Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • 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
• • 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
  • A61K9/2009—Inorganic 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • 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
  • A61K9/2095—Tabletting processes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2813—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates to pharmaceutical compositions comprising (4- ⁇ 4-[5-(6- trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl ⁇ -cyclohexyl)-acetic acid, or a pharmaceutically acceptable salt thereof, e.g. the sodium salt thereof, as the active ingredient in a suitable carrier.
• the present invention also relates to the processes for their preparation and to their use as medicaments.
• parenteral administration may be employed in the treatment of a condition or a disorder such as inflammatory conditions, obesity, diabetes and related metabolic disorders.
• Administration of such pharmaceutical agents via the oral route is preferred to parenteral administration because it allows self-administration by patients whereas parenteral formulations have to be administered in most cases by a physician or paramedical personnel. It is also important that dosage units which are
• the formulation must have a good dissolution profile and an optimal in-vivo drug-release profile with minimal unit-to-unit variability.
• the compound of formula (I), or a pharmaceutically acceptable salt thereof, in particular the sodium salt thereof is a drug substance which is difficult to formulate due to its physicochemical properties. More particularly, the sodium salt of the compound of formula (I), depicted above as the compound of formula (II), is hygroscopic, poorly soluble and highly permeable, with a high moisture uptake at 95% relative humidity. It is also plate like, very fluffy, and sticky in nature. It also exhibits poor flow characteristics.
• the invention thus provides a pharmaceutical composition of the compound of formula (I), or a pharmaceutically acceptable salt thereof, which exhibits one or more, e.g. 1 , 2 or 3, of the following desirable characteristics;
• dissolution profile which is suitable for the administration of the therapeutic agent, -a compression profile with a wide hardness window which still provides acceptable friability, hardness, disintegration time and dissolution; - sufficient stability to achieve a reasonable shelf life;
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a) a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, b) one or more, e.g. 1 , 2 or 3, surfactants with lubricant properties; c) one or more, e.g. 1, 2 or 3, dry binders with disintegrant properties; d) one or more, e.g. 1, 2 or 3, fillers, and e) one or more, e.g. 1, 2 or 3, disintegrants.
• the pharmaceutical composition in accordance with the present invention is, as defined in claim 1.
• the use of the specificied excipients surprisingly overcomes the problems of formulating the compound of formula (I), or a pharmaceutically acceptable salt, in particular the sodium salt of formula (II), into a solid oral dosage form.
• the present invention provides a composition which shows good physical and chemical stability during storage, which has a good dissolution profile, which is not sensitive to manufacturing parameters, and in which the unit to unit variation in drug release is minimized.
• the present invention also provides a process which enables maximum drug load to be achieved and which is not sensitive to manufacturing parameters.
• the present inventors have found that the presence of a surfactant which also has lubricant properties considerably reduces the sticking tendency of the formulation, as well as improving the dissolution and processing properties of the compositions of the present invention.
• the pharmaceutical compositions of the present invention contain one or more, e.g. 1 , 2 or 3, surfactants which have lubricant properties.
• the surfactants to be employed in accordance in the present invention include, without limitation, sodium lauryl sulfate (SLS), stearic acid, palmitic acid, myristic acid, poloxamers and polyethylene glycols such as PEG 4000-8000, Tween series of surfactants, Brij series of surfactants (i.e., Brij 80), Triton X-100, and
• SLS Sodium lauryl sulfate
• the surfactant or combination of surfactants may be employed in an amount ranging from about 0.1% to about 5%, preferably from about 0.5% to about 3%, e.g. 2%, by weight of the tablet (prior to any optional film coating). These percentages are based on the compound of the formula (I) and if a salt is used the percentages will be adapted accordingly.
• compositions of the present invention in addition contain one or more, e.g. 1 , 2 or 3, binders with lubricant properties.
• the dry binders to be employed in accordance in the present invention include, without limitation, polyethylene glycols (PEG), e.g., PEG 4000; pregelatinized starch; starch; chitosan; guar gum, microcrystalline cellulose; methyl cellulose;
• PEG polyethylene glycols
• hydroxypropylmethyl cellulose or hydroxypropyl cellulose both preferably of medium to high viscosity, e.g., viscosity grades 3 or 6 cps, e.g. low substituted hydroxypropyl cellulose (L-HPC LH-21); and combinations thereof.
• a most preferred binder is low substituted hydroxypropyl cellulose (L-HPC LH-21).
• the dry binder or or combination of dry binders may be employed in an amount ranging from about 2% to about 20%, preferably from about 5% to about 15%, e.g. about 10% by weight of the tablet (prior to any optional film coating). These percentages are based on the compound of the formula (I) and if a salt is used the percentages will be adapted accordingly.
