WO2006110815A1 - Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs - Google Patents

Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs Download PDF

Info

Publication number
WO2006110815A1
WO2006110815A1 PCT/US2006/013651 US2006013651W WO2006110815A1 WO 2006110815 A1 WO2006110815 A1 WO 2006110815A1 US 2006013651 W US2006013651 W US 2006013651W WO 2006110815 A1 WO2006110815 A1 WO 2006110815A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
modifier
dissolution
salt
ionizable
Prior art date
Application number
PCT/US2006/013651
Other languages
French (fr)
Inventor
Huailiang Wu
Geoff Zhang
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MEP-2012-250A priority Critical patent/ME02003B/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to DK06740898.9T priority patent/DK1868581T3/en
Priority to ES06740898T priority patent/ES2384333T3/en
Priority to PL06740898T priority patent/PL1868581T3/en
Priority to JP2008506637A priority patent/JP5284777B2/en
Priority to MX2007012642A priority patent/MX2007012642A/en
Priority to SI200631326T priority patent/SI1868581T1/en
Priority to RS20120250A priority patent/RS52354B/en
Priority to CA2603783A priority patent/CA2603783C/en
Priority to EP06740898A priority patent/EP1868581B1/en
Priority to AT06740898T priority patent/ATE549016T1/en
Publication of WO2006110815A1 publication Critical patent/WO2006110815A1/en
Priority to HRP20120502TT priority patent/HRP20120502T1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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

