Classifications

• • 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
  • A61K31/33—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
  • A61K31/63—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
  • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • 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
• • 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
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• • 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
• • 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
• • 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
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • 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
  • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• • 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

Definitions

• the present invention relates to an oral unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir and to a monolithic tablet comprising darunavir and ritonavir and their use to treat HIV infection.
• the invention further relates to methods of preparing the oral dosage forms containing the above pharmaceutical active agents.
• Tenofovir the systematic chemical name for which is ( ⁇ [(2R)-l-(6-amino-9H-purin- 9-yl) propan-2-yl] oxy ⁇ methyl) phosphonic acid, is a nucleoside reverse transcriptase inhibitor (NRTI) which is used to treat infection by HIV-I. Its synthesis, analogs, formulation and use are described in various publications including, inter alia, U.S. Patent Nos. 5,922,695; 5,935,946, 5,977,089 and 6, 043, 230.
• NRTI non- nucleoside reverse transcriptase inhibitor
• PI protease inhibitor
• TDF Tenofovir disoproxil fumarate
• VIREAD ® a prodrug form of tenofovir.
• VIREAD tablets are available in strengths of 150, 200, 250, and 300 mg of tenofovir disoproxil fumarate, which are equivalent to 123, 163, 204 and 245 mg of tenofovir disoproxil, respectively.
• the tablet also includes the following inactive ingredients: croscarmellose sodium, lactose
• TRUVADA tenofovir disoproxil fumarate
• the tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.
• the total weight of the TRUVADA tablet is 1045mg, having the dimensions of 19 mm x 8.5 mm.
• Emtricitabine the systematic chemical name for which is 4-amino-5-fluoro-l- [2- (hydroxymethyl)-l, 3-oxathiolan-5-yl]-pyrimidin-2-one, is another nucleoside reverse transcriptase inhibitor (NRTI) which is used to treat infection by HIV-I.
• NRTI nucleoside reverse transcriptase inhibitor
• Emtricitabine is marketed by Gilead Sciences under the trade name
• EMTRIVA ® is available as capsules or as an oral solution. Each capsule contains 200 mg of emtricitabine and also the following inactive ingredients: crospovidone, magnesium stearate, microcrystalline cellulose, povidone, titanium dioxide, gelatin, and FD&C blue No. 2.
• PREZISTA Darunavir is marketed by Tibotec (Janssen) under the trade name PREZISTA ® .
• PREZISTA tablets are available in strengths of 75 mg, 150 mg, 400 mg, 600 mg, and 800 mg. Each tablet also contains the inactive ingredients colloidal silicon dioxide,
• the 800 mg tablet also contains hypromellose.
• the total weight of the PREZISTA 800 mg tablet is 1048 mg, having the dimensions of 20 mm x 8 mm.
• Ritonavir is marketed by Abbott Laboratories under the trade name NORVIR ® .
• Norvir® is available as 100 mg tablet or capsule and as an 80mg/ml oral solution.
• Ritonavir is BCS (biopharmaceutical classification system) class IV material.
• BCS biopharmaceutical classification system
• ritonavir has very low solubility and permeability.
• Abbott developed Norvir® tablet, using an amorphous ritonavir in a hot melt extrusion manufacturing process, with a high amount of polymer (NDA 22-417- chemistry review,
• the Norvir® tablet contains: 100 mg ritonavir, copovidone, sorbitan laurate, calcium hydrogen phosphate anhydrous, anhydrous colloidal silica, sodium stearyl fumarate and are coated with a film-coating formed of hypromellose, titanium dioxide (El 71), macrogols, hydroxypropyl cellulose, talc, anhydrous colloidal silica and polysorbate 80.
• the total weight of Norvir® tablet is 800mg, and the tablet has dimensions of 17.2x5.8mm.
• HAART highly active antiretroviral therapy
• WO2009/081 174 describes a dual combination formulation of ritonavir and darunavir; wherein ritonavir is in a first layer and darunavir is in a second layer. According to this disclosure, ritonavir and darunavir, when admixed, results in incompatibilities in which the stability of the active agents is compromised. Accordingly, WO2009/081 174 discloses that the two active agents must be separated from each other, i.e., by the provision of a composition in which each agent is present in separate layers. Nevertheless, from the point of view of ease of manufacture, monolithic compositions are generally preferred over multilayer compositions. However, the successful formulation of monolithic dosage forms, is dependent on ensuring that the stability of the active agents in the dosage form is not compromised, as well as ensuring that the dosage form is of a size that enables it to be easily administered.
• WO2013057469 describes a combination composition in a kit form.
• the kit can comprise separate unit dosage forms of various antiretroviral drugs with a set of instructions for their administration. Nevertheless, the administration of separate dosage forms in accordance with a set of instructions does not provide an optimal improvement of patient compliance, especially if the dosage forms are to be taken at different times. Moreover, the instructions may be misplaced, or may be incorrectly followed by the patient.
• emtricitabine tenofovir, darunavir and ritonavir
• a composition that can be readily administered so as to further improve patient compliance.
• less onerous dosage regimen such as once daily oral dosing, optimally, in a one pill, having the required stability and bioavailability.
