Classifications

• • 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
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • 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
  • A61K31/4704—2-Quinolinones, e.g. carbostyril
• • 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
  • A61K47/40—Cyclodextrins; 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
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/20—Oxygen atoms
  • C07D215/22—Oxygen atoms attached in position 2 or 4
  • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
• • 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

Definitions

• the present invention relates to the active agent (2R)-2-[4-(7-bromo-2- quinolyloxy)phenoxy]propanoic acid, and, in particular, a novel pharmaceutical formulation for parenteral administration of (2R)-2-[4-(7-bromo-2- quinolyloxy)phenoxy]propanoic acid or a pharmaceutically acceptable salt thereof.
• (2R)-2-[4-(7-Bromo-2-quinolyloxy)phenoxy]pro ⁇ anoic acid may be administered as a liquid parenteral formulation.
• (2R)-2- [4-(7-bromo-2-quinolyloxy)phenoxy]propanoic acid was found to cause a degree of hemolysis when infused at 10 mg/mL or greater as a simple phosphate buffer formulation. Since significant hemolysis can cause anemia, the hemolytic effect of (2R)-
• 2-[4-(7-bromo-2-quinolyloxy)phenoxy]propanoic acid is an undesirable property for a pharmaceutical composition.
• formulations containing (2R)-2-[4-(7-bromo-2- quinolyloxy)phenoxy] ⁇ ropanoic acid being capable of reducing drug-induced hemolysis.
• cyclodextrins have been reported to reduce drug-induced hemolysis in vitro, such reduction does not necessarily predict activity in in vivo environments, especially during IV infusion. It was hypothesized that cyclodextrins provided hemolytic protection through the formation of inclusion complexes with at least a portion of drug, resulting in less free drug that can interact with erythrocytes. This mechanism may apply to in vitro tests where there is no significant dilution of the drug solution (such as > 0.9 ml of solution mixing with 0.1 ml of erythrocyte suspension as described in most reports), which may keep a portion of drug in complexed form.
• drugs disassociate from cyclodextrin cavities rapidly and completely upon administration to the dynamic blood stream due to extensive dilution. This makes the in vivo effectiveness unpredictable.
• the present invention is based on the discovery that adding a cyclodextrin to a pharmaceutical formulation of (2R)-2-[4-(7-bromo-2-quinolyloxy)phenoxy]propanoic acid reduces drug-induced hemolysis of (2R)-2-[4-(7-bromo-2- quinolyloxy)phenoxy]propanoic acid in both in vitro and in vivo conditions, without affecting the pharmacological activity of the drug.
• the present invention also provides methods of treatment comprising administration of the pharmaceutical formulations of the instant invention.
• PBS phosphate buffered solution qs quantity sufficient, i.e. a sufficient quantity to achieve a total volume indicated
• active ingredient and “active principle,” as used herein, refer to (2R)-2-[4- (7-bromo-2-quinolyloxy)phenoxy]propanoic acid or pharmaceutically acceptable salts thereof.
• Cyclodextrins are oligosaccharides containing a toroidal, hydrophobic central cavity and a hydrophilic outer surface.
• the term "cyclodextrin,” as used herein, may refer to a cyclodextrin or a cyclodextrin derivative.
• Captisol ® is a sulfobutyl ether betacyclodextrin available from CyDex, LLC.
• hemolysis refers to the alteration or destruction of red blood cells in such a manner that hemoglobin is liberated into the blood stream.
• solid tumor cancer is used in its medically accepted sense, and does not include cancers of the blood such as leukemias.
• the invention relates to pharmaceutically acceptable aqueous formulations comprising (2R)-2-[4-(7-bromo-2-quinolyloxy)phenoxy]propanoic acid or one of its pharmaceutically acceptable salts, a physiologically acceptable cyclodextrin (including combinations of cyclodextrins), and at least one solubility-enhancing agent; the formulation generally having a pH between about 4 and about 9, preferably having a pH between about 5 and about 8.
