CN108553465A - A kind of Ketoconazol/Clobetasol Propionate topical composition for fungal infection - Google Patents
A kind of Ketoconazol/Clobetasol Propionate topical composition for fungal infection Download PDFInfo
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- CN108553465A CN108553465A CN201810355125.4A CN201810355125A CN108553465A CN 108553465 A CN108553465 A CN 108553465A CN 201810355125 A CN201810355125 A CN 201810355125A CN 108553465 A CN108553465 A CN 108553465A
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- China
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- composition
- ketoconazole
- ketoconazol
- fungal infection
- clobetasol propionate
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- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 title claims abstract description 54
- 229960004125 ketoconazole Drugs 0.000 title claims abstract description 53
- 239000000203 mixture Substances 0.000 title claims abstract description 34
- 230000000699 topical effect Effects 0.000 title claims abstract description 17
- 229960004703 clobetasol propionate Drugs 0.000 title claims abstract description 16
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 title claims abstract description 16
- 206010017533 Fungal infection Diseases 0.000 title claims abstract description 15
- 208000031888 Mycoses Diseases 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 239000000463 material Substances 0.000 claims abstract description 8
- 229920002678 cellulose Polymers 0.000 claims abstract description 7
- 239000001913 cellulose Substances 0.000 claims abstract description 7
- 239000004909 Moisturizer Substances 0.000 claims abstract description 5
- 239000003349 gelling agent Substances 0.000 claims abstract description 5
- 230000001333 moisturizer Effects 0.000 claims abstract description 5
- 239000003755 preservative agent Substances 0.000 claims abstract description 5
- 230000002335 preservative effect Effects 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 3
- 239000004094 surface-active agent Substances 0.000 claims abstract description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 20
- 230000000694 effects Effects 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 10
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 10
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 10
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical group CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 10
- 235000011187 glycerol Nutrition 0.000 claims description 10
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 6
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 6
- CNGRGEDXKHIFIL-UHFFFAOYSA-N 2-chloro-1h-quinazolin-4-one Chemical class C1=CC=C2NC(Cl)=NC(=O)C2=C1 CNGRGEDXKHIFIL-UHFFFAOYSA-N 0.000 claims description 4
- 150000003851 azoles Chemical class 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 229920000609 methyl cellulose Polymers 0.000 claims description 4
- 239000001923 methylcellulose Substances 0.000 claims description 4
- 235000010981 methylcellulose Nutrition 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- 239000006071 cream Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000000470 constituent Substances 0.000 abstract description 5
- 239000003002 pH adjusting agent Substances 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract 2
- PMJHHCWVYXUKFD-SNAWJCMRSA-N (E)-1,3-pentadiene Chemical compound C\C=C\C=C PMJHHCWVYXUKFD-SNAWJCMRSA-N 0.000 abstract 1
- ZQEPZZRFTQROLP-UHFFFAOYSA-N N1=CNC(C2=CC=CC=C12)=O.[Cl] Chemical compound N1=CNC(C2=CC=CC=C12)=O.[Cl] ZQEPZZRFTQROLP-UHFFFAOYSA-N 0.000 abstract 1
- 229940073608 benzyl chloride Drugs 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 26
- 241000894006 Bacteria Species 0.000 description 16
- 239000011734 sodium Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 10
- 241000233866 Fungi Species 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 239000000499 gel Substances 0.000 description 8
- 239000001965 potato dextrose agar Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 241000222122 Candida albicans Species 0.000 description 5
- 229940095731 candida albicans Drugs 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 208000001840 Dandruff Diseases 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000001857 anti-mycotic effect Effects 0.000 description 3
- 239000002543 antimycotic Substances 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000013316 zoning Methods 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 206010040880 Skin irritation Diseases 0.000 description 2
- 241000723873 Tobacco mosaic virus Species 0.000 description 2
- 241000223229 Trichophyton rubrum Species 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 230000001408 fungistatic effect Effects 0.000 description 2
