CN108066342A - A kind of Compound Ketoconazole Cream agent and preparation method thereof - Google Patents
A kind of Compound Ketoconazole Cream agent and preparation method thereof Download PDFInfo
- Publication number
- CN108066342A CN108066342A CN201611010840.1A CN201611010840A CN108066342A CN 108066342 A CN108066342 A CN 108066342A CN 201611010840 A CN201611010840 A CN 201611010840A CN 108066342 A CN108066342 A CN 108066342A
- Authority
- CN
- China
- Prior art keywords
- ketoconazole
- paeonol
- evalution
- liposomes
- cream agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Classifications
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- 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
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
The invention belongs to pharmaceutical technology fields, are related to a kind of Compound Ketoconazole Cream agent and preparation method thereof.Specifically, the Compound Ketoconazole Cream agent of the present invention is made of ketoconazole Evalution of Paeonol Liposomes, oil phase substrate, aqueous phase substrate and emulsifier, and wherein ketoconazole Evalution of Paeonol Liposomes is made up of ketoconazole, Paeonol, lecithin, cholesterol, polyoxyethylene sorbitan monoleate, vitamin E and pH value of 6.5~7.5 phosphate buffer of film dispersion method.Ketoconazole and Paeonol are combined by the cream of the present invention, improve antibacterial activity；Liposome has selectively acting to skin, has to drug and promotees saturating and slow releasing function, ketoconazole and Paeonol are encapsulated in liposome simultaneously, can improve the dissolubility and stability of two medicines simultaneously.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of Compound Ketoconazole Cream agent and preparation method thereof.
Background technology
Ketoconazole is a kind of broad-spectrum antifungal drug, reaches therapeutic purposes in a manner of inhibiting fungi growth and breeding.For
Raising antiphlogistic effects, often with clobetasol propionate compatible use.It can cause to connect however, external application contains corticosteroid medication
Property allergic reaction is touched, long-time service is present with the adverse reactions such as telangiectasis, the thinning, atrophoderma of epidermis.In addition, ketone health
The water solubility of azoles is low, oxidizable, limits larger range of application.
For example, 103432148 A (denominations of invention of Chinese invention patent application CN：A kind of preparation of Compound Ketoconazole Cream
Method) in disclose a kind of Compound Ketoconazole Cream, it is raw materials used including ketoconazole, clobetasol propionate, neomycinsulphate, ten
Six octadecyl alcolols, albolene, liquid paraffin, levelling agent, hygroscopic agent, preservative, dimethyl sulfoxide (DMSO), essence and purified water.For a long time
Using the drug containing corticosteroid hormone, side effect is big, and ingredient is various, complicated for operation.
For another example, 105250219 A (denominations of invention of Chinese invention patent application CN：A kind of ketoconazole carrier micelle and its system
Preparation Method) in disclose a kind of ketoconazole carrier micelle, ketoconazole and mono methoxy polyethylene glycol-poly- valerolactone are dissolved in third
Micella is made using film hydration method in ketone.Although this method is easy to operate, particle diameter distribution is uniform, overcomes ketoconazole water solubility
The defects of low, but the stability of micella is general, can not keep the chemical property of drug activity substance steady in a longer period of time
It is fixed.
Paeonol is a kind of active ingredient extracted from the dry root skin of ranunculaceae peony.The medicine of Paeonol
Reason effect is extensive, has the effects that antibacterial, antiviral, anti-inflammatory, antiallergy, for dermatitis, pruitus, psoriasis, eczema etc.
With preferable therapeutic effect.However, the solubility due to Paeonol in water is low, property is unstable, volatile, sees the easy oxygen of light
Change and decompose, so as to seriously affect his use and curative effect.
Through retrieval, there is no so far by ketoconazole and Paeonol compatible use to treat the document report of fungal infection.
