WO2010123440A1 - Composition pharmaceutique comprenant de l'hydrogénosulfate de 4-amino-8-(2-fluoro-6-méthoxy-phényl)-n-propylcinnoline-3-carboxamide et polymère de régulation de la vitesse - Google Patents

Composition pharmaceutique comprenant de l'hydrogénosulfate de 4-amino-8-(2-fluoro-6-méthoxy-phényl)-n-propylcinnoline-3-carboxamide et polymère de régulation de la vitesse Download PDF

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Publication number
WO2010123440A1
WO2010123440A1 PCT/SE2010/050423 SE2010050423W WO2010123440A1 WO 2010123440 A1 WO2010123440 A1 WO 2010123440A1 SE 2010050423 W SE2010050423 W SE 2010050423W WO 2010123440 A1 WO2010123440 A1 WO 2010123440A1
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Prior art keywords
cinnoline derivative
weight
filler
formulation
cinnoline
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PCT/SE2010/050423
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English (en)
Inventor
Dmytro Avilov
Daniel Brown
Richard Creekmore
Marilu Reus Medina
Sharon Schultz
Avadhesh Sharma
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Astrazeneca Ab
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Publication of WO2010123440A1 publication Critical patent/WO2010123440A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—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
    • A61K9/2022—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
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics

Definitions

  • composition comprising 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N- propylcinnoline-3-carboxamide hydrogen sulphate and rate-controlling polymer.
  • the present invention relates to pharmaceutical compositions of 4-Amino-8-(2-fluoro-6- methoxy-pheny ⁇ -N-propylcinnoline-S-carboxamide or pharmaceutical acceptable salts thereof (hereafter "cinnoline derivative”) with an extended release of cinnoline derivative in the gastrointestinal environment. More particularly, it relates to pharmaceutical compositions of cinnoline derivative which are ingested daily as a single oral administration.
  • U.S. Pat. No. 7,465,795 describes a method of preparing 4-Amino-8-(2-fluoro-6- methoxy-phenyl)-N-propylcinnoline-3-carboxamide, which modulates GABAA receptor activity. It is shown that 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3- carboxamide is effective in treating anxiety.
  • FIG 1 shows the dissolution profiles in simulated gastric fluid (“SGF”) and simulated intestinal fluid (“SIF”) of Example 1
  • Figure 2 shows the dissolution profiles of formulations 2-9 in SGF
  • FIG. 3 shows the dissolution profiles of formulations 2-9 in SIF
  • Figure 4 shows the erosion profiles of formulations 10 and 11
  • Figure 5 shows the dissolution profiles in SGF and SIF for formulations 10 and 11
  • Figure 6 shows the dissolution and erosion profiles of formulation 12
  • Figure 7 shows the dissolution and erosion profiles of formulations 13-16
  • Figure 8 shows the dissolution profiles in SGF for formulations 17 and 18
  • Figure 9 shows the dissolution profiles in SGF for formulations 17 and 18 DETAILED DESCRIPTION
  • the extended release (ER) formulations of the present invention which comprise a pharmaceutically acceptable polymer, provide extended release cinnoline derivative in vivo when given once daily.
  • Maximum concentrations (Cmax) of cinnoline derivative in plasma are statistically lower than the IR formulation given twice daily, and area under the plasma concentration-time curve (AUC) and the minimum plasma concentration are maintained over 24 hours.
  • the compositions of the invention may have a reduction in incidence rates for euphoria compared to the IR formulation.
  • the present invention relates to a pharmaceutical composition for extended release of the cinnoline derivative in the gastrointestinal environment, comprising the cinnoline derivative and a pharmaceutically acceptable polymer, so that when ingested orally, the composition induces statistically lower mean fluctuation index in the plasma than an immediate release composition of the cinnoline derivative while maintaining bioavailability substantially equivalent to that of the immediate release composition of the cinnoline derivative.
  • the present invention relates to a pharmaceutical composition for extended release of an cinnoline derivative in the gastrointestinal environment, comprising an cinnoline derivative and a pharmaceutically acceptable polymer, so that upon oral ingestion, maximum peak concentrations of the cinnoline derivative are statistically significantly lower than those produced by an immediate release pharmaceutical composition, and an area under the concentration-time curve and the minimum plasma concentration are substantially equivalent to that of the immediate release pharmaceutical composition.
