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 an immunomodulator and anti-retroviral 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 aiso 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 cfass 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®), lamivudine 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®), peptidomimetic 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 further. 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. However, 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 concerns 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.
Curcumin (diferuloylmethane) is the yellow pigment in turmeric (Curcuma longa L.) that is widely used as a spice, food coloring (curry) and preservative. Curcumin exhibits a variety of pharmacological effects including antitumor, anti-inflammatory, and anti-infectious activities and is currently in clinical trials for AIDS patients. (A. Mujumdar, K.Raghavan, J. Weinstein, K. Kohn and Y. Pommier, Inhibition of Human Immunodeficiency Virus Type-1 Integrase by Curcumin, Biochemical Pharmacology, Vol. 49, No. 8. pp. 1165-1170, 1995).

Different pharmacological activities of Curcuma longa L. (Zingiberaceae), such as anti inflammatory, anti-human immunodeficiency virus, anti-bacteria, antioxidant effects and nematocidal activities have been described by CAC Araujo and LL Leon in Biological Activities of Curcuma longa L., Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 96(5): 723-728, July 2001.
A review focusing on certain pharmacological potentials about turmeric such as anti inflammatory, antimicrobial, anti-fertility, anticancer, anti diabetic, antioxidant, hypolipidemic, anti venom, anti hepato-toxic, nephroprotective, anticoagulant etc. have been described by J. Naizi, P. Poonia, V.Gupta, N. Kaur in Pharmacotherapeutics of Curcuma longa- A Potent Patent. International Journal Of Pharma Professional's Research, Voume 1, Issue 1, July 2010.
Curcumin and its boron complexes are modest inhibitors of HIV-1 and HIV-2 and has been described by Z. Sui, R. Salto, J. Li, C. Craik and P, Montellano in Inhibition of the HIV-1 and HIV-2 proteases by curcumin and curcumin boron complexes Bioorganic & Medicinal Chemistry, Volume 1, Issue 6, December 1993, Pages 415-422.
Structure models for the interaction of curcumin with HIV-I integrase (IN) and protease (PR) were investigated using computational docking by O. Vairagupta, P. Boonchoong, G. Morris, A. Aulson in Active site binding modes of curcumin in HIV-1 protease and integrase, Bioorganic & Medicinal Chemistry Letters 15 (2005) 3364-3368.
Biological actions and medicinal applications of turmeric and curcumin are described by I. Chattopadhyay, K. Biswas, U. Bandyopadhyay and R. Banerjeein Turmeric and curcumin: Biological actions and medicinal applications, Current Science. Vol. 87, No. 1, 10 July 2004.
Traditional Indian medicine and homeopathy has been commonly used by most practitioners and also 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/A1DS: a review of the literature, AIDS Research and Therapy 2008, 5:25).
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.
EP1299406 relates to curcumin derivatives having improved water solubility as compared to curcumin, which are characterized in that the curcumin part is linked to a saccharide. EP1299406 further discloses medicaments containing these derivatives and their use for treating diseases associated with a retrovirus infection such as HIV.
WO2007069204 discloses antiviral, virucidal and immunomoduiant composition made of officinal plants Curcuma longa, Eucalyptus globulus, Vinca rosea, Illicium verum, Albizia gummifera, and Zea mais for the treatment of viral origin diseases, particularly HIV infection.
WO05020958 discloses a lipid vehicle composition comprising curcumin, lipid(s) and an aqueous so/vent for aerosof delivery, useful for treating viral infections such as HIV.
US6696094 discloses a pharmaceutical composition for treating patients with HIV infection comprising Herba Hedyotidis diffusae (diffuse hedyotis), Rhizoma Bistortae (bistort rhizome), Rhizoma Polygoni Cuspidati (giant knotweed rhizome), Fructus Schisandrae (Chinese magnoliavine fruit), Rhizoma Menispermi (Asiatic moonseed rhizome). Radix Scutellariae (baical skullcap root); bovine biliary powder, Radix Curcumae (tumeric root-tuber), Fructus Crataegi (hawthorn fruit), Radix Notoginseng (sanqi), Fructus Lycii (barbary wolfberry fruit), Radix Scorphulariae (figwort root), Radix Angelicae sinensis (Chinese angelica) and Radix Astragali (mifkvetch root).
US7700584 discloses curcumol derivatives for prevention or treatment of tumor, and in medicaments for treatment of viral infections e.g. HIV, influenza, hepatitis and herpes.

