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WO2011061155A1 - Formulations antifongiques et leur utilisation - Google Patents

Formulations antifongiques et leur utilisation Download PDF

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Publication number
WO2011061155A1
WO2011061155A1 PCT/EP2010/067501 EP2010067501W WO2011061155A1 WO 2011061155 A1 WO2011061155 A1 WO 2011061155A1 EP 2010067501 W EP2010067501 W EP 2010067501W WO 2011061155 A1 WO2011061155 A1 WO 2011061155A1
Authority
WO
WIPO (PCT)
Prior art keywords
film forming
formulation
amount
bifonazole
present
Prior art date
Application number
PCT/EP2010/067501
Other languages
English (en)
Inventor
Jerome Aubert
Original Assignee
Bayer Consumer Care Ag
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 Bayer Consumer Care Ag filed Critical Bayer Consumer Care Ag
Publication of WO2011061155A1 publication Critical patent/WO2011061155A1/fr

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on

Definitions

  • Bifonazole is an antimycotic agent and was first synthesized at Bayer Pharmaceuticals in 1974. Its systematic name is l -[phenyl(4-phenylphenyl)methyl]- lH-imidazole (formula I) and it forms colorless, odorless, and tasteless crystals.
  • Bifonazole can only be used as a topical antimycotic due to its fast metabolism, generating metabolites without antimycotic activity when administered orally.
  • the substance is minimally absorbed after topical application of 1 % formulations. Concentrations in blood serum usually remain below 5 ng/mL, even after daily application over two to three weeks of a skin area of about 200 cm 2 .
  • the topical applications are well tolerated. Skin irritations and allergic reactions are rarely observed and seem to be mainly due to the galenic formulation i.e. its excipients and the skin disease to which it is applied (e.g., fatty preparations on acute, inflammative lesions).
  • Film-forming preparations are generally known in the art.
  • US-A-6325990 provides lipophilic vitamins etc. in the absence of water and in the presence of adhesive polysiloxane, an absorption promoter and a volatile solvent, sprayable from an aerosol can.
  • Antimycotic agents with ketoconazole as example are mentioned, however, no information on pharmacological activity is provided.
  • the formulation according to the invention was surprisingly found to have improved wear properties when compared to bifonazole formulation of the state of the art, i.e. the film is partially water resistant and resistant to friction and still ensures enhanced bifonazole delivery even when the skin is exposed to a short shower, sweat or to humid ambient conditions. Furthermore, the film formulation according to the invention is capable of delivering approximately twice the amount of bifonazole into the stratum corneum in comparison with a solution spray formulation and eight times the amount of a standard cream formulation as proved by in vitro experiments.
  • the solvent can be selected from the group of ethanol, isopropanol, aqueous methanol, aqueous ethanol and aqueous isopropyl alcohol (containing approx. 3 % water), acetone, ethyl acetate, or methylene chloride.
  • Ethanol and isopropanol are preferred solvents.
  • Ethanol is particularly preferred, and it is a particular advantage of the present invention that considerably smaller amounts of ethanol need to be used for the dissolution of bifonazole, by comparison with the ethanolic spray formulation of the art.
  • the at least one cosolvent according to the inventive formulation may be an even better solvent for bifonazole than ethanol and can be selected from the group of benzyl alcohol, propylene glycol, polyethylene glycol, propylene carbonate, dimethyl sulphoxide, glycerin, isopropyl myristate, tetraglycol, cyclomethicone, N-methyl-2 pyrrolidone, Transcutol®, which is diethylene glycol monoethyl ether or Arlasolve®, which is dimethy isosorbide, and oleic acid.
  • benzyl alcohol, isopropyl myristate, Transcutol® or Arlasolve® alone or as mixture.
  • the amounts of the cosolvent are chosen to be between 0,05 % to 7% each, preferably between 1 and 4%, most preferably between 2,5 and 3%.
  • At least one further excipient is present which may have a further favourable effect on the film forming formulation.
  • These effects may lie in the field of consumer needs such as aesthetic requirements (gloss, colour, etc.) or may add to the performance of the film forming formulation such as e.g. further anti-nucleating agents to further stabilize the resulting supersaturated system.
  • the film forming formulation of the present invention can thus be further combined with any other suitable additive or pharmaceutically or cosmetically acceptable excipient.
  • the solvent is present in an amount of 10 to 40% and the at least one cosolvent is present in an amount of 0,05 to 7% each, the film forming agent is present in an amount of 1-10%, the propellant is present in an amount of 50 to 90%, and optionally fragrance is present in an amount of 0,1 to 1,2%.
