WO2014184553A1 - Pharmaceutical antiretroviral compositions - Google Patents

Pharmaceutical antiretroviral compositions Download PDF

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Publication number
WO2014184553A1
WO2014184553A1 PCT/GB2014/051478 GB2014051478W WO2014184553A1 WO 2014184553 A1 WO2014184553 A1 WO 2014184553A1 GB 2014051478 W GB2014051478 W GB 2014051478W WO 2014184553 A1 WO2014184553 A1 WO 2014184553A1
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WIPO (PCT)
Prior art keywords
pharmaceutical antiretroviral
darunavir
ritonavir
composition according
antiretroviral composition
Prior art date
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PCT/GB2014/051478
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English (en)
French (fr)
Inventor
Shrinivas Madhukar Purandare
Geena Malhotra
Original Assignee
Cipla Limited
Turner, Craig Robert
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Application filed by Cipla Limited, Turner, Craig Robert filed Critical Cipla Limited
Publication of WO2014184553A1 publication Critical patent/WO2014184553A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • 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.
  • India 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.
  • AIDS Acquired Immune Deficiency Syndrome
  • HTLV-1 1 1 human T- lymphotropic retrovirus 1 1 1
  • HIV human immunodeficiency viruses
  • HIV Human immunodeficiency virus
  • AIDS Acquired Immune Deficiency Syndrome
  • 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.
  • HAART Highly Active Antiretroviral Therapy
  • ARV antiretroviral drugs
  • nucleoside reverse transcriptase inhibitors 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 (Rescript
  • HAART therapy 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.
  • adherence 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.
  • 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.
  • 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.
  • the route of drug administration, appearance, color, taste, tablet size and dosing regimen are most important parameters that govern patient compliance.
  • 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.
  • oral administration of bitter drugs with an acceptable degree of palatability is a key issue for health care providers, especially for pediatric patients.
  • kits comprising compositions of HIV drugs in line of the therapy or dosing regimens generally recommended.
  • the present invention attempts to overcome the problems of patient adherence for the treatment of HIV.
  • the object of the present invention is to provide a pharmaceutical antiretroviral composition comprising at least one reverse transcriptase inhibitor or at least one integrase inhibitor and at least one protease inhibitor, preferably wherein said composition is in the form of a kit.
  • Another object of the present invention is to provide a pharmaceutical antiretroviral composition comprising at least one reverse transcriptase inhibitor or at least one integrase inhibitor and at least one protease inhibitor, optionally with one or more pharmaceutically acceptable excipients, preferably wherein said composition is in the form of a kit comprising a plurality of antiretroviral agents which have been co- formulated, or a plurality of dosage forms containing one or more antiretroviral agents.
  • Yet another object of the present invention is to provide a pharmaceutical antiretroviral composition for once or twice a day administration comprising at least one reverse transcriptase inhibitor or at least one integrase inhibitor and at least one protease inhibitor, optionally with one or more pharmaceutically acceptable excipients, preferably wherein said composition is in the form of a kit comprising a plurality of antiretroviral agents which have been co-formulated, or a plurality of dosage forms containing one or more antiretroviral agents.
  • Yet another object of the present invention is to provide a process for manufacturing a pharmaceutical antiretroviral composition for once or twice daily administration comprising at least one reverse transcriptase inhibitor or at least one integrase inhibitor and at least one protease inhibitor, optionally with one or more pharmaceutically acceptable excipients, preferably wherein said composition is in the form of a kit.
  • Another object of the present invention is to provide a method of prevention, treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, which method comprises administering a pharmaceutical antiretroviral composition comprising at least one reverse transcriptase inhibitor or at least one integrase inhibitor and at least one protease inhibitor to a patient in need thereof, preferably wherein said composition is in the form of a kit.
  • Yet another object of the present invention is to provide the use of a pharmaceutical antiretroviral composition
  • a pharmaceutical antiretroviral composition comprising at least one reverse transcriptase inhibitor or at least one integrase inhibitor and at least one protease inhibitor for the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, wherein said composition is for once or twice a day administration and is preferably in the form of a kit.
  • the present invention provides a pharmaceutical antiretroviral composition
  • a pharmaceutical antiretroviral composition comprising:
  • At least one reverse transcriptase inhibitor comprising: zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine; emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir; elvucitabine; tenofovir; festinavir; racivir; lersivirine; rilpivirine; etravirine; SP1093V and/or stampidine, and/or
  • At least one integrase inhibitor comprising: raltegravir; dolutegravir and/or elvitegravir, and
  • At least one protease inhibitor comprising: saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir; fosamprenavir; darunavir; and/or tiprinavir,
  • composition optionally further comprises one or more pharmaceutically acceptable excipients.
  • the zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine; emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir; elvucitabine; tenofovir; festinavir; racivir; lersivirine; rilpivirine; etravirine; SP 1093V; stampidine; raltegravir elvitegravir; dolutegravir; saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir; indinavir; nelfinavir; atazanavir; lasinavir; palinavir; fosamprenavir; darunavir; and/or tiprinavir may be in the form of a pharmaceutically acceptable derivative thereof
  • the pharmaceutically acceptable derivative may be a salt, solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, enantiomer, polymorph or prodrug.
  • the reverse transcriptase inhibitor may comprise: lamivudine; zidovudine; tenofovir; emtricitabine and/or abacavir.
  • the integrase inhibitor may comprise: raltegravir and/or dolutegravir.
  • the protease inhibitor may comprise: ritonavir and/or darunavir.
  • the pharmaceutical antiretroviral composition may comprise lamivudine, zidovudine, darunavir and ritonavir.
  • the pharmaceutical antiretroviral composition may comprise lamivudine, tenofovir, darunavir and ritonavir.
  • the pharmaceutical antiretroviral composition may comprise tenofovir, emtricitabine, darunavir and ritonavir.
  • the pharmaceutical antiretroviral composition may comprise abacavir, lamivudine, darunavir and ritonavir.
  • the pharmaceutical antiretroviral composition may comprise raltegravir or dolutegravir, darunavir and ritonavir.
  • the pharmaceutical antiretroviral composition may comprise: at least two reverse transcriptase inhibitors, wherein the at least two reverse transcriptase inhibitors are provided in a separate single unit dosage form; at least two protease inhibitors, wherein the at least two protease inhibitors are provided in a separate single unit dosage form; and/or at least one integrase inhibitor, wherein the at least one integrase inhibitor is provided in a separate single unit dosage form.
  • the pharmaceutical antiretroviral composition may comprise darunavir and ritonavir provided in a separate single unit dosage form.
  • the pharmaceutical antiretroviral composition may comprise raltegravir or dolutegravir provided in a separate single unit dosage form.
  • the pharmaceutical antiretroviral composition may comprise lamivudine and zidovudine provided in a separate single unit dosage form.
  • the pharmaceutical antiretroviral composition may comprise tenofovir and emtricitabine provided in a separate single unit dosage form.
  • the pharmaceutical antiretroviral composition may comprise abacavir and lamivudine provided in a separate single unit dosage form.
  • the pharmaceutical antiretroviral composition may comprise lamivudine and tenofovir provided in a separate single unit dosage form.
  • the composition may be provided as a kit comprising instructions for administration.
  • the pharmaceutical antiretroviral composition may be for once or twice daily administration.
  • the at least one reverse transcriptase inhibitor, the at least one integrase inhibitor and the at least one protease inhibitor may be provided in a dosage form selected from: a tablet, a mini-tablet, sprinkles comprising a plurality of particles, a capsule, or a liquid.
  • the tablet may be a disintegrating tablet, a dissolving tablet, a dispersible tablet, a mouth-dissolving tablet, a tablet for oral suspension, an immediate release tablet, an extended release tablet, an immediate and extended release tablet, or a matrix tablet.
