WO2005009429A1 - Compositions containing prodrugs of florfenicol and methods of use - Google Patents

Compositions containing prodrugs of florfenicol and methods of use Download PDF

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Publication number
WO2005009429A1
WO2005009429A1 PCT/US2004/021260 US2004021260W WO2005009429A1 WO 2005009429 A1 WO2005009429 A1 WO 2005009429A1 US 2004021260 W US2004021260 W US 2004021260W WO 2005009429 A1 WO2005009429 A1 WO 2005009429A1
Authority
WO
WIPO (PCT)
Prior art keywords
florfenicol
composition
butyrate
prodrag
hexanoate
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2004/021260
Other languages
English (en)
French (fr)
Inventor
Yerramilli Murthy
Robert H. Suva
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Idexx Laboratories Inc
Original Assignee
Idexx Laboratories Inc
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 Idexx Laboratories Inc filed Critical Idexx Laboratories Inc
Priority to CA002531223A priority Critical patent/CA2531223A1/en
Priority to AU2004258876A priority patent/AU2004258876B2/en
Priority to JP2006521089A priority patent/JP2006528177A/ja
Priority to EP04777420A priority patent/EP1651202A4/en
Publication of WO2005009429A1 publication Critical patent/WO2005009429A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • 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
    • A61K9/0012—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
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton

Definitions

  • the present invention pertains to prodrugs for use in mammals.
  • Florfenicol is a structural analog of chloramphenicol and thiamphenicol, having a fluorine atom instead of the hydroxyl group located at C-3 in the structure of chloramphenicol and thiamphenicol.
  • Bacterial resistance to chloramphenicol and thiamphenicol is usually attributed to acetylation of the 3' hydroxyl group by the action of chloramphenicol acetyl transferase. Since florfenicol does not possess the 3' hydroxyl group such a mechanism of inactivation is not possible with florfenicol, thus making florfenicol a highly useful antibiotic.
  • prodrug ester groups and external acids examples include acetyl, propionyl, butyryl, pentanyl, hexanyl, heptanyl, octanyl, nonyl, decanyl, undecanyl, dodecanyl, and phthalyl.
  • suitable prodrug ester groups and external acids can be found in the book "Pro-drugs as Novel Delivery Systems,” by Higuchi and Stella, Vol. 14 of the American Chemical Society Symposium Series, American Chemical Society (1975).
  • a “pharmaceutically acceptable carrier” is meant a non-toxic, inert, solid, semi- solid, or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type.
  • the pharmaceutically acceptable carrier is propylene glycol. But many other carriers are available.
  • the present invention provides pharmaceutical compositions for administration to a mammal.
  • the pharmaceutical compositions contain one or more compounds described herein and a pharmaceutically acceptable carrier, which can be supplied in an injectable form.
  • the depot then becomes a source of prodrug, and therefore active drag, for the treated mammal.
  • the drag depot can be created and situated in a muscle of the mammal by infra-muscular injection, but can also be situated in other tissue types such as in the dermal layer or in connective tissue.
  • the depot emits prodrag and the prodrag is converted into active drag in the body.
  • the prodrug is converted into active drag at or near the drag depot, hi another embodiment the composition in its entirety acts as a drug depot.
  • the present invention provides methods of administering florfenicol to a mammal.
  • the methods involve injecting into the mammal a composition comprising one or more compounds of the present invention, wherein the one or more compounds is/are converted into florfenicol in vivo by the action of one or more endogenous esterases.
  • the one or more compounds is/are present in the composition at a concentration of at least 250 mg/ml.
  • Figures 9a-n provide illustrations of examples of compounds of the present invention.
  • Figure 3 illustrates the release kinetics for each florfenicol prodrag.
  • the acetate prodrug was found to display faster release kinetics compared to florfenicol, while the butyrate and hexanoate derivatives displayed slower release kinetics compared to native florfenicol.
  • Example 4 Minimum Inhibitory Concentrations
  • This example describes the administration of various florfenicol ester prodrag formulations by injection into cattle with the seram being analyzed for the presence of florfenicol and prodrug.
  • florfenicol butyrate was formulated at 350 mg/ml in 10% propylene glycol in glycerol formal and injected subcutaneously into five cats at a dosage of 40 mg/kg.
  • Commercially available NUFLOR was used as a control and was also injected at a dosage of 40 mg/kg.
  • Serum samples from the injected animals were analyzed for the presence of florfenicol, and the results are graphically depicted in Figure 8. Concentrations of NUFLOR R built up rapidly in the serum and then declined rapidly over two days. Conversely, the concentration of florfenicol butyrate built up less rapidly and declined more slowly than that of NUFLOR .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Pathology (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Toxicology (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Communicable Diseases (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
PCT/US2004/021260 2003-07-18 2004-06-29 Compositions containing prodrugs of florfenicol and methods of use Ceased WO2005009429A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002531223A CA2531223A1 (en) 2003-07-18 2004-06-29 Compositions containing prodrugs of florfenicol and methods of use
AU2004258876A AU2004258876B2 (en) 2003-07-18 2004-06-29 Compositions containing prodrugs of florfenicol and methods of use
JP2006521089A JP2006528177A (ja) 2003-07-18 2004-06-29 フロルフェニコールのプロドラッグを含む組成物
EP04777420A EP1651202A4 (en) 2003-07-18 2004-06-29 COMPOSITIONS WITH PROFORUGS OF FLORFENICOL AND METHOD OF USE