• the fillers to be employed in accordance in the present invention include, without limitation, microcrystalline cellulose (e.g., cellulose MK GR and products available under the registered trade marks AVICEL, FILTRAK, HEWETEN or PHARMACEL, Vivapur, emcocel, tabulose), low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, Anhydrous Dicalcium Phosphate,
• the filler is microcrystalline cellulose, Anhydrous Dicalcium Phosphate and Anhydrous Lactose , or a mixture thereof.
• Combination of fillers may be used such as combinations of microcrystalline cellulose and Anhydrous Dicalcium Phosphate, and combinations of microcrystalline cellulose and lactose.
• the filler or combination of fillers may be employed in an amount ranging from about 4% to about 85%, preferably from about 20% to about 85%, most preferably from about 50-80%, e.g, 50-65% or 70-80% by weight of the tablet (prior to any optional film coating). These percentages are based on the compound of the formula (I) and if a salt is used the percentages will be adapted accordingly.
• fillers When combinations of fillers are used, they may be used in a ratio of from 1:1 to 1:5, preferably 1 :2 ratio.
• the filler is a combination of microcrystalline cellulose and another filler, e.g. Anhydrous Dicalcium Phosphate, or lactose, wherein the ratio of the microcrystalline cellulose to lactose, or of microcrystalline cellulose to anhydrous dicalcium phosphate is 1 :2.
• another filler e.g. Anhydrous Dicalcium Phosphate, or lactose, wherein the ratio of the microcrystalline cellulose to lactose, or of microcrystalline cellulose to anhydrous dicalcium phosphate is 1 :2.
• the disintegrants to be employed in the pharmaceutical compositions of the present invention can be extragranular or intragranular, or both.
• examples of disintegrants to be employed in accordance in the present invention include, without limitation, carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC- Na) or crosscarmellose sodium, e.g. AC-DI-SOL, Sodium Starch Glycollate (SSG); alginic acid, sodium alginate and guar gum; preferably crosscarmellose sodium, e.g. AC-DI-SOL, cross-linked polyvinyl pyrrolidone (e.g. CROSPOVIDONE, POLYPLASDONE or KOLLIDON XL), Sodium Starch Glycollate (SSG).
• a most preferred disintegrant is Sodium Starch Glycollate (SSG).
• the disintegrant or combination of disintegrants may be employed in an amount ranging from about 0.5% to about 25%, preferably from about 1% to about 10%, most preferably from about 1% to about 6%, by weight of the tablet (prior to any optional film coating). In one embodiment, the disintegrant is present in an amount which is 2, 6 or 9% by weight of the tablet. These percentages are based on the compound of the formula (I) and if a salt is used the percentages will be adapted accordingly.
• Lubricants may provide advantages in the formulation of a pharmaceutical composition when the drug substance is poorly water soluble and a compaction process, such as a roller compaction process, is used with drug loads as high as 25% w/w.
• the pharmaceutical compositions of the present invention may in addition contain one or more, e.g. 1 , 2 or 3, lubricants.
• the lubricants to be employed in accordance in the present invention include, without limitation, magnesium stearate, aluminum or calcium silicate, stearic acid, cutina, PEG 4000-8000, talc and combinations thereof, preferably Sodium Stearyl Fumarate or magnesium stearate, more preferably Sodium Stearyl Fumarate.
• the lubricant or lubricants may be employed in an amount ranging from about 0.1% to about 10%, preferably from about 0.5% to about 5%, e.g. 2-3%, by weight of the tablet (prior to any optional film coating). These percentages are based on the compound of the formula (I) and if a salt is used the percentages will be adapted accordingly.
• the compound of formula (I), or a pharmaceutically acceptable salt may be employed in an amount ranging from about 0.1% to about 50%, preferably from about 0.5% to about 30%, most preferably from about 1-30%o, by weight of the pharmaceutical compositions (prior to any optional film coating).
• the compound of formula (I) may be present in 2, 10, 15, 20, 25 and 30 % by weight of the
• compositions are based on the compound of the formula (I) and if a salt is used the percentages will be adapted accordingly.
• the amount of each additive in a pharmaceutical oral fixed dose combination may vary within ranges conventional in the art.
• Suitable glidants include, without limitation, colloidal silicon dioxide (e.g., Aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc and combinations thereof.
• a glidant or glidants in the layer containing component a) may be employed in an amount ranging from about 00.05% to about 5%, preferably from about 0.1% to about 1%, more preferably from about 0.25% to about 1%., e.g. 0.25 or 0.5%, by weight of the tablet (prior to any optional film coating). These percentages are based on the compound of the formula (I) and if a salt is used the percentages will be adapted accordingly.
• the invention provides a pharmacceutical composition, as described in claim 1.