  • the film formulation or a medicament comprising the film formulation is capable of delivering approximately twice the amount of bifonazole into the stratum corneum in comparison with a solution spray formulation and eight times the amount of a standard cream formulation as proved by in vitro experiments making it especially suitable for the treatment of the above mentioned infections. It was surprisingly found that although high bifonazole concentrations in the stratum corneum are achieved by the inventive film formulation or a medicament comprising the film formulation, this does not lead to enhanced levels of bifonazole in the receptor department representing the blood stream in the in vitro experiment although penetration enhancers are present. Consequently, the inventive film formulation or a medicament comprising the film formulation ensures an excellent topical performance without causing a systemic strain on the patient.
  • Fig. 1 shows the dependence of the permeation of bifonazole into the stratum corneum from the concentration of benzyl alcohol and transcutol in the film forming formulation as disclosed e.g. in Example A1-A3, A5-A8 and A13-A16.
  • Fig. 7 shows the total amounts of bifonazole ⁇ g/cm 2 , mean ⁇ standard deviation) detected in the skin compartments and in the receptor fluid in comparison with the Canesten® Extra solution spray formulation.
  • Fig. 3 the total amounts of bifonazole ⁇ g/cm 2 , mean ⁇ standard deviation) detected in the skin compartments and in the receptor fluid.
  • Arlasolve® and benzyl alcohol that are known to act as penetration enhancers present in the formulation A9, no enhanced level of bifonazole is detected in the receptor fluid representing the blood serum in the in vitro experiment.
  • One Caucasian skin biopsy was obtained from a bank of human skin from cosmetic surgery from 48 years old individual, frozen from January 2008. The skin biopsy was cleared of adhering subcutaneous fat with a scalpel. Then, each skin was sliced with a dermatome at a theoretical constant thickness of about 250/500 ⁇ using a BrownTM dermatome (Zimmer, 25460 ETUPES, France). Quality control of the skin thickness was performed for each skin sample before being mounted on a diffusion cell using a specific device (thickness control system with a reading to 1/100 mm - Ets G. Boutillon - 21300 Chenove, France). Skin samples were then randomized and mounted in the diffusion cells without being subject to any other treatment.
  • the diffusion cells were prepared on the day of the application of the formulations. After control of the quality of the skin samples, approximately 10 mg (amount exactly known) of the formulations (corresponding to 5 mg of formulation/cm 2 ) were applied on the entire surface of the epidermis circumscribed by the cylinder. Because of their differing viscosities, the formulations were accurately weighed. As mentioned before, the skin surface was left opened in contact with the atmosphere of the laboratory.
  • the horny layer was first removed by tape stripping with a 3MTM (MagicTM Tape Scotch) adhesive tape applied on the skin during a few seconds under a constant controlled pressure (45 g/cm 2 ). Two strips were collected and the first one was put in a polypropylene vial "SI” while the other one was put in another polypropylene vial "S2". Then, viable epidermis was separated from the dermis using forceps. The dermis was cut and separated from the adjacent compartment to the application site.
  • 3MTM MagneticTM Tape Scotch
  • Formulations A9, Al l, A17, A18, A19 were selected and placebos were prepared for comparative assessment.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une formulation filmogène comprenant du bifonazole, un procédé pour sa préparation et son utilisation dans le traitement d'infections fongiques ou d'infections associées à des infections fongiques de la peau.
PCT/EP2010/067501 2009-11-17 2010-11-15 Formulations antifongiques et leur utilisation WO2011061155A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP09290867 2009-11-17
EP09290867.2 2009-11-17

Publications (1)

Publication Number Publication Date
WO2011061155A1 true WO2011061155A1 (fr) 2011-05-26

Family

ID=43617894

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/067501 WO2011061155A1 (fr) 2009-11-17 2010-11-15 Formulations antifongiques et leur utilisation

Country Status (1)

Country Link
WO (1) WO2011061155A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013522620A (ja) * 2010-03-16 2013-06-13 サラダックス バイオメディカル インコーポレイテッド リスペリドンイムノアッセイ
US8883747B1 (en) 2013-10-09 2014-11-11 Craig W. Carver Topical antifungal compositions and methods of use thereof
EP3861981A1 (fr) * 2020-02-07 2021-08-11 Dr. Pfleger Arzneimittel GmbH Nouvelles compositions de sertaconazole
CN115463086A (zh) * 2022-09-08 2022-12-13 江苏知原药业股份有限公司 一种联苯苄唑溶液剂及其生产工艺及其生产设备