  • the plurality of particles of the sprinkles may be provide in the form of granules, powders, powders for reconstitution, beads, pellets, mini-tablets, film-coated tablets, film coated tablets MUPS, orally disintegrating MUPS, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, effervescent granules, or microspheres.
  • the sprinkles may be provided in a sachet, a packet or a capsule.
  • the one or more pharmaceutically acceptable excipient may comprise: a diluent, filler, bulking agent, disintegrant, binder, glidant, anti-adherent, lubricant, water soluble polymer, water insoluble polymer, water swellable polymer, plasticizer, and any mixture thereof.
  • the present invention provides a process for preparing the pharmaceutical antiretroviral composition according to any preceding claim, comprising: admixing the at least one reverse transcriptase inhibitor or the at least one integrase inhibitor and the at least one protease inhibitor, optionally with the one or more pharmaceutically acceptable excipient.
  • the present invention provides a method of preventing, treating or prophylaxis of a disease caused by a retrovirus, specifically acquired immune deficiency syndrome or an HIV infection, which method comprises administering to a patient in need thereof a pharmaceutical antiretroviral composition of the present invention.
  • the present invention provides a pharmaceutical composition of the invention for use in the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, in a patient in need thereof.
  • the present invention provides a use of the pharmaceutical antiretroviral composition of the invention for the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection.
  • a pharmaceutical antiretroviral composition comprising:
  • At least one reverse transcriptase inhibitor comprising zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine; emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir; elvucitabine; tenofovir; festinavir; racivir; lersivirine; rilpivirine; etravirine; SP 1093V and stampidine, and/or
  • At least one integrase inhibitor comprising raltegravir; elvitegravir; and/or dolutegravir and
  • At least one protease inhibitor comprising saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir;; fosamprenavir; darunavir; and/or tipranavir, and optionally
  • said composition is for once or twice a day administration and may be in the form of a kit comprising a plurality of antiretroviral agents have been co-formulated, or a plurality of dosage forms containing one or more antiretroviral agents.
  • a pharmaceutical antiretroviral composition comprising:
  • At least one reverse transcriptase inhibitor comprising zidovudine, lamivudine, tenofovir, abacavir and emtricitabine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; or
  • At least one integrase inhibitor comprising raltegravir or dolutegravir or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof and
  • At least one protease inhibitor comprising darunavir and ritonavir, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof;
  • said composition is for once or twice a day administration and may be in the form of a kit comprising a plurality of antiretroviral agents have been co-formulated, or a plurality of dosage forms containing one or more antiretroviral agents.
  • a process of manufacturing a pharmaceutical antiretroviral composition comprising: (i) at least one reverse transcriptase inhibitor comprising zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine; emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir; elvucitabine; tenofovir; festinavir; racivir; lersivirine; rilpivirine; etravirine; SP 1093V and stampidine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; or
  • At least one integrase inhibitor comprising raltegravir; elvitegravir; dolutegravir or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof and
  • protease inhibitor comprising saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir; fosamprenavir; darunavir; and tipranavir, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and optionally
  • composition is for once or twice a day administration and is preferably in the form of a kit.
  • a process of manufacturing a pharmaceutical antiretroviral composition comprising:
  • At least one reverse transcriptase inhibitor comprising zidovudine, lamivudine, tenofovir, abacavir and emtricitabine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; or
  • At least one integrase inhibitor comprising raltegravir or dolutegravir or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof and
  • At least one protease inhibitor comprising darunavir and ritonavir, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and optionally
  • composition is for once or twice a day administration and is preferably in the form of a kit.
  • a pharmaceutical antiretroviral composition comprising:
  • At least one reverse transcriptase inhibitor comprising zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine; emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir; elvucitabine; tenofovir; festinavir; racivir; lersivirine; rilpivirine; etravirine; SP 1093V and stampidine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; or
  • At least one integrase inhibitor comprising raltegravir; elvitegravir; dolutegravir or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof and
  • At least one protease inhibitor comprising saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir; fosamprenavir; darunavir; and tipranavir, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and optionally
  • composition is in the form of a kit.
  • a pharmaceutical antiretroviral composition comprising:
  • At least one reverse transcriptase comprising zidovudine, lamivudine, tenofovir, abacavir and emtricitabine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; or
  • At least one integrase inhibitor comprising raltegravir dolutegravir or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof and
  • At least one protease inhibitor comprising darunavir and ritonavir, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and optionally
  • composition is for once or twice a day administration and is preferably in the form of a kit.
  • a pharmaceutical antiretroviral composition comprising:
  • At least one reverse transcriptase inhibitor comprising zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine; emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir; elvucitabine; tenofovir; festinavir; racivir; lersivirine; rilpivirine; etravirine; SP 1093V and stampidine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; or
  • At least one integrase inhibitor comprising raltegravir; elvitegravir; dolutegravir or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof and
  • protease inhibitor comprising saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir; fosamprenavir; darunavir; and tipranavir, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; and optionally
  • composition for the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, wherein said composition is for once or twice a day administration and is preferably in the form of a kit.
  • a pharmaceutical antiretroviral composition comprising:
  • At least one reverse transcriptase inhibitor comprising zidovudine, lamivudine, tenofovir, abacavir and emtricitabine, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof; or
  • At least one integrase inhibitor comprising raltegravir dolutegravir or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof and
  • At least one protease inhibitor comprising darunavir and ritonavir, or a pharmaceutically acceptable salts, solvates, hydrates, esters, enantiomers, polymorphs, prodrugs, complexes, derivatives thereof;
  • compositions for the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, wherein said composition is for once or twice a day administration and is preferably in the form of a kit.
  • a suitable pharmaceutical antiretroviral composition in the form of a once or twice a day composition, comprising at least one reverse transcriptase inhibitor or at least one integrase inhibitor and at least one protease inhibitor which would not only be convenient for patient administration, but would also maintain or improve patient adherence to the therapy.
  • the therapy for the treatment of HIV infection comprises a combination of actives such as nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors and protease inhibitors (Pis).
  • NRTIs nucleoside reverse transcriptase inhibitors
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • integrase inhibitors and protease inhibitors Pis
  • the dose regimen of these drugs is such that the patient needs to administer several drugs throughout the day and at different time intervals. Further, this dosage regimen has to be followed throughout the patient's lifetime. This long-term therapy may generally cause great inconvenience to the patient.
  • the patient is provided with the means that allows the patient to eliminate the inconvenience caused to him, such as remembering the administration of the medication, as well as the time at which it is to be administered.
  • the present invention provides a kit comprising a combination of NRTIs, NtRTIs, integrase inhibitors and Pis that provides the patient with his daily regimen of drugs in a single package. This further facilitates the patient in getting the drug regimen of the entire day in a single package, which also enables the patient to avoid carrying of numerous medications, and also confirms if the same are administered.
  • the kit of the present invention may comprise a single dosage form in which a plurality of antiretroviral agents have been co-formulated, or a plurality of dosage forms containing one or more antiretroviral agents.
  • the present invention thus provides a pharmaceutical antiretroviral composition
  • a pharmaceutical antiretroviral composition comprising at least one reverse transcriptase inhibitor or at least one integrase inhibitor and at least one protease inhibitor as a combined preparation in a kit form, for simultaneous or separate use in the treatment of an HIV infection.
  • the respective therapeutic agents of the combined preparation can be administered simultaneously, either in the same or different pharmaceutical composition or dosage form, or separately. If there is separate administration, it will also be appreciated that the subsequently administered therapeutic agents should be administered to a patient within a time-scale so as to achieve, or more particularly optimize, a synergistic therapeutic effect of such a combined preparation.
  • Preferred protease inhibitors that may be employed in a pharmaceutical antiretroviral composition of the present invention are darunavir and ritonavir.