  • the present invention relates to a method of using an extended release, pharmaceutical composition comprising the cinnoline derivative and a pharmaceutically acceptable polymer, comprising administering the composition in an effective amount for the treatment of bacterial infection in a mammal, whereby an area under the concentration-time curve equivalent to that for an immediate release pharmaceutical composition of the cinnoline derivative is maintained.
  • the present invention is an extended release pharmaceutical composition
  • the cinnoline derivative and a pharmaceutically acceptable polymer, wherein the composition has an improved adverse effect profile relative to the immediate release formulation.
  • Cmax means maximum plasma concentration of the cinnoline derivative, produced by the ingestion of the composition of the invention.
  • Cmin as used herein, means minimum plasma concentration of the cinnoline derivative, produced by the ingestion of the composition of the invention.
  • Tmax time to the maximum observed plasma concentration.
  • AUC area under the plasma concentration-time curve, as calculated by the trapezoidal rule over the complete 24-hour interval for all the formulations.
  • DFL Degree of Fluctuation
  • Cinnoline derivative as used herein, means 4-Amino-8-(2-fluoro-6-methoxy-phenyl)- N-propylcinnoline-3-carboxamide or pharmaceutically acceptable salts thereof.
  • Adverse effects means those physiological effects to various systems in the body such as cardiovascular systems, central nervous system, digestive system, and body as a whole, which cause pain and discomfort to the individual subject.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a “therapeutically effective amount” refers to amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician and can be readily determined by a clinician by using numerous methods already known in the art, an example of which is the BPRS cluster score that can be used to assess levels of hostility and positive symptoms.
  • the term “treating” within the context of the present invention is meant to encompass the administration a therapeutically effective amount of the compound of cinnoline derivative to mitigate or inhibit either a pre-existing disease state, acute or chronic, or a recurring symptom or condition. Also encompassed are prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.
  • the term "mammal” is meant to refer to any warm-blooded animal, preferably a human.
  • the mammal is in need of treatment because it is suffering from or prone to developing one or more of the symptoms, diseases or disorders described above.
  • the pharmaceutical composition of the invention comprises a pharmaceutically active compound and a pharmaceutically acceptable rate-controlling polymer.
  • the pharmaceutically active compound is a cinnoline derivative.
  • the cinnoline derivative is 4-Amino-8-(2- fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide hydrogen sulphate. More preferably, the cinnoline derivative is a crystalline 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N- propylcinnoline-3-carboxamide hydrogen sulphate.
  • the amount of the cinnoline derivative varies from about 0.1% to about 50% by weight of the composition.
  • the composition comprises about 0.1% to about 25% by weight of the cinnoline derivative. More preferably, the composition comprises about 1% to about 25% by weight of the cinnoline derivative.
  • the pharmaceutically acceptable rate-controlling polymer is a water-soluble hydrophilic polymer selected from the group consisting of polyvinylpyrrolidine, hydro xypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, vinyl acetate/crotonic acid copolymers, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof.
  • the polymer is selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and methyl cellulose. More preferably, the polymer is hydroxypropyl cellulose or hydroxypropylmethyl cellulose.
  • the amount of the rate-controlling polymer in the composition generally varies from about 5% to about 50% by weight of the composition.
  • the amount of polymers varies from about 10% to about 35% by weight of the composition.
  • the amount of polymer varies from about 10% to about 30% by weight of the polymer.
  • the solid formulations of the invention can further contain at least one ingredient selected from a filler, a binder, a suspending agent, a coating agent, a sweetener, a flavoring, a lubricant, or other ingredient.
  • the solid formulation comprises an excipient selected from an inorganic salt filler, a cellulose filler, an oligosaccharide filler, a non- cellulosic binder, and a lubricant.
  • Suitable fillers include, for example, oligosaccharides (e.g., lactose), sugars, starches, modified starches, sugar alcohols (e.g. mannitol, sorbitol, xylitol, lactitol), inorganic salts, cellulose or cellulose derivatives (e.g. microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, hypromellose), calcium sulfate, aluminum and magnesium silicate complexes and oxides, and the like.