• Embodiment 2 a pharmacceutical composition, according to embodiment 1 , wherein the surfactant with lubricant properties is selected from, sodium lauryl sulfate (SLS), stearic acid, palmitic acid, myristic acid, poloxamers and polyethylene glycols such as PEG 4000-8000, Tween series of surfactants, Brij series of surfactants (i.e., Brij 80), Triton X-100, and combinations thereof, preferably Sodium lauryl sulfate (SLS).
• SLS sodium lauryl sulfate
• stearic acid stearic acid
• palmitic acid palmitic acid
• myristic acid poloxamers
• polyethylene glycols such as PEG 4000-8000
• Tween series of surfactants i.e., Brij 80
• Triton X-100 Triton X-100
• SLS Sodium lauryl sulfate
• Embodiment 3 a pharmacceutical composition, according to embodiment 1 or 2, wherein the dry binder is selected from polyethylene glycols (PEG), e.g., PEG 4000; pregelatinized starch; starch; chitosan; guar gum, microcrystalline cellulose; methyl cellulose; calcium carboxymethylcellulose; sodium carboxymethylcellulose, alginic acid and/or its sodium salt; hydroxypropylmethyl cellulose or hydroxypropyl cellulose, both preferably of medium to high viscosity, e.g., viscosity grades 3 or 6 cps, e.g. low substituted hydroxypropyl cellulose (L-HPC LH-21); and combinations thereof, most preferably, low substituted hydroxypropyl cellulose (L-HPC LH-21).
• PEG polyethylene glycols
• PEG 4000 pregelatinized starch
• starch chitosan
• guar gum microcrystalline cellulose
• methyl cellulose calcium carboxymethyl
• Embodiment 4 a pharmacceutical composition, according to any one of
• embodiments 1 to 3 wherein the filler is selected from microcrystalline cellulose (e.g., cellulose MK GR and products available under the registered trade marks AVICEL, FILTRAK, HEWETEN or PHARMACEL, Vivapur, emcocel, tabulose), low- substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, Anhydrous Dicalcium Phosphate, Dicalcium Phosphate, lactose,
• microcrystalline cellulose e.g., cellulose MK GR and products available under the registered trade marks AVICEL, FILTRAK, HEWETEN or PHARMACEL, Vivapur, emcocel, tabulose
• low- substituted hydroxypropyl cellulose hydroxyethyl cellulose, hydroxypropyl methyl cellulose
• Anhydrous Dicalcium Phosphate Dicalcium Phosphate, lactose
• Embodiment 5 a pharmacceutical composition, according to any one of embodiments 1 to 4, wherein the disintegrant is selected from carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC- Na) or crosscarmellose sodium, e.g. AC-DI-SOL, Sodium Starch Glycollate (SSG); alginic acid, sodium alginate and guar gum; preferably crosscarmellose sodium, e.g. AC-DI-SOL, cross-linked polyvinyl pyrrolidone (e.g. CROSPOVIDONE, POLYPLASDONE or KOLLIDON XL), Sodium Starch Glycollate (SSG).
• the pharmaceutical compositions provided herein may contain in addition, lubricants, glidants, colorants, and combinations thereof, as detailed above.
• the amounts of each of the excipients, and the amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, are as described herein, and as described in the Examples.
• Hardness commonly also referred to as “breaking force” or “resistance to crushing” as used herein refers to the force required to cause a tablet to fail (i.e., break) in a specific plane.
• the hardness is measured by standard methods known to the person skilled in the art, see the harmonized procedure set forth in the pharmacopeias USP ⁇ 1217> and EP 2.9.8 and JP. If the tablet is too soft, it will not withstand handling during the subsequent processing, such as coating or packaging and shipping operations.
• release profile refers to a process by which the pharmaceutical oral fixed dose combination is brought into contact with a fluid and the fluid transports the drug(s) outside the dosage form into the fluid that surrounds the dosage form.
• the combination of delivery rate and delivery duration exhibited by a given dosage form in a patient can be described as its in vivo release profile.
• the release/dissolution profiles of dosage forms may exhibit different rates and durations of release and may be continuous.
• Continuous release profiles include release profiles in which one or more, e.g. 1 , 2 or 3, active ingredients are released continuously, either at a constant or variable rate.
• An adequate drug release profile for the pharmaceutical composition may be e.g. 80% within 45 minutes.
• Disintegration refers to a process where the pharmaceutical oral fixed dose combination, typically by means of a fluid, falls apart into separate particles and is dispersed. Disintegration is achieved when the solid oral dosage form is in a state in which any residue of the solid oral dosage form, except fragments of insoluble coating or capsule shell, if present, remaining on the screen of the test apparatus is a soft mass having no palpably firm core in
• the fluid for determining the disintegration property is water, such as tap water or deionized water.
