WO1994014446A1 - Procedes et compositions de cetoconazole (+) utlises dans le traitement des mycoses, des infections aux levures et des dermatophytoses - Google Patents

Procedes et compositions de cetoconazole (+) utlises dans le traitement des mycoses, des infections aux levures et des dermatophytoses Download PDF

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Publication number
WO1994014446A1
WO1994014446A1 PCT/US1993/012327 US9312327W WO9414446A1 WO 1994014446 A1 WO1994014446 A1 WO 1994014446A1 US 9312327 W US9312327 W US 9312327W WO 9414446 A1 WO9414446 A1 WO 9414446A1
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ketoconazole
amount
pharmaceutically acceptable
acceptable salt
composition according
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PCT/US1993/012327
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English (en)
Inventor
Nancy M. Gray
Raymond L. Woosley
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Sepracor, Inc.
Georgetown University
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Priority to AU58515/94A priority Critical patent/AU5851594A/en
Publication of WO1994014446A1 publication Critical patent/WO1994014446A1/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

Definitions

  • This invention relates to novel compositions of matter containing optically pure (+) ketoconazole. These compositions possess potent activity in treating local and systemic fungal, yeast and dermatophyte infections while avoiding adverse effects associated with the administration of the racemic mixture of ketoconazole. Adverse effects include, but are not limited to, hepatotoxicity, arrhythmia, hypersensitivit.y reactions, including urticaria, nausea, vomiting, abdominal pain, headache, dizziness, and elevations in serum liver enzymes. Also disclosed are methods for treating the foregoing infections in a human while avoiding the adverse effects that are associated with the racemic mixture of ketoconazole by administering the (+) isomer of ketoconazole to said human.
  • the active compound of these compositions and methods is an optical isomer of ketoconazole, which is described by Heeres et al., J. Med. Chem. 2 ⁇ ., (8), 1003-1005 (1979); Heel et al. , Drugs, 23., 1-36, (1982) and in United States Patents 4,144,346, 4,223,036 and 4,358,449.
  • the active compound is the (+) isomer of cis-l-acetyl-4-[4-[ [2- (2,4-dichlorophenyl)-2-(lH-imidazole-1-ylmethyl)-1,3- dioxolan-4-yl]methoxy]phenyl] piperazine (I) .
  • This isomer will hereinafter be referred to as (+) ketoconazole.
  • Ketoconazole is available commercially only as the racemic cis diastereomer, (R,S) plus (S,R) in a 1:1 ratio, and the generic name ketoconazole refers to this enantiomeric mixture.
  • the racemic mixture of ketoconazole that is commercially available for administration is a free base, but the pharmacology of salts will be essentially similar.
  • D and L commonly used only with sugars, amino acids and related compounds
  • R and S universalally used
  • the prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane- polarized light by the compound, with (-) or 1 meaning that the compound , is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • D-lactic acid is the same as (-) lactic acid
  • L-lactic acid is (+) .
  • stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
  • Ketoconazole is an orally active, broad-spectrum anti-fungal agent.
  • the compound an imidazole derivative structurally related to miconazole and clotrimazole, impairs the synthesis of ergosterol, which is the principal sterol of fungal cell membranes. This presumably results in an increased permeability and leakage of intracellular content.
  • ergosterol which is the principal sterol of fungal cell membranes.
  • ketoconazole provides, at lower doses, a linear increase in serum concentration.
  • the compound is eventually metabolized to several inactive metabolites through oxidation and degradation of the imidazole and piperazine rings, dealkylation, and hydroxylation.
  • ketoconazole is presently used primarily as an antifungal agent for such systemic infections as candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, paracoccidi ⁇ idomycosis, candidiasis, chronic mucocutaneous candidiasis, and oral thrush.
  • systemic infections as candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, paracoccidi ⁇ idomycosis, candidiasis, chronic mucocutaneous candidiasis, and oral thrush.
  • the compound is also indicated for severe cutaneous dermatophyte infections in patients who have not responded to topical therapy or oral griseofulvin.
  • Systemic fungal diseases are usually chronic, very slowly developing conditions induced by opportunistic causative fungi which may not normally be pathogenic. However when they enter a host compromised by HIV infection, ionizing irradiation, corticosteroids, immunosuppressives, etc. or by such conditions as emphysema, bronchiectasis, diabetes mellitus, leukemia, burns and the like, they may become pathogenic. Symptoms in such fungal diseases are generally not intense, and may include fever, chills, anorexia and weight loss, malaise, and depression.
  • Fungal diseases are often confined to typical anatomic distributions, and many involve a primary focus in the lung, with more characteristic manifestations of specific fungal infections when the fungus disseminates from a primary focus.