• the present invention addresses for the first time the preparation of a unit dose form containing emtricitabine, tenofovir, darunavir and ritonavir and of a monolithic tablet containing darunavir and ritonavir
• the present invention provides a pharmaceutical formulation in a unit dosage form comprising:
• ritonavir or a physiologically functional derivative thereof.
• the present invention provides a monolithic tablet comprising: darunavir or a physiologically functional derivative thereof, and
• ritonavir or a physiologically functional derivative thereof.
• the present invention further provides the above unit dose formulation or the above monolithic tablet for use as a medicament.
• the present invention further provides the above unit dose formulation or the above monolithic tablet for use in the treatment of HIV- 1 infection.
• the present invention further provides a method for treating HIV-1 infection comprising administration of a pharmaceutically effective amount of the above unit dose formulation or of the above monolithic tablet.
• the compounds or their combinations of the invention may be referred to as "active ingredients” or “pharmaceutically active agents.”
• physiologically functional derivative includes any: pharmaceutically acceptable salts, pharmaceutically acceptable enantiomers, pharmaceutically acceptable solid state form (crystalline, semi-crystalline or amorphous), pharmaceutically acceptable polymorphs, pharmaceutically acceptable solvates, pharmaceutically acceptable metabolites or pharmaceutically acceptable prodrugs thereof (for example, wherein the prodrug is an ester), or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph, solvate, metabolite or prodrug (e.g. an ester prodrug).
• the terms "Emtricitabine”, “Tenofovir”, “Darunavir” and “Ritonavir” are mentioned throughout in a broad sense to include not only emtricitabine, tenofovir, darunavir and ritonavir, per se, but also their physiologically functional derivatives.
• the tenofovir is in the form of its product, tenofovir disoproxil. More preferably the tenofovir disoproxil is in the form of its fumarate salt, i.e. tenofovir disoproxil fumarate.
• the darunavir is in the form of darunavir or its physiologically functional derivatives, e.g. darunavir can be darunavir ethanolate, hydrate, or any other crystalline form as well as amorphous darunavir.
• the ritonavir is in the form of ritonavir or its physiologically functional derivatives. More preferably the ritonavir is in the form of its crystalline form as well as amorphous ritonavir, i.e., crystalline form can be for example, Form I or Form II, substantially as described in EP 1097148.
• Characteristic peaks of in the powder X-ray diffraction pattern of Ritonavir Form I can be found in 3.33° ⁇ 0.1°, 6.76° ⁇ 0.1°, 8.33° ⁇ 0.1 °, 14.61° ⁇ 0.1°, 16.33° ⁇ 0.1°, 16.76° ⁇ 0.1°, 17.03° ⁇ 0.1°, 18.02° ⁇ 0.1 °, 18.62° ⁇ 0.1°, 19.47° ⁇ 0.1°, 19.86° ⁇ 0.1 °, 20.25° ⁇ 0.1 °, 21.46° ⁇ 0.1°, 23.46° ⁇ 0.1° and 24.36° ⁇ 0.1 0 (two theta). Characteristic peaks of in the powder X-ray diffraction pattern of Ritonavir Form II can be found in 8.67° ⁇ 0.1°,
• a reference to weight% of the dosage form mean the weight% relative to the weight of the dosage form excluding, in the case of a tablet, any finishing/cosmetic coating, and in the case of a capsule, the weight of the dosage form refers to the total weight of the capsule contents, i.e. excluding the capsule shell.
• chemical stability means that the active ingredients in the combination are substantially stable to chemical degradation. Preferably, they are sufficiently stable in physical combination to permit commercially useful shelf life of the combination product. Typically, “chemically stable” means that a first component of the mixture does not act to degrade a second component when the two are brought into physical combination to form a pharmaceutical dosage form.
• the term “chemically stable” refers to a formulation which, when stored at 40°C and at 75% relative humidity for 1 month to 6 months, the amounts of each of darunavir and ritonavir; and/or the amount of each of tenofovir and emtricitabine, do not significantly diminish compared with the amounts of each of darunavir and ritonavir ; and/or the amount of each of tenofovir and emtricitabine, in the formulation prior to storage.
• a formulation according to any aspect or embodiment of the present invention may be considered to be chemically stable if at least about 97%, preferably at least about 98%, more preferably at least about 99%, most preferably at least about 99.5%, and especially at least about 99.9% of each of the darunavir and ritonavir content, and/or each of tenofovir and emtricitabine content in the formulation immediately before storage is retained after storage at 40°C and at 75% relative humidity for 1 month to 6 months.
• the term "chemically stable” refers to a formulation in which from about 90% to about 100%, about 95% to about 100%, about 98% to about 100%, about 99% to about 100%, 99.5% to about 100%) or 99.9% to about 100%) of each of the darunavir and ritonavir content and/or each of tenofovir and emtricitabine content in the formulation immediately before storage is retained following storage of the formulation at 40°C and at 75% relative humidity for 1 month to 6 months. More preferably, about 99.95% to about 100% is retained.
• the term “chemically stable” refers to a formulation in which at least about 99.95% of each of the darunavir and ritonavir content and/or each of tenofovir and emtricitabine content in the formulation immediately before storage is retained after storage at 40°C and at 75% relative humidity for 1 month to 6 months.