  • NRTIs nucleoside reverse transcriptase inhibitors
  • NRTIs Preferred nucleoside reverse transcriptase inhibitors
  • the NRTI may be lamivudine and/or zidovudine.
  • the NRTI may be lamivudine and/or emtricitabine.
  • a preferred nucleotide reverse transcriptase inhibitor (NtRTI) that may be employed in a pharmaceutical antiretroviral composition of the present invention is tenofovir.
  • a preferred integrase inhibitor that may be employed in a pharmaceutical antiretroviral composition of the present invention is raltegravir or dolutegravir.
  • a preferred reverse transcriptase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is lamivudine.
  • a preferred reverse transcriptase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is zidovudine.
  • a preferred reverse transcriptase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is emtricitabine.
  • a preferred reverse transcriptase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is tenofovir.
  • a preferred reverse transcriptase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is abacavir.
  • a preferred integrase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is raltegravir.
  • a preferred integrase inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is dolutegravir.
  • a preferred protease inhibitor that may be employed in any pharmaceutical antiretroviral composition of the present invention is ritonavir.
  • the present invention may provide a pharmaceutical antiretroviral composition comprising lamivudine, zidovudine, darunavir and ritonavir.
  • said composition is formulated for, or suitable for, once or twice a day administration.
  • Said composition may be in the form of a kit.
  • the present invention may provide a pharmaceutical antiretroviral composition
  • a pharmaceutical antiretroviral composition comprising lamivudine, tenofovir, darunavir and ritonavir.
  • said composition is formulated for, or suitable for, once or twice a day administration.
  • Said composition may be in the form of a kit.
  • the present invention may provide a pharmaceutical antiretroviral composition
  • a pharmaceutical antiretroviral composition comprising tenofovir, emtricitabine, darunavir and ritonavir.
  • said composition is formulated for, or is suitable for, once or twice a day administration.
  • Said composition may be in the form of a kit.
  • the present invention may provide a pharmaceutical antiretroviral composition
  • a pharmaceutical antiretroviral composition comprising raltegravir or dolutegravir, darunavir and ritonavir.
  • said composition is formulated for, or is suitable for once or twice a day administration.
  • Said composition may be in the form of a kit.
  • the pharmaceutical antiretroviral composition in accordance with the present invention may be provided for use in the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, in a patient in need thereof.
  • any references herein to an antiretroviral agent for example, "zidovudine”; “didanosine”; “stavudine”; “lamivudine”; “abacavir”; “adefovir”; “lobucavir”; “entecavir”; “apricitabine”; “emtricitabine”; “zalcitabine”; “dexelvucitabine”; “alovudine”; “amdoxovir”; “elvucitabine”; “tenofovir”; "festinavir”; “racivir”; “lersivinne”; “nlpivirine”; “etravinne”; “SP 1093V”, "stampidine”, “raltegravir”, “elvitegravir”, “dolutegravir”, “saquinavir”; “ritonavir”; “nelfinavir”; “amprenavir”; “lopinavir”,
  • Suitable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes, and the like.
  • tenofovir as used herein by definition includes not only the phosphonic acid form, but also its prodrug form tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate.
  • the term "darunavir” as used herein by edition includes not darunavir per se, but also its solvates, such as darunavir ethanolate, and its hydrates, such as darunavir hydrate.
  • Tenofovir disoproxil fumarate is also known as PMPA.
  • Tenofovir DF is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir.
  • Tenofovir disoproxil fumarate is 9-[(R)-2-[[bis[[(isopropoxycarbonyl) oxy] methoxy] phosphinyl] methoxy] propyl] adenine fumarate (1 : 1).
  • Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate.
  • Tenofovir diphosphate inhibits the activity of HTV reverse transcriptase by competing with the natural substrate deoxyadenosine 5 '- triphosphate and, after incorporation into DNA, by DNA chain termination.
  • Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases alpha & beta and of mitochondrial DNA polymerase.
  • Tenofovir disoproxil fumarate is an analog of adefovir and is classified as a nucleotide reverse transcriptase inhibitor (NtRTI).
  • NtRTI nucleotide reverse transcriptase inhibitor
  • Tenofovir DF is a competitive inhibitor of other naturally occurring nucleotides, and its ultimate biological activity is viral DNA chain termination.
  • Tenofovir DF is a novel nucleotide analog with antiviral activity against both HIV and HBV.
  • tenofovir DF The mechanism of tenofovir DF is similar to that of nucleoside analogs, which interferes with reverse transcriptase and prevents translation of viral genetic material into viral DNA.
  • nucleoside analogs the nucleotide reverse transcriptase inhibitors are chemically pre-activated with the presence of phosphate group. Since the phosphorylation step is not necessary, nucleotide analogs can incorporate into viral DNA chain more rapidly than nucleoside analogs. More importantly, this will bypass a viral mechanism of nucleoside resistance.
  • a preferred dosage of tenofovir disoproxil for use in a pharmaceutical antiretroviral composition of the present invention is in an amount from about 75mg to 300 mg.
  • Emtricitabine is chemically known as 4-amino-5-fluoro-l- [2- (hydroxymethyl) - 1, 3- oxathiolan-5-yl] - pyrimidin-2-one, belongs to a category of nucleoside reverse transcriptase inhibitor (NRTI) which is used to treat infection by HIV-I. Specifically, emtricitabine inhibits HBV DNA polymerase and HIV-1 reverse transcriptase (RT) both in vivo and in vitro. Emtricitabine is anabolized to its triphosphate form which is the active moiety that inhibits the polymerase.
  • a preferred dosage of emtricitabine for use in a pharmaceutical antiretroviral composition of the present invention is in an amount form 9 mg to 300 mg.
  • Zidovudine chemically known as 3'-azido-3'deoxythymidine, is a pyrimidine nucleoside analogue, which is well established as an important and useful chemotherapeutic agent for the treatment and / or prophylaxis of HIV infections including related clinical conditions such as AIDS, AIDS-related complex (ARC), AIDS dementia complex (ADC) and also for the treatment of patients who have an asymptomatic HIV infection and who are anti-HIV antibody positive.
  • lamivudine also exhibits antiviral activity against other viruses such as HBV.
  • a preferred dosage of zidovudine for use in a pharmaceutical antiretroviral composition of the present invention is in an amount from about 60 mg to about 600 mg.
  • Lamivudine (also known as 3TC) is a synthetic nucleoside analogue, chemically known as (2R, cis)-4-amino-l-(2-hydroxymethyl-l, 3-oxathiolan-5-yl)-(lH)-pyrimidin-2- one.
  • 2R, cis is a synthetic nucleoside analogue, chemically known as (2R, cis)-4-amino-l-(2-hydroxymethyl-l, 3-oxathiolan-5-yl)-(lH)-pyrimidin-2- one.
  • L-TP lamivudine triphosphate
  • the principal mode of action of L-TP is the inhibition of HIV-I reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleoside analogue into viral DNA.
  • L-TP is a weak inhibitor of mammalian DNA polymerases (alpha) and (beta), and mitochondrial DNA polymerase (gamma).
  • Lamivudine has also been referred to as (-)-l-[(2R, 5S) 2-(Hy droxym ethyl)- 1,3- oxathiolan-5-yl] cytosine, (Hydroxymethyl)-l,3-oxathiolan-5-yl] cytosine and it has proven antiviral activity against human immunodeficiency virus (HIV) and other viruses such as hepatitis B.
  • a preferred dosage of lamivudine for use in a pharmaceutical antiretroviral composition of the present invention is in an amount from about 30 mg to about 300 mg.
  • Darunavir (TMC-1 14, UIC-94017) is chemically known as [(3R,3aS,6aR)-2,3,3a,4,5,6a- Hexahydrofuro[5,4-b]furan-3-yl]N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2- methylpropyl) amino]-3-hydroxy-l-phenylbutan-2 yljcarbamate
  • a preferred dosage of darunavir for use in a pharmaceutical antiretroviral composition of the present invention is in an amount from about 350 mg to about 1200 mg.
  • Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(l-methylethyl)-l - [2-(l- methylethyl)-4thiazolyl]- 3,6-dioxo-8,l l-bis(phenylmethyl)-2,4,7,12- tetraazatridecan- 13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,1 1R*)].
  • Ritonavir is a peptidomimetic inhibitor of the HIV-1 protease. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to production of noninfectious immature HIV particles.
  • a preferred dosage of ritonavir for use in a pharmaceutical antiretroviral composition of the present invention is in an amount from about 33 mg to about 100 mg.
  • Abacavir is a synthetic carbocyclic nucleoside analog and reverse transcriptase inhibitor which is used typically in combination with other agents in the therapy of the human immunodeficiency virus (HIV) infection.
  • the activated triphosphate metabolite of abacavir is incorporated into the viral DNA instead of the natural substrate deoxyguanosine, thereby inhibiting human immunodeficiency virus (HIV) reverse transcriptase (RT) and the replication of the viral DNA and infectious viral particles. This agent decreases HIV viral loads, retards or prevents the damage to the immune system, and reduces the risk of developing AIDS.
  • a preferred dosage of abacavir is from about 60 mg to about 600 mg.
  • Raltegravir is a human immunodeficiency virus integrase strand transfer inhibitor.
  • Raltegravir inhibits the catalytic activity of HIV- 1 integrase, an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus.
  • the provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection.
  • Raltegravir did not significantly inhibit human phosphoryltransferases including DNA polymerases ⁇ , ⁇ , and ⁇ .
  • a preferred dosage of raltegravir is from about 40 mg to about 1200 mg.
  • Dolutegravir is an orally active integrase inhibitor, and has been approved for the treatment of HIV infections. It is a HIV-1 integrase strand transfer inhibitor which inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid integration which is essential for the HIV replication cycle.
  • a preferred dosage of dolutegravir is from about 1 mg to about 100 mg.
  • the present invention provide a pharmaceutical antiretroviral composition
  • a pharmaceutical antiretroviral composition comprising lamivudine, zidovudine, darunavir and ritonavir in a kit form.
  • said composition is for once or twice a day administration.
  • the pharmaceutical antiretroviral composition in kit form may comprise a separate unit dosage form of lamivudine, a separate unit dosage form of zidovudine, a separate unit dosage form of darunavir and a separate unit dosage form of ritonavir.
  • the present invention may provide a pharmaceutical antiretroviral composition
  • a pharmaceutical antiretroviral composition comprising lamivudine, tenofovir, darunavir and ritonavir in a kit form.
  • said composition is for once or twice a day administration.
  • the pharmaceutical antiretroviral composition in kit form may comprise a separate unit dosage form of lamivudine, a separate unit dosage form of tenofovir, a separate unit dosage form of darunavir and a separate unit dosage form of ritonavir.
  • the present invention may provide a pharmaceutical antiretroviral composition
  • a pharmaceutical antiretroviral composition comprising emtricitabine, tenofovir, darunavir and ritonavir in a kit form.
  • said composition is for once or twice a day administration.
  • the pharmaceutical antiretroviral composition in kit form may comprise a separate unit dosage form of emtricitabine, a separate unit dosage form of tenofovir, a separate unit dosage form of darunavir and a separate unit dosage form of ritonavir.
  • the present invention may provide a pharmaceutical antiretroviral composition
  • a pharmaceutical antiretroviral composition comprising abacavir, lamivudine, darunavir and ritonavir in a kit form.
  • said composition is for once or twice a day administration.
  • the pharmaceutical antiretroviral composition in kit form may comprise a separate unit dosage form of abacavir, a separate unit dosage form of lamivudine, a separate unit dosage form of darunavir and a separate unit dosage form of ritonavir.
  • the present invention may provide a pharmaceutical antiretroviral composition
  • a pharmaceutical antiretroviral composition comprising raltegravir or dolutegravir, darunavir and ritonavir in a kit form.
  • said composition is for once or twice a day administration.
  • the pharmaceutical antiretroviral composition in kit form may comprise a separate unit dosage form of raltegravir a separate unit dosage form of darunavir and a separate unit dosage form of ritonavir.
  • the pharmaceutical antiretroviral composition in kit form may comprise a separate unit dosage form of dolutegravir a separate unit dosage form of darunavir and a separate unit dosage form of ritonavir.
  • the pharmaceutical antiretroviral composition of the composition of the present invention may comprise darunavir and ritonavir in a single unit dosage form.
  • the pharmaceutical antiretroviral composition of the present invention may comprise lamivudine and tenofovir in a single unit dosage form.
  • the pharmaceutical antiretroviral composition of the present invention may comprise lamivudine and zidovudine in a single unit dosage form.
  • the pharmaceutical antiretroviral composition of the present invention comprises tenofovir and emtricitabine in a single unit dosage form.
  • the pharmaceutical antiretroviral composition of the present invention comprises abacavir and lamivudine in a single unit dosage form.
  • the pharmaceutical antiretroviral composition of the present invention comprises raltegravir in a single unit dosage form. In any of the above compositions, where appropriate, the pharmaceutical antiretroviral composition of the present invention comprises dolutegravir in a single unit dosage form.
  • the pharmaceutical antiretroviral composition of the present invention comprises darunavir and ritonavir, raltegravir dolutegravir, lamivudine and tenofovir, lamivudine and zidovudine, tenofovir and emtricitabine, abacavir and lamivudine are each provided in a separate single unit dosage forms.
  • any two of the at least one reverse transcriptase inhibitor, the at least one integrase inhibitor and the at least one protease inhibitor may be provided in a single unit dosage form.
  • any three of the at least one reverse transcriptase inhibitor, the at least one integrase inhibitor and the at least one protease inhibitor are provided in a single unit dosage form.
  • compositions where appropriate, all of the at least one reverse transcriptase inhibitor, the at least one integrase inhibitor and the at least one protease inhibitor are provided in a single unit dosage form.
  • the antiretroviral agents When formulated as a single unit dose, the antiretroviral agents may initially be co- formulated with one or more pharmaceutically acceptable excipients to provide a single uniform composition or they may initially be formulated as individual compositions. When formulated individually, the individual compositions may subsequently be co- formulated as a single unit dosage form, where the unit dosage form may comprise two or more layers, each layer comprising a composition of at least one antiretroviral agent (i.e. the individually formulated compositions). Preferably, the single unit dosage form is suitable for once or twice daily administration.
  • the pharmaceutical antiretroviral composition according to the present invention are presented in solid dosage form, conveniently in unit dosage form, and include dosage form suitable for oral and buccal administration.
  • dosage forms such as liquid dosage forms and the like, may be envisaged under the ambit of the present invention.
  • Unit dosage forms are preferably in the form of a tablet (disintegrating tablet, dissolving tablet, dispersible tablets, mouth dissolving tablets, tablets for oral suspension immediate release tablets, extended release tablet, immediate and extended release tablets, matrix tablets), mini-tablet, granules, sprinkles (filled with powders, powders for reconstitution; beads; pellets; mini-tablets; film coated tablets; film coated tablets MUPS (multiple unit pellet system); orally disintegrating MUPS; pills; micro-pellets; small tablet units; MUPS; disintegrating tablets; dispersible tablets; granules; effervescent granules; microspheres) or capsules filled with (powders, powders for reconstitution; beads; pellets; mini-tablets; film coated tablets; film coated tablets MUPS; orally disintegrating MUPS; pills; micro-pellets; small tablet units; MUPS; disintegrating tablets; dispersible tablets; granules; effervescent granules; microspheres)
  • the pharmaceutical antiretroviral composition may be administered orally through known solid unit dosage forms including capsule and sachets or packets (filled with powders, powders for reconstitution; beads; pellets; mini-tablets; film coated tablets; film coated tablets MUPS; orally disintegrating MUPS; pills; micro-pellets; small tablet units; MUPS; disintegrating tablets; dispersible tablets; granules; effervescent granules; microspheres).
