CN109464444A - One kind being used for gynaecology's antifungal compound clotrimazole composition - Google Patents
One kind being used for gynaecology's antifungal compound clotrimazole composition Download PDFInfo
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- CN109464444A CN109464444A CN201811637654.XA CN201811637654A CN109464444A CN 109464444 A CN109464444 A CN 109464444A CN 201811637654 A CN201811637654 A CN 201811637654A CN 109464444 A CN109464444 A CN 109464444A
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- Prior art keywords
- clotrimazole
- composition
- gynaecology
- platycodin
- antifungal compound
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- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 229960004022 clotrimazole Drugs 0.000 title claims abstract description 48
- 239000000203 mixture Substances 0.000 title claims abstract description 31
- 150000001875 compounds Chemical class 0.000 title claims abstract description 20
- 230000000843 anti-fungal effect Effects 0.000 title claims abstract description 12
- 229940121375 antifungal agent Drugs 0.000 title claims abstract description 12
- 240000007087 Apium graveolens Species 0.000 claims abstract description 20
- 235000015849 Apium graveolens Dulce Group Nutrition 0.000 claims abstract description 20
- 235000010591 Appio Nutrition 0.000 claims abstract description 20
- GWBIYORWNUYYMZ-UHFFFAOYSA-N platycodin D Natural products CC1OC(OC2C(O)C(O)COC2OC(=O)C34CCC(C)(C)CC3C5=CCC6C7(C)CC(O)C(OC8CC(CO)C(O)C(O)C8O)C(CO)(CO)C7CCC6(C)C5(C)CC4O)C(O)C(O)C1OC9OCC(O)C(OC%10OCC(O)(CO)C%10O)C9O GWBIYORWNUYYMZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- CYBWUNOAQPMRBA-NDTOZIJESA-N platycodin D Chemical compound O([C@H]1[C@@H](O)C[C@]2(C)[C@H]3CC=C4[C@@H]5CC(C)(C)CC[C@@]5([C@@H](C[C@@]4(C)[C@]3(C)CC[C@H]2C1(CO)CO)O)C(=O)O[C@@H]1OC[C@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@H]([C@@H]([C@@H](O)[C@H]1O)O[C@H]1[C@@H]([C@@H](O[C@H]2[C@@H]([C@@](O)(CO)CO2)O)[C@H](O)CO1)O)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O CYBWUNOAQPMRBA-NDTOZIJESA-N 0.000 claims abstract description 20
- 239000000470 constituent Substances 0.000 claims abstract description 13
- 239000003349 gelling agent Substances 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000000463 material Substances 0.000 claims abstract description 5
- 210000001215 vagina Anatomy 0.000 claims abstract description 5
- 239000006071 cream Substances 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 150000003851 azoles Chemical class 0.000 claims description 4
- 239000004909 Moisturizer Substances 0.000 claims description 3
- 229920002678 cellulose Polymers 0.000 claims description 3
- 239000001913 cellulose Substances 0.000 claims description 3
- 230000001333 moisturizer Effects 0.000 claims description 3
- 239000003002 pH adjusting agent Substances 0.000 claims description 3
- 239000003755 preservative agent Substances 0.000 claims description 3
- 230000002335 preservative effect Effects 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 241000894006 Bacteria Species 0.000 description 26
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 26
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- 239000011734 sodium Substances 0.000 description 20
- 241000222122 Candida albicans Species 0.000 description 15
- 229940095731 candida albicans Drugs 0.000 description 15
- 239000000499 gel Substances 0.000 description 13
- 235000011187 glycerol Nutrition 0.000 description 13
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 12
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 12
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 12
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 12
- 239000001963 growth medium Substances 0.000 description 12
- 239000002002 slurry Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- 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 description 9
- 239000001768 carboxy methyl cellulose Substances 0.000 description 9
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 9
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 9
- 230000000694 effects Effects 0.000 description 7
- 230000006698 induction Effects 0.000 description 7
- 239000007974 sodium acetate buffer Substances 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003595 mist Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 206010020565 Hyperaemia Diseases 0.000 description 5
- 206010030113 Oedema Diseases 0.000 description 5
- 230000003628 erosive effect Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000001408 fungistatic effect Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 239000001965 potato dextrose agar Substances 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 241000208671 Campanulaceae Species 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 4
- 239000006159 Sabouraud's agar Substances 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 241000894007 species Species 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 206010062717 Increased upper airway secretion Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 230000001857 anti-mycotic effect Effects 0.000 description 2
- 239000002543 antimycotic Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 208000026435 phlegm Diseases 0.000 description 2
- 238000007747 plating Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229930182490 saponin Natural products 0.000 description 2
- 235000017709 saponins Nutrition 0.000 description 2
- -1 saponins compound Chemical class 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000013316 zoning Methods 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 241000222173 Candida parapsilosis Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000726221 Gemma 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
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010068319 Oropharyngeal pain Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 206010046914 Vaginal infection Diseases 0.000 description 1
- 201000008100 Vaginitis Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940071110 amino-cerv Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 238000004500 asepsis Methods 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 229940055022 candida parapsilosis Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 210000001647 gastrula Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 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
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002255 vaccination Methods 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
One kind being used for gynaecology's antifungal compound clotrimazole composition, and the compound clotrimazole composition is by the clotrimazole as active constituent and celery sugar Platycodin D and at least one auxiliary material for vagina administration preparation is gone to form；In the composition clotrimazole with go celery sugar Platycodin D mass ratio be 4~8:1.The composition is prepared into gelling agent or cream, and the weight percentage of clotrimazole is 1%~3% in the composition.
