through out India. Indian material medica describes the use this plant in a variety of ailments. Different parts of plant like stem, flower, seed, leaves, root etc are known to possess therapeutic potential and have been used, by traditional medicinal practitioners, as expectorant, analgesic, anticancer, antiasthamatic, antiemetic, diaphoretic, antidiabetic, antifertility, hepatoprotective, hypotensive and antistress agent. Tulsi has also been used in treatment of fever, bronchitis, arthritis, convulsion etc.
Chemically the main constituents of Ocimun sanctum include eugeneol (l-hydroxy-2-methoxy-4-allylbenzene) and ursolic acid as described in Therapeutic uses of Ocimum sanctum linn with a note on eugenol and its pharmacological actions: A short review (P. Prakash and Neelu Gupta, Indian Journal of Physiology and Pharmacology, 2005; 49 (2): 125-131).
Further, the leaves contain an essential oil, which contains eugenol. eugenal, carvacrol, methylchavicol, limatrol and caryophylline. The seeds contain oil composed of fatty acids and sitosterol. The roots contain sitosterol and three triterpenes A, B, and C. The leaves also contain ursolic acid and n-triacontanol. Eugenol, its methyl ether, nerol, caryophyllene, terpinen 4-decylaldehyde, selinene, pinenes, camphene and a-pinene have been identified in essential oil. Additionally, it also contains rosmarinic acid, thymol, linalool and methyl chavicol and citral etc.
Green tea is the nonoxidized, unfermented product of leaves from the evergreen plant Camellia sinensis. Green tea is produced by steaming fresh leaves at high temperatures, thereby inactivating the oxidizing enzymes and leaving the polyphenol content intact. The polyphenols found in tea are more commonly known as flavanols or catechins, and comprise 30-40 percent of the extractable solids of dried green tea leaves.
Green tea polyphenols have demonstrated significant antioxidant, anticarcinogenic, antiinflammatory, thermogenic, probiotic, and antimicrobial properties in numerous human, animal, and in vitro studies.

Camellia sinensis or Green tea contains 10-15% catechin, which includes several isomers, (-)-EGCg, (-)-epicatechin (EC), (-)-epicatechin gallate (ECg), (-)-epigallocatechin (EGC) and (+)-catechin. AM of these catechins have a main structure of flavan-3-ols, and additional pyrogallol or galloyl groups that contribute to their biological activities. EGCg is the most potent compound of those isomers since it possesses both pyrogallol and galloyl moieties.
Tinospora cordifolia commonly known as Guduchi is used in ayurvedic, "Rasayanas" to improve the immune system and body resistance against infections. Tinospora cordifolia has demonstrated immunomodulatory activity, hypoglycemic activity, hypolipidemic activity, anti-infective activity, antipyretic effect, antistress activity, antinflamatory activity, antineoplastic activity, antioxidant effects and radio-protective effects.
A variety of constituents have been isolated from Tinospora cordifolia plant and their structures were elucidated. They belong to different classes such as alkaloids, diterpenoid lactones, glycosides, steroids, sesquiterpenoid, phenolics, aliphatic compounds and polysaccharides. Some constituents that have been isolated from plant mainly include tinosporone, tinosporic acid, cordifolisides A to E, syringen, berberine, giloin, gilenin, crude giloininand, arabinogalactan polysaccharide, picrotene, bergenin, gilosterol, tinosporol, tinosporidine, sitosterol, cordifol, heptacosanol, octacosonal, tinosporide, columbin, chasmanthin, palmarin, palmatosides C and F, amritosides, cordioside, tinosponone, ecdysterone, makisterone A, hydroxyecdysone, magnoflorine, tembetarine, syringine, glucan polysaccharide, syringine apiosylglycoside, isocolumbin, palmatine, tetrahydropalmaitine, jatrorrhizine respectively.
Antiretroviral agents for the purpose of the present invention may be selected from nucleoside and nucleotide reverse Transcription inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs). protease inhibitors (Pls), integrase inhibitors.
The composition may contain as antiretroviral agent at least one of the materials in the
following classes (i) to (v) along with Ocimum sanctum, Tinospora cordifolia, Camellia
sinensis
(i) at least one nucleoside reverse transcriptase inhibitor

