EP3038607A2 - Unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir and a monolithic tablet comprising darunavir and ritonavir - Google Patents
Unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir and a monolithic tablet comprising darunavir and ritonavirInfo
- Publication number
- EP3038607A2 EP3038607A2 EP14790289.4A EP14790289A EP3038607A2 EP 3038607 A2 EP3038607 A2 EP 3038607A2 EP 14790289 A EP14790289 A EP 14790289A EP 3038607 A2 EP3038607 A2 EP 3038607A2
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- EP
- European Patent Office
- Prior art keywords
- ritonavir
- darunavir
- tablet
- pharmaceutical formulation
- weight
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
The present invention relates to an oral unit dosage form comprising Emtricitabine, Tenofovir, Darunavir and Ritonavir and a monolithic tablet comprising Darunavir and Ritonavir and their use to treat HIV infection.
Description
UNIT DOSAGE FORM COMPRISING EMTRICITABINE, TENOFOVIR, DARUNAVIR AND RITONAVIR AND A MONOLITHIC TABLET COMPRISING
DARUNAVIR AND RITONAVIR
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 61/871 ,674 entitled "UNIT DOSAGE FORM COMPRISING EMTRICITABINE, TENOFOVIR, DARUNAVIR AND RITONAVIR AND A MONOLITHIC TABLET COMPRISING DARUNAVIR AND RITONAVIR," filed on August 29, 2013, the contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to an oral unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir and to a monolithic tablet comprising darunavir and ritonavir and their use to treat HIV infection. The invention further relates to methods of preparing the oral dosage forms containing the above pharmaceutical active agents.
BACKGROUND OF THE INVENTION
Tenofovir, the systematic chemical name for which is ({[(2R)-l-(6-amino-9H-purin- 9-yl) propan-2-yl] oxy} methyl) phosphonic acid, is a nucleoside reverse transcriptase inhibitor (NRTI) which is used to treat infection by HIV-I. Its synthesis, analogs, formulation and use are described in various publications including, inter alia, U.S. Patent Nos. 5,922,695; 5,935,946, 5,977,089 and 6, 043, 230.
Pharmaceutical formulations comprising combinations of tenofovir and another non- nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) are described in various publications including, inter alia, US 8, 592, 397, US 8, 716, 264 and US20140037732.
Tenofovir disoproxil fumarate (TDF) is a prodrug form of tenofovir. TDF is marketed by Gilead Sciences under the trade name VIREAD®. 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. Its synthesis and use are described in various publications including, inter alia, U.S. Patent Nos. 5,210,085; 5,814,639; 5,914,331 , 6, 642, 245 and 7,402,588.
Emtricitabine (FTC) 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, the systematic name for which is [(lR,5S,6R)-2,8- dioxabicyclo[3.3.0]oct-6-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2- methylpropyl)amino]-3-hydroxy-l-phenyl-butan-2-yl] carbamate, is another antiretroviral drug of the protease inhibitor (PI) class which is used to treat HIV-I. Its synthesis, use, salts, formulation and combinations thereof are described in various publications including U.S. Patent Nos. 6,335,460; 6,248,775, 5,843,946, USRE43596 and WO2013004816.
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.
Ritonavir is marketed by Abbott Laboratories under the trade name NORVIR®. Norvir® is available as 100 mg tablet or capsule and as an 80mg/ml oral solution. Ritonavir is BCS (biopharmaceutical classification system) class IV material. Thus, 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,
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022417s000_ChemR.pdf). The Norvir® tablet contains: 100 mg ritonavir, copovidone, sorbitan laurate, calcium hydrogen phosphate anhydrous, anhydrous colloidal silica, sodium stearyl fumarate and are coated with a film-coating formed of hypromellose, titanium dioxide (El 71), macrogols, hydroxypropyl cellulose, talc, anhydrous colloidal silica and polysorbate 80. The total weight of Norvir® tablet is 800mg, and the tablet has dimensions of 17.2x5.8mm.
Administered alone, most antiretroviral agents have proved only partially effective, often unable to block HIV replication sufficient to obtain an optimal reduction in viral load or prevent its rise.
To overcome this deficiency, highly active antiretroviral therapy (HAART) has been developed over the years. HAART consists of co-administration of three antiretroviral agents. The three drugs may be administered separately or administered as a unit dosage form containing three active ingredients.
Administration of three or four active ingredients, for the treatment of human immunodeficiency virus (HIV) in humans, was suggested in WO 201 1/061302 and WO 201 1/061303. The manufacture of triple fixed dose combinations are disclosed in WO 1996/030025 and WO 2006/135933.
WO2009/081 174 describes a dual combination formulation of ritonavir and darunavir; wherein ritonavir is in a first layer and darunavir is in a second layer. According to this disclosure, ritonavir and darunavir, when admixed, results in incompatibilities in which the stability of the active agents is compromised. Accordingly, WO2009/081 174 discloses that the two active agents must be separated from each other, i.e., by the provision of a composition in which each agent is present in separate layers. Nevertheless, from the
point of view of ease of manufacture, monolithic compositions are generally preferred over multilayer compositions. However, the successful formulation of monolithic dosage forms, is dependent on ensuring that the stability of the active agents in the dosage form is not compromised, as well as ensuring that the dosage form is of a size that enables it to be easily administered.
WO2013057469 describes a combination composition in a kit form. The kit can comprise separate unit dosage forms of various antiretroviral drugs with a set of instructions for their administration. Nevertheless, the administration of separate dosage forms in accordance with a set of instructions does not provide an optimal improvement of patient compliance, especially if the dosage forms are to be taken at different times. Moreover, the instructions may be misplaced, or may be incorrectly followed by the patient.
There is thus a need to provide a chemically stable dosage form containing ritonavir and darunavir which has the advantage of ease of manufacture. There is an additional need to provide dosage forms in which combinations of antiretroviral drugs such as
emtricitabine, tenofovir, darunavir and ritonavir, are provided in a composition that can be readily administered so as to further improve patient compliance. In particular, there is a need for less onerous dosage regimen, such as once daily oral dosing, optimally, in a one pill, having the required stability and bioavailability.
The present invention addresses for the first time the preparation of a unit dose form containing emtricitabine, tenofovir, darunavir and ritonavir and of a monolithic tablet containing darunavir and ritonavir
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a pharmaceutical formulation in a unit dosage form comprising:
tenofovir or a physiologically functional derivative thereof,
emtricitabine or a physiologically functional derivative thereof,
darunavir or a physiologically functional derivative thereof, and
ritonavir or a physiologically functional derivative thereof.
In a further aspect, the present invention provides a monolithic tablet comprising: darunavir or a physiologically functional derivative thereof, and
ritonavir or a physiologically functional derivative thereof.
The present invention further provides the above unit dose formulation or the above monolithic tablet for use as a medicament.
The present invention further provides the above unit dose formulation or the above monolithic tablet for use in the treatment of HIV- 1 infection.
The present invention further provides a method for treating HIV-1 infection comprising administration of a pharmaceutically effective amount of the above unit dose formulation or of the above monolithic tablet.
