CN1130062A - Syringene oxide used as antifungal - Google Patents
Syringene oxide used as antifungal Download PDFInfo
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- CN1130062A CN1130062A CN 95119433 CN95119433A CN1130062A CN 1130062 A CN1130062 A CN 1130062A CN 95119433 CN95119433 CN 95119433 CN 95119433 A CN95119433 A CN 95119433A CN 1130062 A CN1130062 A CN 1130062A
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Abstract
This invention discloses the features of oxidated caryophyllene on fungus resistance and bacteria killing, especially its inhibiting effect on dermatic tricophye. Oxidated caryo-phyllene features curing dermatic mycosis, especially being a new antifungal agent for short-term curing mycosis A, strong unguis permeability, bacteria killing, good dermatic drug-resistance, dispelling inflammation, function of permeability-aid, and anti-inducer of cancer.
Description
The present invention relates to the new purposes of trans-Caryophyllene oxide (caryophyllene oxide).
Dermatophytes and bacterial infection are global infectious disease, and its generation is along with the use of broad-spectrum antibiotic, environmental pollution, immunosuppressant especially immune deficiency or inhibition crowd such as rolling up of AIDS VICTIMS and increase.Wherein tinea unguium (onychomycosis) is the most common, infection rate 10-40%, account for the 18-40% of finger (toe) first disease, account for 40% of all skin fungus diseases (dermatophytose), and the external or the oral dermatologic medicine of existing clinical use seem powerless like that, as griseofulvin (griseofulvin) as one of a kind of medicine commonly used for the treatment of tinea unguium, oral 18 months (toenail tinea) and 12 months (fingernail tinea) effective percentage reach 40% and 70% respectively, wherein 20% patient recurrence again after a year; Hexamethylene is given a tongue-lashing ketone cholamine (ciclopirox) effective percentage and is also had only 60%.Cause the reason of this situation mainly to be: the antifungal poor selectivity of existing clinical use, negative interaction is big, low, the saturating first ability of skin drug resistance (nail penetration) is weak and treatment cycle is long etc.
The purpose of this invention is to provide a kind of inexpensive, specially good effect, kill antibacterial, drug resistance is good and the strong new antifungal of finger (toe) first ability thoroughly.
The realization of the object of the invention is based on finds that trans-Caryophyllene oxide has antifungal and antibacterial characteristic, and has good saturating first ability, thereby has found a kind of new antifungal.
Antifungal feature of the present invention is the trans-Caryophyllene oxide that contains effective dose.
Trans-Caryophyllene oxide is the oxidation caryophyllene again, and its molecular formula is CG
15H
24O, chemical structural formula is:
It is a white crystal, molecular weight 220.36, fusing point 45-59 ℃, freezing point＞230 (110 ℃).It is a kind of many plant volatile oils that are present in, especially the sesquiterpene of Oleum Caryophylli (sesquiterpenoid) material also is plant such as Herba Menthae, Herba Buddlejae Lindleyanae, Betula platyphylla Suk., lavandula angustifolia, presses one of phytovolatilization maiies body of oil such as tree, slender acanthopanax tree, Drymotaenium miyoshianum (Mak.) Mak., Salvia japonica Thunb., Fructus Piperis, Cuculus polioephalus and Fructus Cannabis.Under naturalness, trans-Caryophyllene oxide normal with α-, the fragrant alkene of β-et γ-J (α-, β-et γ-caryophyllene) mixes existence.
Trans-Caryophyllene oxide is widely used in human food's additive for a long time, cosmetic essence or spice and pharmaceutical preparation adjuvant drug (drug adjuvant), its nothing (little, weak) poison and well drug resistance (medicinal oral or external, zest, sensitivity, heliosensitivity, mutagenicity etc.) by many studies confirm that of modern times.United States Patent (USP) Oleum Caryophylli perfume in 1978 is that the homologue with trans-Caryophyllene oxide and bis oxide hydrogen Flos Caryophylli alkene is made into; Discovered that this material had anti-inflammatory effect to the Mus pawl edema that is caused by carrageenin in 1994; The work in the same year confirms that then trans-Caryophyllene oxide kills skin (tinea) demodicid mite (common anaphylactogen in the room air) effect; 1994 and nineteen ninety-five Cornwell P.A. and Barry B.W. be the good skin permeation-promoter with hydrophilic 5-fluorouracil and lipophilic estradiol at the diffusion profile statistical confirmation trans-Caryophyllene oxide of skin; In addition, the anti-of this material lures cancer thing, anthelmintic, anti-food leaf ant and the effect of commensalism bacterium thereof all to be confirmed by modern study.
But prior art about the report of trans-Caryophyllene oxide treatment fungus and bacterial dermatosis, does not have the record of its saturating first ability aspect yet.