  • An example of an inorganic salt filler is a phosphate salt such as dibasic calcium phosphate dihydrate or salts of sulfates.
  • Suitable binders include, for example, povidone, lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatin, sodium alginate, and the like.
  • Non- cellulosic binders include polymeric and other binders lacking a cellulose backbone.
  • non-cellulosic binders examples include povidone, lactose, starches, modified starches, gums, guar gum, pectin, waxes, gelatins, alginates, and the like.
  • Suitable lubricants include, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols, sodium stearyl fumarate, and the like.
  • Sweeteners that may be used include artificial and natural sweeteners such as aspartame, acesulfame potassium, saccharin, saccharin sodium, sucralose, stevia, rebiana, as well as sugar sweeteners such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolyzed starch (such as maltitol syrup) or corn syrup solids and sugar alcohols such as sorbitol, xylitol, mannitol, glycerin and combinations thereof.
  • the type of glycerin used is U.S.P. grade.
  • Flavoring agents that are suitable include, and are not limited to, natural flavors, natural fruit flavors, artificial flavors, artificial fruit flavors, flavor enhancers or mixtures thereof.
  • Natural flavors, artificial flavors or mixtures thereof include, and are not limited to, mint (such as peppermint or spearmint), menthol, cinnamon, vanilla, artificial vanilla, chocolate, artificial chocolate or bubblegum.
  • Natural fruit flavors, artificial fruit flavors or mixtures thereof include, and are not limited to, cherry, grape, orange, strawberry or lemon.
  • Flavor enhancers include, and are not limited to, citric acid.
  • Suitable suspending agents include, for example, pre-gelatinized starch, powdered cellulose, microcrystalline cellulose, methylcellulose, ethylmethylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose, attapulgile (colloidal magnesium aluminum silicate), bentonite (colloidal aluminum silicate), hectorite (colloidal magnesium aluminum silicate), sepiolite (magnesium silicate), magnesium aluminum silicate, silica gel, colloidal silicon dioxide, acacia, agar, carrageenan, guar gum, karaya gum, locust bean gum, pectin, sodium alginate, propylene glycol alginate, tamarind gum, tragacanth, xanthan gum, carbomer, povidone, polyethylene glycols, gelatin, glycyrrhizin and sodium starch
  • Suitable sustained release coatings agents include ethylcellulose, polymethacrylates, and the like.
  • Additional conventional excipients include preservatives, stabilizers, anti-oxidants, silica flow conditioners, antiadherents or glidants.
  • Preservatives include but are not limited to sodium benzoate, potassium sorbate, salts of edetate (also known as salts of ethylenediaminetetraacetic acid, or EDTA, such as disodium edetate), parabens (such as methyl, ethyl, propyl and butyl p-hydroxybenzoic acids esters or mixtures thereof) or mixtures thereof.
  • the solid formulations of the invention can include, for example, about 0.1 to about 99%, about 0.1 to about 90, about 0.1 to about 85, about 0.1 to about 80, about 0.1 to about 75, about 0.1 to about 70, about 0.1 to about 65, about 0.1 to about 60, about 0.1 to about 55, about 0.1 to about 50, about 0.1 to about 45, about 0.1 to about 40, about 0.1 to about 35, about 0.1 to about 30, about 0.1 to about 25, about 0.1 to about 20, about 0.1 to about 15, about 0.1 to about 12, about 0.1 to about 10, about 0.1 to about 8, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1.5, about 0.1 to about 1, or about 0.1 to about 0.5 % by weight of cinnoline derivative.
  • the solid formulation contains about 0.1 to about 0.3, about 0.7 to about 2.0, about 4.0 to about 10.0, about 14.0 to about 37.0, or about 40.0 to about 60.0 % by weight of cinnoline derivative. In some embodiments, the solid formulation contains about 0.2, about 0.8, about 1.0, about 1.7, about 5.0, about 8.3, about 10.0, about 16.7, about 25.0, about 33.3, or about 50.0 % by weight of cinnoline derivative.