The content of the invention
For the present situation that there is no the resisting mycotic infection of superficial part drug by ketoconazole Yu Paeonol compatible use at present, Yi Jixian
The problems such as side effect present in some Ketoconazol/Clobetasol Propionate preparations is big, ingredient is various, preparation process is complicated, stability is poor, this hair
It is bright to be intended to provide a kind of Compound Ketoconazole Cream agent for being combined ketoconazole and Paeonol and preparation method thereof.
Specifically, the present invention adopts the following technical scheme that：
A kind of Compound Ketoconazole Cream agent, by ketoconazole-Evalution of Paeonol Liposomes, oil phase substrate, aqueous phase substrate and emulsification
Agent is made, wherein the ketoconazole-Evalution of Paeonol Liposomes by ketoconazole, Paeonol, lecithin, cholesterol, Tween-80,
Phosphate buffer that vitamin E and pH value are 6.5~7.5 (using sodium dihydrogen phosphate/disodium hydrogen phosphate as buffer to) pass through
Film dispersion method is made.
Preferably, in parts by weight, 25~35g ketoconazoles-Paeonol fat is included in every 100 parts of Compound Ketoconazole Cream agent
Plastid, 1 part of emulsifier, 17~20 parts of oil phase substrates, surplus is aqueous phase substrate.
In above-mentioned Compound Ketoconazole Cream agent, the ketoconazole-Evalution of Paeonol Liposomes is by 10~30 in parts by weight
Part ketoconazole, 10~30 parts of Paeonols, 200~600 parts of lecithin, 50~200 parts of cholesterol, 5~15 parts of Tween-80s, 5
~15 parts of vitamin Es and 10~30 parts of phosphate buffers are made.
In above-mentioned Compound Ketoconazole Cream agent, the specific preparation method of the ketoconazole-Evalution of Paeonol Liposomes is as follows：
A ketoconazole, Paeonol, lecithin, cholesterol and the vitamin E of formula ratio) are weighed, is added to suitable organic molten
It is dissolved in agent, obtains oily solution, oily solution is then depressurized into rotary evaporation under 40~55 DEG C of water bath conditions, removed organic
After solvent, homogeneous, transparent oiliness film is formed；
B the Tween-80 of formula ratio) is weighed, the pH value for being added to formula ratio is 6.5~7.5 phosphate buffer
Middle dissolving, obtains aqueous solution, then with aqueous solution hydration step A) in obtained oiliness film, up to no insoluble substance
In the presence of obtaining dispersion；
C) by step B) in obtained dispersion in power be 80~130W, frequency surpasses under conditions of being 30~60kHz
Sonication 5~10 minutes obtains ketoconazole-Evalution of Paeonol Liposomes suspension；
D) by step C) in obtained ketoconazole-Evalution of Paeonol Liposomes suspension by 0.45 μm of filtering with microporous membrane, obtain
To ketoconazole-Evalution of Paeonol Liposomes (grain size is 100~200nm, and the envelop rate of two kinds of drugs is more than 80%).
Preferably, organic solvent described in above-mentioned ketoconazole-Evalution of Paeonol Liposomes preparation method is selected from methanol, ethyl alcohol, ether, chlorine
Any one or more in imitative, preferably chloroform.
Preferably, rotary evaporation is depressurized described in above-mentioned ketoconazole-Evalution of Paeonol Liposomes preparation method to use equipped with vacuum pump
Rotary Evaporators are completed.
In above-mentioned Compound Ketoconazole Cream agent, the emulsifier is selected from lauryl sodium sulfate, paregal O, single tristearin
Any one or more in acid glyceride.
In above-mentioned Compound Ketoconazole Cream agent, the oil phase substrate is selected from octadecyl alcolol, hexadecanol, albolene, liquid
Any one or more in paraffin.
In above-mentioned Compound Ketoconazole Cream agent, the aqueous phase substrate is glycerine and/or the mixture of propylene glycol and water.
Preferably, also comprising preservative, preferably parabens preservative, more preferable Buddhist nun in above-mentioned Compound Ketoconazole Cream agent
The golden ethyl ester of pool (also known as ethyl-para-hydroxybenzoate, ethyl hydroxy benzoate), the weight percent of the preservative is 0.1%.