• the term “chemically stable” refers to a formulation in which at least about 99.95% of each of the darunavir and ritonavir content and/or each of tenofovir and emtricitabine content in the formulation immediately before storage is retained after storage at 40°C and at 75% relative humidity for 1 month to 6 months.
• “chemically stable” refers to a formulation in which there is no detectable change in the darunavir and ritonavir content and/or each of tenofovir and emtricitabine content, in the formulation immediately before storage and after storage at 40°C and at 75% relative humidity for 1 month to 6 months.
• emtricitabine contents of the formulations can be measured by standard analytical techniques well known to the skilled person.
• HPLC is a preferred method for this purpose.
• an HPLC assay using standard solutions may be employed, an example of which is set out below.
• Reference to weight % or % by weight of pharmaceutically acceptable salts of emtricitabine, tenofovir, darunavir and ritonavir refer to the amount relative to the free base form. Where the emtricitabine, tenofovir, darunavir and/or ritonavir is in the form of a prodrug, the weight % refers to the amount relative to the form of the prodrug. Thus, for example, reference to weight% of tenofovir disoproxil fumarate is the amount relative to tenofovir disoproxil.
• bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. Enhancement of the bioavailability of a pharmaceutically active agent can provide a more efficient and effective treatment for patients because, for a given dose, more of the pharmaceutically active agent will be available at the targeted tissue sites.
• bioavailability of a pharmaceutical composition can be determined, for example, by any pharmacokinetic parameter known to the person skilled in the art.
• ti /2 half-life
• C m j n minimum plasma concentration
• C trough concentration C max
• AUC area under the curve
• T m ax time to maximal concentration
• C ss steady state concentration
• the assessment of same/comparable pharmacokinetic bioavailability can be based on 90% confidence intervals for the ratio of the population geometric means (test/reference) for the parameters under consideration. This method can be equivalent to two one-sided tests with the null hypothesis of bioinequivalence at the 5% significance level.
• the pharmacokinetic parameters under consideration can be analyzed using
• ANOVA The data can be transformed prior to analysis using a logarithmic transformation.
• a confidence interval for the difference between formulations on the log-transformed scale can be obtained from the ANOVA model. This confidence interval can then back- transformed to obtain the desired confidence interval for the ratio on the original scale.
• Ritonavir may be used as 'pharmacokinetic enhancer' (booster) to increase the blood levels of darunavir. Accordingly, the bioavailability of darunavir may be compared to the bioavailability of the commercial darunavir when administered with the commercial ritonavir (Norvir ® ) as a pharmacokinetic enhancer.
• references hereinafter to a pharmaceutical formulation refer unless otherwise stated to a pharmaceutical formulation containing the combination or also their
• the unit dosage form of the 4 APIs enable patients greater freedom from multiple dosage medication regimens and ease the needed diligence required in remembering and complying with complex daily dosing times and schedules.
• the desired daily regimen may be presented in a single dose per day.
• the pharmaceutical formulations of co-formulated tenofovir, emtricitabine, darunavir, and ritonavir may be administered as a single dose form, once per day.
• the pharmaceutical formulation should be administered to achieve peak plasma concentrations of each of the compounds/active pharmaceutical ingredients when administered in a separated unit doses containing each one of the active pharmaceutical ingredients separately, while avoiding compromising the stability and the size of the pharmaceutical formulation.
• the pharmaceutical formulation may be formulated in a unit dosage formulation comprising an amount of each compound/active pharmaceutical ingredient that is suitable for a daily dose to ensure the desired therapeutic effect.
• the present invention provides a pharmaceutical formulation in a unit dosage form comprising:
• the above pharmaceutical formulation comprising tenofovir disoproxil or a physiologically functional derivative thereof, emtricitabine or a physiologically functional derivative thereof, darunavir or a physiologically functional derivative thereof and ritonavir or a physiologically functional derivative thereof can be chemically stable.
• the total weight of the pharmaceutical formulation of the present invention can be less than or equal to about 2.800g, less than or equal to about 2.600g, less than or equal to about 2.500g,less than or equal to about 2.400g, less than or equal to about 2.300g, less than or equal to about 2.200g, less than or equal to about 1.900g or less than or equal to about 1.800g, or less than or equal to about 1.700g, or less than or equal to about 1.600g, or less than or equal to about 1.500g.
• the total dosage form weight is between 1.500g to about 1.600g, to about 1.700g, to about 1.800g, to about 1.900g, to about 2.000g, to about 2.200g, to about 2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g, or between 1.600g, to about 1.700g, to about 1.800g, to about 1.900g, to about 2.000g, to about 2.200g, to about 2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g, or between 1.700g, to about 1.800g, to about 1.900g, to about 2.000g, to about 2.200g, to about 2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g,or between 1.800g, to about 1.900g, to about 2.000g, to about 2.200g, to about 2.300g, to about 2.400g, to about 2.500g, to about
• the pharmaceutical formulation of the present invention comprises about 150 mg to 350mg of tenofovir disoproxil fumarate, about lOOmg to 300mg of emtricitabine, about 75mg to 800mg of darunavir and about lOOmg of ritonavir.
