Classifications

• • 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
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• • 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
  • A61K31/66—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
  • 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
  • A61K9/2086—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
  • 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 an oral unit dosage form comprising as active agents, emtricitabine, tenofovir, darunavir and ritonavir and to a monolithic tablet comprising as active agents, 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 pharmaceutically 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;
• 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 monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.
• Tenofovir is also available in a fixed-dose combination with emtricitabine in a product with the brand name TRUVADA , which has been approved for once-a-day dosing.
• Each TRUVADA tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, (which is equivalent to 245 mg of tenofovir disoproxil), as active ingredients.
• 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' 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.
• 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, crospovidone, magnesium stearate, and microcrystalline cellulose. 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 the systematic chemical name for which is l,3-thiazol-5-ylmethyl N- [(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2- ⁇ [methyl( ⁇ [2-(propan-2-yl)-l,3-thiazol-4- yl]methyl ⁇ )carbamoyl]amino ⁇ butanamido]-l,6-diphenylhexan-2-yl]carbamate, is another antiretroviral drug of the protease inhibitor (PI) class which is used to treat infection by HIV-I Its synthesis use, formulation and combinations thereof are described in various publications including, inter alia, U.S. Patent Nos. 5,541,206; 5,648,497, 6,037, 157, 7, 364, 752 and US8, 268, 349.
• PI protease inhibitor
• Norvir® is available as 100 mg tablet or capsule and as an 80mg/ml oral solution.
• Ritonavir is a BCS (biopharmaceutical classification system) class IV material.
• BCS biological pharmaceutical 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 (E171), macrogols, hydroxypropyl cellulose, talc, anhydrous colloidal silica and polysorbate 80.
• the total weight of the Norvir® tablet is 800mg, and the tablet has dimensions of 17.2x5.8mm.
• HAART highly active antiretroviral therapy
• WO2009/081174 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, WO2009/081174 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.
• 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 is less than about lOOmg.
• the present invention further provides a monolithic tablet comprising:
• ritonavir or a physiologically functional derivative thereof, wherein the amount of ritonavir is less than or equal to about 70mg.
• the present invention further provides a monolithic tablet comprising:
• the present invention further provides a monolithic tablet comprising:
• ritonavir or a physiologically functional derivative thereof, wherein the ritonavir is in the form of its crystalline form II and/or wherein the amount of ritonavir is less than or equal to about 70mg.
• the present invention further provides a monolithic tablet comprising:
• the present invention further provides a monolithic tablet comprising:
• the present invention further provides a monolithic tablet in a unit dosage form comprising: (a) about 300 mg of tenofovir disoproxil fumarate,
• ritonavir is less than about lOOmg and wherein the ritonavir is in the form of ritonavir pre-mix.
• the present invention further provides a monolithic tablet comprising:
• darunavir or a physiologically functional derivative thereof preferably darunavir hydrate or darunavir ethanolate
• the amount of darunavir is 800 mg and
• ritonavir or a physiologically functional derivative thereof; wherein the amount of ritonavir is less than or equal to about 70 mg.
• the present invention further provides a monolithic tablet comprising:
• darunavir or a physiologically functional derivative thereof preferably darunavir hydrate or darunavir ethanolate
• ritonavir or a physiologically functional derivative thereof; wherein the amount of ritonavir is less than or equal to about 70 mg and wherein the ritonavir is in the form of ritonavir crystalline form II.
• 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.
• physiologically functional derivative includes any: pharmaceutically acceptable salts, pharmaceutically acceptable enantiomers, pharmaceutically acceptable solid state form (crystalline, semi-crystalline or amorphous), pharmaceutically acceptable
• polymorphs for example, wherein the prodrug is an ester
• 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 prodrug, 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.
• a ritonavir hot melt-extrusion process comprises the steps of preparing a homogeneous melt of ritonavir or a combination of ritonavir and another therapeutic agent(s), water-soluble polymer and surfactant, and then cooling the melt until it solidifies.
• Melting means a transition into a liquid or rubbery state in which it is possible for one component to get embedded homogeneously in the other. Typically, one component will melt and the active ingredient(s) will dissolve in the melt thus forming a solution. Melting usually involves heating above the softening point of the water-soluble 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 components can be mixed first and then melted, or be simultaneously mixed and melted.
• the melt is homogenized in order to disperse the active ingredients efficiently.
• it may be convenient first to melt the water-soluble polymer and then to mix in and homogenize the active ingredients.
• the hot melt extrusion process requires the use of a large ratio of polymer to drug in order to form the melt.
• the process results in the production of mixture containing amorphous ritonavir in the polymeric mass. Due to the high polymer content required, the preparation of ritonavir compositions by hot melt extrusion is not preferred when formulating unit dosage forms containing more than one drug due to limitations on the size of the dosage form for administration by, e.g. swallowing.
• the ritonavir in the unit dosage form of the present invention can be prepared by a process that avoids the use of hot melt extrusion process.
• the ritonavir which may preferably be crystalline Form I or Form II as described above, can be prepared by wet or dry granulation or by blending, optionally with excipients and/or one or more of the other active agents in the dosage form.
• a reference to weight% of the dosage form means 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.
• the finishing/cosmetic coating can add, e.g. about 2% to about 5%, preferably about 2 to about 4% and particularly about 3% by weight to the total weight of the tablet.
• the term "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
• 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 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.
• any change in the darunavir and ritonavir contents, and/or tenofovir and 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. Examples of such parameters include: t 2 (half-life), C m i n (minimal plasma concentration), C trough
• C max maximal plasma concentration
• AUC area under the curve
• T max 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 ) at recommended effective doses as a pharmacokinetic enhancer.
• references hereinafter to a pharmaceutical formulation refer unless otherwise stated to a pharmaceutical formulation containing the combination or also their physiologically functional derivatives.
• 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.
• emtricitabine, tenofovir and darunavir and ritonavir may be formulated to produce a composition in which the peak plasma concentrations of each of the active agents in the formulation are similar or the same as (i.e. "bioequivalent to”) the peak plasma concentrations achieved by separate administration of each active, when administered to individual.
• ritonavir-mediated pharmacokinetic enhancement of darunavir may still be achieved even if the peak plasma concentrations of the ritonavir in the formulations do not reach those of the commercially available lOOmg ritonavir tablet composition (Norvir®) (i.e. effective pharmacokinetic enhancement of darunavir by ritonavir in the compositions according to any aspect of the present invention does not require bioequivalence with the commercially available lOOmg Norvir® tablet).
• the ritonavir in the formulations containing emtricitabine, tenofovir, darunavir and ritonavir, or the monolithic tablet comprising ritonavir and darunavir is not bioequivalent to the commercially available 100 mg ritonavir tablet composition (Norvir®).
• the ritonavir can be present in any of the formulations of the present invention in an amount of less than about 100 mg, less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg, e.g.
• the ritonavir can be present in any of the formulations of the present invention in an amount of between about 50 mg to about 60 mg, to about 70 mg, to about 80 mg, to about 100 mg, between about 60 mg to about 70 mg, to about 80 mg, to about 100 mg, between about 80 mg, to about 100 mg, preferably, the ritonavir can be present in any of the formulations of the present invention in an amount of about 70 mg.
• Non-bioequivalent ritonavir refers to a formulation in which the ritonavir exhibits statistically significant difference in the bioavailability compared to the bioavailability of the reference product, i.e. the commercially available Norvir® tablet as marketed by Abbott Laboratories and as described above.
• Bioavailability and hence bioequivalence/non- bioequivalence can be determined by reference to pharmacokinetic parameters such as AUC 0-t , AUCo-oo and C max in accordance with the regulatory guidelines - for example US Food and Drug Administration (FDA) "Guidance for Industry” - Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations, March 2003, Revision 1; http://www.fda.
• FDA US Food and Drug Administration
• non-bioequivalence requires pharmacokinetic parameters (particularly AUCo- t and C max ) in which 90% confidence interval (CI) values of the ratio of the test and the reference product are within the range of at least 80.00% and not more than 125.00%.
• non-bioequivalence refers to pharmacokinetic parameters (particularly AUCo-t and C max ) in which 90% confidence interval values of the ratio of the test and the reference product are outside of this range.
• non-bioequivalence for ritonavir preferably refers to pharmacokinetic parameters (preferably one or both of AUCo- t and C max ) in which 90% confidence interval values of the ratio of the test (i.e.
• the ritonavir in the formulation is non-bioequivalent to the commercially available Norvir® tablet, particularly wherein the 90% confidence interval for the ratio of the ritonavir and the corresponding commercially available lOOmg ritonavir (Norvir®) is from about 30 up to but not including 80.00%, from about 35 up to but not including 80.00%, from about 40 up to but not including 80.00%, from about 45 up to but not including 80.00%, from about 50 up to but not including 80.00%, from about 55 up to but not including 80.00%, from about 60 up to but not including 80.00%, from about 65 up to but not including 80.00%, from about 70 up to but not including 80.00%, or from about 75 % up to but not including 80.00%.
• the ritonavir in the formulation is non-bioequivalent to the commercially available Norvir® tablet, particularly wherein the 90% confidence interval for the ratio of the ritonavir and the corresponding commercially available lOOmg ritonavir (Norvir®) is from about 30: to about 35, 40, 45, 50, 55, 60, 65, 70, or 75%; or from about 35: to about 40, 45, 50, 55, 60, 65, 70, or 75%; or from about 40: to about 45, 50, 55, 60, 65, 70, or 75%; or from about 45: to about 50, 55, 60, 65, 70 or 75%; or from about 50: to about 55, 60, 65, 70 or 75 %; or from about 55: to about 60, 65, 70, or 75 %; or from about 60: to about 65, 70, or 75 %; or from about 70 to about 75 %.
