Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
• • A—HUMAN NECESSITIES
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  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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  • 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
  • A61K31/415—1,2-Diazoles
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  • 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
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
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  • 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
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • 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
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
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  • 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
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  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1611—Inorganic compounds
• • A—HUMAN NECESSITIES
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  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
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  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
  • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—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
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  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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
  • A61P3/08—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• This disclosure generally relates to amorphous compounds, solid dispersions of amorphous compounds, pharmaceutical compositions comprising the same and their use in the treatment and prevention of diseases and disorders.
• CBi receptor inhibitors for the potential treatment of obesity and the metabolic disorder associated therewith, referred to as metabolic syndrome.
• Rimonabant was shown effective in treating metabolic syndrome but caused neuropsychiatric (i.e. CNS-related) side effects, which resulted in its withdrawal from the market.
• the present technology relates to a solid dispersion comprising a compound dispersed in a solid matrix comprising a pharmaceutically acceptable polymer having a glass transition temperature of at least 50°C, wherein the compound is of Formula I (a):
• R 2 is halogen
• R 3 is halogen or halogenated C 1-6 alkyl
• R 4 is hydrogen
• R 5 is C 1-6 alkyl or C 1-6 alkylC(O)NH
• X is SO 2 ; a is 0 and R 1 is absent; and b and c are each 1 ; or a tautomer or a pharmaceutically acceptable salt thereof; wherein the polymercompound weight ratio is within the range of 1:2 to 10:1 and wherein the compound concentration in the solid dispersion is within the range of about 15% to about 60% by weight.
• R 2 is a chlorine atom.
• R 3 is trifluoromethyl.
• R 5 is methyl or CH 3 C(O)NH.
• the solid dispersion has a polymercompound weight ratio within the range of 1 : 1 to 6: 1 , or 1:1 to 4: 1 , or 2: 1 to 5: 1 , or 3:1 to 5:1, or 1 :1 to 3:1.
• the compound concentration in the solid dispersion is within the range of about 18% to about 40% by weight, or within the range of about 20% to about 40% by weight, or within the range of about 30% to about 50% by weight.
• the present technology relates to a solid dispersion comprising a compound dispersed in a solid matrix comprising a pharmaceutically acceptable polymer having a glass transition temperature of at least 50°C, wherein the compound is of Formula I:
• R 1 , R 2 , and R 3 are each independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyl, acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phosphonyl, optionally substituted phosphinyl, optionally substituted boronate, optionally substituted silyl, and imino;
• R 4 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyl, acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phosphonyl, optionally substituted phosphinyl, optionally substituted boronate, optionally substituted silyl, and imino;
• R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted alkylC(O)NH, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyl, acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phosphonyl, optionally substituted phosphinyl, optionally substituted boronate, optionally substituted silyl, and imino;
• compound is of Formula 1(a):
• Formula 1(a) or a tautomer or a pharmaceutically acceptable salt thereof wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, a, b, and c are as defined above.
• R 4 is H.
• R 5 is C 1-6 alkyl or C 1-6 alkylC(O)NH.
• R 5 is C 1-6 alkyl (e.g. methyl).
• R 5 is Ci- 6 alkylC(O)NH (e.g. CH 3 C(O)NH).
• X may be SO2.
• a is 0 and/or b is 1 and R 2 is halogen and/or c is 1 and R 3 is halogen or halogenated C 1-6 alkyl, e.g. trifluoromethyl.
• the compound is selected from Compounds 1 to 26 as defined herein, or a tautomer or a pharmaceutically acceptable salt thereof.
• the compound is Compound 1.
• the polymer has a glass transition temperature of at least 80°C, or at least 100°C, or at least 120°C, or at least 140°C, or between 50°C and 200°C, or between 80°C and 200°C, or between 100°C and 180°C.
• a polymer is a polyvinylpyrrolidone or a copolymer thereof, such as a polyvinylpyrrolidone having an average molecular weight of between 5,000 and 100,000.
• the polymer is cellulose or a cellulose derivative like an esterified hydroxyalkyl methylcellulose, e.g. hydroxypropyl methylcellulose acetate succinate.
• the polymer is a polyethylene glycol, polylactic acid or polymethacrylate.
• the polymercompound weight ratio is within the range of 1:2 to 10:1, or 1:1 to 6:1, or between 1:1 and 4:1, or between 2:1 and 5:1, or between 3:1 and 5:1, or between 1:1 and 3:1.
• the solid dispersion further comprises a pharmaceutically acceptable surfactant.
• the pharmaceutically acceptable surfactant comprises at least one surfactant selected from long chain alkyl or alkenyl sulfate salts (e.g. sulfates of C 8 to C 20 alcohols, such as sodium lauryl sulfate, sodium laureth sulfate, ammonium lauryl sulfate, sodium pareth sulfate, and the like); alkyl sulfonate salts (e.g. perfluorooctanesulfonate, perfluorobutanesulfonate, docusate, and the like); sorbitan long chain carboxylic acid esters (e.g.
• C 8 to C 20 carboxylic acids such as oleate, stearate, laurate, and the like
• pegylated sorbitan long chain carboxylic acid esters e.g. Tween 20, Tween 40, Tween 60, Tween 80
• polyethylene- polypropylene glycol block copolymers e.g. poloxamers
• pegylated or non-pegylated mono, di, and tri glyceride long chain carboxylic acid esters e.g.
• the pharmaceutically acceptable surfactant is a long chain alkyl sulfate (e.g. sodium lauryl sulfate, sodium laureth sulfate, ammonium lauryl sulfate, sodium pareth sulfate, and the like).
• the polymersurfactant weight ratio is within the range of 5: 1 to 20: 1 , or of 10: 1 to 15:1.
• the compound comprises less than of less than 5% of crystalline form, or less than 2% of crystalline form, or less than 1% of crystalline form, or even less than 0.5% of crystalline form.
• the solid dispersion described herein and according to any of the aforementioned embodiments is in powder form.
• the solid dispersion described herein and according to any of the aforementioned embodiments is in particulate form.
• the present technology relates to a process for the preparation of a solid dispersion as defined herein, comprising a step of mixing the compound and the polymer.