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000045795A2 (fr) 1999-02-05 2000-08-10 Cipla Limited Sprays topiques
US6325990B1 (en) 1995-10-20 2001-12-04 Laboratoire L. Lafon Film forming composition for spraying on the skin
US20030152611A1 (en) 2000-05-12 2003-08-14 Brigitte Illel Pharmaceutical compositions for transdermal administration of anti-inflammatory agents
US20060269485A1 (en) * 2002-11-29 2006-11-30 Foamix Ltd. Antibiotic kit and composition and uses thereof
WO2007031753A2 (fr) 2005-09-14 2007-03-22 Medpharm Limited Formulations topiques
US20070196323A1 (en) * 2004-06-07 2007-08-23 Jie Zhang Polyvinyl alcohol-containing compositions and methods for dermal delivery of drugs
WO2007099396A2 (fr) * 2005-06-07 2007-09-07 Foamix Ltd. Kit et composition antibiotiques et leurs utilisations
US20070292355A1 (en) * 2002-10-25 2007-12-20 Foamix Ltd. Anti-infection augmentation foamable compositions and kit and uses thereof
WO2009062746A2 (fr) * 2007-11-17 2009-05-22 Bayer Consumer Care Ag Médicaments topiques pour le traitement antimycotique

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6325990B1 (en) 1995-10-20 2001-12-04 Laboratoire L. Lafon Film forming composition for spraying on the skin
WO2000045795A2 (fr) 1999-02-05 2000-08-10 Cipla Limited Sprays topiques
US20030152611A1 (en) 2000-05-12 2003-08-14 Brigitte Illel Pharmaceutical compositions for transdermal administration of anti-inflammatory agents
US20070292355A1 (en) * 2002-10-25 2007-12-20 Foamix Ltd. Anti-infection augmentation foamable compositions and kit and uses thereof
US20060269485A1 (en) * 2002-11-29 2006-11-30 Foamix Ltd. Antibiotic kit and composition and uses thereof
US20070196323A1 (en) * 2004-06-07 2007-08-23 Jie Zhang Polyvinyl alcohol-containing compositions and methods for dermal delivery of drugs
WO2007099396A2 (fr) * 2005-06-07 2007-09-07 Foamix Ltd. Kit et composition antibiotiques et leurs utilisations
WO2007031753A2 (fr) 2005-09-14 2007-03-22 Medpharm Limited Formulations topiques
WO2009062746A2 (fr) * 2007-11-17 2009-05-22 Bayer Consumer Care Ag Médicaments topiques pour le traitement antimycotique

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Encvclopedia of Pharmaceutical Technology", 2002, MARCEL DEKKER
"Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT WILLIAMS & WILKINS
"Theorv and Practice of Industrial Pharmacv", 1986, LIPPINCOTT WILLIAMS & WILKINS
ROUGIER A.: "water and the stratum corneum", 1994, CRC PRESS, article "TEWL and transcutaneous absorption, in Bioengineering of the skin", pages: 103 - 113

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013522620A (ja) * 2010-03-16 2013-06-13 サラダックス バイオメディカル インコーポレイテッド リスペリドンイムノアッセイ
US8883747B1 (en) 2013-10-09 2014-11-11 Craig W. Carver Topical antifungal compositions and methods of use thereof
US10086008B2 (en) 2013-10-09 2018-10-02 Revolution Pharma Llc Topical antifungal compositions and methods of use thereof
EP3861981A1 (fr) * 2020-02-07 2021-08-11 Dr. Pfleger Arzneimittel GmbH Nouvelles compositions de sertaconazole
EP3861983A1 (fr) * 2020-02-07 2021-08-11 Dr. Pfleger Arzneimittel GmbH Nouvelles compositions de sertaconazole
CN115463086A (zh) * 2022-09-08 2022-12-13 江苏知原药业股份有限公司 一种联苯苄唑溶液剂及其生产工艺及其生产设备
CN115463086B (zh) * 2022-09-08 2023-12-26 江苏知原药业股份有限公司 一种联苯苄唑溶液剂的生产工艺

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