• rate of release or “release rate” of a drug refers to the amount or percentage (preferably percentage) of drug released from a dosage form per unit time, e.g., a weight % of drug released (relative to the total weight % of that drug in the dosage form) within a particular time (wt%/x minutes).
• Drug release rates for dosage forms are typically measured in vitro as an amount or percentage (preferably percentage) of drug released from the dosage form, after a particular time measured under appropriate conditions and in a suitable fluid.
• drug release rate is determined using 1800ml of 2% Brij-35 (30% solution in water) in 0.05M phosphate buffer, having a pH of 3.0, using paddles apparatus (USP apparatus II) at 75 rpm, at a temperature of 37°C ⁇ 0.5 °C.
• 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:
• ritonavir or a physiologically functional derivative thereof; wherein the amount of ritonavir is less than about lOOmg.
• 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 (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 less than about 100 mg, less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg, e.g. the amount of ritonavir can be between about 50 mg to about 60 mg, to about 70 mg, to about 80 mg, to about 100 mg, between about 60 mg to about 70 mg, to about 80 mg, to about 100 mg, between about 80 mg, to about 100 mg, preferably, the amount of ritonavir can be about 70 mg.
• the said ritonavir can be in a crystalline form as well as amorphous ritonavir, for example, the said ritonavir can be in a crystalline form and/or amorphous ritonavir, i.e., the crystalline form can be for example, Form I or Form II, preferably, ritonavir Form II.
• the pharmaceutical formulation of the present invention comprises about 300mg of tenofovir disoproxil fumarate, about 200mg of emtricitabine, about 800mg of darunavir and less than or equal to about 70 mg 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 of any embodiment of the present invention may be divisible into one or more subunits.
• the tablet may be provided with one or more score lines (e.g. indentations or grooves) enabling it to be divided into a plurality of parts.
• a tablet of any embodiment of the present invention may be provided with score lines to enable the tablet to be divided into two, three or four parts.
• the tablet may be provided with a score line across the tablet, enabling it to be divided into two (preferably substantially equal) parts - e.g. for a round tablet, a score line may be provided across a diameter of the tablet, enabling the tablet to be divided (broken) into two substantially equal halves.
• a tablet according to any embodiment of the present invention may be provided with two score lines enabling it to be divided into three (preferably substantially equal) portions.
• the tablet in the case of a round tablet, the tablet may be provided with three score lines extending radially from the centre, enabling the tablet to be divided into three parts.
• a tablet according to any embodiment of the invention may be provided with three score lines, in order to enable the tablet to be divided into four (preferably substantially equal) parts.
• the tablet in the case of a round tablet, the tablet may be provided with two perpendicular score lines across the diameter of the tablet, thus enabling the tablet to be divided into four parts.
• the score line(s) may provided on one face of the tablet, and optionally additionally on the sides of the tablet to further facilitate division of the tablet.
• the score line(s) may be provided on both faces of the tablet and optionally additionally on the sides of the tablet.
• the score lines are preferably formed by a continuous indentation (groove) across a surface of the tablet.
• Score lines may be provided by any known method. Preferably, score lines are provided during the tablet compression step.
• the die used for the compression can be shaped so as to provide a score line during tablet compression.
• the tablet can have a weight as mentioned above for the total weight of the
• 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; preferably, 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 11mm, most preferably, the largest maximum diameter can be about 25mm and the depth can be about 11mm.
• the hardness of the tablet of the present invention comprising the 4 APIs, can be about 75 Strong-Cobb Units (SCU) to about 20 SCU, preferably, about 55 SCU to about 25 SCU, more preferably, about 35 SCU to about 30 SCU as measured by Electronic D-64291
• 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, or ⁇ 100mg, or preferably ⁇ 70mg, 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 total tablet weight of the tablet of the present invention comprising: a) about 300 mg of tenofovir disoproxil fumarate,
• ritonavir or a physiologically functional derivative thereof wherein the amount of ritonavir is less than about lOOmg, 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.
• ritonavir or a physiologically functional derivative thereof, wherein the amount of ritonavir is less than about lOOmg 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.
• the said darunavir can be darunavir ethanolate, hydrate, or any other crystalline form as well as darunavir amorphous.
• the amount of ritonavir can be less than about 100 mg, less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg, e.g. the amount of ritonavir can be between about 50 mg to about 60 mg, to about 70 mg, to about 80 mg, to about 100 mg, between about 60 mg to about 70 mg, to about 80 mg, to about 100 mg, between about 80 mg, to about 100 mg, preferably, the amount of ritonavir can be about 70 mg.
• the said ritonavir can be in a crystalline form as well as amorphous ritonavir, for example, the said ritonavir can be in a crystalline form and/or amorphous ritonavir, i.e., crystalline form can be for example, Form I or Form II, preferably, ritonavir Form II.
• the tablet of the present invention comprises about 300mg of tenofovir disoproxil fumarate, about 200mg of emtricitabine, about 800mg of darunavir and less than or equal to about 70 mg of ritonavir.
• the present invention further provides a pharmaceutical formulation in a unit dosage form comprising:
• ritonavir or a physiologically functional derivative thereof, wherein the amount of ritonavir is less than about lOOmg, and wherein the ritonavir is in the form of a pre-mix, and wherein:
• ritonavir - at least 45% to 55% of ritonavir is released from the formulation within 10 minutes, or 65% to 75% of ritonavir is released from the formulation within 30 minutes.
• the pharmaceutical formulation may provide a release rate of tenofovir, emtricitabine, darunavir and ritonavir as specified above.
• the present invention additionally provides a pharmaceutical formulation in a unit dosage form comprising:
• darunavir at least 25% to 30% of darunavir is released from the formulation within 10 minutes, or 60% to 65% of darunavir is released within 30 minutes; or
• the pharmaceutical formulation may provide a release rate of tenofovir, emtricitabine, darunavir and ritonavir as specified above.
• 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 multilayer 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
• 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.
• the single layer can include a granulate of darunavir and a granules comprising emtricitabine, tenofovir and ritonavir.
• 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
• Darunavir can be mixed with at least one disintegrant such as Croscarmellose Sodium (Ac-Di-Sol), prior to the top spray process.
• the obtained milled granulate of darunavir can then be mixed with ritonavir pre-mix or with ritonavir Form II, at least one filler such as microcrystalline cellulose, at least one disintegrant such as crospovidone, and at least one glidant such as silicon dioxide.
• 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 extra-granular ritonavir).
• Ritonavir form II can be wet granulated prior to the mixing with the granulate of darunavir and the other excipients, in providing the darunavir with extra-granular ritonavir.
• ritonavir form II can be wet granulated with at least one filler such as microcrystalline cellulose, followed by drying the wet granulate and milling the dry granulate.
• 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), by a top spray process on a mixture of darunavir and ritonavir pre-mix or on a mixture of darunavir and ritonavir Form II, followed by drying the wet granulate and milling the dry granulate.
• a suitable liquid e.g. water
• Darunavir and ritonavir can be mixed with at least one disintegrant such as Croscarmellose Sodium (Ac-Di-Sol), prior to the top spray process.
• 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).
• the disintegrant used prior to the top spray process can be in an amount of about 2% to about 30% by weight of total weight of the tablet, or from about 5% to about 30%, or from about 5% to about 20%, or from about 5% to about 15%, or from about 5% to 10% by weight of total weight of the tablet.
• the weight ratio of disintegrant (preferably croscarmellose sodium (Ac-Di-Sol) to darunavir is from about 1:5 to about 1 :25, preferably from about 1:8 to about 1:20, more preferably from about 1 : 10 to about 1: 15.
• the ritonavir pre-mix can be a co-precipitate of ritonavir with a pharmaceutically acceptable carrier, and optionally other pharmaceutically acceptable excipients.
• the pharmaceutically acceptable carrier can preferably be copovidone.
• Other pharmaceutically acceptable excipients in the coprecipitate may include a solubilizer (such as sorbitan laurate), and a glidant (such as colloidal silica).
• the ritonavir pre-mix can be a coprecipitate comprising ritonavir and copovidone.
• the ritonavir pre-mix can be a coprecipitate comprising Ritonavir, copovidone, sorbitan laurate and colloidal silica.
• the ritonavir in the pre-mix can be preferably in an amorphous form.
• the ritonavir is in the form of a pre-mix comprising a co-precipitate of ritonavir with a pharmaceutically acceptable carrier, and optionally other pharmaceutically acceptable excipients.
• Copovidone is a preferred pharmaceutically acceptable carrier.
• Other pharmaceutically acceptable excipients may include: a solubilizer (preferably sorbitan laurate), and/or a glidant (preferably colloidal silica).
• a preferred pre-mix comprises ritonavir in the form of a co-precipitate comprising ritonavir, copovidone, sorbitan laurate and colloidal silica.
• the co-precipitate of ritonavir and a carrier contains a weight ratio of carrier: ritonavir of: about 1:2 to about 1: 10, about 1:2 to about 1:7, about 1 :3 to about 1:7, about 1:3 to about 1:6, or about 1:3 to about 1:5.
• the co-precipitate comprises the carrier, preferably copovidone, in an amount of about 5 to about 30 wt%, about 10 to about 28 wt%, about 12 to about 25 wt%, or about 15 to about 23 wt%.