Description
Technical field:
The present invention provides a kind of gynaecology's composition, the antimycotic Amino-Cerv of especially a kind of compound containing clotrimazole.
Background technique:
Clotrimazole (CAS:23593-75-1) is pyroles broad-spectrum antifungal medicine.To fungies such as Candida albicans, have aobvious
Write inhibiting effect.It can be by inhibiting its gemma of Candida albicans to be changed into the mycelia of tool invasion.Therefore it is widely used in
The treatment of the diseases such as the microbial colpomycosis of Candida albicans.The existing clotrimazole system for colpomycosis treatment
Agent mainly has the cream of 0.15g and 0.5g/ pieces of suppository and 1% (5g).Due to being widely used, Candida albicans to gram
Mould azoles drug resistance is more and more stronger.How to improve clotrimazole becomes the fungistatic effect of drug resistance fungal to improve and guarantee its curative effect
The emphasis studied in the prior art
Campanulaceae as Chinese medicine is the dry root of Campanulaceae campanulaceae, bitter in taste, pungent, flat.It is distributed in lung channel, there is a surname
The effect of lung, relieving sore-throat, eliminating the phlegm, apocenosis.It include saponin(e, polysaccharide, flavones, sterol etc. in the chemical component that campanulaceae extracts.Go celery
Sugared Platycodin D (CAS:78763-58-3) is a kind of saponins compound for extracting from campanulaceae, be considered to have it is anti-inflammatory,
Eliminating the phlegm, liver protection, it is hypoglycemic the effects of.It finds in earlier research, for artificial induction to the drug resistant Candida albicans of clotrimazole, adds
Enter the fungistatic effect for going celery sugar Platycodin D that clotrimazole can be enhanced on a small quantity, be based on this, how to obtain a kind of anti-true for gynaecology
The compound clotrimazole composition of bacterium becomes urgent problem to be solved in the prior art.
Summary of the invention:
Based on earlier research, to solve aforementioned technical problem, technical solution provided by the invention are as follows:
Gynaecology's antifungal compound clotrimazole composition is used for containing one kind, it is characterised in that the compound clotrimazole combination
Object is by the clotrimazole as active constituent and removes celery sugar Platycodin D and at least one auxiliary material group for vagina administration preparation
At；In the composition clotrimazole with go celery sugar Platycodin D mass ratio be 4~8:1.
It is described to be used for gynaecology's antifungal compound clotrimazole composition containing a kind of, it is characterised in that clotrimazole and to go celery
The mass ratio of sugared Platycodin D is preferably 6~7:1.
Described is used for gynaecology's antifungal compound clotrimazole composition containing a kind of, it is characterised in that the composition system
Standby to become gelling agent or cream, the weight percentage of clotrimazole is 1%~3% in the composition.
Described is used for gynaecology's antifungal compound clotrimazole composition containing a kind of, it is characterised in that the composition system
It is standby to become gelling agent, the auxiliary material includes cellulose derivative, moisturizer, solvent, preservative, pH adjusting agent and and surplus
Water.
The cellulose is derivative fine selected from sodium carboxymethylcellulose (CMC-Na), methylcellulose (MC), hydroxypropyl methyl
One of plain (HPMC), preferably sodium carboxymethylcellulose (CMC-Na) are tieed up, the sodium carboxymethylcellulose dosage is combination
The 4%~8% of object gross mass.The moisturizer is glycerine, and dosage is 10%~15%, and the preservative is selected from nipalgin
Ethyl ester, dosage are 0.1%~0.2%, and the solvent is selected from propylene glycol, and the pH adjusting agent is selected from acetic acid/sodium-acetate buffer,
The pH value of the gel is 4~5.