• the mixing step comprises the steps of: (a) dissolving the compound and polymer in a solvent; and (b) drying the mixture obtained in (a).
• the drying step is carried out by spray drying.
• the mixing step is carried out by rapid acoustic mixing, extrusion, planetary mixing and ball milling.
• the present technology relates to a solid oral pharmaceutical composition comprising a solid dispersion as defined herein.
• the solid oral pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent or excipient.
• the said carrier, diluent or excipient is a binder such as a binder selected from cellulose-based substances such as microcrystalline cellulose and carboxymethylcellulose, and other binders like gum acacia, gelatin, corn starch, gum tragacanth, sodium alginate, lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate, dicalcium phosphate, and polyethylene glycol (PEG), e.g. microcrystalline cellulose.
• a binder such as a binder selected from cellulose-based substances such as microcrystalline cellulose and carboxymethylcellulose, and other binders like gum acacia, gelatin, corn starch, gum tragacanth, sodium alginate, lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate, dicalcium phosphate, and polyethylene glycol (PEG), e
• the compound is present in the composition at a concentration of between 5 wt.% and 50 wt.%, or between 10 wt.% and 40 wt.%.
• the solid oral pharmaceutical composition is in the form of a tablet or capsule.
• the solid oral pharmaceutical composition further comprises a coating.
• the solid oral pharmaceutical composition is in unit dosage form comprising the compound in an amount within the range of 20 to 200 mg per dose.
• the present technology relates to the use of a solid dispersion as defined herein or a solid oral pharmaceutical composition as defined herein for the treatment of a disease or disorder selected from obesity(type I or II), non-alcoholic and alcoholic fatty liver disease (a risk factor for insulin resistance), a co-morbidity of obesity, a co-morbidity of diabetes, Prader-Willi Syndrome (PWS), Pro-opiomelanocortin (POMC) deficiency obesity, LepR deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl syndrome, Alstrom syndrome, dyslipidemia predisposing to arteriosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases such as Idiopathic Pulmonary Fibrosis (IPF) and Hermansky-Pudlak Syndrome pulmonary fibrosis (HPS-PF), and gout.
• a disease or disorder selected from obesity(type I or II), non
• the co-morbidity of obesity is selected from metabolic syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, degenerative arthritis, venous statis ulcer, pulmonary hypoventilation syndrome, sleep apnea, snoring, coronary artery disease, arterial sclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies of the liver, ovaries, cervix, uterus, breasts, prostate, or gallbladder.
• the co-morbidity of diabetes e.g. type I
• the disease or disorder is selected from diabetes (type 1 or 2), obesity, and non-alcoholic fatty liver disease (e.g. nonalcoholic steatohepatitis).
• Other aspects of the present technology relates to a method for the treatment of a disease or disorder selected from obesity, diabetes(type I or II), non-alcoholic and alcoholic fatty liver disease (a risk factor for insulin resistance), a co-morbidity of obesity, a co-morbidity of diabetes, Prader- Willi Syndrome (PWS), Pro-opiomelanocortin (POMC) deficiency obesity, LepR deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl syndrome, Alstrom syndrome, dyslipidemia predisposing to arteriosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases such as Idiopathic Pulmonary Fibrosis (IPF) and Hermansky-Pudlak Syndrome pulmonary fibrosis
• the co-morbidity of obesity is selected from metabolic syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, degenerative arthritis, venous statis ulcer, pulmonary hypoventilation syndrome, sleep apnea, snoring, coronary artery disease, arterial sclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies of the liver, ovaries, cervix, uterus, breasts, prostate, or gallbladder.
• the co-morbidity of diabetes e.g. type I
• the disease or disorder is selected from diabetes (type 1 or 2), obesity, and non-alcoholic fatty liver disease (e.g. non-alcoholic steatohepatitis).
• diabetes type 1 or 2
• obesity e.g. obesity
• non-alcoholic fatty liver disease e.g. non-alcoholic steatohepatitis
• Figure 1 shows x-ray powder diffraction patterns of formulations F1, compared to F-MP, F- SEDDS, and Compound 1 as described in Example 2.
• Figure 2 shows x-ray powder diffraction patterns of formulations F2, F3, F4, F5 and Compound 1 as described in Example 2.
• the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e. , the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.
• the terms “compounds”, “active ingredient”, and equivalent expressions refer to compounds described in the present application and in U.S. Patent No. 9,765,031, e.g. those encompassed by structural Formulae I and l(a), optionally with reference to any of the applicable embodiments, and also includes exemplary compounds, such as Compounds 1 to 3, as well as their pharmaceutically acceptable salts, tautomeric forms, solvates, esters, and prodrugs when applicable.
• the compound When a zwitterionic form is possible, the compound may be drawn as its neutral form for practical purposes, but the compound is understood to also include its zwitterionic form. Embodiments herein may also exclude one or more of the compounds. Compounds may be identified either by their chemical structure or their chemical name. In a case where the chemical structure and chemical name would conflict, the chemical structure will prevail.
• structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure when applicable; for example, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present description.
• the therapeutic compounds unless otherwise noted, also encompasses all possible tautomeric forms of the illustrated compound, if any.
• the term also includes isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass most abundantly found in nature.
• isotopes examples include, but are not limited to, 2 H (D), 3 H (T), 11 C, 13 C, 14 C, 15 N, 18 0, 17 0, any one of the isotopes of sulfur, etc.
• the compounds may also exist in unsolvated forms as well as solvated forms, including hydrated forms.
• the compounds may exist in multiple crystalline or amorphous forms. However, amorphous or substantially amorphous forms are preferred for the formulations contemplated herein.
• amorphous generally designates a non-crystalline state lacking the long-range order characteristic of a crystal.
• substantially amorphous refers to a solid state which is mainly in an amorphous state, for instance, containing less than 5% by weight of crystalline solid.
• the amorphous nature of a solid may be determined by standard methods, including X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC) or Fourier transform (FT) Raman spectroscopy.
• a particular enantiomer may, in some embodiments be provided substantially free of the corresponding enantiomer and may also be enantiomerically enriched.