  • coccidioidomycosis occurs in a primary form as an acute, benign, self- limiting respiratory disease, with progressive disease developing from the primary form as a chronic, often fatal infection of the skin, lymph glands, spleen and liver.
  • blastomycosis primarily involves the lungs, and occasionally spreads to the skin.
  • infectious diseases such as paracoccidioidomycosis and candidiasis offer a different course, and depending on the etiology may exhibit several forms involving the skin, mucous membranes, lymph nodes, and internal organs.
  • the diagnosis of specific fungal diseases may be made by isolation of the causative fungus from sputum, urine, blood, or the bone marrow, or with prevalent fungus types by evidence of tissue invasion.
  • Superficial fungal infections are caused by dermatophytes or fungi that involve the outer layers of the skin, hair or nails. The infections may result in a mild inflammation, and cause intermittent remissions and exacerbations of a gradually extending, scaling, raised lesion.
  • Yeast infections including candidiasis, and oral candidiasis (thrush) are usually restricted to the skin, and mucous membranes, and the symptoms vary with the site of infection. Commonly, infections appear as erythe atous, often itchy, exudative patches in the axillas, umbilicus, groin, between toes, and on finger-webs.
  • Oral thrush involves an inflamed tongue, or buccal mucosa and presents as white patches of exudate, while chronic mucocutaneous candidiasis is characterized by red, pustular, crusted, thickened lesions on the forehead or nose.
  • ketoconazole antifungal agents include, but are not limited to, nausea, vomiting, anemia, thrombocytosis, hypersensitivity reactions, hepatotoxicity and some central nervous system toxicity.
  • the racemic mixture of ketoconazole has been found to cause nausea and vomiting, anorexia, headache, and dizziness.
  • Hypersensitivity reactions including urticaria, abdominal pain, and hepatotoxicity and elevations in serum liver enzymes are also associated with the administration of the drug.
  • the most common side effects are gastrointestinal, and they occur in 5 to 10% of patients. Hepatoxicity is less common but more serious.
  • racemic ketoconazole may be associated with an increased risk of cardiac arrhythmia.
  • Arrhythmia has not been heretofore reported as a side effect of systemic racemic ketoconazole, although a particular subtype of arrhythmia, torsades de pointes, has been reported when racemic ketoconazole was administered concurrently with terfenadine.
  • the lack of clinical reports of arrhythmia or QT anomalies may simply be a reflection of the fact that oral racemic ketoconazole is only indicated as a later resort when other preferred therapies have failed, and thus there is a relatively small subject population.
  • it would be particularly desirable to find a compound with the advantages of the racemic mixture of ketoconazole which would not have the aforementioned disadvantages.
  • the optically pure (+) isomer of ketoconazole is an effective agent for treating local and systemic fungal, yeast, and dermatophyte infections that avoids adverse effects associated with the administration of the racemic mixture, including but not limited to hepatotoxicity, arrhythmogenicity, dizziness, elevations in serum liver enzymes, hypersensitivity reactions, urticaria, headache, nausea, vomiting and abdominal pain.
  • the present invention also includes methods for treating local and systemic fungal, yeast and dermatophyte infections in a human while avoiding the adverse effects that are associated with the racemic mixture of ketoconazole, by administering the optically pure (+) isomer of ketoconazole to said human.
  • the present invention encompasses a method of treating local and systemic fungal, yeast and dermatophyte infections in a human, which comprises administering to a human in need of such antiinfective therapy, an amount of (+) ketoconazole, or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer, said amount being sufficient to alleviate such infections.
  • the method avoids the concomitant liability of adverse effects associated with the administration of racemic ketoconazole by providing an amount of (+) ketoconazole which is insufficient to cause the adverse effects associated with the racemic mixture of ketoconazole.
  • the present invention also encompasses an antiinfective composition for the treatment of a human in need of therapy for systemic or topical fungal, yeast or dermatophyte infection, which comprises an amount of (+) ketoconazole, or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer, said amount being sufficient to alleviate said infection.
  • the composition should provide a dose which is insufficient to cause the adverse effects associated with racemic ketoconazole.
  • ketoconazole i.e. a 1:1 racemic mixture of the two enantiomers of the cis diastereomer
  • This racemic mixture while offering the expectation of efficacy, causes adverse effects.
  • Utilizing the substantially optically pure or optically pure isomer of ketoconazole results in clearer dose related definitions of efficacy, diminished adverse effects, and accordingly, an improved therapeutic index. It is therefore more desirable to administer the (+) isomer of ketoconazole than racemic ketoconazole.