  • the filler includes an inorganic salt such as alkali metal or alkaline earth metal salts of chloride, phosphates, sulfates, and the like. In some embodiments, the filler contains dibasic calcium phosphate dihydrate. In some embodiments, the inorganic filler is present in an amount of about 1 to about 25, about 1 to about 20, or about 3 to about 17 % by weight. In some embodiments, the inorganic filler is present in an amount of about 3, about 4, about 5, about 6, about 7, about 8, about 10, about 11, about 12, about 13, about 14, about 15, about 16, or about 17 % by weight. In some embodiments, the formulations of the invention include a cellulose filler such as microcrystalline cellulose or silicified microcrystalline cellulose.
  • the cellulose filled can be present in an amount of about 10 to about 95, about 10 to about 75, about 10 to about 60, about 15 to about 50, about 40 to about 90, or about 50 to about 90 % by weight of a cellulose filler.
  • the microcrystalline cellulose is present in an amount of about 15 to about 50 % by weight.
  • silicif ⁇ ed microcrystalline cellulose is present in an amount of about 50 to about 90 % by weight.
  • the cellulose is present in an amount of about 15, about 16, about 17, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 53, about 54, about 55, about 76, about 77, about 78, about 81, about 82, about 83, about 84, about 85, or about 86 % by weight.
  • the present formulations include an oligosaccharide filler such as lactose.
  • the oligosaccharide filler is present in an amount of about 15 to about 50, about 15 to about 45, or about 18 to about 43 % by weight.
  • the oligosaccharide filler is present in an amount of about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, or about 44 % by weight.
  • formulations contain a non-cellulosic binder such as povidone or copovidone.
  • the binder is present in an amount of about 0.5 to about 15, about 0.5 to about 10, or about 1 to about 10 % by weight. In some embodiments, the binder is present in an amount of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 % by weight.
  • the formulations of the invention contain a lubricant such as magnesium stearate or sodium stearyl fumarate.
  • the lubricant can be present in an amount of about 0.1 to about 8, about 0.5 to about 6, about 0.5 to about 5, or about 0.5 to about 3 % by weight.
  • the lubricant can be present in an amount of about 0.5, about 0.75, about 1, about 1.5, about 2, about 3, about 4, or about 5 % by weight.
  • the formulation contains a suspending agent.
  • the suspending agent can be present in an amount of about 1 to about 10 %, about 1 to about 8 %, or about 1 to about 5 % by weight. In some embodiments, the suspending agent is present in an amount of about 4, about 5, or about 6 % by weight.
  • the formulation contains a coating agent.
  • the coating agent can be present in an amount of about 1 to about 15 %, about 1 to about 10%, about 1 to abut 8 %, or about 1 to about 5 % by weight. In some embodiments, the coating agent is present in an amount of about 9, about 10, or about 11 % by weight.
  • the solid formulation contains about 0.1 to about 50 % by weight of cinnoline derivative; about 1 to about 25 % by weight of said pharmaceutically acceptable polymer; about 10 to about 95 % by weight of a cellulose filler; about 15 to about 50 % by weight of an oligosaccharide filler; about 0.5 to about 15 % by weight of a non-cellulosic binder; and about 0.1 to about 8 % by weight of a lubricant.
  • the solid formulation contains comprising about 0.1 to about 20 % by weight of said cinnoline derivative; about 10 to about 35 % by weight of said pharmaceutically acceptable polymer; about 10 to about 95 % by weight of a cellulose filler; about 15 to about 50 % by weight of an oligosaccharide filler; and about 0.1 to about 8 % by weight of a lubricant.
  • the solid formulations of the invention can be used to prepare solid dosage forms such as tablets, caplets, capsules, sachets, and the like.
  • the solid dosage form is suitable for oral administration.
  • the amount of cinnoline derivative in a solid dosage form can be about 0.1 to about 100 mg, about 0.1 to about 75 mg, or about 0.1 to about 50 mg.
  • the amount of cinnoline derivative present in a solid dosage form is about 1 , about 2, about 2.5, about 3, about 4, about 5, about 10, about 25, about 50, or about 100.
  • the total weight (e.g., active ingredients plus excipients, coatings, etc.) of the solid dosage form is about 50 to about 1000 mg.
  • the total weight of the solid dosage form is about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, or about 1000.
  • the active ingredient cinnoline derivative can be formulated as a powder dosage form suitable for preparation of a suspension just prior to use or alternatively suitable for addition to food.
  • the formulation is typically a free flowing powder with a light bulk density.