(ii) at least one nucleotide reverse transcriptase inhibitor (iii) at least one non-nucleoside reverse transcriptase inhibitor (iv) at least one protease inhibitor. (v) at least one integrase inhibitor
In an embodiment, the composition may include at least one compound from two of the classes (i) to (v), in particular (i) and (ii); (i) and (iii); (i) and (iv); (i) and (v); (ii) and (iii); (ii) and (iv); (ii) and (v); and (iii) and (iv); and (iii) and (v); and (iv) and (v).
In an embodiment, the composition may include at least one compound from three of the classes (i) to (v), in particular (i), (ii) and (iii); (i), (iii) and (iv); (i), (ii) and (v); and (ii), (iii) and (iv); (ii), (iii) and (v).
In an embodiment, the composition may include at least one compound from all five of the classes (i) to (v).
The term "nucleoside and nucleotide reverse transcriptase inhibitors" (NRTls) as used herein means nucleosides and nucleotides and analogues thereof that inhibit the activity of HIV-1 reverse transcriptase, the enzyme which catalyzes the conversion of viral genomic HIV-1 RNA into proviral HIV-1 DNA. Recent progress in development of RTI and PI inhibitors has been reviewed (F. M. Uckun and O. J. D'Cruz, Exp. Opin. Ther. Pat. 2006 16:265-293; L. Menendez-Arias, Eur. Pharmacother. 2006 94-96 and S. Rusconi and O. Vigano, Future Drugs 2006 3(l):79-88).
Suitable protease inhibitors (Pls) that may be employed in the pharmaceutical composition of the present invention may comprise saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir; tirpranavir: fosamprenavir; darunavir; tipranavir; DMP450, a cyclic urea under development by Triangle Pharmaceuticals; BMS-2322623, an azapeptide under development by Bristol-Myers Squibb as a 2nd-generation HIV-I PI; GS3333; KNI-413; KNI-272; LG-71350; CGP-61755;PD 173606;PD 177298; PD 178390;PD 178392; U-140690; and AG-1549 an imidazole carbamate under development by Agouron Pharmaceuticals, Inc. Additional Pls in preclinical development include N-cycloalkylglycines by BMS, a-

hydroxyarylbutanamides by Enanta Pharmaceuticals; a-hydroxy-y-[[(carbocyclic- or
heterocyclic-substituted)amino)carbonyl]alkanamide derivatives; y-hydroxy-2-
(fluoroalkylaminocarbonyl)-1 -piperazinepentanamides by Merck; dihydropyrone derivatives and a- and p-amino acid hydroxyethylamino sulfonamides by Pfizer; and N-aminoacid substituted L-lysine derivatives by Procyon.
Suitable nucleoside reverse transcriptase inhibitors (NRTIs) that may be employed in the pharmaceutical composition of the present invention may comprise Zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine; emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir; elvucitabine;; BCH-189; phosphazid; racivir; SP1093V; stampidine; a nucleoside reverse transcriptase inhibitor disclosed in EP-0358154 and EP-0736533; BCH-10652, a reverse transcriptase inhibitor (in the form of a racemic mixture of BCH-10618 and BCH-10619) under development by Biochem Pharma; β-L-FD4 (also called β-L-D4C and named β-L-2',3'-dicleoxy-5-fluoro-cytidene) licensed Vion Pharmaceuticals; DAPD, the purine nucleoside, (-)-β-D-2,6-diamino-purine dioxolane disclosed in EP-0656778 and licensed to Triangle Pharmaceuticals; and lodenosine (FddA), 9-(2.3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine, an acid stable purine-based reverse transcriptase inhibitor under development by U.S. Bioscience Inc.
Suitable nucleotide reverse transcriptase inhibitors (NtRTIs) that may be employed in the pharmaceutical composition of the present invention may comprise tenofovir and/or adefovir.
Suitable non-nucleotide reverse transcriptase inhibitors (NNRTIs) that may be employed
in the pharmaceutical composition of the present invention may comprise nevirapine,
rilpivirine, delaviridine, efavirenz, etravirine, rilpiverine. Other NNRTIs currently under
investigation include PNU-142721, a furopyridine-thiopyrimide under development by
Pfizer; capravirine (S-1153 or AG-1 549; 5-(3,5-dichlorophenyl)-thio-4-isopropyl-l-(4-
pyridyI)methyl-1H-imidazol-2- -ylmethyl carbonate) by Shionogi and Pfizer; emivirine
[MKC-442; (l-(ethoxy-methyl)-5-(l-methylethyl)-6-(phenylmethyl)-(2,4(lH!3H)-
pyrimid- inedione)] by Mitsubishi Chemical Co. and Triangle Pharmaceuticals; (+)-calanolide A (NSC-67545 1) and B, coumarin derivatives disclosed in NIH U.S. Pat. No.