- 229910052602 gypsum Inorganic materials 0.000 description 2
- 239000010440 gypsum Substances 0.000 description 2
- 231100000753 hepatic injury Toxicity 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000037311 normal skin Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000007747 plating Methods 0.000 description 2
- 230000036556 skin irritation Effects 0.000 description 2
- 231100000475 skin irritation Toxicity 0.000 description 2
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 1
- 241001480043 Arthrodermataceae Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 208000007163 Dermatomycoses Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 244000137852 Petrea volubilis Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 241000222126 [Candida] glabrata Species 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000629 anti-dermatophyte Effects 0.000 description 1
- 239000012871 anti-fungal composition Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000004500 asepsis Methods 0.000 description 1
- 208000032343 candida glabrata infection Diseases 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000000280 densification Methods 0.000 description 1
- 230000002951 depilatory effect Effects 0.000 description 1
- 230000037304 dermatophytes Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000003746 feather Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940084434 fungoid Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- -1 hydroxypropyl methyl Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 238000010422 painting Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- QYZLKGVUSQXAMU-UHFFFAOYSA-N penta-1,4-diene Chemical compound C=CCC=C QYZLKGVUSQXAMU-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940126532 prescription medicine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Dermatology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A kind of Ketoconazol/Clobetasol Propionate topical composition for fungal infection, the composition is by the ketoconazole and (3 (6 chlorine 4 (3H) quinazolinone)) (2 (2 benzyl chloride oxygroup) phenyl 5 (2 pyridyl group) 1 of methyl 1 as active constituent, 4 pentadiene, 3 ketoxime ether (I13) and at least one auxiliary material suitable for external preparation for skin form；Determination of Ketoconazole is 0.6~0.8% in the composition, and the mass ratio of compound (I13) and ketoconazole is 1:1.2~1.8.Gelling agent is made in the composition, and the auxiliary material is selected from the water of one or more of cellulose derivative, moisturizer, solvent, preservative, surfactant, pH adjusting agent and surplus.
Description
Technical field：
The present invention provides a kind of external application antifungal compositions.
Background technology：
Fungal dermatopathy refers to by human skin and mucous membrane, the hair and first-class cutaneous appendages caused by disease fungus
A major class infectious diseases.Disease fungus such as Trichophyton rubrum, alpha fungus, the gypsum of typical fungal dermatopathy are small
Pityrosporion ovale and candida albicans etc..In antifungal drug, ketoconazole (ketoconazole, CAS：65277-42-1) it is a kind of miaow
Azole broad-spectrum antifungal medicine is widely used in the various dermatophytid infections for the treatment of, but due to be easy to causeing serious hepatic injury,
The production that China stopped ketoconazole oral preparation in 2015, and will be existing a variety of outer containing ketoconazole
Medication is redefined as prescription medicine.Due to the use with the danger for causing serious side effects, ketoconazole receive it is prodigious
Limitation, existing ketoconazole external-use preparation Determination of Ketoconazole are 1%~2%.
Chinese patent literature CN 106749046A disclose the 1,4- pentadiene -3- ketoxime ethers of serial Quinazolinone-containing
Derivative, and specifically disclose compound (3- (chloro- 4 (3H)-quinazolinones of 6-)) methyl-1-(2- (2- benzyl chlorides oxygroup) phenyl-
5- (2- pyridyl groups)-Isosorbide-5-Nitrae-pentadiene -3- ketoxime ethers (I13), compound (I13) have tobacco mosaic virus (TMV) relatively limited
Control effect.We have surprisingly found that under study for action, and compound (I13) and ketoconazole drug combination can improve fungoid skin
The fungistatic effect of skin disease encountered pathogenic.Based on the discovery, in prior art basis, compound is rationally formed, one kind is provided and is used for
The Ketoconazol/Clobetasol Propionate topical composition of fungal infection improves the effect of ketoconazole preparation, and by reducing ketone health in external preparation
Azoles dosage avoids it the potential side effect of hepatic injury is caused to become urgent problem to be solved in the prior art.
