WO2008043024A2 - Formulation pharmaceutique orale comprenant un sulfonyle bicyclique modulateur de ppar pour le traitement d'une maladie - Google Patents

Formulation pharmaceutique orale comprenant un sulfonyle bicyclique modulateur de ppar pour le traitement d'une maladie Download PDF

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Publication number
WO2008043024A2
WO2008043024A2 PCT/US2007/080454 US2007080454W WO2008043024A2 WO 2008043024 A2 WO2008043024 A2 WO 2008043024A2 US 2007080454 W US2007080454 W US 2007080454W WO 2008043024 A2 WO2008043024 A2 WO 2008043024A2
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WO
WIPO (PCT)
Prior art keywords
capsule
recited
sulfonyl
indan
trifluoromethoxy
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PCT/US2007/080454
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English (en)
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WO2008043024A3 (fr
Inventor
James L. Gallagher
Robyn A. Rourick
Shawn A. Scranton
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Kalypsys, Inc.
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Publication of WO2008043024A2 publication Critical patent/WO2008043024A2/fr
Publication of WO2008043024A3 publication Critical patent/WO2008043024A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • PPARs peroxisome proliferator activated receptors
  • Biological processes modulated by PPAR include plasma lipid transport, fatty acid catabolism, regulation of insulin sensitivity and blood glucose levels, and macrophage differentiation, which lead to the formation of atherosclerotic plaques, inflammatory response, carcinogenesis, hyperplasia, and adipocyte differentiation.
  • Subtypes of PPAR include PPAR ⁇ , PPAR ⁇ / ⁇ , and PPAR ⁇ .
  • Novel formulations for oral delivery comprising 4-[c ⁇ -2,6-dimethyl-4-(4- trifluoromethoxy-phenyl)-piperazine-l -sulfonyl] -indan-2-carboxylic acid, or a salt, ester, or prodrug thereof, being well-tolerated, stable, and convenient to administer, are obtainable when the compositions are formulated as disclosed herein.
  • Formulations for oral delivery which have good storage stability and other physical properties, such as particle size, compressibility, flowability, hygroscopicity, dissolution profile, and statics, which render it useful as a medicament for oral delivery.
  • the formulations comprise a compound active as a modulator of PPAR, in particular PPAR ⁇ , namely, 4-[c ⁇ -2,6-dimethyl-4-(4- trifluoromethoxy-phenyl)-piperazine-l-sulfonyl]-indan-2-carboxylic acid.
  • the formulation is a capsule or a tablet.
  • the compound is substantially present as the isolated enantiomer, (S)-4-[c ⁇ -2,6-dimethyl- 4-(4-trifluoromethoxy-phenyl)-piperazine- 1 -sulfonyl] -indan-2-carboxylic acid.
  • the compound is present as the para-toluenesulfonate salt (the tosylate salt), to form 4-[c ⁇ -2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-l- sulfonyl] -indan-2-carboxylic acid tosylate.
  • the formulation comprises a capsule containing 30mg, 60mg, 80mg, or lOOmg of 4-[c ⁇ - 2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-l-sulfonyl]-indan-2-carboxylic acid tosylate, hereinafter known alternatively as Compound 1.
  • the compound may be formulated as capsule comprising 0.2-50% of 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine- l-sulfonyl]-indan-2-carboxylic acid tosylate; 0-99.8% of a filler selected from the group consisting of lactose monohydrate, microcrystalline cellulose, and PROSOLV; 0-10% of a disintegrant selected from the group consisting of crospovidone and povidone; 0-5% of a lubricant selected from the group consisting of magnesium stearate and stearic acid; and 0-5% of a glidant selected from the group consisting of silicon dioxide and a poloxamer.
  • the filler is lactose monohydrate; the disintegrant is crospovidone; the lubricant is magnesium stearate; and the glidant is silicon dioxide.
  • the capsule has a Carr index of less than about 20.
  • particles of (S)-4-[c ⁇ -2,6-dimethyl-4-(4- trifluoromethoxy-phenyl)-piperazine-l -sulfonyl] -indan-2-carboxylic acid tosylate are adsorbed on the surfaces of the lactose monohydrate.
  • the capsule has an increase in moisture content of less than about 10% over an 18-month period. In further embodiments the capsule has an increase in moisture content of less than about 2% over an 18-month period.
  • about 66.6% of the particles of said (S)-4-[cis-2,6- dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-l-sulfonyl]-indan-2-carboxylic acid tosylate range in size from about 140 to about 200 microns.
  • the capsule comprises 2.24% (S)-4-[cis-2,6- dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-l-sulfonyl]-indan-2-carboxylic acid tosylate; 90.76% lactose monohydrate; 5% crospovidone; 1% magnesium stearate; and 1% silicon dioxide; having a fill weight of 300 mg.
  • the capsule is about 64% to about 85% dissolved at 15 minutes, about 84% to about 92% dissolved at 30 minutes, about 86% to about 94% dissolved thereafter up to 60 minutes when placed in 10OmL 3% sodium dodecyl sulphate solution in a 15OmL vessel and agitated at 200 ⁇ 2 RPM and 37 ⁇ 0.5 0 C.
  • the capsule comprises 8.97% (S)-4-[cis-2,6- dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-l-sulfonyl]-indan-2-carboxylic acid tosylate; 84.03% lactose monohydrate; 5% crospovidone; 1% magnesium stearate; and 1% silicon dioxide; having a fill weight of 300 mg.