• the disintegration time is measured by standard methods known to the person skilled in the art, see the harmonized procedure set forth in the pharmacopeias USP ⁇ 701> and EP 2.9.1 and JP.
• Dissolution rate refers to a process by which a solid substance, here the active ingredients, is dispersed in molecular form in a medium.
• the dissolution rate of the active ingredients of the pharmaceutical oral fixed dose combination of the invention is defined by the amount of drug substance that goes in solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition.
• the dissolution rate is measured by standard methods known to the person skilled in the art, see the harmonized procedure set forth in the pharmacopeias USP ⁇ 711> and EP 2.9.3 and JP.
• the test is for measuring the dissolution of the individual active ingredients is performed following pharmacopeia USP ⁇ 711> at pH 4.5 using a paddle stirring element at 75 rpm (rotations per minute).
• the dissolution medium is preferably a buffer, typically a phosphate buffer, especially one as described in the example "Dissolution Test".
• the molarity of the buffer is preferably 0.1 M.
• An adequate dissolution profile for a slowly dissolving or poorly water soluble drug may mean for example, more than 80%, e.g. 85%, dissolution within 30, 45, or 60 minutes, see e.g. Guidance for Industry: Dissolution Testing of
• the particulates have an average size of lower than about 3 mm, preferably between about 1 ⁇ to 3 mm.
• average particle size it is meant that at least 50% of the particulates have a particle size of less than about the given value, by weight.
• the particle size may be determined on the basis of the weight average particle size as measured by conventional particle size measuring techniques well known to those skilled in the art. Such techniques include, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, and disk centrifugation.
• effective amount refers to the amount of the active ingredient or agent which halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition.
• prophylactically effective amount refers to the amount of the active ingredient or agent prevents the onset of the disease, condition or disorder.
• warm-blooded animal or patient are used interchangeably herein and include, but are not limited to, humans, dogs, cats, horses, pigs, cows, monkeys, rabbits, mice and laboratory animals. In one embodiment, the mammals are humans.
• treatment means the management and care of a patient for the purpose of preventing, combating or delaying progression of the disease, condition or disorder, preferably for the purpose of combating the disease, condition or disorder, and in particular it also prophylactic treatment.
• prevention preventing are to be understood as meaning the
• prophylactic administration of a drug such as a combined preparation or
• composition to healthy patients to prevent the outbreak of the disease, condition or disorder.
• delay of progressionTdelaying progression are to be understood as meaning the administration of a drug, such as a combined preparation or pharmaceutical composition, to patients being in a pre-stage of the disease, condition or disorder.
• drug active substance
• active ingredient active agent
• the invention provides in another of its aspects a process of making a solid oral dosage form as hereinabove described.
• a solid oral dosage form may be produced by working up the final composition defined hereinabove in appropriate amounts, to form unit dosage forms.
• a process for preparing a pharmaceutical composition according to any one of the preceding claims comprising the steps of mixing compound of formula (I), or a pharmaceutically acceptable salt thereof, with at least one pharmaceutically acceptable excipient to form a blend; compacting, such as roller compacting, said blend; optionally mixing with further pharmaceutically acceptable excipients, and optionally compressing the final blend into a solid oral dosage form.
• a further embodiment of the present invention is a process for the manufacture of a tablet according to the present invention.
• the pharmaceutical oral fixed compositions of the invention are tablets of low friability. Preferably the friability is not more than 0.8%. The friability is measured by standard methods known to the person skilled in the art, see the harmonized procedure set forth in the pharmacopeias USP ⁇ 1216> and EP 2.9.7 and JP.
• the pharmaceutical oral fixed compositions of the invention are tablets of suitable hardness (e.g. an average hardness ranging from about 30 N to about 110 N).
• a preferred embodiment of this invention is directed to pharmaceutical oral compositions which are film-coated.
• suitable film coatings are known and commercially available or can be made according to known methods.
• the film coating material is a polymeric film coating material comprising materials such as hydroxypropylmethyl cellulose or polyvinyl alcohol, polyethylene glycol, lecithin, talc and colorant.
• a film coating material is applied in such an amount as to provide a film coating that ranges from about 1% to about 6% by weight of the film-coated tablet.
• a coating comprising polyvinyl alcohol and materials such as polyethylene glycol, talc, and colorants (such as Opadry AMB or Opadry II 85F) can be applied as a moisture barrier to provide additional moisture protection to prevent conversion of the active ingredient to other polymorphic forms.