Heretofore described percentage is the weight percent for accounting for composition.
It is provided by the invention to contain a kind of the antimycotic for gynaecology of ratio for preferably removing celery sugar Platycodin D and clotrimazole
Compound clotrimazole composition can be significantly improved resistance to for artificial induction's clotrimazole by preferred two kinds of active components ratio
The fungistatic effect of the Candida albicans of medicine is combined from the more preferable compound clotrimazole of a kind of pair of drug resistance Candida albicans fungistatic effect is obtained
Object.And in further experiments it was found that above-mentioned synergy, in clotrimazole and to go celery sugar Platycodin D ratio be 6~7:
It is more apparent when 1.
Specific embodiment:
Pharmacological Examples 1
The preparation of Pharmacological Examples 1, antibody-resistant bacterium
Preparation method
1) reference culture uses Candida albicans (Candida albicans), and (number: ATCC10231) reads white
The reference culture of pearl bacterium continuous transferred species 2 times (35 DEG C of cultivation temperature) on sabouraud's agar (SDA) culture medium after culture for 24 hours, is chosen
Bacterium colony of 5 diameters greater than 1cm shakes 15s in 5mL sterile saline, and bacteria suspension is made, and is 0.5 than turbid instrument measurement concentration
Maxwell turbidity unit, with blood cell counting plate by its concentration correction be 1~5 × 105CFU/mL。
2) detection clotrimazole carries out, matter the minimal inhibitory concentration (MIC) of Candida albicans according to CLSIM38-2 scheme
Control bacterial strain is Candida parapsilosis (ATCC 22019)；To the MIC result and negative control group phase of Candida albicans reference culture
Than the Cmin that can significantly inhibit fungi growth (about 80%) is minimal inhibitory concentration
3) induction of antibody-resistant bacterium according to MIC measure as a result, the clotrimazole medical fluid YEPD for preparing 2 times of MIC concentration is cultivated
Base takes 0.1mL bacteria suspension into 5mL drug containing YEPD culture medium after 35 DEG C carry out culture 48h, take 0.1mL bacterium solution to 4 times grams it is mould
On the YEPD culture medium of azoles MIC concentration after 35 DEG C carry out culture 48h, take 0.1mL bacterium solution to 8 times of clotrimazole MIC concentration
It is cultivated on YEPD culture medium in 35 DEG C.It is to induce first 8 times, and cultivate in SDA to clotrimazole MIC concentration with bacterial strain after induction
Base remains to MIC value and remains to remain first 8 times of induction or more after passing on 2 times, as the standard of success inducible resistance, if not up to this mark
Standard, then repeatedly abovementioned steps.
One, 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 medium is added in each test tube and is prepared into slant medium；20ml culture medium is 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, using three zoning collimation methods,
35 DEG C of constant incubators are placed in, are 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 base, candida albicans is placed in 35 DEG C
Insulating box, culture are inoculated in the good culture medium colour developing of Kerma (unit of kinetic energy) and identify kind after 2 days.
The bacterial strain that this experiment uses is respectively Candida albicans reference culture and antibody-resistant bacterium in Pharmacological Examples 1.
2.2 production bacteria suspensions
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, fullys shake and elutes spore, adjusts bacteria suspension turbidity to 5 × 10 using hemacytometer6~10 × 106CFU/
mL。
2.3 production plates containing bacterium
It extracts 0.5ml bacteria suspension and is placed in PDA plating medium, be allowed to be uniformly distributed in culture base table with sterilizing spreading rod
Face.
2.4 punching dosings
It is punched on applying the culture medium after bacterium with the punch of diameter 6mm, chooses agar in hole, drug to be tested is distinguished
It squeezes into 1ml asepsis injector, 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
2.5 cultures and outcome measurement
Drug sensitive experiment plate is placed in 35 DEG C of constant incubators, cultivates 2 days.Use the antibacterial ring size of every kind of medicine of vernier caliper measurement
Radius records inhibition zone radius mm value around each medicine hole.Every plant of bacterium is cooked 3 plates simultaneously.
As a result following (unit mm, n=3, means ± s)
The experimental results showed that although for reference culture substantially without promoted fungistatic effect effect, experimental group 2~3
The result shows that two kinds of compounds of certain proportion can significantly improve the inhibitory effect to antibody-resistant bacterium, prepare based on this result with gram
Mould azoles makes example of formulations with celery sugar Platycodin D ratio is gone for 4~8:1.