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 HIV 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 pharmaceutical composition which is in an acceptable form and which provides reduced side effects, as well as is 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 Curcuma longa with at least one anti-retroviral agent.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising Curcuma longa with at least one anti-retroviral agent optionally with one or more pharmaceutically acceptable excipients.
According to a yet another aspect of the present invention there is provided a process of manufacturing the pharmaceutical composition comprising Curcuma longa with at least one anti-retroviral agent optionally with one or more pharmaceutically 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 the pharmaceutical composition comprising Curcuma longa and at least one anti-retroviral agent.
According to another aspect of the present invention there is provided a method of preventing, treating or prophylaxis of diseases caused by retroviruses, especially acquired

immune deficiency syndrome or an HIV infection, which method comprises administering to a patient in need thereof the pharmaceutical composition comprising Curcuma longa 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 and which 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 which 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 an herbal drug such as Curcuma longa 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 pharmaceutical composition comprising Curcuma longa and one or more antiretro viral agents.
In particular, the present invention provides a pharmaceutical composition comprising Curcuma longa and at least one anti-retroviral agent 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 Curcuma longa and one or more antiretroviral drugs as employed.
The terms "Curcuma longa" is used throughout the description in broad sense to include not only Curcuma longa per se but also the extract prepared using any parts of the plant

such as roots, stem, flower, fruit may be used. Any suitable commercially available Curcuma longa extract may also be used provided that the said extract possesses immune stimulating activity.
For the purpose of the present invention, all parts of the plant of Curcuma longa may be used to obtain the extract.
For the purpose of the present invention, suitable extract of Curcuma longa 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.
Curcuma Longa commonly known as Turmeric belongs to Zingibearaceae family and contains curcumin (diferuloylmethane) as the major constituent having a chemical name as (1E, 6E)-l, 7-bis (4-hydroxy-3-methoxyphenyI) -1, 6-heptadiene-3, 5 -dione. Curcumin can exist in at least two tautomeric forms, keto and enol.

Turmeric also contains protein (6.3%), fat (5.1%), minerals (3.5%), carbohydrates (69.4%) and moisture (13.1%). Phenolic diketone, curcumin (diferuloylmethane) (3-4%) is responsible for the yellow colour, and comprises curcumin 1 (94%), curcumin II (6%) and curcumin III (0.3%). Other phenolic diketones demethoxycurcumin and bis-demethoxycurcumin have also been isolated from the rhizomes of Curcuma longa. Presence of tumerones (a and b), curdione, curzerenone, mono- and di-demethoxycurcumin have been reported in the rhizomes. The essential oil (5.8%) obtained by steam distillation of rhizomes has α-phellandrene (1%), sabinene (0.6%), cineol (1%), borneol (0.5%), zingiberene (25%) and sesquiterpines (53%). The essential oils of leaves of Curcuma longa have been analyzed by GLC (Perkin-Elmer auto-system fitted with capillary column carbowax 20 m of 50 m length flux ionization detector) and