5,489,697, licensed to Sarawak/Advanced Life Sciences; dapivirine; 4-{4-[4-((E)-2-
cyano-vinyl)-2,6-dimethyl-phenylamino]-pyrimidin-2-ylamino- }-benzonitrile) by
Tibotec-Virco and Johnson & Johnson; BILR-355 BS (12-ethy[-8-[2-(l-hydroxy-
quinolin-4-yloxy)-ethyl]-5-methyl-11,12-dihydro-5H-l ,5,10,12-tetraaza
dibenzo[a,e]cycloocten-6-one by Boehringer-Ingleheim; PHI-236 (7-bromo-3-[2-(2,5-
dimethoxy-phenyl)-ethyl]-3,4-dihydro-1H-pyrido[ 1,2-a][- 1,3,5]triazine-2-thione) and
PHI-443 (TMC-278, l-(5-bromo-pyridin-2-yli)-3-(2-thiophen-2-yl-ethyl)-thiourea) by
Paradigm Pharmaceuticals.
Suitable integrase inhibitors that may be employed in the pharmaceutical composition of the present invention may comprise raltegravir, elvitegravir.
The antiretroviral agents of the present invention may be used in the form of salts or esters derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others.
In one embodiment, the pharmaceutical composition according to the present invention comprises Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and at least one nucleoside reverse transcriptase inhibitor (NRTI) with one or more pharmaceutically acceptable excipient. Preferably the NRTI is emtricitabine.

In another embodiment, the pharmaceutical composition according to the present invention comprises Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and at least one nucleotide reverse transcriptase inhibitor (NtRTI) with one or more pharmaceutically acceptable excipient. Preferably the NtRTI is tenofovir, more preferably tenofovir disoproxil fumarate.
In another embodiment, the pharmaceutical composition according to the present invention comprises Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and at least one non-nucleoside reverse transcriptase inhibitor (NNRTI) with one or more pharmaceutically acceptable excipient. Preferably the NNRTI is efavirenz or rilpivirine.
In a further embodiment, the pharmaceutical composition according to the present invention comprises Ocimum sanctum, Tinospora cordifolia, Camellia sinensis at least one of nucleoside reverse transcriptase inhibitor, at least one of nucleotide reverse transcriptase inhibitor and at least one non-nucleoside reverse transcriptase inhibitor (NNRTI) with one or more pharmaceutically acceptable excipient. Preferably, the said combination comprises Ocimum sanctum, Tinospora cordifolia, Camellia sinensis, tenofovir, efavirenz, emtricitabine with one or more pharmaceutically acceptable excipient.
In another embodiment, the pharmaceutical composition according to the present invention comprises Ocimum sanctum, Tinospora cordifolia, Camellia sinensis at least one of nucleotide reverse transcriptase inhibitor and at least one non-nucleoside reverse transcriptase inhibitor (NNRTI) with one or more pharmaceutically acceptable excipient. Preferably, the said combination comprises Ocimum sanctum. Tinospora cordifolia, Camellia sinensis, tenofovir, rilpivirine with one or more pharmaceutically acceptable excipient.
In yet another embodiment, the pharmaceutical composition according to the present invention comprises Ocimum sanctum, Tinospora cordifolia, Camellia sinensis at least one of nucleotide reverse transcriptase inhibitor and at least one non-nucleoside reverse transcriptase inhibitor (NNRTI) with one or more pharmaceutically acceptable excipient. Preferably, the said combination comprises Ocimum sanctum, Tinospora cordifolia,

