CN112089823B - Composition of aureobasidin A and nystatin and composite ointment, gel and spray thereof - Google Patents
Composition of aureobasidin A and nystatin and composite ointment, gel and spray thereof Download PDFInfo
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- CN112089823B CN112089823B CN202011020936.2A CN202011020936A CN112089823B CN 112089823 B CN112089823 B CN 112089823B CN 202011020936 A CN202011020936 A CN 202011020936A CN 112089823 B CN112089823 B CN 112089823B
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- Prior art keywords
- aureobasidin
- nystatin
- composition
- medicament
- composite
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- RLMLFADXHJLPSQ-NPPFTVEMSA-N (3s,6s,9s,12s,15s,18s,21s,24r,27s)-3,6-dibenzyl-12,24-bis[(2r)-butan-2-yl]-15-(2-hydroxypropan-2-yl)-4,10,16,22-tetramethyl-18-(2-methylpropyl)-9,21-di(propan-2-yl)-13-oxa-1,4,7,10,16,19,22,25-octazabicyclo[25.3.0]triacontane-2,5,8,11,14,17,20,23,26-nonon Chemical group C([C@H]1C(=O)N2CCC[C@H]2C(=O)N[C@@H](C(N(C)[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N(C)[C@H](C(=O)O[C@H](C(=O)N(C)[C@@H](C(C)C)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N1C)[C@H](C)CC)C(C)(C)O)=O)[C@H](C)CC)C1=CC=CC=C1 RLMLFADXHJLPSQ-NPPFTVEMSA-N 0.000 title claims abstract description 140
- 108010008887 aureobasidin A Proteins 0.000 title claims abstract description 140
- 229960000988 nystatin Drugs 0.000 title claims abstract description 137
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 title claims abstract description 132
- 239000000203 mixture Substances 0.000 title claims abstract description 113
- 239000007921 spray Substances 0.000 title claims abstract description 51
- 239000002674 ointment Substances 0.000 title claims abstract description 44
- 239000002131 composite material Substances 0.000 title claims description 65
- 239000000499 gel Substances 0.000 title abstract description 41
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 239000003814 drug Substances 0.000 claims abstract description 36
- 208000007027 Oral Candidiasis Diseases 0.000 claims abstract description 22
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 47
- 239000002994 raw material Substances 0.000 claims description 19
- 235000011187 glycerol Nutrition 0.000 claims description 17
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 16
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 16
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 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 description 12
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 12
- 239000008213 purified water Substances 0.000 claims description 12
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 11
- 229920002674 hyaluronan Polymers 0.000 claims description 11
- 229960003160 hyaluronic acid Drugs 0.000 claims description 11
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 8
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 8
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 8
- 229940057995 liquid paraffin Drugs 0.000 claims description 8
- 229920001983 poloxamer Polymers 0.000 claims description 8
- 229960000502 poloxamer Drugs 0.000 claims description 8
- 239000003871 white petrolatum Substances 0.000 claims description 8
- 229920001661 Chitosan Polymers 0.000 claims description 7
- 235000019501 Lemon oil Nutrition 0.000 claims description 7
- 239000010501 lemon oil Substances 0.000 claims description 7
- 239000001525 mentha piperita l. herb oil Substances 0.000 claims description 7
- 235000019477 peppermint oil Nutrition 0.000 claims description 7
- 229920000858 Cyclodextrin Polymers 0.000 claims description 6
- 239000001856 Ethyl cellulose Substances 0.000 claims description 6
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 6
- 239000001116 FEMA 4028 Substances 0.000 claims description 6
- 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
- 229960004853 betadex Drugs 0.000 claims description 6
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- 239000007765 cera alba Substances 0.000 claims description 6
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 6
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- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 6
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- 235000010981 methylcellulose Nutrition 0.000 claims description 6
- 229960002216 methylparaben Drugs 0.000 claims description 6
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 claims description 6
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 6
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 6
- 239000001194 polyoxyethylene (40) stearate Substances 0.000 claims description 5
- 235000011185 polyoxyethylene (40) stearate Nutrition 0.000 claims description 5
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical group CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- 229960000541 cetyl alcohol Drugs 0.000 claims description 4
- 229920001993 poloxamer 188 Polymers 0.000 claims description 4
- 229940044519 poloxamer 188 Drugs 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000000694 effects Effects 0.000 abstract description 13
- 238000002474 experimental method Methods 0.000 abstract description 6
- 206010059866 Drug resistance Diseases 0.000 abstract description 4
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- 241000222122 Candida albicans Species 0.000 description 39
- 229940095731 candida albicans Drugs 0.000 description 39
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- 241000699670 Mus sp. Species 0.000 description 18
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- -1 cyclic ester Chemical class 0.000 description 6
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- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 2
- 206010007134 Candida infections Diseases 0.000 description 2
- 229920000742 Cotton Polymers 0.000 description 2
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 2
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 2
- 206010048685 Oral infection Diseases 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940106189 ceramide Drugs 0.000 description 2
