WO2009136214A1 - Combination compositions comprising antimycotic agents and statins and the use thereof - Google Patents

Combination compositions comprising antimycotic agents and statins and the use thereof Download PDF

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WO2009136214A1
WO2009136214A1 PCT/HU2009/000043 HU2009000043W WO2009136214A1 WO 2009136214 A1 WO2009136214 A1 WO 2009136214A1 HU 2009000043 W HU2009000043 W HU 2009000043W WO 2009136214 A1 WO2009136214 A1 WO 2009136214A1
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PCT/HU2009/000043
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French (fr)
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Csaba VÁGVÖLGYI
Ildikó NYILASI
Tamás PAPP
Miklós PESTI
Gyöngyi LUKÁCS
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Pannonpharma Gyógyszergyártó Kft.
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Priority to EP09742410A priority Critical patent/EP2296644A1/en
Publication of WO2009136214A1 publication Critical patent/WO2009136214A1/en

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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
    • A61K31/21—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
    • 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
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • compositions comprising antimycotic agents and statins and the use thereof
  • the present invention relates to combinations comprising one or more active component(s) having antimycotic activity and one or more statin(s) or a prodrug or a metabolite thereof for use as agents inhibiting the growth of fungi.
  • the present invention relates to combinations comprising (a) one or more active component(s) having antimycotic activity selected from the group consisting of amphotericin B, nystatin, griseofulvin, primycin, terbinafme, components of azole type, particularly ketoconazole, miconazole, fluconazole, itraconazole, clotrimazole, posaconazole, voriconazole, and prodrugs and metabolites thereof, and (b) one or more statin(s) selected from the group concicting of lovastatin, simvastatin, fluvastatin, pravastatin, rosuvastatin, atorvastatin, cerivastatin, pitavastatin, a prodrug and a metabolite thereof for the use as an agent inhibiting the growth of fungi, with the proviso that the combination is different from: amphotericin B and fluvastatin; ketoconazole and lovastatin;
  • the present invention relates to combination compositions having antimycotic effect as well as to the use of these combinations in the therapy.
  • Lukacs el al. have studied the effect of lovastatin on species of Rhisomucor miehei and Rhisomucor piisillus [Journal of Clinical Microbiology, 2004, 42(1 1):5400-5402], They have found that lovastatin inhibited the growth of the said species, but the levels of inhibition were very different.
  • the dose necessary for inhbiting the growth of Rhisomucor miehei was fifty- to sixty-fold higher as compared with that for the other species. Consequently, the inhibiting effect of lovastatin is different from species to species and depends on the circumstances of cultivation.
  • the above reference does not mention any use of drug-combinations.
  • Gyetvai et al. have disclosed that although lovastatin showed a fungistatic effect in the case of Candida albicans (i.e. inhibited the growth of the fungus), it did not exert an apoptotic effect against the said fungus [FEMS Yeast Research, 2006, 6(8):1 140-1148]. This reference does not mention any combination.
  • Macreadie et al. have studied antifungal activity of simvastatin and atorvastatin against several species of Candida ⁇ Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis) and Aspergillus fumigatus in 2006 [FEMS Microbiology Letters, 2007, 262:9-13]. Both simvastatin and atorvastatin, at certain concentrations, caused reduction and inhibition of growth, respectively, in the case of spp. Candida and Aspergillus fumigatus. The authors stated that inhibition of growth caused by statins could be ceased by adding argosterol or cholesterol. Neither this reference mentions any combination.
  • Nash et al. have studied the effect of the combinations fluvastatin/fluconazole and pravastatin/fluconazole in the case of Candida albicans, but in these studies fluvastatin and pravastatin were applied at clinically reachable concentrations [Journal of Medical Microbiology, 2002, 51(2): 105-
  • the used antifungal agent is a protein of low molecular weight which is not used in the clinical practice and does not belong to the scope of substances studied in connection with the present invention.
  • the applied doses were, however, higher than the low levels acceptable in the clinical practice (in vivo).
  • the studied species of fungus (baker's yeast) is not a pathogen but a species used as model-organism; therefore, the antimycotic effect found by the inventors of the present invention and claimed in this application is not deducible from the above results in general.
  • PCT publication No. WO2006013602 discloses the combined use of at least one statin, at least one omega-3 fatty acid and other substances for the treatment of cardiovascular diseases as well as diabetes, where the said substances show a synergic effect.
  • PCT publication No. WO2006090756 relates to the combined use of phenylpropionic acid derivatives and statins for the treatment of obesity and diabetes, since the said substances together, by a synergic or additive effect, may lower the lipid concentration of the organism.
  • Patent application No. PCT/IB98/01220 relates to the combined use of amlodipine and statins for the treatment of arterosclerosis, hyperlipidaemia, angina pectoris and other cardiac diseases.