Definitions

  • This invention pertains to pharmaceutical compositions having improved dissolution profiles for drugs therein.
  • FIG. 1 shows dissolution profiles of formulations containing various amounts of crystallization inhibitor for EXAMPLE 1.
  • FIG. 2 shows dissolution profiles of formulations containing a pH modifier and a crystallization inhibitor for EXAMPLE 1.
  • FIG. 3 shows dissolution profiles of formulations containing a pH modifier and a crystallization inhibitor for 5,5-diphenylhydantoin, sodium salt.
  • FIG. 4 shows dissolution profiles of formulations containing a pH modifier and a crystallization inhibitor for potassium mefenamate.
  • one embodiment of this invention comprises compositions comprising an ionizable drug or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drug.
  • compositions comprising an ionizable drug or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a reduced variability in dissolution.
  • compositions comprising a salt of an ionizable drug, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drug.
  • Still another embodiment comprises compositions comprising l-(6-amino-3,5- difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-l-yl)-4-oxo-l,4- dihydroquinoline-3-carboxylic acid or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drag.
  • Still another embodiment comprises compositions comprising the megluamine salt of 1 -(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidm- 1 -yl)-4- oxo-l,4-dihydroquinoline-3-carboxylic acid, a crystallization inhibitor and apH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drag.
  • Another embodiment comprises a method for treating disease in a patient comprising administering thereto a composition comprising an ionizable drag or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drag.
  • Another embodiment comprises a method for treating disease in a patient comprising administering thereto a composition comprising an ionizable drag or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a reduced variability in dissolution.
  • Another embodiment comprises a method for treating disease in a patient comprising administering thereto a composition comprising an ionizable drag, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drug.
  • Another embodiment comprises a method for treating disease in a patient comprising administering thereto a composition comprising l-(6-amino-3,5- difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-l-yl)-4-oxo-l,4- dihydroquinoline-3-carboxylic acid or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drag.
  • Another embodiment comprises a method for treating disease in a patient comprising administering thereto a composition comprising the megluamine salt of l-(6- amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-l-yl)-4-oxo-l,4- dihydroquinoline-3-carboxylic acid, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drug.
  • crystallization inhibitor means an agent that facilitates prevention of precipitation of a drug in a composition comprising the agent, a pH modifier and the drug.
  • crystallization inhibitors include, but are not limited to hydroxypropylmethylcelluose, polyvinypyrrolidone, hydroxypropylcelluose and the like.
  • ionizable drug means a compound having an acidic or basic moiety that is useful for treating a disease state or an adverse physiological event.
  • measurable improvement in dissolution rate means at least a 5% increase in dissolution rate at a particular temperature and pH.
  • pH modifier means a compound that is capable of changing the pH of a solution.
  • pH modifiers include, but are not limited to NaOH, LiOH, KOH, Na 2 CO 3 , NaHCO 3 , K 2 CO 3 , KHCO 3 , NaH 2 PO 4 , Na 2 HPO 4 , Na 3 PO 4 , KH 2 PO 4 , K 2 HPO 4 , K 3 PO 4 , megluamine, Ca(OH) 2 , Mg(OH) 2 , Zn(OH) 2 , Al(OH) 3 , pyridoxine, triethanolamine, ammonium hydroxide, cytosine, diethylamine, meglumine, ornithine, glycine, lysine, arginine, valine, proline, aspartic acid, alanine, asparagine, isoleucine, leucine, methionine, threonine, choline hydroxide, procaine, dieth
  • compositions means a combination of substances, at least one of which is a drug, or a therapeutically acceptable salt thereof.
  • q.s. means as much as suffices.
  • Compounds having formula (T) may exist as acid addition salts, basic addition salts or zwitterions. Salts of compounds having formula (I) are prepared during their isolation or following their purification. Acid addition salts are those derived from the reaction of a compound having formula (I) with acid.
  • salts including the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, megluamine, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, para- toluenesulfonate and undecano
  • Compounds having formula (I) may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperintoneally intrasternally, intravenously, subcutaneously), rectally, topically, transdermally, vaginally and intraarterially as well as by intraarticular injection, infusion, and placement in the body, such as, for example, the vasculature.
  • Therapeutically effective amounts of the drugs of this invention depend on recipient of treatment, disease treated and severity thereof, composition comprising it, time of administration, route of administration, duration of treatment, potency, rate of clearance and whether or not another drug is co-administered.
  • the amount of a compound having formula (I) used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight. Single dose compositions contain these amounts or a combination of submultiples thereof.
  • Compounds having formula (I) may be administered with or without an excipient.
  • Excipients include, but are not limited to, encapsulators and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, mixtures thereof and the like.
  • encapsulators and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising a compound having formula (I) to be administered orally include, but are not limited to, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crosspovidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil
  • Excipients for preparation of compositions comprising a compound having formula (I) to be administered ophthalmically or orally include, but are not limited to, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising a compound having formula (I) to be administered osmotically include, but are not limited to, chlorofluorohydrocarbons, ethanol, water, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising a compound having formula (I) to be administered parenterally include, but are not limited to, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising a compound having formula (I) to be administered rectally or vaginally include, but are not limited to, cocoa butter, polyethylene glycol, wax, mixtures thereof and the like.
  • PVP Polyvinylpyrrolidine
  • HPMC hydroxypropylmethylcelluose
  • Mixtures of EXAMPLE 1 and Na 2 CO 3 were dry mixed in a granulator for 5 minutes, treated with PVP or HPMC solution over 1 minute with water addition to assure optimal granulation, dried at 5O 0 C until the loss on drying (LOD) was less than 1% (typicallyl ⁇ hours) and passed through a 20 mesh screen.
  • the screened powder was blended with the extragranular for 3 minutes.
  • the tablets were compressed to a hardness of 18-20 SCU using a Carver presser with tooling #A2201 Record compression forces or manually filled into appropriate size capsules to provide a fill of 500 mg/unit.
  • 0.1 N HCl (pH 1.0) or 0.1 N HCl (900 mL) with various concentrations of HPMC (0.001%-l%) at 37 0 C ⁇ 0.5 0 C were used with a USP Dissolution Apparatus 2 at a speed of 50 or 100 ⁇ 4% rpm.
  • One test tablet or capsule was added to the medium, and 10 mL of samples were removed at 15, 30, 45, 60, 120 and 240 minutes and assayed by UV absorption at 282 run.
  • one test tablet or capsule was added to 0.1 N HCl (500 mL) at 37 0 C ⁇ 0.5 0 C.
  • Dissolution samples were removed at 15, 30, 45, 60, 120 and 240 minutes and assayed by UV absorption at 282 nm, and the dissolution medium was treated with 0.118M sodium phosphate buffer (pre- warmed to 37 0 C ⁇ 0.5 0 C).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Physiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Pharmaceutical compositions having improved dissolution profiles for drugs therein is disclosed.