  • antiinfective activity i.e. a 1:1 racemic mixture of the two enantiomers of the cis diastereomer
  • This racemic mixture while offering the expectation of efficacy, causes adverse effects.
  • Utilizing the substantially optically pure or optically pure isomer of ketoconazole results in clearer dose related definitions of efficacy, diminished adverse effects, and accordingly, an improved therapeutic index. It is therefore more desirable to administer the (+) isomer of ketoconazole than racemic ketoconazole.
  • compositions contain a greater proportion of the (+) isomer of ketoconazole in relation to the (-) isomer.
  • the term “substantially free of its (-) isomer” as used herein means that the composition is at least 90% by weight of (+) ketoconazole and 10% by weight or less of (-) ketoconazole.
  • the term “substantially free of the (-) stereoisomer” means that the composition contains at least 99% by weight of (+) ketoconazole, and 1% or less of (-) ketoconazole.
  • the term "substantially free of its (-) stereoisomer” as used herein means that the composition contains greater than 99% by weight of (+) ketoconazole. These percentages are based upon the total amount of ketoconazole in the composition.
  • the terms “substantially optically pure (+) isomer of ketoconazole” or “substantially optically pure (+) ketoconazole” and “optically pure (+) isomer of ketoconazole” and “optically pure (+) ketoconazole” are also encompassed by the above-described amounts.
  • ketoconazole The chemical synthesis of the racemic mixture of ketoconazole can be performed by the method described in Heeres, J. et al., J. Med. Chem, . 22. 1003-1005 (1979) and in United States Patents 4,144,346 and 4,223,036.
  • Individual isomers of ketoconazole may be obtained by resolution of the racemic mixture of enantiomers using conventional means.
  • the ketoconazole may be resolved with an optically active acid such as tartaric acid at the imidazo-dioxolane alcohol or ester state or at the final product.
  • Other standard methods of resolution known to those skilled in the art, including but not limited to simple crystallization and chromatographic resolution, can be used. [See for example.
  • the optically pure (+) isomer can be prepared from the racemic mixture by enzymatic biocatalytic resolution. See for example, U.S. Patent Nos. 5,057,427 and 5,077,217, the disclosures of which are incorporated herein by reference.
  • an ester of the 2-(imidazolylmethyl)dioxolane-4- acetic acid intermediate can be enzymatically resolved.
  • ketoconazole The four possible stereoisomers of ketoconazole have recently been prepared by stereocontrolled synthesis from optically active dioxolane precursor [Rotstein et al. J ⁇ . Med. Chem. 35. 2818-2825 (1992)].
  • the (+) isomer of cis ketoconazole which is the subject of the present invention, appears to be of the (2R,4S) configuration.
  • the two enantiomers were found to have varying relative potencies as inhibitors depending on the particular enzyme.
  • a prophylactic or therapeutic dose of (+) ketoconazole in the acute or chronic management of disease will vary with the severity of the condition to be treated, and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose range, for (+) ketoconazole, for the conditions described herein is from about 50 g to about 1200 mg, in single or divided doses.
  • a daily dose range should be between about 100 mg to about 1000 mg, in single or divided doses, while most preferably, a daily dose range should be between about 200 mg to about 600 mg, in single or divided doses.
  • the therapy should be initiated at a lower dose, perhaps about 100 mg to about 300 mg, and increased up to about 600 mg or higher depending on the patient's global response. It is further recommended that children, and patients over 65 years, and those with impaired renal, or hepatic function, initially receive low doses, and that they be titrated based on individual response(s) and blood level(s). It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response. The term "an amount sufficient to alleviate such infections but insufficient to cause said adverse effects" is encompassed by the above-described dosage amounts and dose frequency schedule.
  • Any suitable route of administration may be employed for providing the patient with an effective dosage of (+) ketoconazole.
  • oral, rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, topical and like forms of administration may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, ointments, creams, shampoos and the like.
  • compositions of the present invention comprise (+) ketoconazole as the active ingredient. Or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
  • salts or “a pharmaceutically acceptable salt thereof” refer to salts prepared from pharmaceutically acceptable non- toxic acids or bases including inorganic acids and bases and organic acids and bases. Since the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non- toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic, benzenesulfonic (besylate) , benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic (mesylate) , mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like.
  • compositions of the present invention include compositions such as suspensions, solutions, elixirs, aerosols, and solid dosage forms.
  • Carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, are commonly used in the case of oral solid preparations (such as powders, capsules, and tablets) , with the oral solid preparations being preferred over the oral liquid preparations.