Camellia sinensis, tenofovir, riipivirine, emtricitabine with one or more pharmaceutically acceptable excipient.
In a further embodiment, the pharmaceutical composition according to the present invention comprises Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and at least one anti-retroviral agent selected from nucleoside reverse transcriptase inhibitor, nucleotide reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) with one or more pharmaceutically acceptable excipient. Preferably, the said combination comprises Ocimum sanctum, Tinospora cordifolia, Camellia sinensis, rilpivirine with one or more anti-retroviral agent and one or more pharmaceutically acceptable excipient.
In a further embodiment, the pharmaceutical composition according to the present invention comprises Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and at least one anti-retroviral agent selected from nucleoside reverse transcriptase inhibitor, nucleotide reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) with one or more pharmaceutically acceptable excipient. Preferably, the said combination comprises Ocimum sanctum, Tinospora cordifolia, Camellia sinensis, efavirenz with one or more anti-retroviral agent and one or more pharmaceutically acceptable excipient.
The amount of Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and antiretroviral agent that may be combined with suitable pharmaceutically acceptable excipient to produce a single dosage form individually or in combination may vary depending upon the host treated and the particular mode of administration and the drug category chosen.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.

Alternatively the pharmaceutical composition of the present invention is in the form of a kit comprising separate dosage forms for each of the Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and antiretroviral agents which may be administered simultaneously, sequentially or separately.
The pharmaceutical composition of the present invention may be formulated into dosage forms suitable for oral, nasal, rectal, vaginal, topical (including buccal and sub-lingual), ocular, local (powders, ointments or drops) transdermal, or parenteral (including intramuscular, subcutaneous, intrasternal, infusions and intravenous) administration. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmaceutical formulation. All methods preferably include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, providing the product into the desired formulation.
Moreover, the pharmaceutical composition of the present invention can be formulated into any suitable dosage forms comprising liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations.
Solid dosage forms for oral administration may include capsules, tablets including uncoated and coated tablets, pills, powders, powder for suspension, and granules. Uncoated tablets may be chewable tablet, effervescent tablet, lozenge tablet, soluble tablet, and sublingual tablet; coated tablets may be enteric coated tablet, film coated tablet, implant, sugar coated tablet, and modified-release tablet.
In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, additional substances known in the art, other than inert diluents, e.g., lubricating agents such as magnesium stearate.

In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Other processes of manufacturing solid dosage forms may be employed to develop the pharmaceutical composition of the present invention, such as wet granulation, dry granulation, direct compression, hot melt extrusion, hot melt granulation or other methods known in the art.
When provided as a tablet, the tablet may be multilayer, for example bilayer. A different antiretroviral agent may be provided in each layer.
According to the present invention suitable pharmaceutically acceptable excipients may be used for formulating the solid dosage forms.
According to the present invention, pharmaceutically acceptable excipients include but not limited to carriers, diluents or fillers like lactose (for example, spray-dried lactose, a-lactose, β-lactose) lactose available under the trade mark Tablettose, various grades of lactose available under the trade mark Pharmatose or other commercially available forms of lactose, lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystaliine cellulose (for example, microcrystalline cellulose available under the trade mark Avicel), hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethyl hydroxyethylcellulose and other cellulose derivatives, starches or modified starches (including potato starch, corn starch, maize starch and rice starch) and mixtures thereof.
According to the present invention, glidants, anti-adherents and lubricants may also be incorporated in the pharmaceutical 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) and glycerides, light mineral oil, PEG, silica acid or a derivative or salt thereof (for

example, silicates, silicon dioxide, colloidal silicon dioxide and polymers thereof, crospovidone, magnesium aluminosilicate and/ or magnesium alumino metasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil), or mixtures thereof.
According to the present invention, suitable binders may also present in the in the pharmaceutical 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, or mixtures thereof or any other suitable binder.
According to the present invention, suitable disintegrants may also be present in the in the pharmaceutical composition of the present invention, which may comprise one or more, but not limited to hydroxylpropyl cellulose (HPC), low density HPC, carboxymethylcellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium; starches exemplified under examples of fillers and also carboxymethyl starch, hydroxylpropyl starch, modified starch; crystalline cellulose, sodium starch glycolate; alginic acid or a salt thereof, such as sodium alginate or their equivalents and mixtures thereof.
Oral liquid preparations may be in the form of. for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as, but not limited to, suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives, sweeteners, vehicle/wetting agents, coloring agents, flavoring agents, viscosity enhancing/thickening agents.
The parenteral preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are