  • the capsules may be hard gelatin capsules.
  • Sachets or packets may be filled with powders, powders for reconstitution; beads; pellets; mini-tablets; film coated tablets; film coated tablets MUPS; orally disintegrating MUPS; pills; micro-pellets; small tablet units; MUPS; disintegrating tablets; dispersible tablets; granules; effervescent granules; microsphere that are suitable for direct administration.
  • the present invention may be administered as mini- tablets or granules filled in hard gelatin capsules, sachets or packets.
  • the mini-tablets or granules filled in such hard gelatin capsules, sachets or packets are directly administered or by sprinkling the mini-tablet or granules on regular meals.
  • the mini-tablets or granules filled in hard gelatin capsules, sachets or packets may be administered with liquid or semi-solid beverages such as but not limited to, fruit juices, water, milk, baby formulas, soft foods, apple sauce or yogurt and the like.
  • mini-tablets or granules may also optionally be coated.
  • mini-tablets or granules, according to the present invention may be film coated. More preferably, the mini-tablets or granules may be seal coated and then film coated and further filled in hard gelatin capsules, sachets or packets.
  • a tablet formulation is the preferred solid dosage form due to its greater stability, less risk of chemical interaction between different medicaments, smaller bulk, accurate dosage, and ease of production.
  • Solid unit dosage forms are preferably in the form of tablets but other conventional dosages such as powders, pellets, capsules, sachets or packets may fall within the scope of this invention.
  • Kit compositions of the type disclosed herein have an advantage over other packaged dosage forms since the patient always has access to the set of instructions for administration contained in the kit.
  • the inclusion of a set of instructions for administration has been shown to improve patient compliance.
  • the pharmaceutical antiretroviral composition may be administered simultaneously, separately or sequentially in a single unit dosage form wherein the drugs and excipients are present in one or more single layer tablets (such as a tablet or mini tablet in a capsule or sprinkle).
  • the pharmaceutical antiretroviral composition may be in the form of one or more bilayered or multilayered unit dosage forms.
  • the pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form comprising lamivudine and zidovudine and a further separate unit dosage form comprising darunavir and ritonavir.
  • the pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form comprising lamivudine and tenofovir and a further separate unit dosage form comprising darunavir and ritonavir.
  • the pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form comprising emtricitabine and tenofovir and a further separate unit dosage form comprising darunavir and ritonavir.
  • the pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form comprising abacavir and lamivudine and a further separate unit dosage form comprising darunavir and ritonavir.
  • the pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form comprising raltegravir and a further separate unit dosage form comprising darunavir and ritonavir.
  • the pharmaceutical antiretroviral composition in a kit form may comprise a separate unit dosage form comprising dolutegravir and a further separate unit dosage form comprising darunavir and ritonavir.
  • Suitable excipients may be used for formulating the various dosage forms according to the present invention.
  • pharmaceutically acceptable diluents or fillers for use in the pharmaceutical antiretroviral composition of the present invention may comprise one or more, but not limited to lactose (for example, spray-dried lactose, a-lactose, ⁇ - lactose) lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers, hydroxy ethyl cellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethyl hydroxyethylcellulose and other cellulose derivatives, starches or modified starches (including potato starch, corn starch,
  • the amount of diluents or fillers that may be present in the pharmaceutical antiretroviral composition can range from about 20% to about 70%.
  • glidants, anti-adherents and lubricants may also be incorporated in the pharmaceutical antiretroviral composition of the present invention, which may comprise one or more, but not limited to stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, sodium stearyl fumarate or other metallic stearate), talc, waxes (for example, microcrystalline waxes), glycerides, light mineral oil, PEG, silica acid or a derivative or salt thereof (for example, silicates, silicon dioxide, colloidal silicon dioxide and polymers thereof, magnesium aluminosilicate and/ or magnesium alumino metasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil) and combinations thereof.
  • stearic acid and pharmaceutically acceptable salts or esters thereof for example, magnesium stearate, calcium stearate, sodium stearyl fumarate or other metallic stearate
  • the amount of glidants, anti-adherents and lubricants that may be present in the pharmaceutical antiretroviral composition can range from about 0.3% to about 2%.
  • suitable binders may also be present in the in the pharmaceutical antiretroviral composition of the present invention, which may comprise one or more, but not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene glycol(s), acacia, alginic acid, agar, calcium carragenan, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, anhydrous dibasic calcium phosphate and combinations thereof or any other suitable binder.
  • polyvinyl pyrrolidone also known as povidone
  • polyethylene glycol(s) polyethylene glycol(s)
  • acacia alginic acid
  • agar calcium carragenan
  • cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl
  • the amount of binders that may be present in the pharmaceutical antiretroviral composition can range from about 1% to about 7%.
  • suitable disintegrants may also be present in the pharmaceutical antiretroviral composition of the present invention, which may comprise one or more, but not limited to hydroxylpropyl cellulose (HPC), low density HPC, carboxymethylcellulose (CMC), crospovidone, sodium CMC, calcium CMC, croscarmellose sodium; starches exemplified under examples of fillers and carboxymethyl starch, hydroxylpropyl starch, modified starch, pregelatinized starch, crystalline cellulose, sodium starch glycolate; alginic acid or a salt thereof, such as sodium alginate or their equivalents and combinations thereof.
  • HPC hydroxylpropyl cellulose
  • CMC carboxymethylcellulose
  • crospovidone sodium CMC
  • calcium CMC calcium CMC
  • croscarmellose sodium croscarmellose sodium
  • starches exemplified under examples of fillers and carboxymethyl starch, hydroxylpropyl starch, modified starch, pregelatinized starch, crystalline cellulose
  • the amount of disintegrants that may be present in the pharmaceutical antiretroviral composition can range from about 0.7% to about 5%.
  • the present invention also provides a hot melt extruded pharmaceutical antiretroviral composition
  • a hot melt extruded pharmaceutical antiretroviral composition comprising antiretroviral drug/drugs and at least one water soluble and/or water swellable and/or water insoluble polymer or combination thereof and one or more optional pharmaceutically acceptable excipients.
  • Water soluble polymers which may be used in the pharmaceutical antiretroviral composition of the present invention, include, but are not limited to, homopolymers and co-polymers of N- vinyl lactams, especially homopolymers and co-polymers of N- vinyl pyrrolidone e.g.
  • polyvinylpyrrolidone PVP
  • co-polymers of PVP and vinyl acetate copolymers of N-vinyl pyrrolidone and vinyl acetate (Copovidone) or vinyl propionate
  • dextrins such as grades of maltodextrin, cellulose esters and cellulose ethers
  • high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and co-polymers of ethylene oxide, propylene oxide and combinations thereof.
  • the amount of water soluble polymers that may be present in the pharmaceutical antiretroviral composition can range from about 10% to about 50%.
  • Water insoluble polymers which may be used in the pharmaceutical antiretroviral composition of the present invention, include, but are not limited to, acrylic copolymers e.g. Eudragit El 00 or Eudragit EPO; Eudragit L30D-55, Eudragit FS30D, Eudragit RL30D, Eudragit RS30D, Eudragit NE30D, Acryl-Eze (Colorcon Co.); polyvinylacetate, for example, Kollicoat SR 30D (BASF Co.); cellulose derivatives such as ethylcellulose, cellulose acetate e.g. Surelease (Colorcon Co.), Aquacoat ECD and Aquacoat CPD (FMC Co.) and combinations thereof.