  • This formulation can be prepared by using a combination of excipients including, for example, a filler, a sweetener, and a suspending agent.
  • fillers include lactose, starch, maltodextrin, hypromellose, microcrystalline cellulose, and the like.
  • sweeteners include aspartame, lactitol, sacchrin, sucrose, fructose, xylitol, and the like.
  • suspending agents include carboxymethylcellulose calcium, xantham gum, ceraonia, saponite, maltitol , hypromellose, colloidal silicon dioxide, and the like.
  • the formulations may be prepared by dry granulation and direct compression.
  • the formulations may be prepared by dry blending the rate-controlling polymer, filler, cinnoline derivative, and other excipients followed by granulating the mixture until proper granulation is obtained.
  • the granulation is done by methods known in the art.
  • the granules are sifted and ground to appropriate size.
  • Lubricating agents are mixed with the granulation, which may be further compressed to obtain the final formulation.
  • the compositions of the invention can be administered orally in the form of tablets, pills, capsules, or suspensions.
  • the tablets can be prepared by techniques known in the art and contain a therapeutically useful amount of cinnoline derivative and such excipients as are necessary to form the tablet by such techniques.
  • Tablets, pills and other dosage forms can additionally be prepared with enteric coatings or other release-controlling coatings for the purpose of further release controls.
  • the coating may be colored with a pharmaceutically accepted dye or pigment.
  • the amount of dye, pigments and other excipients in the coating liquid may vary.
  • the coating liquid generally comprises film-forming polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose ester or ether, an acrylic polymer or a mixture of polymers.
  • the coating solution is generally an aqueous solution further comprising propylene glycol, sorbitan monoleate, sorbic acid, opacifers such as titanium dioxide, a pharmaceutically acceptable dye.
  • the daily dose of the extended release composition of this invention administered to a host in single dose can be in the amounts from 1 mg to 100 mg once a day. In a particular embodiment, the daily dose of the extended release composition of this invention administered to a host in single dose can be in the amounts from 5 mg to 50 mg once a day.
  • the present invention provides an oral dosage form of the solid formulation of the invention.
  • the oral dosage form may be a tablet, caplet, capsule, or sachet.
  • the oral dosage form contains about 1 mg to about 50 mg of the cinnoline derivative.
  • the present invention provides a method of treating anxiety disorders comprising administering a therapeutically effective amount of the solid formulation described above to a patient in need thereof.
  • the present invention provides a method of treating anxiety disorders comprising administering the oral dosage described above once daily to a patient in need thereof.
  • the symptoms and conditions that may be treated using an effective amount of the solid formulation of the invention include depressive disorders (e.g., major depressive disorder), anxiety disorders (e.g., generalized anxiety disorder), sleep disorders, and substance-related disorders.
  • depressive disorders e.g., major depressive disorder
  • anxiety disorders e.g., generalized anxiety disorder
  • sleep disorders e.g., sleep disorders, and substance-related disorders.
  • the present invention further provides methods of treating at least one symptom or condition described herein by administering to a mammal a pharmaceutically effective amount of a solid formulation of the invention and a therapeutically effective amount of at least one other therapeutically active agent selected from benzodiazepines, 5-HT 1 A ligands, 5-HT 1B ligands, 5- HT 1 D ligands, mGluR2A agonists, mGluR5 antagonists, antipsychotics, NKl receptor antagonists, antidepressants, serotonin reuptake inhibitors, and mood stabilizers.
  • benzodiazepines 5-HT 1 A ligands, 5-HT 1B ligands, 5- HT 1 D ligands, mGluR2A agonists, mGluR5 antagonists, antipsychotics, NKl receptor antagonists, antidepressants, serotonin reuptake inhibitors, and mood stabilizers.
  • Administration of two or more active agents can be carried out in combination, e.g., as part of the same formulation, or separately (e.g., serially or consecutively) as part of an appropriate dose regimen designed to obtain the benefits of combination therapy.
  • the appropriate dose regimen, the amount of each dose of an active agent administered, and the specific intervals between doses of each active agent will depend upon the subject being treated, the specific active agent being administered and the nature and severity of the specific disorder or condition being treated.