DETAILED DESCRIPTION OF THE INVENTION
Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:
The compounds or their combinations of the invention may be referred to as "active ingredients" or "pharmaceutically active agents."
The term "physiologically functional derivative" includes any: pharmaceutically acceptable salts, pharmaceutically acceptable enantiomers, pharmaceutically acceptable solid state form (crystalline, semi-crystalline or amorphous), pharmaceutically acceptable polymorphs, pharmaceutically acceptable solvates, pharmaceutically acceptable metabolites or pharmaceutically acceptable prodrugs thereof (for example, wherein the prodrug is an ester), or a pharmaceutically acceptable salt of the enantiomer, solid state form, polymorph, solvate, metabolite or prodrug (e.g. an ester prodrug).
The terms "Emtricitabine", "Tenofovir", "Darunavir" and "Ritonavir" are mentioned throughout in a broad sense to include not only emtricitabine, tenofovir, darunavir and ritonavir, per se, but also their physiologically functional derivatives. Preferably in any embodiment or any aspect of the present invention, the tenofovir is in the form of its product, tenofovir disoproxil. More preferably the tenofovir disoproxil is in the form of its fumarate salt, i.e. tenofovir disoproxil fumarate. Preferably in any embodiment or any aspect of the present invention, 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.
Preferably in any embodiment or any aspect of the present invention, the ritonavir is in the form of ritonavir or its physiologically functional derivatives. More preferably the ritonavir is in the form of its crystalline form as well as amorphous ritonavir, i.e., crystalline form can be for example, Form I or Form II, substantially as described in EP 1097148.
Characteristic peaks of in the powder X-ray diffraction pattern of Ritonavir Form I can be found in 3.33° ± 0.1°, 6.76° ± 0.1°, 8.33° ± 0.1 °, 14.61° ± 0.1°, 16.33° ± 0.1°, 16.76° ± 0.1°, 17.03° ± 0.1°, 18.02° ± 0.1 °, 18.62° ± 0.1°, 19.47° ± 0.1°, 19.86° ± 0.1 °, 20.25° ± 0.1 °,
21.46° ± 0.1°, 23.46° ± 0.1° and 24.36° ± 0.1 0 (two theta). Characteristic peaks of in the powder X-ray diffraction pattern of Ritonavir Form II can be found in 8.67°±0.1°,
9.88°±0. , 16.1 1°±0.1°, 16.70°±0.1°, 17.36°±0.1°, 17.78°±0.1°, 18.40°±0.1 °, 18.93°±0.1 °, 20.07°±0.1 °, 20.65°±0.1 °, 21.71 °±0.1° and 25.38°±0.1° (two theta).
Unless otherwise indicated, a reference to weight% of the dosage form mean the weight% relative to the weight of the dosage form excluding, in the case of a tablet, any finishing/cosmetic coating, and in the case of a capsule, the weight of the dosage form refers to the total weight of the capsule contents, i.e. excluding the capsule shell.
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 pharmaceutical dosage form. Preferably "chemically stable" in any embodiment of any aspect of the present invention, 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.
In particular, 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.
Preferably, in accordance with any aspect or embodiment of the present invention, 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. In a
particularly preferred embodiment of the present invention, 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. In especially preferred embodiments of the present invention, 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. For example, 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.
The term "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.
The 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: ti/2 (half-life), Cmjn (minimal plasma concentration), C trough concentration, Cmax (maximal plasma concentration), AUC (area under the curve), Tmax (time to maximal concentration), and Css (steady state concentration).
The assessment of same/comparable pharmacokinetic bioavailability can be based on 90% confidence intervals for the ratio of the population geometric means (test/reference)
for the parameters under consideration. This method can be equivalent to two one-sided tests with the null hypothesis of bioinequivalence at the 5% significance level.
The pharmacokinetic parameters under consideration can be analyzed using
ANOVA. The data can be transformed prior to analysis using a logarithmic transformation. A confidence interval for the difference between formulations on the log-transformed scale can be obtained from the ANOVA model. This confidence interval can then back- transformed to obtain the desired confidence interval for the ratio on the original scale.
Ritonavir, may be used as 'pharmacokinetic enhancer' (booster) to increase the blood levels of darunavir. Accordingly, the bioavailability of darunavir may be compared to the bioavailability of the commercial darunavir when administered with the commercial ritonavir (Norvir®) as a pharmacokinetic enhancer.
The 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. By combining tenofovir disoproxil, emtricitabine, darunavir and ritonavir into a single dosage form, 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.
Ideally the pharmaceutical formulation should be administered to achieve peak plasma concentrations of each of the compounds/active pharmaceutical ingredients when administered in a separated unit doses containing each one of the active pharmaceutical ingredients separately, while avoiding compromising the stability and the size of the pharmaceutical formulation.
The pharmaceutical formulation may be formulated in a unit dosage formulation comprising an amount of each compound/active pharmaceutical ingredient that is suitable for a daily dose to ensure the desired therapeutic effect.
The present invention provides a pharmaceutical formulation in a unit dosage form comprising:
tenofovir or a physiologically functional derivative thereof,
emtricitabine or a physiologically functional derivative thereof,
darunavir or a physiologically functional derivative thereof and
ritonavir or a physiologically functional derivative thereof;
The above pharmaceutical formulation comprising tenofovir disoproxil or a physiologically functional derivative thereof, emtricitabine or a physiologically functional derivative thereof, darunavir or a physiologically functional derivative thereof and ritonavir or a physiologically functional derivative thereof can be chemically stable.
The total weight of the pharmaceutical formulation of the present invention, comprising the above 4 APIs, 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. In a specific embodiment of the present invention 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 2.600g, to about 2.800g, or between 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 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 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 about 2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g, or between about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g, or between about 2.500g, to about 2.600g, to about 2.800g, or between about 2.600g to about 2.800g.
By way of example, 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 lOOmg of ritonavir (corresponding to the dose of the commercially available of Norvir® tablet).
Preferably, the pharmaceutical formulation of the present invention comprises about 300mg of tenofovir disoproxil fumarate, about 200mg of emtricitabine, about 800mg of darunavir and about 1 OOmg of ritonavir.
In certain embodiments, 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 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 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 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 55%, to about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about 85%, or from about 60% to about 65%, to about 70%, to about 75%, to about 80%, or to about 85%, or from about 65% to about 70%, to about 75%, to about 80%, or to about 85%, or from about 70% to about 75%, to about 80%, or to about 85%, or from about 75%, to about 80%, or to about 85%, or from about 80% to about 85% by weight of all 4 pharmaceutically active ingredients.
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. For example, 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. Preferably, the oral dosage form is a tablet. The tablet can be chemically stable.
The tablet can have a weight as mentioned above for the total weight of the pharmaceutical formulation of the present invention, comprising the above 4 APIs.
The largest maximum diameter of the tablet of the present invention, comprising the 4 APIs, can be about 27mm or less and the depth can be less than about 12.5mm;
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 1 1mm, most preferably, the largest maximum diameter can be about 25mm and the depth can be about 1 1mm.
The hardness of the tablet of the present invention, comprising the 4 APIs, can be about 75 Strong-Cobb Units (SCU) to about 20 C, preferably, about 55 SCU to about 25 SCU, as measured by Electronic D-64291 Darmstadt 100-240V.