• Sufficient moisture protection can also be achieved through various packaging, including but not limited to: heat- induction sealed HDPE bottles with or without desiccant, and blister packaging materials known in the industry to have low moisture vapor permeation rates (i.e. aluminum/aluminum, PVC/PCTFE (polyvinylchloride/polychlorotrifluoroethylene), ACLAR).
• the invention provides a process for the preparation of pharmaceutical oral compositions as described herein above.
• Such pharmaceutical oral fixed dose combination may be produced by working up components as defined herein above in the appropriate amounts, to form unit pharmaceutical oral fixed dose combinations.
• the pharmaceutical compositions are useful in treating or preventing a condition or disorder associated with DGAT1 activity.
• the conditions for which the instant invention is useful include, without limitation, a metabolic disorder such as obesity, diabetes, anorexia nervosa, bulimia, cachexia, syndrome X, insulin resistance, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia,
• hypercholesterolemia hyperlipidemia, dyslipidemia, mixed dyslipidemia,
• cardiovascular diseases such as atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease,
• neoplastic diseases such as solid tumors, skin cancer, melanoma, lymphoma, and endothelial cancers, for example, breast cancer, lung cancer, colorectal cancer, stomach cancer, other cancers of the gastrointestinal tract (for example, esophageal cancer and pancreatic cancer), prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer, and ovarian cancer; dermatological conditions, such as acne vulgaris.
• the pharmaceutical compositions are useful as an anorectic.
• the present invention thus provides a method for treating or preventing a condition or disorder associated with DGAT1 activity, comprising administering to an animal, including a human patient, in need of such treatment a therapeutically effective amount of the pharmaceutical composition according to the present invention.
• the present invention likewise provides the use of a pharmaceutical composition according to the present invention for the manufacture of a medicament for treating or preventing a condition or disorder associated with DGAT1 activity.
• the present invention likewise provides a pharmaceutical composition according to the present invention for use in treating or preventing a condition or disorder associated with DGAT1 activity.
• the exact dose of the active agent and the particular formulation to be administered depend on a number of factors, e.g., the condition to be treated, the desired duration of the treatment and the rate of release of the active agent.
• the amount of the active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.
• the tablets of the Examples are tested for their dissolution in 900 ml of pH 6.8 phosphate buffer with paddles at 75 rpm.
• the assembly consists of the following: a covered vessel made of glass or other inert, transparent material; a motor, and a paddle formed from a blade and shaft as the stirring element.
• the vessel is partially immersed in a suitable water bath of any convenient size or placed in a heating jacket.
• the water bath or heating jacket permits holding the temperature inside the vessels at 37 ⁇ 0.5° during the test and keeping the bath fluid in constant, smooth motion. No part of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation, or vibration beyond that due to the smoothly rotating stirring element.
• Apparatus that permits observation of the specimen and stirring element during the test is has the following dimensions and capacities: the height is 160 mm to 210 mm and its inside diameter is 98 mm to 106 mm. Its sides are flanged at the top. A fitted cover may be used to retard evaporation.
• the shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel and rotates smoothly without significant wobble.
• the vertical center line of the blade passes through the axis of the shaft so that the bottom of the blade is flush with the bottom of the shaft.
• the design of the paddle is as shown in USP ⁇ 711>, Fig. 2. The distance of 25 ⁇ 2 mm between the blade and the inside bottom of the vessel is maintained during the test.
• the metallic or suitably inert, rigid blade and shaft comprise a single entity.
• a suitable two-part detachable design may be used provided the assembly remains firmly engaged during the test.
• the paddle blade and shaft may be coated with a suitable inert coating.
• the dosage unit is allowed to sink to the bottom of the vessel before rotation of the blade is started.
• a small, loose piece of nonreactive material such as not more than a few turns of wire helix may be attached to dosage units that would otherwise float.
• Other validated sinker devices may be used.
• a specimen(> 1 ml) is withdrawn from a zone midway between the surface of the Dissolution Medium and the top of the rotating blade, not less than 1 cm from the vessel wall.
• a specimen(> 1 ml) is withdrawn from a zone midway between the surface of the Dissolution Medium and the top of the rotating blade, not less than 1 cm from the vessel wall.
• the vessel is kept covered for the duration of the test, and the temperature of the mixture under test at suitable times is verified.] .
• the specimen is filtered through a suitable filter, e.g. a 0.45 ⁇ PVDF filter (Millipore) and the first mis (2 to 3 ml) of the filtrate are discarded.
• the analysis is performed by HPLC or UV detection.
• the test is repeated at least 6 times, with additional dosage form units.
• a Schleuniger 8M Hardness tester was used to perform tablet hardness testing. Tablets were positioned on the instrument stage. Each tablet was oriented in the lengthwise same position according to distinguishing marks (when applicable).