• the co-precipitate comprises Ritonavir in an amount of about 50 to about 95 wt%, about 60 to about 85 wt%, about 70 to about 85 wt%, about 70 to about 80 wt%, about 72 to about 80 wt%, or about 75 to about 77 wt%.
• 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 such as microcrystalline cellulose, at least one binder such as pregelatinized starch and at least one disintegrant such as croscarmellose sodium, wet granulating the mixture with water, drying the wet granulate and milling the dry granulate.
• filler such as microcrystalline cellulose
• binder such as pregelatinized starch
• disintegrant such as croscarmellose sodium
• the obtained granulate of emtricitabine and tenofovir can be mixed with the final blend of darunavir-ritonavir(i.e., darunavir with extra-granular ritonavir or darunavir with intra-granular ritonavir, as described above ) and at least one filer such as microcrystalline cellulose, at least one disintegrant selected from: croscarmellose sodium (Ac-Di-Sol) and/or crospovidone, and at least one glidant such as silicon dioxide.
• at least one lubricant such as sodium stearyl fumarate can be added to the obtained mixture to obtain 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.
• the 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 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 be 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.
• Granules of emtricitabine, tenofovir and ritonavir can be prepared by combining emtricitabine, tenofovir and ritonavir form II with at least one filler such as microcrystalline cellulose, at least one binder such as 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, followed by drying the wet granulate and milling the dry granulate.
• filler such as microcrystalline cellulose
• binder such as pregelatinized starch
• disintegrant such as croscarmellose sodium
• a bi-layer tablet comprising emtricitabine, tenofovir, darunavir and ritonavir according to the present invention is composed of two distinct layers of the compounds/active
• 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). 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.
• 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); (b) compressing the two blend layers into a tablet; and
• 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
• the present invention provides a monolithic tablet comprising:
• darunavir or a physiologically functional derivative thereof and 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 l.
• 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 less than about 100 mg, less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg, e.g. the amount of ritonavir can be between about 50 mg to about 60 mg, to about 70 mg, to about 80 mg, to about 100 mg, between about 60 mg to about 70 mg, to about 80 mg, to about 100 mg, between about 80 mg, to about 100 mg, preferably, the amount of ritonavir can be about 70 mg.
• the said ritonavir can be in a crystalline form as well as amorphous ritonavir, for example, the said ritonavir can be in a crystalline form and/or amorphous ritonavir, i.e., crystalline form can be for example, Form I or Form II, preferably, ritonavir Form II.
• the tablet of the present invention comprises about 300mg of tenofovir disoproxil fumarate, about 200mg of emtricitabine, about 800mg of darunavir and less than or equal to about 70 mg 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 PH102 having or PH101), 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.
• Suitable binders include, for example, cellulose polymers (e.g., hydroxypropylmethyl 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
• croscarmellose sodium swelling polysaccharide, for example soy 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.
• swelling polysaccharide for example soy 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.
• a pharmaceutical formulation in a unit dosage form comprising:
• physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi-crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph, solvate, metabolite or prodrug (such as an ester).
• the physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi-crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph, solvate, metabolite or prodrug (such as an
• tenofovir is in the form of its prodrug tenofovir disoproxil, or wherein the tenofovir disoproxil is in the form of its fumarate salt.
• darunavir is in the form of darunavir ethanolate, hydrate, or any other crystalline form as well as amorphous darunavir, preferably, hydrate.
• ritonavir is in the form of its crystalline form as well as amorphous ritonavir.
• ritonavir is in the form of its crystalline form and/or amorphous ritonavir.
• the ritonavir is in the form of its crystalline form or amorphous ritonavir.
• a pharmaceutical formulation according to any preceding paragraph in the form of a tablet in the form of a tablet.
• a pharmaceutical formulation according to any preceding paragraph in the form of a film-coated tablet in the form of a film-coated tablet.
• a pharmaceutical formulation according to any preceding paragraph in the form of a single unit dosage form for administration once per day.
• a pharmaceutical formulation according to any preceding paragraph wherein the amount of ritonavir is between about 50 mg to about 60 mg, to about 70 mg, to about 80 mg, to about 100 mg, between about 60 mg to about 70 mg, to about 80 mg, to about 100 mg, between about 80 mg, to about 100 mg.
• a pharmaceutical formulation according to any preceding paragraph wherein the amount of ritonavir is less than or equal to about 70 mg.
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form has a total weight of between 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.
• a pharmaceutical formulation according to any preceding paragraph wherein the hardness of the tablet of the present invention, comprising the 4 APIs, can be about 75 Strong-Cobb Units (SCU) to about 20 SCU, preferably, about 55 SCU to about 25 SCU, more preferably, about 35 SCU to about 30 SCU.
• SCU Strong-Cobb Units
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form comprises:
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form comprises about 20% to about 85% by weight of active agents (a)-(d).
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form comprises about 55%: to about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about 85% by weight of active agents (a)-(d).
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form comprises about 60%: to about 65%, to about 70%, to about 75%, to about 80%, or to about 85% by weight of active agents (a)-(d).
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form comprises about 65%: to about 70%, to about 75%, to about 80%, or to about 85% by weight of active agents (a)-(d).
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form comprises about 70%: to about 75%, to about 80%, or to about 85% by weight of active agents (a)-(d).
• a pharmaceutical formulation according to any preceding paragraph wherein the unit dosage form comprises about 75%: to about 80%, or to about 85%, or from about 80% to about 85% by weight of active agents (a)-(d).
• a pharmaceutical formulation according to any preceding paragraph in the form of a monolithic tablet wherein the active agents (a)-(d) are mixed and compressed to a single layer (monolithic) tablet.
• a pharmaceutical formulation according to Paragraph 39 wherein the single layer comprises:
• a pharmaceutical formulation according to Paragraph 40 wherein the granulate of darunavir is prepared by wet granulation of darunavir by top spray process of at least one binder (preferably hypromellose) dissolved in a suitable liquid (preferably water) on darunavir , followed by drying the wet granulate and milling the dry granulate.
• binder preferably hypromellose
• ritonavir form II at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone), and at least one glidant (preferably silicon di-oxide)
• at least one lubricant preferably sodium stearyl fumarate
• a pharmaceutical formulation according to Paragraph 40 wherein the granulate of darunavir-ritonavir is prepared by wet granulation of darunavir with ritonavir form II by top spray process of at least one binder (preferably hypromellose) dissolved in a suitable liquid (preferably water), on a mixture of darunavir and ritonavir, followed by drying the wet granulate and milling the dry granulate.
• a binder preferably hypromellose
• at least one filler preferably microcrystalline cellulose
• at least one disintegrant preferably crospovidone
• at least one glidant preferably silicon di-oxide
• disintegrant such as Croscarmellose Sodium (Ac-Di-Sol)
• disintegrant preferably croscarmellose sodium (Ac-Di-Sol)
• Darunavir is from about 1:5 to about 1:25, preferably from about 1:8 to about 1 :20, more preferably from about 1 : 10 to about 1 : 15.
• microcrystalline cellulose preferably microcrystalline cellulose
• at least one binder preferably pregelatinized starch
• at least one disintegrant preferably croscarmellose sodium
• a pharmaceutical formulation according to any of Paragraphs 40-49 wherein the granules of emtricitabine, tenofovir and ritonavir are prepared by combining emtricitabine, tenofovir and ritonavir form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium), granulating the mixture with water, drying the wet granulate and milling the dry granulate.
• at least one filler preferably microcrystalline cellulose
• at least one binder preferably pregelatinized starch
• disintegrant preferably croscarmellose sodium
• a pharmaceutical formulation according to any preceding paragraph further comprising one or more pharmaceutically acceptable excipients.
• pharmaceutically acceptable excipient is selected from the group consisting of fillers, binders, disintegrants, surfactants, glidants and lubricants.
• a pharmaceutical formulation according to Paragraph 52 wherein the filler (diluent) is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PHI 02 having or PH101), 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.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PHI 02 having or PH101), lactose in its various forms (e.g. lactose USP, anhydrous or spray dried), sorbitol, dextrose,
• hydroxypropylmethyl cellulose hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone polyvinyl alcohol
• starch or pregelatinized starch and the like or any combinations thereof.
• the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose, swelling polysaccharide, for example soy polysaccharide, carrageenan, agar, pectin, starch and derivatives thereof, protein, for example
• a pharmaceutical formulation according to any of Paragraphs 52-57 wherein the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates, sorbitans (particularly sorbitan laurate), polyoxyethylene sorbitans, polyoxylglycerides, or polyoxyethylene castor oil derivatives, and preferably wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.
• the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates, sorbitans (particularly sorbitan laurate), polyoxyethylene sorbitans, polyoxylglycerides, or polyoxyethylene castor oil derivatives, and preferably wherein the surfactant is selected from one
• a pharmaceutical formulation according to any of Paragraphs 1-58 for use as a medicament for use as a medicament.
• a pharmaceutical formulation according to any of Paragraphs 1-58 for use in the treatment of HIV- 1 infection comprising administration of a
• a process for the preparation of a pharmaceutical formulation according to any of Paragraphs 1-58 comprising combining:
• darunavir with extra- granular ritonavir or darunavir with intra- granular ritonavir i.e. a granulate of darunavir-ritonavir
• tenofovir preferably tenofovir disoproxil, and more preferably tenofovir disoproxil fumarate
• tenofovir optionally in the presence of one or more pharmaceutically acceptable excipients to form a blend.