Description

PHARMACEUTICAL COMPOSITIONS HAVING IMPROVED DISSOLUTION PROFILES FOR POORLY SOLUBLE DRUGS
FIELD OF THE INVENTION
This invention pertains to pharmaceutical compositions having improved dissolution profiles for drugs therein.
BACKGROUND OF THE INVENTION
Absorption of poorly soluble drugs is a major obstacle in pharmaceutical development. For ionizable compounds, salt formation is often used to improve solubility. This approach, however, may not work for compounds that precipitatate at lower pH, such as gastric pH. There is therefore an existing need in the pharmaceutical development arts for compositions which provide improved dissolution profiles of drugs.
BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows dissolution profiles of formulations containing various amounts of crystallization inhibitor for EXAMPLE 1.
FIG. 2 shows dissolution profiles of formulations containing a pH modifier and a crystallization inhibitor for EXAMPLE 1.
FIG. 3 shows dissolution profiles of formulations containing a pH modifier and a crystallization inhibitor for 5,5-diphenylhydantoin, sodium salt.
FIG. 4 shows dissolution profiles of formulations containing a pH modifier and a crystallization inhibitor for potassium mefenamate.
SUMMARY OF THE INVENTION Accordingly, one embodiment of this invention comprises compositions comprising an ionizable drug or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drug.
Another embodiment of this invention comprises compositions comprising an ionizable drug or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a reduced variability in dissolution. Another embodiment comprises compositions comprising a salt of an ionizable drug, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drug.
Still another embodiment comprises compositions comprising l-(6-amino-3,5- difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-l-yl)-4-oxo-l,4- dihydroquinoline-3-carboxylic acid or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drag.
Still another embodiment comprises compositions comprising the megluamine salt of 1 -(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidm- 1 -yl)-4- oxo-l,4-dihydroquinoline-3-carboxylic acid, a crystallization inhibitor and apH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drag.
Another embodiment comprises a method for treating disease in a patient comprising administering thereto a composition comprising an ionizable drag or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drag.
Another embodiment comprises a method for treating disease in a patient comprising administering thereto a composition comprising an ionizable drag or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a reduced variability in dissolution.
Another embodiment comprises a method for treating disease in a patient comprising administering thereto a composition comprising an ionizable drag, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drug.
Another embodiment comprises a method for treating disease in a patient comprising administering thereto a composition comprising l-(6-amino-3,5- difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-l-yl)-4-oxo-l,4- dihydroquinoline-3-carboxylic acid or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drag.
Another embodiment comprises a method for treating disease in a patient comprising administering thereto a composition comprising the megluamine salt of l-(6- amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-l-yl)-4-oxo-l,4- dihydroquinoline-3-carboxylic acid, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drug. DETAILED DESCRIPTION OF THE INVENTION
The term "crystallization inhibitor," as used herein, means an agent that facilitates prevention of precipitation of a drug in a composition comprising the agent, a pH modifier and the drug. Examples of crystallization inhibitors include, but are not limited to hydroxypropylmethylcelluose, polyvinypyrrolidone, hydroxypropylcelluose and the like.
The term "ionizable drug," as used herein, means a compound having an acidic or basic moiety that is useful for treating a disease state or an adverse physiological event.
The term "measurable improvement in dissolution rate," as used herein, means at least a 5% increase in dissolution rate at a particular temperature and pH.
The term "pH modifier," as used herein, means a compound that is capable of changing the pH of a solution. Examples of pH modifiers include, but are not limited to NaOH, LiOH, KOH, Na2CO3, NaHCO3, K2CO3, KHCO3, NaH2PO4, Na2HPO4, Na3PO4, KH2PO4, K2HPO4, K3PO4, megluamine, Ca(OH)2, Mg(OH)2, Zn(OH)2, Al(OH)3, pyridoxine, triethanolamine, ammonium hydroxide, cytosine, diethylamine, meglumine, ornithine, glycine, lysine, arginine, valine, proline, aspartic acid, alanine, asparagine, isoleucine, leucine, methionine, threonine, choline hydroxide, procaine, diethylethanolamine, glucosamine, guanine, nicotinamide, piperazine, guanidine, olamine, piperidine, triethylamine, tromethamine, benzathine, benzathine, adenine, mixtures thereof and the like.
The term "pharmaceutical compositions," as used herein, means a combination of substances, at least one of which is a drug, or a therapeutically acceptable salt thereof. The term "q.s.," as used herein, means as much as suffices. Compounds having formula (T) may exist as acid addition salts, basic addition salts or zwitterions. Salts of compounds having formula (I) are prepared during their isolation or following their purification. Acid addition salts are those derived from the reaction of a compound having formula (I) with acid. Accordingly, salts including the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, megluamine, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, para- toluenesulfonate and undecanoate salts of the compounds having formula (T) are meant to be embraced by this invention. Basic addition salts of compounds are those derived from the reaction of the compounds having formula (I) with the bicarbonate, carbonate, hydroxide or phosphate of cations such as lithium, sodium, potassium, calcium and magnesium.
Compounds having formula (I) may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperintoneally intrasternally, intravenously, subcutaneously), rectally, topically, transdermally, vaginally and intraarterially as well as by intraarticular injection, infusion, and placement in the body, such as, for example, the vasculature.
Therapeutically effective amounts of the drugs of this invention depend on recipient of treatment, disease treated and severity thereof, composition comprising it, time of administration, route of administration, duration of treatment, potency, rate of clearance and whether or not another drug is co-administered. The amount of a compound having formula (I) used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight. Single dose compositions contain these amounts or a combination of submultiples thereof. Compounds having formula (I) may be administered with or without an excipient.
Excipients include, but are not limited to, encapsulators and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, mixtures thereof and the like.