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 229960005150 glycerol Drugs 0.000 description 2
- 229960000367 inositol Drugs 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 210000002200 mouth mucosa Anatomy 0.000 description 2
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 2
- 210000001584 soft palate Anatomy 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000002105 tongue Anatomy 0.000 description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- 241000223678 Aureobasidium pullulans Species 0.000 description 1
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- 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000002579 Sphingosine N-acyltransferase Human genes 0.000 description 1
- 108020004714 Sphingosine N-acyltransferase Proteins 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
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- 238000007598 dipping method Methods 0.000 description 1
- 230000007140 dysbiosis Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
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- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
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- 230000007774 longterm Effects 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
- 239000006916 nutrient agar Substances 0.000 description 1
- VQOXZBDYSJBXMA-RKEBNKJGSA-N nystatin a1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@@H]1OC1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)CC(O)CC(O)CC(O)CCC(O)C(O)C[C@](O)(CC(O)C2C(O)=O)OC2C1 VQOXZBDYSJBXMA-RKEBNKJGSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
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- 125000001095 phosphatidyl group Chemical group 0.000 description 1
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- 239000011148 porous material Substances 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A—HUMAN NECESSITIES
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- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A—HUMAN NECESSITIES
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- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- 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
Abstract
The invention relates to a composition of aureobasidin A and nystatin and a compound ointment, gel and spray thereof; in the composition, the mass ratio of the aureobasidin A to the nystatin is 1.29-4:1; the composition can be used for treating oral candidiasis. The medicine containing the composition avoids the problem of drug resistance caused by single antibiotic administration. Meanwhile, the invention also provides a compound ointment, a compound gel and a compound spray containing the composition, and animal experiments prove that the finished medicament with the three textures has a treatment effect on oral candidiasis which is obviously higher than that of a medicament with single component on the market.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a composition of aureobasidin A and nystatin, and a compound ointment, gel and spray thereof.
Background
Aureobasidin A (AbA) is also called Aureobasidin A, and is a cyclic ester peptide antifungal antibiotic derived from Aureobasidium pullulans, and can effectively inhibit the activity of fungi such as Saccharomyces cerevisiae, candida albicans, cryptococcus, etc. The action mechanism of the aureobasidin A is to inhibit the synthesis of ceramide to inositol phosphatidyl ceramide by inhibiting the activity of inositol phosphatidyl ceramide synthetase which depends on the growth of fungi, so that the cell membrane of the fungi is broken, and the fungi are killed. The foreign literature shows that aureobasidin A has antibacterial activity on candida albicans (Munusamy K., vadivalu J. & Tay ST.A study on Candida biofilm growth characteristics and its susceptibility to aureobasidin A.2016; 1130-1406) and has certain drug application potential.
Oral candidiasis is a disease of the oral mucosa caused by candida infection, of which candida albicans is the most predominant pathogen. In recent years, due to the wide clinical application of antibiotics and immunosuppressants, there are increasing numbers of patients suffering from a dysbacteriosis or a reduced immunity, which leads to candida albicans infection. The first-line medicine for clinically treating oral candidiasis is antifungal antibiotic nystatin, and other antifungal medicines such as fluconazole, miconazole and itraconazole are used for auxiliary treatment, but the broad-spectrum antifungal medicines can generate drug resistance after long-term use, so that the disease state is repeatedly started, and the treatment effect of a patient is affected.
For oral candidiasis, nystatin tablets (zhuyuan) and nystatin tablets (Lu Kang) are commercially available at present, but since both contain only one active ingredient, drug resistance still exists.
In addition, the complexity of the oral environment is higher than that of other internal environments in a human body, so that the texture of the medicine has great influence on the effective antibacterial degree of the medicine during actual administration. The quality of the medicine in the prior art is single, and the problem that the bacteriostasis degree is difficult to smear or is greatly reduced after the smearing exists.
Disclosure of Invention
The invention aims to solve the technical problem of providing a composition of aureobasidin A and nystatin, and a compound ointment, gel and spray thereof.
The technical scheme for solving the technical problems is as follows: a composition of aureobasidin A and nystatin, wherein the mass ratio of aureobasidin A to nystatin in the composition is 1.29-4:1.
Further, in the composition, the mass ratio of the aureobasidin A to the nystatin is 1.67-2.33:1.
The invention provides an application of the aureobasidin A and nystatin composition in treating oral candidiasis.
The invention provides a medicine for treating oral candidiasis, which contains aureobasidin A and nystatin composition.