Two, example of formulations
It is prepared into gelling agent by described in example of formulations, the content uniform specification of the middle clotrimazole of all gelling agents is
With 50mg/5g
Embodiment 1
Clotrimazole 1g, celery sugar Platycodin D 0.15g is removed
Sodium carboxymethylcellulose 5g, glycerine 10g,
Ethylparaben 0.1g distilled water adds to 100g
CMC-Na and glycerine are mixed to get CMC-Na slurry, another taking ethylparaben is dissolved in hot water, is then added
CMC-Na slurry, stirring becomes gel, then active constituent micro mist is dissolved in being added to be gradually added into after propylene glycol and is stirred evenly, using acetic acid/
Sodium-acetate buffer adjusts pH to 4~5.The water for supplying surplus stirs evenly up to clear gel.
Embodiment 2
Clotrimazole 1g, celery sugar Platycodin D 0.2g is removed
Sodium carboxymethylcellulose 5g, glycerine 10g,
Ethylparaben 0.1g distilled water adds to 100g
CMC-Na and glycerine are mixed to get CMC-Na slurry, another taking ethylparaben is dissolved in hot water, is then added
CMC-Na slurry, stirring becomes gel, then active constituent micro mist is dissolved in being added to be gradually added into after propylene glycol and is stirred evenly, using acetic acid/
Sodium-acetate buffer adjusts pH to 4~5.The water for supplying surplus stirs evenly up to clear gel.
Embodiment 3
Clotrimazole 1g, celery sugar Platycodin D 0.25g is removed
Sodium carboxymethylcellulose 5g, glycerine 10g,
Ethylparaben 0.1g distilled water adds to 100g
CMC-Na and glycerine are mixed to get CMC-Na slurry, another taking ethylparaben is dissolved in hot water, is then added
CMC-Na slurry, stirring becomes gel, then active constituent micro mist is dissolved in being added to be gradually added into after propylene glycol and is stirred evenly, using acetic acid/
Sodium-acetate buffer adjusts pH to 4~5.The water for supplying surplus stirs evenly up to clear gel..
Embodiment 4
Clotrimazole 1g, celery sugar Platycodin D 0.125g is removed
Sodium carboxymethylcellulose 5g, glycerine 10g,
Ethylparaben 0.1g distilled water adds to 100g
CMC-Na and glycerine are mixed to get CMC-Na slurry, another taking ethylparaben is dissolved in hot water, is then added
CMC-Na slurry, stirring becomes gel, then active constituent micro mist is dissolved in being added to be gradually added into after propylene glycol and is stirred evenly, using acetic acid/
Sodium-acetate buffer adjusts pH to 4~5.The water for supplying surplus stirs evenly up to clear gel..
Comparative example 1
Clotrimazole 1g, celery sugar Platycodin D 0.1g is removed
Sodium carboxymethylcellulose 5g, glycerine 10g,
Ethylparaben 0.1g distilled water adds to 100g
CMC-Na and glycerine are mixed to get CMC-Na slurry, another taking ethylparaben is dissolved in hot water, is then added
CMC-Na slurry, stirring becomes gel, then active constituent micro mist is dissolved in being added to be gradually added into after propylene glycol and is stirred evenly, using acetic acid/
Sodium-acetate buffer adjusts pH to 4~5.The water for supplying surplus stirs evenly up to clear gel...
Comparative example 2
Clotrimazole 1g, celery sugar Platycodin D 0.3g is removed
Sodium carboxymethylcellulose 5g, glycerine 10g,
Ethylparaben 0.1g distilled water adds to 100g
CMC-Na and glycerine are mixed to get CMC-Na slurry, another taking ethylparaben is dissolved in hot water, is then added
CMC-Na slurry, stirring becomes gel, then active constituent micro mist is dissolved in being added to be gradually added into after propylene glycol and is stirred evenly, using acetic acid/
Sodium-acetate buffer adjusts pH to 4~5.The water for supplying surplus stirs evenly up to clear gel...
Comparative example 3
According to the formula of embodiment 1, active constituent is changed to clotrimazole 1.5g.
Comparative example 4
According to the formula of embodiment 1, active constituent is changed to celery sugar Platycodin D 1.5g.
2 zoopery of Pharmacological Examples
The Female New Zealand White Rabbit of 2.5~3kg of weight is selected, 6d starts before being inoculated with bacterium solution, subcutaneous injection benzene first
Sour estradiol finish 0.05ml, injection in every two days later cause the false heat state of rabbit, increase once up to model foundation success
The probability infected greatly.