  • the combinations of statins and amlodipine show additive or synergic effect in the treamtent of said diseases.
  • PCT publication No. WO9311777 discloses the combined use of amphotericin B and a glycerol ether for the treatment of fungal infection of mammals.
  • concentration of amphotericin B necessary for reaching the efficiency, can be reduced; thus, these substances together show synergic interaction and inhibit particularly the growth of Cryptococcus neoformans and Candida albicans.
  • PCT publication No. WO03045319 discloses a therapeutic agent linked to a rifamycin derivative.
  • the therapeutic agent may be, among others, a statin.
  • statins atorvastatin, rosuvastatin, lovastatin, simvastatin, pravastatin, cerivastatin and fulvastatin are mentioned and claimed particularly.
  • the therapeutic agent is appropriate for preventing and treating microbial infections.
  • microbial infections such as fungal infections, those caused by, among others, Candida spp. are disclosed and claimed. Neither of the last two documents discloses the increased antimycotic activity of the combinations or does not mention the combination of the present invention.
  • EP1631279 relates to a combination composition and a method for the treatment of neoplasms.
  • the composition comprises a HMG-CoA reductase inhibitor and an azole compound.
  • HMG-CoA inhibitors there are particularly mentioned and claimed, among others, simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin and pitavastatin
  • azole compounds there are particularly mentioned and claimed, among others, fluconazole, itraconazole, posaconazole, ketoconazole, clotrimazole and miconazole.
  • neoplasms there are mentioned cancer of colon and lung, non small-cell lung carcinoma, cancer of ovary and prostate, and leukaemia.
  • PCT publication No. WO03086418 relates to a method for treating mammals afflicted by tumor/cancer by administering a polyene macrolide antibiotic and, preferably, an agent lowering the level of cholesterol.
  • a polyene macrolide antibiotic there is particularly mentioned and claimed, among others, nystatin, whereas among the agents lowering the level of cholesterol there are particularly mentioned and claimed, among others, pravastatin, simvastatin, lovastatin, fluvastatin, cerivastatin and atorvastatin.
  • the mentioned tumors/cancers are cancer of prostate, breast, ovary, tumor of kidney and epidermal carcinoma of mouth.
  • PCT publication No. WO07041677 discloses a device consisting of a combination of an implant and a drug which device inhibits scarring and formation of connective tissue between the implant and the tissues.
  • the combination of lovastatin and itraconazole furthermore in general, a combination of an azole compound with a HMG-CoA reductase inhibitor and, more generally, a combination of an antimycotic agent and a HMG-CoA reductase inhibitor.
  • US2005276836 discloses a vaginal device for delivery of therapeutic and sanitary substances.
  • substances used to coat the device there are mentioned, among many others, inhibitors of COXl and COX2, such as lovastatin, furthermore, as possible combination partners, amphothericin B, clotrimazole, fluconazole, itraconazole, ketoconazole, miconazole, nystatin and voriconazole.
  • This application does, however, not mention either the fact that the said substances could be used as combinations having two members, or the enhanced antimycotic effect of the said combinations.
  • WO2006072881 discloses combination compositions comprising a therapeutically effective amount of the 2S,4R-enantiomer of ketoconazole and an agent lowering the level of cholesterol such as an HMG-CoA reductase inhibitor selected from the group of statins.
  • an HMG-CoA reductase inhibitor selected from the group of statins.
  • statins such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and rosuvastatin
  • statins such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and rosuvastatin
  • hyperglycaemia insulin resistance
  • lipidaemias and several forms of diabetic retinopathy, nephropathy and neuropathy.
  • PCT publication No. WO2005023228 discloses a pharmaceutical formulation system enhancing the release of the substances having no or limited water-solubility into an aqueous environment.
  • acitve ingredients of the pharmaceutical formulation to be administered orally there are particularly mentioned and claimed, among others, amphotericin B, fluconazole, ketoconazole, griseofulvin, itraconazole, miconazole, terbinafine, atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, simvastatin and combinations thereof.
  • PCT publication No. WO2007143557 discloses a method for treating gastro-intestinal parasitic infections of mammals.
  • the treatment comprises, among others, administration of a pharmaceutical composition.
  • inhibitors of HMG-CoA such as lovastatin;
  • the pharmaceutical composition may comprise, among others, antimycotic agents, such as fluconazole, itraconazole, ketoconazole, voriconazole, amphotericin B and nystatin.
  • PCT publication No. WO0048636 discloses pharmaceutical compositions comprising one or more active ingredient(s) and a special pharmaceutical component enhancing the absorption of the active ingredient(s), moreover phosphatidylcholine.