  • the capsule is about 63% to about 71% dissolved at 15 minutes, about 71% to about 80% dissolved at 30 minutes, about 73% to about 82% dissolved at 45 minutes, and about 74% to about 82% dissolved at 60 minutes when placed in 10OmL 3% sodium dodecyl sulphate solution in a 15OmL vessel and agitated at 200 ⁇ 2 RPM and 37 ⁇ 0.5 0 C.
  • the capsule or tablet comprises 0.2-50% (S)-4-[cis- 2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-l-sulfonyl]-indan-2-carboxylic acid tosylate; 0-99.8% of a filler selected from the group consisting of microcrystalline cellulose, lactose monohydrate, dibasic calcium phosphate, corn starch, and mannitol; 0-10% of a binder selected from the group consisting of copolyvidone, hydroxypropyl- cellulose, hydroxypropylmethylcellulose, and povidone; 0-5% of a surfactant selected from the group consisting of polyoxy ethylene (20) sorbitan monooleate, a poloxamer, and sodium lauryl sulfate; 0-10% of an intergranular disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glyconate, and cro
  • the capsule filler is lactose monohydrate; the disintegrant is crospovidone; the lubricant is magnesium stearate; the binder is povidone; and the surfactant is sodium lauryl sulfate.
  • the capsule comprises 36.7% (S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)- piperazine-l-sulfonyl]-indan-2-carboxylic acid tosylate; 53.8% lactose monohydrate; 3% povidone; 5% crospovidone; 0.5% sodium lauryl sulfate; and 1% magnesium stearate.
  • the capsule has a fill weight selected from the group consisting of 225 mg and 300 mg.
  • the oral pharmaceutical formulation comprises 0.2- 50% (S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-l-sulfonyl]- indan-2-carboxylic acid tosylate; 0-99.8% of a filler selected from the group consisting of microcrystalline cellulose, lactose monohydrate, dibasic calcium phosphate, corn starch, and mannitol; 0-10% of a binder selected from the group consisting of copolyvidone, hydroxypropyl-cellulose, hydroxypropylmethylcellulose, and povidone; 0-5% of a surfactant selected from the group consisting of polyoxy ethylene (20) sorbitan monooleate, a poloxamer, and sodium lauryl sulfate; 0-10% of an intergranular disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glyconate, and crospo
  • the filler is lactose monohydrate; the disintegrant is crospovidone; the lubricant is magnesium stearate; the binder is povidone; and the surfactant is sodium lauryl sulfate.
  • the oral pharmaceutical formulation comprises 36.7% (S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-l- sulfonyl]-indan-2-carboxylic acid tosylate; 53.8% lactose monohydrate; 3% povidone; 5% crospovidone; 0.5% sodium lauryl sulfate; and 1% magnesium stearate.
  • the oral pharmaceutical formulation is formulated as a capsule having a fill weight selected from the group consisting of 225 mg and 300 mg.
  • the process for the preparation of a pharmaceutical composition comprising (S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)- piperazine-l-sulfonyl]-indan-2-carboxylic acid tosylate, a filler, a binder, an intergranular disintegrant, and a surfactant, comprises the steps of: mixing said (S)-4- [cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-l-sulfonyl]-indan-2- carboxylic acid tosylate, a filler, and a disintegrant; spraying an aqueous granulating solution comprising a binder and a surfactant onto said mixture of (S)-4-[cis-2
  • the filler is lactose monohydrate; the binder is povidone; the surfactant is sodium lauryl sulfate; the extragranular disintegrant is crospovidone; the intergranular disintegrant is crospovidone; and the lubricant is magnesium stearate.
  • formulations for oral delivery comprising 4-[c ⁇ -2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine- 1 -sulfonyl]- indan-2-carboxylic acid, or a salt, ester, or prodrug thereof, for use as a medicament.
  • said formulation comprises a capsule.
  • said capsule is useful for the treatment or prevention of a PPAR ⁇ - mediated disease.
  • a method achieving an effect in a patient comprising the administration of a capsule comprising 4-[c ⁇ -2,6-dimethyl-4- (4-trifluoromethoxy-phenyl)-piperazine-l-sulfonyl]-indan-2-carboxylic acid, or a salt, ester, or prodrug thereof, to a patient in need thereof, wherein said effect is selected from the group consisting of lowering of LDL, raising of HDL, lowering of CRP, lowering of triglycerides, and treatment of a PPAR-mediated disease.
  • said disease is selected from the group consisting of diabetes, hyperglycemia, metabolic syndrome, obesity, and atherosclerosis.
  • carrier is meant to be interchangeable with the terms "vehicle,” “excipient,” and “diluent.” All these terms refer to an inert (i.e., non-drug) substance forming part of a pharmaceutical formulation. Though technically inert, such carriers, diluents, etc. may have properties yielding beneficial effects in terms of, for example, improved solubility or distribution, compressibility, delayed release, and the like.
  • compound is meant to be interchangeable with the term “active compound” or “drug,” and refers to a compound having beneficial prophylactic and/or therapeutic properties when administered to a patient and/or activity against a biological target which is associated with a disease.
  • fill weight refers to the total weigh of the contents of a capsule, including or excluding (but generally excluding) the weight of the capsule itself.
  • composition as used herein is intended to be synonymous with the term "composition,” or "pharmaceutical composition,” any of which herein refer to a composition comprising an active therapeutic compound, together with any pharmaceutically acceptable carriers needed to make said active therapeutic compound suitable for administration to a patient by whatever route is desirable.