The present invention directly is located away from the fungus of dermatosis patient and normal population and external antifungal and the antibacterial characteristic that bacterial studies has been found trans-Caryophyllene oxide with 33 kinds, continues it, and according to its anti-skin fungus effectiveness, its good saturating first ability is proved.
Verified, trans-Caryophyllene oxide is preferably 60-500 μ g/mL as the inhibition concentration of the inhibitor of dermatophytosis, and all the other are solvent and/or other adjuvant.
Trans-Caryophyllene oxide is non-specific antibacterial antibacterial, and the antibacterial of especially relevant with bromhidrosis and beriberi skin bacterium can be used for the treatment of beriberi and bromhidrosis.
Trans-Caryophyllene oxide sees through the keratin first in a short time soon, suppresses or kills pathomycete.
Trans-Caryophyllene oxide can be as the externally used solution concentration expressed in percentage by weight of preparation of treatment tinea unguium and is not less than 1%, is preferably 3-8%, 5-8% more preferably, and all the other are solvent and/or other adjuvant.
Trans-Caryophyllene oxide can be mixed and made into medicament with common solvent in any this area or adjuvant.Described solvent or adjuvant be dimethyl sulfoxide, polysorbate85, sterilized water or its mixture etc. for example.
Trans-Caryophyllene oxide of the present invention is as new antifungal, it is sick as tinea capitis, tinea corporis, tinea unguium, the tinea manuum and tinea barbae to be used for the treatment of skin fungus, especially treat mycosis ungualis, have specially good effect, saturating first ability strong, kill thin (preventing antibacterial repeated infection), do not have (little, low) poison, the skin drug resistance is good, antiinflammatory, permeation-promoter effect, the anti-advantage such as cancer thing that lures.
Describe the present invention in detail below by concrete experiment.The experiment with the trans-Caryophyllene oxide sample purchase in ALDRICH CHimie sar1 (SIGMA-ALDRICH-Chimie, 1 ' lsle D ' abeau chesnes, Fallavier, FRANCE).
Experiment 1
This experiment is for confirming the antifungal effectiveness of trans-Caryophyllene oxide.
One, research method
1, for examination skin pathomycete and culture medium
17 kinds of skin pathomycetes are subordinate to dermatophytosis, ferment vehicle fungus and filamentary mould (crying the condition pathomycete again), and list is as follows:
Skin tinea (moss) bacterium Dermatophyytes)
Trichophyton rubrum (red moss bacterium)
Trichophyton mentagrophytes (beard and hair moss bacterium)
Trichophyton soudanense (the Sudan Nai Sifa moss bacterium)
Trichophyton violaceum (violet moss bacterium)
Trichophyton interdigitale (sending out the moss bacterium between toe)
Epidermatophton floccosum (cotton-shaped epidermis moss bacterium)
Microsporum canis (the little spore bacterium of Canis familiaris L.)
Microsporumgypseum (the little spore of Gypsum Fibrosum shape is mould)
Yeast type fungus (Pathogenic yeasts)
Cryptococcus neoformans (novel Cryptococcus)
Pityrosporum ovale (ovum pityrosporum ovale)
Candida krusei (candida krusei)
Candida parapsilopsis (Candida parapsilosis)
Candida albicans (candida albicans, Candida albicans)
Torulopsis glabrata (torulopsis glabrata)
Filamentary mould (Filamentous fungi or opportunists)
Aspergillus fumigatus (the cigarette allusion quotation is mould)
Aspergillus flavus (yellow allusion quotation is mould)
Scopulariopsis brevicaulis (the short handle broom is mould) illustrates: middle translated name the Sudan Nai Sifa moss bacterium (Trichophyton soudanense) is translated from " drawing Chinese microorganism noun " (Chinese Medicine science and technology publishing house); Send out moss bacterium (Trichophyton interdigitale) between toe and be translated from " drawing Chinese medicine to learn vocabulary " (Science and Technology of Shanghai publishing house, 1981), other fungus all is translated from " cryptogam noun and title " (Science Press, nineteen ninety).
These funguses are directly to be separated on one's body from dermatosis patient by Besancon CHR hospital, but wherein novel Cryptococcus by separate in HIV (human immunodeficiency virus) patient or AIDS (AIDS) patient blood (Angers University, France); The ovum pityrosporum ovale is provided by Pasteur institute.