• a process for the preparation of a pharmaceutical formulation according to any of Paragraphs 1-58 comprising combining:
• darunavir with extra- granular ritonavir or darunavir with intra- granular ritonavir i.e. a granulate of darunavir-ritonavir
• a process for the preparation of a pharmaceutical formulation according to any of Paragraphs 1-58 comprising combining:
• acceptable excipient comprises at least one excipient selected from a filler (preferably microcrystalline cellulose), a disintegrant (preferably crospovidone and /or croscarmellose sodium), a glidant (preferably silicon di-oxide) and a lubricant (preferably sodium stearyl fumarate).
• a filler preferably microcrystalline cellulose
• a disintegrant preferably crospovidone and /or croscarmellose sodium
• a glidant preferably silicon di-oxide
• a lubricant preferably sodium stearyl fumarate
• excipient comprises microcrystalline cellulose, crospovidone and /or croscarmellose sodium, silicon di-oxide and sodium stearyl fumarate.
• a process according to any of Paragraphs 62-67 further comprising processing the blend to provide a solid dosage form.
• a process according to any of Paragraphs 62-67 comprising compressing the blend to form a tablet, and optionally coating the tablet with a film coating material to form a film coated tablet.
• binder preferably hypromellose
• darunavir-ritonavir preferably darunavir with extra-granular ritonavir
• a binder preferably hypromellose
• at least one filler preferably microcrystalline cellulose
• at least one disintegrant preferably crospovidone
• at least one glidant preferably silicon dioxide
• darunavir is mixed with at least one disintegrant such as Croscarmellose Sodium (Ac-Di-Sol), preferably wherein the disintegrant in an amount of about 2% to about 30% by weight of total weight of the dosage form, or from about 5% to about 30%, or from about 5% to about 20%, or from about 5% to about 15%, or from about 5% to 10% by weight of total weight of the dosage form.
• disintegrant such as Croscarmellose Sodium (Ac-Di-Sol
• croscarmellose sodium (Ac-Di-Sol) to darunavir is from about 1:5 to about 1:25, preferably from about 1 :8 to about 1:20, more preferably from about 1: 10 to about 1 : 15.
• at least one filler preferably lactose
• at least one disintegrant preferably crospovidone
• emtricitabine granules are prepared by combining emtricitabine with at least one filler (preferably microcrystalline cellulose and/or pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium) to obtain a mixture, combining the mixture with a solution of a binder (preferably an aqueous solution of povidone), to form wet granules, and drying the wet granules.
• at least one filler preferably microcrystalline cellulose and/or pregelatinized starch
• at least one disintegrant preferably croscarmellose sodium
• at least one filler preferably microcrystalline cellulose (e.g. Avicel®)
• at least one disintegrant/binder preferably pregelatinized starch
• tenofovir is wet granulated with at least one filler (preferably lactose), at least one disintegrant (preferably crospovidone) and at least one binder (preferably povidone) and optionally at least one lubricant (preferably magnesium stearate), with a granulating liquid (preferably water) to provide wet granules, and drying the wet granules.
• filler preferably lactose
• disintegrant preferably crospovidone
• binder preferably povidone
• optionally at least one lubricant preferably magnesium stearate
• at least one filler preferably microcrystalline cellulose and/or pregelatinized starch
• a granulating liquid preferably water
• emtricitabine and tenofovir are prepared by combining emtricitabine and tenofovir with at least one pharmaceutically acceptable excipient and wet granulating, to form wet granules, and drying the wet granules.
• At least one filler preferably lactose
• at least one disintegrant preferably crospovidone
• at least one binder preferably pregelatinized starch or povidone
• emtricitabine and tenofovir are prepared by combining emtricitabine and tenofovir with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium) granulating the mixture with water, drying the wet granulate and milling the dry granulate.
• filler preferably microcrystalline cellulose
• binder preferably pregelatinized starch
• disintegrant preferably croscarmellose sodium
• emtricitabine, tenofovir and ritonavir form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium), granulating the mixture with water, drying the wet granulate and milling the dry granulate.
• filler preferably microcrystalline cellulose
• binder preferably pregelatinized starch
• disintegrant preferably croscarmellose sodium
• compositions preferably selected from one or more of the group consisting of fillers, binders, disintegrants, surfactants, glidants and lubricants.
• a process for the preparation of a pharmaceutical formulation according to Paragraph 90 wherein the filler (diluent) is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), 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.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), lactose in its various forms (e.g. lactose USP, anhydrous or spray dried), sorbito
• a process for the preparation of a pharmaceutical formulation to Paragraph 90-91 wherein the binder is selected from one or more of the group consisting of cellulose polymers (e.g. hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch and the like or any combinations thereof.
• cellulose polymers e.g. hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone polyvinyl alcohol
• starch or pregelatinized starch and the like or any combinations thereof.
• the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose, swelling polysaccharide, for example soy 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.
• a monolithic tablet comprising:
• ritonavir or a physiologically functional derivative thereof, wherein the amount of ritonavir is less than or equal to about 70mg.
• a monolithic tablet according to Paragraph 1A wherein the physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi-crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph, solvate, metabolite or prodrug (such as an ester).
• the physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi-crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph, solv
• darunavir is in the form of darunavir ethanolate, hydrate, or any other crystalline form as well as amorphous darunavir, preferably, hydrate.
• ritonavir is in the form of its crystalline form as well as amorphous ritonavir.
• ritonavir is in the form of its crystalline form and/or amorphous ritonavir.
• the ritonavir is in the form of its crystalline form or amorphous ritonavir.
• ritonavir is in the form of ritonavir crystalline form II.
• a monolithic tablet according to any preceding paragraph wherein the hardness of the tablet of the present invention, comprising the 4 APIs, can be about 75
• Strong-Cobb Units SCU to about 20 SCU, preferably, about 55 SCU to about 25
• SCU more preferably, about 35 SCU to about 30 SCU.
• a monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises:
• a A monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• a A monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• a monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• a monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• a monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises about 65%: to about 70%, to about 75%, to about 80%, or to about 85% by weight of active agents (a)-(d).
• binder preferably hypromellose
• ritonavir form II at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone), and at least one glidant (preferably silicon di-oxide)
• at least one lubricant preferably sodium stearyl fumarate
• a binder preferably hypromellose
• at least one filler preferably microcrystalline cellulose
• at least one disintegrant preferably crospovidone
• at least one glidant preferably silicon di-oxide
• a disintegrant such as Croscarmellose Sodium (Ac-Di-Sol)
• disintegrant preferably croscarmellose sodium (Ac-Di-Sol)
• Darunavir is from about 1:5 to about 1 :25, preferably from about 1 :8 to about 1:20, more preferably from about 1 : 10 to about 1: 15.
• at least one filler preferably microcrystalline cellulose
• At least one binder preferably pregelatinized starch
• at least one disintegrant preferably croscarmellose sodium
• a A monolithic tablet according to any of Paragraphs 35A-43A wherein the granules comprising emtricitabine, tenofovir and ritonavir are prepared by combining emtricitabine, tenofovir and ritonavir form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium), granulating the mixture with water, drying the wet granulate and milling the dry granulate.
• a A monolithic tablet according to any preceding paragraph further comprising one or more pharmaceutically acceptable excipients.
• a monolithic tablet according to Paragraph 47 A wherein the filler (diluent) is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), 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.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), lactose in its various forms (e.g. lactose USP, anhydrous or spray dried), sorbitol, dex
• hydroxypropylmethyl cellulose hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone polyvinyl alcohol
• starch or pregelatinized starch and the like or any combinations thereof.
• the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose, swelling polysaccharide, for example soy polysaccharide, carrageenan, agar, pectin, starch and derivatives thereof,
• a monolithic tablet according to any of Paragraphs 47A-52A wherein the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates, sorbitans (particularly sorbitan laurate), polyoxyethylene sorbitans, polyoxylglycerides, or polyoxyethylene castor oil derivatives, and preferably wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.
• the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates, sorbitans (particularly sorbitan laurate), polyoxyethylene sorbitans, polyoxylglycerides, or polyoxyethylene castor oil derivatives, and preferably wherein the surfactant
• a monolithic tablet according to any of Paragraphs 1 A-53A for use as a medicament is provided.
• a method for treating HIV-1 infection comprising administration of a pharmaceutically effective amount of the monolithic tablet according to any of Paragraphs 1A-53A.
• a monolithic tablet comprising:
• ritonavir or a physiologically functional derivative thereof, wherein the ritonavir is in the form of its crystalline form II.
• a monolithic tablet according to Paragraph IB wherein the physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi -crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph, solvate, metabolite or prodrug (such as an ester).
• the physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi -crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph,
• darunavir is in the form of darunavir ethanolate, hydrate, or any other crystalline form as well as amorphous darunavir, preferably, hydrate.
• the largest maximum diameter of the tablet of the present invention comprising the 4 APIs, is about 27mm or less and the depth is less than about 12.5mm; preferably, the largest maximum diameter is between about 26mm to about 27mm and the depth is between about 12.5mm to about 10mm, more preferably, the largest maximum diameter is about 25mm and the depth can be about 11mm.
• a monolithic tablet according to any preceding paragraph wherein the hardness of the tablet of the present invention, comprising the 4 APIs, can be about 75 Strong- Cobb Units (SCU) to about 20 SCU, preferably, about 55 SCU to about 25 SCU, more preferably, about 35 SCU to about 30 SCU.
• SCU Strong- Cobb Units
• the unit dosage form comprises 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 active agents (a)-(d).