• (2R)-2-[4-(7-Bromo-2-quinolyloxy)phenoxy]propanoic acid, or one of its pharmaceutically acceptable salts is present in the pharmaceutical formulations of the invention in a proportion of about 0.1% to about 5% (w/v), for example in a proportion of about 0.2% to about 3% (w/v).
• preferred formulations contain from about 0.5% to about 2% (w/v) of (2R)-2-[4-(7-bromo-2-quinolyloxy)phenoxy]propanoic acid or of one of its pharmaceutically acceptable salts.
• cyclodextrins can be used to carry out the present invention, including alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, and delta- cyclodextrins, and which cyclodextrins may be in the form of derivatives such as sulfoalkylether cyclodextrins (e.g., sulfobutyl ether ⁇ -cyclodextrin), hydroxyalkyl cyclodextrins, (e.g., hydroxypropyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin ), alkylcyclodextrins (e.g., methyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, trimethyl- ⁇ -cyclodextrin, diethyl- ⁇ -cyclodextrin), or carboxyalkyl
• sulfobutyl ether ⁇ -cyclodextrin or hydroxy-propyl ⁇ -cyclodextrin It is preferable to use sulfobutyl ether ⁇ -cyclodextrin or hydroxy-propyl ⁇ -cyclodextrin.
• the above cyclodextrins make it possible in particular to reduce or prevent drug induced hemolysis of (2R)-2-[4-(7-bromo-2-quinolyloxy)phenoxy]propanoic acid or of its pharmaceutically acceptable salts.
• the cyclodextrin is incorporated in the formulations in an amount of from about 1% to about 50% (w/v), preferably from about 5% to about 20% (w/v), for example 10% (w/v). It is preferred that the cyclodextrin be present in an amount effective to substantially reduce hemolysis caused by (2R) ⁇ 2-[4-(7-bromo-2- quinolyloxy)phenoxy]propanoic acid or a pharmaceutically acceptable salt thereof.
• substantially reduce it is meant that the cyclodextrin is present in an amount effective to reduce hemolysis of the active principle by about 30% or more relative to the amount of hemolysis caused by the active principle in the absence of the cyclodextrin.
• the cyclodextrin is present in an amount effective to reduce hemolysis of the active principle by about 50% or more relative to the amount of hemolysis caused by the active principle in the absence of the cyclodextrin.
• the amount of cyclodextrin sufficient to substantially reduce hemolysis of the active principle is dependent upon the concentration of the active ingredient in the formulation.
• the pharmaceutical formulations contain at least one solubility- enhancing agent.
• a solubility-enhancing agent of the present invention is an agent or agents that enhance(s) the solubility of the active principle in the aqueous formulation.
• (2R)-2-[4-(7-bromo-2-quinolyloxy)phenoxy]propanoic acid is an acidic compound with pH dependent solubility.
• suitable solubility-enhancing agents include pharmaceutically acceptable pH adjusting agents and/or buffering agents capable of dissolving the active principle and/or maintaining solution at a physiologically acceptable range, for example, acids/acidic agents, such as citric acid, lactic acid, boric acid, acetic acid, phosphoric acid, hydrochloric acid, sulfuric acids, and sodium phosphate monobasic; and bases/basic agents, such as sodium hydroxide, sodium citrate, sodium borate, sodium acetate, sodium sulfate, sodium phosphate dibasic, sodium phosphate tribasic, sodium carbonate, sodium bicarbonate, tris- hydroxymethylaminomethane, diethylamine, triethylamine, and ammonium hydroxide.
• acids/acidic agents such as citric acid, lactic acid, boric acid, acetic acid, phosphoric acid, hydrochloric acid, sulfuric acids, and sodium phosphate monobasic
• bases/basic agents such as sodium hydroxide, sodium citrate, sodium
• the solubility-enhancing agent is a physiologically acceptable buffering agent.
• the buffering agent is capable both of dissolving the active principle and of maintaining the pH of the formulation between about 4 and about 9, preferably between about pH 5 and about pH 8.