These for examination bacterium inoculation and cultivate sabouraud's agar (Sabouraud Agar) (France), it is composed as follows to fill a prescription for LaboratoryAES, Combourg:
Meat soup pepsin peptone (Meat pepsic peptone) 10g
Glucose (Glucose) 20g
Agar (Agar) 15
Chloromycetin (Chloramphenicol) 0.05g
Distilled water (Distilled water) 1000mL
(PH6.5)
Wherein Pityrosporum ovale cultivates in the DST improvement and joins on the foster base, and is composed as follows:
DST agar (DST agar
*) 40g
Tween 80 (Tween 80) 20mL
Chloromycetin (Chloramphenicol) 0.05g
Distilled water (Distilled water) 1000mL
(PH5-6 (regulating)) with 1N HCl
Indicate: * diagnostic sensitization test antibiotics agar
*(Diagnistic?Sensivity?Test?DST)Antibiotic?Agar(Laboratory?AES，Combourg，France)
It is as follows to fill a prescription:
Peptone (Peptone proteose) 10.00g
Carnis Bovis seu Bubali cream (Beef extract) 10.00g
Glucose (Glucose) 2.00g
Sodium chloride (Sodium chloride) 3.00g
Sodium hydrogen phosphate (Disodic phosphatee) 2.00g
Sodium acetate (Sodium acetate) 1.00g
Adenine sulfate (Adenine sulfate) 0.01g
Guanine hydrochlorate (Guanine chlorydrate) 0.01g
Uracil (Uracile) 0.01g
Xanthine (Xanthine) 0.01g
Agar (Agar) 12.00g
100g
2, the drug solution mother solution of the mensuration 10% of minimal inhibitory concentration MIC (minimal inhibitory concentration) be by trans-Caryophyllene oxide under 55-60 ℃ of temperature, be dissolved in DMSO (dimethylsulfoxide) (dimethyl sulfoxide), and be diluted to variable concentrations.
The mensuration of MIC is the medicine that contains in culture medium by geometrical progression concentration, and inoculation is for the examination bacterium, after cultivating, and observed result and getting.0.05ml the DMSO drug solution be mixed in the hot culture medium of 9.95ml, after the cooling, extract the bacterium colony piece (25-36mm that contains mycelium and microgonidium (byphae and microconidia)
2), place sabouraud's agar with the bacterium colony surface.But for yeast type fungus, filamentary mould and Microsporum gypseum then make all spore suspension (sporesuspension) once check and correction, smear on culture medium.Incubation time was different with strain, saw Table I from 2 days to 12 days.
3, the mother liquid medicine of the mensuration 10% of minimal bactericidal concentration MFC (minimal fungicidal concentration) be trans-Caryophyllene oxide under 55-60 ℃ temperature, be dissolved in a polysorbate85, add 4 parts of isothermal sterilized water again, be stirred to cooling.
This drug solution dilutes the diluent that is made into from 60 to 500 μ g/ml gradually, picking dermatophytosis bacterium colony piece (25-36mm
2), join in each diluent, hatch 22 ℃, from 7 hours and 1,2,3,5,7 days incubation time every in.From diluent, 2 bacterium colony pieces of picking inoculate on the solid sabouraud's agar, and 22 ℃, 7 days.
What deserves to be explained is, the Cmin that MIC and MFC value suppress fully or kill for fungus, all experiments all repeat 4-5 time, and establish blank.
Two results
From Table I as can be seen, all yeast type funguses and filamentary mould are below drug level 500 μ g/ml, and all not oxidized Flos Caryophylli alkene institute suppresses fully.On the contrary, this medicine can suppress all effectively fully for examination dermatophytosis, its minimal inhibitory concentration MIC60-300 μ g/ml.Moreover with Tr.rubrum, Tr.mentagrophytes and Tr.interdigitale are that three sterilization experiment results for the examination bacterium show that trans-Caryophyllene oxide is the antifungal inhibitor under 500 μ g/ml concentration.
Three, conclusion
Trans-Caryophyllene oxide is a kind of to the specific antifungal of dermatophytosis (dermatophytes), dermatophytosis is according to its form and cultural characteristic, can be divided into three Pseudomonas: trichophyton (Trichophyton), Epidermophyton (Epidermophyton) and sporidiole tinea Pseudomonas (Microsporum).It mainly invades the horny layer of the shallow table of human body, as skin, hair with refer to (toe) first, causes skin fungus disease (dermatophytose), and the source of infection mostly is the ringworm patient, and the domestic animal (Canis familiaris L., cat etc.) and the formites of tinea arranged.The prison bed is gone up the common skin mycosis tinea capitis (tinea alba, tinea capitis, bald in vain), (scalp tinea, favus, ringworn and kerion), tinea unguium (tinea unguium) (onychomycose), tinea corporis (garden tinea, tinea circinata) (circinate herpes, corporal tinea), the tinea manuum (hand tinea), foot (foot) tinea (plantar epidermophytose, Hong-Kong ' sfoot, pes tinea), tinea barbae, (trichophytic sycosis), folliculitis (folliculitis, perifollicultis), it is the most common on the prison bed with tinea unguium.Experiment 2.