• the amount of darunavir can be 75mg, 150mg, 300mg, 400mg 600mg, or 800mg
• the said darunavir can be darunavir ethanolate, hydrate, or any other crystalline form as well as darunavir amorphous.
• the amount of ritonavir can be lOOmg of ritonavir (corresponding to the dose of the commercially available of Norvir® tablet).
• the pharmaceutical formulation of the present invention comprises about 300mg of tenofovir disoproxil fumarate, about 200mg of emtricitabine, about 800mg of darunavir and about 1 OOmg of ritonavir.
• the pharmaceutical formulation of the present invention comprises from about 20% to about 85% by weight of total weight of all 4 pharmaceutically active ingredients.
• the pharmaceutical formulation of the present invention comprises from about 20% to about 25%, to about 30%, to about 35%, to about 40%, to about 45%, to about 50%, to about 55%, to about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about 85% by weight of total weight of all 4 pharmaceutically active ingredients, or from about 25% to about 30%, to about 35%, to about 40%, to about 45%, to about 50%, to about 55%, to about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about 85%, or from about 30% to about 35%, to about 40%, to about 45%, to about 50%, to about 55%, to about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about 85%, or from about 30% to about 35%, to about 40%, to about 45%, to about 50%, to about 5
• the pharmaceutical formulation of the present invention can be suitable for oral administration.
• Oral dosage forms for the purpose of the present invention include capsules, tablets, pellets, granules, powders and pharmaceutical formulations thereof.
• the pharmaceutical composition can be formulated in the form of coated or uncoated, effervescent, soluble, orodispersible, enteric or modified-release tablets; sugar-coated tablets; hard capsules; soft capsules; granules; pills; pastilles.
• the oral dosage form is a tablet.
• the tablet can be chemically stable.
• the tablet can have a weight as mentioned above for the total weight of the pharmaceutical formulation of the present invention, comprising the above 4 APIs.
• the largest maximum diameter of the tablet of the present invention comprising the 4 APIs, can be about 27mm or less and the depth can be less than about 12.5mm;
• the largest maximum diameter can be between about 26mm to about 27mm and the depth can be between about 12.5mm to about 10mm; more preferably, the largest maximum diameter can be between about 25mm to about 26mm and the depth can be between about 12mm to about 1 1mm, most preferably, the largest maximum diameter can be about 25mm and the depth can be about 1 1mm.
• the hardness of the tablet of the present invention comprising the 4 APIs, can be about 75 Strong-Cobb Units (SCU) to about 20 C, preferably, about 55 SCU to about 25 SCU, as measured by Electronic D-64291 Darmstadt 100-240V.
• SCU Strong-Cobb Units
• the tablet of the present invention comprises about 150 mg to 350mg of tenofovir disoproxil fumarate, about lOOmg to 300mg of emtricitabine, about 75mg to 800mg of darunavir and about lOOmg of ritonavir.
• the amount of darunavir can be 75mg, 150mg, 300mg, 400mg 600mg, or 800mg (corresponding to the doses of
• the said darunavir can be darunavir ethanolate, hydrate, or any other crystalline form as well as darunavir amorphous.
• the amount of ritonavir can be lOOmg of ritonavir (corresponding to the dose of the commercially available of Norvir® tablet).
• the tablet of the present invention comprises about 300mg of tenofovir disoproxil fumarate, about 200mg of emtricitabine, about 800mg of darunavir and lOOmg of ritonavir.
• the tablet of the present invention comprises from about 20% to about 70% by weight of total weight of the pharmaceutically active ingredients.
• the tablet of the present invention comprises from about 20% to about 85% by weight of total weight of all 4 pharmaceutically active ingredients.
• the pharmaceutical formulation of the present invention comprises from about 20% to about 25%, to about 30%, to about 35%, to about 40%, to about 45%, to about 50%, to about 55%, to about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about 85% by weight of total weight of all 4 pharmaceutically active ingredients, or from about 25% to about 30%, to about 35%, to about 40%, to about 45%, to about 50%, to about 55%, to about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about 85%, or from about 30% to about 35%, to about 40%, to about 45%, to about 50%, to about 55%, to about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about 85%
• the present invention provides tablets which optionally can be divided into two or more discrete segments, for example, by dividing grooves. Said dividing grooves facilitate breaking the dosage into the corresponding fragments and therefore provide an easy division into partial doses which contain approximately equal proportions of the active substances.
• the tablets of the present invention may, for example have one to three, preferably two, laterally extending grooves on the top and bottom surfaces and a small laterally opening groove on the sides, to facilitate ease in breaking the tablet.
• compositions in the form of a tablet according to the present invention can be provided for example as a monolithic tablet (single layer), bi-layer (two layers) or multi-layer tablet (three or more distinct layers), preferably the formulation can be a monolithic tablet.
• a monolithic tablet according to the present invention can include the four compounds/active pharmaceutical ingredients mixed and compressed to a single layer tablet.