• “Enantiomerically enriched” means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
• Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high- pressure liquid chromatography (HPLC) or supercritical Fluid Chromatography (SFC) on chiral support, or by the formation and crystallization of chiral salts or be prepared by asymmetric syntheses.
• HPLC high- pressure liquid chromatography
• SFC supercritical Fluid Chromatography
• pharmaceutically acceptable salt refers to those salts of the compounds of the present description which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
• the salts can be prepared in situ during the final isolation and purification of the compounds of the present description, or separately by reacting a free base function of the compound with a suitable organic or inorganic acid (acid addition salts) or by reacting an acidic function of the compound with a suitable organic or inorganic base (base-addition salts).
• solvate refers to a physical association of one of the present compound with one or more solvent molecules, including water and non-aqueous solvent molecules. This physical association may include hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
• solvate encompasses both solution-phase and isolable solvates.
• Exemplary solvates include, without limitation, hydrates, hemihydrates, ethanolates, hemiethanolates, n-propanolates, iso-propanolates, 1-butanolates, 2-butanolate, and solvates of other physiologically acceptable solvents, such as the Class 3 solvents described in the International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvents (1997). Accordingly, the compound as herein described also includes each of its solvates and mixtures thereof.
• ester refers to esters of the compounds formed by the process of the present description which may hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
• Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
• esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates of hydroxyl groups, and alkyl esters of an acidic group.
• Other ester groups include sulfonate or sulfate esters.
• prodrugs refers to those prodrugs of the compounds formed by the process of the present description which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
• Prodrug as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to afford any compound delineated by the formulae of the instant description.
• the number of carbon atoms in a hydrocarbon substituent can be indicated by the prefix “C x -C y " or "C x-y " where x is the minimum and y is the maximum number of carbon atoms in the substituent.
• x and y are associated with a group incorporating one or more heteroatom(s) by definition (e.g. heterocycloalkyl, heteroaryl, etc).
• x and y define respectively the minimum and maximum number of atoms in the cycle, including carbon atoms as well as heteroatom(s).
• alkyl refers to a saturated, straight- or branched-chain hydrocarbon radical typically containing from 1 to 20 carbon atoms.
• “Ci-C 8 alkyl” contains from one to eight carbon atoms.
• alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert- butyl, neopentyl, n-hexyl, heptyl, octyl radicals and the like.
• alkenyl denotes a straight- or branched-chain hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms.
• C2- 8 alkenyl contains from two to eight carbon atoms.
• Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl and the like.
• alkynyl denotes a straight- or branched-chain hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms.
• C2-8 alkynyl contains from two to eight carbon atoms.
• Representative alkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
• cycloalkyl refers to a group comprising a saturated or partially unsaturated (non-aromatic) carbocyclic ring in a monocyclic or polycyclic ring system, including spiro (sharing one atom), fused (sharing at least one bond) or bridged (sharing two or more bonds) carbocyclic ring systems, having from three to fifteen ring members.
• cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonanyl, norbornyl, and the like.
• the term cycloalkyl includes both unsubstituted cycloalkyl groups and substituted cycloalkyl groups.
• C 3 -C n cycloalkyl refers to a cycloalkyl group having from 3 to the indicated “n” number of carbon atoms in the ring structure. Unless the number of carbons is otherwise specified, “lower cycloalkyl” groups as herein used, have at least 3 and equal or less than 8 carbon atoms in their ring structure.
• heterocycle As used herein, the terms “heterocycle”, “heterocycloalkyl”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a chemically stable 3- to 7- membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
• nitrogen includes a substituted nitrogen.
• the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl).
• a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure and any of the ring atoms can be optionally substituted.
• heterocycloalkyl groups include, but are not limited to, 1 ,3-dioxolanyl, pyrrolidinyl, pyrrolidonyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrodithienyl, tetrahydrothienyl, thiomorpholino, thioxanyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepiny
• Heterocyclic groups also include groups in which a heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, chromenyl, phenanthridinyl, 2- azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring.
• a heterocyclyl group may be mono- or bicyclic.
• heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
• C 3-n heterocycloalkyl refers to a heterocycloalkyl group having from 3 to the indicated “n” number of atoms in the ring structure, including carbon atoms and heteroatoms.
• partially unsaturated refers to a ring moiety that includes at least one double or triple bond between ring atoms but is not aromatic.
• partially unsaturated is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.
• aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, “aryloxy”, or “aryloxyalkyl”, refers to aromatic groups having 4n+2 conjugated tt(r ⁇ ) electrons, wherein n is an integer from 1 to 3, in a monocyclic moiety or a bicyclic or tricyclic fused ring system having a total of six to 15 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
• aryl may be used interchangeably with the term “aryl ring”.
• aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, azulenyl, anthracyl and the like, which may bear one or more substituents.
• aralkyl or “arylalkyl” refers to an alkyl residue attached to an aryl ring. Examples of aralkyl include, but are not limited to, benzyl, phenethyl, and the like.
• aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, indenyl, phthalimidyl, naphthimidyl, fluorenyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
• C 6-n aryl refers to a aryl group having from 6 to the indicated “n” number of atoms in the ring structure.
• heteroaryl used alone or as part of a larger moiety, e.g., "heteroaralkyl”, or “heteroaralkoxy”, refers to aromatic groups having 4n+2 conjugated tt(r ⁇ ) electrons, wherein n is an integer from 1 to 3 (e.g. having 5 to 18 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 p electrons shared in a cyclic array); and having, in addition to carbon atoms, from one to five heteroatoms.
• heteroatom includes but is not limited to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
• heteroaryl may be a single ring, or two or more fused rings.
• heteroaryl also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings, where the radical or point of attachment is on the heteroaromatic ring.
• heteroaryl groups include thienyl, furanyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, 3H-indolyl, isoindolyl, indolizinyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolopyridinyl (e.g.
• pyrrolo[3,2- bjpyridinyl or pyrrolo[3,2-c] pyridinyl) pyrazolopyridinyl (e.g. pyrazolo[1,5-a]pyridinyl), furopyridinyl, purinyl, imidazopyrazinyl (e.g.