• B A monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• binder preferably hypromellose
• ritonavir form II at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone), and at least one glidant (preferably silicon di-oxide)
• at least one lubricant preferably sodium stearyl fumarate
• a binder preferably hypromellose
• Croscarmellose Sodium preferably in an amount of about 2% to about 30% by weight of total weight of the dosage form, or from about 5% to about 30%, or from about 5% to about 20%, or from about 5% to about 15%, or from about 5% to 10% by weight of total weight of the dosage form.
• disintegrant preferably croscarmellose sodium (Ac-Di-Sol)
• Darunavir is from about 1:5 to about 1 :25, preferably from about 1 :8 to about 1 :20, more preferably from about 1: 10 to about 1: 15.
• at least one filler preferably microcrystalline cellulose
• at least one filler preferably microcrystalline cellulose
• at least one binder preferably pregelatinized starch
• at least one disintegrant preferably croscarmellose sodium
• a monolithic tablet according to any of Paragraphs 33B-41B wherein the granules comprising emtricitabine, tenofovir and ritonavir are prepared by combining emtricitabine, tenofovir and ritonavir form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium), granulating the mixture with water, drying the wet granulate and milling the dry granulate.
• the filler preferably microcrystalline cellulose
• at least one binder preferably pregelatinized starch
• disintegrant preferably croscarmellose sodium
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), 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.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), lactose in its various forms (e.g. lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol,
• hydroxypropylmethyl cellulose hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone polyvinyl alcohol, starch or
• pregelatinized starch and the like or any combinations thereof.
• carboxymethyl starch cross-linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose, swelling polysaccharide, for example soy 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.
• Cross-linked polyvinylpyrrolidone Cross-linked polyvinylpyrrolidone
• sodium carboxymethyl glycolate for example Explotab®
• croscarmellose swelling polysaccharide, for example soy 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.
• the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyltnmethylammonium salts, alcohol ethoxylates, sorbitans (particularly sorbitan laurate), polyoxyethylene sorbitans, polyoxylglycerides, or polyoxyethylene castor oil derivatives, and preferably wherein the surfact
• a method for treating HIV-1 infection comprising administration of a pharmaceutically effective amount of the monolithic tablet according to any of
• a monolithic tablet comprising:
• ritonavir or a physiologically functional derivative thereof, wherein the ritonavir is in the form of its crystalline form II and/or wherein the amount of ritonavir is less than or equal to about 70mg.
• a monolithic tablet according to Paragraph 1C wherein the physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi -crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph, solvate, metabolite or prodrug (such as an ester).
• the physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi -crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph,
• darunavir is in the form of darunavir ethanolate, hydrate, or any other crystalline form as well as amorphous darunavir, preferably, hydrate.
• the largest maximum diameter of the tablet of the present invention comprising the 4 APIs, is about 27mm or less and the depth is less than about 12.5mm; preferably, the largest maximum diameter is between about 26mm to about 27mm and the depth is between about 12.5mm to about 10mm, more preferably, the largest maximum diameter is about 25mm and the depth can be about 11mm.
• a monolithic tablet according to any preceding paragraph wherein the hardness of the tablet of the present invention, comprising the 4 APIs, can be about 75 Strong- Cobb Units (SCU) to about 20 SCU, preferably, about 55 SCU to about 25 SCU, more preferably, about 35 SCU to about 30 SCU.
• SCU Strong- Cobb Units
• C A monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• C A monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises about 55%: to about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about 85% by weight of active agents (a)-(d).
• a binder preferably hypromellose
• ritonavir form II at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone), and at least one glidant (preferably silicon di-oxide)
• at least one lubricant preferably sodium stearyl fumarate
• a binder preferably hypromellose
• at least one filler preferably microcrystalline cellulose
• at least one disintegrant preferably crospovidone
• at least one glidant preferably silicon di-oxide
• C A monolithic tablet according to Paragraph 37C wherein the weight ratio of disintegrant (preferably croscarmellose sodium (Ac-Di-Sol) to Darunavir is from about 1:5 to about 1 :25, preferably from about 1:8 to about 1:20, more preferably from about 1: 10 to about 1: 15.
• at least one filler preferably microcrystalline cellulose
• at least one binder preferably pregelatinized starch
• at least one disintegrant preferably croscarmellose sodium
• emtricitabine, tenofovir and ritonavir form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium), granulating the mixture with water, drying the wet granulate and milling the dry granulate.
• filler preferably microcrystalline cellulose
• binder preferably pregelatinized starch
• disintegrant preferably croscarmellose sodium
• a monolithic tablet according to any preceding paragraph further comprising one or more pharmaceutically acceptable excipients.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), 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.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), lactose in its various forms (e.g. lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol,
• hydroxypropylmethyl cellulose hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone polyvinyl alcohol, starch or
• pregelatinized starch and the like or any combinations thereof.
• carboxymethyl starch cross-linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose, swelling polysaccharide, for example soy 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.
• Cross-linked polyvinylpyrrolidone Cross-linked polyvinylpyrrolidone
• sodium carboxymethyl glycolate for example Explotab®
• croscarmellose swelling polysaccharide, for example soy 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.
• C A monolithic tablet according to any of Paragraphs 1C-50C for use as a medicament.
• a method for treating HIV-1 infection comprising administration of a pharmaceutically effective amount of the monolithic tablet according to any of Paragraphs 1C-50C.
• a monolithic tablet comprising:
• a monolithic tablet according to Paragraph ID wherein the physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi -crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph, solvate, metabolite or prodrug (such as an ester).
• the physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi -crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph,
• darunavir is in the form of darunavir ethanolate, hydrate, or any other crystalline form as well as amorphous darunavir, preferably, hydrate.
• ritonavir is in the form of its crystalline form as well as amorphous ritonavir.
• ritonavir is in the form of its crystalline form and/or amorphous ritonavir.
• the ritonavir is in the form of its crystalline form or amorphous ritonavir.
• ritonavir is in the form of ritonavir crystalline form II.
• D A monolithic tablet according to paragraph 9D wherein the tablet is provided with score line enabling the tablet to be divided into two, three or four, preferably substantially equal, parts, and preferably two substantially equal parts.
• D A monolithic tablet according to any preceding paragraph wherein the hardness of the tablet of the present invention, comprising the 4 APIs, can be about 75 Strong- Cobb Units (SCU) to about 20 SCU, preferably, about 55 SCU to about 25 SCU, more preferably, about 35 SCU to about 30 SCU.
• SCU Strong- Cobb Units
• D A monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• emtricitabine granules preferably tenofovir disoproxil, and more preferably tenofovir disoproxil fumarate; or
• D A monolithic tablet according to Paragraph 33D wherein the granulate of darunavir is prepared by wet granulation of darunavir by top spray process of at least one binder (preferably hypromellose) dissolved in a suitable liquid (preferably water) on darunavir , followed by drying the wet granulate and milling the dry granulate.
• ritonavir form II at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone), and at least one glidant (preferably silicon di-oxide)
• at least one lubricant preferably sodium stearyl fumarate
• a binder preferably hypromellose
• at least one filler preferably microcrystalline cellulose
• at least one disintegrant preferably crospovidone
• at least one glidant preferably silicon di-oxide
• Croscarmellose Sodium preferably in an amount of about 2% to about 30% by weight of total weight of the dosage form, or from about 5% to about 30%, or from about 5% to about 20%, or from about 5% to about 15%, or from about 5% to 10% by weight of total weight of the dosage form.
• disintegrant preferably croscarmellose sodium (Ac-Di-Sol)
• Darunavir is from about 1:5 to about 1 :25, preferably from about 1 :8 to about 1:20, more preferably from about 1: 10 to about 1: 15.
• at least one filler preferably microcrystalhne cellulose
• at least one filler preferably microcrystalline cellulose
• at least one binder preferably pregelatinized starch
• at least one disintegrant preferably croscarmellose sodium
• emtricitabine, tenofovir and ritonavir form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium), granulating the mixture with water, drying the wet granulate and milling the dry granulate.
• filler preferably microcrystalline cellulose
• binder preferably pregelatinized starch
• disintegrant preferably croscarmellose sodium
• a monolithic tablet according to any preceding paragraph further comprising one or more pharmaceutically acceptable excipients.
• D A monolithic tablet according to Paragraph 45D, wherein the filler (diluent) is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), 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.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), lactose in its various forms (e.g. lactose USP, anhydrous or spray dried), sorbitol,
• binder is selected from one or more of the group consisting of cellulose polymers (e.g. hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or
• pregelatinized starch and the like or any combinations thereof.
• D A monolithic tablet according to any of Paragraphs 45D-47D wherein the lubricant is selected from one or more of the group consisting of 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.
• carboxymethyl starch cross-linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose, swelling polysaccharide, for example soy 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.
• Cross-linked polyvinylpyrrolidone Cross-linked polyvinylpyrrolidone
• sodium carboxymethyl glycolate for example Explotab®
• croscarmellose swelling polysaccharide, for example soy 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.
• a monolithic tablet according to any of Paragraphs 45D-50D wherein the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyltnmethylammonium salts, alcohol ethoxylates, sorbitans (particularly sorbitan laurate), polyoxyethylene sorbitans, polyoxylglycerides, or polyoxyethylene castor oil derivatives, and preferably wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.
• the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyltnmethylammonium salts, alcohol ethoxylates, sorbitans (particularly sorbitan laurate), polyoxyethylene sorbitans, polyoxylglycerides, or polyoxyethylene castor oil derivatives, and preferably wherein the surfact
• a method for treating HIV-1 infection comprising administration of a pharmaceutically effective amount of the monolithic tablet according to any of Paragraphs 1D-51D.