  • antibiotics such as primycin
  • antimycotic agents such as amphotericin B, nystatin, griseofulvin, terbinafine, clotrimazole, ketoconazole, miconazole, fluconazole, itraconazole and HMG-CoA reductase inhibitors, such as lovastatin, pravastatin and simvastatin.
  • US20020071822 discloses a polymer for the treatment of Parkins.on's disease, wherein the polymer comprises, among others, one or more biologically active substance(s).
  • the biologically active substances may be, among others, atorvastatin, pravastatin, fluvastatin, amphotericin B, primycin and nystatin.
  • EP 1275373 discloses a drug delivery system for avoiding interactions between several active ingredients and other contaminants that could negatively influence the release time and/or release site of the active ingredient.
  • active ingredients and contaminants there are particularly mentioned, among others, itraconazole, ketoconazole, lovastatin, fluvastatin, simvastatin, atorvastatin and combinations thereof.
  • Published US application No. US200501 182272 relates to a fast releasing medicine or medicinal foodstuff comprising at least one active ingredient, at least one wetting agent and at least one solvent.
  • ketoconazole ketoconazole
  • miconazole miconazole
  • voriconazole pitavastatin
  • pitavastatin pitavastatin
  • rosuvastatin rosuvastatin
  • the aim of the present invention was to develop combination compositions the use of which at low doses effectively inhibits the growth of fungi, thereby making possible the reduction of the used amounts of the anitmycotic agents.
  • the aim was, furthermore, to develop combinations wherein the similar solubility of the comprised agents enables the administration thereof in uniform pharmaceutical formulas to be applied externally or internally such as particularly in the form of tablets, capsules, creams, gels, ointments, powders, lacquers, solutions, foams etc.
  • the present invention is based on the recognition that certain combinations which have not been known till now show enhanced antimycotic effect. Furthermore, we have recognized that combinations described in the state of the art for other indications show enhanced antimycotic effect. The occurrence of a synergic interaction between the different active agents cannot be afore-seen on the basis of the known features of the different active agents. This is supported by the fact that certain combinations formed from active agents does not show such an advantageous activity as combinations formed from structurally similar other active agents. This fact can be concluded also from the documents forming the state of the art.
  • statin as used in the present specification, it is meant a kind of medicine lowering the level of cholesterol the effect of which is based on the selective inhibition of 3-hydroxy-3-methyl- glutaryl coenzyme A (HMG-CoA) reductase enzyme.
  • HMG-CoA 3-hydroxy-3-methyl- glutaryl coenzyme A
  • the enzyme catalyzes the conversion of HMG- CoA into mevalonic acid which step determines the speed of the isoprenoid biosynthetic pathway. Inhibition of the enzyme results in the early blocking of the cholesterol biosynthetic pathway.
  • statin involves all structural and optical isomers of statins and all christal forms and modifications thereof, too.
  • antimycotic agent and “antifungal agent”, which are equivalent as used in the present specification, it is meant a medicinal substance used for the treatment or prevention of local and/or systemic infections caused by fungi.
  • antimycotic agent of azole type and "antifungal agent of azole type", which are equivalent as used in the present specification, it is meant a compound of natural or synthetic origin containing a five-membered aromatic heterocycle comprising at least one nitrogen, sulfur or oxygen atom beside carbon atoms and exerting an effective antimycotic (antifungal) activity.
  • the antimycotic (antifungal) azole compounds inhibit the action of the enzyme citochrome P450 14 ⁇ -demethylase which is an enzyme component of the biosynthetic pathway of ergosterol, a component of the cell-membrane of fungi.
  • antimycotic agent (and antifungal agent) of azole type involves all structural and optical isomers of the said compounds and all christal forms and modifications thereof, too.
  • dose as used in the present specification, it is meant a portion, an amount of a medicine to be taken according to the physician's prescription, regardles of its expression form as unit. In the present specification and claims a dose may be expressed in the forms of mg/kg body weight pro day, mg/day, % by weight, % by volume, % by weight/volume etc.
  • serum level as used in the present specification, it is meant a concentration of the substance in question in the blood-serum.
  • prodrug as used in the present specification, it is meant a substance wherefrom another substance, an element of the synthetic pathway of the substance in question, is formed by chemical reactions which result in a stable end-product of the synthetic pathway,
  • metabolism a substance taking part in the metabolism (decomposition), a substance taking part or being formed in the decomposition of complex organic compounds or in metabolic processes.
  • synergism is in general sense: if a combination of two active components enhances the intensity or duration of the effects of the components by a greater extent than the algebraical sum of the separate effects.
  • synergism an interaction calculated by the mathematical relation (Abbott's formula) used for determinig the synergism:
  • Y represents the percentage of inhibition caused by the antifungal agent itself. If the obtained value is 0.5 ⁇ IR ⁇ 1.5, the interaction is additive; if IR > 1.5, the interaction is synergic, whereas if IR ⁇ 0.5, the interaction is antagonistic.