  • a formulation for oral administration might comprise, in addition to the active compound, fillers, binders, and/or a capsule.
  • a formulation for topical administration on the skin might comprise, in addition to the active compound, a gel or cream base, dermal penetration enhancers, coloring agents, and/or fragrance.
  • high shear granulation refers to a process of preparing a granular pharmaceutical composition.
  • an active compound and excipients such as fillers, binders, or disintergrants are powdered and mixed together in a high shear granulator (high shear granulating equipment is commercially available from vendors such as Bohle, Fluidaire or Glatt).
  • a solution of a binder, optionally including a surfactant, is added to the mixture of powders. The mixture is agitated thoroughly within the granulator utilizing an internal impeller until a wet massing endpoint is reached.
  • the wet-massed granulation obtained from the wet-massing step is dried and the dried blend is generally processed further by sizing the granulation through a mill or screen.
  • the dried granules thus obtained may be mixed with other exipients such as a disintegrant or lubricant and further processed into capsules, tablets, or other dosage forms.
  • particles refers to, when the compound is crystalline, individual crystals of the compound. When the compound is amorphous, 'particles" refers to individual particles comprising compound in amorphous form.
  • a particularly preferred and simple method for the achievement of particles of uniform size is sieving. Sieving involves the agitation of a solid form of a substance (i.e., crystals or powder) over screens of various pore sizes to eliminate particles that are either too large or too small and retain particles of desired size.
  • Another method of homogenizing particle size, particularly of forming small particles of compound involves breaking larger diameter particles into smaller diameter particles. Particle size reduction may be accomplished by any conventional method, such as by milling or grinding.
  • Exemplary milling devices include a chaser mill, ball mill, vibrating ball mill, hammer mill, impact grinding mill, fluid energy mill (jet mill), cryogenic mill, and centrifugal-impact pulverizers. Regardless of the process used to form particles of adequate and uniform size, such method will ideally not alter the polymorph profile of the compound.
  • small particles may be formed by atomization or precipitation.
  • One method for reducing the compound particle size is jet milling.
  • Small compound particles can also be formed by other means, such as dissolution in a solvent such as alcohol or water followed by precipitation by mixing with a non- solvent.
  • Another method to reduce particle size is by melting or dissolving the compound in a solvent and atomizing the resulting liquid by spray congealing or spray drying to form a powder.
  • the size of the compound particles needed to achieve ideal compound dissolution compared with the bulk crystalline form of the compound will depend on the particular compound. In general, however, dissolution rate tends to increase as the compound particle size decreases. Thus, increasing the rate of dissolution of the compound by reduction of particle size can yield at least temporarily a higher maximum compound concentration than that achieved by dissolution of larger compound particles.
  • patient means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • the phrase "therapeutically effective” is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the disease or disorder.
  • the term "therapeutically acceptable” refers to those compounds (or salts, esters, prodrugs or zwitterions, etc. thereof) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • the compounds comprised by formulations can exist as therapeutically acceptable salts. Provided herein are compounds listed above in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids.
  • Such acid addition salts will normally be pharmaceutically acceptable.
  • salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question.
  • Salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question.
  • salt represents salts or zwitterionic forms of compounds which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
  • the salt is the tosylate (p- toluenesulfonate) salt of a compound.
  • esters generally refers to a carboxyl group bridging two moieties linked at carbon atoms, but may also refer to a thioester. In the present context it may refer to a particular type of prodrug.
  • prodrug refers to a compound that is made more active in vivo. Certain compounds disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism : Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley- VHC A, Zurich, Switzerland 2003).
  • Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds disclosed herein may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.
  • compositions for oral delivery comprising Compound 1 or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, together with one or more pharmaceutically acceptable excipients or carriers thereof and optionally one or more other therapeutic ingredients.
  • the excipient(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Excipients may be utilized to formulate the drug and polymer into tablets, capsules, suspensions, powders for suspension, granules, and the like.
  • Excipients may include, without limitation, surfactants, pH modifiers, fillers, disintegrants, pigments, binders, lubricants, glidants, flavorants, colorants, preservatives, and any other conventional formulation excipients well-known in the art (e.g., as described in Remington: The Science and Practice of Pharmacy 2Qth ed. 2000). Such excipients may be used for customary purposes and in typical amounts without adversely affecting the properties of the compositions.
  • fillers include, without limitation, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, microcrystalline cellulose (MCC), powdered cellulose, cornstarch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers such as polyethylene oxide, and hydroxypropyl methyl cellulose.
  • MCC microcrystalline cellulose
  • Fillers may have complexed solvent molecules, such as in the case where the lactose used is lactose monohydrate. Fillers may also be proprietary, such in the case of the filler PROSOL V® (available from JRS Pharma).
  • PROSOLV is a proprietary, optionally high-density, silicified microcrystalline cellulose composed of 98% micro crystalline cellulose and 2% colloidal silicon dioxide. Silicification of the microcrystalline cellulose is achieved by a patented process, resulting in an intimate association between the colloidal silicon dioxide and microcrystalline cellulose.
  • ProSolv comes in different grades based on particle size, and is a white or almost white, fine or granular powder, practically insoluble in water, acetone, ethanol, toluene and dilute acids and in a 50g/l solution of sodium hydroxide.