water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, conventionally used fatty acids such as oleic acid find use in the preparation of injectables.
Alternatively, the active ingredients may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
The pharmaceutical composition of the present invention may also be applied in the form of topical composition comprising pharmaceutically acceptable excipients as desired for topical administration. Solid dosage forms for topical administration may include, spot-on, gel; a spray; a foam; a cream; a wash; a pessary: an ovule; a lotion; an ointment; a film; a foaming tablet; a tampon; a vaginal spray; solution; a bath; a liniment; a patch; a pad; a bandage.
According to the present invention suitable pharmaceutically acceptable excipients may be used for formulating topical dosage forms.
According to one embodiment, the pharmaceutically acceptable excipients for topical composition may include, but are not limited to, one or more surfactant, emollient or humectant, pH adjusting agent, fatty alcohol, preservative, organic solvent, gelling agents, chelating agents, film forming polymers, antioxidants, propellants or combinations thereof.
The surfactants may be selected from, but not limited to, Polyoxyethylene alcohol, alkylphenol ethoxylate, polysorbate 80, polysorbate 60, polymethylsiloxane, alkylphenol ethoxylate, poloxomer 407, sorbitan monostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, polyethylene glycol (PEG) stearic acid esters (e.g. polyethylene glycol 100 stearate).

Suitable humectants and/or emollients provide smoothness and lubricity which, in turn, facilitate the loading and dispensing of the formulation. The emollients and/or humectants may be selected from, but not limited to, polyhydric alcohols such as glycols, and polysaccharides, such as ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, dipropylene glycol, glycerin, diglycerin, sorbitol, malvitol, trehalose, raffinose, xylitol, mannitol, polyethylene glycol, propylene glycol, polyglycerin, cholesterol, squaline, fatty acids, octyldodecanol, myristyl alcohol, urea, lanolin, lactic acid, esters such as isopropyl stearate, isopropyl myristate, isopropyl palmitate and isopropyl laurate and the like.
The pH adjusting agents may be selected from, but not limited to, lactic acid, sodium hydroxide, acetic acid, citric acid, tartaric acid, propionic acid, sodium phosphate, ammonia solution, triethanolamine, sodium borate, sodium carbonate, potassium hydroxide and like.
The preservatives may be selected from, but not limited to, benzyl alcohol, hydroxybenzoates (parabens), benzoic Acid, chlorphenesin, sorbic acid, phenoxyethanol and like.
The gelling agents may be selected from, but not limited to, alginic acid, sodium alginate, potassium alginate, agar, carrageenan, pectin, gelatin, calcium alginate, carbomers, methyl cellulose, sodium carboxy methyl cellulose, hydroxy ethyl cellulose and other cellulose derivatives, carbopol, bentonite (preferably carbomers) may be used in combination with bioadhesives which includes, but not limited to, gelatin, carbopol 934, polycarbophil, cross-linked polymethacrylic acid, hydroxypropyl methyl cellulose, ethyl cellulose, preferably carbopol & methyl cellulose.
The chelating agents may be selected from, but not limited to disodium edetate, sodium citrate, condensed sodium phosphate, diethylenetriamine penta-acetic acid and like.
Film forming polymers may be selected from, but are not limited to carbomers such as carboxymethylene polymers including acrylic acid polymers, and acrylic acid copolymers, acrylic acid alkyl ester monomers, maleic acid alkyl esters, crotonic acid