This experiment is for obtaining the antibacterium feature (Antibacterial property) of trans-Caryophyllene oxide.
One, method
1, for examination antibacterial bacterium pearl and culture medium
As follows for examination bacterium list:
Middle translated name, numbering and source for the examination skin bacterium
Antibacterial bacterium pearl numbering international numbering source
The normal fauna antibacterial of foot (Microflora of normal feet)
Moraxella sp. (moraxella) H7SV1/*
Acinetobacter sp. (acinetobacter) H5DC1/*
Alcaligenes sp. (alcaligenes) H4TV1/*
The antibacterial relevant (Causative species of the foot odour) with beriberi
Micrococcus luteus (micrococcus luteus) 1C5/*
Micrococcus sedentarius (set micrococcus luteus) △ 7B5/*
Corynebecterium sp.group B (Corynebacterium B family) 16C3/*
Corynebacterium sp.group D
2(Corynebacterium D
2Family) 19C1/*
Corynebacterium sp.group C (Corynebacterium C family) 3C3/*
Staphylococcus epidermidis (staphylococcus epidermidis) 1S2/*
Staphylococcus hominis (human-like staphylococcus) △ 8S2/*
Staphylococcus cohnii (staphylococcus cohnii) 6S3/*
The normal fauna antibacterial of armpit (Microflora of the normal axilla)
Micrococcus luteus (micrococcus luteus) CIP 53.45 ATCC93.41
Staphylococcus haemolyticus (staphylococcus haemolyticus) △ CIP 81.56 ATCC29.970
Staphylococcus xylosus (staphylococcus xylosus) △ CIP 81.66 ATCC29.971
Staphylococcus epidermidis (staphylococcus epidermidis) CIP 55.109 NCTC98.55
The antibacterial relevant (Causative specie of the axillary odour) with bromhidrosis
1. Corynebacterium xerosis (drying rod bacillus) CIP 52.16/* has symbol " * " person, and Docteur MARSHALL (Leeds University, the bacterial strain that England) provides are provided.2. 3. 4. NCTC:National Collection of Type Culture London (London allusion quotation of ATCC:American Type Culture Collection (U.S. typical case culture collection specimen) of CIP:Collection of Institute Pasteur (French Pasteur medical college collection specimen)
Type culture collection specimen) translated name is all from " bacteria name " in 5. above, Science Press, 1980.6. middle translated name has " △ " symbol person, is that the inventor translates by Latin.
All for the examination antibacterials all inoculated and cultured on agar sausage culture medium (nutrient broth) (FRANCE), it is composed as follows to fill a prescription for bioM é rieux, Marcy I ' Etoile:
Meat soup (Meat extract) 1g
Yeast extract (Yeast extract) 2g
Peptone (Peptone) 5g
Sodium chloride (Sodium chloride) 5g
Agar (Agar) 15g
Distilled water (Distilled water) 100mL
(PH7.4±0.2)
2. the mensuration of minimal inhibitory concentration MIC
Homogeneous bacterial suspension through check and correction smears on the agar broth bouillon, hatches and the observed result time: 37 ℃, and 24 hours.
3. the trans-Caryophyllene oxide drug dilution solution of mensuration 18ml concentration from 100 to the 500 μ g/ml of minimal bactericidal concentration MBC (minimal bactericidal concentration) adds the 2ml bacterial suspension.37 ℃, after hatching in 24 hours, this drug solution is inoculated on the solid agar broth bouillon, 37 ℃, 30 hours, hatches and whether observes bacterial growth.
Two, result
16 kinds very big to the sensitivity difference of trans-Caryophyllene oxide for the examination antibacterial.In the antibacterial relevant with beriberi, except that staphylococcus (Staphylococcus) under the concentration that is lower than 500 μ g/ml the drug resistance, other antibacterial such as excellent bacillus (Corynebacterinm) and micrococcus luteus (Micrococcus) all can be suppressed well.The antibacterial drying rod bacillus relevant with bromhidrosis (Corynebacterium xerosis) also is sensitive organism.Sterilization experiment shows that this medicine is the antibacterial antibacterial.
The MIC and the MBC of trans-Caryophyllene oxide see Table II.
Three, conclusion
Trans-Caryophyllene oxide is non-specific antibacterial antibacterial, and particularly relevant with beriberi and bromhidrosis antibacterial can be used for the treatment of beriberi and bromhidrosis as medicine for external use.
Experiment 3
This experiment is the saturating first ability determination experiment of trans-Caryophyllene oxide.
(keratinic?penetration?facility?and?eficacy?againstthe?dermatophytes?causative?of?onychomycosis)。
One, research method
This method is the similarity that refers to (toe) first structure and tissue according to Bauhinia purpurea keratin (ovine hoof horn keratin) and people, and the design of the particularity of nail matrix microecological environment.