A kind of preparation method of Compound Ketoconazole Cream agent, includes the following steps：
1) ketoconazole-Evalution of Paeonol Liposomes is prepared：
A ketoconazole, Paeonol, lecithin, cholesterol and vitamin E) are weighed, is added to molten in suitable organic solvent
Solution, obtains oily solution, and oily solution is then depressurized rotary evaporation under 40~55 DEG C of water bath conditions, removes organic solvent
Afterwards, homogeneous, transparent oiliness film is formed；
B Tween-80) is weighed, is added in the phosphate buffer that pH value is 6.5~7.5 and dissolves, obtain aqueous molten
Liquid then uses aqueous solution hydration step A) in obtained oiliness film, up to the presence of no insoluble substance, obtain dispersion
System；
C) by step B) in obtained dispersion in power be 80~130W, frequency surpasses under conditions of being 30~60kHz
Sonication 5~10 minutes obtains ketoconazole-Evalution of Paeonol Liposomes suspension；
D) by step C) in obtained ketoconazole-Evalution of Paeonol Liposomes suspension by 0.45 μm of filtering with microporous membrane, obtain
To ketoconazole-Evalution of Paeonol Liposomes；
2) oil phase is prepared：
Oil phase substrate is weighed, heating melting obtains oil phase after 70~80 DEG C of heat preservations；
3) water phase is prepared：
Emulsifier is weighed, dissolving in aqueous phase substrate is added to and, after 70~80 DEG C of heat preservations, obtains water phase；
4) cream is prepared：
Under agitation, the oil phase obtained in step 2) is added in the water phase obtained in step 3), stirred evenly
After be cooled to 50~60 DEG C, add in obtained ketoconazole-Evalution of Paeonol Liposomes in step 1) thereto, cool down while stirring, directly
Until room temperature is down to, Compound Ketoconazole Cream agent is obtained.
In above-mentioned preparation method, organic solvent described in step 1) is arbitrary in methanol, ethyl alcohol, ether, chloroform
One or more, preferably chloroform.
In above-mentioned preparation method, described in step 1) depressurize rotary evaporation using the Rotary Evaporators equipped with vacuum pump come
It completes.
In above-mentioned preparation method, oil phase substrate described in step 2) is selected from octadecyl alcolol, hexadecanol, albolene, liquid
Any one or more in paraffin.
In above-mentioned preparation method, emulsifier described in step 3) is selected from lauryl sodium sulfate, paregal O, single tristearin
Any one or more in acid glyceride.
In above-mentioned preparation method, aqueous phase substrate described in step 3) is glycerine and/or the mixture of propylene glycol and water.
In above-mentioned preparation method, stirring described in step 4) is using mechanical stirring device or magnetic stirring apparatus come complete
Into.
Compared with prior art, there is following advantageous effect using the present invention of above-mentioned technical proposal：
1) ketoconazole is a kind of broad-spectrum antifungal drug, and Paeonol has antibacterial, anti-inflammatory, itching-relieving action, and the combination of two medicines can
To improve antibacterial activity, drug resistance is reduced.The shortcomings that Paeonol percutaneous dosing can overcome classical hormonal class adverse drug reaction big.