  • acrylic copolymers e.g. Eudragit El 00 or Eudragit EPO
  • Eudragit L30D-55 Eudragit FS30D
  • Eudragit RL30D Eudragit RS30D
  • Eudragit NE30D Eudragit NE30D
  • the amount of water insoluble polymers that may be present in the pharmaceutical antiretroviral composition can range from about 3% to about 15%).
  • Water swellable polymers that may be used, according to the present invention include, but are not limited to polyethylene oxide; poly (hydroxy alkyl methacrylate); poly (vinyl) alcohol, having a low acetal residue, which is cross-linked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of from 200 to 30,000; a mixture of methyl cellulose, cross- linked agar and carboxymethyl cellulose; Carbopol ® carbomer which is an acidic carboxy polymer; Cyanamer ® polyacrylamides; cross-linked water swellable indene- maleic anhydride polymers; Goodrich ® polyacrylic acid; starch graft copolymers; Aqua Keeps ® acrylate polymer polysaccharides composed of condensed glucose units such as diester cross-linked polyglucan, and the like; Amberlite ® ion exchange resins; Explotab ® sodium starch glycolate; Ac-Di-Sol
  • the amount of water swellable polymers that may be present in the pharmaceutical antiretroviral composition can range from about 1%> to about 10%).
  • One or more optional pharmaceutically acceptable excipients may include plasticizer.
  • Plasticizers reduce the viscosity of the polymer melt and thereby allow for lower processing temperature and extruder torque during hot melt extrusion. They further decrease the glass transition temperature of the polymer.
  • Plasticizers which may be used in the pharmaceutical antiretroviral composition of the present invention, include, but are not limited to, polysorbates such as sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate; citrate ester type plasticizers like triethyl citrate, citrate phthalate; propylene glycol; glycerin; polyethylene glycol (low & high molecular weight); triacetin; dibutyl sebacate, tributyl sebacate; dibutyltartrate, dibutyl phthalate, glycerol palmitosterate and combinations thereof.
  • polysorbates such as sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate
  • citrate ester type plasticizers like triethyl citrate, citrate phthalate
  • propylene glycol g
  • the amount of plasticizers that may be present in the pharmaceutical antiretroviral composition can range from about 0.4% to about 3%.
  • the pharmaceutical antiretroviral composition may be prepared through various techniques or processes known in the art which includes, but are not limited to direct compression, wet granulation, dry granulation, melt granulation, melt extrusion, spray drying, solution evaporation or combinations thereof.
  • the dosage form of the present invention may be prepared by hot melt extrusion.
  • the process of hot melt extrusion is carried out in the conventional extruders as known to a person having a skill in the art.
  • the melt-extrusion process comprises the steps of preparing a homogeneous melt of one or more drugs, the polymer and the excipients, and cooling the melt until it solidifies.
  • Melting usually involves heating above the softening point of the polymer.
  • the preparation of the melt can take place in a variety of ways.
  • the mixing of the components can take place before, during or after the formation of the melt.
  • the melt temperature is in the range of about 50° C to about 200° C.
  • Suitable extruders include single screw extruders, intermeshing screw extruders or else multi screw extruders, preferably twin screw extruders, which can be co - rotating or counter - rotating and, optionally, be equipped with kneading disks.
  • the extrudates can be in the form of beads, granulates, tube, strand or cylinder and this can be further processed into any desired shape.
  • the present invention may further be allowed to form granules which may be compressed to form tablets, or the granules may be filled into capsules, sachets, pellets in capsules or in a similar dosage form.
  • This process involves heating the polymer(s) to soften it, without melting it, and mixing the active ingredient(s) with polymer(s), to form granules.
  • the process can be carried out in the same type of extrusion apparatus as the hot melt extrusion process, except that the product is not extruded through the extrusion nozzle of the apparatus.
  • the extrudates/granules so obtained according to the present invention may then be admixed with other suitable one or more pharmaceutically acceptable excipients.
  • the pharmaceutical antiretroviral composition of the present invention may processed by wet granulation of lamivudine and zidovudine wherein the diluent, the disintegrant along with the actives lamivudine and zidovudine are treated with the binder solution to form granules.
  • Granules are lubricated and compressed to provide a single layered tablet or compressed separately to provide a bilayered tablet which may optionally be coated.
  • the granules so obtained are filled into hard gelatin capsules or sachets or by compressing the granules to form mini-tablets which may also be filled into capsules or sachets and can be sprinkled onto food.
  • the pharmaceutical antiretroviral composition of the present invention may be processed by mixing darunavir with intragranular excipients such as diluents, disintegrants to form granules.
  • diluents such as diluents, disintegrants
  • diluents such as diluents, disintegrants
  • polymers i.e. either water soluble and/or water swellable or/and water insoluble or mixture thereof
  • one or more plasticizer i.e. either water soluble and/or water swellable or/and water insoluble or mixture thereof
  • one or more plasticizer i.e. either water soluble and/or water swellable or/and water insoluble or mixture thereof
  • disintegrants one or more lubricants and glidants
  • Granules are lubricated and compressed to provide a single layered tablet or compressed separately to provide a bilayered tablet which may optionally be coated.
  • the granules so obtained are filled into hard gelatin capsules or sachets or by compressing the granules to form mini-tablets which may also be filled into capsules or sachets and can be sprinkled onto food.
  • the granules comprising darunavir and ritonavir as obtained above may be further mixed, sieved, sifted and compressed into a single tablet.
  • the tablet may be seal coated and finally film coated or the tablet may be film coated and then seal coated.
  • the granules comprising darunavir and ritonavir as obtained above may be individually compressed into two tablets and finally compacted and compressed into a bilayer tablet.
  • the tablet may be seal coated and finally film coated or the tablet may be film coated and then seal coated.
  • the pharmaceutical antiretroviral composition of the present invention may be processed by wet granulation of tenofovir and emtricitabine wherein the diluent, the disintegrant along with the actives tenofovir and emtricitabine are sifted and dried. Then, binder solution is prepared by first dissolving the binder in purified water.
  • Granulation is carried out by spraying of the binder solution to the above dry mixture of the ingredients, after which the formed granules are dried, sifted through the specified mesh. After unloading, the granules of tenofovir, emtricitabine were lubricated. The granules as obtained above are compressed to provide a single layered tablet or compressed separately to provide a bilayered tablet. The tablets thus obtained via the process are then sprayed with a coating suspension.
  • the pharmaceutical antiretroviral composition of the present invention may be processed by wet granulation of tenofovir and lamivudine wherein the diluent, the disintegrant along with the actives tenofovir and lamivudine are sifted and dried.
  • binder solution is prepared by first dissolving the binder in purified water. Granulation is carried out by spraying of the binder solution to the above dry mixture of the ingredients, after which the formed granules are dried, sifted through the specified mesh. After unloading, the granules of tenofovir, lamivudine were lubricated. The granules as obtained above are compressed to provide a single layered tablet or compressed separately to provide a bilayered tablet. The tablets thus obtained via the process are then sprayed with a coating suspension.
  • Additional excipients such as film forming polymers, solvents, plasticizers, anti- adherents, opacifiers, colorants, pigments, antifoaming agents, and polishing agents can be used in coatings.
  • Suitable seal forming material may comprise: hydroxypropylmethylcellulose (optionally HPMC 6 CPS, or HPMC 6 CPS to HPMC 15CPS grade); hydroxypropylcellulose; polyvinylpyrrolidone; methylcellulose; carboxymethylcellulose; hypromellose; acacia; gelatin; or any combination thereof, to increase adherence and coherence of the seal coat.
  • the seal coat comprises hydroxypropylmethylcellulose.
  • the amount of seal forming materials that may be present in the pharmaceutical antiretroviral composition can range from about 0.2% to about 10%.