1, experiment antifungal
Trans-Caryophyllene oxide solution 0.5,1,3,5 and 8%
(caryophyllene?oxide?solution?0.5％，1％，3％，5％and?8％)
Trans-Caryophyllene oxide is dissolved in mixed solvent (polysorbate85: sterile distilled water, 1: 4) and gets under 55-60 ℃ temperature.
Trans-Caryophyllene oxide fingernail glued membrane 5% and 8% (caryophyllene oxide nail lacquer5%and 8%) (excipient: Eudragit RL 100 or acrylates and cationicmethacrylate copolymere 10%, acetone35.6%, methylene chloride53.4%, Citroflex-2 or triiethyl citrate 1%)
Following three kinds is the first-selected antifungal that prison bed is gone up treatment tinea unguium commonly used, and commercial product on sale on the market is in the present invention as control experiment and relatively more saturating first ability of trans-Caryophyllene oxide and fungistatic effect.
Ciclopiroxolamine (6-cyclohexyl-1-hydroxy-4-methyl-2-(1H)-pyridone ethanolamine) solution1% (ring pyrrole department ethanolamine solutions 1%) (Mycoster, Pierre Fabre medicament, SINBIO Laboratory, Boulogne, France)
Ciclopirox (6-cyclohexyl-1-hydroxy-4-methyl-2-(1H)-pyridone) nail lacquer8% (Brafen fingernail glued membrane 8%) (Mycoster, Pierre Fabre medicament, SINBIO).
([4{3-[p-(1 for Amorolfine, 1-dimethylpropyl) phelnyl]-2-methyl-propyl}-2,6-cis-dimethylmorpholine hydrochloride] naillacquer 5% (amorolfine fingernail glued membrane 5%) (Loc é ryl, ROCHE, Neuilly-sur-Seine, FRANCE).
2, for the examination bacterium
For the examination bacterium is four tinea unguium, especially mould bacterial type tinea unguium
(dermatophytic onychomycose) modal pathomycete.
Trichophyton rubrum (red moss bacterium)
Trichophyton mentagrophytes (beard and hair moss bacterium)
Trichophyton interdigitale (sending out the moss bacterium between toe)
Epidermophyton floccosum (cotton-shaped epidermis moss bacterium)
3, the preparation of keratin first (ovine hoof horn keratin)
Radix Rumicis Japonici (ovine hoof) derives from the cotton sheep of newly butchering, the keratin first garden sheet evenly shinny hard tissue of Bauhinia variegata Linn outside central authorities that has drawn from, wipe inboard soft tissue off, clean air-dry after, the sterilization of ethylene oxide (ethylene oxide) detoxicating, the keratin first of making at last is directly through 1.3cm, thickness 1.3-1.5mm.Its morphological characteristic approaches the people and refers to (toe) first meansigma methods.
4, the simulation of design of Experiment System and tinea unguium is infected
Directly place that straight the latter fills a small amount of sterilized water in the big culture dish of 99mm, to keep inner air water saturation state and to prevent the fungus dehydrate through organic culture dish of 55mm.The sheet outside, keratin first garden is towards being placed down on the onesize sterilized filter paper (1～2) tinea unguium pathomycete inoculum (blockinoculum) (16-25mm
2) flicking is promptly inboard on the keratin first.
5, three kinds of " part " medications
Medication (timely treatment) simultaneously: carry out simultaneously for infection of examination bacterium and medication, hatched 22 ℃ 10 days.
Previous medication (pretreatment): the medication of keratin first, hatched four days, 22 ℃, fungal infection was cultivated 22 ℃ again 10 days.
Hysteresis medication (post-treatment): keratin first fungal infection, to cultivate 5-6 days, medication was cultivated 22 ℃ again 10.
6, " feeding " of antifungal dosage and confession examination fungus
In the aseptic filter paper of drug solution below microsyringe injector angle egg first, per two days once, each 20 μ l; Nail lacquer membranous type antifungal smears in the keratin outside with small brushes, and per two days once.
" feed " (it is as follows to fill a prescription) with the liquid sabouraud culture medium for the examination fungus, per two days once, and each 20 μ l soak on bacterium colony.