Excipients for preparation of compositions comprising a compound having formula (I) to be administered orally include, but are not limited to, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crosspovidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (I) to be administered ophthalmically or orally include, but are not limited to, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (I) to be administered osmotically include, but are not limited to, chlorofluorohydrocarbons, ethanol, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (I) to be administered parenterally include, but are not limited to, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (I) to be administered rectally or vaginally include, but are not limited to, cocoa butter, polyethylene glycol, wax, mixtures thereof and the like.
EXAMPLE 1 l-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-l-yl)-4-oxo-
1 ,4-dihydroquinoline-3-carboxylic acid This compound was prepared as described in US 6,133,284, the specification of which is hereby incorporated by reference into this specification.
EXAMPLE 2 l-deoxy-l-(methylammonium)-D-glucitol l-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro- 6-fluoro-7-(3-hydroxyazetidin-l-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylate
A mixture of EXAMPLE 1 (29.6Kg) and l-deoxy-l-(methylamino)-D-glucitol (18.4Kg) was diluted with water (133Kg), stirred at 600C until all solids dissolved, cooled to 380C and held there until solid formed, cooled to O0C and filtered. The filtrant was washed with isopropanol and dried at 5O0C. Ingredients were weighed out according to the formulas described in the tables of components and compositions of control tablet or capsule formulations shown in TABLE 1 TABLE 2 and TABLE 3. Polyvinylpyrrolidine (PVP) or hydroxypropylmethylcelluose (HPMC) in 15.5 rnL (25% of total batch size: 50 g) of water. Mixtures of EXAMPLE 1 and Na2CO3 were dry mixed in a granulator for 5 minutes, treated with PVP or HPMC solution over 1 minute with water addition to assure optimal granulation, dried at 5O0C until the loss on drying (LOD) was less than 1% (typicallylδ hours) and passed through a 20 mesh screen. The screened powder was blended with the extragranular for 3 minutes. The tablets were compressed to a hardness of 18-20 SCU using a Carver presser with tooling #A2201 Record compression forces or manually filled into appropriate size capsules to provide a fill of 500 mg/unit.
For the single pH dissolution medium experiment, 0.1 N HCl (pH 1.0) or 0.1 N HCl (900 mL) with various concentrations of HPMC (0.001%-l%) at 370C ± 0.50C were used with a USP Dissolution Apparatus 2 at a speed of 50 or 100 ± 4% rpm. One test tablet or capsule was added to the medium, and 10 mL of samples were removed at 15, 30, 45, 60, 120 and 240 minutes and assayed by UV absorption at 282 run.
For the dual pH dissolution medium experiment, one test tablet or capsule was added to 0.1 N HCl (500 mL) at 370C ± 0.50C. Dissolution samples were removed at 15, 30, 45, 60, 120 and 240 minutes and assayed by UV absorption at 282 nm, and the dissolution medium was treated with 0.118M sodium phosphate buffer (pre- warmed to 370C ± 0.50C).
TABLE l
Figure imgf000007_0001
TABLE 2
Figure imgf000008_0001
TABLE 3
Figure imgf000008_0002
*megluamine
Little or no drug was released in the low pH (1.2) medium within one hour for all tested formulations. Following adjustment to pH 7.5 for 2 hours, release of the drug from the control tablets were about 20% and almost the same as that from the formulation containing 0.1% polyvinyl pyrrolidinone (PVP K30). Dissolution of the drug was improved with an increase in amount of PVP K30. High dissolution extent (>80%) was obtained for formulations containing 1-3% PVP K30. Inclusion of hydroxypropylmethylcelluose (HPMC E5) showed a similar impact on drug dissolution.
For the tablets made by adding PVP solution as granulation liquid with no Na2COs, dissolution increases with moderate variability in spite of the release pH 1.0 medium being low. Average percentage released increases to 85% in higher pH medium at the 2 hour time point. Direct compression of drug with a higher percentage of HPMC (E5 LV) resulted in a reduction in dissolution variability although a large amount of HPMC would be expected to slow dissolution rate. These results are summarized in Figure 1.
Dissolution of tablets granulated with PVP solution and Na2COs is rapid in the dual pH media. More interestingly, in pH 1.0 medium, there was about 12% of drug released at the 1 hour time point with an EXAMPLE 1 concentration about 20-fold greater than its intrinsic solubility. The pH of the solution at this time point was 1.0. The differences in dissolution rate/extant and variability among the formulations tested are summarized in TABLE 3 with data from the last pull point at pH 7.5 used as the example. These results are summarized in Figure 2.
TABLE 4
Figure imgf000009_0001
^relative standard deviation
These data show the increased dissolution of a drug in the presence of a pH modifier and polymer. As seen in Figure 2, there is little drug released into the low pH medium even after increasing the duration of the capsules in pH 1.0. However, duration time in low pH media does effect the dissolution profile of EXAMPLE 1 in the dual pH media after the pH has been adjusted to 7.5. In general, the shorter exposure time in low pH resulted in a higher extent dissolution.
Similar experiments were conducted with 5,5-diphenylhydantoin, sodium salt (NaPh). The solubility of 5,5-diphenylhydantoin at varying pH's is reported in J. Pharm. Sci. Vol. 82(3), March 1993. The dissolution study for the purpose of this invention was conducted in pH 7 buffer (900 mL) at 370C ± 0.50C with a paddle rotation speed of 50 rpm. Samples were removed at pre-determined time points and analyzed for concentration or drug. Formulations of NaPh are shown in TABLE 3.
TABLE 5
Formulation: F G H
Figure imgf000010_0001
The results of the study, shown in Figure 3, illustrate the higher extent of dissolution. These data stand in contrast to the observation that 5,5-diphenylhydantoin, sodium salt forms an insoluble plug during dissolution at lower pH.
Figure imgf000010_0002
Similar experiments were conducted with potassium mefenamate (MEF-K). The intrinsic solubility (aqueous medium/lower pH) of mefanamic acid is 0.0423 μg/mL. The dissolution study for the purpose of this invention was conducted in pH 6.8 buffer (900 mL) at 370C ± 0.50C with a paddle rotation speed of 50 rpm. Samples were removed at pre-determined time points and analyzed for concentration or drug. The results of this experiment are shown in Figure 4 and illustrate the improved dissolution of the formulation comprising potassium mefenamate. In this case, the concentration in the dissolution medium exceeded the solubility of the drug.
The foregoing is merely illustrative of the invention and is not intended to limit the same to the disclosed compounds and processes. Variations and changes which are obvious to one skilled in the art, as defined in the claims, are intended to be within the scope and nature of the invention.