  • disintegrants include, without limitation, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, povidone, crospovidone (polyvinylpolypyrrolidone), methyl cellulose, microcrystalline cellulose, powdered cellulose, low-substituted hydroxy propyl cellulose, starch, pregelatinized starch, and sodium alginate.
  • Examples of lubricants include, without limitation, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • Examples of glidants include, without limitation, silicon dioxide (SiO 2 ), talc cornstarch, and poloxamers.
  • Poloxamers are A-B-A block copolymers in which the A segment is a hydrophilic polyethylene glycol homopolymer and the B segment is hydrophobic polypropylene glycol homopolymer.
  • Examples of tablet binders include, without limitation, acacia, algini c acid, carbomer, carboxymethyl cellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, copolyvidone, methyl cellulose, liquid glucose, maltodextrin, polymethacrylates, povidone, pregelatinized starch, sodium alginate, starch, sucrose, tragacanth, and zein.
  • surfactants include, without limitation, fatty acid and alkyl sulfonates; commercial surfactants such as benzethanium chloride (HY AMINE® 1622, available from Lonza, Inc., Fairlawn, N.J.); DOCUSATE SODIUM® (available from Mallinckrodt Spec. Chem., St.
  • polyoxyethylene sorbitan fatty acid esters TWEEN®, available from ICl Americas Inc., Wilmington, DE; LIPOSORB® P-20, available from Lipochem Inc., Patterson NJ; CAPMUL® POE-O, available from Abitec Corp., Janesville, WI
  • polyoxyethylene (20) sorbitan monooleate TWEEN 80®, available from ICl Americas Inc., Wilmington, DE
  • natural surfactants such as sodium taurocholic acid, l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, and other phospholipids and mono- and diglycerides.
  • Such materials can advantageously be employed to increase the rate of dissolution by facilitating wetting, thereby increasing the maximum dissolved concentration, and also to inhibit crystallization or precipitation of drug by interacting with the dissolved drug by mechanisms such as complexation, formation of inclusion complexes, formation of micelles or adsorbing to the surface of solid drug
  • Examples of drug complexing agents or solubilizers include, without limitation, the polyethylene glycols, caffeine, xanthene, gentisic acid and cylodextrins.
  • the addition of pH modifiers such as acids, bases, or buffers may also be beneficial, retarding or enhancing the rate of dissolution of the composition, or, alternatively, helping to improve the chemical stability of the composition.
  • the formulations provided herein may include other agents conventional in the art having regard to the type of formulation in question. Proper formulation is dependent upon the route of administration chosen.
  • compositions suitable for oral administration may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • formulations suitable for oral administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • All methods include the step of bringing into association a compound or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a compound or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid such as glycine, or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • compositions which can be used orally include, without limitation, tablets, push- fit capsules made of gelatin or hydroxypropyl methylcellulose (HPMC), as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by direct compression or molding, optionally with one or more accessory ingredients.
  • HPMC hydroxypropyl methylcellulose
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules (formed by any method, such as dry or wet granulation, spray drying, or spray-dried dispersion), optionally mixed one or more excipients such as binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets of any shape may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • a powder or granules formed by any method, such as dry or wet granulation, spray drying, or spray-dried dispersion
  • excipients such as binders, inert diluents, or lubricating, surface active or dispersing agents.
  • the push- fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquid excipients, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • suitable liquid excipients such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. All formulations for oral administration
  • a functional coating such as an enteric polymer
  • enteric coating materials include HPMCAS, HPMCP, CAP, CAT, carboxymethylethyl cellulose, carboxylic acid-functionalized polymethacrylates, and carboxylic acid- functionalized polyacrylates.
  • a "non-functional" coating such as a sugar-containing coating to facilitate swallowing, which does not substantially affect dissolution or other pharmacokinetic properties, may be used.
  • compositions of the drug and polymer may be administered in a controlled release dosage form.
  • the composition of the drug and polymer is incorporated into an erodible polymeric matrix device.
  • an erodible matrix is meant aqueous-erodible or water-swellable or aqueous-soluble in the sense of being either erodible or swellable or dissolvable in pure water or requiring the presence of an acid or base to ionize the polymeric matrix sufficiently to cause erosion or dissolution.
  • the erodible polymeric matrix When contacted with the aqueous environment of use, the erodible polymeric matrix imbibes water and forms an aqueous-swollen gel or "matrix" that entraps the particles of low-solubility drug that are at least partially coated with a precipitation-inhibiting polymer.
  • the aqueous-swollen matrix gradually erodes, swells, disintegrates or dissolves in the environment of use, thereby controlling the release of the drug mixture to the environment of use.
  • compounds may be administered by or incorporated into a non-erodible matrix device.
  • compounds may be delivered using a coated osmotic controlled release dosage form.
  • This dosage form has two components: (a) the core which contains an osmotic agent and the coated compound particles; and (b) an outer coating surrounding the core, the outer coating controlling the influx of water to the core from an aqueous environment of use so as to cause compound release by extrusion of some or all of the core to the environment of use.
  • the osmotic agent contained in the core of this device may be an aqueous-swellable hydrophilic polymer, hydrogel, osmogen, or osmagent.
  • the outer coating surrounding the core is preferably polymeric, aqueous-permeable, and has at least one delivery port.
  • compounds may be delivered via a coated hydrogel controlled release dosage form having three components: (a) a compound-containing composition containing the coated compound particles, (b) a water-swellable composition wherein the water-swellable composition is in a separate region within a core formed by the compound-containing composition and the water-swellable composition, and (c) an outer coating around the core that is water- permeable, and has at least one delivery port therethrough.