Further, the medicine is a compound ointment, the compound ointment is composed of the following raw materials, and the mass of each raw material in each 1000g of the compound ointment is respectively as follows: 16g of aureobasidin A and nystatin composition, 10g of cetyl alcohol, 0 to 100g of liquid paraffin, 25g of polyoxyethylene (40) stearate, 0 to 25g of propylene carbonate, 0 to 25g of ethyl formate, 200g of glycerol, 0 to 624g of white vaseline and 0 to 624g of white beeswax; wherein the composition of aureobasidin A and nystatin comprises 9-11g of aureobasidin A and 5-7g of nystatin.
Further, the aureobasidin A and nystatin composition in the compound ointment contains 10g of aureobasidin A and 6g of nystatin; the liquid paraffin in the compound ointment is 100g; ethyl formate 25g; 624g of white vaseline; propylene carbonate 0g; white beeswax is 0g.
Further, the medicine is a gel, the composite gel is composed of the following raw materials, and the mass of each raw material in each 1000ml of the composite gel is respectively as follows: 15g of aureobasidin A and nystatin composition, 230g of poloxamer, 20g of chitosan, 20g of hyaluronic acid, 0-25g of methylcellulose or hydroxypropyl methylcellulose, 0-25g of carboxypropyl-beta-cyclodextrin, 50g of glycerin, 5g of methylparaben and purified water to 1000ml; wherein the aureobasidin A and nystatin composition contains 9-10 g aureobasidin A and 5-6 g nystatin.
Further, the aureobasidin A and nystatin composition contains 9.5g of aureobasidin A and 5.5g of nystatin per 1000ml of the composite gel; the methyl cellulose is 0g; the carboxypropyl-beta-cyclodextrin is 0g; the hydroxypropyl methylcellulose is 25g; the poloxamer is poloxamer 188.
Further, the medicine is a composite spray, the composite spray is composed of the following raw materials, and the mass of each raw material in each 50ml of the composite spray is respectively as follows: 0.5g of aureobasidin A and nystatin composition, 0 to 3g of peppermint oil, 0 to 2g of lemon oil, 0 to 3g of glycerol, 1g of sodium bicarbonate, 0 to 1.5g of sodium carboxymethyl cellulose, 0 to 1.5g of hydroxypropyl methyl cellulose, 0 to 1.5g of ethyl cellulose and 3g of hyaluronic acid; purified water is added to 50ml; wherein the aureobasidin A and nystatin composition contains 0.3g-0.4g of aureobasidin A and 0.1g-0.2g of nystatin.
Further, in each 50ml of the composite spray, the aureobasidin A and nystatin composite contains 0.35g of aureobasidin A and 0.15g of nystatin;
3g of peppermint oil; 2g of lemon oil; the glycerin is 0g; the sodium carboxymethyl cellulose is 1.5g; the hydroxypropyl methylcellulose is 1.5g; the ethyl cellulose is 0g.
The invention has the beneficial effects that: the aureobasidin A and the nystatin are combined, the antibacterial effect of the composition is obviously higher than that of the single components of the aureobasidin A and the nystatin, and the antibacterial effect of the composition is not the simple addition of the antibacterial effect of the single components of the aureobasidin A and the nystatin, so that the drug resistance problem caused by the single antibiotic administration is avoided in the application of the drug with the composition. Meanwhile, the invention also provides a compound ointment, a compound gel and a compound spray containing the composition, and animal experiments prove that the finished medicament with the three textures has a treatment effect on oral candidiasis which is obviously higher than that of a medicament with single component on the market.
Drawings
FIG. 1 is a graph showing the rate of decrease in the number of Candida albicans in the oral cavity of mice administered to each experimental group within 72 hours after administration in example 6 of the present invention.
Detailed Description
The principles and features of the present invention are described below with reference to the drawings, the examples are illustrated for the purpose of illustrating the invention and are not to be construed as limiting the scope of the invention.
The technical scheme for solving the technical problems is as follows: a composition of aureobasidin A and nystatin, wherein the mass ratio of aureobasidin A to nystatin is 1.29-4:1.
Preferably, in the composition, the mass ratio of the aureobasidin A to the nystatin is 1.67-2.33:1.
The invention provides an application of the aureobasidin A and nystatin composition in treating oral candidiasis.
The invention provides a medicine for treating oral candidiasis, which contains aureobasidin A and nystatin composition.
Further, the medicine is a compound ointment which is composed of the following raw materials, and the mass of each raw material in each 1000g of compound ointment is respectively as follows: 16g of aureobasidin A and nystatin composition, 10g of cetyl alcohol, 0 to 100g of liquid paraffin, 25g of polyoxyethylene (40) stearate, 0 to 25g of ethyl formate, 200g of glycerol, 0 to 25g of propylene carbonate, 0 to 624g of white vaseline and 0 to 624g of white beeswax; wherein the composition of aureobasidin A and nystatin comprises 9-11g of aureobasidin A and 5-7g of nystatin.