Invention content：
Under study for action we have found that.Based on above-mentioned discovery, technical solution provided by the invention is：
A kind of Ketoconazol/Clobetasol Propionate topical composition for fungal infection, it is characterised in that the composition is by as activity
The ketoconazole of ingredient and (3- (chloro- 4 (3H)-quinazolinones of 6-)) methyl-1-(2- (2- benzyl chlorides oxygroup) phenyl-5- (2- pyridines
Base)-Isosorbide-5-Nitrae-pentadiene -3- ketoxime ethers (I13) and at least one auxiliary material suitable for external preparation for skin form；In the composition
Determination of Ketoconazole is 0.6~0.8%, and the mass ratio of compound (I13) and ketoconazole is 1:1.2~1.8.
A kind of Ketoconazol/Clobetasol Propionate topical composition for fungal infection, it is characterised in that the compound (I13) and ketone
The mass ratio of health azoles is 1:1.4~1.6.
A kind of Ketoconazol/Clobetasol Propionate topical composition for fungal infection, it is characterised in that the composition is made
One kind in gelling agent, cream, ointment.
A kind of Ketoconazol/Clobetasol Propionate topical composition for fungal infection, it is characterised in that the composition is made
Gelling agent, the auxiliary material in cellulose derivative, moisturizer, solvent, preservative, surfactant, pH adjusting agent one
Kind or several and surplus water.
The cellulose derives fine selected from sodium carboxymethylcellulose (CMC-Na), methylcellulose (MC), hydroxypropyl methyl
Dimension is plain (HPMC), and the dosage of the cellulose derivative is the 4%~8% of composition gross mass.The solvent preferred alcohol.Institute
The moisturizer stated is glycerine, and dosage is 10%~15%.The preservative is ethylparaben.
Heretofore described percentage is the weight percent for accounting for composition.
A kind of Ketoconazol/Clobetasol Propionate topical composition for fungal infection provided by the invention, by compound (I13) and ketone
The proportioning of health azoles is determined as 1:1.2~1.8, it has obtained a kind of to generate more preferably the common mycotic cause of disease of human skin
Therapeutic effect Ketoconazol/Clobetasol Propionate topical composition.Toxicity test is carried out to compound (I13) and skin irritation test shows
Compound (I13) belongs to low toxicity material and without apparent skin irritation and oral cumulative toxicity.Animal experiments show that this hair
The Ketoconazol/Clobetasol Propionate topical composition of bright offer, which is higher than the therapeutic effect of dermatophytid infection, is administered alone ketoconazole and change
Object (I13) is closed, illustrates that the compound (I13) of special ratios produces the antimycotic skin infection effect cooperateed with ketoconazole,
Determination of Ketoconazole can show preferable therapeutic effect in the case of being less than 1%.In Vitro Bacteriostasis effect experiment in advance shows
Compound (I13) and the proportioning of ketoconazole are about 1:When 1.5, apparent collaboration anti-mycotic efficiency is produced.Implement to preparation
, it was also found that compound (I13) and the proportioning of ketoconazole are 1 when example progress anti-mycotic efficiency detection:When 1.4~1.6, collaboration is anti-
Antifungal effect is more notable.And when carrying out prescription screening in advance it was found that compound (I13) and the compatibility of ketoconazole have
Specificity, in common antifungal drug, only ketoconazole can generate synergistic effect with compound (I13).
Specific implementation mode：
The preparation of compound (I13) prepares (3- according to method disclosed in Chinese patent literature CN CN106749046A
(chloro- 4 (3H)-quinazolinones of 6-)) methyl-1-(2- (2- benzyl chlorides oxygroup) phenyl-5- (2- pyridyl groups)-1,4- pentadiene-3- ketone
Oxime ether (I13) bulk pharmaceutical chemicals, 98% or more content.
Pharmacological Examples 1, In Vitro Bacteriostasis effect experiment
1, the preparation of culture medium
Potato dextrose agar (PDA), mass fraction are potato 20%, glucose 2%, agar 1.8%.