  • the core imbibes water through the outer coating, swelling the water-swellable composition and increasing the pressure within the core, and fluidizing the compound-containing composition. Because the outer coating surrounding the core remains intact, the compound-containing composition is extruded out of the delivery port into an environment of use.
  • compositions having controlled release of at least a portion of the compound contained in the dosage form over a sustained length of time may have utility where it is desired to release at least a portion of the compound in a target organ such as the stomach, the small intestine, the colon, or any combination of these.
  • the compound may be coated with an enteric, precipitation-inhibiting polymer.
  • enteric precipitation-inhibiting polymers include HPMCAS, CAP, CAT, HPMCP, and CMEC.
  • the compound particles may be fully encapsulated with the precipitation-inhibiting polymer to prevent early dissolution of the compound in a gastric environment.
  • the precipitation- inhibiting polymer may be water impermeable at low pH to prevent the compound from dissolving and leaching out of the dosage form in the gastric environment.
  • This embodiment has particular utility for providing controlled release of low-solubility, basic compounds to the small intestine or colon.
  • compounds may be delivered via a rapid-melt or rapidly disintegrating tablet, for the purpose of enhancing delivery across mucosal membranes.
  • Additional optional excipients for such a dosage form might include effervescent agents or taste-masking agents.
  • Such a dosage form would be deliverable buccally or sublingually, and might find use where improved bioavailability or accelerated the onset of action of some active drug ingredients is desired.
  • Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
  • the compounds disclosed herein may be at a dose of from 0.001 to 500 mg/kg per day.
  • the dose range for adult humans is generally from 1 mg to 2 g/day. In certain embodiments, the dose range is from about 1 to about 100 mg/day.
  • Capsules or other forms of presentation provided in discrete units may conveniently contain an amount of compound disclosed herein which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated.
  • the route of administration may vary depending on the condition and its severity.
  • the compounds described herein may be administered in combination with another therapeutic agent.
  • another therapeutic agent such as a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the benefit of experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • another therapeutic agent which also includes a therapeutic regimen
  • increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • statin and/or other lipid lowering drugs for example MTP inhibitors and LDLR upregulators
  • antidiabetic agents e.g. metformin, sulfonylureas, or PPAR-gamma, PPAR-alpha and PPAR-alpha/gamma modulators (for example thiazolidinediones such as e.g. Pioglitazone and Rosiglitazone)
  • antihypertensive agents such as angiotensin antagonists, e.g., telmisartan, calcium channel antagonists, e.g. lacidipine and ACE inhibitors, e.g., enalapril.
  • the multiple therapeutic agents may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.
  • provided herein is methods for treating PPAR- mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a formulation effective to reduce or prevent said disorder in the subject in combination with at least one additional agent for the treatment of said disorder that is known in the art.
  • formulations comprising Compound 1 in combination with one or more additional agents for the treatment of PPAR-mediated disorders.
  • the compounds disclosed herein are useful in the treatment of a disease or condition ameliorated by the modulation of a PPAR ⁇ .
  • Specific diseases and conditions modulated by PPAR ⁇ and for which the compounds and compositions are useful include but are not limited to dyslipidemia, syndrome X, atherosclerosis, obesity, heart failure, hypercholesteremia, cardiovascular disease, type II diabetes mellitus, type 1 diabetes, hyperglycemia, insulin resistance hyperlipidemia, and inflammation.
  • Other indications include reduction of scarring and wound healing.
  • the compounds disclosed herein may also be used (a) for raising HDL in a subject; (b) for treating Type 2 diabetes, decreasing insulin resistance or lowering blood pressure in a subject; (c) for decreasing LDLc in a subject; (d) for shifting LDL particle size from small dense to normal dense LDL in a subject; (e) for reducing cholesterol absorption or increasing cholesterol excretion in a subject; (f) for reducing the expression of NPClLl in a subject; (g) for treating atherosclerotic diseases including vascular disease, coronary heart disease, cerebrovascular disease and peripheral vessel disease in a subject; and (h) for treating inflammatory diseases, including asthma, rheumatoid arthritis, osteoarthritis, disorders associated with oxidative stress, inflammatory response to tissue injury, psoriasis, ulcerative colitis, dermatitis, and autoimmune disease in a subject.
  • inflammatory diseases including asthma, rheumatoid arthritis, osteoarthritis, disorders associated with oxidative stress,
  • the compounds disclosed herein may also be used for treating, ameliorating, or preventing a disease or condition selected from the group consisting of hyperinsulinemia, polycystic ovary syndrome, climacteric, disorders associated with oxidative stress, inflammatory response to tissue injury, pathogenesis of emphysema, ischemia-associated organ injury, doxorubicin-induced cardiac injury, drug-induced hepatotoxicity, atherosclerosis, and hypertoxic lung injury.
  • a disease or condition selected from the group consisting of hyperinsulinemia, polycystic ovary syndrome, climacteric, disorders associated with oxidative stress, inflammatory response to tissue injury, pathogenesis of emphysema, ischemia-associated organ injury, doxorubicin-induced cardiac injury, drug-induced hepatotoxicity, atherosclerosis, and hypertoxic lung injury.