• Example 1 Reference Example frans-(4- ⁇ 4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl ⁇ -cyclohexyl)- acetic acid, sodium salt along with Microcrystalline Cellulose (partial), and
• Crospovidone (intragranular) are mixed in a low shear mixer.
• the mixed contents, along with remaining Microcrystalline Cellulose are passed through an oscillating mill equipped with a suitable screen.
• the screened contents are mixed in a low shear mixer for a suitable amount of time.
• Colloidal silicon dioxide screened through an appropriate screen is mixed with the blend from earlier step and the contents are mixed for a suitable amount of time.
• Magnesium Stearate, screened through a suitable screen size is added to the preblend and mixed for a suitable amount of time.
• the lubricated intragranular preblend is passed through a roller compaction system for densification at the optimized parameters for feed rate, roll speed and roll force.
• the ribbons from the process are collected and passed through an oscillating mill equipped with a suitable screen to get the desired milled material.
• the milled material is then mixed with extragranular prescreened Crospovidone and mixed in a low shear mixer for a suitable amount of time.
• prescreened Crospovidone is then mixed with extragranular prescreened Crospovidone and mixed in a low shear mixer for a suitable amount of time.
• Magnesium Stearate is added and mixed for a suitable amount of time. The final blend is then compressed to the desired tablet weight to achieve the optimized thickness, hardness and disintegration time.
• Example 1 A Uncoated tablet comprising a DGAT1 inhibitor, (5 mq of active ingredient, based on free acid of Compound 1) Ingredients mg/tab
• Example 1B Uncoated tablet comprising a DGAT1 inhibitor, (10 mg of active ingredient, based on free acid of Compound 1)
• Example 1.A The Table below shows the dissolution of tablets of Example 1.A which are compressed at two different hardness i.e. 6 kN and 12 kN.
• the dissolution for the batches was performed using USP-2 Paddle / 0.4% CTAB/ pH 6.8 buffer/ 50 rpm.
• Example 2 Effect of surfactant with lubricant properties
• Method for preparing a pharmaceutical composition :
• Microcrystalline cellulose (Avicel), surfactant (sodium lauryl sulfate), disintegrant (Internal), and glidant (Aerosil 200) (Internal) are added to the therapeutic agent.
• the mixture is sieved and blended prior to lubrication..
• the lubricant (Internal) is then added to the bin blender and blended for an appropriate amount of time.
• the mixture is roller compacted using a roller compactor, and then milled.
• Disintegrant (External), and glidant (Aerosil 200) (External) are added to the mixture and bin blended. Thereafter, the obtained mixture is blended with lubricant (external excipient), sieved in a bin blender.
• the obtained final mixture is then compressed into a tablet weighing about 100 mg .
• Aerosil 200 (Internal) 0.25 0.25
• Aerosil 200 (External) 0.25 0.25
• the dissolution comparison clearly indicates the faster rate of dissolution at the initial two time points for the formulation with 2% w/w of SLS. Moreover, during the processing of the batch containing SLS, it was observed that the sticking tendency to the rolls of the compactor was also significantly reduced. Hence the advantages from the dissolution and processing standpoint made it crucial to include a surfactant with lubricant properties in the formulation.
• Example 3B The effect of a dry binder with disintegrant properties can be evaluated as follows.
• Example 3B the non-inclusion of L-HPC LH-21 was compensated by a similar amount of Avicel PH-102 in the external phase.
• Aerosil 200 (External) 0.25 0.25
• Aerosil 200 (Internal) 0.25 0.25
• Aerosil 200 (External) 0.25 0.25
• Example 4A and 4B are given in the Table below.
• the therapeutic agent in these examples is the compound of formula (II).
• the table below shows the formulation for Examples 5A, 5B and 5C having 25 mg of therapeutic agent-the 25 mg refers to the amount of the compound of formula (I).
• Examples 5A, 5B and 5C provide possible embodiments of a tablet dosage form using various disintegrants. icrocrystalline cellulose (Avicel). sodium lauryl sulfate, disintegrant (Internal), and Aerosil 200 (Internal) are added to the therapeutic agent. The mixture is sieved and blended prior to lubrication.. The Sodium Stearyl Fumarate (Internal), is then added to the bin blender and blended for an appropriate amount of time. The mixture is roller compacted using a roller compactor, and then milled.
• Disintegrant (External), and Aerosil 200 (External) are added to the mixture and bin blended. Thereafter, the obtained mixture is blended with Sodium Stearyl Fumarate (external excipient), sieved in a bin blender. The obtained final mixture is then compressed into a tablet weighing about 100 mg .
• the dissolution data of these examples at pH 6.8 are shown in the Table below.
