WO2004108114A2 - Composition antifongique et son procede de fabrication - Google Patents

Composition antifongique et son procede de fabrication Download PDF

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Publication number
WO2004108114A2
WO2004108114A2 PCT/IN2004/000076 IN2004000076W WO2004108114A2 WO 2004108114 A2 WO2004108114 A2 WO 2004108114A2 IN 2004000076 W IN2004000076 W IN 2004000076W WO 2004108114 A2 WO2004108114 A2 WO 2004108114A2
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fungal
methyl
triazole
pharmaceutical composition
anyone
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PCT/IN2004/000076
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WO2004108114A3 (fr
WO2004108114B1 (fr
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Dinesh Shantilal Patel
Sachin Dinesh Patel
Shashikant Prabhudas Kurani
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Dinesh Shantilal Patel
Sachin Dinesh Patel
Shashikant Prabhudas Kurani
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Publication of WO2004108114A2 publication Critical patent/WO2004108114A2/fr
Publication of WO2004108114A3 publication Critical patent/WO2004108114A3/fr
Publication of WO2004108114B1 publication Critical patent/WO2004108114B1/fr

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • 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

Definitions

  • This invention relates to anti-fungal pharmaceutical composition suitable tor parenteral, oral or local administration involving various anti-fungal agents such as, anti-fungal Azole, Triazole and Allylamines especially compounds like ⁇ -(2,4-Difluorophenyl)- ⁇ -( 1H- 1,2,4- triazole-l-ylmethyl)-lH-l,2,4-triazole-l-ethanol and N-[(2E)-6,6-Dimethyl-2-hepten-4- ynyl]-N-methyl-l-naphthalenen ⁇ ethanamine hydrochloride and alike, useful for the treatment of fungal infections caused in animals including mammals and humans.
  • anti-fungal Azole Triazole and Allylamines especially compounds like ⁇ -(2,4-Difluorophenyl)- ⁇ -( 1H- 1,2,4- triazole-l-ylmethyl)-lH-l,2,4-triazole-l-ethanol and N-[(
  • US Patent 4416682 describes ⁇ -(2,4 ⁇ Difluorophenyl)- ⁇ -(lH-l,2,4-triazole-l-ylmethyl)- lH-l,2,4-triazole-l-ethanol and its use thereof as an anti-fungal agent.
  • US Patent Application 2001046478 (corresponding to EP 0515312) describes the anti- infective combination of two drugs for use in topical application in infection of toe nails and finger nails.
  • US Patent Application 2001046478 deals with a combination of a topical and a systemic antimycotic and a physiologically acceptable lacquer base suitable for the treatment and prophylaxis of onychomycoses.
  • US Patent 4, 404,236 describes anti-fungal derivatives of l,3-bis-triazoyl-2-propanol.
  • NZ 3, 315, 184 describes the use of ⁇ -(2,4-Difluorophenyl)- -(lH-l,2,4-triazole-l- ylmethyl)- 1 H-l,2,4-triazole-l -ethanol for inhibiting the growth or cancer and viral infection.
  • Application No. WO 1.997US 15987, 1997907 describes the anti-fungal combination therapy.
  • US Patent 4,404216 describes the ⁇ -(2,4-Difluorophenyl)- ⁇ -(lH-l,2,4-triazole-l- ylmethyl)-lH-l,2,4-triazole-l-ethanol and the use thereof as an anti-fungal agent.
  • WO2001EP00562 20000120 (EP 1259261) describes a pharmaceutical composition comprising of solid oral dosage forms of the compound and its rapid disintegration along with taste masking preparations.
  • WO0211764 describes a topical application of the above drug using the laser beam technique for the treatment of fungus infection.
  • WO 01/54675 A2 describes a pharmaceutical composition of the compound in emulsifiable or self-emulsifying oral formulations.
  • WO 02/078648 A2 describes the topical application of the compound along with a second drug viz., Diclofenac or Indomethacin for the treatment of fungal infections.
  • WO 01/95890 A2 describes the oral administration of a pharmaceutical composition of N- [(2E)-6,6-Dimethyl-2-hepten-4-ynyl]-N-methyl-l-naphthalenemethanamine hydrochloride comprising of Sustained Release dosage form.
  • anti-fungal such as ⁇ -(2,4-Difluorophenyl)- ⁇ -(lH-l,2,4-triazole-l- ylmethyl)-lH-l,2,4-triazole-l-ethanol required to treat widely rampant and menacing infections caused due to mycoses
  • anti-fungal such as ⁇ -(2,4-Difluorophenyl)- ⁇ -(lH-l,2,4-triazole-l- ylmethyl)-lH-l,2,4-triazole-l-ethanol required to treat widely rampant and menacing infections caused due to mycoses
  • the solubility of ⁇ -(2,4-Difluorophenyl)- -(lH-l,2,4-triazole-l- ylmethyl)-lH-l,2,4-triazole-l-ethanol in saline is at a maximum of about 8 mg/ml leading to difficulties in formulating preparations.