  • the formulations provided herein can be administered to a mammal in an amount up to about 100 mg of the cinnoline derivative per day, particularly from about 1 mg to about 75 mg per day, in single or divided doses.
  • the formulations provided herein may be administered to a mammal in an amount from about 1 mg to about 50 mg per day. In a further aspect of the invention, the formulations provided herein may be administered in an amount from about 1 mg to about 30 mg per day.
  • the formulation may be administered on a regimen of up to 6 times per day, 1 to 4 times per day, or once per day. Variations can occur depending upon the mammal being treated and the individual response to the treatment, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases larger doses may be employed to achieve the desired effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • the formulation is administered comprising a predetermined dosage to a mammal between one and four times a day, wherein the predetermined dosage is from about 1 mg to about 25 mg.
  • any or all of the solid formulations described herein, including any combination thereof, can be used in the preparation of a medicament for the treatment of any of the diseases, disorders, or conditions described herein.
  • the bioavailability study for the formulations of the invention can be done by administering the ER formulation in a tablet form to healthy subjects and measuring the levels of cinnoline derivative in the plasma at different time intervals over a period of twenty four hours.
  • Plasma samples are assayed for cinnoline derivative at BAS Analytics (West Lafayette, Ind.) using a validated high-performance liquid chromatographic procedure similar to that described in the literature. See for example, Chu S-Y, et al., "Simultaneous determination of cinnoline derivative and 14(R)-hydroxycinnoline derivative in plasma and urine using high- performance liquid chromatography with electrochemical detection", J. Chromatog., 571, pp 199-208 (1991).
  • Adverse effects including those related to the digestive system, central nervous system, respiratory system and special senses are measured by dosing subjects with multiple doses of 2 to 50 mg of ER and IR tablets per day, respectively. The adverse effects are monitored, reported spontaneously by subjects and recorded on case report forms for the study database.
  • METHOCEL K 100 LV available from the Dow Chemical Company was loaded into a mixer, and dry blended with the fillers and the cinnoline derivative. The mixture is granulated until proper granulation is obtained. Magnesium stearate is screened and blended with dry granulation. The granulation is then loaded into hopper and compressed into tablets. Composition of the tablets is given in table 1.
  • Binder HPMC (Methocel KlOO Premium LV) 20.00%
  • Dissolution profiles of the formed tablets in SGF and SIF are shown in Figure 1.
  • the drug release profile (Figure 1) shows that >95% is released at 4 hrs in SGF and -73% in SIF. It was thought that using a 20% w/w HPMC 100 cP would give a longer than desired duration (100% released in ⁇ 3 hrs) but this data shows that is achievable using the minimum polymer level recommended (>20% w/w) to get gel robustness.
  • Binder HPMC Metalolose 90SH-100SR, Type 2208
  • Filler Mannitol Parteck M200
  • Binder HPMC Metalolose 90SH-100SR, Type 2208
  • Filler Mannitol Parteck M200
  • Binder HPMC Metalolose 90SH-100SR, Type 2208
  • Filler Mannitol Parteck M200
  • Binder HPMC Metalolose 90SH-100SR, Type 2208
  • Filler Mannitol Parteck M200
  • Binder HPMC Metalolose 90SH-100SR, Type 2208
  • Filler Mannitol Parteck M200
  • Binder HPMC Metalolose 90SH-100SR, Type 2208
  • Filler Mannitol Parteck M200
  • Binder HPMC Metalolose 90SH-100SR, Type 2208
  • Filler Mannitol Parteck M200
  • Binder HPMC Metalolose 90SH-100SR, Type 2208
  • Filler Mannitol Parteck M200
  • the dissolution profiles in SGF for formulations 2-9 are shown in FIG. 2 and the dissolution profiles in SIF for formulation 2-9 are shown in FIG. 3, respectively.
  • the dissolution data indicates, in general, that a decrease in API load and polymer load increases the dissolution rate.
  • HPMC with low HP content provides faster release.
  • Example 10 Using the same procedure as Example 1, formulations 10-11, which contain HPMC having a higher viscosity grade (e.g. 4000 cP), are prepared. The compositions of these two formulations are summarized in Tables 10 and 11. Table 10 (Formulation 10)
  • Binder HPMC (Metolose 90SH-100SR) 15.00%
  • Binder HPMC (Metolose 90SH-4000SR) 5.00%
  • Binder HPMC (Metolose 90SH-100SR) 15.00%
  • Binder HPMC (Metolose 90SH-4000SR) 8.00%
  • the erosion profiles of formulations 10 and 11 are summarized in FIG. 4.