By way of example, the tablet of the present invention comprises about 150 mg to 350mg of tenofovir disoproxil fumarate, about lOOmg to 300mg of emtricitabine, about 75mg to 800mg of darunavir and about lOOmg of ritonavir. The amount of darunavir can be 75mg, 150mg, 300mg, 400mg 600mg, or 800mg (corresponding to the doses of
commercially available of Prezista®). The said darunavir can be darunavir ethanolate, hydrate, or any other crystalline form as well as darunavir amorphous. The amount of ritonavir can be lOOmg of ritonavir (corresponding to the dose of the commercially available of Norvir® tablet).
Preferably, the tablet of the present invention comprises about 300mg of tenofovir disoproxil fumarate, about 200mg of emtricitabine, about 800mg of darunavir and lOOmg of ritonavir.
In certain embodiments, 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%, or from 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 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 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 55%, to about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about 85%, or from about 60% to about 65%, to about 70%, to about 75%, to about 80%, or to about 85%, or from about 65% to about 70%, to about 75%, to about 80%, or to about 85%, or from about 70% to about 75%, to about 80%, or to about 85%, or from about 75%, to about 80%, or to about 85%, or from about 80% to about 85% by weight of all 4 pharmaceutically active ingredients.
According to some embodiments, 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.
Pharmaceutical formulations in the form of a tablet according to the present invention can be provided for example as a monolithic tablet (single layer), bi-layer (two layers) or multi-layer tablet (three or more distinct layers), preferably the formulation can be a monolithic tablet.
A monolithic tablet according to the present invention can include the four compounds/active pharmaceutical ingredients mixed and compressed to a single layer tablet. The single layer can include darunavir with extra- granular ritonavir or darunavir with intra- granular ritonavir, (i.e., a granulate of darunavir-ritonavir) emtricitabine granules, and tenofovir granules, or granules comprising both emtricitabine and tenofovir. To these can be added at least one disintegrant such as Croscarmellose Sodium (Ac-Di-Sol)
to form a blend that is then compressed into a tablet core. The tablet core can then be coated with a film coating material to produce a film coated tablet.
The granulate of darunavir-ritonavir can be prepared by wet granulation of darunavir. The wet granulation can include top spray process of at least one binder such as hypromellose dissolved in a suitable liquid (e.g., water) on darunavir, obtaining a wet granulate followed by drying the wet granulate and milling the dry granulate.
Then at least one lubricant such as sodium stearyl fumarate can be added to the obtained mixture to obtain the final blend of darunavir-ritonavir(/'.e., darunavir with extra- granular ritonavir).
Alternatively, the granulate of darunavir-ritonavir can be prepared by wet granulation, at least one binder such as hypromellose dissolved in a suitable liquid (e.g. water), can be top spray process on a mixture of darunavir and ritonavir pre-mix or, followed by drying the wet granulate and milling the dry granulate. 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. Optionally, castor oil can be added to the obtained mixture. Then at least one lubricant such as sodium stearyl fumarate can be added to the obtained mixture to obtain the final blend of darunavir-ritonavir (i.e., darunavir with intra-granular ritonavir).
Ritonavir pre-mix can be prepared by mixing ritonavir with at least one carrier such as copovidone, optionally also with at least one solubilizer such as sorbitan laurate and with at least one glidant such as silica, providing a mixture that is the combined with a solvent, such as ethanol to yield a second mixture. 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 9μηι, D(0.5) about 55μη , D(0.9) about 176μηι).
Granules comprising both emtricitabine and tenofovir can be prepared by combining both APIs and at least one filler selected from: microcrystalline cellulose, lactose and/ or pregelatinized starch and optionally at least one disintegrant such as croscarmellose sodium to obtain a powdery mixture that can then combined with water in the wet granulation process. The wet granulation process provides wet granules that can then be dried.
Alternatively emtricitabine and tenofovir can be granulated by the same method separately to produce separate emtricitabine and tenofovir granulates.
Alternatively, emtricitabine granulate can be prepared by combining emtricitabine with at least one filler selected from: microcrystalline cellulose, pregelatinized starch and at least one disintegrant such as croscarmellose sodium to obtain a powdery mixture that can then granulated with water in the wet granulation process. The wet granulation process provides wet granules that can then be dried. Tenofovir granulate can be prepared by combining Tenofovir with at least one filler selected from: microcrystalline cellulose and pregelatinized starch to obtain a powdery mixture that can then granulated with water in the wet granulation process. The wet granulation process provides wet granules that can then be dried.
A bi-layer tablet comprising emtricitabine, tenofovir, darunavir and ritonavir according to the present invention is composed of two distinct layers of the
compounds/active pharmaceutical ingredients. For example, 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.
Pharmaceutical formulations 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. For example, 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. According to some embodiments, 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 μπι to about 100 μηι.
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). Depending on the solubility of the constituents, 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. For example, the copolymer of ethyl acrylate and methyl methacrylate may be used in an aqueous dispersion, with one or more water-soluble adjuncts, such as lactose, polyvinyl pyrrolidine, polyethylene glycol or hydroxypropylmethylcellulose.
Suitable plasticizers for the protective top coat include, for example, triacetin, diethyl phthalate, dibutyl sebacate, tributyl sebacate polyethylene glycol, and mixtures thereof. Polyethylene glycol is a preferred plasticizer.
Suitable anti-adherent or glidants for the protective top coat include, for example, talc, fumed silica, magnesium stearate, and mixtures thereof.
The tablet of the present invention can be prepared by a process comprising:
(a) Blending a mixture comprising tenofovir disoproxil, emtricitabine, darunavir, ritonavir and optionally one or more pharmaceutically acceptable excipients;
(b) Compressing the blend into tablet cores; and
(c) Optionally applying one or more coating layers over the tablet cores.
Preferably, the tablet obtained by this process is a monolithic tablet.
Alternatively, the tablet of the present invention can be prepared by a process comprising:
(a) Providing two blend layers, wherein:
(i) the first layer comprises either a mixture of emtricitabine granulates and tenofovir granulates, or a granulate comprising a mixture of emtricitabine and tenofovir; and
(ii) 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
(c) optionally applying one or more coating layers over the tablet cores.
Preferably, 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. However, other means for compacting the API mixture, e.g., compaction into slugs (or "slugging"), may be used.
Alternatively, 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. For example, to facilitate a uniform drying process, 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. For example, the final blends can be compressed using tabletting machine. Purity analysis can be accomplished using conventional equipment. For example HPLC.
The present invention provides a monolithic tablet comprising:
darunavir or a physiologically functional derivative thereof, and
ritonavir or a physiologically functional derivative thereof.