  • N-[(2E)-6,6-Dimethyl-2-hepten-4-ynyl]-N- methyl- 1 -nap hthalenemethanamine- hydrochloride an allylamine anti-fungal agent
  • an emulsion form is known to be used along with a vehicle but this form has an inherent drawback viz., of limited solubility in aqueous media thus making it difficult to be easily formulated.
  • the anti-fungal actives such as -(2,4-Difluorophenyl)- ⁇ -(lH-l,2,4-triazole-l-ylmethy ⁇ )-lH- 1,2,4-triazole-l-ethanol and N-[(2E)-6,6-Dimethyl-2-hepten-4-ynyl]-N-methyl-l- naphthalenemethanamine- hydrochloride is required in higher concentrations which cannot be provided due to limitations in solubility of the said ⁇ -(2,4-Difluorophenyl)- ⁇ -(lH- l,2,4-triazole-l-ylmethyl)-lH-l,2,4-triazole-l-ethanol and N-[(2E)-6,6-Dimethyl-2-hepten- 4-ynyl]-N- methyl- 1 -naphthalenemethanamine- hydrochloride.
  • Another object of the present invention is to provide a simple and cost effective anti-fungal formulation, which would be simple to manufacture but would serve as a good anti -fungal preparations with good bio-availability and patient compliance.
  • Another object of the present invention is directed to provide a solution to the much required readily obtainable anti -fungal preparation, which would be safe and suitable for oral, parenteral as well as topical administration.
  • Yet further object of the present invention is directed to provide simple and cost-effective anti -fungal formulations suitable for oral, parenteral and topical application, which would be storage, stable.
  • an anti -fungal pharmaceutical composition comprising at least one anti -fungal agent selected from anti -fungal azoles, anti-fungal allylamines, anti-fungal hydr ⁇ xy pyridines and anti-fungal polymers in a carrier media selected from 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol and its derivatives.
  • the anti -fungal azoles suitable for use can be selected from 1 -[(2-chlorophenyl)- diphenylmethyl]-lH-imidazole;l-[2-(2,4-dichlorophenyl)-2-[(2,4- dichlorophenyl)methoxy]ethyl]-lH-imidazole; l-[2-[(2-chloro-3-thienyl) methoxy]-2-(2,4- dichlorophenyl)ethyl]-lH-imidazole; cis-l -acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(lH- imidazol-l -ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]piperazine;l-[2-[(4- c lorophenyl)-methoxy]-2-(2,4-dichloro-pheny
  • the anti-fungal allylamines suitable for use can be selected from N-[(2E )-6,6-Dimethyl-2- hepten-4-ynyl]-N-methyl-l -naphthalenemethanamine hydrochloride; (E)-N-methyl-N- (3-phenyl-2-propeny!-l -naphthalenemethanamine; N-[[4-(l , l-dimethylethyl) ⁇ henyl] methyl]-N-methyl- ' l -naphthalenemethanamine.
  • the anti-fungal hydroxy pyridines suitable for use can be selected from Hydroxy pyridinessuch as 6-cyclohexyl-l-hydroxy-4-meethyl-2(lH)-pyridone, 2-aminoethanol salt,polymers .
  • the anti-fungal polymers suitable for use can be selected from Nystatin and
  • anti-fungal agents such as ⁇ - (2,4-Difluorophenyl)- ⁇ -(l H-l ,2,4-triazole- 1 -ylmethyl)- 1 H-l ,2,4-triazole- 1 -ethanol and N- [(2E)-6,6-Dimethyl-2-hepten-4-ynyl]-N-methyl-l -naphthalenemethanamine- hydrochloride can be effectively solubilized by the use of the selected carrier 2,5-di-O- methyl- 1, 4 :3,6-dianhydro-D-glucitol and its derivatives.
  • the above pharmaceutical composition of the invention resolves all the existing difficulties in the preparation of anti-fungal compositions through a simple technology, whereby anti- fungal compounds, which are otherwise difficult to solubilize can be selectively solubilized to be easily prepared in various formulations.
  • anti-fungal agent selected from anti -fungal azoles, anti-fungal allylamines, anti-fungal hydroxy pyridines and anti-fungal polymers in a selective carrier media comprising at least one of 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol and its derivatives.
  • the formulations can be prepared by dissolving at least one of said anti-fungal agents such as atleast one of ⁇ -(2,4-DifluorophenyI)- -(lH-l,2,4-triazole-l-ylmethyl)-lH- 1 ,2,4-triazole- 1 -ethanol; and N-[(2E)-6,6-Dimethyl-2-hepten-4ynyl]-N-methyl- 1 - naphthalenemethanamine hydrochloride in the selective carrier 2,5-di-O-methyl-l,4:3,6- dianhydro-D-glucitol or its derivatives.
  • said anti-fungal agents such as atleast one of ⁇ -(2,4-DifluorophenyI)- -(lH-l,2,4-triazole-l-ylmethyl)-lH- 1 ,2,4-triazole- 1 -ethanol