• a monolithic tablet comprising:
• ritonavir less than or equal to about 70 mg of ritonavir, wherein the ritonavir is in the form of its crystalline form II.
• a monolithic tablet according to Paragraph IE wherein the physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi -crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph, solvate, metabolite or prodrug (such as an ester).
• the physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi -crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph,
• darunavir is in the form of darunavir ethanolate, hydrate, or any other crystalline form as well as amorphous darunavir, preferably, hydrate.
• E A monolithic tablet according to any preceding paragraph wherein the amount of ritonavir is less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg.
• E A monolithic tablet according to any preceding paragraph wherein the amount of ritonavir is between about 50 mg to about 60 mg, to about 70 mg.
• the largest maximum diameter of the tablet of the present invention comprising the 4 APIs, is about 27mm or less and the depth is less than about 12.5mm; preferably, the largest maximum diameter is between about 26mm to about 27mm and the depth is between about 12.5mm to about 10mm, more preferably, the largest maximum diameter is about 25mm and the depth can be about 11mm.
• a monolithic tablet according to any preceding paragraph wherein the hardness of the tablet of the present invention, comprising the 4 APIs, can be about 75 Strong- Cobb Units (SCU) to about 20 SCU, preferably, about 55 SCU to about 25 SCU, more preferably, about 35 SCU to about 30 SCU.
• SCU Strong- Cobb Units
• a monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• a monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• E A monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises 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 active agents (a)-(d).
• a monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises about 65%: to about 70%, to about 75%, to about 80%, or to about 85% by weight of active agents (a)-(d). 27. E A monolithic tablet according to any preceding paragraph wherein the unit dosage form comprises about 70%: to about 75%, to about 80%, or to about 85% by weight of active agents (a)-(d).
• dosage form comprises about 75%: to about 80%, or to about 85%, or from about 80% to about 85% by weight of active agents (a)-(d).
• binder preferably hypromellose
• ritonavir form II at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone), and at least one glidant (preferably silicon di-oxide)
• at least one lubricant preferably sodium stearyl fumarate
• a binder preferably hypromellose
• at least one filler preferably microcrystalline cellulose
• at least one disintegrant preferably crospovidone
• at least one glidant preferably silicon di-oxide
• disintegrant such as Croscarmellose Sodium (Ac-Di-Sol)
• disintegrant preferably croscarmellose sodium (Ac-Di-Sol)
• Darunavir is from about 1:5 to about 1 :25, preferably from about 1 :8 to about 1:20, more preferably from about 1: 10 to about 1: 15.
• at least one filler preferably microcrystalline cellulose
• at least one filler preferably microcrystalline cellulose
• at least one binder preferably pregelatinized starch
• at least one disintegrant preferably croscarmellose sodium
• emtricitabine, tenofovir and ritonavir form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium), granulating the mixture with water, drying the wet granulate and milling the dry granulate.
• filler preferably microcrystalline cellulose
• binder preferably pregelatinized starch
• disintegrant preferably croscarmellose sodium
• a monolithic tablet according to any preceding paragraph further comprising one or more pharmaceutically acceptable excipients.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), 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.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), lactose in its various forms (e.g. lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol,
• hydroxypropylmethyl cellulose hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone polyvinyl alcohol, starch or
• pregelatinized starch and the like or any combinations thereof.
• the glidant is selected from one or more of the group consisting of colloidal silica, silica gel, precipitated silica or talc, and the like or any combinations thereof.
• the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose, swelling polysaccharide, for example soy polysaccharide, carrageenan, agar, pectin, starch and derivatives thereof, protein, for
• the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.
• a method for treating HIV- 1 infection comprising administration of a pharmaceutically effective amount of the monolithic tablet according to any of Paragraphs 1E-48E.
• a monolithic tablet in a unit dosage form comprising:
• ritonavir or a physiologically functional derivative thereof, wherein the amount of ritonavir is less than about lOOmg and wherein the ritonavir is in the form of ritonavir pre-mix.
• the physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi-crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph, solvate, metabolite or prodrug (such as an ester).
• the physiologically functional derivative is a pharmaceutically acceptable derivative selected from the group consisting of salt, enantiomer, solid state form (crystalline, semi-crystalline or amorphous), polymorph, solvate, metabolite or prodrug in the case of (a) or (b)-(d) , preferably wherein the prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph, solvate, metabolite or prodrug (such as
• darunavir is in the form of darunavir ethanolate, hydrate, or any other crystalline form as well as amorphous darunavir, preferably, hydrate.
• pharmaceutically acceptable excipients include a solubilizer (preferably sorbitan laurate), and/or a glidant (preferably colloidal silica).
• the carrier preferably copovidone
• the co- precipitate comprises ritonavir in an amount of about 50 to about 95 wt%, about 60 to about 85 wt%, about 70 to about 85 wt%, about 70 to about 80 wt%, about 72 to about 80 wt%, or about 75 to about 77 wt%.
• FA monolithic tablet according to any preceding paragraph in the form of a single unit dosage form for administration once per day.
• FA monolithic tablet according to paragraph 14F wherein the tablet is provided with score line enabling the tablet to be divided into two, three or four, preferably substantially equal, parts, and preferably two substantially equal parts.
• the amount of ritonavir is less than or equal to about 75 mg, less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg.
• FA monolithic tablet according to any preceding paragraph wherein the amount of ritonavir is between about 50 mg to about 60 mg, to about 70 mg, to about 75 mg, to about 80 mg, to about 100 mg, between about 60 mg to about 70 mg, to about 75 mg, to about 80 mg, to about 100 mg, between about 80 mg, to about 100 mg.
• the unit dosage form has a total weight of between 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.
• the unit dosage form has a total weight of between about 1.800g, to about 1.900g, to about 2.000g.
• the largest maximum diameter of the tablet of the present invention comprising the 4 APIs, is about 27mm or less and the depth is less than about 12.5mm; preferably, the largest maximum diameter is between about 26mm to about 27mm and the depth is between about 12.5mm to about 10mm, more preferably, the largest maximum diameter is about 25mm and the depth can be about 11mm.
• SCU Strong-Cobb Units
• the unit dosage form comprises:
• the unit dosage form comprises about 20% to about 85% by weight of active agents (a)- (d).
• the unit dosage form comprises 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 active agents (a)-(d).
• the unit dosage form comprises 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 active agents (a)- (d).
• the unit dosage form comprises 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 active agents (a)-(d).
• the unit dosage form comprises 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 active agents (a)-(d).
• the unit dosage form comprises 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 active agents (a)-(d).
• the unit dosage form comprises 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 active agents (a)-(d).
• the unit dosage form comprises about 60%: to about 65%, to about 70%, to about 75%, to about 80%, or to about 85% by weight of active agents (a)-(d).
• the unit dosage form comprises about 65%: to about 70%, to about 75%, to about 80%, or to about 85% by weight of active agents (a)-(d).
• the unit dosage form comprises about 70%: to about 75%, to about 80%, or to about 85% by weight of active agents (a)-(d).
• the unit dosage form comprises about 75%: to about 80%, or to about 85%, or from about 80% to about 85% by weight of active agents (a)-(d).
• darunavir (preferably water) on darunavir , followed by drying the wet granulate and milling the dry granulate.
• FA monolithic tablet according to Paragraph 41F wherein the granulate of darunavir is further mixed with ritonavir pre-mix, at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone), and at least one glidant (preferably silicon di-oxide), followed by addition of at least one lubricant (preferably sodium stearyl fumarate) to the obtained mixture to obtain the final blend of darunavir-ritonavir (preferably darunavir with extra- granular ritonavir).
• ritonavir pre-mix at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone), and at least one glidant (preferably silicon di-oxide)
• at least one lubricant preferably sodium stearyl fumarate
• FA monolithic tablet according to Paragraph 40F wherein the granulate of darunavir-ritonavir is prepared by wet granulation of darunavir with ritonavir pre- mix by top spray process of at least one binder (preferably hypromellose) dissolved in a suitable liquid (preferably water), on a mixture of darunavir and ritonavir, followed by drying the wet granulate and milling the dry granulate.
• a binder preferably hypromellose
• FA monolithic tablet according to Paragraph 43F wherein the granulate of darunavir-ritonavir is mixed with at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone), and at least one glidant (preferably silicon di-oxide), followed by addition of at least one lubricant (preferably sodium stearyl fumarate) to the obtained mixture to obtain the final blend of darunavir-ritonavir (preferably darunavir with intra-granular ritonavir).
• at least one filler preferably microcrystalline cellulose
• at least one disintegrant preferably crospovidone
• at least one glidant preferably silicon di-oxide
• disintegrant such as Croscarmellose Sodium (Ac-Di-Sol)
• disintegrant preferably croscarmellose sodium (Ac-Di-Sol)
• Darunavir is from about 1:5 to about 1:25, preferably from about 1:8 to about 1:20, more preferably from about 1: 10 to about 1: 15.
• ritonavir is in the form of a pre-mix
• ritonavir pre-mix is prepared by mixing ritonavir with at least one excipient (preferably a carrier, and more preferably copovidone) in a solvent (preferably ethanol) to form a solution, and evaporating the solvent.
• excipient preferably a carrier, and more preferably copovidone
• solvent preferably ethanol
• the ritonavir pre-mix is prepared by mixing ritonavir with at least one excipient (preferably a carrier and more preferably copovidone), optionally with at least one solubilizer (preferably sorbitan laurate) and at least one glidant (preferably silica) in a solvent (preferably ethanol), followed by removal of the solvent by evaporation to form a solid, and optionally milling the resulting solid.