  • the most preferred oral solid preparation is tablets.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • a second preferred route of administration is topically, for which creams, ointments, shampoos, and the like are well suited.
  • the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S.Patent Nos. : 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719; the disclosures of which are hereby incorporated by reference.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contains from about 100 mg to about 300 mg of the active ingredient.
  • the tablet, cachet or capsule contains either one of three dosages, about 50 mg, about 100 mg, or about 200 mg of the active ingredient.
  • viscous to semi-solid or solid forms comprising a carrier compatible with topical application and having a dynamic viscosity preferably greater than water.
  • suitable formulations include but are not limited to solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, aerosols, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g., preservatives, stabilizers, wetting agents, buffers or salts for influencing osmotic pressure, etc.
  • sprayable aerosol preparations wherein the active ingredient, preferably in combination with a solid or liquid inert carrier material, is packaged in a squeeze bottle or in admixture with a pressurized volatile, normally gaseous propellant, e.g., a freon.
  • a pressurized volatile, normally gaseous propellant e.g., a freon.
  • Microbiological and pharmacologic studies can be used to determine the relative potency and the profile of specificity of the optically pure enantiomers, and the racemic mixture of ketoconazole as antimycotic agents with a broad spectrum of activity against many fungi, yeast, and dermatophytes.
  • Antifungal imidazoles may be evaluated .in vitro at several concentrations (in ⁇ g/ l) against a number of fungi and bacteria. (see Godefroi et al., J. Med. Chem. 10. 1160, 1967; Heeres, J. et al. , J. Med. Chem. 22, (8), 1003-1005, 1979 and U.S. Patent 4,144,346).
  • the fungistatic assay is carried out in Sabouraud's liquid (1 g of neopeptone Difco and 2 g of glucose Difco per 100 mL of distilled water) in 16 X 160 mm test tubes, each containing 4.5 mL of liquid medium which has been autoclaved at 120° for 5 min.
  • the compounds to be tested are dissolved in 50% alcohol at initial concentration of 20 mg/mL.
  • the solutions are subsequently diluted with sterile distilled water to give a concentration of 10 mg/mL. Successive decimal dilutions are made in distilled water.
  • Control tubes are prepared by adding 0.5 mL of distilled water to 4.5 of mL medium, alcohol being added to give concentrations identical with the tubes containing 1000 and 500 ⁇ g of the drug.
  • the filamentous fungi are incubated in Sabouraud's agar at 25° for 2-3 weeks. A block of 2 X 2 X 2 mm is then inoculated into the medium. All cultures are made in duplicate and are incubated at 25° for 14 days.
  • Ketoconazole antifungal activity is enhanced .in vitro in Sabouraud broth containing 10% inactivated bovine serum, and depends on the test medium used. Complete or marked inhibition of growth in Sabouraud broth after 14 days of incubation may be observed with microsporum canis, trichophyton mentagrophytes , Candida tropicalis, Candida albicans, and other fungi and bacteria. Concentration/response curves may be compared for ketoconazole, its isomers, and such standard agents as miconazole, as regards scope, and potency.
  • In vivo activity of ketoconazole and the optically pure enantiomers may be compared against experimental cutaneous candidosis in guinea pigs, and vaginal candidosis in rats.
  • the jLn vivo activity of the compounds in vaginal candidosis is evaluated by inducing vaginal infection with C. albicans in ovariectomized and hysterectomized Wistar rats (lOOg) which are treated weekly with 100 ⁇ g of estradiol undecanoate in sesame oil, subcutaneously. Animals in pseudooestrus are infected intravaginally with a fixed concentration of C. albicans in saline.
  • Control of infection or cure is estimated by taking vaginal smears at fixed days after infection.
  • Drugs to be evaluated, and compared on a mg/kg basis may be given prophylactically, or therapeutically and their efficacy judged by comparison the ratio of negative animals to the total number in each drug group.
  • the activity against cutaneous candidosis in guinea pigs provides the basis of comparison between the racemate and enantiomers of ketoconazole.
  • the potential for promoting arrhythmia is evaluated by examining the effects of the optically pure isomers of ketoconazole on cardiac action potential and contractility in human and canine hearts.
  • Torsades de pointes is a well known side effect of antiarrhythmic drugs, such as quinidine, sotalol and acetyl-procainamide, which cause a prolongation of cardiac repolarization. All of these drugs have in common the ability to block a cellular potassium channel called the delayed rectifier (I k ) , and it is generally assumed that this is mechanistically linked to their ability to induce the syndrome of torsades de pointes. [See Zehender et al. Cardiovascular Dru ⁇ s Ther.. 5 515-530 (1991).]