  • composition of the invention in solution form can be added to formulate tablets containing excipients such as starch or lactose or may be directly filled in capsules, alone or with suitable excipient/s, or in the form of drops or suspension containing flavouring or coloring agents or directly for parenteral administration.
  • excipients such as starch or lactose
  • suitable excipient/s or in the form of drops or suspension containing flavouring or coloring agents or directly for parenteral administration.
  • the pharmaceutical composition of the invention in sterile solution form can be directly administered intramuscularly or intravenously or by diluting it in an infusion.
  • the invention thus provides a simple method for formulating compositions especially of anti-fungal agent such as ⁇ -(2,4-Difluorophenyl)- ⁇ -(lH-l,2,4-triazole-l-ylmethy ⁇ )-lH-
  • anti-fungal agent such as ⁇ -(2,4-Difluorophenyl)- ⁇ -(lH-l,2,4-triazole-l-ylmethy ⁇ )-lH-
  • the invention by way of the selective carrier avoids the problems of providing simple and cost-effective anti-fungal formulation which can be administered in saline or glucose infusions or can be administered in the form of syrups or suspension or it can be applied directly to skin or it can be administered orally in the form of tablets for a longer duration till a patient responds to such infection.
  • compositions of the invention is thus a simple, safe and cost effective formulation which can be administered either directly or by modifications therein.
  • compositions comprising of anti-fungals like ⁇ -(2,4-Difluorophenyl)- ⁇ -(lH-l,2,4-triazole-l-ylmethy ⁇ )- lH-l,2,4-triazole-l-ethanol and N-[(2E)-6,6-Dimethyl-2-hepten-4-ynyl]-N-methyl-l- naphthalenemethanamine- hydrochloride in 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol as a selected pharmaceutical composition suitable for parenteral, oral and local administration as solutions, tablets, eye and ear drops, lotions, ointments, pastes, dusting powders, gels and sprays.
  • the compositions can also be used for the preparation of nail polishes, suppositories, pessaries, etc.
  • the process for the preparation of the anti-fungal composition comprise of: providing of ⁇ -(2,4-Difluorophenyl)- ⁇ -(lH-l,2,4-triazole-l-ylmethyl)-lH-l,2,4-triazole- 1-ethanol in 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol as a carrier media followed by stirring, heating and cooling to obtain clear solution.
  • the process for preparation of the composition comprise of: providing N-[(2E)-6,6-Dimethyl-2-hepten-4-ynyl]-N-methyl-l-na ⁇ hthalenemethanamine hydrochloride in 2,5-di-O-methyl-l,4:3,6-dianhydro-D-gl ⁇ citol as a carrier media followed by stirring, heating and cooling to obtain clear solution.
  • anti-fungals such as ⁇ -(2,4-Difluorophenyl)- ⁇ -(lH- l,2,4-triazole-l-ylmethyl)-lH-l,2,4-triazole-l-ethanol and N-[(2E)-6,6-Dimethyl-2-hepten- 4-ynyl]-N-methyl-l-naphthalene-methanamine hydrochloride formulation as described above can be directly administered orally or can be easily incorporated in the form of tablets, capsules, oral liquids, injectables or by direct application as gel, cream, lotion, suppositories.
  • compositions in the desired concentrated solution form can achieve the therapeutic level of the drug if chosen for such application, as the solvent 2,5-di-O-methyl- l,4:3,6-dianhydro-D-glucitol and its derivatives have good aqueous solubility and are further safe, cost effective and efficacious in terms of drug delivery.
  • compositions in solution form prepared in the solvent, can be readily used as single or multi dose vials for therapeutical applications.
  • the solution can be used in the injectable form for quick availability of the drugs in the blood, since if a drug is injected intravenously or intramuscularly the drug can by pass the first pass metabolism.
  • the formulation of the present invention offers an advantage of administering the anti- fungal actives in solution either through Intramuscular or Intravenous route or through rectal suppositories Further the formulation of such composition can be used for the treatment of yeast infections in the form of vaginal pessaries.
  • anti-fungal in capsules from in the range of 50 mg/cap - 250mg/cap or as tablet containing 125 - 250 mg. of the drug or can be administered directly as an oral drop without diluting or formulating in the oral syrup form in the concentration of 125mg - 250 mg/5ml with necessary excipeints, or for the local application as 1% (lOmg/gm) sprays, lotions, creams, gels, ointments with the necessary excipients.