alkyl ester monomers, vinyl ester monomers, cellulose derivatives, vinylpyrrolidone-
vinyl acetate copolymers, polyurethane, preferably carbopol, hydroxyethyl cellulose,
methyl cellulose, vinylpyrrolidone-vinyl acetate copolymers.
Antioxidants may be selected from but are not limited to ascorbate, BHT. BHA, sodium metabisulphite, alpha-tocopherol or its synthetic derivatives, EDTA and like.
Propellants may be selected from volatile hydrocarbons such as butane, propane, isobutane and fiuorocarbon gases or mixtures thereof, fluorohydrocarbon (HFCs) propellants such as 1,1,1,2-tetrafluorethane, and 1,1,1,2,3,3,3-heptafluoropropane, 1,1-difluoro ethane and 1,1,1,3,3,3-hexafluoropropane, preferably HFC 134a or HFA 227.
According to one embodiment the pharmaceutical composition of the present invention, may be prepared by a process which comprises (i) dissolving preservatives to pre-heated humectant, (ii) adding gelling agent to the above solution to form an organic phase, (iii) adding chelating agent to the purified water and then adding drug to it to form a drug phase, (iv) adding Ocimum sanctum, Tinospora cordifolia and Camellia sinensis to the purified water and filtering through suitable filter to form a herbal phase, (v) adding drug phase to organic phase and stirring to form a gel. (vi) finally adding herbal phase to step (v) to form a gel.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Suppositories for rectal administration of the drug may also be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug. Suitably other pharmaceutical excipients used in suppositories may also be employed.
According to the present invention there is provided a method for boosting the immune system, reducing the retroviral load and increasing the CD4 cells and CD8 cell count,

which method comprises administering to a patient in need thereof the pharmaceutical composition comprising Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and at least one anti-retroviral agent.
In a farther embodiment, there is provided a method of preventing or treating HIV infection or alleviating the symptoms associated with HIV infection comprising administering to a patient in need thereof the pharmaceutical composition comprising Ocimum sanctum, Tinospora cordifolia, Camellia sinensis and at least one anti-retroviral agent.
The following example is for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the present invention.

Example 1:
Sr. No. Ingredients Qty (%w/w)
1 Tenofovir disoproxil fumarate 1.00
2 Ocimum sanctum 0.5
3 Tinospora cordifolia 0.5
4 Camellia sinensis 0.5
5 Disodium edetate 0.05
6 Citric acid 1.00
7 Methyl Paraben 0.18
8 Propyl Paraben 0.02
9 Glycerin 20.0
10 Hydroxy Ethyl Cellulose 2.00
11 Purified Water Up to 100%
12 Sodium Hydroxide Up to pH 4.5
13 Hydrochloric acid q.s to dissolve drug
Process:
1. Methyl paraben and Propyl paraben were added to the heated glycerin and stirred to dissolve.

2. To the above formed solution, hydroxy ethylcellulose (HEC) was added and dispersed. This was the organic phase.
3. Disodium edetate and citric acid were added to purified water in another SS vessel. The mixture was stirred to get a clear colourless solution.
4. Tenofovir was added and dispersed in the above solution under stirring. The pH of the solution was adjusted to 4.5. This was the drug phase.
5. Ocimum sanctum, Tinospora cordifolia and Camellia sinensis were added to small amount of water under continuous stirring.
6. Above solution was then filtered through suitable filter to get brown coloured solution. This was herbal phase.
7. The drug phase was added to the organic phase under continuous stirring to form clear, transparent colorless gel.
8. Herbal phase was then added to the above formed gel to form clear, transparent, brown colored gel.
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 polymer" includes a single polymer as well as two or more different polymers; reference to a "plasticizer" refers to a single plasticizer or to combinations of two or more plasticizer, and the like.