Preferably, the aureobasidin A and nystatin composition in the compound ointment contains 10g of aureobasidin A and 6g of nystatin; the liquid paraffin in the compound ointment is 100g; ethyl formate 25g; 624g of white vaseline; propylene carbonate 0g; white beeswax is 0g.
The preparation method of the compound ointment comprises the following steps:
s1, putting aureobasidin A and nystatin in a mixing tank, adding polyoxyethylene (40) stearate and ethyl formate, mixing and stirring at 40 ℃ for 5min to obtain an active ingredient solution;
s2, placing white vaseline, liquid paraffin and glycerol in a mixing tank, heating and stirring at 78 ℃ until all the components are melted to obtain a matrix solution;
and S3, cooling the active ingredient solution and the matrix solution obtained in the step S1 and the step S2 to 50 ℃ and uniformly mixing to obtain the compound ointment containing the aureobasidin A and nystatin composition.
Preferably, the medicine is a gel, the composite gel is composed of the following raw materials, and the mass of each raw material in each 1000ml of the composite gel is respectively as follows: 15g of aureobasidin A and nystatin composition, 230g of poloxamer, 20g of chitosan, 20g of hyaluronic acid, 0-25g of carboxypropyl-beta-cyclodextrin, 0-25g of methylcellulose or hypromellose, 50g of glycerol, 5g of methylparaben and purified water to 1000ml; wherein, the composition of aureobasidin A and nystatin contains 9g-10g of aureobasidin A and 5g-6g of nystatin.
Preferably, the aureobasidin A and nystatin composition contains 9.5g aureobasidin A and 5.5g nystatin per 1000ml of the composite gel; methyl cellulose 0g; the carboxypropyl-beta-cyclodextrin is 0g; the hydroxypropyl methylcellulose is 25g; the poloxamer is poloxamer 188.
The preparation method of the composite gel comprises the following steps:
d1, placing poloxamer in a mixing tank, adding purified water, uniformly stirring, standing and swelling for 24 hours to obtain poloxamer solution;
d2, placing chitosan and hyaluronic acid in a mixing tank, adding purified water, and stirring until the chitosan and the hyaluronic acid are completely dissolved to obtain a mixed solution of chitosan and hyaluronic acid;
and D3, mixing the two solutions in the step D1 and the step D2, sequentially and slowly adding aureobasidin A, nystatin, glycerol, hypromellose and methylparaben, stirring until the aureobasidin A, the nystatin A, the glycerol, the hypromellose and the methylparaben are completely dissolved, sieving and packaging to obtain the compound gel containing the aureobasidin A and the nystatin composition.
Preferably, the medicine is a composite spray, the composite spray consists of the following raw materials, and the mass of each raw material in each 50ml of composite spray is as follows: 0.5g of aureobasidin A and nystatin composition, 0 to 3g of peppermint oil, 0 to 2g of lemon oil, 0 to 3g of glycerol, 1g of sodium bicarbonate, 0 to 1.5g of sodium carboxymethyl cellulose, 0 to 1.5g of hydroxypropyl methyl cellulose, 0 to 1.5g of ethyl cellulose and 3g of hyaluronic acid; purified water is added to 50ml; wherein, the composition of aureobasidin A and nystatin contains 0.3g-0.4g of aureobasidin A and 0.1g-0.2g of nystatin.
Preferably, the aureobasidin A and nystatin composition contains 0.35g aureobasidin A and 0.15g nystatin per 50ml of the composite spray; 3g of peppermint oil; lemon oil 2g; glycerol 0g; sodium carboxymethylcellulose 1.5g; hydroxypropyl methylcellulose 1.5g; ethyl cellulose was 0g.
The preparation method of the composite spray comprises the following steps:
m1, weighing aureobasidin A and nystatin in a clean beaker, respectively adding sodium bicarbonate, 3g of hyaluronic acid and purified water, and continuously stirring until all components are fully dissolved;
m2, sequentially adding peppermint oil, lemon oil, sodium hydroxymethyl cellulose and hydroxypropyl methyl cellulose into the solution obtained in the step M1, heating and stirring in a water bath kettle at 45 ℃, and continuously supplementing purified water to 50ml in the heating process until all components are completely dissolved;
m3, filtering the solution obtained in the step M2 by using a filter membrane with the pore diameter of 0.22 mu M when the solution is hot, and subpackaging the solution into sterile spray bottles to obtain the spray containing the aureobasidin A and nystatin composition.