  • a disease or condition selected from the group consisting of hyperinsulinemia, polycystic ovary syndrome, climacteric
  • the salt may be selected from the group consisting of the hydrochloride, hydrobromide, sulfonate, citrate, tartrate, phosphonate, lactate, pyruvate, acetate, succinate, oxalate, fumarate, maleate, oxaloacetate, methanesulfonate, ethanesulfonate, p-toluenesulfonate (tosylate), benzenesulfonate (besylate) and isethionate salts of (S)-4-[c ⁇ -2,6-dimethyl-4-(4-trifluoromethoxy- phenyl)-piperazine- 1 -sulfonyl]-indan-2-carboxylic acid.
  • the compounds and formulations are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • Step 1 32% HCI is added to a solution of sodium nitrite in water and acetonitrile at 0 0 C.
  • the solution is cooled to -5 0 C and a solution of (R,S)-4-amino- indan-2-carboxylic acid methyl ester hydrochloride in water, acetonitrile, and 32% HCl is added, keeping the temperature between -7 and -10 0 C.
  • the resulting cold diazonium solution is added to a solution of potassium ethyixanthogenate, in water and acetonitrile, at 60 0 C. After heating at 60 0 C, the mixture is cooled to room temperature and extracted from dichloromethane.
  • the organic solution is charged into the reactor and concentrated under reduced pressure. Dichloromethane and water are added, the mixture cooled to 5 0 C, and chlorine gas passed through the mixture. The organic solution is separated and the aqueous solution is extracted from dichloromethane. The combined organic solution is dried over magnesium sulfate and concentrated under reduced pressure to afford (R,S)-4-chlorosulfonyl-indan-2-carboxylic acid. HPLC may be used to monitor the reaction.
  • Step 2 Potassium carbonate is added to a mixture of c ⁇ -3,5-dimethyl-l-(4- trifluoromethoxy-phenyl)-piperazine hydrochloride in dichloromethane and water. After stirring at room temperature, the organic phase is collected and the aqueous layer extracted from dichloromethane. The combined organic solution is charged into the reactor and concentrated under reduced pressure, followed by the addition of acetonitrile and potassium carbonate. A solution of (R,S)-4-chlorosulfonyl-indan-2- carboxylic acid, in acetonitrile, is added to the reaction mixture. After heating at 50 0 C, the reaction mixture is cooled to 20 0 C.
  • the mixture is transferred into a 200 L movable agitation feed tank, which is charged with Celite, and the suspension is stirred.
  • the suspension is filtered, filter cake washed with acetonitrile, and the filtrate is concentrated under reduced pressure, cooled to 0-5 0 C, and 32% HCl added.
  • Step 3 Simulated moving bed (SMB) chromatography was used to separate the S- and R-enantiomers of (R,S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy- phenyl)-piperazine-l-sulfonyl]-indan-2-carboxylic acid methyl ester.
  • SMB Simulated moving bed
  • the SMB method uses a Chiralpak AS column and nheptane/isopropanol (1 :1 v/v) to yield the S- enantiomer, (S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine- 1 - suIfonyl]-indan-2-carboxylic acid methyl ester (>99.0% by chiral HPLC).
  • Step 4 To a solution of (S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy- phenyl)-piperazine-l-suIfonyl]-indan-2-carboxylic acid methyl ester, in THF, is added a solution of lithium hydroxide in water, which is stirred at 20 0 C and concentrated under reduced pressure. The reaction mixture is cooled to 9 0 C, neutralized with 32% HCl, and extracted from toluene. Water is removed from the organic solution by azeotropic distillation. Following distillation, the organic solution is cooled to ambient temperature and transferred to a feeding vessel.
  • the reactor is charged with p- toluenesulfonic acid in toluene and water is removed by azeotropic distillation.
  • the solution is cooled to 60 0 C, followed by the addition of the organic solution from the feeding vessel.
  • the mixture is stirred at 83 0 C, then cooled to 10 0 C to induce crystallization.
  • the product suspension is filtered, the filter cake rinsed with heptane, and dried on a rotovap, at 40 0 C, to afford (S)-4-[cis-2,6-dimethyl-4-(4- trifluoromethoxy-phenyl)-piperazine-l-sulfonyl] -indan-2-carboxylic acid tosylate, Compound 1.
  • Blending and capsule fill for Compound 1 Capsule 20 mg Compound 1 is passed between two sieve screens to produce a consistent particle size in the range of 53 to 250 ⁇ m. Particle size and XRPD in-process control (IPC) testing are performed, for information only, to profile the particle size distribution and evaluate the solid-state characteristics of Compound 1 following the sieve step. An appropriate amount of Compound 1 is weighed for each batch. The excipients are passed through a 250 ⁇ m sieve, collected, and weighed. Approximately half of the excipients are added to the container for blending. Compound 1 is added to the container, followed by the remaining half of the excipients, such that Compound 1 is sandwiched between the excipients.
  • IPC in-process control
  • Blend uniformity IPC testing is performed after blending by sampling 3 points within the container (top, middle, and bottom) and testing each sample for potency. A test result of 95-105% of target, with an RSD of 5%, must be achieved before the process can continue. Additional blend time is allowed to achieve a uniform blend if the IPC test results are not within the specified range.
  • a measured aliquot of the Compound 1 stock formulation is separated to manufacture the lower strengths. This aliquot is removed from the manufacturing area. Magnesium stearate is passed through a 75 ⁇ m sieve, collected, weighed, added to the blender as a lubricant, and mixed until dispersed. The final blend is weighed and reconciled.