• imidazo[4,5-b]pyrazinyl quinolyl (quinolinyl), isoquinolyl (isoquinolinyl), quinolonyl, isoquinolonyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, naphthyridinyl, and pteridinyl carbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one.
• a heteroaryl group may be mono- or bicyclic. Heteroaryl groups include rings that are optionally substituted.
• heteroaryl groups include rings that are optionally substituted.
• heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl and the like.
• Cs- n heteroaryl refers to a heteroaryl group having from 5 to the indicated “n” number of atoms in the ring structure, including carbon atoms and heteroatoms.
• halogen designates a halogen atom, i.e. a fluorine, chlorine, bromine or iodine atom, preferably fluorine or chlorine.
• compounds of the present description may contain “optionally substituted” moieties.
• substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
• an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
• Combinations of substituents envisioned under the present description are preferably those that result in the formation of chemically stable or chemically feasible compounds.
• chemically stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
• optionally substituted thus refers to groups that are substituted or unsubstituted by independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to F, Cl, Br, I, OH, CO2H, alkoxy, oxo, thiooxo, NO2, CN, CF 3 , NH2, NHalkyl, NHalkenyl, NHalkynyl, NHcycloalkyl, NHaryl, NHheteroaryl, NHheterocyclic, dialkylamino, diarylamino, diheteroarylamino, O-alkyl, O-alkenyl, O-alkynyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-haloalkyl, O-heterocyclic, C(O)alkyl, C(O)alkenyl, C(O)alkynyl, C(C(O
• NHC(NH)heterocycloalkyl C(NH)NHalkyl, C(NH)NHalkenyl, C(NH)NHalkynyl, C(NH)NHcycloalkyl, C(NH)NHaryl, C(NH)NHheteroaryl, C(NH)NHheterocycloalkyl, S(O)alkyl, S(O)alkenyl, S(O)alkynyl, S(O)cycloalkyl, S(O)aryl, S(O) 2 alkyl, S(O) 2 alkenyl, S(O) 2 alkynyl, S(O) 2 cycloalkyl, S(O) 2 aryl, S(O)heteroaryl, S(O)heterocycloalkyl, SO2NH2, SO 2 NHalkyl, SO 2 NHalkenyl, SO 2 NHalkynyl, SO 2 NHcycloalkyl, SO 2 NHaryl, SO
• the present technology therefore relates to the preparation of a solid dispersion of an amorphous compound in a solid matrix which prevents the compound from reverting to its crystalline form, to these solid dispersions, to compositions and solid dosage forms comprising them as well as their medical uses.
• the solid dispersion will be, for instance, in the form of particles, powder, etc.
• R 1 , R 2 , and R 3 are each independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyl, acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phosphonyl, optionally substituted phosphinyl, optionally substituted boronate, optionally substituted silyl, and imino;
• R 4 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyl, acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phosphonyl, optionally substituted phosphinyl, optionally substituted boronate, optionally substituted silyl, and imino;
• R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted alkylC(O)NH, optionally substituted sulfonyl, optionally substituted
• R 4 is H.
• R 5 is C 1-6 alkyl (e.g. methyl) or C 1-6 alkylC(O)NH (e.g. CH 3 C(O)NH).
• X is SO2.
• a is 0 and R 1 is absent, i.e. all five free carbon atoms of the aryl group being linked to a hydrogen atom.
• b is 1 and R 2 is halogen and/or c is 1 and R 3 is halogen (e.g. chlorine) or halogenated C 1-6 alkyl, e.g. trifluoromethyl.
• the compound will be in a substantially amorphous state when included in the present solid dispersion.
• the compound in the solid dispersion comprises less than 5% of crystalline form, or less than 2% of crystalline form, or less than 1% of crystalline form, or even less than 0.5% of crystalline form.
• the compound is dispersed in a matrix which prevents its reconversion to a crystalline state.
• the matrix comprises a pharmaceutically acceptable polymer having a glass transition temperature of at least 50°C, or at least 80°C, or at least 100°C, or at least 120°C, or at least 140°C, or between 50°C and 200°C, or between 80°C and 200°C, or between 100°C and 180°C.
• polymers examples include polyvinylpyrrolidones and copolymers thereof, cellulose and cellulose derivatives, polyethylene glycol, polylactic acid and polymethacrylate having a glass transition temperature of at least 50°C. These polymers should also be soluble in an organic solvent and be chemically stable over time.
• the polymer is a polyvinylpyrrolidone or a copolymer thereof (e.g. a N-vinyl-2-pyrrolidone and vinyl acetate copolymer) having an average molecular weight of between 5,000 and 100,000.
• the polymer is a cellulose derivative such as an esterified hydroxyalkyl methylcellulose, of which hydroxypropyl methylcellulose acetate succinate is an example.
• the weight ratio of polymer and compound in the solid dispersion may be adjusted to achieve a stable amorphous state of the compound and will vary depending on the compound.
• Examples of polymercompound weight ratios are between 1 :2 to 10:1, or between 1:1 to 6:1, or between 1:1 and 4:1, or between 2: 1 and 5:1, or between 3: 1 and 5:1, or between 1 : 1 and 3: 1.
• the solid dispersion further comprises a pharmaceutically acceptable surfactant.
• surfactant includes long chain alkyl or alkenyl sulfate salts (e.g. sulfates of C 8 to C 20 alcohols, such as sodium lauryl sulfate, sodium laureth sulfate, ammonium lauryl sulfate, sodium pareth sulfate, and the like); alkyl sulfonate salts (e.g. perfluorooctanesulfonate, perfluorobutanesulfonate, docusate, and the like); sorbitan long chain carboxylic acid esters (e.g.
• C 8 to C 20 carboxylic acids such as oleate, stearate, laurate, and the like); pegylated sorbitan long chain carboxylic acid esters (e.g. Tween 20, Tween 40, Tween 60, Tween 80); polyethylene-polypropylene glycol block copolymers (e.g. poloxamers); pegylated or non-pegylated mono, di, and tri glyceride long chain carboxylic acid esters (e.g.