The liquid sabouraud culture medium (bioM é ieux, Marcy I ' Etoile, FRANCE):
Casein pancreas enzymic digestion thing (Pancreatic digest of casein (bio-Trypcase) 5g
Animal tissue's pepsin digestion thing (Peptic digest of animal tissue (bio-Thione) 5g
Dextrose (glucose) is 20g (Dextrose)
Distilled water (Distilled water) 10000mL
(PH5.7)
7, the cultivation again of keratin first
Above-mentioned experiment finishes, and promptly the keratin first after infection and the medication is hatched 10, because from preparing experiment, continues to cultivate (until 40 days), and observed result is identical, and the keratin first is put on the solid sabouraud culture medium again, hatches 22 ℃ 7 days
What be worth emphasizing is, how much should strictly grasping and operation of this experiment Chinese medicine dosage and fluid medium, its consumption is made an amendment with different dosage forms and drug form, to guarantee that medicine and culture medium can be at diffusive mixing around the sheet of keratin first garden, and blank and repeated experiments number of times are necessary.
Two, the result (Table III, IV, V)
1, the sensitivity of dermatophytosis: all four the most responsive for examination fungus Tr.rubrum and Tr.mentagrophytes, and the drug resistance of Tr.interdigitale is strong by contrast.This is consistent Table I with their antifungal property).
2, the saturating first ability and the effectiveness of trans-Caryophyllene oxide: trans-Caryophyllene oxide can pass the Radix Rumicis Japonici keratin soon, arrives fungus breeding vitellarium (being equivalent to focus).1% solution external has more weak inhibition or several no regressive effect, and the drug solution of 3-5% then presents significantly or the complete inhibition effect, and 8% trans-Caryophyllene oxide solution suppresses or complete regressive effect fully to all having for the examination fungus.
3, the difference on effect of three kinds of different medications: before the fungal infection, antifungal has diffused in the first, and this has explained in the previous medication experiment, and the more difficult or trans-Caryophyllene oxide of breeding of fungus and growth seems more effective; On the other hand, in the experiment that lags behind, reach the increase of the drug level of the conk that disappears fully, reflected and treated the difficulty that has infected fungus keratin first, but this experimental technique is more reasonable, actual near human body prison bed.
4, the comparison of saturating first ability between different antifungal and pharmaceutical dosage form: from experimental result, the antifungal of three kinds of commercial uses also can see through the keratin first, but under this experiment condition, they can not suppress the growth of dermatophytosis fully, obviously, the saturating first ability of trans-Caryophyllene oxide is better than ciclopiroxolamine, ciclopirox and amorolfine.With regard to pharmaceutical dosage form, the saturating first ability of trans-Caryophyllene oxide solution is better than the fingernail glued membrane slightly, but does not have significant difference.
5, the mycology evaluation of keratin first: all infect to cultivate with the keratin first of medication again and are positive.Can think, 10 days medication is obviously not enough, on the prison bed, the time of the treatment tinea unguium of having reported is very long, it generally is 6-12 month, but trans-Caryophyllene oxide shows under this physical condition is better than cilopiroxolamine, and the saturating first ability of ciclopirox and amorolfine and suppress effectiveness prove that trans-Caryophyllene oxide is the new antifungal drug of a kind of short-term or ultrashort phase treating tinea unguium.
Three, conclusion
Trans-Caryophyllene oxide can pass the Radix Rumicis Japonici keratin, arrives dermatophytosis growth and breeding position (first inner disease foci) rapidly, and the effectiveness of this first will cause, (in vivo) ideal therapeutic effect in the body.The drug solution of 5-8% or 8% fingernail glued membrane, in 10 days spraying cycle, the active drug amount that it penetrates in the first is enough to suppress or kill pathomycete, and this is that the prison bed is gone up the medicine for external use concentration of often using.Trans-Caryophyllene oxide is the external skin new drug of a kind of short term therapy tinea unguium, especially mycosis ungualis (dermatophyticonychomycose).