Preferably, 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. In a specific embodiment of the present invention the tablet weight is between 0.550g to about 0.600g, to about 0.700g, to about 0.900g, to about l .OOOg, to about 1.1 OOg, to about 1.200g, to about 1.300g, or between 0.600g to about 0.700g, to about 0.900g, to about l .OOOg, to about 1.1 OOg, to about 1.200g, or to about 1.3 OOg, or between 0.700g to about 0.900g, to about l .OOOg, to about 1.1 OOg, to about 1.300g, or between0.900g to about l .OOOg, to about 1.1 OOg, to about 1.200g, or to about 1.300g, or between l .OOOg to about 1.1 OOg, to about 1.200g, to about 1.300g, or between 1.1 OOg to about 1.200g, or to about 1.300g, or between 1.200g to about 1.300g.
The monolithic tablet comprising darunavir and ritonavir of the present invention provides a chemically stable formulation of the active agents, and moreover, is suitable for once daily administration in a single pill. Advantageously, 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, comprising darunavir and ritonavir, 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.
By way of example, the tablet of the present invention comprises about 150 mg to 350mg of tenofovir disoproxil fumarate, about lOOmg to 300mg of emtricitabine, about 75mg to 800mg of darunavir and about lOOmg of ritonavir. The amount of darunavir can be 75mg, 150mg, 300mg, 400mg 600mg, or 800mg (corresponding to the doses of
commercially available of Prezista®). The said darunavir can be darunavir ethanolate, hydrate, or any other crystalline form as well as darunavir amorphous. The amount of ritonavir can be lOOmg of ritonavir (corresponding to the dose of the commercially available of Norvir® tablet).
Preferably, the tablet of the present invention comprises about 300mg of tenofovir disoproxil fumarate, about 200mg of emtricitabine, about 800mg of darunavir and lOOmg of ritonavir.
In certain embodiments, 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 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 45% to about 50%, to about 55%, to about 60%, to about 65%, or to about 70%, to about 75%, to about 80% or to about 85%, or from 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 55%, to about 60%, to about 65% or to about 70%, to about 75%, to about 80% or to about 85%, or from about 60% to about 65%, to about 70%, to about 75%, to about 80%, or to about 85%, or from about 65%, to about 70%, to about 75%, to about 80%, or to about 85%, or from about 70% to about 75%, to about 80%, or to about 85%, or form about 75% to about 80% or to about 85%, or from about 80% to about 85% by weight of the two pharmaceutically active ingredients.
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.
According to some embodiments, 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.
The pharmaceutical formulations 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 (diluents) include, for example, water soluble polymer, water insoluble polymer, microcrystalline cellulose (for example, Avicel PHI 02 having or PHlOl), lactose in its various forms (e.g., lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyols, fructose, guar gum, magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like or any combinations thereof.
Suitable binders include, for example, cellulose polymers (e.g., hydroxypropyl- methyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch and the like or any combinations thereof.
Suitable lubricants include, for example, sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate or hydrogenated vegetable oils, and the like or any combinations thereof.
Suitable glidants can be used to improve the flowability. Suitable glidants include, for example, colloidal silica, silica gel, precipitated silica or talc, and the like or any combinations thereof.
Suitable disintegrants include, for example, sodium carboxymethyl starch, cross- linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate (for example Explotab®), croscarmellose sodium, swelling polysaccharide, for example soy
polysaccharide, 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. In particular, 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.
The present invention is illustrated by the following examples, which are not intended to limit the scope of the invention. It will be appreciated that various
modifications are within the spirit and scope of the invention.
ANALYTICAL METHOD
Assay Analytical method for tablet comprising darunavir and ritonavir
Chromatographic System
Column & Packing: Phenomenex Luna C18(2) 5μιη,100Α
250x4.6mm
Column Temperature 30
Mobile Phase: Buffer sol. (pH 3.2):Acetonitrile (40:60)
Flow Rate: 1.0 mL/min.
Detector: UV at 240 nm, 10 mm flow cell path length
Analytical method for tablet comprising emtricitabine, tenofovir, darunavir, ritonavir: Impurities and Degradants Determination Chromatographic conditions for
emtricitabine/tenofovir/darunavir:
Column: Inertsil ODS-3, 150x4.6mm, 3um
Column temperature: 40°C
Mobile phase:
Sol. A: Acetate buff. pH 4.6:MeOH (95:5 v/v)
Sol. B: acetonitrile (ACN)
By gradient:
Flow: 0.8mL/min
Detector: UV at 262nm (by PDA),
10mm flow cell path length
Assay Chromatographic conditions:
Column: Phenomenex Luna CI 8(2), 250x4.6mm, 5um
Column temperature: 30°C
Mobile phase:
Sol. A: H20 (pH 3.2):ACN (90: 10 v/v)
Sol. B: ACN
By gradient:
Detector: UV at 240nm, 10mm flow cell path length
Impurities and Degradants Determination
Chromatographic conditions for Ritonavir.
Column: ACQUITY UPLC BEH C8 1.7um, 2.1x100mm
Column temperature: 50°C
Mobile phase:
Sol. A = Buffer: tetrahydrofuran (THF):n-Butanol (87:8:5
Sol. B = ACN:THF:n-Butanol (87:8:5 v/v)
By gradient:
Flow: 0.6mL/min
Detector: U V at 240nm (by PDA),
10mm flow cell path length
EXAMPLES Example 1: Preparation of ritonavir pre-mix
Ritonavir and the excipients were dissolved in ethanol. Ethanol was evaporated to obtain dry powder. The powder was then milled to lower particle size
Example 2: Preparation of a monolithic tablet containing darunavir - ritonavir extr granular
Raw Material Mg/tablet
Darunavir Hydrate 865.75
Hypromellose (Methocel E-15) 12.20
microcrystalline cellulose (Avicel 101) 14.00
Ex-Granular (Part I) microcrystalline cellulose (Avicel 102) 150.26
Crospovidone LX 30.50
Silicon di-oxide (Aerosil) 3.04
Ritonavir Pre mix (example 1) 130.00
Ex-Granular (Part II)
Sodium Stearyl Fumarate 12.00
Total Tablet weight 1217.75
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.
The wet granulated material was then dried in Fluid bed drier and milled to lower particle size.
Darunavir granulate, ritonavir pre mix (prepared according to example 1), crospovidone, microcrystalline cellulose (Avicel 102) 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)
Raw Material mg/tablet
Darunavir Hydrate 865.75
Hypromellose (Methocel E-15) 12.20
Ritonavir Pre mix (example 1) 130.00
Ex-Granular (Part I) microcrystalline cellulose (Avicel 102) 164.26
Crospovidone LX 30.50
Silicon di-oxide (Aerosil) 3.05
Ex-Granular (Part II)
Sodium stearyl fumarate 12.00
Total Tablet weight 1217.76
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.
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).
Example 4: Preparation of emtricitabine/ tenofovir granulate
Raw Material A B
mg/tablet mg/tablet
Emtricitabine 200 200
Tenofovir disoproxil fumarate 300 300
microcrystalline cellulose 90.30 90.30
Emtricitabine/ tenofovir disoproxil fumarate were wet granulated by High Shear Mixer with microcrystalline cellulose (Avicel 102), Lactose monohydrate, Pregelatinized Starch and Croscarmellose Sodium (Ac-Di-Sol). The granules were then dried by Fluid Bed Drier and milled to lower particle size [see above comments]. Optionally, croscarmellose Sodium was then added as an extra-granular disintegrant.