• the surfactant is a long chain alkyl sulfate, such as sodium lauryl sulfate, sodium laureth sulfate, ammonium lauryl sulfate, sodium pareth sulfate, and the like.
• the weight ratio of polymer to surfactant in the solid dispersion will be adjusted to obtain a homogeneous dispersion, and will depend on the compound, polymer and surfactant used.
• examples of polymer: surfactant weight ratios range from 5:1 to 20:1, or of 10:1 to 15:1.
• the present solid dispersions may be prepared by dry or wet mixing methods. For instance, methods include such as rapid acoustic mixing, extrusion, planetary mixing, ball milling, and other similar mixing methods, or may be dissolved together with the polymer and the optional surfactant and dried by a method such as spray drying to form the solid dispersion.
• the solid dispersion as defined herein can be formulated in a solid oral pharmaceutical composition for administration to a subject, the solid dispersion being optionally admixed with a pharmaceutically acceptable carrier, diluent, or excipient.
• the active compound is present in the oral formulation at a concentration of between 5 wt.% and 50 wt.%, or between 10 wt.% and 40 wt.%.
• pharmaceutically acceptable carrier, diluent, or excipient and equivalent expressions, refer to a non-toxic carrier, diluent, or excipient that does not destroy the pharmacological activity of the compound or the integrity of the solid dispersion with which it is formulated.
• compositions of this disclosure include, but are not limited to, binders, sweeteners, disintegrating agents, diluents, flavorings, coating agents, preservatives, lubricants, and/or polymer.
• binders include cellulose-based substances such as microcrystalline cellulose and carboxymethylcellulose, and other binders like gum acacia, gelatin, corn starch, gum tragacanth, sodium alginate, or polyethylene glycol (PEG).
• sweeteners include sucrose, lactose, glucose, aspartame or saccharine.
• Disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
• diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate.
• Flavoring agents include peppermint oil, oil of wintergreen, cherry, orange, or raspberry flavoring.
• Coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten.
• Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
• Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
• excipients may further include a polymer selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylpyrrolidone- vinylacetate copolymer (PVP-VA), hydroxypropylmethylcellulose (HPMC), hypromellose-acetate- succinate (HPMCAS), and mixtures thereof.
• PVP polyvinylpyrrolidone
• PVP-VA polyvinylpyrrolidone- vinylacetate copolymer
• HPMC hydroxypropylmethylcellulose
• HPMCAS hypromellose-acetate- succinate
• solid dosage forms for oral administration include capsules, tablets, pills, and granules.
• the composition is a solid dosage form which comprises the solid dispersion as described herein and at least one binder as defined in the preceding paragraph, the binder preferably comprising microcrystalline cellulose.
• the solid dispersions and compositions may also be employed as fillers in soft and hard-filled capsules.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The composition may also be in micro- encapsulated form with one or more excipients as noted above.
• the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
• therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in treatment, healing, prevention, or amelioration of a disease, disorder, or symptom thereof, or a decrease in the rate of advancement of a disease or disorder.
• the term also includes within its scope amounts effective to enhance normal physiological function.
• treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
• treatment may be administered after one or more symptoms have developed.
• treatment may be administered in the absence of symptoms.
• treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
• patient refers to an animal such as a mammal.
• a subject may therefore refer to, for example, mice, rats, dogs, cats, horses, cows, pigs, guinea pigs, primates including humans and the like.
• the subject is a human.
• the compounds included in the present solid dispersions are useful for the treatment of diseases and disorders where inhibition of the cannabinoid receptor CBi is indicated, for instance such as those described in U.S. Patent No. 9,765,031.
• diseases and disorders are generally related to diabetes and metabolic disorders (e.g. metabolic syndrome).
• the active ingredient selective targets the CBi receptor in peripheral tissue (e.g. adipose tissue, liver, muscle, lung, kidney, macrophages, pancreatic beta cells and gastrointestinal tract), while not interacting with CBi receptors in brain tissue, thereby avoiding or reducing CNS-related side effects.
• the effect of the present compounds may include reduced food intake, reduced body weight, reversed insulin and leptin resistance, reverse hepatic steatosis (fatty liver) and improved dyslipidemia.
• diseases and disorders to be treated include obesity, diabetes (type I or II), non-alcoholic and alcoholic fatty liver disease (a risk factor for insulin resistance), a co- morbidity of obesity, a co-morbidity of diabetes, Prader-Willi Syndrome (PWS), Proopiomelanocortin (POMC) deficiency obesity, LepR deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl syndrome, Alstrom syndrome, dyslipidemia predisposing to arteriosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases such as Idiopathic Pulmonary Fibrosis (IPF) and Hermansky-Pudlak Syndrome pulmonary fibrosis (HPS-PF), and gout.
• the co-morbidity of obesity is selected from metabolic syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, degenerative arthritis, venous statis ulcer, pulmonary hypoventilation syndrome, sleep apnea, snoring, coronary artery disease, arterial sclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies of the liver, ovaries, cervix, uterus, breasts, prostate, or gallbladder.
• the disease or disorder include diabetes (type 1 or 2), obesity, and non-alcoholic fatty liver disease (e.g. non-alcoholic steatohepatitis).
• co-morbidities of diabetes e.g. type I
• co-morbidities of diabetes include diabetic nephropathy, chronic kidney disease, diabetic retinopathy, and peripheral and autonomic neuropathy.
• the present solid dispersions and compositions may also be used in a method for preventing or reversing the deposition of adipose tissue in a subject, which is expected to contribute to a reduction of incidence or severity of obesity, which in turn would reduce the incidence or severity of associated co-morbidities.
• the present description provides a method of treating a disorder (as described herein) in a subject, comprising administering to the subject identified as in need thereof, a solid dispersion or composition of the present description.
• a disorder as described herein
• the identification of those patients who are in need of treatment for the disorders described above is well within the ability and knowledge of one skilled in the art.
• Certain of the methods for identification of patients which are at risk of developing the above disorders which can be treated by the subject method are appreciated in the medical arts, such as family history, and the presence of risk factors associated with the development of that disease state in the subject patient.
• a clinician skilled in the art can readily identify such candidate patients, by the use of, for example, clinical tests, physical examination, medical/family history, and genetic determination.