• Preferred buffering agents of the invention include, for example, buffer systems chosen from succinic acid/alkali metal succinate, citric acid/alkali metal citrate, tartaric acid/alkali metal tartrate, lactic acid/alkali metal lactate, maleic acid/alkali metal maleate, acetic acid/alkali metal acetate, fumaric acid/alkali metal fumarate methanesulphonic acid/alkali metal methanesulphonate, alkali metal sulfates, alkali metal hydrogen sulfates, phosphate acid/monoalkali metal phosphate, alkali metal dihydrogen phosphate/dialkali metal hydrogen phosphate, trialkali metal citrate, alkali metal phosphate, akal
• a preferred buffering agent is monoalkali metal phosphate/dialkali metal phosphate, for example monosodium phosphate/disodium phosphate.
• Preferred buffer solutions include about 0.01 to about 0.3 molar, more preferably about 0.05 to about 0.2 molar, aqueous buffer solutions of alkali metal dihydrogen phosphate/dialkali metal hydrogen phosphate, for example monosodium phosphate/disodium phosphate.
• Additional solubility enhancing agents include pharmaceutically acceptable cosolvents (e.g., ethanol, propylene glycol and the like), surfactants (e.g., Polysorbate 80 and polaxamer), and polymers (e.g., polyvinylpyrrolidone).
• the cyclodextrin may also be used to increase the solubility of the active ingredient in the aqueous formulation.
• the ability of the cyclodextrin to increase the solubility of the active ingredient is pH dependent.
• the formulations according to the invention may include tonicity modifiers, for example electrolytes such as sodium chloride, calcium chloride, non- reducing sugars, and sugar alcohols such as mannitol, sorbitol, xylitol or glycerin.
• tonicity modifiers for example electrolytes such as sodium chloride, calcium chloride, non- reducing sugars, and sugar alcohols such as mannitol, sorbitol, xylitol or glycerin.
• the pharmaceutical formulations according to the present invention may optionally include antioxidants (e.g., sodium bisulfite, sodium thiosulfate, and ascorbic acid).
• the formulation according to the invention may also include one or more preservatives.
• Any suitable preservative may be used to carry out the present invention, including but not limited to benzalkonium chloride, benzyl alcohol, cresol, parabens, phenol, and thimerosal.
• the amount of preservative will in general be present in the amount of about 0.1% to about 1%.
• compositions of the invention can be prepared using conventional techniques known to those skilled in the art.
• the pharmaceutical formulations of the present invention preferably contain a therapeutically effective amount of the active principle.
• therapeutically effective amount refers to an amount of the active principle present in the pharmaceutical formulation being administered that is sufficient to elicit the desired pharmacological or therapeutic effect(s) and/or to prevent development of or alleviate to some extent one or more of the symptoms of the disease being treated.
• a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
• the pharmaceutical formulations of the present invention are generally administered to patients, which include, but are not limited to, mammals, for example, humans, by, intravenous administration (including IV bolus injection and IV infusion), intramuscular administration, and other parenteral routes.
• patients which include, but are not limited to, mammals, for example, humans, by, intravenous administration (including IV bolus injection and IV infusion), intramuscular administration, and other parenteral routes.
• intravenous administration including IV bolus injection and IV infusion
• intramuscular administration intramuscular administration
• other parenteral routes e.g., a parenteral routes.
• the pharmaceutical formulations are administered by IV infusion.
• compositions can be prepared wherein the formulations of the invention are spray dried or lyophilized to form a powder for constitution.
• the compositions can be reconstituted with an aqueous liquid to form a parenteral formulation.
• Such compositions comprising (2R)-2-[4-(7-bromo-2-quinolyloxy)phenoxy]propanoic acid or a pharmaceutically acceptable salt thereof, a physiologically acceptable cyclodextrin, and at least one solubility-enhancing agent, are a further aspect of the present invention.