  • additive is in general sense: if a combination of two active components enhances the intensity or duration of the effects of the components and this effect is equal to the algebraical sum of the separate effects.
  • additive as used in the present specification, it is meant an interaction calculated by the mathematical relation (Abbott's formula) used for determinig the synergism.
  • the present invention relates, in a first aspect, to a combination comprising one or more active component(s) having antimycotic activity [i.e. antimycotic agent(s)] and one or more statin(s), a prodrug or a metabolite thereof for the use as an agent inhibiting the growth of fungi.
  • the antimycotic agent may be a compound of azole type, without to be limited thereto.
  • An antimycotic agent used in the present invention is preferably selected from the group of amphotericin B, nystatin, griseofulvin, primycin, ketoconazole, miconazole, fluconazole, itraconazole, clotrimazole, posaconazole, voriconazole, terbinafine, a prodrug thereof or a metabolite thereof.
  • the statin used in the present invention is preferably selected from the group of lovastatin, simvastatin, fluvastatin, pravastatin, rosuvastatin, atorvastatin, cerivastatin, pitavastatin or a prodrug or a metabolite of the said compounds.
  • the combination of the present invention may comprise one or more whether of the antimycotic agent(s) or of the statin(s), with the proviso that the combination is different from the following ones: amphotericin B and fluvastatin; ketoconazole and lovastatin; fluconazole and lovastatin; fluconazole and fluvastatin; fluconazole and pravastatin; itraconazole and fluvastatin; voriconazole and lovastatin; voriconazole and fluvastatin.
  • the combination of the present invention comprising one or more of antimycotic agent(s) and statin(s) or a prodrug or a metabolite of the said compounds, comprises the active components preferably in a clinically acceptable dose.
  • the clinically acceptable daily dose as used in the present specification and claims, for an adult person with a body weight of 65 to 70 kg is preferably
  • (xiii) in the case of voriconazole if administered orally, 0.1 to 400 mg/day, preferably 0.1 to 100 mg/day, more preferably 0.1 to 50 mg/day; if administered intavenously, 0.1 to 12 mg/kg body weight/day; if adminstered topically, a concentration of 0.001 to 5 % by weight;
  • the present invention relates to a combination composition having antimycotic effect comprising a combination of an active component having antimycotic activity and a statin, a prodrug or a metabolite of the said compounds selected from the goup consisting of (i) amphotericin B and rosuvastatin, (ii) amphotericin B and pitavastatin, (iii) primycin and rosuvastatin, (iv) primycin and cerivastatin, (v) primycin and pitavastatin, (vi) voriconazole and simvastatin, (vii) voriconazole and pravastatin, (viii) voriconazole and atorvastatin, (ix) voriconazole and cerivastatin, and optionally pharmaceutically acceptable excipients.
  • the preferred composition of the invention comprises the active components in a clinically acceptable dose.
  • the clinically acceptable doses contain in the case of combination (i), 0.1 to 99 % by weight of amphotericin B and 0.1 to 99 % by weight of rosuvastatin; in the case of combination (ii), 0.1 to 99 % by weight of amphotericin B and 0.1 to 99 % by weight of pitavastatin, in the case of combination (iii), 0.1 to 99 % by weight of primycin and 0.1 to 99 % by weight of rosuvastatin, in the case of combination (iv), 0.1 to 99 % by weight of primycin and 0.1 to 99 % by weight of cerivastatin, in the case of combination (v), 0.1 to 99 % by weight of primycin and 0.1 to 99 % by weight of pitavastatin, in the case of combination (vi), 0.1 to 99 % by weight of voriconazole and 0.1 to 99 % by weight of simvastatin, in the case of combination (vii), 0.1
  • Candida spp. such as Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, Candida giiillermondii, Candida krusei and Candida kefyr
  • Cryptococcus spp. such as Cryptococcus neoformans
  • Pneumocystis carinii Aspergillus spp. (such as Aspergillus flavus, Aspergillus fiimigatus, Aspergillus terreus, Aspergillus repens, Aspergillus versicolor), Mucor spp.
  • Rhizomucor spp. such as Rhizomucor pusillus, Rhizomucor iniehei
  • Rhi ⁇ opus spp. such as Rhizopus oryzae, Rhizopus microsporus var. microporus, Rhizopus microsporus var.
  • rhizopodiformis Rhizopus schipperae
  • Absidia such as Absidia corymbifera
  • Apophysomyces such as Apophysomyces elegans
  • Cunninghamella such as Cunninghamella bertholletiae
  • Saksenaea such as Saksenaea vasiformis
  • Cokeromyces such as Cokeromyces recurvatus
  • Syncephalastrum such as Syncephalastrum racemosum
  • Basidiobolus such as Basidiobolus ranarum
  • Conidiobolus such as Conidiobolus coronatus
  • Coccidioides spp. (such as Coccidioides immitis), Paracoccidioides spp.