  • Coni-Snap capsules (Swedish orange) are opened and the body of the capsule is placed on a Pro fill tray (holding 100 units) and the cap is placed on the corresponding tray. Blended materials are then flood fed into the body of the capsules using a spatula. The trays may be tamped to settle the blend in each capsule to assure uniform target fill weight. The capsules are then sealed by combining the filled bodies with the caps. Fill weight uniformity IPC testing is performed following encapsulation. Thirteen capsules are removed from a tray of 100 and weighed. This test result must be within the target fill weight (376 ⁇ 15 mg, including capsule weight) to pass. If the target fill weight specification is not met, the entire tray of 100 is weight checked and capsules not meeting weight specification are rejected. Following successful fill weight check, capsules are inspected, de-dusted, reconciled, and placed into a suitable in-process storage container.
  • Blending and capsule fill for Compound 1 Capsule 5 mg and Compound 1 Capsule 1 mg Compound 1 stock formulation aliquot can be used to manufacture the lower strengths using serial dilutions. The excipients are passed through a 250 ⁇ m sieve, collected, and weighed. Approximately half of the excipients are added to the container for blending. Compound 1 stock formulation aliquot is added to the container, followed by the remaining half of the excipients, such that Compound 1 stock formulation aliquot is sandwiched between the excipients. The blend is then mixed until uniform. Blend uniformity IPC testing is performed after blending by sampling 3 points within the container (top, middle, and bottom) and testing each sample for potency.
  • an aliquot of Compound 1 stock formulation can be removed to manufacture the 1 mg strength. This aliquot is removed from the manufacturing area. Magnesium stearate is passed through a 75 ⁇ m sieve, collected, weighed, and added to the blender as a lubricant and mixed until dispersed. The final blend is weighed and reconciled.
  • the Coni-Snap capsules (5 mg, dark green or 1 mg, white) are opened and the body of the capsule is placed on a Pro fill tray (holding 100 units) and the cap is placed on the corresponding tray. Blended materials are then flood fed into the body of the capsules using a spatula. The trays may be tamped to settle the blend in each capsule to assure uniform target fill weight. The capsules are then sealed by combining the filled bodies with the caps. Fill weight uniformity IPC testing is performed following encapsulation. Thirteen capsules are removed from a tray of 100 and weighed. This test result must be within the target fill weight (376 ⁇ 15 mg, including capsule weight) to pass. If the target fill weight specification is not met, the entire tray of 100 is weight checked and capsules not meeting weight specification are rejected. Following successful fill weight check, capsules are inspected, de-dusted, reconciled, and placed into a suitable in-process storage container.
  • Blending and capsule fill for Compound 1 Capsule 80 mg An appropriate amount of Compound 1, a filler such as lactose monohydrate, and a disintegrant such as crospovidone are de-lumped by screening or milled prior to being charged to a granulator, such as a Bohle, Fluidaire or Glatt high shear granulator. The dry ingredients are mixed within the granulator utilizing an internal impeller. Granulating solution, consisting of purified water, a binder such as povidone, and a surfactant such as sodium lauryl sulfate is sprayed through a nozzle into the dry ingredients within the granulator.
  • a filler such as lactose monohydrate
  • a disintegrant such as crospovidone
  • the granulating solution is added at a controlled rate for 1 - 10 minutes while the ingredients are mixed within the granulator.
  • An internal chopper is used to break up large agglomerates within the granulator.
  • the granulated material is wet massed for a time period between 1 - 5 minutes to promote granule growth.
  • the in-process moisture level of the wet granulated material is monitored and compared to the target value of 20%.
  • the wet granulated material is sized upon discharge either by passing it through a screen or performing a wet milling step to de-lump the granulated material prior to the drying step.
  • the wet granulated material is then transferred to a either a tray dryer or a fluid bed dryer such as a Fluid-Aire, Blue M or Glatt dryer.
  • the wet granulated material is dried at a controlled inlet air temperature such as 60 0 C until the granulated material has a residual moisture content of 2% or less.
  • the moisture content can be measured during the process and at the drying endpoint by a loss on drying, Karl Fisher, or near infrared measurement.
  • the dried granules are screened or milled as needed after the drying step to achieve a free flowing powder.
  • Additional disintegrant such as crospovidone and lubricant such as magnesium stearate are combined to the dried granules and mixed in a blender, such as a Turbula, V-blender or bin blender until uniform.
  • the content uniformity of the final powder can be measured either by sampling and assay, or by near infrared analysis.
  • the final blend is filled into capsules using a ProFill, Stokes or IMA encapsulator to produce a drug product with 80mg active ingredient in a capsule with a target weight of 300mg.
  • the final blend may be compacted into a tablet using commercially available compression equipment, such as Stokes, Manesty or IMA tablet presses.
  • Carr index is the percent compressibility, which may be calculated as follows:
  • Total fill weight of capsule is 300mg, not including capsule weight.
  • Target compound dosage as free base is 1 mg per capsule.
  • Total fill weight of capsule is 300mg, not including capsule weight.
  • Target compound dosage as free base is 5 mg per capsule.
  • Total fill weight of capsule is 300mg, not including capsule weight.
  • Target compound dosage as free base is 20 mg per capsule.
  • Total fill weight of capsule is 300mg.
  • Target compound dosage as free base is 0 mg per capsule.
  • Capsule contents may be enclosed in a white, green or Swedish orange capsule.
  • Total fill weight of capsule is 300mg.