WE CLAIM:
1. A pharmaceutical composition comprising a combination of Ocimum sanctum, Tinospora cordifolia. Camellia sinensis along with at least one anti-retroviral agent.
2. A pharmaceutical composition according to any one of the preceding claims, wherein the antiretroviral agent comprises at least one of the following groups (i) to (v): (i) at least one nucleoside reverse Transcription inhibitor; (ii) at least one nucleotide reverse Transcription inhibitors (iii) at least one non-nucleoside reverse transcriptase inhibitor; (iv) and at least one protease inhibitor (v) at least one integrase inhibitor.
3. A pharmaceutical composition according to any one of the preceding claims, wherein the nucleoside reverse transcription inhibitor comprises one or more of Zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine; emtricitabine; zalcitabine; dexelvucitabine; alovudine: amdoxovir; elvucitabine; BCH-189; phosphazid; racivir; SP1093V; stampidine; BCH-10652, the purine nucleoside, (-)-β-D-2,6-diamino-purine dioxolane, lodenosine (FddA), 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl) adenine.
4. A pharmaceutical composition according to any one of the preceding claims, wherein the nucleotide reverse transcription inhibitor comprises one or more of tenofovir and/or adefovir.
5. A pharmaceutical composition according to any one of the preceding claims, wherein the non-nucleoside reverse transcriptase inhibitor comprises one or more of nevirapine, delaviridine, efavirenz, etravirine, rilpivirine, PNU-142721, a furopyridine-thiopyrimide; capravirine; 5-(3.5-dichlorophenyI)-thio-4-isopropyl-l-(4-pyridyl)methyl-1H-imidazol-2- -ylmethyl carbonate); emivirine; (l-(ethoxy-methyl)-5-(l-methylethyl)-6-(phenylmethyl)-(2,4(lH,3H)-pyrimid- inedione)]; (+)-calanolide A (NSC-67545 1) and B, coumarin derivatives; dapivirine; 4-{4-[4-((E)-

2-cyano-vinyl)-2,6-dimethyl-phenylamino]-pyrimidin-2-ylamino-}-benzonitrile); BILR-355 BS (12-ethyI-8-[2-(l-hydroxy-quinolin-4-yloxy)-ethyl]-5-methyl-n,12-dihydro-5H-l,5,10,12-tetraaza-dibenzo[a,e]cycloocten-6-one; PHI-236 (7-bromo-3-[2-(2,5-dimethoxy-phenyl)-ethyl]-3,4-dihydro-1 H-pyrido[ 1 ;2-a][- 1,3,5]triazine-2-thione) and PHI-443, 1-(5-bromo-pyridin-2-yl)-3-(2-thiophen-2-yl-ethyl)-thiourea.
6. A pharmaceutical composition according to any one of the preceding claims, wherein the protease inhibitors comprises one or more of saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir; nelfinavir; lasinavir; palinavir; darunavir; tipranavir; DMP450, BMS-2322623, GS3333; KNI-413; KNI-272; LG-71350; CGP-61755; PD 173606; PD 177298; PD 178390; PD 178392; U-140690: and AG-1549 N-cycloalkylglycines, α-hydroxyarylbutanamides; α-hydroxy-y-[(carbocyclic- or heterocyclic-substituted)amino)carbonyl]alkanamide derivatives; y-hydroxy-2-(fluoroalkylaminocarbonyl)-l-piperazinepentanamides; dihydropyrone derivatives and a- and p-amino acid hydroxyethylamino sulfonamides; and N-aminoacid substituted L-lysine derivatives.
7. A pharmaceutical composition according to any one of the preceding claims, wherein the integrase inhibitor comprises one or more of raltegravir, elvitegravir.
8. A pharmaceutical composition according to any one of the preceding claims, wherein the antiretroviral agent includes emtricitabine.
9. A pharmaceutical composition according to any one of the preceding claims, wherein the antiretroviral agent includes tenofovir, preferably tenofovir disoproxil fumarate.
10. A pharmaceutical composition according to any one of the preceding claims, wherein the antiretroviral agent includes efavirenz.
11. A pharmaceutical composition according to any one of the preceding claims, wherein the antiretroviral agent includes rilpivirine.
12. A pharmaceutical composition according to any one of the preceding claims, wherein the antiretroviral agent includes tenofovir, preferably tenofovir disoproxil fumarate; efavirenz; and emtricitabine.

13. A pharmaceutical composition according to any one of the preceding claims, wherein the antiretroviral agent includes rilpivirine and tenofovir.
14. A pharmaceutical composition according to any one of the preceding claims, wherein the antiretroviral agent includes rilpivirine, emtricitabine and tenofovir.
15. A pharmaceutical composition according to any one of the preceding claims comprises one or more of antiretroviral agent and rilpivirine.
16. A pharmaceutical composition according to any preceding claim, which is formulated for oral, parenteral, sublingual, inhalation, rectal, nasal, vaginal, transdermal, topical administration and the like.
17. A pharmaceutical composition substantially herein described with reference to the accompanying examples.