  • the hearts were perfused with an oxygenated Tyrode•s solution, containing 0.0; 1.0; 5.0 or 10.0 ⁇ M of ketoconazole.
  • QT duration and action potential duration were measured from cardiac electrodes. APD was measured at 50% (APD-50) and 90% (APD-90) .
  • N is the number of hearts, and QT and APD are measured in milliseconds.
  • mongrel dogs of either sex weighing 5-20 kg are anesthetized and instrumented by standard techniques for blood pressure and EKG.
  • a solid state transducer for dP/dT is placed in the left cardiac ventricle, and an epicardial electrode is put into place.
  • the test compound is infused at progressively higher doses, beginning at 1 ⁇ g/kg/min for 15 minutes and increased incrementally until a cardiovascular collapse ensues.
  • Parameters measured are: blood pressure, heart rate, dP/dT, and the QT-interval. Measurements of hemodynamics and electrical activity are made in response to the (+) enantiomer, (-) enantiomer and racemate.
  • Hepatic microsomes are prepared from human liver. Tissue is thawed and then homogenized in 0.15 M KCl in a Polytron homogenizer. The homogenate is centrifuged and the pellet is resuspended and homogenized in 0.15 M KCl. Aliquots are frozen and stored at -70° C.
  • Human lymphocytes are aseptically isolated from fresh, heparinized human blood. Blood is diluted with Eagle's minimal essential medium and layered on Ficoll-Paque.
  • lymphocytes are then removed from the aqueous-Ficoll interface and suspended in medium (15Mm HEPES, pH, 7.4).
  • medium 15Mm HEPES, pH, 7.4
  • the cells are then centrifuged, washed once in the HEPES medium, and resuspended.
  • Cytotoxicity is assessed by the conversion of 3- (4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to a purple formazan.
  • MTT 3- (4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
  • the conversion of MTT to dye is done in multiwell plates. After preparation, hepatic microsomes or lymphocytes are incubated alone or with the test compound in a concentration range from 1 to 400 ⁇ M at 37" C in a humidified incubator. After incubation, the microsomes/cells are washed with 5% albumin in HEPES- buffered medium and resuspended. The microsomes/cells are then incubated at 37° C in a humidified incubator. After the incubation, 125 ⁇ g of MTT is added to each well. The plates are incubated at 37° C and centrifuged. After centrifugation, 100 ⁇ L of is
  • the active ingredient, (+) ketoconazole is sieved and blended with the excipients.
  • the mixture is filled into suitably sized two-piece hard gelatin capsules using suitable machinery.
  • Other doses may be prepared by altering the fill weight and if necessary, changing the capsule size to suit.
  • the active ingredient is blended with the lactose until a uniform blend is formed.
  • the smaller quantity of cornstarch is blended with the water to form the resulting cornstarch paste. This is then mixed with the uniform blend until a uniform wet mass is formed and the remaining cornstarch is added and mixed until uniform granules are obtained.
  • the granules are screened through a suitable milling machine using a 1/4" stainless steel screen. The milled granules are dried in a suitable drying oven and milled through a suitable milling machine again. The magnesium stearate is then blended and the resulting mixture is compressed into tablets of desired shape, thickness, hardness and disintegration.

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Abstract

L'invention se rapporte à des procédés et à des compositions utilisant l'isomère (+) optiquement pur de cétoconazole. Ce composant est un médicament puissant utilisé dans le traitement des dermatophytoses, des infections aux levures et des mycoses locales et systémiques, et évite les risques d'apparition simultanée d'effets secondaires associés au mélange racémique du cétoconazole.
PCT/US1993/012327 1992-12-22 1993-12-17 Procedes et compositions de cetoconazole (+) utlises dans le traitement des mycoses, des infections aux levures et des dermatophytoses WO1994014446A1 (fr)

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US9918984B2 (en) 2005-01-10 2018-03-20 Cortendo Ab (Publ) Methods and compositions for treating diabetes, metabolic syndrome and other conditions

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US10098877B2 (en) 2005-01-10 2018-10-16 Strongbridge Ireland Limited Methods and compositions for treating diabetes, metabolic syndrome and other conditions
US10517868B2 (en) 2005-01-10 2019-12-31 Strongbridge Dublin Limited Methods and compositions for treating diabetes, metabolic syndrome and other conditions
US10835530B2 (en) 2005-01-10 2020-11-17 Strongbridge Dublin Limited Methods and compositions for treating diabetes, metabolic syndrome and other conditions
US11478471B2 (en) 2005-01-10 2022-10-25 Strongbridge Dublin Limited Methods and compositions for treating diabetes, metabolic syndrome and other conditions
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