  • spp. such as Paracoccidioides brasiliensis
  • Histoplasma spp. such as Histoplasma capsulatum
  • Blastomyces spp. such as Blastomyces dermatitidis
  • Trichophyton spp. such as Trichophyton mentagrophytes, Trichophyton rubrum
  • Microsporum spp. such as Microsporum canis, Microsporum gypseum
  • Epidermophyton spp. such s Epidermophyton floccosum
  • Geotrichum such as Geotrichum clavatum, Geotrichum candidum
  • Trichosporon such as Trichosporon beigelii
  • Blastoschi ⁇ omyces such as Blastoschizomyces capitatus
  • Sporothrix such as Sporothrix schenckii
  • Scedosporium such as Scedosporium apiosperum, Scedosporium proli ⁇ cans
  • Cladosporium such as Cladosporium cladosporioides, Cladosporium sphaerospermum
  • Acremonium spp such as Pityrosporum orbiculare (Malassezia furfur)
  • Geotrichum such as Geotrichum clavatum, Geotrichum candidum
  • Trichosporon such as Trichosporon beigelii
  • Blastoschi ⁇ omyces such as Blastoschizomyces capitatus
  • Sporothrix such as Sporothrix schenckii
  • compositions according to the present invention can be used preferably against the following species of fungi: Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, Candida giiillermondii, Candida krusei, Candida kefyr, Aspergillus flavus, Aspergillus fiimigatus, Rhizopus oryzae, Trichophyton mentagrophytes, Trichophyton rubrum, Microspomm canis, Microsponim gypseiim, Pityrosponim orbicitlare.
  • the present invention relates to the combination composition of the ionvention formulated as a medicine.
  • the medicine may be in a form to be administered externally or internally, such as particularly, but not limited to, a tablet, capsule, cream, gel, ointment, powder, lacquer, solution, foam.
  • the present invention relates to the combination composition of the invention for the use as medicine, especially as a medicine having antimycotic effect.
  • the present invention relates to the use of the combinations of active components of the invention for preparing compositions having enhanced antimycotic effect.
  • statins are based upon the selective inhibition of 3-hydroxy- 3-methylglutaryl-coenzyme A (HMG-CoA) reductase enzyme.
  • HMG-CoA 3-hydroxy- 3-methylglutaryl-coenzyme A reductase enzyme.
  • the enzyme catalyzes the conversion of HMG-CoA into mevalonic acid which step determines the speed of the isoprenoid biosynthetic pathway, thus the statins inhibit the biosynthesis of sterols. Since ergosterol, also a compound of isoprenoid type, is one of the components of the cell membrane of fungi, statins are effective in inhibition of the growth of fungi.
  • the antimycotic agents exploiting the difference between the human cells and the cells of fungi, selectively inhibit the proliferation of fungi. Their mechanism of action can be extraordinarily diverse.
  • the joint use of both agents inhibiting the growth of fungi strenghtens the intensity and duration of each other's effect, which may be greater than the algebraical sum of the separate effects; consequently, statins and the antifungal agents show synergic interaction, thus, their joint use can result in the production of a more effective antimycotic composition.
  • Example 1 Study of the interactions of combinations comprising fluvastatin and ketoconazole in vitro in Candida albicans
  • MOPA morpholinopropanesulfonic acid
  • 40 mg of the active agent were dissolved in 1 ml of methanol and further diluted with methanol, and the stock-solution of a concentration of 2,5 mg/ml so obtained was used for producing series of dilution.
  • the stock-solutions of fluvastatin were prepared always freshly.
  • ketoconazole (Sigma) a stock-solution of a concentration of 5 mg/ml was prepared by dissolving the compound in dimethylsulphoxide (DMSO) which was then diluted with DMSO to a concentration of 1.6 mg/ml.
  • DMSO dimethylsulphoxide
  • Stock-solutions of ketoconazole were stored at a temperature of -70°C for at most 6 months. Stock-solutions produced from the store of -70°C were used in the studies.
  • Y represents the percentage of inhibition caused by ketoconazole itself.
  • Ketoconazole itself causes an inhibition of about 70% even at the lowest concentration, but the level of inhibition cannot be increased by using higher concentrations.
  • Fluvastatin itself causes a total inhibition at a concentration of 6.25 ⁇ g/ml, but the use of combinations at concentrations as low as 0.78 35 ⁇ g/ml of fluvastatin and 0.06 ⁇ g/ml of ketoconazole or 1.56 ⁇ g/ml of fluvastatin and 0.03 ⁇ g/ml of ketoconazole can result in a total inhibition.