Table I: trans-Caryophyllene oxide is to the minimal inhibitory concentration (μ g/ml) (CMI at μ g/ml of caryophyllene oxide against various pathogenicfungi of the skin) of the pathogenic straight bacterium of skin
Dermatophytosis (Dermatophytes)
Trichophyton rubrum (27 ℃, 7 days) 60
Trichophyton mentagrophytes (27 ℃, 7 days) 80
Trichophyton soudanense (27 ℃, 7 days) 60
Trichophyton violaceum (27 ℃, 7 days) 80
Trichophyton interdigitale (27 ℃, 7 days) 300
Epidermophyton floccosum (27 ℃, 7 days) 120
Microsporum canis (27 ℃, 5 days) 120
Microsporum gypseum (27 ℃, 2 days) 80
Yeast type fungus (pathogenic yeasts)
Cryptococcus neoformans (37 ℃, 3 days)＞500
Pityrosporum ovale (37 ℃, 2 days)＞500
Candida krusei (37 ℃, 2 days)＞500
Candida parapsiloopsis (37 ℃, 2 days)＞500
Candica albicans (37 ℃, 2 days)＞500
Torulopsis glabrata (27 ℃, 2 days)＞500
Filamentary mould (Filamentous fungi or opportunists)
Aspergillus fumigatus (37 ℃, 2 days)＞500
Aspergillus flavus (37 ℃, 2 days)＞500
Scopulariopsis brevicaulis (27 ℃, 2 days)＞500
Table II: trans-Caryophyllene oxide is to the minimal inhibitory concentration MIC (μ g/ml) and the minimal bactericidal concentration MBC (μ g/ml) of skin bacterium
(MIC and MBC at μ g/ml of caryophyllene oxide againstcommensal bacteria of the skin) bacterial isolates MIC MCB
The normal fauna antibacterial of foot (Microflora of the normal feet)
Moraxella?sp.H7SV1????????????????????????60????????????????100
Acinetobacter?sp.H5DC1????????????????????＞500?????????????＞500
Alcaligenes?sp.H4TV1??????????????????????＞500?????????????＞500
The antibacterial relevant (Causative species of the foot odout) with beriberi
Micrococcus?luteus?1C5????????????????????100???????????????300
Micrococcus?sedentarius?7B5???????????????130???????????????200
Corynebacteriun?sp.groupe?B16C3???????????180???????????????200
Corynebacterium?sp.groupe?D219C1??????????200???????????????200
Corynebacterium?sp.groupe?C3C3????????????＞500?????????????＞500
Staphylococcus?epidermidis?1S2????????????＞500?????????????＞500
Staphylococcus?hominis?8S2????????????????＞500?????????????＞500
Staphylococcus?cohnii??6S3????????????????＞500?????????????＞500
The normal fauna antibacterial of armpit (Microflora of the normal axilla)
Micrococcus?luteus?CIP?53.45??????????????100???????????????300
Staphylococcus?heemolyticus?CIP81.56??????200???????????????200
Staphylococcus?xylosus?CIP81.66???????????500???????????????＞500
Staphylococcus?epidermidis?CIP55.109??????＞500?????????????＞500
The antibacterial relevant (Causative specie of the axillary odour) with bromhidrosis
Corynebacterium xerosis CIP52.16 100 150 Table III: the saturating first experiment of medication is explained (penetration by hoof infection and timely treatment) with the result in the time of trans-Caryophyllene oxide
Continuous Table III
Table III and Table IV note:
| For the examination fungi-medicine | Trichophyton ???rubrum | ?Trichophyton ?mentagrophytes | ?Tfichophyton ?interdigitale | ?Epidermophyton ?floccosum |
| Trans-Caryophyllene oxide solution 8% | ????0 | ????0 | ????0 | ????0 |
| Trans-Caryophyllene oxide solution 5% | ????0 | ????0 | ????+ | ????0 |
| Trans-Caryophyllene oxide solution 3% | ????0 | 0 or+ | ????++ | ????+ |
| Trans-Caryophyllene oxide solution 1% | ????+ | ????+ | ++ or +++ | ????++ |
| Trans-Caryophyllene oxide solution 0.5% | ????++ | ????+++ | ????+++ | ????+++ |
| Trans-Caryophyllene oxide fingernail glued membrane 5% | ????0 | 0 or+ | ????++ | ????+ |
| Trans-Caryophyllene oxide fingernail glued membrane 5% | ????0 | 0 or+ | ????+ | ????0 |
| Ciclopiroxolamine solution 1% | ????++ | ????+ | ????++ | ????++ |
| Ciclopirox fingernail glued membrane 8% | ????++ | ????+ | ????++ | ????++ |
| Amorolfine fingernail glued membrane 5% | + or 0 | ????+ | ????+ | ????+ |
| Contrast | ????+++ | ????+++ | ????+++ | ????+++ |
0: suppress fully ,+: important inhibition,
++: part suppresses,
+++: is without any suppressing or be equivalent to the control experiment Table IV: the previous medication experiment of trans-Caryophyllene oxide and result explain
(penetration?by?hoof?infection?and?pretreatment)
Continuous Table IV
The saturating first experiment of the hysteresis of Table V trans-Caryophyllene oxide is explained (penetration by hoof infection and post-treatmen with the result
Continuous Table V
The Table V note:
| For the examination fungi-medicine | Trichophyton ???rubrum | ?Trichophyton ?mentagrophytes | ?Trichophyton ?interdigitale | ?Epidermophyton ????floccosum |
| Trans-Caryophyllene oxide solution 8% | ????0 | ????0 | ????0 | ????0 |
| Trans-Caryophyllene oxide solution 5% | ????0 | ????0 | ????0 | ????0 |