In the following examples, example 1 measured the Minimum Inhibitory Concentration (MIC) of a composition of aureobasidin a and nystatin against candida albicans; examples 2 to 4 respectively determine the antibacterial diameters of compound ointments, compound gels and compound sprays containing aureobasidin A and nystatin of different formulations; example 5 stability of various formulations of compound ointments, compound gels and compound sprays containing aureobasidin a and nystatin was determined; example 6 comparative tests were performed on different formulations of compound ointments, compound gels containing aureobasidin a and nystatin, compound sprays with commercially available related drugs for inhibition of candida albicans in the oral cavity.
In the examples of the present invention, candida albicans standard strain SC5314 was used, purchased from american type culture collection (American Tissue Culture Collection, USA); the nystatin used was purchased from sigma aldrich (Shanghai) trade limited; the aureobasidin A used was purchased from Beijing Soy Biotechnology Co.
In the embodiment of the invention, the bacteriostasis test method is that in an ultra-clean workbench, a 1-loop of fresh candida albicans preserved bacteria is selected and inoculated into 4ml of a glucose broth culture medium. After the inoculation, the culture tube is placed in a shaking table and cultured for 8 hours at 220rpm at 37 ℃. And (3) uniformly smearing 100 mu l of cultured candida albicans suspension on the surface of a nutrient agar culture medium, respectively taking 0.5g of each experimental group, adding the experimental groups into oxford cups, putting the culture dishes into a 37 ℃ incubator, respectively taking out the compound ointment of each group of formulas at 30min, 1h, 2h, 4h, 6h and 8h, and respectively taking out the culture dishes to observe the diameter (cm) of a bacteriostasis ring.
Example 1
The Minimum Inhibitory Concentration (MIC) of the combination of aureobasidin a and nystatin against candida albicans was determined.
The experimental method comprises the following steps: inoculating candida albicans suspension into a broth culture medium, culturing overnight at 37 ℃, correcting bacterial liquid to be equivalent to 0.5 Mirabilitum standard, and diluting with the broth culture medium according to the ratio of 1:200 for later use.
Preparing 11 test tubes, taking one test tube to prepare 2ml of aureobasidin A broth culture medium solution with the working concentration of 50 mug/ml, taking 1ml to be added into the test tube containing 1ml broth culture medium, sucking out 1ml to be added into a third tube after uniform mixing, sucking out 1ml to be discarded after the 11 th tube is similarly reached, and sequentially obtaining the final content of aureobasidin A in each test tube of 50, 25, 12.5, 6.25, 3.125, 1.562, 0.781, 0.391, 0.195, 0.098 and 0.049 mug/ml.
A nystatin broth medium solution was prepared at a working concentration of 50. Mu.g/ml according to the procedure described above, and was similarly subjected to gradient dilution.
A broth medium solution containing 37.5. Mu.g/ml aureobasidin A and 25. Mu.g/ml nystatin was prepared according to the above method and similarly subjected to gradient dilution.
The final concentration of aureobasidin A in each tube was 37.5, 18.75, 9.375, 4.687, 2.344, 1.172, 0.586, 0.293, 0.146, 0.073, 0.037. Mu.g/ml, and the concentration of nystatin in each tube was 25, 12.5, 6.25, 3.125, 1.562, 0.781, 0.391, 0.195, 0.098, 0.049, 0.025. Mu.g/ml, respectively, and the volume of each tube was 1ml. A blank broth control group was also included for control.
The candida albicans suspension with corrected concentration is sequentially added into each test tube, the addition amount of each test tube is 0.05ml, and the test tubes are uniformly mixed after the addition. After each test tube was incubated at 37℃for 18 hours, the presence or absence of macroscopic turbidity was observed, and if macroscopic turbidity was observed, the visual turbidity was expressed as "[ V ] and the invisible turbidity was expressed as" \ ", and the results were shown in tables 1-1 and 1-2.
TABLE 1-1 minimum inhibitory concentrations MIC (μg/ml) of aureobasidin A and nystatin, respectively, for Candida albicans
TABLE 1-2 minimum inhibitory concentration MIC of aureobasidin A and nystatin compositions for Candida albicans (μg/ml)
From the test results in tables 1-1 and 1-2, it was found that the minimum inhibitory concentration of aureobasidin A against Candida albicans was between 1.562 and 3.125. Mu.g/ml, the minimum inhibitory concentration of nystatin against Candida albicans was between 0.781 and 1.562. Mu.g/ml, and both antibiotics had good antibacterial activity against Candida albicans.
The minimum antibacterial concentration of the composition of the aureobasidin A and the nystatin on candida albicans is between 0.073 and 0.146 mug/ml when the mass concentration ratio of the aureobasidin A to the nystatin is 1.5:1, which shows that the antibacterial effect of the composition of the aureobasidin A and the nystatin on candida albicans is obviously stronger than that of the composition of the aureobasidin A and the nystatin on candida albicans when the composition is used independently.