  • the Dissolution profiles in SGF and SIF for formulations 10 and 11 are summarized in FIG. 5.
  • the Formulation 10 shows a fast drug release (-80% at 60 min in SGF).
  • the Formulation 11 batch gives a slower release (-80% at 240 min in SGF).
  • formulation 12 which contains Hydroxypropylcellulose (HPC) as the controlled release polymer, is prepared.
  • HPC Hydroxypropylcellulose
  • Tablet wt. 200 mg (8 mm SRC)
  • the erosion and dissolution profiles of formulation 12 shown in FIG. 6 show that using a
  • formulations 13-16 which contains higher molecular weight (Mw) HPC such as Klucel® LXF (Hercules, Wilmington, DE, Mw -95,000) or Klucel®GXF ( Hercules, Wilmington, DE, Mw -370,000) as the controlled release polymer, are prepared.
  • Mw molecular weight
  • Klucel® LXF Hercules, Wilmington, DE, Mw -95,000
  • Klucel®GXF Hercules, Wilmington, DE, Mw -370,000
  • formulations 17-18 which contains both LXF HPC and GXF HPC at different ratios as the controlled release polymer, are prepared.
  • the compositions of these two formulations are summarized in Tables 17-18.
  • the release profiles of these formulations are studied using active tablet erosion. Table 17 (Formulation 17)
  • Binder HPC (Klucel EXF Pharm) 8.00%
  • Binder HPC (Klucel EXF Pharm) 15.00% Filler Mannitol (Parteck M200) 28.59%
  • the dissolution profiles for the 30% GXF and the 22:8 GXF:EXF in both SGF (FIG 8.) and SIF (FIG. 9) appear to be zero order.
  • the 15:15 GXF:EXF release profile is too fast (>80% released at 3 hrs).
  • HPC is more robust (similar release up to a 180 min at both rpm). Taking into consideration the process (dry granulation), HPC is more appropriate as it will provide binding properties as well as the particle size is more suitable for dry granulation. Therefore, HPC is chosen as the polymer for further formulation optimization/process definition.
  • Solid cinnoline derivative, povidone, dibasic calcium phosphate, and a portion of the microcrystalline cellulose and sodium starch glycolate are mixed with water in a granulator to form granules.
  • the granules are dried in a dryer and then sized used using a mill fitted with the appropriate screen.
  • the remainder of the microcrystalline cellulose and sodium starch glycolate along with lactose is added and blended.
  • the magnesium stearate is added and blended further.
  • This mixture is compressed into tablets using a tablet compression machine or filled into capsules using an encapsulation device or filled into sachets.
  • Example wet granulation formulations are provided in the tables below. Table A
  • Cinnoline derivative and copovidone are blended. To this mixture, the dibasic calcium phosphate, microcrystalline cellulose, lactose, and sodium starch glycolate are added and blended further. The magnesium stearate is then added and blended further. This mixture is compressed into tablets using a tablet compression machine or filled into capsules using an encapsulation device or filled into sachets. Table I
  • Cinnoline derivative and crospovidone are blended. To this mixture, the silicified microcrystalline cellulose is added and blended further. Next, the sodium stearyl fumarate is added and blended. This mixture is compressed into tablets using a tablet compression machine or filled into capsules using an encapsulation device or filled into sachets. Table J
  • Cinnoline derivative is blended with crospovidone. A portion of the microcrystalline cellulose, lactose, and magnesium stearate is added and blended further. The blend is compacted using a roller compactor and milled. The remainder of the microcrystalline cellulose and lactose are added and blended. Magnesium stearate is added and blended. This mixture is compressed into tablets using a tablet compression machine or filled into capsules using an encapsulation device or filled into sachets.
  • An example roller compression formulation is provided in Table K.
  • Example 11 Powder Formulation for Suspension (IR formulation)
  • the cinnoline derivative can be formulated as a powder dosage form that can be converted to a suspension just prior to use or alternatively added to food.