• Aerosil 200 (Internal) 0.25 0.25 0.25
• Aerosil 200 (External) 0.25 0.25 0.25
• SSG Sodium Starch Glycollate
• PVP- XL Cross linked polyvinyl pyrollidone
• L- HPC 21 low substituted hydroxypropyl cellulose
• Dissolution medium 900ml pH 6.8 Phosphate + 0.05% CTAB; Paddle at 75 rpm; HPLC method; rapid stir 45 to 60 min.
• a most preferred disintegrant is sodium starch glycollate, which also gives a good friability level.
• the therapeutic agent in these examples is the compound of formula (II).
• the table below shows the formulation for Examples 6.1 to 6.4 having 25 mg of therapeutic agent-the 25 mg refers to the amount of the compound of formula (I). Tablets for examples 6.1 to 6.4 were made by the same process as described in example 2. Table : Uncoated 25mg variants with different levels of disintegrant
• Example 6.1 Example 6.2
• Example 6.3 Example 6.4
• Aerosil 200 (Internal) 0.25 0.25 0.25 0.25 0.25 0.25
• Aerosil 200 (External) 0.25 0.25 0.25 0.25 0.25 0.25
• Dissolution medium 900ml pH 6.8 Phosphate + 0.05% CTAB (cetyltrimethyl ammonium bromide); Paddle at 75 rpm; HPLC method; rapid stir 45 to 60 min.
• CTAB cetyltrimethyl ammonium bromide
• the dissolution profiles show a clear rank order in terms of level of disintegrant and the rate of dissolution up to 6% level. There was no significant difference in the release rates between 6% and 9%. Greater than 90% of the therapeutic agent is released from Examples with a disintegrant. Disintegrants usually decrease the compressibility of the formulation and higher levels will lead to decreased tablet hardness and/or friability problems. Thus, a fine balance must be struck between the amount of disintegrant and other properties of the formulation. The disintegrant is distributed equally between the the internal and external components. E.g. 6% is distributed as 3% internal and 3% external components, respectively, and 2% is distributed as 1% internal and 1% external components, respectively
• the therapeutic agent in this example is the compound of formula (II).
• Tables below show the formulation for Example 7 having 2 mg of therapeutic agent; the 2 mg refers to the amount of the compound of formula (I).
• Aerosil 200 (External) 0.25
• Example 8 20 mg Strength uncoated tablets with 6% disintegrant, and 2% disintegrant
• the therapeutic agent in these examples is the compound of formula (II).
• Table below shows the formulation for Examples 8.1 and 8.2 having 20 mg of therapeutic agent-the 20 mg refers to the amount of the compound of formula (I).
• Aerosil 200 (Internal) 0.25 0.25
• Aerosil 200 (External) 0.25 0.25
• RH relative humidity
• Example 10 Bioavailability of tablet formulations.
• a single center, randomized, open-label, single dose, parallel-group study is carried out to assess the relative bioavailability of the therapeutic agent following oral administration of a single dose of the compound of formula (II) as tablet (20 mg) formulations administered to healthy subjects under fasting or fed conditions
• T2 one 20 mg tablet (Example 8.2) under fasting condition
• T3 two 10 mg tablets( Reference Example 1.B) under fasting condition
• T4 one 20 mg tablet (Example 8.1) under fed condition
• T5 one 20 mg tablet (Example 8.2) under fed condition All subjects participate in a screening period of up to 20-days (Day -21 to -2), a baseline period (Day -1), a single-dose treatment period followed by 36 days of outpatient follow-up visits, and an end-of-study evaluation (Day 36). Subjects who comply with the inclusion/exclusion criteria at screening are admitted for baseline evaluations on the day before dosing. All baseline safety evaluation results must be available prior to dosing.
• PK pharmacokinetic
• Safety assessments include physical examinations, ECGs, vital signs, standard clinical laboratory evaluations hematology, blood chemistry, urinalysis, adverse event and serious adverse event monitoring.
• Pharmacokinetic assessments include physical examinations, ECGs, vital signs, standard clinical laboratory evaluations hematology, blood chemistry, urinalysis, adverse event and serious adverse event monitoring.
• PK blood collection (3 ml. in EDTA tubes (plasma)): Pre-dose, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 240, 312, 408, 504, 672, 840 hours post-dose.
• PK parameters of compound of formula (II) (to be determined for each of the tablet formulation): Cmax, Tmax, AUCO-last, AUCO-inf, t1/2, CL/F, and Vd/F
• PK evaluations Descriptive statistics of all calculated PK parameters are provided.