Claims

WE CLAM:
1. A composition comprising an ionizable drug or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drug.
2. A composition comprising an ionizable drug or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a reduced variability in dissolution.
3. A composition comprising a salt of an ionizable drug, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drug.
4. A composition comprising l-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro- 6-fiuoro-7-(3-hydroxyazetidin-l-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drug.
5. A composition comprising the megluamine salt of 1 -(6-amino-3,5- difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-l-yl)-4-oxo-l,4- dihydroquinoline-3-carboxylic acid, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drug.
6. A method for treating disease in a patient comprising administering thereto a composition comprising an ionizable drug or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drug.
7. A method for treating disease in a patient comprising administering thereto a composition comprising an ionizable drug or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a reduced variability in dissolution.
8. A method for treating disease in a patient comprising administering thereto a composition comprising an ionizable drug, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drag.
9. A method for treating disease in a patient comprising administering thereto a composition comprising l-(6-ammo-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3- hydroxyazetidin-l-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid or a salt thereof, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drag.
10. A method for treating disease in a patient comprising administering thereto a composition comprising the megluamine salt of l-(6-amino-3,5-difluoropyridin-2-yl)-8- chloro-6-fluoro-7-(3-hydroxyazetidin-l-yl)-4-oxo-l,4-dihydroquinolme-3-carboxylic acid, a crystallization inhibitor and a pH modifier, said composition providing a measurable improvement in dissolution rate of the ionizable drag.
PCT/US2006/013651 2005-04-11 2006-04-11 Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs WO2006110815A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
MX2007012642A MX2007012642A (en) 2005-04-11 2006-04-11 Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs.
DK06740898.9T DK1868581T3 (en) 2005-04-11 2006-04-11 Pharmaceutical compositions with improved dissolution profiles for poorly soluble drugs
ES06740898T ES2384333T3 (en) 2005-04-11 2006-04-11 Pharmaceutical compositions that have improved dissolution profiles for poorly soluble drugs
PL06740898T PL1868581T3 (en) 2005-04-11 2006-04-11 Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs
JP2008506637A JP5284777B2 (en) 2005-04-11 2006-04-11 Pharmaceutical composition with improved dissolution profile of poorly soluble drugs
MEP-2012-250A ME02003B (en) 2005-04-11 2006-04-11 Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs
SI200631326T SI1868581T1 (en) 2005-04-11 2006-04-11 Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs
EP06740898A EP1868581B1 (en) 2005-04-11 2006-04-11 Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs
CA2603783A CA2603783C (en) 2005-04-11 2006-04-11 Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs
RS20120250A RS52354B (en) 2005-04-11 2006-04-11 Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs
AT06740898T ATE549016T1 (en) 2005-04-11 2006-04-11 PHARMACEUTICAL COMPOSITIONS WITH IMPROVED DISSOLUTION PROFILES FOR POORLY SOLUBLE ACTIVE INGREDIENTS
HRP20120502TT HRP20120502T1 (en) 2005-04-11 2012-06-14 Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US67020705P 2005-04-11 2005-04-11
US60/670,207 2005-04-11