• the single layer can include darunavir with extra- granular ritonavir or darunavir with intra- granular ritonavir, (i.e., a granulate of darunavir-ritonavir) emtricitabine granules, and tenofovir granules, or granules comprising both emtricitabine and tenofovir.
• a disintegrant such as Croscarmellose Sodium (Ac-Di-Sol) to form a blend that is then compressed into a tablet core.
• the tablet core can then be coated with a film coating material to produce a film coated tablet.
• the granulate of darunavir-ritonavir can be prepared by wet granulation of darunavir.
• the wet granulation can include top spray process of at least one binder such as hypromellose dissolved in a suitable liquid (e.g., water) on darunavir, obtaining a wet granulate followed by drying the wet granulate and milling the dry granulate.
• a suitable liquid e.g., water
• At least one lubricant such as sodium stearyl fumarate can be added to the obtained mixture to obtain the final blend of darunavir-ritonavir(/ ' .e., darunavir with extra- granular ritonavir).
• the granulate of darunavir-ritonavir can be prepared by wet granulation, at least one binder such as hypromellose dissolved in a suitable liquid (e.g. water), can be top spray process on a mixture of darunavir and ritonavir pre-mix or, followed by drying the wet granulate and milling the dry granulate.
• a suitable liquid e.g. water
• the obtained granulate of darunavir and ritonavir can then be mixed with at least one filler such as microcrystalline cellulose, at least one disintegrant such as crospovidone, and at least one glidant such as silicon dioxide.
• castor oil can be added to the obtained mixture.
• At least one lubricant such as sodium stearyl fumarate can be added to the obtained mixture to obtain the final blend of darunavir-ritonavir (i.e., darunavir with intra-granular ritonavir).
• Ritonavir pre-mix can be prepared by mixing ritonavir with at least one carrier such as copovidone, optionally also with at least one solubilizer such as sorbitan laurate and with at least one glidant such as silica, providing a mixture that is the combined with a solvent, such as ethanol to yield a second mixture.
• a solvent such as ethanol to yield a second mixture.
• the solvent is then removed from the second mixture by evaporation techniques such as spray drying.
• the resulting mixture may be in the form of a powder, which may be subjected to a particle size reduction step (e.g., by milling, to D(0.1) about 9 ⁇ , D(0.5) about 55 ⁇ , D(0.9) about 176 ⁇ ).
• Granules comprising both emtricitabine and tenofovir can be prepared by combining both APIs and at least one filler selected from: microcrystalline cellulose, lactose and/ or pregelatinized starch and optionally at least one disintegrant such as croscarmellose sodium to obtain a powdery mixture that can then combined with water in the wet granulation process.
• the wet granulation process provides wet granules that can then be dried.
• emtricitabine and tenofovir can be granulated by the same method separately to produce separate emtricitabine and tenofovir granulates.
• emtricitabine granulate can be prepared by combining emtricitabine with at least one filler selected from: microcrystalline cellulose, pregelatinized starch and at least one disintegrant such as croscarmellose sodium to obtain a powdery mixture that can then granulated with water in the wet granulation process. The wet granulation process provides wet granules that can then be dried.
• Tenofovir granulate can be prepared by combining Tenofovir with at least one filler selected from: microcrystalline cellulose and pregelatinized starch to obtain a powdery mixture that can then granulated with water in the wet granulation process.
• the wet granulation process provides wet granules that can then be dried.
• a bi-layer tablet comprising emtricitabine, tenofovir, darunavir and ritonavir according to the present invention is composed of two distinct layers of the
• the first layer can have emtricitabine and tenofovir and the second can have darunavir and ritonavir.
• the first layer may further include at least one lubricant such as magnesium stearate to form the blend of the first layer.
• the blend of the second layer can include the above described granulate of darunavir-ritonavir (i.e., darunavir and ritonavir as extra-granular or darunavir and ritonavir as intra- granular). Both blends can then be compressed into one tablet core that has two distinct layers. The tablet core can then be coated with film coating material.
• a multi-layer tablet according to the present invention is composed of three or more distinct layers of the compounds/active pharmaceutical ingredients.
• compositions in the form of a tablet according to the present invention may be uncoated or may be coated by known techniques including
• microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
• the Pharmaceutical formulations in the form of a tablet according to the present invention may be further coated with a coating layer.
• the coating layer may comprise, for example, a protective top coat which is disposed over the drug layer.
• the protective top coat layer may comprise a coating polymer and optionally one or more excipients such as, for example, a plasticiser, an anti-adherent or glidant, one or more pigments/opacifying agents, and combinations thereof.
• the coating may be a water-soluble film coating that has no influence on the release of the active substance.
• the thickness of a soluble film coating may be from about 20 ⁇ to about 100 ⁇ .
• Suitable film coating materials include, for example, cellulose derivatives, such as cellulose ethers, for example methylcellulose, hydroxypropylcellulose or
• hydroxypropylmethylcellulose mixtures of polyvinyl pyrrolidone or of a copolymer of polyvinyl pyrrolidone and polyvinyl acetate with hydroxypropylmethylcellulose; mixtures of shellac with hydroxypropylmethylcellulose, polyvinyl acetate or copolymers thereof with polyvinyl pyrrolidone; or mixtures of water-soluble cellulose derivatives, such as hydroxypropylmethylcellulose, and water-insoluble ethylcellulose.
