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WO 2014/184553 Al 20 November 2014 (20.11.2014) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/184553 Al 20 November 2014 (20.11.2014) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/34 (2006.01) A61K 31/535 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/427 (2006.01) A61P 31/18 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/513 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/GB20 14/05 1478 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 14 May 2014 (14.05.2014) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (25) Filing Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (26) Publication Language: English ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 1749/MUM/2013 15 May 2013 (15.05.2013) IN kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicant: CIPLA LIMITED [—/IN]; Cipla House, Pen UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, insula Business Park, Ganpatrao Kadam Marg, Lower TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Parel, Mumbai-400 013 (IN). EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (71) Applicant (for M W only): TURNER, Craig Robert TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, [GB/GB]; 235 High Holborn, London Greater London KM, ML, MR, NE, SN, TD, TG). WC1V 7LE (GB). Published: (72) Inventors: PURANDARE, Shrinivas Madhukar; B/25, Naperol Towers, Opposite R.A., Kidwai Road, Opposite — with international search report (Art. 21(3)) Gyaneshwar Vidyalaya, Wadala, Maharashtra, Mumbai — before the expiration of the time limit for amending the 400 031 (IN). MALHOTRA, Geena; 4 Anderson House, claims and to be republished in the event of receipt of Opposite Mazgaon Post Office, Mazgaon, Maharashtra, amendments (Rule 48.2(h)) Mumbai 400 010 (IN). (74) Agent: A. A. THORNTON & CO; 10 Old Bailey, Lon don EC4M 7NG (GB). (54) Title: PHARMACEUTICAL ANTIRETROVIRAL COMPOSITIONS (57) Abstract: The present invention relates to pharmaceutical antiretroviral compositions comprising a combination of antiretrovir - al agents, the manufacturing process thereof and use of the said compositions for the prevention, treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection. PHARMACEUTICAL ANTIRETROVIRAL COMPOSITIONS FIELD OF INVENTION The present invention relates to pharmaceutical antiretroviral compositions comprising a combination of antiretroviral agents, the manufacturing process thereof and use of the said compositions for the prevention, treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection. BACKGROUND AND PRIOR ART Demographically the second largest country in the world, India also has the third largest number of people living with HIV/AIDS. The total number of people living with HIV (PLHIV) in India is estimated at 2.4 million with uncertainty bounds of 1.93 to 3.04 million in 2009. Children under 15 years of age account for 4.4% of all infections, whilst people aged 15 to 49 years account for 82.4% of all infections. Thirty-nine percent of all HIV infections are estimated to be among women. This amounts to 0.93 million women with HIV in India. Acquired Immune Deficiency Syndrome (AIDS) causes a gradual breakdown of the body's immune system as well as progressive deterioration of the central and peripheral nervous systems. Since its initial recognition in the early 1980's, AIDS has spread rapidly and has now reached epidemic proportions within a relatively limited segment of the population. Intensive research has led to the discovery of the responsible agent, human T- lymphotropic retrovirus 111 (HTLV-1 11), now more commonly referred to as the human immunodeficiency viruses or HIV. Human immunodeficiency virus (HIV) is the etiological agent of Acquired Immune Deficiency Syndrome (AIDS) that has created a major health care problem not only in India but also globally. HIV is a member of the class of viruses known as retroviruses. The retroviral genome is composed of RNA, which is converted to DNA by reverse transcription. This retroviral DNA is then stably integrated into a host cell's chromosome and, employing the replicative processes of the host cells, produces new retroviral particles and advances the infection to other cells. HIV appears to have a particular affinity for the human T- 4 lymphocyte cell which plays a vital role in the body's immune system. HIV infection of these white blood cells depletes this white cell population. Eventually, the immune system is rendered inoperative and ineffective against various opportunistic diseases. The current strategy recommended for the treatment of HIV infection is Highly Active Antiretroviral Therapy (HAART). HAART normally consists of a combination of three or