• excipient preferably a carrier and more preferably copovidone
• solubilizer preferably sorbitan laurate
• at least one glidant preferably silica
• FA monolithic tablet according to any of Paragraphs 40F-48F wherein the granules of emtricitabine and tenofovir are prepared by a process comprising combining emtricitabine and tenofovir with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium) wet granulating the mixture with water, drying the wet granulate and milling the dry granulate.
• at least one filler preferably microcrystalline cellulose
• at least one binder preferably pregelatinized starch
• disintegrant preferably croscarmellose sodium
• FA monolithic tablet according to any of Paragraphs 40F-49F wherein the granules of emtricitabine, tenofovir and ritonavir are prepared by combining emtricitabine, tenofovir and ritonavir pre-mix with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium), granulating the mixture with water, drying the wet granulate and milling the dry granulate.
• filler preferably microcrystalline cellulose
• binder preferably pregelatinized starch
• disintegrant preferably croscarmellose sodium
• FA monolithic tablet according to any preceding paragraph further comprising one or more pharmaceutically acceptable excipients.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PHI 02 having or PH101), 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.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PHI 02 having or PH101), lactose in its various forms (e.g. lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol,
• the binder is selected from one or more of the group consisting of cellulose polymers (e.g. hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch and the like or any combinations thereof.
• cellulose polymers e.g. hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone e.g. hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone e.g. hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone e.g. hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethy
• the lubricant is selected from one or more of the group consisting of sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate or hydrogenated vegetable oils, and the like or any
• FA monolithic tablet according to any of Paragraphs 51F-55F, wherein the glidant is selected from one or more of the group consisting of colloidal silica, silica gel, precipitated silica or talc, and the like or any combinations thereof.
• the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose, swelling polysaccharide, for example soy 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.
• the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose, swelling polysaccharide, for example soy polysaccharide, carrageenan, agar, pectin, starch and derivatives thereof, protein, for example formaldehyde-casein, sodium bicarbonate,
• the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates, sorbitans (particularly sorbitan laurate), polyoxyethylene sorbitans, polyoxylglycerides, or polyoxyethylene castor oil derivatives, and preferably wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.
• FA monolithic tablet according to any of Paragraphs 1F-58F for use as a medicament FA monolithic tablet according to any of Paragraphs 1F-58F for use as a medicament.
• FA method for treating HIV-1 infection comprising administration of a pharmaceutically effective amount of the monolithic tablet according to any of Paragraphs 1F-58F.
• a monolithic tablet comprising:
• darunavir hydrate or darunavir ethanolate wherein the amount of darunavir is 800 mg and
• a monolithic tablet according to Paragraph 1G which is chemically stable.
• a monolithic tablet according to any of Paragraphs 1G-9G comprising from about
• a monolithic tablet according to any of Paragraphs 1G-10G comprising from about
• a monolithic tablet according to any of Paragraphs lG-11G comprising from about
• a monolithic tablet according to any of Paragraphs 1G-12G comprising from about
• 30% to about 35% about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about 55%, about 30% to about 60%, about 30% to about 65%, about 30% to about 70%, about 30% to about 75%, about 30% to about 80%, or about 30% to about 85% by weight of darunavir and ritonavir.
• a monolithic tablet according to any of Paragraphs 1G-13G comprising from about
• a monolithic tablet according to any of Paragraphs 1G-14G comprising from about
• a monolithic tablet according to any of Paragraphs 1G-15G comprising from about
• a monolithic tablet according to any of Paragraphs 1G-16G comprising from about
• a monolithic tablet according to any of Paragraphs 1G-17G comprising from about
• a monolithic tablet according to any of Paragraphs 1G-18G comprising from about
• 65% to about 70% about 65% to about 75%, about 65% to about 80%, or about 65% to about 85% by weight of darunavir and ritonavir.
• a monolithic tablet according to any of Paragraphs 1G-19G comprising from about
• a monolithic tablet according to any of Paragraphs 1G-20G comprising from about
• a monolithic tablet according to any of Paragraphs 1G-21G comprising from about
• a monolithic tablet according to any of Paragraphs 1G-22G further comprising at least one lubricant (preferably sodium stearyl fumarate) to form a blend that is then compressed into a tablet core.
• at least one lubricant preferably sodium stearyl fumarate
• 1 G-27G comprising combining darunavir with extra-granular ritonavir or darunavir with intra-granular ritonavir, (i.e. a granulate of darunavir-ritonavir), optionally in the presence of one or more pharmaceutically acceptable excipients to form a blend.
• the pharmaceutically acceptable excipient comprises at least one excipient selected from a filler (preferably microcrystalline cellulose), a disintegrant (preferably crospovidone and/or croscarmellose sodium), a glidant (preferably silicon di-oxide) and a lubricant (preferably sodium stearyl fumarate).
• a process according to Paragraph 28G wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose, crospovidone and/or croscarmellose sodium, silicon di-oxide and sodium stearyl fumarate.
• a process according to any of Paragraphs 27G-29G further comprising processing the blend to provide a solid dosage form.
• a process according to any of Paragraphs 27G-30G comprising compressing the blend to form a tablet, and optionally coating the tablet with a film coating material to form a film coated tablet.
• darunavir-ritonavir preferably darunavir with extra-granular ritonavir.
• a binder preferably hypromellose
• at least one filler preferably microcrystalline cellulose
• at least one disintegrant preferably crospovidone
• at least one glidant preferably silicon di-oxide
• a method for treating HIV-1 infection comprising administration of a
• a monolithic tablet according to any preceding paragraph further comprising one or more pharmaceutically acceptable excipients, preferably selected from one or more of the group consisting of fillers, binders, disintegrants, surfactants, glidants and lubricants.
• a monolithic tablet according to Paragraph 41G wherein the filler (diluent) is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), 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.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), lactose in its various forms (e.g. lactose USP, anhydrous or spray dried), sorbitol, dex
• a monolithic tablet according to Paragraph 41G-42G wherein the binder is selected from one or more of the group consisting of 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 e.g. hydroxypropyl- methyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone e.g. hydroxypropyl- methyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone e.g.
• the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose, swelling polysaccharide, for example soy polysaccharide, carrageenan, agar, pectin, starch and derivatives thereof, protein
• the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates, sorbitans (particularly sorbitan laurate), polyoxyethylene sorbitans, polyoxylglycerides, or polyoxyethylene castor oil derivatives, and preferably wherein the surfactant is
• a monolithic tablet comprising:
• darunavir or a physiologically functional derivative thereof (preferably
• darunavir hydrate or darunavir ethanolate wherein the amount of 800 mg and b) ritonavir or a physiologically functional derivative thereof; wherein the amount of ritonavir is less than or equal to about 70 mg and wherein the ritonavir is in the form of ritonavir crystalline form II.
• a monolithic tablet according to any of Paragraphs 1H-8H comprising from about
• a monolithic tablet according to any of Paragraphs 1H-9H comprising from about
• a monolithic tablet according to any of Paragraphs 1H-10H comprising from about
• a monolithic tablet according to any of Paragraphs lH-11H comprising from about
• 30% to about 35% about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about 55%, about 30% to about 60%, about 30% to about 65%, about 30% to about 70%, about 30% to about 75%, about 30% to about 80%, or about 30% to about 85% by weight of darunavir and ritonavir.
• a monolithic tablet according to any of Paragraphs 1H-12H comprising from about
• a monolithic tablet according to any of Paragraphs 1H-13H comprising from about
• a monolithic tablet according to any of Paragraphs 1H-14H comprising from about
• a monolithic tablet according to any of Paragraphs 1H-15H comprising from about
• a monolithic tablet according to any of Paragraphs 1H-16H comprising from about
• a monolithic tablet according to any of Paragraphs 1H-17H comprising from about
• 65% to about 70% about 65% to about 75%, about 65% to about 80%, or about 65% to about 85% by weight of darunavir and ritonavir.
• a monolithic tablet according to any of Paragraphs 1H-18H comprising from about
• a monolithic tablet according to any of Paragraphs 1H-19H comprising from about
• a monolithic tablet according to any of Paragraphs 1H-20H comprising from about
• a monolithic tablet according to any of Paragraphs 1H-21H further comprising at least one lubricant (preferably sodium stearyl fumarate) to form a blend that is then compressed into a tablet core.
• at least one lubricant preferably sodium stearyl fumarate
• 1H-25H comprising combining darunavir with extra-granular ritonavir or darunavir with intra-granular ritonavir, (i.e. a granulate of darunavir-ritonavir), optionally in the presence of one or more pharmaceutically acceptable excipients to form a blend.
• the pharmaceutically acceptable excipient comprises at least one excipient selected from a filler (preferably microcrystalline cellulose), a disintegrant (preferably crospovidone and/or croscarmellose sodium), a glidant (preferably silicon di-oxide) and a lubricant (preferably sodium stearyl fumarate).
• a process according to any of Paragraphs 26H-28H further comprising processing the blend to provide a solid dosage form.
• a process according to any of Paragraphs 26H-29H comprising compressing the blend to form a tablet, and optionally coating the tablet with a film coating material to form a film coated tablet.
• darunavir-ritonavir preferably darunavir with extra-granular ritonavir.