  • this concentrated solution following the present invention offers desired varied and effective therapeutic use of the anti-fungal agents not possible under the prevailing state-of-art of anti-fungal formulations and their uses.
  • the concentrated solution prepared by way of the present invention can be filled directly in the capsules in the concentration range of 50 - 250 mg/cap with or without diluents or can be prepared as tablets in the concentration range of 50 - 125 mg/ml solution with necessary diluents or can be administered Intramuscularly or Intravenously, which can be further diluted with water to achieve the desired concentration required in the treatment of extensive systemic Mycotic infection.
  • the concentrated solution of the invention can further be administered as drops (50 - 125 mg/ml) directly or as a syrup in the same concentration by adding the necessary diluents. Furthermore, this solution can be used in the preparation of sprays, lotions, gels, creams, ointments & laquers containing 1% - 2.5% of the drug. Suppositories and pessaries of 50 mg-250 mg can be prepared by mixing of the drug with the necessary excipients.
  • Example I ⁇ -(2,4-Difluorophenyl)- ⁇ -(lH-l,2,4-triazole-l-ylmethyl)-lH-l,2,4-triazole-l-ethanol clear solution can be obtained as 0.0327 mole of ⁇ -(2,4-Difluorophenyl)- ⁇ -(lH-l,2,4-triazole-l- ylmethyl)-lH-l,2,4-triazole-l-ethanol, which is taken in a round bottom flask having the facility to stir and to flush nitrogen.
  • This solution is filtered through 0.22 ⁇ filter and fill and sealed in suitable vials under hermatic conditions which can be used for preparing infusion, oral dosage forms such as drops or liquids by incorporating necessary excipients hke diluents/sweetners flavouring agents, stabilizer for oral liquid or by diluting with alcohol & propellent to prepare spray or by filling the ⁇ liquid in soft gel or hard filled capsule of suitable size or can be used for preparing vaginal pessaries or suppositories, eye drops or ear drops.
  • Example III 0.0327 of ⁇ -(2,4-Difluorophenyl)- ⁇ -(lH-l,2,4-triazole-l-ylmethyl)-lH-l,2,4-triazole-l- ethanol is taken in a 100 ml round bottom flask containing 50 ml of 2,5-di-O-methyl- l,4:3,6-dihydro-D-glucitol which has the facilities to sir and flush Nitrogen. Heat the solution at 40°C for 30 minutes, cool the mixture at 25°C. Add 50 ml injectable grade water along with 0.7 mmole of chlorocresol and the resultant solution is made to 100 ml.
  • this solution is measured potentiometrically, which is about 6. Then this solution is aseptically filtered through 0.2 ⁇ filters and filled in suitable vial. Omitting chlorocresol and by adding necessary diluents the oral dosage forms like oral liquid, gel, cream and spray, ear and eye drops can be prepared.
  • This solution can be used as concentrate for making infusion or added as a dispersing agent for the preparation of tablets or is directly filled in soft/hard gelatin capsules or prepared as oral liquid using a suitable sweetening agent, flavouring agent and stabilizer or can be used for preparing pessaries or suppositories or can be used for preparing external applications such as sprays, lotions, lacquers, nail polishes or gels, ointments, creams, ear and eye drops for treating infections caused due to mycoses.
  • Example V 0.0343 mole of N-[(2E)-6,6-Dimethyl-2-hepten-4-ynyl]-N-methyl-l- naphthalenemethanamine is taken in a 100ml round bottom flask having the facility for stirring and for flushing of Nitrogen. 50ml of 2,5-di-O-methyl-l,4:3,6-dianhydro-D- glucitol is added and stirred for half an hour at 45°C. 0.236 mmole of ⁇ Tocopherol acetate is added while stirring and stirred further for half an hour.
  • This solution can be used directly for intramuscular or intravenous use or infusion can be prepared for suitable therapeutic use, or oral formulations like tablets can be prepared by dispersing in suitable diluents or can be directly filled in suitable hard filled or soft gelating capsules or can be used as drops by suitably mixing with a sweetning flavour and stabilizing agent or can be used as lotion for local application or mixed with suitable vehicle to prepare sprays, lacquers, nail polishes, creams, gels, ointments or for the preparation of pessaries, suppositories or ear and eye drops.
  • This solution without chlorocresol can be used to prepare oral drops, oral liquid, lotions for local application or can be used for preparing gels, creams or for sprays.
  • 2-hepten-4-ynyl]-N-methyl-l -naphthalenemethanamine hydrochloride in the concentration of up to 100 mg/ml with or without water and with or without antioxidant is chemically

