WO2006126825A1 - Composition comprenant des derives tetraflurobenzyle ou des sels de ceux-ci pour injection - Google Patents

Composition comprenant des derives tetraflurobenzyle ou des sels de ceux-ci pour injection Download PDF

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Publication number
WO2006126825A1
WO2006126825A1 PCT/KR2006/001934 KR2006001934W WO2006126825A1 WO 2006126825 A1 WO2006126825 A1 WO 2006126825A1 KR 2006001934 W KR2006001934 W KR 2006001934W WO 2006126825 A1 WO2006126825 A1 WO 2006126825A1
Authority
WO
WIPO (PCT)
Prior art keywords
tetrafluoro
benzylamino
trifluoromethyl
benzoic acid
hydroxy
Prior art date
Application number
PCT/KR2006/001934
Other languages
English (en)
Inventor
Seung-Taek Oh
Sang-Heon Lee
Original Assignee
Choongwae Pharma Corporation
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
Application filed by Choongwae Pharma Corporation filed Critical Choongwae Pharma Corporation
Publication of WO2006126825A1 publication Critical patent/WO2006126825A1/fr

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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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K31/02—Halogenated hydrocarbons
    • A61K31/025—Halogenated hydrocarbons carbocyclic
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids

Definitions

  • This invention relates to an injectable pharmaceutical composition
  • R , R and R are hydrogen or halogen, respectively;
  • R is hydroxy, alkyl, alkoxy, halogen, alkoxy substituted with halogen, alkanoyloxy or nitro, and
  • R is carboxylic acid or ester of carboxylic acid substituted with C1-C4 alkyl, car- boxyamide, sulfonic acid, halogen or nitro.
  • Tetrafluorobenzyl derivatives or their pharmaceutically acceptable salts published in the PCT application (WO 2004/000786), are therapeutically effective for the prevention and treatment of acute and chronic neurodegenerative diseases.
  • the tetrafluorobenzyl derivatives of this invention can effectively be used to prevent and treat neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease, convulsive brain diseases such as epilepsy, and ischemic brain diseases such as stroke.
  • the injectable solution containing a tetrafluorobenzyl derivative is susceptible to temperature or humidity, resulting in discoloration, precipitation, or loss of active ingredient during distribution or storage.
  • the inventors conducted intensive and thorough research in order to overcome the shortcomings associated with injectable solutions containing a tetrafluorobenzyl derivative as the active ingredient. By adjusting the pH, the inventors succeeded in sol- ubilizing the active ingredient to produce an injectable pharmaceutical composition with increased stability of formulation for long-term storage.
  • the object of this invention is to provide an injectable composition containing a tetrafluorobenzyl derivative as the active ingredient; therapeutically effective for the treatment of neurodegenerative diseases. Also, the invention prevents the decomposition, discoloration or precipitation of the active ingredient during the manufacturing, distribution or storage of the injectable solution.
  • This invention provides an injectable pharmaceutical composition containing a tetrafluorobenzyl derivative and its pharmaceutically acceptable salt with increased stability of formulation achieved by adjusting the pH of the injectable solution to 5-7.
  • a further aspect of this invention provides an injectable pharmaceutical composition containing an antioxidant to ensure improved stability of the pharmaceutical composition formulation.
  • R , R and R are hydrogen or halogen, respectively;
  • R is hydroxy, alkyl, alkoxy, halogen, alkoxy substituted with halogen, alkanoyloxy or nitro, and
  • R is carboxylic acid or ester of carboxylic acid substituted with C1-C4 alkyl, car- boxyamide, sulfonic acid, halogen or nitro.
  • Alkyl group is C1-C4 alkyl; and more preferably C1-C2 alkyl.
  • Alkoxy group is C1-C4 alkoxy; and more preferably Cl - C2 alkoxy.
  • Alkanoyloxy is C2-C10 alkanoyloxy; and more preferably C3-C5 alkanoyloxy.
  • the preferred tetrafluorobenzyl derivatives of this invention include 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-nitro-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-bromo-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-methylbenzylamino)-benzoic acid, 2-methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-methoxy-5-(2,3,5,6-tetrafluoro-4-tri
  • the pharmaceutically acceptable salts of this invention include alkali metals such as lithium, sodium or potassium, and alkaline earth metals such as calcium or magnesium. Preferably, they include water-soluble salts selected from the group consisting of sodium salts, potassium salts or lithium salts.
  • Formula I may be produced via a method described in WO 2004/000786.
  • the injectable composition of this invention contains the tetrafluorobenzyl derivative of 0.1-50 mg/ml, preferably 0.2-10 mg/ml.
  • pH buffer solutions such as acidic aqueous solution or phosphate