5ml culture mediums are added in each test tube and are prepared into slant medium；20ml culture mediums are added in the plate of diameter 90mm to be prepared into
Plating medium
2, experimental method
The processing of 2.1 bacterial strains
1. by positive bacterium colony using disinfection inoculation ring transferred species in plate PDA culture medium activated strains, Filamentous type fungi is taken
One zoning collimation method is placed in 28 DEG C of constant incubators, cultivates 7 days；Candida albicans uses three zoning collimation methods, is placed in 35 DEG C of constant temperature incubations
Case is cultivated 2 days.
2. the free of contamination bacterium colony of picking takes three zoning collimation method transferred speciess to carry out point pure a, condition of culture in plate PDA culture medium
Ditto.
3. picking individually purifies bacterium colony with " Z " font transferred species in inclined-plane SDA Tube propagation bases, Filamentous type fungi is placed in
28 DEG C of constant incubators, through the small culture identification of slide to kind after cultivating 10 days；Candida albicans is placed in 35 DEG C of insulating boxs, after cultivating 2 days
It is inoculated in the good culture medium colour developing of Kerma (unit of kinetic energy) and identifies kind.
The bacterial strain that this experiment uses is respectively the Trichophyton rubrum for belonging to dermatophyte, alpha fungus, the small spore of gypsum
Daughter bacteria and the Candida albicans and Candida glabrata for belonging to candida albicans
2.2 make bacteria suspension
The appropriate bacterium colony agglomerate of picking is dissolved in 0.9% sterile saline that Tween 80 is added in 1mL.It is shaken with micro oscillator
2min is swung, fully shaking elutes spore, and bacteria suspension turbidity is adjusted to 5 × 10 using hemacytometer6~10 × 106CFU/
mL。
2.3 make tablet containing bacterium
It extracts 0.5ml bacteria suspensions and is placed in PDA plating mediums, be allowed to be uniformly distributed in culture base table with sterilizing spreading rod
Face.
2.4 punching dosings
It is punched on the culture medium after applying bacterium with the card punch of diameter 6mm, chooses agar in hole, drug to be tested is distinguished
It squeezes into 1ml asepsis injectors, dosing 0.1ml in every hole.
Active constituent is dissolved in after DMSO after concentration shown according to the form below is configured to mixed solution again, as the to be tested of each group
Drug
| Test group number | 1 | 2 | 3 | 4 | 5 | 6 |
| Compound (I13) % | 1.1 | 0.9 | 0.7 | 0.5 | 1.5 | 0 |
| Ketoconazole % | 0.4 | 0.6 | 0.8 | 1.0 | 0 | 1.5 |
2.5 cultures and outcome measurement
Drug sensitive experiment tablet is placed in 28 DEG C of constant incubators, cultivates 10 days.Use the antibacterial of vernier caliper measurement each medicine
Ring radius records inhibition zone radius mm values around each medicine hole.Every plant of bacterium is cooked 3 tablets simultaneously.
As a result following (unit mm, n=3, means ± s)
Antibacterial experiment in vitro the result shows that, in each experimental group, only the ratio of compound (I13) and ketoconazole is 1:
1.5 experimental group 3 shows the significantly more antibacterial effect compared with experimental group 5/6 and other experimental groups that active constituent is applied alone
Fruit.Based on above-mentioned experimental result, the topical composition of example of formulations is prepared based on the ratio.
.Embodiment 1
Compound (I13) 5g ketoconazole 6g,
Sodium carboxymethylcellulose 60g, glycerine 150g
Ethylparaben 2g distilled water adds to 1000g
CMC-Na and glycerine are mixed to get CMC-Na slurries, another taking ethylparaben is dissolved in hot water, is then added
CMC-Na is starched, and stirring becomes gel, will be dissolved in being gradually added into after ethanol in proper amount by ketoconazole and compound (I13) again and stir evenly, and is mended
The water of sufficient surplus stirs evenly up to clear gel.