Publications (1)

Publication Number Publication Date
WO2006110815A1 true WO2006110815A1 (en) 2006-10-19

Family

ID=36648686

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/013651 WO2006110815A1 (en) 2005-04-11 2006-04-11 Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs

Country Status (16)

Country Link
US (4) US20060228411A1 (en)
EP (2) EP1868581B1 (en)
JP (2) JP5284777B2 (en)
AT (1) ATE549016T1 (en)
CA (1) CA2603783C (en)
CY (1) CY1112980T1 (en)
DK (1) DK1868581T3 (en)
ES (1) ES2384333T3 (en)
HR (1) HRP20120502T1 (en)
ME (1) ME02003B (en)
MX (1) MX2007012642A (en)
PL (1) PL1868581T3 (en)
PT (1) PT1868581E (en)
RS (1) RS52354B (en)
SI (1) SI1868581T1 (en)
WO (1) WO2006110815A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010036329A2 (en) 2008-09-24 2010-04-01 Rib-X Pharmaceuticals, Inc. Process for making quinolone compounds
WO2010056872A2 (en) 2008-11-15 2010-05-20 Rib-X Pharmaceuticals, Inc. Antimicrobial compositions
CN104098548A (en) * 2013-04-11 2014-10-15 上海医药工业研究院 Delafloxacin purifying method
US10471046B2 (en) 2014-11-14 2019-11-12 Melinta Subsidary Corp. Method for treating, preventing, or reducing the risk of skin infection
EP3581180A1 (en) 2014-06-20 2019-12-18 Melinta Subsidiary Corp. Antimicrobial compositions with effervescent agents

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2009313867A1 (en) * 2008-11-14 2011-06-30 Patheon Inc. Solid composition for controlled release of ionizable active agents with poor aqueous solubility at low pH and methods of use thereof
EP2523657A1 (en) * 2010-01-12 2012-11-21 Portola Pharmaceuticals, Inc. Pharmaceutical composition and dosage forms of elinogrel and methods of use thereof
WO2012043696A1 (en) * 2010-09-30 2012-04-05 富山化学工業株式会社 Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide
TW201605447A (en) * 2014-06-20 2016-02-16 美林塔治療學有限公司 Methods for treating infections
EP3960204A4 (en) * 2019-04-26 2022-07-06 Neuboron Medtech Ltd. Bpa lyophilized preparation and preparation method therefor

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2213275A1 (en) * 1972-03-18 1973-09-27 Klinke Desitin Werk Sodium 5,5-diphenylhydantoin infusion concentrates - contg 2-amino-2-(hydroxymethyl) propane-1,3-diol as solvent aid
EP0257320A2 (en) * 1986-08-08 1988-03-02 Bayer Ag Parenteral solution
US4748174A (en) * 1986-01-03 1988-05-31 Therapicon S.R.L. Water soluble salts of an NSAID with meglumine/glucamine
EP0411619A1 (en) * 1989-08-02 1991-02-06 Warner-Lambert Company Formulations of phenytoin sodium for intravenous administration
EP0852140A1 (en) * 1995-08-11 1998-07-08 Nissan Chemical Industries, Limited Methods for making hardly soluble medicine amorphous
US6133284A (en) * 1995-09-22 2000-10-17 Wakunaga Pharmaceutical Co., Ltd. Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components
EP1219618A1 (en) * 1999-09-02 2002-07-03 Wakunaga Pharmaceutical Co., Ltd. Quinolinecarboxylic acid derivative or its salt
JP2003300882A (en) * 2002-04-11 2003-10-21 St Marianna Univ School Of Medicine Emulsion containing pyridonecarboxylic acid compound