2) liposome has selectively acting to skin, has preferable compatibility between phosphatide constituents and skin, right
Drug has rush thoroughly and slow releasing function, and higher drug concentration, long action time, systemic Absorption medicine can be kept in dermal topical application
Measure it is less, have synergy, shorten the course for the treatment of and reduce adverse reaction the features such as, be the comparatively ideal carrier of percutaneous drug delivery, by ketoconazole
It is encapsulated in simultaneously in liposome with Paeonol, the dissolubility and stability of two medicines can be improved simultaneously；
3) existing hydrophilic phenolic hydroxyl group in the structure of Paeonol, and have the methoxyl group and acetyl group of lipophilic, logP is
2.054 (it has been generally acknowledged that the drug that logP is 0~3 is easier to through skin barrier), the molecular weight of Paeonol is smaller, is only 166.18
(it has been generally acknowledged that drug of the molecular weight less than 600 influences less permeability), and Paeonol also has volatility, these properties
So that Paeonol has significant transdermal penetration performance, ketoconazole can be promoted transdermal, and then inhibit deep fungal, improve fungi
The therapeutic effect of infection；
4) since ketoconazole and Paeonol are practically insoluble in water, used when preparing ketoconazole-Evalution of Paeonol Liposomes
Higher medicine fat ratio, while the cholesterol dosage in oil phase is improved, the poly- mountain of surfactant is in addition added in also in water phase
Pear ester -80, these factors each contribute to improve the envelop rate of liposome；
5) since oxidation deterioration easily occurs for phosphatide constituents, when preparing ketoconazole-Evalution of Paeonol Liposomes, in oil phase
Middle addition antioxidant vitamin E improves the stability of liposome；
6) preparation process of Compound Ketoconazole Cream agent of the invention is simple, of low cost, is suitable for industrialized production.
Specific embodiment
Further description is made to technical scheme below in conjunction with specific embodiment.Unless otherwise stated,
Instrument, material, reagent used in the following example etc. can be obtained by routine business means.
Embodiment 1-9：The test of entrapment efficiency in the preparation of ketoconazole-Evalution of Paeonol Liposomes and liposome.
First, orthogonal test is carried out according to the factor in table 1-level design, by the ketoconazole weighed, Paeonol, lecithin
Fat and cholesterol are placed in small beaker, and add in the dissolving of 20mL chloroforms, and then oily solution is transferred in round-bottomed flask, is adopted
Rotary evaporation is depressurized under 45 DEG C of water bath conditions with the Rotary Evaporators equipped with vacuum pump, until chloroform is removed completely,
Ultimately form homogeneous, transparent oiliness film；
Then, (made with suitable phosphate buffer containing Tween-80 with sodium dihydrogen phosphate/disodium hydrogen phosphate
For buffering to) the above-mentioned oiliness film of aquation, until no insoluble matter presence, obtain dispersion；
Then, above-mentioned dispersion is ultrasonically treated (power 100W, frequency 40kHz) 5min, obtains ketoconazole-pellet
Skin phenol liposome turbid liquor；
Finally, by above-mentioned suspension with 0.45 μm of filtering with microporous membrane to get ketoconazole-Evalution of Paeonol Liposomes.
Due to little as influence of the vitamin E that antioxidant uses for entrapment efficiency in liposome, so will
Its omission is disregarded.
The result of above-mentioned orthogonal test is as shown in table 2 and table 3.
1. quadrature factors of table-level design table
| Project | A (medicine/lecithin) | B (Phospholipid/Cholesterol) | C(pH) |
| 1 | 1:8 | 1:2 | 6.5 |
| 2 | 1:10 | 1:3 | 7.0 |
| 3 | 1:13 | 1:4 | 7.5 |
2. ketoconazole envelop rate result of table
3. Paeonol envelop rate result of table
From the result in table 2 and table 3：Each factor is A to the influence size sequence of entrapment efficiency in liposome>B>
C, each factor take the best prescription of optimum level comprehensive analysis as A2B2C1, i.e. medicine/lecithin=1:10, Phospholipid/Cholesterol
=1:3, pH=6.5.Liposome is prepared according to optimal prescription, the envelop rate for measuring ketoconazole is 81.23%, the encapsulating of Paeonol
Rate is 85.49%, average grain diameter 186nm.