Example 2
Compound ointments of aureobasidin a and nystatin compositions of various formulations were prepared and the antibacterial activity of the compound ointments of each formulation against candida albicans was examined.
Composite ointments containing aureobasidin A and nystatin compositions of different components were prepared according to the formulations in Table 2 and were divided into groups A1 to A9 according to the different formulations, wherein the components not contained were expressed as "\".
Composite ointments containing aureobasidin A and nystatin compositions of the above A1-A9 formulations were prepared according to the method of the present invention, and antibacterial tests were performed on each of the above composite ointments, respectively, with antibacterial diameters at different times shown in Table 3.
Table 2A 1-A9 group composite ointment formulations containing Aureobasidin A and nystatin compositions
Table 3 results of antibacterial tests of Aureobasidin A and nystatin composite ointments prepared from different formulations on candida albicans
As can be seen from Table 3, the compound ointment containing aureobasidin A and nystatin composite prepared by the formulations of the A1 group, the A2 group, the A4 group, the A5 group and the A7 group has the maximum inhibition effect on candida albicans within 8 hours, wherein the compound ointment prepared by the formulation of the A4 group has the maximum inhibition effect on candida albicans, and the compound ointment has the most preferable formulation of aureobasidin A and nystatin composite, and the formulation contains 16g of aureobasidin A and nystatin composite, 10g of cetyl alcohol, 624g of white vaseline, 100g of liquid paraffin, 25g of polyoxyethylene (40) stearate, 25g of ethyl formate and 200g of glycerin; wherein the aureobasidin A and nystatin composition contains 10g of aureobasidin A and 6g of nystatin.
Example 3
Preparing composite gel of aureobasidin A and nystatin composite of various formulas and detecting the bacteriostasis of the composite gel of each formula on candida albicans.
The gels containing aureobasidin A and nystatin compositions of the different components were prepared according to the formulations in Table 4 and were divided into groups B1-B9 according to the different formulations, wherein the components not contained were expressed as "\".
Preparing composite gel containing aureobasidin A and nystatin composite of the formula of the groups B1-B9 according to the method of the invention, and respectively carrying out bacteriostasis test on each group of composite gel; the antibacterial diameters of the composite gels of each group at different times are shown in table 5.
Table 4 formulation of composite gels of groups B1-B9 containing Aureobasidin A and nystatin compositions
Table 5 results of antibacterial tests of Aureobasidin A and nystatin composite gel prepared from different formulations on candida albicans
According to Table 5, the compound gel containing aureobasidin A and nystatin composite prepared by the formulations of the groups B2, B4, B5 and B7 has the inhibition effect on the growth effect of candida albicans in 8 hours, wherein the diameter of the inhibition zone of the aureobasidin A and nystatin compound gel prepared by the formulation of the group B5 is the largest, the inhibition effect on candida albicans is the best, and the compound gel is the most preferable formulation of the aureobasidin A and nystatin compound gel.
In the formula of the B5 group, the raw materials and the weight ratio are that 15g of aureobasidin A and nystatin composition, 230g of poloxamer 188, 20g of chitosan, 20g of hyaluronic acid, 25g of hypromellose, 50g of glycerol, 5g of methylparaben and purified water are supplemented to 1000ml; wherein, the composition of aureobasidin A and nystatin contains 9.5g of aureobasidin A and 5.5g of nystatin.
Example 4
Preparing a composite spray of aureobasidin A and nystatin compositions of various formulas and detecting the bacteriostasis of the composite spray of each formula on candida albicans.
Sprays containing aureobasidin A and nystatin compositions of different compositions were prepared according to the formulations in Table 6 and were divided into groups C1-C9 according to the different formulations, wherein the non-contained components were indicated as "\".
According to the method, preparing the compound spray containing the aureobasidin A and nystatin composite in the C1-C9 group formula, and respectively carrying out bacteriostasis test on each group of compound spray; the antibacterial tests were performed on the above groups of composite sprays, respectively, and the antibacterial diameters of the groups of composite sprays at different times are shown in table 7.
Table 6C 1-C9 group composite spray formulation containing Aureobasidin A and nystatin compositions
Table 7 results of antibacterial tests of Aureobasidin A and nystatin composite sprays prepared from different formulations on candida albicans
As shown in Table 7, the compound spray of aureobasidin A and nystatin prepared in the formulations of C2, C3, C4 and C9 in example 6 can inhibit the growth effect of candida albicans within 8 hours, wherein the compound spray of aureobasidin A and nystatin prepared in the formulation of C4 has the largest inhibition zone diameter and has the best inhibition effect on candida albicans, and the compound spray of aureobasidin A and nystatin is the most preferable formulation.