reported to contain α-pinene. β-pinene, sabinene, myrcene, α-phellandrene, l,8-cineole,p-
cymene, C8-aldehyde, Hnalool, caryophyllene, geraniol and methyl heptanone, one novel
sesquiterpene with new skeleton, (6S)-2-methyl-6-(4-hydroxyphenyl-3-methyI)-2-hepten-
4-one, two new bisabolane sesquiterpenes, (6S)-2-methyl-6-(4-hydroxyphenyl)-2-hepten-
4-one, (6S)-2-methyl-6-(4-formylphenyl)-2-hepten-4-one, and two calebin derivatives,
4"-(4'"-hydroxyphenyl-3,"-methoxy)-2"-oxo-3"-butenyI-3-(4'-hydroxyphenyl)-propenoate
and 4"-(4'"-hydroxyphenyl)-2"-oxo-3"-butenyl-3-(4,-hydroxyphenyl-3,-methoxy)-
propenoate.
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 Curcuma longa
(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" (NRTIs) 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.
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-1 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, α-
hydroxyarylbutanamides by Enanta Pharmaceuticals; a-hydroxy-y-[[(carbocyclic- or
heterocyclic-substituted)amino)carbonyl]alkanamide derivatives; y-hydroxy-2-
(fluoroalkylaminocarbonyl)-l-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-0358I54 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 (NNRTls) that may be employed
in the pharmaceutical composition of the present invention may comprise nevirapine,
rilpivirine, delaviridine, efavirenz, etravirine. Other NNRTls currently under investigation
include PNU-142721, a furopyridjne-thiopyrimide under development by Pfizer;
capravirinc (S-l}53 or AG-i 549; 5-(3,5-dich}orophenyl)-thio-4-isopropyl-1-(4-
pyridyI)methyl-lH-imidazol-2- -ylmethyl carbonate) by Shionogi and Pfizer; emivirine
[MKC-442; (1-(ethoxy-methyl)-5-(I-methylethyl)-6-(phenylmethyl)-(2,4(lH,3H)-
pyrimid- inedione)] by Mitsubishi Chemical Co. and Triangle Pharmaceuticals; (+)-
calanolide A (NSC-67545 I) 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-(1-hydroxy-
quinolin-4-yloxy)-ethyl]-5-methyl-l 1,12-dihydro- -5H-1,5,10,12-tetraaza-
dibenzo[a,e]cycloocten-6-one by Boehringer-fngieheim; 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 (TMC-278, l-(5-bromo-pyridin-2-yl)-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 Curcuma longa 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 Curcuma longa 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 Curcuma longa and at least one non-nucleoside reverse transcriptase inhibitor (NNRTI) with one or more pharmaceuticaliy acceptable excipient. Preferably the NNRTI is efavirenz or rilpivirine.
In a further embodiment, the pharmaceutical composition according to the present invention comprises Curcuma longa, 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 pharmaceuticaliy acceptable excipient. Preferably, the said combination comprises Curcuma longa, tenofovir, efavirenz, emtricitabine with one or more pharmaceuticaliy acceptable excipient.
In another embodiment, the pharmaceutical composition according to the present invention comprises Curcuma longa 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 Curcuma longa, tenofovir, rilpivirine with one or more pharmaceutically acceptable excipient.
In yet another embodiment, the pharmaceutical composition according to the present invention comprises Curcuma longa 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 Curcuma longa, tenofovir, rilpivirine, emtricitabine with one or more pharmaceutically acceptable excipient.
In a further embodiment, the pharmaceutical composition according to the present invention comprises Curcuma longa 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 Curcuma longa, 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 Curcuma longa 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 Curcuma longa, efavirenz with one or more anti-retroviral agent and one or more pharmaceutically acceptable excipient.
The amount of Curcuma longa and antiretroviral agent that may be combined with suitable pharmaceutically acceptable excipients to produce a 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 Curcuma longa and antiretroviral agents which may be administered simultaneously, sequentially or separately.
The pharmaceutical composition according to 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 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
actives 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 form, including but not limited to 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 actives 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, such as not limited to, lubricating agents, fillers, glidants, anti-adherents, lubricants, binders, disintegrants.
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.
Suitable excipients may be used for formulating the various dosage forms according to the present invention.
In one aspect of the present invention the pharmaceutical invention may be formulated as a solid dosage form.
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, microcrystalline 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 pharmaceutical!)' 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 arable, 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 pharmaceutical composition of the present invention, may also be formulated for parenteral administration (e.g., by injection, for example continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The formulation may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain agents such as suspending, stabilizing and/or dispersing 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 fluorocarbon 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 Curcuma longa to 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 recta) temperature and will therefore melt in the rectum and release the drug.
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 comprising administering to a patient in need thereof the pharmaceutical composition comprising Curcuma longa and at least one anti-retroviral agent.
In a further 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 Curcuma longa 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 Curcuma longa 0.5

3 Disodium edetate 0.05
4 Citric acid 1.00
5 Methyl Paraben 0.18
6 Propyl Paraben 0.02
7 Glycerin 20.0
8 Hydroxy Ethyl Cellulose 2.00
9 Purified Water Up to 100%
10 Sodium Hydroxide Up to pH 4.5
11 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 dear 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. Curcuma longa was 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 singfe plasticizer or to combinations of two or more plasticizer, and the like.

WE CLAIM:
1. A pharmaceutical composition comprising a combination of Curcuma Longa 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-p-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-dichlorophenyl)-thio-4-isopropy]-l-(4-pyridyl)methyl-lH-imidazol-2- -ylmethyl carbonate); emivirine; (l-(ethoxy-methyl)-5-(l-methylethyl)-6-(phenylmethyl)-(2,4tlH,3H)-pyrimid- inedione)]; (+)-calanolide A (NSC-67545 I) and B, coumarin derivatives; dapivirine; 4-{4-[4-((E)-2-cyano-vinyl)-2,6-dimethyl-phenylamino]-pyrimidin-2-ylamino-}-benzonitrile); BILR-355 BS (12-ethyl-8-[2-(l-hydroxy-quinolin-4-yloxy)-ethyl]-5-methyl-l 1,12-

dihydro-5H-l,5,10,12-tetraaza-dibenzo[a,e]cycloocten-6-one; PH1-236 (7-bromo-3-[2-(2,5-dimethoxy-phenyl)-ethyl]-3,4-dihydro-lH-pyrido[l,2-a][- l,3,5]triazine-2-thione) and PHI-443, l-(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-6I755; PD 173606; PD 177298; PD 178390; PD 178392; U-I40690; and AG-1549 N-cycloalkylglycines, a-hydroxyarylbutanamides; a-hydroxy-y-[(carbocyclic- or heterocyclic-substituted)amino)carbonyl]alkanamide derivatives; Y-hydroxy-2-(fluoroaIkylaminocarbonyl)-l-piperazinepentanamides; dihydropyrone derivatives and α- and β-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 an tiretro viral agent includes efavirenz.
11. A pharmaceutical composition according to any one of the preceding claims, wherein the anti retroviral 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, rectal, nasal, vaginal, transdermal, topical administration.
17. A pharmaceutical composition substantially herein described with reference to the accompanying examples.