Example 5: Preparation of emtricitabine granulate
Emtrcitabine is mixed with excipients and wet granulated using povidone solution in purified water. The wet granulate is then dried in a fluid bed dryer.
Example 5A: Preparation of emtricitabine granulate
Ingredient mg/tablet
Emtricitabine 200.00
Microcrystalline cellulose 25.00
(Avicel pH 101)
Croscarmellose Sodium (Ac- 25.00
Di-Sol)
Pregelatinized starch 1500 50.00
Emtricitabine granulate total: 350.00
Emtrcitabine was mixed with excipients and wet granulated using povidone solution in purified water. The wet granulate was then dried in a fluid bed dryer.
Example 6: Preparation of tenofovir Disoproxil Fumarate granulate
Tenofovir Disoproxil Fumarate was mixed with excipients and wet granulated using purified water. The wet granulate was then dried in a fluid bed dryer.
Example 7: Preparation of tenofovir disoproxil fumarate granulate by dry mixing
Tenofovir granulation is produced by dry mixing of tenofovir Disoproxil together with the excipients.
Example 7A: Preparation of Tenofovir Disoproxil Fumarate granulate
Ingredient mg/tablet
Tenofovir Disoproxil 300.00
Fumarate
Microcrystalline cellulose 230.00
(Avicel PH 101)
Pregelatinized starch 50.00
Tenofovir granulate total: 580.00
Tenofovir Disoproxil Fumarate was mixed with excipients and wet granulated using purified water. The wet granulate was then dried in a fluid bed dryer.
Example 8: preparation of a monolithic tablet containing emtricitabine, tenofovir, darunavir and ritonavir (extra-granular).
Emtricitabine/ tenofovir granulate including the extra-granular disintegrant, was prepared according to example 4 A or 4B. Then darunavir-ritonavir formulations, prepared according to example 2, were added. Then, the final mixture was further compressed into tablet cores.
The tablet cores were then coated with a film coating material to produce film coated tablets. (Approximately 3% weight gain).
Example 9: Preparation of a bi-layer tablet containing emtricitabine and tenofovir in the first layer, darunavir and ritonavir (extra-granular) in the second layer.
Raw Material mg/tablet
Emtricitabine/ Tenofovir 700.00
Disoproxil fumarate
Granulate including the
extra-granular disintegrant,
prepared according to
example 4A
Magnesium stearate 7.00
Darunavir - Ritonavir extra- 1217.75
granular, prepared according
to example 2, excluding the
compression step.
Final blend Is layer:
Emtricitabine/ tenofovir granulate including the extra-granular disintegrant is prepared according to example 4A, then it is mixed with Magnesium stearate.
Final blend 2nd layer:
Darunavir-ritonavir formulation, prepared according to example 2, excluding the compression step.
The two blends are then compressed into tablet cores.
The tablet cores are then coated with a film coating material to produce film coated tablets. (Approximately 3% weight gain).
Example 10: Preparation of a monolithic tablet containing emtricitabine, tenofovir, darunavir and ritonavir (intra-granular).
Emtricitabine/ tenofovir granulate including the extra-granular disintegrant, was prepared according to example 4A or 4B. Then darunavir-ritonavir formulation, prepared according to example 3 was added, excluding the compression step. Then, the final mixing was further compressed into tablet cores.
The tablet cores were then coated with a film coating material to produce film coated tablets. (Approximately 3% weight gain).
Example 11: Preparation of a bi-layer tablet containing emtricitabine and tenofovir in the first layer, darunavir and ritonavir (intra-granular) in the second layer.
Final blend 1st layer:
Emtricitabine/ tenofovir granulate including the extra-granular disintegrant, is prepared according to example 4A, then it is mixed with magnesium stearate.
Final blend 2nd layer:
Darunavir-ritonavir formulation, prepared according to example 3, excluding the compression step.
The two blends are then compressed into tablet cores.
The tablet cores are then coated with a film coating material to produce film coated tablets. (Approximately 3% weight gain).
Claims
1. A pharmaceutical formulation in a unit dosage form comprising:
(a) tenofovir or a physiologically functional derivative thereof,
(b) emtricitabine or a physiologically functional derivative thereof,
(c) darunavir or a physiologically functional derivative thereof and
(d) ritonavir or a physiologically functional derivative thereof.
2. A pharmaceutical formulation according to Claim 1 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 (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).
3. A pharmaceutical formulation according to any preceding claim, wherein the tenofovir disoproxil is in the form of its fumarate salt.
4. A pharmaceutical formulation according to any preceding claim, wherein the darunavir is in the form of darunavir ethanolate, hydrate, or any other crystalline form as well as amorphous darunavir, preferably, hydrate.
5. A pharmaceutical formulation according to any preceding claim, wherein the ritonavir is in the form of its crystalline form as well as amorphous ritonavir.
6. A pharmaceutical formulation according to any preceding claim in the form of a solid unit dosage form.
7. A pharmaceutical formulation according to any preceding claim for oral
administration.
8. A pharmaceutical formulation according to any preceding claim in the form of a capsule (such as hard or soft capsules), tablet (such as a coated or uncoated, effervescent, soluble, orodispersible, enteric or modified-release tablet or a sugar- coated tablet), granules, pellets, pills, powders, pastilles, and pharmaceutical formulations thereof.
9. A pharmaceutical formulation according to any preceding claim in the form of a tablet or capsule.
10. A pharmaceutical formulation according to any preceding claim in the form of a film-coated tablet.
1 1. A pharmaceutical formulation according to any preceding claim wherein the pharmaceutical dosage form is a tablet, which can be monolithic (single layer) or can comprise two layers (bi-layer) or more than two layers (multi-layers).
12. A pharmaceutical formulation according to any preceding claim in the form of a monolithic tablet.
13. A pharmaceutical formulation according to any preceding claim in the form of a single unit dosage form for administration once per day.
14. A pharmaceutical formulation according to any preceding claim wherein peak plasma concentrations of each of the active agent (a)-(d) are achieved compared with the administration of the active agents (a)-(d) as separate unit doses.
15. A pharmaceutical formulation according to any preceding claim which is
chemically stable.
16. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form has a total weight of 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.
17. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form has a total weight of between about 1.500g to about 1.600g, to about 1.700g, to about 1.800g, to about 1.900g, to about 2.000g, to about 2.2'OOg, to about 2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g.
18. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form has a total weight of between 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.
19. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form has a total weight of between 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.
20. A pharmaceutical formulation according to any preceding claim 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.
21. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form has a total weight of between 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.
22. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form has a total weight of between 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.
23. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form has a total weight of between about 2.200g, to about 2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g.
24. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form has a total weight of between about 2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g.
25. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form has a total weight of between about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g.
26. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form has a total weight of between about 2.500g, to about 2.600g, to about 2.800g, or between about 2.600g to about 2.800g.
27. A pharmaceutical formulation according to any preceding claim wherein 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.
28. A pharmaceutical formulation according to any preceding claim 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.
29. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form comprises:
(a) about 150 to about 350 mg of tenofovir disoproxil,
(b) about 100 to about 300 mg of emtricitabine
(c) about 75 to about 800 mg of darunavir and
(d) about 100 mg of ritonavir.
30. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form comprises:
(a) about 300 mg of tenofovir disoproxil,
(b) about 200 mg of emtricitabine,
(c) about 800 mg of darunavir and
(d) about 100 mg of ritonavir.
31. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form comprises about 20% to about 85% by weight of active agents (a)-
(d).
32. A pharmaceutical formulation according to any preceding claim 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).
33. A pharmaceutical formulation according to any preceding claim 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).
34. A pharmaceutical formulation according to any preceding claim 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).
35. A pharmaceutical formulation according to any preceding claim 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).
36. A pharmaceutical formulation according to any preceding claim 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).
37. A pharmaceutical formulation according to any preceding claim 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).
38. A pharmaceutical formulation according to any preceding claim 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).
39. A pharmaceutical formulation according to any preceding claim 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).
40. A pharmaceutical formulation according to any preceding claim 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).
41. A pharmaceutical formulation according to any preceding claim 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).
42. A pharmaceutical formulation according to any preceding claim wherein the unit dosage form comprises about 75%: to about 80%, or to about 85%, or from about 80% to about 85%o by weight of active agents (a)-(d).
43. A pharmaceutical formulation according to any preceding claim in the form of a monolithic tablet wherein the active agents (a)-(d) are mixed and compressed to a single layer (monolithic) tablet.
44. A pharmaceutical formulation according to Claim 43 wherein the single layer comprises:
(a) an admixture of: darunavir with extra- granular ritonavir or darunavir with intra- granular ritonavir, (i.e. a granulate of darunavir- ritonavir), emtricitabine granules, and tenofovir granules (preferably tenofovir disoproxil, and more preferably tenofovir disoproxil fumarate) granules; or
(b) an admixture darunavir with extra- granular ritonavir or darunavir with intra- granular ritonavir, (i.e. a granulate of darunavir- ritonavir), with granules comprising both emtricitabine and tenofovir.
45. A pharmaceutical formulation according to any preceding claim further
comprising one or more pharmaceutically acceptable excipients.
46. A pharmaceutical formulation according to Claim 45 wherein the
pharmaceutically acceptable excipient is selected from the group consisting of disintegrant, filler, and lubricant.
47. A process for preparing a pharmaceutical formulation according to any preceding claim, wherein the pharmaceutical formulation is a tablet, preferably a monolithic tablet, the process comprising:
(a) Blending a mixture comprising tenofovir disoproxil, emtricitabine,
darunavir, ritonavir and optionally one or more pharmaceutically acceptable excipients;
(b) Compressing the blend into tablet cores; and
(c) Optionally applying one or more coating layers over the tablet cores.
48. A process for the preparation of a pharmaceutical formulation according to any of Claims 1- 47 comprising combining:
(a) darunavir with extra- granular ritonavir or darunavir with intra- granular ritonavir, (i.e. a granulate of darunavir-ritonavir),
(b) emtricitabine granules and
(c) tenofovir (preferably tenofovir disoproxil, and more preferably tenofovir disoproxil fumarate) granules, optionally in the presence of one or more
pharmaceutically acceptable excipients to form a blend.
49. A process for the preparation of a pharmaceutical formulation according to any of Claims 1-47 comprising combining:
(a) darunavir with extra- granular ritonavir or darunavir with intra- granular ritonavir, (i.e. a granulate of darunavir-ritonavir),
(b) granules comprising both emtricitabine and tenofovir, optionally in the presence of one or more pharmaceutically acceptable excipients to form a blend.
50. A process according to Claim 47-49 wherein the pharmaceutically acceptable excipient comprises at least one excipient selected from a filler (preferably
microcrystalline cellulose), a disintegrant (preferably crospovidone), a glidant (preferably silicon di-oxide) and a lubricant (preferably sodium stearyl fumarate).
51. A process according to Claim 50 wherein the pharmaceutically acceptable
excipient comprises microcrystalline cellulose, crospovidone, silicon di-oxide and sodium stearyl fumarate.
52. A process according to any of Claims 47-51 further comprising processing the blend to provide a solid dosage form.
53. A process according to any of Claims 47-52 comprising compressing the blend to form a tablet, and optionally coating the tablet with a film coating material to form a film coated tablet.
54. A process according to Claim 53 wherein the blend is optionally combined with one or more pharmaceutically acceptable excipients before compressing into tablets.
55. A process according to any of Claims 48-54 wherein the granulate of darunavir- ritonavir 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.
56. A process according to any of Claims 48-55 wherein the granule of darunavir is 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).
57. A process according to any of Claims 48-57 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.
58. A process according to any of Claims 48-54 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).
59. A process according to any of Claims 47-58 wherein the ritonavir is amorphous ritonavir.
60. A process according to any of Claims 47-59 wherein the ritonavir is in the form of a pre-mix, wherein ritonavir pre-mix is a co-precipitate of ritonavir with at least one pharmaceutically acceptable excipient which 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.
61. A process according to Claim 60, wherein 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.
62. A process according to any of Claims 48-49 or any of Claims 55-72, wherein the emtricitabine granules are prepared by admixing with at least one
pharmaceutically acceptable excipient to form a mixture, and granulating the mixture, e.g. by dry granulation, or by wet granulation followed by drying the wet granulate.
63. A process according to Claim 62 wherein the emtricitabine granules are mixed with at least one filler (preferably lactose), and at least one disintegrant (preferably crospovidone) to provide a mixture, combining the mixture with a solution of a binder (preferably an aqueous solution of povidone), to form wet granules, which are dried.
64. A process according to Claim 62 wherein the 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, which are dried.
65. A process according to any of Claims 47-48, or any of Claims 49-64, wherein the granules of tenofovir are prepared by dry mixing, or by wet granulation followed
by drying, of a mixture of tenofovir with at least one pharmaceutically acceptable excipient.
66. A process according to Claim 65 wherein tenofovir is dry mixed with at least one filler [preferably microcrystalline cellulose (e.g. Avicel®)], and at least one disintegrant/binder (preferably pregelatinized starch).
67. A process according to claim 65 wherein 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, which are dried.
68. A process according to claim 65 wherein tenofovir is wet granulated with at least one filler (preferably microcrystalline cellulose and/or pregelatinized starch) with a granulating liquid (preferably water) to provide wet granules, which are dried.
69. A process according to any of Claims 47-48, or any of Claims 49-68 wherein the granules comprising both emtricitabine and tenofovir are prepared by combining emtricitabine and tenofovir with at least one pharmaceutically acceptable excipient and wet granulating, to form wet granules, followed by drying.
70. A process according to Claim 69 wherein the emtricitabine and tenofovir are
combined with at least one filler (preferably lactose), at least one disintegrant (preferably crospovidone), at least one binder (preferably pregelatinized starch or povidone) to obtain a mixture, granulating the mixture with water, and drying the granules.
71. A pharmaceutical formulation according to any of Claims 11 , or claims 13-40 in the form of a bi-layer tablet comprising a first layer and a second layer.
72. A pharmaceutical formulation according to Claim 71 wherein the first layer
comprises emtricitabine and tenofovir and the second comprises darunavir and ritonavir.