  • One or more pH buffer solutions may be selected from the group consisting of glacial acetate, citric acid, citrate, phosphate, sodium hydroxide, and potassium hydroxide.
  • Phosphate used for this invention may be in the form of salts such as sodium or potassium, or of its anhydride or hydrate.
  • Citric acid may be in the form of its anhydride or hydrate.
  • phosphate buffer solutions include solutions of monobasic potassium phosphate and dibasic sodium phosphate; monobasic sodium phosphate-citric acid buffer solution; as well as solutions of monobasic potassium phosphate and sodium hydroxide.
  • the pH-adjusting buffer solution may be used to adjust the pH of the injectable solution of this invention to 5-7.
  • the water-insoluble tetrafluorobenzyl derivatives may be solubilized by adjusting the pH to 5-7, while preventing the occurrence of precipitate or harmful substances during distribution and storage and loss of active ingredient.
  • the injectable solution of this invention containing a tetrafluorobenzyl derivative may produce a precipitate at an acidic pH
  • the injectable solution of this invention should also contain sodium sulfite or sodium meta sulfite to prevent discoloration and improve the stability of the solution.
  • stabilizing agents for injection include para-hydroxybenzoic acid ester derivatives, alcohol, benzalkonium chloride, phenol derivatives, thimerosal, acetic anhydride, sorbic acid, boric acid, adipic acid, sodium carboxylate, lauryl sulfate, and antioxidants.
  • antioxidants examples include retinol, tocopherol or sodium ascorbate, ascorbic acid, sulfite compounds, amino acid such as L-cysteine, thiodipropionic acid, thiolactic acid, and monothioglycerol.
  • the Korean Patent Registration No. 10-0188318 discloses stabilizer against light, such as sulfurous acid, sulfite, ascorbate, L-cysteine, and tocopherol.
  • the Korean Patent Examined No. 10-1990-0000746 discloses ascorbic acid as a stabilizer of injectable cefamandole nafate.
  • 10-2003-0021935 discloses N-acetyl amino acid as a stabilizer of paclitaxel.
  • the Korean Patent Examined No. 10-1992-0004097 discloses -tocopherol, sodium formaldehyde, or tertiary-butyl hydroquinone as an antioxidant used to ensure increased stability of doxorubicin hydrochloride that is unstable in aqueous systems.
  • the U.K. Patent No. 2,158,714 discloses sodium sulfite as a stabilizer of injectable metoclopramide.
  • the injectable composition of this invention may also contain a pharmaceutically acceptable isotonic agent which reduces pain when injected.
  • the pharmaceutically acceptable isotonic agent may include sodium chloride.
  • This invention provides a stabilized injectable composition containing a tetrafluoro derivative with the following combination of properties: 1) the water-insoluble compound may be solubilized by adjusting its pH to 5-7 for better stability of injectable preparation, 2) the application of sodium sulfite or sodium meta sulfite as an antioxidant may prevent the precipitation during the manufacture of the injectable solution, 3) the active ingredient is not discolored or precipitated, and may be stored under normal storage conditions without substantial degradation.
  • the formulation of this invention allows it to be delivered as an injection to patients with neurodegenerative diseased and increases the stability of the active ingredient; thereby optimizing the injectable solution's safety and efficacy.
  • Table 1 shows the occurrence of precipitation in the injectable solution at different pHs.
  • Example 2 Preparation of pH-ad justed injection composition of this invention
  • a dilute hydrochloric acid solution (0.01 N) and sodium hydroxide solution (0.1 N) the pHs of the injectable solution, as prepared in Example 1, were adjusted to 1.45, 3.25, 5.78, 6.75, 7.68, 8.91, and 12.02
  • Table 2 shows the remaining amount of active ingredient in each injectable solution at different time intervals.
  • the pH of the injectable solution should be maintained at about 5 to 7 in order to ensure an increased stability under normal storage conditions.
  • the preferred amounts of sodium sulfite and sodium meta sulfite are 0.01-0.5 parts by weight and 0.05-0.1 parts by weight per 1 part by weight of a tetrafluorobenzyl derivative, respectively.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cette invention concerne une composition pharmaceutiquement injectable contenant un dérivé de tétrafluorobenzyle ayant une stabilité de formulation accrue et, plus particulièrement, une composition pharmaceutique injectable contenant un dérivé fluorobenzyle ou un sel de celui-ci comme principe actif, avec une stabilité de formulation accrue, par réglage du pH sur 5-7. Dans un autre aspect, cette invention concerne une telle composition pharmaceutique injectable contenant un dérivé tétrafluorobenzyle, à laquelle est ajouté du sulfite de sodium, ou du métasulfite de sodium améliorant ainsi la stabilité de formulation.
PCT/KR2006/001934 2005-05-23 2006-05-23 Composition comprenant des derives tetraflurobenzyle ou des sels de ceux-ci pour injection WO2006126825A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2005-0043359 2005-05-23
KR20050043359 2005-05-23