  • An example formulation is provided below in Table L.
  • the formulation is considered to be a free flowing powder with a light bulk density, This formulation can be prepared by using a combination of appropriate excipients such as a binder, a filler, a sweetener, and a suspending agent.
  • Table M below provides an example sustained release formulation. This formula can be made by formulating the above dosage form and then applying a sustained release barrier or a film coat. Alternatively, the formulation can be prepared by first applying a sustained release coating on the drug substance.
  • Sugar spheres are loaded into a fluidized bed dryer and a solution containing hypromellose is sprayed on the beads.
  • a solution containing the cinnoline deriviative and povidone is sprayed on the beads in the fluidized bed dryer.
  • the solution is sprayed until the proper amount of the cinnoline derivative is applied to the beads.
  • the beads are sprayed with an aqueous ethylcellulose dispersion (SURELEASE® by Colorcon) until an acceptable amount coats the beads.
  • the beads are filled into capsules.
  • Table M Composition of cinnoline derviative coated on to beads and filled in capsules
  • Example 14 Beads in tablets
  • Microcrystalline cellulose spheres are loaded into a fluidized bed dryer and a solution containing hypromellose is sprayed on the beads.
  • a solution containing the cinnoline deriviative and povidone is sprayed on the beads in the fluidized bed dryer.
  • the solution is sprayed until the proper amount of the cinnoline derivative is applied to the beads.
  • the beads are sprayed with an aqueous ethylcellulose dispersion (SURELEASE® by Colorcon) until an acceptable amount coats the beads.
  • the beads are coated with a solution containing hypromellose.
  • the beads are blended with microcrystalline cellulose and blended further with magnesium stearate.
  • the resultant mixture is compressed into tablets. After compression, the tablets are coated with a suspension containing hypromellose, polyethylene glycol 400, titanium dioxide, and ferric oxide, red.
  • the composition is given in Table N below. Table N Composition of cinnoline derviative coated on to beads and compressed into tablets

Abstract

L'invention porte sur une composition pharmaceutique pour une libération prolongée d'un dérivé de cinnoline dans l'environnement gastro-intestinal. La composition comprend un dérivé de cinnoline et un polymère pharmaceutiquement acceptable de telle sorte que, lorsqu'elle est ingérée par voie orale, la composition induit une Cmax dans le plasma statistiquement inférieure à une composition à libération immédiate du dérivé de cinnoline tout en maintenant la biodisponibilité et une concentration minimale sensiblement équivalente à celle de la composition à libération immédiate du dérivé de cinnoline lors de l'administration de doses multiples. Les compositions de l'invention ont des effets secondaires réduits par comparaison à ceux pour la composition à libération immédiate.
PCT/SE2010/050423 2009-04-21 2010-04-20 Composition pharmaceutique comprenant de l'hydrogénosulfate de 4-amino-8-(2-fluoro-6-méthoxy-phényl)-n-propylcinnoline-3-carboxamide et polymère de régulation de la vitesse WO2010123440A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0205272A2 (fr) * 1985-05-30 1986-12-17 Ici Americas Inc. Dérivés de cinnoline
EP0328282A2 (fr) * 1988-02-09 1989-08-16 Ici Americas Inc. Produit pharmaceutique
US20070142382A1 (en) * 2005-12-20 2007-06-21 Astrazeneca Ab Compounds and Uses Thereof
WO2007073283A1 (fr) * 2005-12-20 2007-06-28 Astrazeneca Ab Derives substitues de la cinnoline en tant que modulateurs du recepteur du gabaa et leur procede de synthese

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0205272A2 (fr) * 1985-05-30 1986-12-17 Ici Americas Inc. Dérivés de cinnoline
EP0328282A2 (fr) * 1988-02-09 1989-08-16 Ici Americas Inc. Produit pharmaceutique
US20070142382A1 (en) * 2005-12-20 2007-06-21 Astrazeneca Ab Compounds and Uses Thereof
WO2007073283A1 (fr) * 2005-12-20 2007-06-28 Astrazeneca Ab Derives substitues de la cinnoline en tant que modulateurs du recepteur du gabaa et leur procede de synthese

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Excipients, 3th.ed.", article "Hydroxypropyl Cellulose", pages: 244, XP003027025 *

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