• These coating agents may, if desired, be used in admixture with other adjuncts, such as talc, wetting agents, for example polysorbates (for example for facilitating application), or pigments (for example, for marking purposes).
• these coatings can be applied in aqueous solution or in organic solution (for example, solutions of shellac or ethylcellulose in organic solvents).
• organic solution for example, solutions of shellac or ethylcellulose in organic solvents.
• Mixtures of acrylates that are water-insoluble per se may also be used.
• the copolymer of ethyl acrylate and methyl methacrylate may be used in an aqueous dispersion, with one or more water-soluble adjuncts, such as lactose, polyvinyl pyrrolidine, polyethylene glycol or hydroxypropylmethylcellulose.
• Suitable plasticizers for the protective top coat include, for example, triacetin, diethyl phthalate, dibutyl sebacate, tributyl sebacate polyethylene glycol, and mixtures thereof.
• Polyethylene glycol is a preferred plasticizer.
• Suitable anti-adherent or glidants for the protective top coat include, for example, talc, fumed silica, magnesium stearate, and mixtures thereof.
• the tablet of the present invention can be prepared by a process comprising:
• the tablet obtained by this process is a monolithic tablet.
• the tablet of the present invention can be prepared by a process comprising:
• the first layer comprises either a mixture of emtricitabine granulates and tenofovir granulates, or a granulate comprising a mixture of emtricitabine and tenofovir;
• the second layer comprises darunavir with extra- granular ritonavir or darunavir with intra- granular ritonavir, (i.e., a granulate of darunavir-ritonavir);
• the tablet obtained by this process is a bi layer tablet. Blending can be accomplished using equipment such as tumble blender.
• Compression can be accomplished using for example, the blend of active ingredients and excipients is passed through a roller apparatus for compaction.
• a roller apparatus for compaction.
• other means for compacting the API mixture e.g., compaction into slugs (or “slugging"), may be used.
• the active pharmaceutical ingredients blend of step (a) can be processed into other unitary dosage forms such as capsules, or the like.
• Each of the individual active pharmaceutical ingredients in the mixture in step (a) can be processed prior to blending as described above.
• wet granulation can be accomplished using conventional equipment. For example, the powders were blended in a granulator and then granulated using water. The impeller and chopper speeds were kept constant in the blender at a low setting during the granulation and wet massing operations. After water addition, the impeller and chopper were stopped and the granulator bowl was opened to observe the granulation consistency and texture.
• wet milling can be accomplished using conventional equipment.
• each wet granulation can be deagglomerated with a mill fitted with a screen and an impeller.
• Drying can be accomplished using conventional equipment. For example, milled wet granules can be dried using fluid-bed dryer.
• Dry milling can be accomplished using conventional equipment. For example, all dried granules can be milled using a rotary sieve mill.
• Top spray process can be accomplished using conventional equipment. For example Fluid Bed Dryer equipped with either top spray or wurster coating devices.
• Tablet compression can be accomplished using conventional equipment.
• the final blends can be compressed using tabletting machine.
• Purity analysis can be accomplished using conventional equipment.
• HPLC HPLC.
• the present invention provides a monolithic tablet comprising:
• ritonavir or a physiologically functional derivative thereof.
• the tablet can be chemically stable.
• the total weight of the monolithic tablet comprising Darunavir and Ritonavir of the present invention can be less than or equal to about 1.300g, less than or equal to about 1.200g, less than or equal to about 1.1 OOg, less than or equal to about l .OOOg, less than or equal to about 0.900g, less than or equal to about 0.700, less than or equal to 0.600g, or less than or equal to about 0.550g.
• the tablet weight is between 0.550g to about 0.600g, to about 0.700g, to about 0.900g, to about l .OOOg, to about 1.1 OOg, to about 1.200g, to about 1.300g, or between 0.600g to about 0.700g, to about 0.900g, to about l .OOOg, to about 1.1 OOg, to about 1.200g, or to about 1.3 OOg, or between 0.700g to about 0.900g, to about l .OOOg, to about 1.1 OOg, to about 1.300g, or between0.900g to about l .OOOg, to about 1.1 OOg, to about 1.200g, or to about 1.300g, or between l .OOOg to about 1.1 OOg, to about 1.200g, to about 1.300g, or between l .OOOg to about 1.1 OOg, to about 1.200g, to about 1.300g, or between 1.1 OOg to about 1.200g, or to about 1.300g
• the monolithic tablet comprising darunavir and ritonavir of the present invention provides a chemically stable formulation of the active agents, and moreover, is suitable for once daily administration in a single pill.
• the size and weight of the dosage form is far less than the combined size/weight of commercially available darunavir 800mg tablet (Prezista®, having total weight of 1048 mg) and commercially available ritonavir lOOmg tablet (Norvir®, having a total weight of 800mg).
• the largest maximum diameter of the pharmaceutical formulation of the present invention can be about 22mm or less and the depth can be less than about 9mm; preferably, the largest maximum diameter can be between about 20mm to about 22mm and the depth can be between about 6mm to about 9mm; more preferably, the largest maximum diameter can be between about 20mm to about 21mm and the depth can be between about 8mm to about 7mm, most preferably, the largest maximum diameter can be about 21mm and the depth can be about 7mm.