73. A pharmaceutical formulation according to Claim 71 or Claim 72 wherein the first layer comprises either a mixture of emtricitabine granulates and tenofovir granulates, or a granulate comprising a mixture of emtricitabine, tenofovir, and the second layer comprises darunavir with extra- granular ritonavir or darunavir with intra- granular ritonavir, (i.e. a granulate of darunavir-ritonavir).
74. A pharmaceutical formulation according to any of Claims 71-73 wherein the first layer further includes at least one pharmaceutically acceptable excipient.
75. A pharmaceutical formulation according to Claim 70-74 wherein the first layer comprises at least one disintegrant (preferably croscarmellose sodium) and at least one lubricant (preferably magnesium stearate) to form the blend of the first layer.
76. A pharmaceutical formulation according to any of Claims 71-75 wherein the bi- layer tablet is formed by compression to form a tablet having two distinct layers, and optionally coating the tablet with a film coating material.
77. A process for preparing the pharmaceutical formulation in the form of a bi-layer tablet according to any of Claims 71-76 comprising:
(a) providing a two blend layers, wherein:
(i) the first layer comprises either a mixture of emtricitabine granulates and tenofovir granulates, or a granulate comprising a mixture of emtricitabine and tenofovir,
(ii) 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
(c) optionally applying one or more coating layers over the tablet cores.
78. A process according to Claim 77 wherein the ritonavir is in the form of a pre-mix which is prepared according to any of Claims 60-61.
79. A process according to any of Claims 77-78 wherein darunavir-ritonavir
granulates are prepared according to any of Claim 55-58.
80. A process according to any of Claims 77-79, wherein emtricitabine granules are prepared according to any of Claims 62-64.
81. A process according to any of Claims 77-80 wherein tenofovir granules are
prepared according to any of Claims 65-68.
82. A process according to any of Claims 77-81 wherein granulates comprising a mixture of emtricitabine, tenofovir are prepared according to Claim 69 or Claim 70.
83. A process according to any of Claims 77-82 further comprising compressing the two blend layers to form a tablet, and optionally coating the tablet with a film coating material to form a film coated tablet.
84. A pharmaceutical formulation according to any of Claims 1-44 and 71-76 for use as a medicament.
85. A pharmaceutical formulation according to any of Claims 1-44 and 71-76 for use in the treatment of HIV- 1 infection.
86. A method for treating HIV-1 infection comprising administration of a
pharmaceutically effective amount of the pharmaceutical formulation according to any of Claims 1-44 and 71-76.
87. A monolithic tablet comprising:
(a) darunavir or a physiologically functional derivative thereof (preferably
darunavir hydrate or darunavir ethanolate) and
(b) ritonavir or a physiologically functional derivative thereof.
88. A monolithic tablet according to Claim 87 which is chemically stable.
89. A monolithic tablet according to any of Claims 87-88 wherein the total tablet weight is 1.300g or lower, about 1.200g or lower, about l .lOOg or lower, about l .OOOg or lower, about 0.900g or lower, about 0.700g or lower, 0.600g or lower, about 0.550g or lower.
90. A monolithic tablet according to any of Claims 87-89 wherein the total tablet weight is about 0.550g to about 0.600g, about 0.550g to about 0.700g, about 0.550g to about 0.900g, about 0.550g to about l .OOOg, about 0.550g to about 1.1 OOg, or about 0.550g to about 1.200g, or about 0.550g to about 1.300g.
91. A monolithic tablet according to any of Claims 87-90 wherein the total tablet weight is about 0.600g to about 0.700g, about 0.600g to about 0.900g, about 0.600g to about l .OOOg, about 0.600g to about 1.1 OOg, or about 0.600g to about 1.200g, or about 0.600g to about 1.300g.
92. A monolithic tablet according to any of Claims 87-91 wherein the total tablet weight is about 0.700g to about 0.900g, about 0.700g to about l .OOOg, about 0.700g to about 1.1 OOg, or about 0.700g to about 1.200g, or about 0.700g to about 1.300g.
93. A monolithic tablet according to any of Claims 87-92 wherein the total tablet weight is about 0.900g to about l .OOOg, about 0.900g to about 1.1 OOg, or about 0.900g to about 1.200g, or about 0.900g to about 1.300g.
94. A monolithic tablet according to any of Claims 87-93 wherein the total tablet weight is about l .OOOg to about l . lOOg, or about l .OOOg to about 1.200g, or about l .OOOg to about 1.300g.
95. A monolithic tablet according to any of Claims 87-94 wherein the total tablet weight is about 1.1 OOg to about 1.200g, or about 1.1 OOg to about 1.300g.
96. A monolithic tablet according to any of Claims 87-95 wherein the total tablet weight is about 1.1 OOg to about 1.300g.
97. A monolithic tablet according to any of Claims 87-96 wherein the largest
maximum diameter of the pharmaceutical formulation of the present invention, comprising darunavir and ritonavir, 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.
98. A monolithic tablet according to any of Claims 87-97 comprising about 75 to 800 mg of darunavir and about 100 mg of ritonavir.
99. A monolithic tablet according to any of Claims 87-98 comprising about 800 mg of darunavir and about lOOmg of ritonavir.
100. A monolithic tablet according to any of Claims 87-99 wherein the darunavir is in the form of darunavir ethanolate, hydrate, or any other crystalline form as well as amorphous darunavir, preferably, hydrate.
101. A monolithic tablet according to any of Claims 87-100 ritonavir is
amorphous ritonavir. .
102. A monolithic tablet according to any of Claims 87-101 comprising from
about 20% to about 85% by weight of darunavir and ritonavir.
103. A monolithic tablet according to any of Claims 87-102 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 by weight of darunavir and ritonavir.
104. A monolithic tablet according to any of Claims 87-103 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.
105. A monolithic tablet according to any of Claims 87-104 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.
106. A monolithic tablet according to any of Claims 87-105 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.
107. A monolithic tablet according to any of Claims 87-106 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%o to about 80%, or about 45% to about 85% by weight of darunavir and ritonavir.
108. A monolithic tablet according to any of Claims 87-107 comprising from about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 50% to about 75%, about 50% to about 80%, or about 50% to about 85% by weight of darunavir and ritonavir.
109. A monolithic tablet according to any of Claims 87-108 comprising from about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 55% to about 75%, about 55% to about 80% or about 55% to about 85% by weight of darunavir and ritonavir.
1 10. A monolithic tablet according to any of Claims 87-109 comprising from about 60% to about 65%, about 60% to about 70%, about 60% to about 75%, about 60% to about 80%, or about 60% to about 85% by weight of darunavir and ritonavir.
1 1 1. A monolithic tablet according to any of Claims 87-1 10 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.
1 12. A monolithic tablet according to any of Claims 87-1 1 1 comprising from about 70% to about 75%, about 70% to about 80%, about 70% to about 85% by weight of darunavir and ritonavir.
1 13. A monolithic tablet according to any of Claims 87-1 12 comprising from about 75% to about 80%, about 75% to about 85% by weight of darunavir and ritonavir.