• a method of assessing the efficacy of a treatment in a subject includes determining the pretreatment symptoms of a disorder by methods well known in the art and then administering a therapeutically effective amount of a compound of the present description, to the subject. After an appropriate period of time following the administration of the compound (e.g., 1 week, 2 weeks, one month, six months), the symptoms of the disorder are determined again.
• the modulation (e.g., decrease) of symptoms and/or of a biomarker of the disorder indicates efficacy of the treatment.
• the symptoms and/or biomarker of the disorder may be determined periodically throughout treatment. For example, the symptoms and/or biomarker of the disorder may be checked every few days, weeks or months to assess the further efficacy of the treatment. A decrease in symptoms and/or biomarker of the disorder indicates that the treatment is efficacious.
• compositions provided herein are adapted for oral administration. Such formulations may be administered with or without food.
• the solid dispersions or compositions are formulated in unit dosage forma for ease of administration and uniformity of dosage.
• unit dosage form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the solid dispersions and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.
• compositions may be formulated such that a total daily dosage of, for instance, between 0.01 and 20 mg/kg body weight/day of the compound can be administered to a patient receiving these compositions.
• Single dose compositions may contain such an amount, or the total daily dose may be divided in multiple dosage forms to be taken, for instance, one, two or three times a day.
• a single dose may include between 5 and 500 mg of the active ingredient, or between 20 and 200 mg.
• Treatment regimens may comprise administration to a patient a total amount of from about 10 mg to about 1000 mg of the compound(s) of the present description per day in a single dose or divided in multiple doses.
• the total daily dose of the compound will be decided by the attending physician within the scope of sound medical judgment.
• a specific dosage or treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the symptoms associated with the disease or disorder.
• additional therapeutic agents may also be present in the compositions of this disclosure or co-administered separately.
• Non-limiting examples of additional therapeutic agents which could be used in combination with the present solid dispersions and formulations include antidiabetic agents, cholesterol-lowering agents, antiinflammatory agents, antimicrobial agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, anti-cancer agents, anti-viral agents, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferation compound.
• the treatment may also be complemented with other treatments or interventions such as surgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), a biologic response modifier (e.g., an interferon, an interleukin, tumor necrosis factor (TNF)), and agents used to attenuate an adverse effect of the present compound or of a co-administered ingredient.
• radiotherapy e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes
• a biologic response modifier e.g., an interferon, an interleukin, tumor necrosis factor (TNF)
• agents used to attenuate an adverse effect of the present compound or of a co-administered ingredient e.g., gamma-radiation, neutron beam radiotherapy, electron beam
• Polysorbate 80 (Protameen Chemicals) was added to the molten PEG-8000 (Spectrum) and mixed for 2 minutes. Compound 1 was added and mixed vigorously using an impeller for 30 minutes at 60°C in a hot plate. The molten material was then spread across an aluminum foil. The solidified film of about 2-mm thickness was milled with a Quadro Comil (conical mil) equipped with a grated round 1575 pm opening screen followed by square screen 1143pm and round impeller, spacer 0.25 inch at 1200rpm.
• the F-MP formulation composition is detailed in Table 1.
• KolliphorTM HS 15 was dissolved in about 5 grams of water and mixed with LabrasolTM (Gattefosse). Using the high shear granulator GMX 0.1, Compound 1 was mixed with this solution at 60 rpm for 5 minutes. Magnesium aluminometasilicate (NeusilinTM UFL 2, by Fuji Chemical Industry Co., Ltd.) was added to the creamy mixture and mixed for 2 minutes at 325rpm/1800rpm impeller/chopper speeds. Low substituted hydroxypropyl cellulose (HPC, Nisso America, Inc.) was dissolved in remaining water and the solution was added at 10 g/min and mixed with the powder mixture at 325rpm/1800rpm impeller/chopper speeds.
• HPC Hydropropyl cellulose
• the granules were dried in a conventional oven at 60°C for 2.5 hours.
• the dried material was granulated by hand using a using an 18-mesh sieve.
• the lubricant sodium stearyl fumarate, JRS Pharma
• JRS Pharma was sieved through a 40-mesh sieve and mixed with granules using a V-blender at 25 rpm for 2 minutes.
• the F-SEDDS formulation composition is detailed in Table 2.
• amorphous co-precipitate was obtained from a solution composed of Compound 1 (1%), polyvinyl pyrrolidone (4%) (PlasdoneTM K29/32, Ashland) and a 20:80 w/w mixture of dichloromethane/methanol (95%).
• the solution was spray dried using a Yamato Lab Spray Dryer Model GB22 with internal nozzle diameter 711 ⁇ m, inlet temperature 65°C, atomization air 0.1 MPa, drying air flow 0.5 m 3 /min and spray rate 20 g/min.
• the formulation was then prepared by mixing the amorphous co-precipitate with microcrystalline cellulose (Tabulose 102, Blanver) for 5 minutes at 25 rpm in a V-blender.
• Formulation FVs composition is summarized in Table 3. Table 3. Composition of F1
• Formulations F2(a) to F2(e) were obtained by first dissolving 15 g of povidone (Plasdone K29/32) and 1 g of sodium lauryl sulfate (from Stepan) in 400 g of dichloromethane/methanol (20:80 v/v). Compound 1 (4 g) was added to the solution and dissolved. The solution was spray dried using a Yamato Lab Spray Dryer Model GB210 with internal nozzle diameter 711 ⁇ m, inlet temperature 65°C, atomization air 0.15 MPa, drying air flow 0.4 m 3 /min and spray rate 22 g/min.
• the spray drying dispersion was then spread on a tray and placed in a Fisher Scientific Istotemp Model 655F oven at 60°C for 60 minutes for a secondary drying step.
• the final blend was prepared by mixing for 5 minutes at 25 rpm in a V-blender 8.3 grams of SDD with 1.7 grams of microcrystalline cellulose (Tabulose 102). Cellulose was added in order to ensure proper disintegration of the capsule content due to strong binding properties of PVP.
• the final blend F2 was filled in HPMC “0” type or gelatin AAA type capsules to achieve various Compound 1 doses.