  • Table 1 Interactions of combinations comprising fluvastatin and ketoconazole
  • Example 2 Study of the interactions of combinations comprising pravastatin and miconazole in vitro in Candida glabrata
  • pravastatin In the case of pravastatin (Sigma) 25 mg of the active agent were dissolved in 1 ml of distilled water, then further diluted with distilled water, and the stock-solution of a concentration of 2.5 mg/ml so obtained was used for producing series of dilution.
  • miconazole a stock-solution of a concentration of 5 mg/ml was prepared by dissolving the compound in DMSO and then diluting with DMSO to a concentration of 1.6 mg/ml. Stock-solutions were stored at a temperature of -70°C for at most 6 months. Stock-solutions produced from the store of -70°C were used in the studies.
  • Counting of cells was carried out with the aid of a Burker chamber, l * 10 3 cells/well were used as inoculum. 50 ⁇ l of twenty-five-fold diluted pravastatin, 50 ⁇ l of twenty-five-fold diluted miconazole and 100 ⁇ l of cell suspension were added to each well of the microtiter plate. Consequently, in the wells of the microtiter plate the concentrations of pravastatin were 25 through 0.39 ⁇ g/ml in the series of halving dilution, the concentrations of miconazole were 16 through 0.03 ⁇ g/ml in the series of halving dilution.
  • simvastatin Vasilip, Egis
  • 40 mg of active agent were dissolved in 1 ml of methanol, then the prodrug form was transformed into open-chain acid form by basic hydrolysisn that is by incubating in a solution containing 15% of ethanol and 0.25% by weight/volume of NaOH at a temperature of 60 0 C for 60 minutes.
  • the solution was further diluted with methanol, and the stock- solution of a concentration of 2.5 mg/ml so obtained was used for producing series of dilution.
  • the stock- solutions were always freshly prepared.
  • primycin Pannonpharma
  • a stock-solution of a concentration of 10 mg/ml was prepared by dissolving the compound in DMSO and then diluting with DMSO to a concentration of 6.4 mg/ml.
  • Stock-solutions were stored at a temperature of -70 0 C for at most 6 months.
  • Stock-solutions produced from the store of -7O 0 C were used in the studies.
  • Counting of cells was carried out with the aid of a Burker chamber, l ⁇ l ⁇ 3 cells/well were used as inoculum. 50 ⁇ l of twenty-five-fold diluted simvastatin, 50 ⁇ l of twenty-five-fold diluted primycin and 100 ⁇ l of cell suspension were added to each well of the microtiter plate. Consequently, in the wells of the microtiter plate the concentrations of simvastatin were 25 through 0.39 ⁇ g/ml in the series of halving dilution, the concentrations of primycin were 16 through 0.03 ⁇ g/ml in the series of halving dilution.
  • atorvastatin (Atorvox, Richter) 20 mg of active agent were dissolved in 1 ml of methanol, then the solution was further diluted with methanol, and the stock-solution of atorvastatin of a concentration of 2.5 mg/ml so obtained was used for producing series of dilution. The stock-solutions were always freshly prepared. In the case of itraconazole (Sigma) a stock-solution of a concentration of 5 mg/ml was prepared by dissolving the compound in DMSO and then diluting with DMSO to a concentration of 0.8 mg/ml. Stock-solutions were stored at a temperature of -70 0 C for at most 6 months.
  • Counting of cells was carried out with the aid of a Burker chamber, 1 * 10 4 spores/well were used as inoculum.
  • 50 ⁇ l of twenty-five-fold diluted atorvastatin, 50 ⁇ l of twenty-fivefold diluted itraconazole and 100 ⁇ l of spore susupension were pipetted into each well of the microtiter plate. Consequently, in the wells of the microtiter plate the concentrations . of atorvastatin were 25 through 0.39 ⁇ g/ml in the series of halving dilution, the concentrations of itraconazole were 8 through 0.015 ⁇ g/mi in the series of halving dilution.
  • Atorvastatin by itself shows an inhibition of 40% used at a concentration of 25 ⁇ g/ml
  • itraconazole by itself causes a total inhibition at a concentration of 0.25 ⁇ g/ml.
  • the concentration of itraconazole necessary for a total inhibition can be reduced by one or two dilution stage(s), thus a total inhibition of growth can be achieved by the use of combinations at concentrations as low as 6.25 ⁇ g/ml of atorvastatin and 0.06 ⁇ g/ml of itraconazole or 0.39 ⁇ g/ml of atorvastatin and 0.125 ⁇ g/ml of itraconazole.
  • Table 4 The results of Example 4 are summarized in Table 4.
  • Counting of cells was carried out with the aid of a Burker chamber, 1 * 10 4 spores/well were used as inoculum.