1 14. A monolithic tablet according to any of Claims 87-1 13 comprising from about 80% to about 85% by weight of darunavir and ritonavir.
1 15. A monolithic tablet according to any of Claims 87-1 14 wherein the ritonavir is in the form of a pre-mix.
1 16. A monolithic tablet according to any of Claims 87-1 15 further comprising at least one lubricant (preferably sodium stearyl fumarate) to form a blend that is then compressed into a tablet core.
1 17. The tablet core according to any of Claims 87-1 16 wherein the tablet is coated with a film coating material to produce a film coated tablet.
1 18. A process for the preparation of a monolithic tablet according to any of Claims 87-1 17 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.
1 19. A process according to Claim 1 18 wherein the pharmaceutically acceptable excipient comprises at least one excipient selected from a filler (preferably microcrystalline cellulose), a disintegrant (preferably crospovidone), a glidant (preferably silicon di-oxide) and a lubricant (preferably sodium stearyl fumarate).
120. A process according to Claim 1 19 wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose, crospovidone, silicon di-oxide and sodium stearyl fumarate.
121. A process according to any of Claims 1 18-1 19 further comprising processing the blend to provide a solid dosage form.
122. A process according to any of Claims 1 18-1 19 comprising compressing the blend to form a tablet, and optionally coating the tablet with a film coating material to form a film coated tablet.
123. A process according to 1 18-122 wherein the blend is optionally combined with one or more pharmaceutically acceptable excipients before compressing into tablets.
124. A process according to any of Claims 1 18-123 wherein the granule of
darunavir is 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).
125. A process according to any of 1 18-124 wherein the granulate of darunavir- ritonavir 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.
126. A process according to any of Claims 118-125 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.
127. A process according to any of Claims 1 18-126 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).
128. A process according to any of Claims 1 18-127 wherein the ritonavir is
amorphous.
129. A process according to any of Claims 1 18-128 wherein the ritonavir is in the form of a pre-mix, wherein 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.
130. A process according to Claim 129, wherein 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.
131. A monolithic tablet according to any of Claims 87-1 17 for use as a
medicament.
132. A monolithic tablet according to any of Claims 87-1 17 for use in the
treatment of HIV- 1 infection.
133. A method for treating HIV-1 infection comprising administration of a
pharmaceutically effective amount of a monolithic tablet according to any of Claims 87-1 17.
134. A pharmaceutical formulation, monolithic tablet or process according to any preceding claim 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.
135. A pharmaceutical formulation, monolithic tablet or process according to Claim 134, 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 PHI 01), 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.
136. A pharmaceutical formulation, monolithic tablet or process according to Claim 134 or Claim 135, wherein the binder is selected from one or more of the group consisting of cellulose polymers (e.g. hydro ypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl cellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch and the like or any combinations thereof.
137. A pharmaceutical formulation, monolithic tablet or process according to any of Claims 134-136 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.
138. A pharmaceutical formulation, monolithic tablet or process according to any of Claims 134-137 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.
139. A pharmaceutical formulation, monolithic tablet or process according to any of Claims 134-138 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.
140. A pharmaceutical formulation, monolithic tablet or process according to any of Claims 134-139 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361871674P | 2013-08-29 | 2013-08-29 | |
| PCT/IB2014/001637 WO2015028875A2 (en) | 2013-08-29 | 2014-08-28 | Unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir and a monolithic tablet comprising darunavir and ritonavir |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP3038607A2 true EP3038607A2 (en) | 2016-07-06 |
Family
ID=51830545
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP14790289.4A Withdrawn EP3038607A2 (en) | 2013-08-29 | 2014-08-28 | Unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir and a monolithic tablet comprising darunavir and ritonavir |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP3038607A2 (en) |
| AR (1) | AR097512A1 (en) |
| CA (1) | CA2918707A1 (en) |
| HK (1) | HK1220390A1 (en) |
| IL (1) | IL244107A0 (en) |
| MX (1) | MX2016002560A (en) |
| TW (1) | TW201542212A (en) |
| WO (1) | WO2015028875A2 (en) |
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|---|---|---|---|---|
| EP3129009A1 (en) * | 2014-04-08 | 2017-02-15 | Teva Pharmaceutical Industries Ltd | Unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir |
| CA2937365C (en) | 2016-03-29 | 2018-09-18 | F. Hoffmann-La Roche Ag | Granulate formulation of 5-methyl-1-phenyl-2-(1h)-pyridone and method of making the same |
| KR101777564B1 (en) | 2016-05-30 | 2017-09-12 | 영남대학교 산학협력단 | Tablet composition comprising tenofovir disoproxil free base and preparation method thereof |
| WO2018153977A1 (en) * | 2017-02-24 | 2018-08-30 | Hexal Ag | Stable composition of tenofovir alafenamide |
| CN108727401A (en) * | 2017-04-20 | 2018-11-02 | 盐城迪赛诺制药有限公司 | Darunavir novel crystal forms and its preparation method and application |
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| US8025899B2 (en) | 2003-08-28 | 2011-09-27 | Abbott Laboratories | Solid pharmaceutical dosage form |
| ATE406161T1 (en) * | 2004-07-08 | 2008-09-15 | Tibotec Pharm Ltd | COMBINATION OF TENOFOVIR, RITONAVIR AND TMC114 |
| AR045841A1 (en) * | 2004-09-28 | 2005-11-16 | Richmond Sa Com Ind Y Financie | A SOLID PHARMACEUTICAL COMPOSITION THAT INCLUDES THE TIAZOLIL METHYL ESTER OF THE ACID [5S- (5R *, 8R *, 10R *, 11R *)] -10- HYDROXY-2-METHYL-5- (1-METHYTILE) -1- [2 - (1-METHYLE) -4-TIAZOLIL] -3,6-DIOXO-8,11-BIS (PHENYLMETIL) -2,4,7,12- TETRAAZATRIDECAN-13-OICO AND A PROCEDURE TO PREPARE IT. |
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-
2014
- 2014-08-28 CA CA2918707A patent/CA2918707A1/en not_active Abandoned
- 2014-08-28 MX MX2016002560A patent/MX2016002560A/en unknown
- 2014-08-28 EP EP14790289.4A patent/EP3038607A2/en not_active Withdrawn
- 2014-08-28 WO PCT/IB2014/001637 patent/WO2015028875A2/en active Application Filing
- 2014-08-29 AR ARP140103253A patent/AR097512A1/en unknown
- 2014-08-29 TW TW103129876A patent/TW201542212A/en unknown
-
2016
- 2016-02-14 IL IL244107A patent/IL244107A0/en unknown
- 2016-07-19 HK HK16108535.7A patent/HK1220390A1/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| AR097512A1 (en) | 2016-03-23 |
| WO2015028875A8 (en) | 2016-09-01 |
| MX2016002560A (en) | 2016-10-26 |
| CA2918707A1 (en) | 2015-03-05 |
| WO2015028875A2 (en) | 2015-03-05 |
| IL244107A0 (en) | 2016-04-21 |
| WO2015028875A3 (en) | 2015-11-19 |
| HK1220390A1 (en) | 2017-05-05 |
| TW201542212A (en) | 2015-11-16 |
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