• a binder preferably hypromellose
• at least one filler preferably microcrystalline cellulose
• at least one disintegrant preferably crospovidone
• at least one glidant preferably silicon di- oxide
• adding at least one lubricant preferably sodium stearyl fumarate
• a method for treating HIV-1 infection comprising administration of a
• a monolithic tablet according to any preceding paragraph further comprising one or more pharmaceutically acceptable excipients, preferably selected from one or more of the group consisting of fillers, binders, disintegrants, surfactants, glidants and lubricants.
• a monolithic tablet according to Paragraph 40H wherein the filler (diluent) is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), 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.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), lactose in its various forms (e.g. lactose USP, anhydrous or spray dried), sorbitol, dex
• a monolithic tablet according to Paragraph 40H-41H wherein the binder is selected from one or more of the group consisting of 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 e.g. hydroxypropyl- methyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone e.g. hydroxypropyl- methyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose
• polyvinylpyrrolidone e.g.
• the glidant is selected from one or more of the group consisting of colloidal silica, silica gel, precipitated silica or talc, and the like or any combinations thereof.
• the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose, swelling polysaccharide, for example soy polysaccharide, carrageenan, agar, pectin, starch and derivatives thereof, protein
• the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates, sorbitans (particularly sorbitan laurate), polyoxyethylene sorbitans, polyoxylglycerides, or polyoxyethylene castor oil derivatives, and preferably wherein the surfactant is
• a monolithic tablet comprising:
• darunavir hydrate or darunavir ethanolate wherein the amount of darunavir is 800 mg and
• ritonavir or a physiologically functional derivative thereof; wherein the amount navir is less than or equal to about 70 mg.
• J A monolithic tablet according to any of Paragraphs 1 J-2J wherein the total tablet weight is 1.300g or lower, about 1.200g or lower, about l.lOOg or lower.
• J A monolithic tablet according to any of Paragraphs 1 J-3J wherein the total tablet weight is about l.lOOg, or about l.OOOg to about 1.200g, or about l.OOOg to about 1.300g.
• J A monolithic tablet according to any of Paragraphs 1 J-4J wherein the total tablet weight is about l.lOOg to about 1.200g, or about l. lOOg to about 1.300g.
• maximum diameter of the pharmaceutical formulation of the present invention comprising darunavir and ritonavir, is about 22mm or less and the depth is less than about 9mm; preferably, the largest maximum diameter is between about 20mm to about 22mm and the depth is between about 6mm to about 9mm.
• darunavir is in the form of darunavir ethanolate, hydrate, or any other crystalline form as well as amorphous darunavir, preferably, hydrate.
• J A monolithic tablet according to any of Paragraphs 1 J-9J comprising from about 20% to about 85% by weight of darunavir and ritonavir.
• IJ A monolithic tablet according to any of Paragraphs 1J-10J comprising from about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 20% to about 55%, about 20% to about 60%, about 20% to about 65%, about 20% to about 70%, about 20% to about 75%, about 20% to about 80%, or about 20% to about 85% by weight of darunavir and ritonavir.
• J A monolithic tablet according to any of Paragraphs 1 J- 11 J comprising from about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 25% to about 55%, about 25% to about 60%, about 25% to about 65%, about 25% to about 70%, about 25% to about 75%, about 25% to about 80%, or about 25% to about 85% by weight of darunavir and ritonavir.
• a monolithic tablet according to any of Paragraphs 1J-12J comprising from about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about 55%, about 30% to about 60%, about 30% to about 65%, about 30% to about 70%, about 30% to about 75%, about 30% to about 80%, or about 30% to about 85% by weight of darunavir and ritonavir.
• J A monolithic tablet according to any of Paragraphs 1J-13J comprising from about 40% to about 45%, about 40% to about 50%, about 40% to about 55%, about 40% to about 60%, about 40% to about 65%, about 40% to about 70%, about 40% to about 75%, about 40% to about 80%, or about 40% to about 85% by weight of darunavir and ritonavir.
• J A monolithic tablet according to any of Paragraphs 1J-14J comprising from about 45% to about 50%, about 45% to about 55%, about 45% to about 60%, about 45% to about 65%, about 45% to about 70%, about 45% to about 75%, about 45% to about 80%, or about 45% to about 85% by weight of darunavir and ritonavir.
• J A monolithic tablet according to any of Paragraphs 1J-15J comprising from about
• J A monolithic tablet according to any of Paragraphs 1J-16J comprising from about
• J A monolithic tablet according to any of Paragraphs 1J-17J comprising from about
• J A monolithic tablet according to any of Paragraphs 1J-18J comprising from about
• 65% to about 70% about 65% to about 75%, about 65% to about 80%, or about 65% to about 85% by weight of darunavir and ritonavir.
• J A monolithic tablet according to any of Paragraphs 1J-19J comprising from about
• J A monolithic tablet according to any of Paragraphs 1J-20J comprising from about
• J A monolithic tablet according to any of Paragraphs 1J-21J comprising from about
• at least one lubricant preferably sodium stearyl fumarate
• a process for the preparation of a monolithic tablet according to any of Paragraphs 1 J-26J comprising combining darunavir with extra-granular ritonavir or darunavir with intra-granular ritonavir, (i.e. a granulate of darunavir-ritonavir), optionally in the presence of one or more pharmaceutically acceptable excipients to form a blend.
• the pharmaceutically acceptable excipient comprises at least one excipient selected from a filler (preferably microcrystalline cellulose), a disintegrant (preferably crospovidone and/or croscarmellose sodium), a glidant (preferably silicon di-oxide) and a lubricant (preferably sodium stearyl fumarate).
• a filler preferably microcrystalline cellulose
• a disintegrant preferably crospovidone and/or croscarmellose sodium
• a glidant preferably silicon di-oxide
• a lubricant preferably sodium stearyl fumarate
• excipient comprises microcrystalline cellulose, crospovidone and/or croscarmellose sodium, silicon di-oxide and sodium stearyl fumarate.
• J A monolithic tablet prepared by a process according to any of Paragraphs 27J-36J..
• J A monolithic tablet according to any of Paragraphs 1 J-26J for use as a medicament.
• J A monolithic tablet according to any of Paragraphs 1 J-26J for use in the treatment of
• J A method for treating HIV- 1 infection comprising administration of a
• J A monolithic tablet according to any preceding paragraph further comprising one or more pharmaceutically acceptable excipients, preferably selected from one or more of the group consisting of fillers, binders, disintegrants, surfactants, glidants and lubricants.
• pharmaceutically acceptable excipients preferably selected from one or more of the group consisting of fillers, binders, disintegrants, surfactants, glidants and lubricants.
• J A monolithic tablet according to Paragraph 41 J, wherein the filler (diluent) is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), 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.
• the filler is selected from one or more of the group consisting of water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 having or PH101), lactose in its various forms (e.g. lactose USP, anhydrous or spray dried), sorbitol,
• J A monolithic tablet according to Paragraph 41J-42J, wherein the binder is selected from one or more of the group consisting of 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.
• lubricant is selected from one or more of the group consisting of 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.
• glidant is selected from one or more of the group consisting of colloidal silica, silica gel, precipitated silica or talc, and the like or any combinations thereof.
• J A monolithic tablet according to any of Paragraphs 41 J-45J wherein the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose, swelling polysaccharide, for example soy 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.
• the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose, swelling polysaccharide, for example soy polysaccharide, carrageenan, agar, pectin, starch and derivatives thereof
• J A monolithic tablet according to any of Paragraphs 41 J-46J wherein the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates, sorbitans (particularly sorbitan laurate), polyoxyethylene sorbitans, polyoxylglycerides, or polyoxyethylene castor oil derivatives, and preferably wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.
• the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates, sorbitans (particularly sorbitan laurate), polyoxyethylene sorbitans, polyoxylglycerides, or polyoxyethylene castor oil derivatives, and preferably wherein the surfact
• Analytical method for tablet comprising emtricitabine, tenofovir, darunavir, ritonavir: Impurities and Degradants Determination Chromatographic conditions for
• the dissolution profile (drug release rate) was determined using 1800ml of 2% Brij-35 (30% solution of nonionic polyoxyethylene surfactant in water) in 0.05M phosphate buffer, having a pH of 3.0, using paddles apparatus (USP apparatus II) at 75 rpm, at a temperature of 37°C ⁇ 0.5 °C. In particular the following procedure and conditions were employed.
• Emtricitabine concentration 0.11 mg/mL in dissolution medium.
• Tenofovir concentration 0.17 mg/mL in dissolution medium.
• Darunavir concentration 0.45 mg/mL in dissolution medium.
• Ritonavir concentration 0.038 mg/mL in dissolution medium.
• Example 2 Preparation of a monolithic tablet containing darunavir - ritonavir extra- granular
• 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.
• crospovidone microcrystalline cellulose (Avicel 102) and Silicon di-oxide (Aerosil) -were mixed and then sodium stearyl fumarate was added for final mixing, and the 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 3 Preparation of a monolithic tablet containing darunavir - ritonavir (intra- granular)
• Hypromellose (Methocel E-15) 12.20
• 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.
• Darunavir - ritonavir granulate, crospovidone, microcrystalline cellulose (Avicel 102) and Silicon di-oxide (Aerosil) were mixed and then sodium stearyl fumarate was added for final mixing, and the 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).

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• 2015
  • 2015-04-07 AU AU2015245217A patent/AU2015245217A1/en not_active Abandoned
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  • 2015-04-07 WO PCT/IB2015/052493 patent/WO2015155673A1/en active Application Filing
  • 2015-04-07 EP EP15724361.9A patent/EP3129009A1/de not_active Withdrawn
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• 2016
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