  • 50 ⁇ l of twenty-five-fold diluted fluvastatin, 50 ⁇ l of twenty-five-fold diluted miconazole and 100 ⁇ l of spore suspension were pipetted into each well of the microtiter plate. Consequently, in the wells of the microtiter plate the concentrations of fluvastatin were 25 through 0.39 ⁇ g/ml in the series of halving dilution, the concentrations of miconazole were 16 through 0.03 ⁇ g/ml in the series of halving dilution.
  • Example 6 Study of the interactions of combinations comprising atorvastatin and ketoconazole in vitro in Rhizopus oryzae
  • Counting of cells was carried out with the aid of a Burker chamber, l * 10 4 spores/well were used as inoculum.
  • 50 ⁇ l of twenty-five-fold diluted atorvastatin, 50 ⁇ l of twenty- five-fold diluted ketoconazole and 100 ⁇ l of spore suspension were pipetted into each well of the microtiter plate. Consequently, in the wells of the microtiter plate the concentrations of atorvastatin were 25 through 0.39 ⁇ g/ml in the series of halving dilution, the concentrations of ketoconazole were 16 through 0.03 ⁇ g/ml in the series of halving dilution.
  • Atorvastatin by itself shows an inhibition of 60% used at a concentration of 25 ⁇ g/ml
  • ketoconazole by itself causes a total inhibition at a concentration of 4 ⁇ g/ml.
  • the concentration of ketoconazole necessary for a total inhibition can be reduced by one or two dilution stage(s) when used in combination with atorvastatin, thus a total inhibition of growth can be achieved by the use of combinations at concentrations as low as 3.125 ⁇ g/ml of atorvastatin and 1 ⁇ g/ml of ketoconazole or 0.39 ⁇ g/ml of atorvastatin and 2 ⁇ g/ml of ketoconazole.
  • Table 6 The results of Example 6 are summarized in Table 6.
  • statin used in combination was different from simvastatin, fluvastatin, atorvastatin and pravastatin
  • the stock-solutions were prepared in the following way.
  • lovastatin Mevacor, MSD
  • 40 mg of the active agent were dissolved in 1 ml of methanol, then the prodrug form was transformed into active open-chain acid form by basic hydrolysis, that is by carrying out incubation in a solution containing 15% of ethanol and 0.25% by weight/volume of NaOH at a temperature of 6O 0 C for 60 minutes.
  • the solution was further diluted with methanol, and the stock-solution of lovastatin of a concentration of 2.5 mg/ml so obtained was used for producing series of dilution.
  • rosuvastatin 10 mg of the active agent were dissolved in 1 ml of methanol, then the solution was further diluted with methanol, and the stock-solution of rosuvastatin of a concentration of 2.5 mg/ml so obtained was used for producing series of dilution. The stock-solutions were always freshly prepared.
  • the stock-solutions were prepared in the following way.
  • fluconazole or griseofulvin a stock-solution of a concentration of 10 mg/ml was prepared by dissolving the compound in dimethylformamid (DMF) and then diluting with DMF to a concentration of 6.4 mg/ml.
  • nystatin a stock-solution of a concentration of 5 mg/ml (22,000 U) was prepared by dissolving the active compound in dimethylsulphoxide, which was then diluted with DMSO to a concentration of 0.8 mg/ml.
  • a stock-solution of a concentration of 5 mg/ml was prepared by dissolving the active compound in dimethylsulphoxide and then diluting with DMSO to a concentration of 0.8 mg/ml.
  • Stock-solutions were stored at a temperature of -7O 0 C for at most 6 months.
  • Stock-solutions produced from the store of -7O 0 C were used in the studies.
  • the concentration of the factory-made stock-solution of amphotericin B is 250 ⁇ g/ml. It was stored at a temperature of -2O 0 C in a package protecting from light.
  • synergic interactions between the statins and antifungal agents have been observed in the case of a number of combinations.
  • the level of interactions have been determined with the aid of Abbott's formula.
  • This calculation formula takes into consideration the values of the measured absorbance and the inhibition values claculated therefrom, whereas in the case of other formulas the calculation is based on the subjectively determined value of MIC (Minimal Inhibitory Concentration).
  • MIC Minimum Inhibitory Concentration
  • the calculation with the aid of Abbott's formula demonstrates that the interaction is not synergic but only additive, nevertheless by the use of both agents together a higher level of inhibition can be achieved than those by themselves, or else, a total inhibition can be achieved at lower concentration if the agents are used in combination. In a number of cases it can be observed among the combinations of statins and antifungal agents that the combined use results in a higher effect.
  • statin/antifungal agent combinations are stressed in Table 7 which have shown high levels of inhibition of growth in the case of most fungi even at low concentrations and which show extraordinary effectiveness in the case of certain groups of fungi.