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Abstract

L'invention concerne une composition pharmaceutique comprenant au moins un agent antifongique choisi dans le groupe imidazoles, triazoles, allylamines, leurs dérivés et polyènes, divers composés tels que hydroxy pyridones comme 2,5(1'S,6'R)-7-chloro-2',-4,6-triméthoxy-6'-méthylspiro[benzofurane-2(3H),1'-[2]cyclohexène]-3,4'-dione et acide carbamothioïque-méthyl(3-méthylphényl) O-2-naphthalényl ester, en particulier, α-(2,4-Difluorophényl)- α-(1H-1,2,4-triazole-1-ylméthyl)-1H-1,2,4-triazole-1-éthanol et N-[(2E)-6,6-Diméthyl-2-hepten-4-ynyl]-N-méthyl-1-naphthalène-méthanamine hydrochlorure dans un support sélectif de 2,5-di-O-méthyl-1,4:3,6-dianhydro-D-glucitol et ses dérivés. La préparation est appropriée pour administration par voies parentérale, orale et locale. La préparation en solution peut être administrée directement ou utilisée pour fabriquer des comprimés, des suspensions, des gouttes, des formulations de vernis à ongles et analogues.
PCT/IN2004/000076 2003-03-31 2004-03-31 Composition antifongique et son procede de fabrication WO2004108114A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008008537A2 (fr) * 2006-07-13 2008-01-17 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Compositions et méthodes pour le traitement de la mucormycose et d'autres maladies fongiques