Embodiment 2
Compound (I13) 4.5g ketoconazoles 8g
Sodium carboxymethylcellulose 60g, glycerine 150g
Ethylparaben 2g distilled water adds to 1000g
CMC-Na and glycerine are mixed to get CMC-Na slurries, another taking ethylparaben is dissolved in hot water, is then added
CMC-Na is starched, and stirring becomes gel, will be dissolved in being gradually added into after ethanol in proper amount by ketoconazole and compound (I13) again and stir evenly, and is mended
The water of sufficient surplus stirs evenly up to clear gel.
Embodiment 3
Compound (I13) 4.2g, ketoconazole 6g
Sodium carboxymethylcellulose 60g, glycerine 150g
Ethylparaben 2g distilled water adds to 1000g
CMC-Na and glycerine are mixed to get CMC-Na slurries, another taking ethylparaben is dissolved in hot water, is then added
CMC-Na is starched, and stirring becomes gel, will be dissolved in being gradually added into after ethanol in proper amount by ketoconazole and compound (I13) again and stir evenly, and is mended
The water of sufficient surplus stirs evenly up to clear gel.
Embodiment 4
Compound (I13) 5g, ketoconazole 8g
Sodium carboxymethylcellulose 60g, glycerine 150g
Ethylparaben 2g distilled water adds to 1000g
CMC-Na and glycerine are mixed to get CMC-Na slurries, another taking ethylparaben is dissolved in hot water, is then added
CMC-Na is starched, and stirring becomes gel, will be dissolved in being gradually added into after ethanol in proper amount by ketoconazole and compound (I13) again and stir evenly, and is mended
The water of sufficient surplus stirs evenly up to clear gel...
Comparative example 1
According to the formula of embodiment 1, active constituent is changed to ketoconazole 15g.
Comparative example 2
According to the formula of embodiment 1, active constituent is changed to compound (I13) 15g.
2 fungi fungistatic effect contrast experiment of Pharmacological Examples
1, material
Experimental animal be Hartley cavys, 300 ± 20g of weight, half male and half female,
2, the preparation of bacteria suspension
By alpha fungus bacterial strain on PDA solid mediums continuous passage culture 2 times (28 DEG C), to ensure its vigor.
After second of culture 5d, chooses in its bacterium colony and 0.9% physiological saline, the bacteria suspension of final concentration of 1 × 108CFU/mL is made.
3, modeling
Guinea pig back razor shaving is lost hair or feathers with Japanese depilatory wax, forms two 4.0cm × 4.0cm's of along ridge column symmetry
Without hair-fields.The direct microscopy of fungi and culture are carried out to no hair-fields, result is that feminine gender is confirmed as being carried on the back in cavy with sand paper after feminine gender
On gently equably rub, and 200 μ L of bacteria suspension are spread evenly across back without hair-fields.After painting bacterium 1 time, it is observed continuously 10 days.
4, it is grouped and is administered
The successful experimental animal of modeling is taken to be grouped at random, every group 5, two of every animal give same without hair-fields
Drug, successive administration 7d, and the scoring that administration is preceding and is administered after 7d is recorded,
Standards of grading
4 points：Red, swollen, pachyderma, scurf densification are covered with entire cutaneous lesion.
3 points：It is red, swollen, there is dotted normal skin between cutaneous lesion scurf, adds up to be less than 25%.
2 points：Micro- red, pneumonedema has linear normal skin between cutaneous lesion scurf, adds up to be less than 50%.
1 point：Not red, pneumonedema, between cutaneous lesion has a little scurf, 75% or more skin is normal.
0 point：Not red, pneumonedema, it is normal.
Grouping administration see the table below with experimental result
The experimental results showed that 1~4 group of experiment uses composition provided in an embodiment of the present invention, to fungal infection model
The therapeutic effect of animal is both better than control group, also superior to 5/6 group of the experiment using single active ingredient, illustrates provided by the invention
Composition is improved the therapeutic effect for dermatophytid infection, is especially tested by the ratio of preferred two kinds of active components
3/4 group, in the case where ketoconazole dosage is only 0.6%~0.8%, effect also increases compared with other embodiment, explanation
Particularly preferred compound (I13) and ketoconazole ratio (1:1.4~1.6) better anti-dermatophyte infection effect can be shown
Fruit.