• the tablet of the present invention comprises about 150 mg to 350mg of tenofovir disoproxil fumarate, about lOOmg to 300mg of emtricitabine, about 75mg to 800mg of darunavir and about lOOmg of ritonavir.
• the amount of darunavir can be 75mg, 150mg, 300mg, 400mg 600mg, or 800mg (corresponding to the doses of commercially available of Prezista®).
• the said darunavir can be darunavir ethanolate, hydrate, or any other crystalline form as well as darunavir amorphous.
• the amount of ritonavir can be lOOmg of ritonavir (corresponding to the dose of the commercially available of Norvir® tablet).
• the tablet of the present invention comprises about 300mg of tenofovir disoproxil fumarate, about 200mg of emtricitabine, about 800mg of darunavir and lOOmg of ritonavir.
• the monolithic tablet comprising darunavir and ritonavir of the present invention comprises from about 20% to about 85% by weight of total weight of the two pharmaceutically active ingredients.
• the tablet of the present invention comprises from about 20% to about 25%, to about 30%, to about 35%, to about 40%, to about 45%, to about 50%, to about 55%, to about 60%, to about 65%, to about 70%, to about 75%, to about 80% or to about 85% by weight of total weight of the two pharmaceutically active ingredients, or from about 25% to about 30%, to about 35%, to about 40%, to about 45%, to about 50%, to about 55%, to about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about 85%, or from about 30% to about 35%, to about 40%, to about 45%, to about 50%, to about 55%, to about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about 85%, or from about 30% to about 35%, to about 40%
• the above monolithic tablet comprising darunavir and ritonavir can include the two ' compounds/active pharmaceutical ingredients mixed and compressed to a single layer tablet.
• the single layer can include darunavir and ritonavir as extra- granular or darunavir and ritonavir as intra- granular.
• To these can be added at least one lubricant such as sodium stearyl fumarate to form a blend that can then be compressed into a tablet core.
• the tablet core can then be coated with a film coating material to produce a film coated tablet.
• Darunavir and ritonavir as extra- granular or intra- granular can be processed prior to blending as described above.
• the present invention provides tablets which optionally can be divided into two or more discrete segments, for example, by dividing grooves. Said dividing grooves facilitate breaking the dosage into the corresponding fragments and therefore provide an easy division into partial doses which contain approximately equal proportions of the active substances.
• the tablets of the present invention may, for example have one to three, preferably two, laterally extending grooves on the top and bottom surfaces and a small laterally opening groove on the sides, to facilitate ease in breaking the tablet.
• compositions of the present invention may further comprise one or more pharmaceutically acceptable carriers or excipients as described above and below.
• Examples of pharmaceutical excipients are fillers, binders, disintegrants, surfactants, glidants and lubricants.
• Suitable fillers include, for example, water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PHI 02 having or PHlOl), lactose in its various forms (e.g., lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyols, fructose, guar gum, magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like or any combinations thereof.
• water soluble polymer for example, water insoluble polymer, microcrystalline cellulose (for example, Avicel PHI 02 having or PHlOl)
• lactose in its various forms e.g., lactose USP, anhydrous or spray dried
• sorbitol dextrose
• sucrose sucrose
• mannitol xylitol
• maltose polyol
• Suitable binders include, for example, cellulose polymers (e.g., hydroxypropyl- methyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch and the like or any combinations thereof.
• cellulose polymers e.g., hydroxypropyl- methyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone polyvinyl alcohol
• starch or pregelatinized starch and the like or any combinations thereof.
• Suitable lubricants include, for example, sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate or hydrogenated vegetable oils, and the like or any combinations thereof.
• Suitable glidants can be used to improve the flowability.
• Suitable glidants include, for example, colloidal silica, silica gel, precipitated silica or talc, and the like or any combinations thereof.
• Suitable disintegrants include, for example, sodium carboxymethyl starch, cross- linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab ® ), croscarmellose sodium, swelling polysaccharide, for example soy
• polysaccharide polysaccharide, carrageenan, agar, pectin, starch and derivatives thereof, protein, for example formaldehyde-casein, sodium bicarbonate, ion exchange resin and the like or any combinations thereof.
• Suitable surfactants are substances, which can lower the interfacial tension between two phases, thus enabling or supporting the formation of dispersions or working as a solubilizer.
• Suitable surfactants include, for example, alkyl sulfates (for example sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates, sorbitanes (for example sorbitan laurate), polyoxyethylene sorbitanes, polyoxylglycerides, or polyoxyethylene castor oil derivatives. Sorbitan laurate and sodium lauryl sulfate are preferred surfactants.
• the above disclosed unit dose formulation of the 4 APIs or the above monolithic tablet of the 2 APIs can be used as a medicament.
• the formulations of the present invention can also be used in the treatment of HIV- 1 infection.
• the present invention further provides a method for treating HIV-1 infection comprising administration of a pharmaceutically effective amount of the above unit dose formulation of the 4 APIs or of the above monolithic tablet of the 2 APIs.