  • Target compound dosage as the free base is 80 mg per capsule. Table 6
  • Total fill weight of capsule is 225mg.
  • Target compound dosage as the free base is 60 mg per capsule.
  • Dissolution Analysis and Characterization of Examples 1 , 2 and 3 Dissolution analysis may be conducted per standard USP, European Pharmacopoeia, British Pharmacopoeia, or other protocols. Capsule is placed in 10OmL 3% sodium dodecyl sulphate solution in a 15OmL vessel and agitated at 200 ⁇ 2 RPM and 37 ⁇ 0.5 0 C.
  • the dissolution profile of Examples 1, 2, and 3 is determined by utilizing a standard apparatus (e.g., basket) and removing samples at timed intervals. Samples are analyzed by reverse-phase HPLC chromatography and compared against a known standard to quantify the potency of Compound 1 in solution. Results are shown below in Table 7.
  • Examples 1, 2, and 3 were tested for stability under controlled, accelerated conditions. Capsules of Examples 1, 2, and 3 were stored at 60% relative humidity and 25°C for two months. Results are shown below in Table 8.

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Abstract

La présente invention concerne des formulations pharmaceutiques orales d'acide 4-[cis-2,6-diméthyl-4-(4-trifluorométhoxy-phényl)-pipérazine-1-sulfonyl]-indan-2-carboxylique qui peuvent être utilisées en tant qu'inhibiteurs des récepteurs activés par le proliférateur des peroxysomes (Peroxisome Proliferator Activated Receptors : PPAR) pour le traitement ou la prévention de maladies telles que le diabète, l'hyperglycémie, le syndrome métabolique, l'obésité ou l'athérosclérose.
PCT/US2007/080454 2006-10-04 2007-10-04 Formulation pharmaceutique orale comprenant un sulfonyle bicyclique modulateur de ppar pour le traitement d'une maladie WO2008043024A2 (fr)

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Cited By (7)

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US7863276B2 (en) 2005-10-25 2011-01-04 Kalypsys, Inc Salts of modulators of PPAR and methods of treating metabolic disorders
US7915253B2 (en) 2004-10-29 2011-03-29 Kalypsys, Inc Sulfonyl-substituted bicyclic compounds as modulators of PPAR
US9463189B2 (en) 2007-01-23 2016-10-11 Bpv Holdings, Llc Sulfonyl-substituted bicyclic compounds as PPAR modulators for the treatment of non-alcoholic steatohepatitis
US9884813B1 (en) 2017-03-01 2018-02-06 Rgenix, Inc. Pharmaceutically acceptable salts of B-guanidinopropionic acid with improved properties and uses thereof
US10512623B2 (en) 2015-08-25 2019-12-24 Rgenix, Inc. Pharmaceutically acceptable salts of B-Guanidinopropionic acid with improved properties and uses thereof
US11673877B2 (en) 2017-03-27 2023-06-13 Tesaro, Inc. Niraparib compositions
US11730725B2 (en) * 2017-09-26 2023-08-22 Tesaro, Inc. Niraparib formulations

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WO2004092117A1 (fr) * 2003-04-07 2004-10-28 Kalypsys, Inc. Composes phenyle a substitution para-sulfonyle utilises en tant que modulateurs des ppar
WO2005016881A1 (fr) * 2003-08-02 2005-02-24 Bayer Healthcare Ag Derives bicycliques d'indoline-sulfonamides
US20060167012A1 (en) * 2004-10-29 2006-07-27 Noble Stewart A Sulfonyl-substituted bicyclic compounds as modulators of PPAR

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Publication number Priority date Publication date Assignee Title
WO2004092117A1 (fr) * 2003-04-07 2004-10-28 Kalypsys, Inc. Composes phenyle a substitution para-sulfonyle utilises en tant que modulateurs des ppar
WO2005016881A1 (fr) * 2003-08-02 2005-02-24 Bayer Healthcare Ag Derives bicycliques d'indoline-sulfonamides
US20060167012A1 (en) * 2004-10-29 2006-07-27 Noble Stewart A Sulfonyl-substituted bicyclic compounds as modulators of PPAR

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7915253B2 (en) 2004-10-29 2011-03-29 Kalypsys, Inc Sulfonyl-substituted bicyclic compounds as modulators of PPAR
US7863276B2 (en) 2005-10-25 2011-01-04 Kalypsys, Inc Salts of modulators of PPAR and methods of treating metabolic disorders
US9463189B2 (en) 2007-01-23 2016-10-11 Bpv Holdings, Llc Sulfonyl-substituted bicyclic compounds as PPAR modulators for the treatment of non-alcoholic steatohepatitis
US10512623B2 (en) 2015-08-25 2019-12-24 Rgenix, Inc. Pharmaceutically acceptable salts of B-Guanidinopropionic acid with improved properties and uses thereof
US9884813B1 (en) 2017-03-01 2018-02-06 Rgenix, Inc. Pharmaceutically acceptable salts of B-guanidinopropionic acid with improved properties and uses thereof
WO2018160178A1 (fr) * 2017-03-01 2018-09-07 Rgenix, Inc. Sels pharmaceutiquement acceptables d'acide bêta-guanidinopropionique ayant des propriétés améliorées et utilisations de ceux-ci
US11673877B2 (en) 2017-03-27 2023-06-13 Tesaro, Inc. Niraparib compositions
US11730725B2 (en) * 2017-09-26 2023-08-22 Tesaro, Inc. Niraparib formulations

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