Claims (5)
1. a kind of Ketoconazol/Clobetasol Propionate topical composition for fungal infection, it is characterised in that the composition by as activity at
The ketoconazole and (3- (chloro- 4 (3H)-quinazolinones of 6-)) methyl-1-(2- (2- benzyl chlorides oxygroup) phenyl-5- (2- pyridyl groups)-divided
Isosorbide-5-Nitrae-pentadiene -3- ketoxime ethers (I13) and at least one auxiliary material suitable for external preparation for skin form；Ketone health in the composition
Azoles content is 0.6~0.8%, and the mass ratio of compound (I13) and ketoconazole is 1:1.2~1.8.
2. a kind of Ketoconazol/Clobetasol Propionate topical composition for fungal infection as described in claim 1, it is characterised in that described
The mass ratio of compound (I13) and ketoconazole is 1:1.4~1.6.
3. a kind of Ketoconazol/Clobetasol Propionate topical composition for fungal infection as claimed in claim 1 or 2, it is characterised in that institute
State one kind that composition is made in gelling agent, cream, ointment.
4. a kind of Ketoconazol/Clobetasol Propionate topical composition for fungal infection as claimed in claim 3, it is characterised in that described
Gelling agent is made in composition, and the auxiliary material is selected from cellulose derivative, moisturizer, solvent, preservative, surfactant, pH tune
Save the water of one or more of agent and surplus.
5. a kind of Ketoconazol/Clobetasol Propionate topical composition for fungal infection as claimed in claim 4, it is characterised in that described
Cellulose derives selected from sodium carboxymethylcellulose (CMC-Na), methylcellulose (MC), hydroxypropyl methyl cellulose (HPMC), institute
The dosage for stating cellulose derivative is the 4%~8% of composition gross mass；The solvent preferred alcohol；The moisturizer is
Glycerine, dosage are 10%~15%；The preservative is ethylparaben.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1899291A (en) * | 2006-07-24 | 2007-01-24 | 昆明滇虹药业有限公司 | External use antifungal compound composition and its use |
| CN102218052A (en) * | 2011-04-08 | 2011-10-19 | 中国人民解放军第二军医大学 | Application of kaempferol as synergist of anti-fungal medicaments |
| CN103536613A (en) * | 2013-10-14 | 2014-01-29 | 中国科学院微生物研究所 | Antifungal medicine composition |
| WO2014041424A1 (en) * | 2012-09-14 | 2014-03-20 | Methylgene Inc. | Histone deacetylase inhibitors for enhancing activity of antifungal agents |
| CN106749046A (en) * | 2016-12-08 | 2017-05-31 | 贵州大学 | The ketoxime ether derivative of 1,4 pentadiene 3 of one kind containing 4 (3H) quinazolinones and preparation method thereof |
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2018
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1899291A (en) * | 2006-07-24 | 2007-01-24 | 昆明滇虹药业有限公司 | External use antifungal compound composition and its use |
| CN102218052A (en) * | 2011-04-08 | 2011-10-19 | 中国人民解放军第二军医大学 | Application of kaempferol as synergist of anti-fungal medicaments |
| WO2014041424A1 (en) * | 2012-09-14 | 2014-03-20 | Methylgene Inc. | Histone deacetylase inhibitors for enhancing activity of antifungal agents |
| CN103536613A (en) * | 2013-10-14 | 2014-01-29 | 中国科学院微生物研究所 | Antifungal medicine composition |
| CN106749046A (en) * | 2016-12-08 | 2017-05-31 | 贵州大学 | The ketoxime ether derivative of 1,4 pentadiene 3 of one kind containing 4 (3H) quinazolinones and preparation method thereof |
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