In addition, the dispersion stability test was performed on each group of the composite sprays described above: and (3) placing the prepared aureobasidin A and nystatin composite spray in a centrifugal machine, centrifuging at 3000rpm for 10 minutes at room temperature, standing for 5 minutes after centrifugation, and observing whether turbidity occurs or not.
After testing, the composite spray does not show turbidity, which indicates that each group of composite spray in the embodiment has better dispersion stability.
Example 5
Stability tests were performed on compound ointments, compound gels, and compound sprays containing aureobasidin A and nystatin compositions in examples 2 to 4.
The samples selected in this example were a composite ointment formulated in the A4 formulation of example 2, a composite gel formulated in the B5 formulation of example 3, and a composite spray formulated in the C4 formulation of example 4.
The test method comprises the following steps: the three groups of samples are packaged by an aluminum foil bag and a paper box, and are kept stand for 0 month, 1 month, 2 months, 3 months and 6 months at the temperature of 30+/-2 ℃ and the humidity of 65+/-5% RH, and the appearance, the weight difference and the microorganism limit of the samples are respectively examined and measured, and the results are shown in Table 8:
table 8 stability test results for each group of samples
From the above experimental results, the compound ointment of the formula of the A4 in the example 2, the compound gel of the formula of the B5 in the example 3 and the compound spray of the formula of the C4 in the example 4 have good stability.
Example 6
Comparative experiments on the therapeutic effects of oral candidiasis with commercially available medicines were performed on compound ointments, compound gels, and compound sprays containing aureobasidin A and nystatin compositions in examples 2 to 4.
The samples selected in this example were a composite ointment formulated in the A4 formulation of example 2, a composite gel formulated in the B5 formulation of example 3, and a composite spray formulated in the C4 formulation of example 4.
The test organism of this example is a mouse, specifically, 70 SPF grade ICR mice, female, 7 week old, 30-35g purchased from the medical laboratory animal center in Guangdong province.
The experimental method comprises the following steps: mice were randomly divided into 7 groups of 10, each group of test drugs:
group A: compound ointment formulated in group A4 of example 2;
group B: composite gel prepared by the formula of the group B5 in the embodiment 3;
group C: the composite spray of example 4, formulation C4;
group D: commercially available nystatin tablets (seismometers);
group E: a commercially available nystatin tablet (Lu Kang);
group F: a commercial aureobasidin a powder;
group G: blank control.
The experimental method comprises the following specific steps:
1) Pretreatment of inoculation: intramuscular injection of 8g/l prednisolone at 1d before and 3d after inoculation and 8d promotes immunosuppression of mice, while intraperitoneal injection of 5% chloral hydrate daily for anesthetizing mice before inoculation, followed by dipping with sterile cotton swab at a concentration of 3×10 8 100 μl of CFU/ml candida albicans suspension is smeared and inoculated on the whole oral cavity (including buccal mucosa, soft palate, tongue and other mucosal surfaces of the oral cavity) of a mouse, and each part is smeared under three parts; the mice in the blank group were treated with prednisolone as well, but the mouth of the mice was smeared with sterile normal saline. After 2 weeks, the oral cavity cheek, tongue and other parts of the mice in the experimental group can be seen to form a white patch type biological film,one mouse was sacrificed from each group, the buccal mucosa was fixed in 4% paraformaldehyde, dehydrated embedding was stained with PAS, a large number of hyphae and spores were observed under an optical microscope, and a small number of inflammatory cells were observed to infiltrate, indicating successful modeling.
2) Inoculating: 8 mice which are successfully modeled are selected in each group, 0.5g of the aureobasidin A and nystatin compound ointment of the example 2, 0.5g of the aureobasidin A and nystatin compound spray gel of the example 4 and 0.5ml of the aureobasidin A and nystatin compound spray of the example 6 are respectively taken in 1h, 24h and 48h, and are smeared on infection parts such as oral and buccal mucosa of the mice in the group A-C, and the mice in the group D-E are swallowed in stomach by taking 1 tablet (seismometer) of the commercially available nystatin and 1 tablet (Lu Kang), and 5mg of the powder of the commercially available aureobasidin A is dissolved in purified water to be swallowed in stomach by the mice in the group F; the control group was smeared with 0.9% physiological saline on the oral infection site of group F mice, and the oral infection site (including buccal mucosa, soft palate, tongue and other mucosal surfaces) of the mice was rubbed with a sterile cotton swab for sampling at 12h, 24h, 36h, 48h, 60h, 72h before and after administration, and the colony count of candida albicans in the oral cavity of the mice was measured, and the average number was taken for each group to carry out the statistics of the results.