• Table Summary of pharmacokinetic parameters following single oral administration of 20 mg of the therapeutic agent as Example 8.1, Example 8.2 or Reference Example 1.B tablet under fasted condition or Example 8.1, Example 8.2 under fed condition in healthy subjects
• Example 8.1 Example 8.2 Example 1.B
• Example 8.1 Example 8.2
• Vz/F (mL Mean ⁇ 252000 ⁇ 113000 269000 ⁇ 169000 254000 ⁇ 192000 194000 ⁇ 170000 172000 ⁇ 93000
• Examples 8.1 and 8.2 are thus similar to Reference Example 1.B in terms of the rate and extent of absorption of the therapeutic agent.
• the invention thus provides a pharmaceutical composition of the compound of formula (I), or a pharmaceutically acceptable salt thereof, which exhibits one or more, e.g. 1 , 2 or 3, of the following desirable characteristics; - a dissolution profile which is suitable for the administration of the therapeutic agent, -a compression profile with a wide hardness window which still provides acceptable friability, hardness, disintegration time and dissolution;

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Diabetes (AREA)
• Inorganic Chemistry (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Molecular Biology (AREA)
• Biophysics (AREA)
• Rheumatology (AREA)
• Dermatology (AREA)
• Biochemistry (AREA)
• Pain & Pain Management (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Emergency Medicine (AREA)
• Endocrinology (AREA)
• Child & Adolescent Psychology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Priority Applications (25)

Applications Claiming Priority (2)

Related Child Applications (2)

Publications (1)

Family

ID=44908106

Family Applications (1)

Country Status (30)

Cited By (4)

Families Citing this family (10)

Citations (1)

Family Cites Families (16)

• 2011
  • 2011-10-13 AR ARP110103797A patent/AR083417A1/es unknown
  • 2011-10-14 JP JP2013534025A patent/JP6060081B2/ja active Active
  • 2011-10-14 DK DK11779278.8T patent/DK2627319T3/en active
  • 2011-10-14 PL PL11779278T patent/PL2627319T3/pl unknown
  • 2011-10-14 US US13/825,919 patent/US20130190354A1/en not_active Abandoned
  • 2011-10-14 EP EP11779278.8A patent/EP2627319B1/en active Active
  • 2011-10-14 TR TR2019/02435T patent/TR201902435T4/tr unknown
  • 2011-10-14 PE PE2013000837A patent/PE20140375A1/es not_active Application Discontinuation
  • 2011-10-14 NZ NZ608558A patent/NZ608558A/en not_active IP Right Cessation
  • 2011-10-14 WO PCT/US2011/056275 patent/WO2012051488A1/en not_active Ceased
  • 2011-10-14 PH PH1/2013/500695A patent/PH12013500695A1/en unknown
  • 2011-10-14 AU AU2011316003A patent/AU2011316003B2/en not_active Ceased
  • 2011-10-14 ES ES11779278T patent/ES2712064T3/es active Active
  • 2011-10-14 PT PT11779278T patent/PT2627319T/pt unknown
  • 2011-10-14 CA CA2813781A patent/CA2813781C/en active Active
  • 2011-10-14 SI SI201131677T patent/SI2627319T1/sl unknown
  • 2011-10-14 BR BR112013008757-9A patent/BR112013008757A2/pt not_active IP Right Cessation
  • 2011-10-14 HU HUE11779278A patent/HUE043524T2/hu unknown
  • 2011-10-14 CN CN201180049179.4A patent/CN103179957B/zh active Active
  • 2011-10-14 KR KR1020137009333A patent/KR20130100311A/ko not_active Withdrawn
  • 2011-10-14 MX MX2013004162A patent/MX2013004162A/es not_active Application Discontinuation
  • 2011-10-14 MA MA35806A patent/MA34599B1/fr unknown
  • 2011-10-14 RU RU2013121795/15A patent/RU2595866C2/ru active
  • 2011-10-14 SG SG2013021944A patent/SG189078A1/en unknown
• 2013
  • 2013-03-20 ZA ZA2013/02108A patent/ZA201302108B/en unknown
  • 2013-03-21 IL IL225434A patent/IL225434A0/en unknown
  • 2013-04-11 CO CO13094273A patent/CO6710915A2/es not_active Application Discontinuation
  • 2013-04-11 GT GT201300096A patent/GT201300096A/es unknown
  • 2013-04-12 EC ECSP13012755 patent/ECSP13012755A/es unknown
  • 2013-04-12 CL CL2013001001A patent/CL2013001001A1/es unknown
• 2015
  • 2015-07-22 US US14/805,919 patent/US20150320687A1/en not_active Abandoned
• 2016
  • 2016-09-12 US US15/262,056 patent/US20160374947A1/en not_active Abandoned
• 2018
  • 2018-05-01 US US15/968,104 patent/US10646446B2/en active Active
• 2020
  • 2020-03-31 US US16/835,921 patent/US11304907B2/en active Active

Patent Citations (1)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events