more antiretroviral drugs (ARV) taken together. Currently available antiretroviral drugs for the treatment of HIV include nucleoside reverse transcriptase inhibitors (NRTI) or approved single pill combinations: zidovudine or AZT (Retrovir®), didanosine or DDI (Videx®), stavudine or D4T (Zenith®), lamivudine or 3TC (Epivir®), zalcitabine or DDC (Hivid®), abacavir sulphate (Ziagen®), tenofovir disoproxil fumarate salt (Viread®), emtricitabine (Emtriva®), Combivir® (contains 3TC and AZT), Trizivir® (contains abacavir, 3TC and AZT); non-nucleoside reverse transcriptase inhibitors (NNRTI): nevirapine (Viramune®), delavirdine (Rescriptor®) and efavirenz (Sustiva®), peptidomimetic protease inhibitors or approved formulations: saquinavir (Invirase®, Fortovase®), indinavir (Crixivan®), ritonavir (Norvir®), nelfinavir (Viracept®), amprenavir (Agenerase®), atazanavir (Reyataz®), fosamprenavir (Lexiva®), Kaletra® (contains lopinavir and ritonavir), one fusion inhibitor enfuvirtide (T-20, Fuzeon®), Truvada® (contains Tenofovir and Emtricitabine) and Atripla® (contains fixed- dose triple combination of tenofovir, emtricitabine and efavirenz). The goal of HAART therapy is to maximize viral suppression thus limiting and reversing damage to the immune system, leading to decline of opportunistic infections. The durability of response depends on various factors such as viral, drug and patient related factors. However, the most important patient related factor is adherence, to ensure the success of HAART therapy. The HIV therapy is a life-long therapy coupled with high levels of adherence to the same. This is rather a demanding task for HIV infected patients due to various reasons such as low morale, social stigma, low immunity attributed to the disease. Further, the therapy may involve use of different drug combinations, which are difficult to adhere, because of the different dosage forms for administering each such as antiretroviral drug separately. This is particularly of importance in case of elderly patients. Further some studies have shown that adherence to prescribed drugs over long treatment periods is generally poor. (Jintanat A . et al. Swiss HIV Cohort Study. Failures of 1 week on, 1 week off antiretroviral therapies in a randomized trial AIDS, 2003; 17:F33-F37). Hence, such non-adherence to HAART can lead to rebound in viral replication and, in presence of sub-optimal drug concentration may lead to rapid development of drug resistance. This development of drug resistance can be disastrous because of the complexity and cost associated with second line regimens and the potential for transmission of drug resistant virus in the community. For most of the therapeutic agents, to produce systemic effects, the oral route still represents the preferred way of administration, owing to its several advantages and high patient compliance as compared to any other routes of administration. Tablets and hard gelatin capsules still constitute a major portion of drug delivery systems that are currently available. However, many patient groups such as the elderly, children, and patients who are mentally retarded, uncooperative, nauseated, or on reduced liquid-intake/diets have difficulties swallowing the dosage forms such as tablets and hard gelatin capsules. Further, those who are traveling or have little access to water are similarly affected. Also, the route of drug administration, appearance, color, taste, tablet size and dosing regimen are most important parameters that govern patient compliance. Especially, the geriatric and pediatric patients experience difficulty in swallowing larger sized tablets wherein large size tablet may result in esophageal damage due to its physical characteristics if it is not swallowed properly, which ultimately leads to poor patient compliance. Also, oral administration of bitter drugs with an acceptable degree of palatability is a key issue for health care providers, especially for pediatric patients. Further, there has been an enhanced demand for dosage forms that are more patient- friendly and patient compliant. Since the development cost of a new drug molecule is very high, efforts are now being made to focus on the development of new drug dosage forms for existing drugs with improved safety and efficacy together with reduced dosing frequency as well as which are cost-effective. Although, different treatment methods and dosage regimens have been framed in order to increase the patient adherence for treatment of HIV, there still remains a critical need for developing improved dosage forms such as a kit composition or dosage form by which a patient is encouraged to adhere to his daily dosage regimen.
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