• the pharmaceutical formulations and/or compositions Prior to administration, can be diluted by commonly used intravenous fluids known to those of skill in the art.
• the pharmaceutical formulations may accordingly be prepared in a more concentrated form than that which is described above, and which may later be diluted to the desired concentration.
• the present invention relates to dosage forms comprising the pharmaceutical formulations described herein.
• Each dosage should contain the quantity of active principle calculated to produce the desired therapeutic effect.
• the pharmaceutical formulations will be administered in dosage units containing from about 10 mg to about 4000 mg of the active principle by weight of the composition, with a range of about 100 mg to about 2000 mg being preferred.
• AU components of the present formulations must be pharmaceutically acceptable.
• a "pharmaceutically acceptable" component is one that is suitable for use with humans and/or other animals without undue adverse side effects (such as toxicity, irritation and allergic response) commensurate with a reasonable benefit/risk ratio.
• the present invention further relates to the use of the pharmaceutical formulations of the invention in medicine.
• (2R)-2-[4-(7-Bromo-2-quinolyloxy)phenoxy]propanoic acid is an anti-tumor agent effective against solid tumors.
• the present invention therefore provides therapeutic methods of treating solid tumor cancers, which comprise administering to a patient in need of such treatment a therapeutically effective amount of the formulation of the invention.
• a patient includes a primate, human, rodent, canine, feline, bovine, ovine, equine, swine, caprine, and the like.
• Solid tumor cancers include, but are not limited to, colon cancer, breast cancer, prostate cancer, ovarian cancer, melanoma, and pancreatic cancer.
• a subject of the present invention is the use of a formulation of the present invention in the manufacture of medicinal products for the treatment of solid tumor cancers, such as colon cancer, breast cancer, prostate cancer, ovarian cancer, melanoma, and pancreatic cancer.
• solid tumor cancers such as colon cancer, breast cancer, prostate cancer, ovarian cancer, melanoma, and pancreatic cancer.
• the present invention also provides methods of reducing the hemolysis activity of
• Example 1 Assessment of in vitro hemolytic potential of a simple buffered formulation with dog erythrocytes.
• Dog whole blood was mixed in a 1:1 ratio and a 9:1 ratio with solutions of the active ingredient in the vehicle and with the vehicles alone. Dog whole blood was also mixed in a 1 : 1 ratio and a 9: 1 ratio with a 3% saponin solution as the positive control and saline (0.9% NaCl) as the negative control.
• Hemoglobin concentrate was dosed in the supernatant by spectrophotometry UV/visible (Genesis, technologies) for the assessment of the in vitro hemolytic potential. The percent of hemolysis was calculated based on the results of the saponin samples.
• Example 2 Assessment of in vitro hemolytic potential in dog erythrocytes for formulations containing various additives This study was performed to evaluate the hemolytic reducing potential of various additives reported to reduce drug-induced hemolysis for certain other drugs as compared to the conventional phosphate buffer formulation described in Example 1. Specifically, the following experiment assessed the hemolytic potential of (2R)-2-[4-(7-bromo-2- quinolyloxy)phenoxy]propanoic acid in various vehicles in vitro at concentrations of 10 and 20 mg/mL with dog whole blood.
• the aqueous vehicle solutions tested were a 2% sucrose solution; a 1% human albumin solution; a 0.6% Poloxamer 188 solution; a 1% mannitol solution; a solution composed of 1% mannitol, 0.5% glycine and 0.6% poloxamer 188; a 0.5% glycine solution; and a phosphate buffer solution as the control.
• Dog whole blood was mixed in a 1:1 ratio and a 9:1 ratio with solutions of the active ingredient in the various vehicles and with the vehicles alone.
• Whole blood was also mixed with a saponin solution in the same proportion to use as the positive control. After a 45-minute incubation at 37°C, the samples were centrifuged. The resulting supernatants were analyzed for plasma hemoglobin absorbance on a microplate reader (Dynex technologies, MRX revelation 4.06).