  • the HPMC component of the seal coating may be mixed with a solvent, wherein said solvent may comprise: acetone; methylene chloride; isopropyl alcohol; or any combination thereof.
  • the seal coating may also comprise talc.
  • Suitable film-forming agents include, but are not limited to, cellulose derivatives, such as, soluble alkyl- or hydroalkyl-cellulose derivatives such as methylcelluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethylethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, insoluble cellulose derivatives such as ethylcelluloses and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acids, polyvinyl alcohols, polyvinyl acetates, polyvinylpyrrolidones, polymethacrylates and derivatives thereof, chitosan and derivatives thereof, shellac and derivatives thereof, waxes, fat substances and any combinations or combinations thereof.
  • cellulose derivatives such as, soluble alkyl- or hydroalkyl
  • the amount of film forming agents that may be present in the pharmaceutical antiretroviral composition can range from about 0.2% to about 10%).
  • Suitable enteric coating materials include, but are not limited to, cellulosic polymers like cellulose acetate phthalates, cellulose acetate trimellitates, hydroxypropyl methylcellulose phthalates, polyvinyl acetate phthalates, methacrylic acid polymers, any copolymer thereof, any mixture thereof, or combination thereof.
  • the amount of enteric coating materials that may be present in the pharmaceutical antiretroviral composition can range from about 1%> to about 15%).
  • Some of the excipients are used as adjuvant to the coating process, including excipients such as plasticizers, opacifiers, antiadhesives, polishing agents, and the like.
  • Suitable plasticizers include, but are not limited to, stearic acid, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycols, triacetin, triethyl citrate, or combinations thereof.
  • Suitable opacifiers include, but are not limited to, titanium dioxide.
  • Suitable anti-adhesives include, but are not limited to, talc.
  • Suitable polishing agents include, but are not limited to, polyethylene glycols of various molecular weights or combinations thereof, talc, surfactants (glycerol monostearate and poloxamers), fatty alcohols (stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (carnauba wax, candelilla wax and white wax), or combinations thereof.
  • the amount of polishing agents that may be present in the pharmaceutical antiretro viral composition can range from about 0.2% to about 1%.
  • Suitable solvents used in the processes of preparing the pharmaceutical solid oral composition of the present invention include, but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, N,N- dimethylformamide, tetrahydrofuran, or combinations thereof.
  • the inventors have surprisingly found that when, by a process comprising hot melt extrusion of one or more drugs with at least one or more water insoluble polymers, with at least one or more water soluble polymers, with at least one or more water swellable polymers or a combination of at least one or more water soluble polymers and/or water swellable and/or water insoluble polymer, the resulting product acquires taste masking property wherein the ratio of drug: polymer is 1 : 1 to 1 : 6.
  • the present invention may be formulated for pediatric patients and from the point of view of pediatric patient acceptability suitable bulking agents may be incorporated, in the pharmaceutical antiretroviral composition
  • the pharmaceutical antiretroviral composition comprising saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols but not limited to arabinose, lactose, dextrose, sucrose, fructose, maltose, mannitol, erythritol, sorbitol, xylitol, lactitol, powdered cellulose, microcrystalline cellulose, purified sugar and their derivatives and combination thereof.
  • saccharides including monosaccharides, disaccharides, polysaccharides and sugar alcohols but not limited to arabinose, lactose, dextrose, sucrose, fructose, maltose, mannitol, erythritol, sorbitol, xylitol, lactitol, powdere
  • the present invention may further incorporate suitable pharmaceutically acceptable flavourants, such as but not limited to citric acid, tartaric acid, lactic acid, orange permaseal, strawberry cream flavour or other natural flavourants and sweeteners such as but not limited to aspartame or combination thereof.
  • suitable pharmaceutically acceptable flavourants such as but not limited to citric acid, tartaric acid, lactic acid, orange permaseal, strawberry cream flavour or other natural flavourants and sweeteners such as but not limited to aspartame or combination thereof.
  • the pharmaceutical antiretroviral composition according to the present invention may also comprise the actives in nano size form.
  • the active pharmaceutical ingredients have an average particle size less than about 2000 nm, preferably less than about 1000 nm.
  • Nanonization of hydrophobic or poorly water-soluble drugs generally involves the production of drug nanocrystals through either chemical precipitation (bottom-up technology) or disintegration (top-down technology). Different methods may be utilized to reduce the particle size of the hydrophobic or poorly water soluble drugs. [Huabing Chen et al., discusses the various methods to develop nano-formulations in "Nanonization strategies for poorly water-soluble drugs," Drug Discovery Today, Volume 00, Number 00, March 2010]. Nano-sizing leads to increase in the exposure of surface area of particles leading to an increase in the rate of dissolution.
  • the nanoparticles of the present invention can be obtained by any of the process such as but not limited to milling, precipitation, homogenization, high pressure homogenization, spray-freeze drying, supercritical fluid technology, emulsion/solvent evaporation, PRINT, thermal condensation, ultrasonication and spray drying.
  • the present invention provides method of prevention, treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection, which method comprises administering a pharmaceutical antiretroviral composition of the type hereinbefore described.
  • the pharmaceutical antiretroviral composition of the present invention may comprise: (i) lamivudine, zidovudine, darunavir and ritonavir; (ii) lamivudine, tenofovir, darunavir and ritonavir; (iii) emtricitabine, tenofovir, darunavir and ritonavir (iv) lamivudine, abacavir, darunavir and ritonavir; (v) raltegravir, darunavir and ritonavir or (vi) dolutegravir, darunavir and ritonavir.
  • the present invention also provides use of the pharmaceutical antiretroviral composition of the type hereinbefore described for the treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection.
  • the pharmaceutical antiretroviral composition of the present invention may comprise: (i) lamivudine, zidovudine, darunavir and ritonavir; (ii) lamivudine, tenofovir, darunavir and ritonavir; (iii) emtricitabine, tenofovir, darunavir and ritonavir; (iv) lamivudine, abacavir, darunavir and ritonavir; (v) raltegravir, darunavir and ritonavir or (vi) dolutegravir, darunavir and ritonavir.
  • the present invention further provides pharmaceutical antiretroviral composition of the type hereinbefore described for simultaneous, separate or sequential use in the prevention, treatment or prophylaxis of diseases caused by retroviruses, specifically acquired immune deficiency syndrome or an HIV infection.
  • the pharmaceutical antiretroviral composition may comprise: (i) lamivudine, zidovudine, darunavir and ritonavir; (ii) lamivudine, tenofovir, darunavir and ritonavir; (iii) emtricitabine, tenofovir, darunavir and ritonavir; (iv) lamivudine, abacavir, darunavir and ritonavir; (v) raltegravir, darunavir and ritonavir or (vi) dolutegravir, darunavir and ritonavir.
  • Binder solution was prepared using corn starch, polysorbate 80 and purified water.
  • Binder solution obtained in step (3) was sprayed on the mixture obtained in step (2) to form granules.
  • step (4) Granules obtained in step (4) were dried, sized and lubricated.
  • Emtricitabine, microcrystalline cellulose, crospovidone were sifted.
  • Binder solution was prepared using povidone and purified water.
  • Binder solution obtained in step (3) was sprayed on the mixture obtained in step (2) to form granules.
  • step (4) Granules obtained in step (4) were dried, sized and lubricated.
  • Binder solution was prepared using pregelatinized starch and purified water.
  • Binder solution obtained in step (3) was sprayed on the mixture obtained in step (2) to form granules.
  • step (4) Granules obtained in step (4) were dried, sized and lubricated.
  • step (2) The blend obtained in step (1) was granulated with purified water.
  • Crospovidone, colloidal silicon dioxide and microcrystalline cellulose were added to the granules obtained in step (4) and further lubricated with sodium stearyl monostearate and magnesium stearate.