3) Analysis of experimental results: as a result, as shown in fig. 1, the oral candida albicans numbers in the mice of group A, B, C were decreased faster than those of groups D, E and F, respectively, in the oral candida albicans numbers in the mice of group A, B, C were decreased by 98.5%, 97.1% and 98.5%, respectively, and the oral candida albicans numbers in the mice of groups D, E and F were decreased by 81.8%, 83.5% and 84.8%, respectively, in the 72h post-administration.
From the above experimental results, it was found that the compound ointment, the compound gel, and the compound spray containing aureobasidin a and nystatin composition inhibited killing of candida albicans in the oral cavity at a significantly higher rate than the commercially available nystatin tablets (shakuan), the commercially available nystatin tablets (Lu Kang), and the commercially available aureobasidin a powder. The therapeutic effect after three days of administration is also remarkably improved, so that the aureobasidin A and nystatin composite has excellent effect of inhibiting candida albicans in the oral cavity, and the compound ointment, compound gel and compound spray containing the aureobasidin A and nystatin composite have great application value.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.
Claims (10)
1. The composition is characterized in that the mass ratio of the aureobasidin A to the nystatin is 1.29-4:1.
2. The aureobasidin a and nystatin composition according to claim 1, wherein the mass ratio of aureobasidin a to nystatin in the composition is 1.67-2.33:1.
3. Use of a composition of aureobasidin a and nystatin according to claim 1 or 2, for the preparation of a medicament for the treatment of oral candidiasis.
4. A medicament for the treatment of oral candidiasis, characterized in that it comprises a composition of aureobasidin a and nystatin as defined in claim 1 or 2.
5. A medicament for the treatment of oral candidiasis as claimed in claim 4, wherein the medicament is a compound ointment which consists of the following raw materials, and the mass of each raw material in each 1000g of the compound ointment is: 16g of aureobasidin A and nystatin composition, 10g of cetyl alcohol, 0-100g of liquid paraffin, 25g of polyoxyethylene (40) stearate, 0-25g of ethyl formate, 0-25g of propylene carbonate, 200g of glycerol, 0-624g of white vaseline and 0-624g of white beeswax;
wherein the aureobasidin A and nystatin composition contains 9-11g aureobasidin A and 5-7g nystatin.
6. The medicine for treating oral candidiasis according to claim 5, wherein the composition of aureobasidin a and nystatin in the compound ointment contains 10g of aureobasidin a and 6g of nystatin;
the liquid paraffin is 100g; the ethyl formate is 25g; 624g of white vaseline; the white beeswax is 0g; the propylene carbonate was 0g.
7. A medicament for the treatment of oral candidiasis according to claim 4, characterized in that the medicament is a composite gel, the composite gel is composed of the following raw materials, and the mass of each raw material in each 1000ml of the composite gel is: 15g of aureobasidin A and nystatin composition, 230g of poloxamer, 20g of chitosan, 20g of hyaluronic acid, 0-25g of methylcellulose or hydroxypropyl methylcellulose, 0-25g of carboxypropyl-beta-cyclodextrin, 50g of glycerol, 5g of methylparaben and purified water to 1000ml;
wherein the aureobasidin A and nystatin composition contains 9g-10g of aureobasidin A and 5g-6g of nystatin.
8. A medicament for the treatment of oral candidiasis according to claim 7, characterized in that the aureobasidin a and nystatin composition contains 9.5g of aureobasidin a and 5.5g of nystatin per 1000ml of complex gel;
the methyl cellulose is 0g; the carboxypropyl-beta-cyclodextrin is 0g; the hydroxypropyl methylcellulose is 25g; the poloxamer is poloxamer 188.
9. A medicament for treating oral candidiasis as claimed in claim 4, wherein the medicament is a composite spray, the composite spray is composed of the following raw materials, and the mass of each raw material in each 50ml of the composite spray is as follows: 0.5g of aureobasidin A and nystatin composition, 0-3g of peppermint oil, 0-2g of lemon oil, 0-3g of glycerol, 1g of sodium bicarbonate, 0-1.5g of sodium carboxymethyl cellulose, 0-1.5g of hydroxypropyl methyl cellulose, 0-1.5g of ethyl cellulose and 3g of hyaluronic acid; purified water is added to 50ml;
wherein the aureobasidin A and nystatin composition contains 0.3g-0.4g of aureobasidin A and 0.1g-0.2g of nystatin.
10. A medicament for the treatment of oral candidiasis according to claim 9, characterized in that the aureobasidin a and nystatin composition contains 0.35g of aureobasidin a and 0.15g of nystatin per 50ml of the composite spray;
3g of peppermint oil; 2g of lemon oil; the glycerin is 0g; the sodium carboxymethyl cellulose is 1.5g; the hydroxypropyl methylcellulose is 1.5g; the ethyl cellulose is 0g.
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