The recipe list of ketoconazole-Evalution of Paeonol Liposomes in 4. embodiment 1-9 of table
First, ketoconazole, Paeonol, lecithin, cholesterol and vitamin E are weighed according to the formula ratio in table 4, be placed on
In small beaker, and the dissolving of 20ml chloroforms is added in, then oily solution is transferred in round-bottomed flask, using the rotation equipped with vacuum pump
Turn evaporimeter and depressurize rotary evaporation under 45 DEG C of water bath conditions, until chloroform is removed completely, ultimately form it is homogeneous,
Transparent oiliness film.Then, Tween-80 and phosphate buffer are weighed (with biphosphate according to the formula ratio in table 4
Sodium/phosphorus acid disodium hydrogen as buffering to), the above-mentioned oiliness film of aquation after mixing, until no insoluble matter presence, obtain dispersion
System.Then, above-mentioned dispersion is ultrasonically treated (power 100W, frequency 40kHz) 5min, obtains ketoconazole-Paeonol
Liposome turbid liquor.Finally, using 0.45 μm of above-mentioned liposome turbid liquor of filtering with microporous membrane to get ketoconazole-Paeonol fat
Plastid.
Embodiment 10-12：The preparation of Compound Ketoconazole Cream agent.
The preparation of cream is carried out with liposome obtained in embodiment 5, component and dosage are as shown in table 5.
The recipe list of 5. Compound Ketoconazole Cream agent of table
Specific preparation method is as follows：
(1) oil phase is prepared：The octadecyl alcolol as oil phase substrate, hexadecanol, albolene or atoleine are weighed, heating is molten
Melt after 75 DEG C of heat preservations, be oil phase；
(2) water phase is prepared：It weighs the ethyl hydroxy benzoate as preservative and the lauryl sodium sulfate as emulsifier, put down
Flat plus O or glycerin monostearate, be added to glycerine and/or propylene glycol mixed with purified water after dissolve in the aqueous phase substrate that is formed
It is water phase after 75 DEG C of heat preservations；
(3) cream is prepared：Under mechanical agitation, above-mentioned oil phase is added slowly in water phase, after stirring evenly
50 DEG C are cooled to, ketoconazole-Evalution of Paeonol Liposomes is added in thereto, cools down while stirring, to get multiple until room temperature is down to
Square ketoconazole cream agent.
Experimental example 1：The skin irritation test of Compound Ketoconazole Cream agent
Skin Irritation Test is carried out using the Compound Ketoconazole Cream agent in embodiment 10 to embodiment 12.
Specific experiment process is as follows：The rabbit that selection weight is 2.0~2.5kg is used for 24 hours as experimental animal before experiment
One piece of region is respectively shaved out in scissors and shaver rabbit back backbone both sides of being in, and size is about 10cm × 5cm, wherein the first half
It is divided into intact skin trial zone, the latter half is damaged skin trial zone, and left side applies test medicine or the positive control (name of an article：
Compound ketoconazole ointment, lot number：150901, manufacturer：Jiangsu Ling Bao medicine companies limited company), painting dose is 1mL, right
Side compares for self-blank；Skin scratches skin with scalpel before administration at left and right sides of damaged skin trial zone, is formed " well "
Font (be subject to oozing of blood), damaged area are 2 × 2cm2, residual test medicine or positive right is removed with warm water after coating 15min
According to object.Be administered once daily with method, continuous 7d, and after removing drug 3,7,30d observation coating at skin whether there is erythema and water
Swollen phenomenon, if there is apparent damage, takes skin to make histopathologic examination.
Skin wound repair scoring is carried out to experimental animal according to table 6, after calculating mean scores, according to table 7 into assassination
Swash intensity evaluation.
6. skin wound repair of table scores
7. skin irritatin intensity evaluation of table
| Intensity | Score value |
| It is nonirritant | ＜ 0.5 |
| Slight stimulation | ＜ 2.09 |
| Moderate irritation | ＜ 6.0 |
| Strong and stimulating | ＞ 6.0 |
8. Skin Irritation Test result of table
From the result in table 8, Compound Ketoconazole Cream agent of the invention is after drug removal to the skin of rabbit during 7d
It is negative (i.e. nonirritant) that skin, which stimulates, and positive control has generated slight thorn in the damaged skin area of rabbit at this time
Swash；After drug removal during 30d, Compound Ketoconazole Cream agent of the invention does not generate any thorn yet to the intact skin area of rabbit
Swash, slight stimulation is also only generated to damaged skin area, and positive control is in the breakage of rabbit and intact skin area at this time
All generate moderate stimulation.In comparison, the skin irritatin side effect of Compound Ketoconazole Cream agent of the invention is lower.