| Trans-Caryophyllene oxide solution 3% | ????0 | ????0 | ????+ | ????0 |
| Trans-Caryophyllene oxide solution 1% | 0 or+ | ????+ | ????++ | ????+ |
| Trans-Caryophyllene oxide solution 0.5% | ????+ | ????++ | ????+++ | ????++ |
| Trans-Caryophyllene oxide fingernail glued membrane 5% | ????0 | ????0 | ????0 | ????0 |
| Trans-Caryophyllene oxide fingernail glued membrane 8% | ????0 | ????0 | ????0 | ????0 |
| Ciclopiroxolamine solution 1% | ????+ | ????++ | ????++ | + or ++ |
| Ciclopirox fingernail glued membrane 8% | ????+ | ????+ | ????+ | ????+ |
| Amorolfine fingernail glued membrane 5% | ????0 | ????0 | ????0 | ????0 |
| Contrast | ????+++ | ????+++ | ????+++ | ????+++ |
| For the examination fungi-medicine | Trichophyton ????rubrum | ?Trichophyton ?mentagrophytes | ?Trichophyton ?interdigitale | ?Epidermophyton ?floccosum |
| Trans-Caryophyllene oxide solution 8% | ????0 | ????0 | 0 or X | ????0 |
| Trans-Caryophyllene oxide solution 5% | ????0 | ????0 | ????X | ????0 |
| Trans-Caryophyllene oxide solution 3% | ????X | ????X | ????XX | ????X |
| Trans-Caryophyllene oxide solution 1% | ????XX | ????XX | XX or XX | ????XX |
| Trans-Caryophyllene oxide solution 0.5% | ????XX | ????XX | ????XXX | ????XXX |
| Trans-Caryophyllene oxide fingernail solution 5% | ????0 | 0 or X | ????+ | ????0 |
| Trans-Caryophyllene oxide fingernail solution 8% | ????0 | ????0 | ????+ | ????0 |
| Ciclopiroxolamine solution 1% | XX or XXX | ???XXX | ???XXX | XX or XXX |
| Ciclopirox fingernail glued membrane 8% | ???XX | ???XX | ???XX | ????XX |
| Amorolfine fingernail glued membrane 5% | ???XX | ???XX | ???XX | ????XX |
| Contrast | ???XXX | ???XXX | ???XXX | ????XXX |
0: disappear X fully: important disappearing,
XX: part disappears,
XXX: without any disappearing or being equivalent to control experiment
Claims (10)
1, a kind of antifungal is characterized in that containing the trans-Caryophyllene oxide of effective dose.
2, antifungal as claimed in claim 1 is characterized in that the inhibitor as dermatophytosis, wherein the concentration 60-500 μ g/mL of trans-Caryophyllene oxide.
3, antifungal as claimed in claim 1 is characterized in that wherein the concentration of trans-Caryophyllene oxide is 3-8% (wt) as the externally used solution medicament of treatment tinea unguium.
4,, it is characterized in that all the other compositions are solvent or other adjuvant as the antifungal of one of claim 1 to 3.
5, antifungal as claimed in claim 4 is characterized in that described all the other compositions are dimethyl sulfoxide, polysorbate85 or its mixture water.
6, a kind of purposes of trans-Caryophyllene oxide is characterized in that being used for antifungal.
7, purposes as claimed in claim 6 is characterized in that described fungus is a dermatophytosis.
8, purposes as claimed in claim 6 is characterized in that being used for the treatment of the skin fungus disease.
9, a kind of purposes of trans-Caryophyllene oxide is characterized in that being used for antibacterium.
10, purposes as claimed in claim 9 is characterized in that described antibacterial is excellent bacillus, micrococcus luteus or drying rod bacillus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95119433 CN1130062A (en) | 1995-12-29 | 1995-12-29 | Syringene oxide used as antifungal |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95119433 CN1130062A (en) | 1995-12-29 | 1995-12-29 | Syringene oxide used as antifungal |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1130062A true CN1130062A (en) | 1996-09-04 |
Family
ID=5082022
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 95119433 Pending CN1130062A (en) | 1995-12-29 | 1995-12-29 | Syringene oxide used as antifungal |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1130062A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002078719A1 (en) * | 2001-03-28 | 2002-10-10 | F.P.L. Pharma Inc. | Antitumor methods and compositions comprising sesquiterpene derivatives |
| CN113812421A (en) * | 2020-06-19 | 2021-12-21 | 山东天鹰生物科技有限公司 | A health cleaning agent with antibacterial, antiviral, acarid removing, and antipruritic effects, and its preparation method |
-
1995
- 1995-12-29 CN CN 95119433 patent/CN1130062A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002078719A1 (en) * | 2001-03-28 | 2002-10-10 | F.P.L. Pharma Inc. | Antitumor methods and compositions comprising sesquiterpene derivatives |
| CN113812421A (en) * | 2020-06-19 | 2021-12-21 | 山东天鹰生物科技有限公司 | A health cleaning agent with antibacterial, antiviral, acarid removing, and antipruritic effects, and its preparation method |
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