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5221575B2 (en) * 1972-03-18 1977-06-11
FR2525108B1 (en) * 1982-04-19 1989-05-12 Elan Corp Ltd HIGH-SOLUBILITY MEDICINES AND PROCESS FOR OBTAINING THEM
DE3420743A1 (en) * 1984-06-04 1985-12-05 Bayer Ag, 5090 Leverkusen 7-AMINO-1-CYCLOPROPYL-6,8-DIHALOGEN-1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS
US4696814A (en) * 1985-08-21 1987-09-29 Warner-Lambert Company Parenteral phenytoin compositions
JP2613139B2 (en) * 1990-07-19 1997-05-21 エスエス製薬 株式会社 Quinolonecarboxylic acid derivatives
GB9121316D0 (en) * 1991-10-09 1991-11-20 Wellcome Found Heterocyclic compounds
ES2160582T3 (en) * 1992-04-03 2001-11-16 Nippon Kayaku Kk HARD CITRABINE OCPHOSPHATE CAPSULE.
ES2177644T3 (en) * 1994-04-12 2002-12-16 Arakis Ltd PROCEDURE FOR THE RESOLUTION OF ETODOLAC USING GLUCAMINE DERIVATIVES.
DE59804823D1 (en) * 1997-09-25 2002-08-22 Bayer Ag DRUG FORMULATION WITH CONTROLLED ACTIVE SUBSTANCE RELEASE
WO2001034119A2 (en) * 1999-11-12 2001-05-17 Abbott Laboratories Inhibitors of crystallization in a solid dispersion
GB9929037D0 (en) * 1999-12-08 2000-02-02 Glaxo Wellcome Spa Heterocyclic derivatives
DE10031043A1 (en) * 2000-06-26 2002-02-14 Bayer Ag Retarded preparations of quinolone antibiotics and process for their preparation
JP2006518751A (en) * 2003-02-20 2006-08-17 サンタラス インコーポレイティッド Novel formulation for rapid and sustained suppression of gastric acid, omeprazole antacid complex-immediate release
EP1459739B1 (en) * 2003-03-19 2008-01-02 The Jordanian Pharmaceutical Manufacturing Co. Ltd. Non-hygroscopic pharmaceutical compositions containing non-hydrated quinoline carboxylic acids
US20050085446A1 (en) * 2003-04-14 2005-04-21 Babu M.K. M. Fluoroquinolone formulations and methods of making and using the same
JP2005008625A (en) * 2003-05-23 2005-01-13 Santen Pharmaceut Co Ltd Eye lotion containing quinolone-based antibacterial compound
WO2006042034A2 (en) * 2004-10-08 2006-04-20 Abbott Laboratories Salt and crystalline forms thereof of a drug

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2213275A1 (en) * 1972-03-18 1973-09-27 Klinke Desitin Werk Sodium 5,5-diphenylhydantoin infusion concentrates - contg 2-amino-2-(hydroxymethyl) propane-1,3-diol as solvent aid
US4748174A (en) * 1986-01-03 1988-05-31 Therapicon S.R.L. Water soluble salts of an NSAID with meglumine/glucamine
EP0257320A2 (en) * 1986-08-08 1988-03-02 Bayer Ag Parenteral solution
EP0411619A1 (en) * 1989-08-02 1991-02-06 Warner-Lambert Company Formulations of phenytoin sodium for intravenous administration
EP0852140A1 (en) * 1995-08-11 1998-07-08 Nissan Chemical Industries, Limited Methods for making hardly soluble medicine amorphous
US6133284A (en) * 1995-09-22 2000-10-17 Wakunaga Pharmaceutical Co., Ltd. Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components
EP1219618A1 (en) * 1999-09-02 2002-07-03 Wakunaga Pharmaceutical Co., Ltd. Quinolinecarboxylic acid derivative or its salt
JP2003300882A (en) * 2002-04-11 2003-10-21 St Marianna Univ School Of Medicine Emulsion containing pyridonecarboxylic acid compound