Artificial induction's Candida albicans antibody-resistant bacterium sterile saline that Pharmacological Examples 1 are obtained is by its density tune
It is 2.5 × 107CFU/ml, every rabbit (dip in a small amount of sterile liquid stone with sterilized intragastric administration on mice device set aseptic silica gel pipe
Wax) bacterium solution 0.2ml injection intravaginal is drawn, it is in situ to stop 1-2min, prevent bacterium solution from flowing out.For three days on end, 1 time a day, and in
It takes within the 5th day after final vaccination vaginal fluid to carry out plate coating checking, is positive through microscopy Candida albicans, and by vagina
Secretion is cultivated with sabouraud culture medium, sees that pseudohypha and blastopore have infected white thought to further confirm that after culture
Pearl bacterium, in conjunction with visually observing, whether vaginal fluid increases, whether there is or not the inflammation such as vagina hyperemia, oedema, erosion occur for vaginal mucosa
Variation determines modeling success.
The successful experimental animal grouping of modeling is taken, every group 10, the gelling agent that embodiment and comparative example obtain is respectively adopted
It is treated, 1g is administered every time.
It observes by the naked eye and rank scores is carried out to groups of animals change indicator, standards of grading are as follows:
0 point, no oedema, hyperemia, erosion, secretion do not increase person；
1 point, Mild edema, hyperemia, erosion, secretion do not increase person on a small quantity；
2 points, intermediate edema, hyperemia, erosion, secretion increase more person；
3 points, severe hyperemia, oedema, erosion, secretion largely do not increase person and are.
Continuous application drug 7d, dosage are that preceding and scoring after drug withdrawal 72h respectively is administered
Grouping administration see the table below with experimental result
The experimental results showed that both obvious using the therapeutic effect of the animal pattern of 1~4 compound of the embodiment of the present invention
Better than the experimental group and control group using single active ingredient, also superior to the experimental group using comparative example 1/2, illustrate that the present invention is excellent
The ratio of the two kinds of active components of choosing can significantly improve dynamic for artificial induction's drug resistance candida albicans infection vaginitis model
The therapeutic effect of object.And the effect of experimental group 1 illustrates that its active constituent ratio better effect is prominent also superior to other experimental groups.
Claims (4)
1. one kind is used for gynaecology's antifungal compound clotrimazole composition, it is characterised in that the compound clotrimazole composition is by making
It is formed for the clotrimazole of active constituent with celery sugar Platycodin D and at least one auxiliary material for vagina administration preparation is removed；It is described
In composition clotrimazole with go celery sugar Platycodin D mass ratio be 4~8:1.
2. as described in claim 1 be used for gynaecology's antifungal compound clotrimazole composition containing a kind of, it is characterised in that gram
Mould azoles and the mass ratio for removing celery sugar Platycodin D are preferably 6~7:1.
3. as claimed in claim 1 or 2 be used for gynaecology's antifungal compound clotrimazole composition containing a kind of, it is characterised in that
The composition is prepared into gelling agent or cream, and the weight percentage of clotrimazole is 1%~3% in the composition.
4. as claimed in claim 3 be used for gynaecology's antifungal compound clotrimazole composition containing a kind of, it is characterised in that institute
State composition and be prepared into gelling agent, the auxiliary material include cellulose derivative, moisturizer, solvent, preservative, pH adjusting agent and
And the water of surplus.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1899285A (en) * | 2006-07-14 | 2007-01-24 | 赵宗平 | Mycoporin vaginal soft capsule and its preparing method |
| DE102011088000A1 (en) * | 2011-12-08 | 2012-08-23 | Henkel Ag & Co. Kgaa | Cosmetic, non-therapeutic use of a platycodin compound for influencing the natural pigmentation process of skin and/or skin appendages |
| CN107998072A (en) * | 2017-12-26 | 2018-05-08 | 重庆希尔安药业有限公司 | clotrimazole cream and preparation method thereof |
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2018
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1899285A (en) * | 2006-07-14 | 2007-01-24 | 赵宗平 | Mycoporin vaginal soft capsule and its preparing method |
| DE102011088000A1 (en) * | 2011-12-08 | 2012-08-23 | Henkel Ag & Co. Kgaa | Cosmetic, non-therapeutic use of a platycodin compound for influencing the natural pigmentation process of skin and/or skin appendages |
| CN107998072A (en) * | 2017-12-26 | 2018-05-08 | 重庆希尔安药业有限公司 | clotrimazole cream and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| HWANG, YL ET AL.: "Fermentation of Platycodi radix and bioconversion of platycosides using co-cultures of Saccharomyces cerevisiae KCTC 7928 and Aspergillus awamori FMB S900", 《FOOD SCIENCE AND BIOTECHNOLOGY》 * |
| 朱立芬: "桔梗皂苷D防御口腔黏膜上皮细胞", 《中国病理生理杂志》 * |
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