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10/623,114 US7439268B2 (en) 2003-07-18 2003-07-18 Compositions containing prodrugs of florfenicol and methods of use
US10/623,114 2003-07-18

Publications (1)

Publication Number Publication Date
WO2005009429A1 true WO2005009429A1 (en) 2005-02-03

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/021260 Ceased WO2005009429A1 (en) 2003-07-18 2004-06-29 Compositions containing prodrugs of florfenicol and methods of use

Country Status (6)

Country Link
US (4) US7439268B2 (https=)
EP (2) EP1651202A4 (https=)
JP (1) JP2006528177A (https=)
AU (1) AU2004258876B2 (https=)
CA (1) CA2531223A1 (https=)
WO (1) WO2005009429A1 (https=)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005063257A1 (en) * 2003-12-23 2005-07-14 Schering-Plough Ltd. Florfenicol prodrug having improved water solubility
US7361689B2 (en) 2003-12-31 2008-04-22 Schering-Plough Animal Health Corporation Antibacterial 1-(4-mono- and di-halomethylsulphonylphenyl)-2-acylamino-3-fluoroproponals and preparation thereof
WO2010091306A1 (en) * 2009-02-05 2010-08-12 Tokai Pharmaceuticals Novel prodrugs of steroidal cyp17 inhibitors/antiandrogens
US8084643B2 (en) 2006-12-13 2011-12-27 Intervet Inc. Water-soluble prodrugs of florfenicol and its analogs
US8119667B2 (en) 2005-12-29 2012-02-21 Schering-Plough Animal Health Corporation Carbonates of fenicol antibiotics
CN104490882A (zh) * 2014-11-29 2015-04-08 郑州后羿制药有限公司 一种治疗鸭传染性浆膜炎疾病的中兽药及其制备方法
US9387216B2 (en) 2013-08-12 2016-07-12 Tokai Pharmaceuticals, Inc. Biomarkers for treatment of neoplastic disorders using androgen-targeted therapies
US9439912B2 (en) 2013-03-14 2016-09-13 University Of Maryland, Baltimore Androgen receptor down-regulating agents and uses thereof
US10098896B2 (en) 2005-03-02 2018-10-16 University Of Maryland Baltimore C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens, in vitro biological activities, pharmacokinetics and antitumor activity