  • step (2) The mixture obtained in step (1) was granulated with PVP followed by mixing and lubrication with crospovidone, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate.
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • Manufacturing Process for Ritonavir Layer 1.
  • Ritonavir, colloidal silicon dioxide & dibasic calcium phosphate were sifted and granulated with copovidone and sorbitan monolaureate to form granules
  • step (1) The granules obtained in step (1) were extruded and lubricated with sodium stearyl fumarate
  • step (2) of the darunavir layer and step (2) of the ritonavir layer were compressed to produce a bilayer tablet and coated with opadry orange.
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • step (1) The granules obtained in step (1) were extruded and lubricated with sodium stearyl fumarate
  • step (2) of the darunavir layer and step (2) of the ritonavir layer were compressed to produce a bilayer tablet and coated with opadry orange.
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • step (1) The granules obtained in step (1) were extruded and lubricated by sodium stearyl fumarate.
  • step (2) of the darunavir layer and step (2) of the ritonavir layer were compressed to produce a bilayer tablet and coated with opadry red.
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • step (1) The granules obtained in step (1) were extruded and lubricated with sodium stearyl fumarate.
  • step (2) of the darunavir layer and step (2) of the ritonavir layer were compressed to produce a bilayer tablet and coated with opadry
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • step (2) of the darunavir layer and step (2) of the ritonavir layer were compressed to produce a bilayer tablet and coated with opadry orange.
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • step (1) The granules obtained in step (1) were extruded and lubricated with sodium stearyl fumarate.
  • step (2) of the darunavir layer and step (2) of the ritonavir layer were compressed to produce a bilayer tablet and coated with opadry orange ⁇
  • Hypromellose was sprayed onto darunavir to produce granules.
  • step (1) The granulates obtained in step (1) were dried, sized and mixed with dolutegravir, microcrystalline cellulose, colloidal Silicon Dioxide and crospovidone to produce a mixed blend.
  • step (1) The granules obtained in step (1) were extruded and lubricated with sodium stearyl fumarate.
  • step (3) of the darunavir layer and step (2) of the ritonavir layer were compress to form a bilayer tablet and coated with opadry red.
  • Hypromellose was sprayed onto darunavir to produce granules.
  • step (1) The granulates obtained in step (1) were dried, sized and mixed with dolutegravir, microcrystalline cellulose, colloidal Silicon Dioxide and crospovidone to produce a mixed blend.
  • step (1) The granules obtained in step (1) were extruded and lubricated with sodium stearyl fumarate.
  • step (1) The granules obtained in step (1) were lubricated with sodium starch glycolate and sodium stearyl fumarate.
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • the granules were extruded and colloidal silicon dioxide, dibasic calcium phosphate were further added to the granules which were then lubricated with sodium stearyl fumarate.
  • step (2) of the dolutegravir layer and the step (2) of the darunavir layer and the step (2) of the ritonavir layer were compressed to form a trilayer tablet and coated with opadry orange.
  • step (2) The granules obtained in step (2) were lubricated with sodium starch glycolate and sodium stearyl fumarate.
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • the granules were extruded and lubricated with sodium stearyl fumarate.
  • step (2) of the dolutegravir layer and the step (2) of the darunavir layer and the step (2) of the ritonavir layer were compressed to form a trilayer tablet and coated with opadry orange.
  • step (2) The granules obtained in step (2) were lubricated with sodium starch glycolate and sodium stearyl fumarate.
  • Manufacturing Process for Darunavir Layer :
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • the granules were extruded and lubricated with sodium stearyl fumarate.
  • step (2) of the dolutegravir layer and the step (2) of the darunavir layer and the step (2) of the ritonavir layer were compressed to form a trilayer tablet and coated with opadry red.
  • step (2) The granules obtained in step (2) were lubricated with sodium starch glycolate and sodium stearyl fumarate.
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • step (2) of the dolutegravir layer and the step (2) of the darunavir layer and the step (2) of the ritonavir layer were compressed to form a trilayer tablet and coated with opadry red.
  • step (2) The granules obtained in step (2) were lubricated with magnesium stearate and sodium stearyl fumarate.
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • the granules were extruded and lubricated with sodium stearyl fumarate.
  • step (2) of the dolutegravir layer and the step (2) of the darunavir layer and the step (2) of the ritonavir layer were compressed to form a bilayer tablet and coated with opadry red.
  • step (2) The granules obtained in step (2) were lubricated with magnesium stearate and sodium stearyl fumarate.
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • the granules were extruded and lubricated with sodium stearyl fumarate.
  • step (2) of the dolutegravir layer and the step (2) of the darunavir layer and the step (2) of the ritonavir layer were compressed to form a bilayer tablet and coated with opadry red.
  • Binder solution was prepared using corn starch, polysorbate 80 and purified water.
  • Binder solution obtained in step (3) was sprayed on the mixture obtained in step (2) to form granules.
  • step (4) Granules obtained in step (4) were dried, sized and lubricated.
  • Lamivudine, microcrystalline cellulose, sodium starch glycolate were sifted.
  • Binder solution was prepared using corn starch and purified water.
  • Binder solution obtained in step (3) was sprayed on the mixture obtained in step (2) to form granules.
  • step (4) Granules obtained in step (4) were dried, sized and lubricated.
  • Binder solution was prepared and dry mix obtained from step (1) was granulated.
  • step (3) Granules obtained from step (2) were blended and lubricated and were compressed to form tablet.
  • Lamivudine, zidovudine, microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide were mixed in a blender.
  • step (3) The tablets obtained in step (2) were film coated.
  • step (3) The binder solution obtained in step (2) was sprayed onto the dry mix obtained in step (1) to form granules.
  • step (3) The granules obtained in step (3) were dried and sized and mixed with microcrystalline cellulose and croscarmellose sodium and lubricated with magnesium stearate.
  • Lamivudine, microcrystalline cellulose, sodium starch glycolate were mixed to form a dry mix.
  • step (3) The binder solution obtained in step (2) was sprayed onto the dry mix obtained in step (1) to form granules.
  • step (3) The granules obtained in step (3) were dried and sized and mixed with sodium starch glycolate and lubricated with magnesium stearate.
  • Abacavir Sulfate, microcrystalline cellulose, sodium starch glycolate were mixed to form a dry mix.
  • Hypromellose and purified water were mixed to form a binder solution.
  • step (3) The binder solution obtained in step (2) was sprayed onto the dry mix obtained in step (1) to form granules.
  • step (3) The granules obtained in step (3) were dried and sized
  • Lamivudine, sodium starch glycolate microcrystalline cellulose were mixed to form a dry mix.
  • step (2) Corn Starch and purified water were mixed to form a binder solution.
  • step (3) The binder solution obtained in step (2) was sprayed onto the dry mix obtained in step (1) to form granules.
  • step (3) The granules obtained in step (3) were dried and sized
  • Abacavir granules and lamivudine granules were blended with colloidal silicon dioxide and sodium starch glycolate and lubricated with magnesium stearate.
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • the granules were extruded and lubricated with sodium stearyl fumarate.
  • step (2) of the dolutegravir layer and the step (2) of the darunavir layer and the step (2) of the ritonavir layer were compressed to form a bilayer tablet and coated with opadry red.
  • step (1) The granules obtained in step (1) were lubricated with magnesium stearate.
  • the granules were extruded and lubricated with sodium stearyl fumarate.
  • step (2) of the dolutegravir layer and the step (2) of the darunavir layer and the step (2) of the ritonavir layer were compressed to form a bilayer tablet and coated with opadry red.

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Cited By (19)

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CN104644598A (zh) * 2014-12-05 2015-05-27 乐普药业股份有限公司 富马酸替诺福韦二吡呋酯片
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US20210290548A1 (en) * 2018-06-06 2021-09-23 Merck Sharp & Dohme Corp. Formulations of raltegravir
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