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 2003, no. 12 5 December 2003 (2003-12-05) *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2009297085B2 (en) * 2008-09-24 2015-07-09 Melinta Subsidiary Corp. Process for making quinolone compounds
USRE46617E1 (en) 2008-09-24 2017-11-28 Melinta Therapeutics, Inc. Process for making quinolone compounds
WO2010036329A3 (en) * 2008-09-24 2010-07-01 Rib-X Pharmaceuticals, Inc. Process for making quinolone compounds
US8497378B2 (en) 2008-09-24 2013-07-30 Rib-X Pharmaceuticals, Inc. Process for making quinolone compounds
EP3766876A1 (en) 2008-09-24 2021-01-20 Melinta Subsidiary Corp. Pharmaceutical formulation containing a quinolone derivative
US8871938B2 (en) 2008-09-24 2014-10-28 Melinta Therapeutics, Inc. Process for making quinolone compounds
CN105001207A (en) * 2008-09-24 2015-10-28 麦林塔医疗有限公司 Process for preparing quinolone compounds
KR101775304B1 (en) 2008-09-24 2017-09-05 멜린타 테라퓨틱스, 인크. Process for making quinolone compounds
WO2010036329A2 (en) 2008-09-24 2010-04-01 Rib-X Pharmaceuticals, Inc. Process for making quinolone compounds
EP3214083A1 (en) 2008-09-24 2017-09-06 Melinta Therapeutics, Inc. Process for making quinolone compounds
WO2010056872A2 (en) 2008-11-15 2010-05-20 Rib-X Pharmaceuticals, Inc. Antimicrobial compositions
CN104098548A (en) * 2013-04-11 2014-10-15 上海医药工业研究院 Delafloxacin purifying method
EP3581180A1 (en) 2014-06-20 2019-12-18 Melinta Subsidiary Corp. Antimicrobial compositions with effervescent agents
EP3919057A1 (en) 2014-06-20 2021-12-08 Melinta Subsidiary Corp. Antimicrobial compositions with effervescent agents
US10471046B2 (en) 2014-11-14 2019-11-12 Melinta Subsidary Corp. Method for treating, preventing, or reducing the risk of skin infection

Also Published As

Publication number Publication date
ATE549016T1 (en) 2012-03-15
PT1868581E (en) 2012-06-22
EP1868581B1 (en) 2012-03-14
CA2603783A1 (en) 2006-10-19
JP2008535925A (en) 2008-09-04
EP1868581A1 (en) 2007-12-26
SI1868581T1 (en) 2012-06-29
JP2013121976A (en) 2013-06-20
CY1112980T1 (en) 2016-04-13
CA2603783C (en) 2014-11-18
HRP20120502T1 (en) 2012-07-31
RS52354B (en) 2012-12-31
MX2007012642A (en) 2008-01-11
US20060228411A1 (en) 2006-10-12
US20100324018A1 (en) 2010-12-23
US20150057266A1 (en) 2015-02-26
US20120309740A1 (en) 2012-12-06
ME02003B (en) 2012-12-31
EP2286800A1 (en) 2011-02-23
PL1868581T3 (en) 2012-08-31
ES2384333T3 (en) 2012-07-03
JP5284777B2 (en) 2013-09-11
DK1868581T3 (en) 2012-07-09

Similar Documents

Publication Publication Date Title
US20150057266A1 (en) Pharmaceutical Composition Having Improved Dissolution Profiles For Poorly Soluble Drugs
JP2001081031A (en) Benzamide derivative-containing preparation having improved solubility and oral adsorption
JP4773456B2 (en) Oral preparation with improved bioavailability
KR101840182B1 (en) Pharmaceutical compositions comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactate monohydrate
AU2009321728B2 (en) Solid dosage forms of bendamustine
EP3785698B1 (en) Edaravone pharmaceutical composition
US20140044788A1 (en) Solid Oral Formulations of a Pyridopyrimidinone
JP2021121645A (en) CRYSTALLINE POLYMORPH OF 15β-HYDROXY-OSATERONE ACETATE
EP2701689B1 (en) Pharmaceutical compositions of raltegravir, methods of preparation and use thereof
EP2665477B1 (en) Modified release compositions of epalrestat or a derivative thereof and methods for using the same
US8772346B2 (en) Pharmaceutical composition
PL201388B1 (en) Pharmaceutical agent comprising a benzamide derivative as active ingredient
EP2293791B1 (en) Pharmaceutical compositions of entacapone co-micronized with sugar alcohols
CA2769616A1 (en) Solid oral formulations and crystalline forms of an inhibitor of apoptosis protein
EP2839835A1 (en) Encapsulated formulation
EP1560568B1 (en) Controlled release pharmaceutical compositions containing sodium alginate and sodium calcium alginate
KR101037808B1 (en) Sustained-release tablet containing solubilized niflumic acid
WO2005023221A1 (en) Clarithromycin formulations having improved biovailability
KR20110105550A (en) Tablet for oral administration comprising ecabet or its salt
JPWO2007069675A1 (en) Easy-to-absorb oral preparation of xanthine derivatives
WO2009016577A2 (en) A pharmaceutical composition comprising atorvastatin and niacin

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 2603783

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2008506637

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/a/2007/012642

Country of ref document: MX

Ref document number: 2006740898

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

WWE Wipo information: entry into national phase

Ref document number: P-2012/0250

Country of ref document: RS