WO2010123443A1 - Composition pharmaceutique comprenant de l'hydrogénosulfate de 4-amino-8-(2-fluoro-6-méthoxy-phényl)-n-propylcinnoline-3-carboxamide - Google Patents

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

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WO2010123443A1
WO2010123443A1 PCT/SE2010/050427 SE2010050427W WO2010123443A1 WO 2010123443 A1 WO2010123443 A1 WO 2010123443A1 SE 2010050427 W SE2010050427 W SE 2010050427W WO 2010123443 A1 WO2010123443 A1 WO 2010123443A1
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weight
cinnoline derivative
derivative
cinnoline
solid formulation
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PCT/SE2010/050427
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English (en)
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Dmytro Avilov
Daniel Brown
Richard Creekmore
Marilu Reus Medina
Sharon Schultz
Avadhesh Sharma
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Astrazeneca Ab
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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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.
  • 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").
  • 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. However, there is still a need to develop an oral formulation containing said cinnoline derivative that is effective in treating anxiety.
  • FIG. 1 shows the dissolution profiles of certain tablets of the invention
  • Cinoline derivative as used herein, means 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-
  • N-propylcinnoline-3-carboxamide or pharmaceutically acceptable salts thereof are N-propylcinnoline-3-carboxamide or pharmaceutically acceptable salts thereof.
  • 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.
  • 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.
  • mammal is meant to refer to any warm-blooded animal, preferably a human. In some embodiments, 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 at least one ingredient selected from a filler, a binder, a disintegrant, 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, a disintegrant, and a lubricant.
  • the cinnoline derivative is 4-amino-8-(2-fluoro-6-methoxy-phenyl)-N- propylcinnoline-3-carboxamide hydrogen sulphate.
  • 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.
  • 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. Examples of non-cellulosic binders include povidone, lactose, starches, modified starches, gums, guar gum, pectin, waxes, gelatins, alginates, and the like.
  • Suitable disintegrants include, for example, croscarmellose sodium, crospovidone, sodium starch glycolate, com starch, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, 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, 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.
  • Preferred as a sugar sweetener is high fructose corn syrup and mixtures thereof.
  • 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.
  • 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
  • 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.
  • 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.
  • silicified 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 contain a disintegrant such as sodium starch glycolate or crospovidone.
  • the disintegrant is present in an amount of about 1 to about 15, about 1 to about 12, or about 1 to about 10 % by weight of a disintegrant.
  • the formulations contain about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 % by weight of disintegrant.
  • the formulations of the invention contain a lubricant such as magnesium stearate or sodium stearyl fumarate.
  • 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; about 1 to about 15 % by weight of a disintegrant; 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 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 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.
  • 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 hydroxy-propyl 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 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 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 1A ligands, 5-HT 1B ligands, 5- HT 1D ligands, mGluR2A agonists, mGluR5 antagonists, antipsychotics, NKl receptor antagonists, antidepressants, serotonin reuptake inhibitors, and mood stabilizers.
  • benzodiazepines 5-HT 1A ligands, 5-HT 1B ligands, 5- HT 1D 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.
  • 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 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).
  • Cinnoline derivative Hydrogen Sulfate 1 1. 28 Microcrystalline Cellulose NF (Avicel PH-101) 42 .22 Mannitol (Parteck M200) 50 .00 Crospovidone USP (Polyplasdone XL-10) 5. 00 Magnesium Stearate, non-bovine NF 1 .5
  • Cinnoline derivative freebase is equivalent to 1.28 mg of Cinnoline derivative hydrogen sulfate. 2.5 mg tablets
  • Cinnoline derivative Hydrogen Sulfate 1 3. 21 Microcrystalline Cellulose NF (Avicel PH-101) 41 .50 Mannitol (Parteck M200) 48 .79 Crospovidone USP (Polyplasdone XL-10) 5. 00 Magnesium Stearate, non-bovine NF 1 .5
  • Cinnoline derivative freebase is equivalent to 3.21 mg of Cinnoline derivative hydrogen sulfate.
  • Cinnoline derivative Hydrogen Sulfate 1 4.
  • Microcrystalline Cellulose NF (Avicel PH-101) 39 .09 Mannitol (Parteck M200) 48 .00 Crospovidone USP (Polyplasdone XL-10) 5.
  • Microcrystalline Cellulose NF (Avicel PH-101) 36.72 Mannitol (Parteck M200) 43.96
  • Crospovidone USP Polyplasdone XL- 10) 5.00
  • the cinnoline derivative tablet formulations described above may be manufactured by using the following process to provide acceptable content uniformity (CU): use of a carrier for the cinnoline derivative (polyplasdone XL-10), geometric mixing as well as blend-mill-blend processes, and roller compaction ("RC").
  • CU acceptable content uniformity
  • a carrier for the cinnoline derivative polyplasdone XL-10
  • geometric mixing as well as blend-mill-blend processes
  • RC roller compaction
  • the use of RC not only improves the flow properties of the blend but also achieve a smaller %RSD in the CU values.
  • the tablets are round biconvex, 6 mm diameter with a target compression weight of 100 mg. The dissolution profiles of these tablets are shown in FIG. 1.
  • 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
  • Example 3 Direct Compression Formulations An example of direct compression formulation is provided in Table I.
  • 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
  • a further example compression formulation is provided in Table J. 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 5 Powder Formulation for Suspension
  • 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.

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Abstract

L'invention porte sur une composition pharmaceutique pour un dérivé de cinnoline dans l'environnement gastro-intestinal. La composition comprend un dérivé de cinnoline solide et au moins un excipient pharmaceutique choisi parmi une charge, un liant, un désintégrant, un agent de mise en suspension, un agent d'enrobage, un agent édulcorant, un agent aromatisant et un lubrifiant.
PCT/SE2010/050427 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 WO2010123443A1 (fr)

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US17111809P 2009-04-21 2009-04-21
US61/171,118 2009-04-21

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WO2010123443A1 true WO2010123443A1 (fr) 2010-10-28

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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

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