• the percent of hemolysis was calculated based on the results of the saponin samples. An induced hemolysis was considered significant when the hemoglobin concentration was greater than 2-fold higher than the negative control value obtained by mixing whole blood with homologous plasma in a 1:1 and 9:1 ratio of whole blood to plasma (intrinsic plasma hemoglobin).
• Example 3 Assessment of in vitro hemolytic potential in dog erythrocytes for formulations in various vehicles
• Dog whole blood was mixed in a 1:1 ratio and a 9:1 ratio with solutions of the active ingredient in the vehicle and with the vehicles alone. Dog whole blood was also mixed in a 1 : 1 ratio and a 9: 1 ratio with a 3% saponin solution as the positive control and saline (0.9% NaCl) as the negative control.
• Hemoglobin concentrate was dosed in the supernatant by spectrophotometry UV/visible (Genesis technologies) for the assessment of the in vitro hemolytic potential. The percent of hemolysis was calculated based on the results of the saponin samples.
• Example 4 Assessment of in vitro hemolytic potential in dog erythrocytes for a formulation containing a cyclodextrin.
• the following study was performed to evaluate the hemolytic reducing potential of a formulation containing 10 mg/mL active ingredient as a solution in a 0.05M pH 7 phosphate buffer formulation with 10% (w/v) hydroxypropyl beta cyclodextrin.
• Saline (0.9% NaCl) was used as the negative control
• saponin 3% aqueous solution
• Dog whole blood was mixed in a 1:1 ratio and a 9:1 ratio with solutions of the active ingredient in the vehicle and with the vehicles alone.
• Dog whole blood was also mixed in a 1 : 1 ratio and a 9: 1 ratio with a 3% saponin solution as the positive control and saline (0.9% NaCl) as the negative control.
• Example 5 In vitro hemolytic assessment of cyclodextrin formulation with human blood and plasma The following experiment assessed the potential of a cyclodextrin formulation of the invention to produce in vitro hemolysis in human blood.
• Active ingredient solutions at concentrations of 2 mg/mL, 5 mg/mL, and 10 mg/mL in a vehicle of 10% Captisol ® (w/v) in 0.05 M phosphate buffer were prepared as test solutions.
• a blood to test solution and blood to vehicle ratio of 1:1 and 9:1 were tested.
• Whole blood was mixed with 5% saponin as the positive control.
• the percent of hemolysis was calculated based on the results of the saponin samples. Hemolysis was considered significant when the test solution value was 2-fold higher than the negative control value obtained by mixing whole blood with homologous plasma in a 1 :1 and a 9:1 control.
• the formulations with an active ingredient concentration of 9 mg/mL with 10% Captisol ® provided effective hemolysis protection (Formulations Numbers 2 and 3).
• Example 7 In vivo study in dogs with phosphate buffer formulation, 30-minute infusion Solutions of the active ingredient in 0.1M phosphate buffer at concentrations 10 mg/mL and 20 mg/mL were administered to 1 male and 1 female beagle dog each, by a single intravenous infusion over 30 minutes to obtain a total exposure of 25 and 50 mg/kg, respectively. Sampling for plasma level determination was taken for 1 day at the following intervals: end of infusion (0), 30 minutes, 1 hour, 3 hours, 6 hours, and 24 hours after the end of the infusion.
• Example 8 In vivo studies with phosphate buffer formulation or a cyclodextrin formulation of the invention
• a solution of the active ingredient (10 mg/mL) in an aqueous solution of 0.05 M pH 7 phosphate buffer with 10% hydroxy-propyl ⁇ -cyclodextrin was administered to a female beagle dog by a single intravenous infusion over 1-hour.
• the dosage was 50 mg/kg.
• Sampling was taken for 1 day at the following intervals: end of infusion (0), 30 minutes, 1 hour, 3 hours, 6 hours and 24 hours after the end of the infusion. Results: No ex- vivo hemolysis was noted in the blood samplings.
• Example 10 The following are examples of pharmaceutical formulations of the present invention:

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