• the final F2(a) to F2(e) capsules compositions are shown in Table 4. Table 4. Composition of F2(a) to F2(e) capsules
• Composition F2(d) includes 3 HPMC size “0” capsules, each containing 50 mg of Compound 1 .
• the SDD used in this example is composed of same ingredients as the one prepared in (d) but with a higher drug load of 40%.
• Povidone and sodium lauryl sulfate were immediately dissolved in dichloromethane/methanol (20:80 v/v).
• dichloromethane/methanol 20:80 v/v.
• To complete dissolution of Compound 1 was obtained by adding more dichloromethane (200 mL) to a final solvent system composition of 33:67 (v/v). The dissolved solids content was then of 3.3% (w/w).
• the solution was spray dried using a Yamato Lab Spray Dryer Model GB210 with internal nozzle diameter 711 ⁇ m, inlet temperature 65°C, atomization air 0.15 MPa, drying air flow 0.4 m 3 /min and spray rate 22 g/min.
• the SDD was spread on a tray and placed in a Fisher Scientific Istotemp Model 655F oven at 60°C for 60 minutes for a secondary drying step.
• the final blend was prepared by mixing for 5 minutes at 25 rpm in a V-blender 8.3 grams of SDD with 1.7 grams of microcrystalline cellulose 102.
• the final blend was filled into HPMC capsules size 0 (Table 6).
• the solid dispersion was first prepared following the procedure detailed in Example 1(d) using the weight proportions indicated in the first section of Table 8 (i.e. a drug load of about 40 wt.%) and a dichloromethane/methanol proportion of 33:67 as solvent. Tablets were manufactured by dry granulation (roller compaction) from the solid dispersion.
• the intragranular ingredients in Table 8 were sieved through a No. 30 sieve (600pm nominal aperture) and mixed using a V- blender for 2 min at 25 rpm (pre-mix).
• the intragranular lubricant was sieved through a No. 40 sieve (425pm nominal aperture) and added to the pre-mix for 2 min at 25 rpm.
• the lubricated mixture was roller compacted using aTFC-LaboTM roller compactor (Vector Corporation). Ribbons having thickness about 0.8 mm were obtained using at roll force of 750 psi, and roll/screw feeder speeds of 3.5 ⁇ 0.5 / 40 ⁇ 5 rpm, respectively.
• the ribbons were granulated using a No. 20 mesh sieve (850 pm nominal aperture). The resulting granules were transferred to the V-blender and mixed for 2 min at 25 rpm with the extra granular lubricant previously sieved through a No. 40 sieve.
• the tablets (F6(a) to F6(c)) were compressed with a KORSCH XP1TM one-station tablet press equipped with a gravity feeder and 7 mm, 8mm, round tooling for the 20mg and 35 mg tablets and 6.05 x 17.75 mm capsule shape tooling for the 100mg tablets, respectively.
• the target tablet weights were 114mg, 200mg, and 571 mg for the 20mg, 35mg and 100 mg strengths, respectively. Hardness was adjusted to target disintegration below 30 minutes.
• An F6(d) formulation was also prepared by introducing formulation F6(b) into a capsule.
• Hypromellose acetate succinate and sodium lauryl sulfate were first dissolved in dichloromethane/methanol (50:50 v/v). Compound 1 was added to the solution and dissolved. The solution was spray dried using a Yamato Lab Spray Dryer Model GB210 with internal nozzle diameter 711 ⁇ m, inlet temperature 65°C, atomization air 0.15 MPa, drying air flow 0.4 m 3 /min and spray rate 22 g/min. No secondary drying was needed. The SDD was filled in HPMC capsules size 0. The final F8 capsule composition is shown in Table 10. Table 10. Composition of F8 capsules
• the solid dispersions were obtained by spray-drying a solution containing Compound 1, povidone and sodium lauryl sulfate (4.8% by weight of dissolved solids, see first section of Table 11 for proportions) in a 1:1 mixture of dichloromethane and methanol using a Yamato Lab Spray Dryer Model GB22 with internal nozzle diameter 711 ⁇ m at inlet temperature 65°C, atomization air 0.15 MPa, drying air flow of 0.4 m 3 /min and spray rate 25 ⁇ 2 g/min. To remove potential residual solvents, the spray dried materials were spread on a tray and submitted to a secondary drying at 60°C for 2 hours into a Fisher Scientific Istotemp Model 655F conventional oven to provide the SDD.
• the final blends were manufactured at 40 grams batch size by dry granulation (roller compaction).
• the intragranular ingredients i.e., SDD mixed with ingredients from second section of Table 11
• the intragranular lubricant was sieved through a No. 40 sieve (425 pm nominal aperture) and mixed with the pre-mix for 2 minutes at 25 rpm.
• the lubricated mixture was then roller compacted using a TFC-LaboTM roller compactor (Vector Corporation). Ribbons having thickness about 1 mm were obtained using at roll force of 700 psi, and roll/screw feeder speeds of 3 and 38 rpm, respectively and they were granulated using a No. 20 mesh sieve (850 pm nominal aperture).
• the resulting granules were transferred to the V-blender and mixed for 2 minutes at 25 rpm with the extragranular excipients (see last section of Table 11) previously sieved through a No. 40 sieve and lubricated by mixing for 2 minutes at 25 rpm with magnesium stearate previously sieved through a No. 40 sieve.
• the solid dispersion of Compound 7 in HPMC-AS was obtained by spray-drying using a Yamato Lab Spray Dryer Model GB22 with 711 ⁇ m internal nozzle diameter.
• the solution (5% solids) in acetone was spray-dried at an inlet temperature of 60-65°C, atomization air at 0.15 MPa, drying air flow at 0.4 m 3 /min, and spray rate of 20 g/min.
• the spray dried material also underwent a secondary drying in a Fisher Scientific Isotemp model 280A vacuum oven at 60°C and - 18 in Hg between 15 minutes and 1 hour.
• the formulation was filled manually into appropriately sized hard gelatin capsules for a 20mg Compound 7 capsule. No other ingredients were added.
• the final drug product formulation is presented in Table 12. The total weight excludes the weight of the capsule.