Citations (9)

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US4082881A (en) * 1976-12-23 1978-04-04 E. R. Squibb & Sons, Inc. Topical and other type pharmaceutical formulations containing isosorbide carrier
EP0156507A1 (fr) * 1984-02-23 1985-10-02 Ortho Pharmaceutical Corporation Solution antifongique dermatologique
EP0230226A2 (fr) * 1986-01-15 1987-07-29 Kali-Chemie Pharma GmbH Emulsions antimycosiques
EP0270316A2 (fr) * 1986-12-04 1988-06-08 Pfizer Inc. Compositions topiques contenant des imidazoles 1-substitués et des agents non-steroides anti-inflammatoires pour le traitement de l'acné
WO1989005143A1 (fr) * 1986-08-04 1989-06-15 Research Corporation Technologies, Inc. Procede de traitement d'affections cutanees
WO1991002518A1 (fr) * 1989-08-25 1991-03-07 Bioglan Laboratories Ltd. Preparations pharmaceutiques et appareil en permettant l'administration
WO1993015719A1 (fr) * 1992-02-12 1993-08-19 Janssen Farmaceutici S.P.A. Formulations d'itraconazole liposomiques
WO1997017075A1 (fr) * 1995-11-08 1997-05-15 Pierre Fabre Medicament Composition pharmaceutique topique moussante pour le traitement des dermatoses, induites par pityrosporum ovale
US6455592B1 (en) * 1991-03-08 2002-09-24 Novartis Ag Use of hydrophilic penetration agents in dermatological compositions for the treatment of onychomycoses, and corresponding compositions

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4082881A (en) * 1976-12-23 1978-04-04 E. R. Squibb & Sons, Inc. Topical and other type pharmaceutical formulations containing isosorbide carrier
EP0156507A1 (fr) * 1984-02-23 1985-10-02 Ortho Pharmaceutical Corporation Solution antifongique dermatologique
EP0230226A2 (fr) * 1986-01-15 1987-07-29 Kali-Chemie Pharma GmbH Emulsions antimycosiques
WO1989005143A1 (fr) * 1986-08-04 1989-06-15 Research Corporation Technologies, Inc. Procede de traitement d'affections cutanees
EP0270316A2 (fr) * 1986-12-04 1988-06-08 Pfizer Inc. Compositions topiques contenant des imidazoles 1-substitués et des agents non-steroides anti-inflammatoires pour le traitement de l'acné
WO1991002518A1 (fr) * 1989-08-25 1991-03-07 Bioglan Laboratories Ltd. Preparations pharmaceutiques et appareil en permettant l'administration
US6455592B1 (en) * 1991-03-08 2002-09-24 Novartis Ag Use of hydrophilic penetration agents in dermatological compositions for the treatment of onychomycoses, and corresponding compositions
WO1993015719A1 (fr) * 1992-02-12 1993-08-19 Janssen Farmaceutici S.P.A. Formulations d'itraconazole liposomiques
WO1997017075A1 (fr) * 1995-11-08 1997-05-15 Pierre Fabre Medicament Composition pharmaceutique topique moussante pour le traitement des dermatoses, induites par pityrosporum ovale

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008008537A2 (fr) * 2006-07-13 2008-01-17 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Compositions et méthodes pour le traitement de la mucormycose et d'autres maladies fongiques
WO2008008537A3 (fr) * 2006-07-13 2008-04-24 Los Angeles Biomed Res Inst Compositions et méthodes pour le traitement de la mucormycose et d'autres maladies fongiques
EP2412371A1 (fr) * 2006-07-13 2012-02-01 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center Compositions comprenant des chelauteurs du fer dans l'tutilisation pour le traitement de la mucormycose et autres maladies fongiques

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WO2004108114B1 (fr) 2005-11-17

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