• Detector UV at 240 nm, 10 mm flow cell path length
• Analytical method for tablet comprising emtricitabine, tenofovir, darunavir, ritonavir: Impurities and Degradants Determination Chromatographic conditions for
• Example 2 Preparation of a monolithic tablet containing darunavir - ritonavir extr granular
• Hypromellose (Methocel E-15) 12.20 microcrystalline cellulose (Avicel 101) 14.00
• Darunavir granulation- darunavir was wet granulated by a top spray process using hypromellose (Methocel E-15) as granulation solution and purified water as granulation liquid.
• hypromellose Methodhocel E-15
• the wet granulated material was then dried in Fluid bed drier and milled to lower particle size.
• Darunavir granulate, ritonavir pre mix prepared according to example 1
• crospovidone microcrystalline cellulose
• Avicel 102 microcrystalline cellulose
• Silicon di-oxide Aerosil
• the tablet cores were then coated with a film coating material to produce film coated tablets. (Approximately 3% weight gain).
• Example 3 Preparation of a monolithic tablet containing darunavir - ritonavir (intra- granular)
• Darunavir - Ritonavir granulation- darunavir was wet granulated with ritonavir pre mix (prepared according to example 1) by a top spray process using hypromellose (Methocel E-15) as granulation solution and purified water as granulation liquid.
• ritonavir pre mix prepared according to example 1
• hypromellose Methodhocel E-15
• the wet granulated material was then dried in Fluid bed drier and milled to lower particle size.
• the tablet cores were then coated with a film coating material to produce film coated tablets. (Approximately 3% weight gain).
• Emtricitabine/ tenofovir disoproxil fumarate were wet granulated by High Shear Mixer with microcrystalline cellulose (Avicel 102), Lactose monohydrate, Pregelatinized Starch and Croscarmellose Sodium (Ac-Di-Sol). The granules were then dried by Fluid Bed Drier and milled to lower particle size [see above comments]. Optionally, croscarmellose Sodium was then added as an extra-granular disintegrant.
• Emtrcitabine is mixed with excipients and wet granulated using povidone solution in purified water. The wet granulate is then dried in a fluid bed dryer.
• Example 5A Preparation of emtricitabine granulate
• Emtricitabine granulate total 350.00
• Emtrcitabine was mixed with excipients and wet granulated using povidone solution in purified water. The wet granulate was then dried in a fluid bed dryer.
• Tenofovir Disoproxil Fumarate was mixed with excipients and wet granulated using purified water. The wet granulate was then dried in a fluid bed dryer.
• Example 7 Preparation of tenofovir disoproxil fumarate granulate by dry mixing
• Tenofovir granulation is produced by dry mixing of tenofovir Disoproxil together with the excipients.
• Example 7A Preparation of Tenofovir Disoproxil Fumarate granulate
• Tenofovir granulate total 580.00
• Tenofovir Disoproxil Fumarate was mixed with excipients and wet granulated using purified water. The wet granulate was then dried in a fluid bed dryer.
• Example 8 preparation of a monolithic tablet containing emtricitabine, tenofovir, darunavir and ritonavir (extra-granular).
• Emtricitabine/ tenofovir granulate including the extra-granular disintegrant was prepared according to example 4 A or 4B. Then darunavir-ritonavir formulations, prepared according to example 2, were added. Then, the final mixture was further compressed into tablet cores.
• the tablet cores were then coated with a film coating material to produce film coated tablets. (Approximately 3% weight gain).
• Example 9 Preparation of a bi-layer tablet containing emtricitabine and tenofovir in the first layer, darunavir and ritonavir (extra-granular) in the second layer.
• Emtricitabine/ tenofovir granulate including the extra-granular disintegrant is prepared according to example 4A, then it is mixed with Magnesium stearate.
• Darunavir-ritonavir formulation prepared according to example 2, excluding the compression step.
• the two blends are then compressed into tablet cores.
• the tablet cores are then coated with a film coating material to produce film coated tablets. (Approximately 3% weight gain).
• Example 10 Preparation of a monolithic tablet containing emtricitabine, tenofovir, darunavir and ritonavir (intra-granular).
• Emtricitabine/ tenofovir granulate including the extra-granular disintegrant was prepared according to example 4A or 4B. Then darunavir-ritonavir formulation, prepared according to example 3 was added, excluding the compression step. Then, the final mixing was further compressed into tablet cores.
• the tablet cores were then coated with a film coating material to produce film coated tablets. (Approximately 3% weight gain).
• Example 11 Preparation of a bi-layer tablet containing emtricitabine and tenofovir in the first layer, darunavir and ritonavir (intra-granular) in the second layer.
• Emtricitabine/ tenofovir granulate including the extra-granular disintegrant is prepared according to example 4A, then it is mixed with magnesium stearate.
• Final blend 2 nd layer is prepared according to example 4A, then it is mixed with magnesium stearate.
• Darunavir-ritonavir formulation prepared according to example 3, excluding the compression step.
• the two blends are then compressed into tablet cores.
• the tablet cores are then coated with a film coating material to produce film coated tablets. (Approximately 3% weight gain).

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