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102911877A (zh) * 2012-08-27 2013-02-06 浙江工业大学 一株海洋真菌分枝孢子菌属真菌球孢枝孢及其应用
CN107957477A (zh) * 2017-12-20 2018-04-24 郑州泰丰制药有限公司 一种采用非水滴定法测定泊沙康唑含量的方法
US10406132B2 (en) 2015-03-09 2019-09-10 The Children's Mercy Hospital Dermatophytosis prophylaxis and treatment

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1498139A1 (en) * 2002-04-12 2005-01-19 Kowa Company Ltd. Novel thrombomodulin expression promoters

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1498139A1 (en) * 2002-04-12 2005-01-19 Kowa Company Ltd. Novel thrombomodulin expression promoters

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
GALGÓCZY LÁSZLÓ ET AL: "Interactions between statins and Penicillium chrysogenum antifungal protein (PAF) to inhibit the germination of sporangiospores of different sensitive Zygomycetes.", FEMS MICROBIOLOGY LETTERS MAY 2007, vol. 270, no. 1, May 2007 (2007-05-01), pages 109 - 115, XP002538382, ISSN: 0378-1097 *
GILAD R ET AL: "Rhabdomyolysis induced by simvastatin and ketoconazole treatment.", CLINICAL NEUROPHARMACOLOGY 1999 SEP-OCT, vol. 22, no. 5, September 1999 (1999-09-01), pages 295 - 297, XP009120385, ISSN: 0362-5664 *
HAUGHAN P A ET AL: "Synergism in vitro of lovastatin and miconazole as anti-leishmanial agents", BIOCHEMICAL PHARMACOLOGY, PERGAMON, OXFORD, GB, vol. 44, no. 11, 1 December 1992 (1992-12-01), pages 2199 - 2206, XP023737238, ISSN: 0006-2952, [retrieved on 19921201] *
ISHIGAM M ET AL: "Inhibition of in vitro metabolism of simvastatin by itraconazole in humans and prediction of in vivo drug-drug interactions.", PHARMACEUTICAL RESEARCH MAY 2001, vol. 18, no. 5, May 2001 (2001-05-01), pages 622 - 631, XP002538384, ISSN: 0724-8741 *
KRISHNAN S ET AL: "In Vitro Activities of Statins (Anti-Cholesterol Drugs) Alone and in Combination with Antifungal Drugs against Aspergillus species.", ABSTRACTS OF THE INTERSCIENCE CONFERENCE ON ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 46, 2006, & 46TH INTERSCIENCE CONFERENCE ON ANTIMICROBIAL AGENTS AND CHEMOTHERAPY; SAN FRANCISCO, CA, USA; SEPTEMBER 27 -30, 2006, pages 399, XP001539607, ISSN: 0733-6373 *
MAXA JAN L ET AL: "Rhabdomyolysis after concomitant use of cyclosporine, simvastatin, gemfibrozil, and itraconazole.", THE ANNALS OF PHARMACOTHERAPY MAY 2002, vol. 36, no. 5, May 2002 (2002-05-01), pages 820 - 823, XP009120383, ISSN: 1060-0280 *
MAZZU A L ET AL: "Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin.", CLINICAL PHARMACOLOGY AND THERAPEUTICS OCT 2000, vol. 68, no. 4, October 2000 (2000-10-01), pages 391 - 400, XP009120380, ISSN: 0009-9236 *
QIAO JIANJUN ET AL: "Antifungal activity of statins against Aspergillus species.", MEDICAL MYCOLOGY : OFFICIAL PUBLICATION OF THE INTERNATIONAL SOCIETY FOR HUMAN AND ANIMAL MYCOLOGY NOV 2007, vol. 45, no. 7, November 2007 (2007-11-01), pages 589 - 593, XP009120319, ISSN: 1369-3786 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102911877A (zh) * 2012-08-27 2013-02-06 浙江工业大学 一株海洋真菌分枝孢子菌属真菌球孢枝孢及其应用
CN102911877B (zh) * 2012-08-27 2013-11-13 浙江工业大学 一株海洋真菌分枝孢子菌属真菌球孢枝孢及其应用
US10406132B2 (en) 2015-03-09 2019-09-10 The Children's Mercy Hospital Dermatophytosis prophylaxis and treatment
US11154527B2 (en) 2015-03-09 2021-10-26 The Children's Mercy Hospital Dermatophytosis prophylaxis and treatment
CN107957477A (zh) * 2017-12-20 2018-04-24 郑州泰丰制药有限公司 一种采用非水滴定法测定泊沙康唑含量的方法
CN107957477B (zh) * 2017-12-20 2020-06-19 郑州泰丰制药有限公司 一种采用非水滴定法测定泊沙康唑含量的方法

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