• the spray dried material also underwent a secondary drying in a Fisher Scientific Isotemp 280A vacuum oven at 60°C and - 18 in Hg between 15 minutes and 1 hour.
• the formulation was processed using dry granulation.
• the solid dispersion and powders except lubricant (magnesium stearate) and dibasic calcium phosphate were screened with 30 mesh (600 ⁇ m) sieve and mixed using a V-blender at 25 rpm for 2 minutes.
• the intragranular magnesium stearate was screened through a 40 mesh (425 pm) sieve and mixed with unlubricated pre-mix using a V-blender at 25 rpm for 2 minutes.
• the blend was roller compacted using a TFC-LabTM roller compactor (Vector Corporation). Ribbons having a thickness about 1 mm were obtained using at roll force of 700 psi, roll speed 2.5 ⁇ 0.5 rpm, and screw feeder speed 25 ⁇ 5 rpm. The ribbons were granulated using a 20 mesh (850 pm) sieve. Granules and external phase disintegrant (croscarmellose) and lubricant (magnesium stearate) were mixed 2 minutes each using a V-blender at 25 rpm.
• the 5 and 50 mg tablets were compressed using the KorschTM XP1 equipped with a gravity feeder and with 5 and 12 mm round standard concave tooling, respectively. Composition of the tablets is summarized in Table 13.
• the solid dispersion of Compound 7 in PVP and sodium lauryl sulfate was obtained by spraydrying using a Yamato Lab Spray Dryer Model GB22 with 711 ⁇ m internal nozzle diameter.
• the solution (5% solids) in a 1:1 mixture of dichloromethane and methanol was spray-dried at an inlet temperature of 60-65°C, atomization air at 0.15 MPa, drying airflow at 0.4 m 3 /min, and spray rate of 20 g/min.
• the spray dried material also underwent a secondary drying in a Fisher Scientific Isotemp model 280A vacuum oven at 60°C and - 18 in Hg between 15 minutes and 1 hour. 20mg tablets:
• the 20mg dosage form was processed using dry granulation.
• the powders except lubricant (magnesium stearate) were screened with 30 mesh (600 ⁇ m) sieve and mixed using a V-blender at 25 rpm for 2 minutes.
• the intragranular magnesium stearate was screened through a 40 mesh (425 pm) sieve and mixed with unlubricated pre-mix using a V-blender at 25 rpm for 2 minutes.
• the blend was roller compacted using a TFC-LabTM roller compactor (Vector Corporation). Ribbons having a thickness about 1 mm were obtained using at roll force of 700 psi, roll speed 3.5 ⁇ 0.5 rpm, and screw feeder speed 45 ⁇ 5 rpm.
• the ribbons were granulated using a 20 mesh (850 pm) sieve. Granules and external phase lubricant were mixed using a V-blender at 25 rpm for 2 minutes.
• the 20 mg Compound 7 tablets were compressed using the KorschTM XP 1 equipped with a gravity feeder and 7 mm round standard concave tooling.
• the 100 mg tablets were made using the same SDD as for the 20mg tablets but instead of dry roller compaction, a slugging method was used.
• the ingredients except for lubricant were screened with a 30-mesh sieve and mixed using a mortar/pestle for 2 minutes.
• the slugs having weight 352 ⁇ 2 mg, thickness 5 ⁇ 1 mm, and hardness 1.8 ⁇ 0.2 kp were compressed using a Carver manual hydraulic bench top lab press at 500 Ibf.
• the slugs were crushed and granulated thought an 850 pm sieve.
• the granules were lubricated by mixing with external lubricant for 1 minutes using a mortar/pestle.
• the 100 mg Compound 7 tablets were compressed using the KorschTM XP 1 equipped with a gravity feeder. Table 14 summarizes the composition for the 20 mg and 100 mg F16(a) and F16(b) tablets.
• the solid dispersion of Compound 7 in PVP and sodium lauryl sulfate was obtained as in 1(n) using the weight proportions described in Table 15 below.
• a final blend was then prepared using a dry granulation process.
• the powders except lubricant (magnesium stearate) were screened with 30 mesh (600 ⁇ m) sieve and mixed using a V-blender at 25 rpm for 2 minutes.
• the intragranular magnesium stearate was screened through a 40 mesh (425 pm) sieve and mixed with unlubricated pre-mix using a V-blender at 25 rpm for 2 minutes.
• the blend was roller compacted using a TFC-LabTM roller compactor (Vector Corporation).
• Ribbons having a thickness about 1 mm were obtained using at roll force of 700 psi, roll speed 2.5 ⁇ 0.5 rpm, and screw feeder speed 25 ⁇ 5 rpm.
• the ribbons were granulated using a 20 mesh (850 pm) sieve.
• Granules and external phase lubricant magnesium stearate were mixed 2 minutes each using a V-blender at 25 rpm.
• the 5 and 50 mg tablets were then compressed using the KorschTM XP1 equipped with a gravity feeder and with 5 and 12 mm round standard concave tooling, respectively.
• the F18(a) and F18(b) formulations were prepares as in 1(o) where lactose is replaced with anhydrous dibasic calcium phosphate and meglumine in the intragranular ingredients and croscarmellose is also present in the external phase.
• the granulation process is the same as the one presented in 1(o).
• the final formulation is provided in Table 16.
• Crystal state was verified by X-ray powder diffraction (XRPD).
• XRPD X-ray powder diffraction
• the XRPD pattern was first measured for the spray dried formulation F1 (without surfactant) and compared with XRPD patterns of solid dispersions prepared by other methods (F-MP and F- SEDDS) and with Compound 1 as a reference.
• the XRPD patterns are shown in Figure 1. The results show that a complete amorphous conversion of Compound 1 was only achieved with the high glass transition temperature polymer (in F1) while the melted polymer and S-SEDDS formulations showed residual peaks from Compound 1.
• Stability tests were also performed on the present formulations. Some degradation (around 1%) was observed, for instance, with formulations containing HPMC-AS as a polymer in accelerated degradation 1 -month tests. Formulations containing PVP and SLS were found to be generally more stable and under testing conditions.

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