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FI20022159A0 (fi) * 2002-12-05 2002-12-05 Orion Corp Uusia farmaseuttisia yhdisteitä
US7276257B2 (en) * 2005-07-22 2007-10-02 The Hong Kong University Of Science And Technology Schisandrin B preparation
US8168421B2 (en) 2005-12-09 2012-05-01 University Of Georgia Research Foundation, Inc. Microbial vaccine and vaccine vector
CN101600422A (zh) * 2006-12-13 2009-12-09 先灵-普劳有限公司 在亲脂性溶媒系统中的水溶性苯丙醇前药
PE20091171A1 (es) * 2007-12-14 2009-08-03 Schering Plough Ltd Proceso para recuperar florfenicol y analogos de florfenicol
CN105111234B (zh) * 2015-09-23 2017-05-17 河北远征禾木药业有限公司 一种氟苯尼考磷酸酯的合成方法
CN108096191A (zh) * 2017-12-29 2018-06-01 河北利华药业有限公司 氟苯尼考预混剂及其制备方法
CN110787131B (zh) * 2019-12-13 2022-04-01 河北远征药业有限公司 一种氟苯尼考可溶性粉制剂的制备方法
WO2021207647A1 (en) * 2020-04-09 2021-10-14 Computational International LLC Small molecule drugs as targeted therapeutics
CN111393341A (zh) * 2020-05-07 2020-07-10 中国农业大学 一种水溶性氟苯尼考氨基酸盐的制备方法
CN112345661B (zh) * 2020-10-21 2022-11-15 北京精益捷检测科技有限公司 一种兽药黄栀花口服液中氟苯尼考含量的测定方法
CN113416304B (zh) * 2021-06-22 2022-07-29 四川永诺生物科技有限公司 一种四臂聚乙二醇琥珀酸氟苯尼考化合物的制备方法及应用

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7153842B2 (en) 2003-12-23 2006-12-26 Schering-Plough Animal Health Corporation Florfenicol prodrug having improved water solubility
US7572777B2 (en) 2003-12-23 2009-08-11 Schering-Plough Animal Health Corp. Florfenicol prodrug having improved water solubility
WO2005063257A1 (en) * 2003-12-23 2005-07-14 Schering-Plough Ltd. Florfenicol prodrug having improved water solubility
US7361689B2 (en) 2003-12-31 2008-04-22 Schering-Plough Animal Health Corporation Antibacterial 1-(4-mono- and di-halomethylsulphonylphenyl)-2-acylamino-3-fluoroproponals and preparation thereof
US7713950B2 (en) 2003-12-31 2010-05-11 Intervet Inc. Antibacterial 1-(4-mono-and di-halomethylsulphonylphenyl)-2-acylamino-3-fluoroproponals and preparation thereof
US10098896B2 (en) 2005-03-02 2018-10-16 University Of Maryland Baltimore C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens, in vitro biological activities, pharmacokinetics and antitumor activity
US8119667B2 (en) 2005-12-29 2012-02-21 Schering-Plough Animal Health Corporation Carbonates of fenicol antibiotics
US8084643B2 (en) 2006-12-13 2011-12-27 Intervet Inc. Water-soluble prodrugs of florfenicol and its analogs
US9359395B2 (en) 2009-02-05 2016-06-07 Tokai Pharmaceuticals, Inc. Prodrugs of steroidal CYP17 inhibitors/antiandrogens
WO2010091306A1 (en) * 2009-02-05 2010-08-12 Tokai Pharmaceuticals Novel prodrugs of steroidal cyp17 inhibitors/antiandrogens
US9439912B2 (en) 2013-03-14 2016-09-13 University Of Maryland, Baltimore Androgen receptor down-regulating agents and uses thereof
US9884067B2 (en) 2013-03-14 2018-02-06 University Of Maryland, Baltimore Androgen receptor down-regulating agents and uses thereof
US9387216B2 (en) 2013-08-12 2016-07-12 Tokai Pharmaceuticals, Inc. Biomarkers for treatment of neoplastic disorders using androgen-targeted therapies
US9808472B2 (en) 2013-08-12 2017-11-07 Tokai Pharmaceuticals, Inc. Biomarkers for treatment of neoplastic disorders using androgen-targeted therapies
CN104490882A (zh) * 2014-11-29 2015-04-08 郑州后羿制药有限公司 一种治疗鸭传染性浆膜炎疾病的中兽药及其制备方法

Also Published As

Publication number Publication date
EP1651202A1 (en) 2006-05-03
EP2181706A3 (en) 2010-10-06
EP1651202A4 (en) 2006-08-02
US7662861B2 (en) 2010-02-16
US7786167B2 (en) 2010-08-31
AU2004258876A1 (en) 2005-02-03
EP2181706A2 (en) 2010-05-05
US20080306152A1 (en) 2008-12-11
US20080090912A1 (en) 2008-04-17
CA2531223A1 (en) 2005-02-03
JP2006528177A (ja) 2006-12-14
AU2004258876B2 (en) 2009-02-26
US20070142468A1 (en) 2007-06-21
US20050014828A1 (en) 2005-01-20
US7439268B2 (en) 2008-10-21

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