Publications (1)

Publication Number Publication Date
WO2006126825A1 true WO2006126825A1 (fr) 2006-11-30

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Application Number Title Priority Date Filing Date
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Country Status (2)

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KR (1) KR20060121721A (fr)
WO (1) WO2006126825A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021181159A1 (fr) * 2020-03-11 2021-09-16 Gnt Pharma Co., Ltd. Compositions et méthodes pour traiter une lésion ou une hémorragie de reperfusion après une thérapie de recanalisation
CN116158429A (zh) * 2021-11-25 2023-05-26 沈阳中化农药化工研发有限公司 一种含有联苯类化合物稳定的液体制剂

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102421430B (zh) * 2009-04-06 2014-06-25 纽若泰克制药株式会社 用于预防或治疗烧伤的药物组合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5977164A (en) * 1992-11-27 1999-11-02 Napro Biotherapeutics, Inc. Stabilized pharmaceutical composition
WO2004000786A1 (fr) * 2002-06-19 2003-12-31 Neurotech Co., Ltd. Derives de tetrafluorobenzyle et composition pharmaceutique pour la prevention et le traitement de maladies neurodegeneratives aigues et chroniques affectant le systeme nerveux central contenant lesdits derives
WO2004064844A1 (fr) * 2003-01-20 2004-08-05 Neurotech Pharmaceuticals Co., Ltd. Methode d'inhibition de necrose induite par la neurotrophine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5977164A (en) * 1992-11-27 1999-11-02 Napro Biotherapeutics, Inc. Stabilized pharmaceutical composition
WO2004000786A1 (fr) * 2002-06-19 2003-12-31 Neurotech Co., Ltd. Derives de tetrafluorobenzyle et composition pharmaceutique pour la prevention et le traitement de maladies neurodegeneratives aigues et chroniques affectant le systeme nerveux central contenant lesdits derives
WO2004064844A1 (fr) * 2003-01-20 2004-08-05 Neurotech Pharmaceuticals Co., Ltd. Methode d'inhibition de necrose induite par la neurotrophine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021181159A1 (fr) * 2020-03-11 2021-09-16 Gnt Pharma Co., Ltd. Compositions et méthodes pour traiter une lésion ou une hémorragie de reperfusion après une thérapie de recanalisation
CN115515573A (zh) * 2020-03-11 2022-12-23 Gnt制药有限公司 用于治疗再通疗法之后再灌注损伤或出血的组合物和方法
US11826329B2 (en) 2020-03-11 2023-11-28 Gnt Pharma Co., Ltd. Compositions and methods for treating reperfusion injury or hemorrhage after recanalization therapy
CN116158429A (zh) * 2021-11-25 2023-05-26 沈阳中化农药化工研发有限公司 一种含有联苯类化合物稳定的液体制剂

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Publication number Publication date
KR20060121721A (ko) 2006-11-29

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