Experimental example 2：The percutaneous penetration of Compound Ketoconazole Cream agent.
Percutaneous penetration is carried out using the Compound Ketoconazole Cream agent in embodiment 10 to embodiment 12, and is answered with common
Square ketoconazole cream agent (compound ketoconazole ointment, lot number 150901, Jiangsu Ling Bao medicine companies limited company) carries out comparison and grinds
Study carefully.
The in vitro transdermal experiment process of mouse is as follows：Male mouse of kunming 20g is lost hair or feathers with electric shaver abdomen, at the neck that breaks
Extremely, skin of abdomen is carefully removed, rejects subcutaneous fat；The skin removed carries out penetrating absorption immediately.Using physiological saline as connecing
It is placed in the Franz diffusion cells being preheated that (transdermal area is 3.14cm by liquid2, receive building volume as 15ml, it is entire to test
37 ± 1 DEG C of process constant temperature, 300 ± 10r/min stirrings).Processed good mouse skin is fixed on to the receiving for having added in stirrer
Between room and supply chamber.0.25g embodiments 10 are added in the Compound Ketoconazole Cream agent in embodiment 12 and commercially available compound ketone health
Azoles ointment covers preservative film on mouse skin, and 1ml is sampled from acceptable solution respectively at 0.5,1,2,4,6,8,10,12h, is mended simultaneously
The physiological saline of same volume is filled in acceptance pool, and obtained sample measures content, result (mean ± SD) such as table 9 with HPLC
It is shown.
9. transdermal experiment result of table
The above results show：The percutaneous rate of the Compound Ketoconazole Cream agent of the present invention is soft higher than common Ketoconazol/Clobetasol Propionate
Cream has the characteristics that continue, be delayed transhipment in addition, extends the action time of drug, the bioavilability of the drug of raising.
Experimental example 3：The influence experiment of Compound Ketoconazole Cream agent paraxylene induced mice auricle edema.
Using in embodiment 10 to embodiment 12 Compound Ketoconazole Cream agent carry out mouse ear swelling test, and with it is common
Compound ketoconazole ointment (compound ketoconazole ointment, lot number 150901, Jiangsu Ling Bao medicine companies limited company) carries out comparison and grinds
Study carefully.
Specific experiment process is as follows：20 ± 2g weights kunming mice 40 is taken, is randomly divided into four groups, every group 10, male and female are each
Half.Each group is respectively embodiment 10 groups (A), embodiment 11 groups (B), embodiment 12 groups (C) and positive controls (D), respectively will
Test medicine is applied to the tow sides of each group mouse right ear exterior feature, and 25mg, administration area 2cm are administered every time2, daily administration 2 times, even
Continuous administration 5d, left auricle is as control.1.5h after the last administration first washes away the residual drug on each group mouse right ear with warm water,
It is dried again with cotton balls, then 0.05ml dimethylbenzene is applied to the tow sides of mouse or so auricle for causing inflammation, causes 30min after inflammation
Mouse is put to death, left and right auricle sample is removed in the same area of two ears with the card punch of a diameter of 8mm, weigh and calculates left and right ear
The weight differential (being swelling) of piece sample, result (mean ± SD) is as shown in table 10.
The influence result of 10. Compound Ketoconazole Cream agent paraxylene induced mice auricle edema of table
| Group | Swelling | Inhibiting rate (%) |
| A | 14.85±3.4 | 44.53 |
| B | 16.34±4.2 | 39.01 |
| C | 15.66±4.5 | 42.10 |
| D | 18.29±4.6 | 31.86 |
Experimental result is shown：The compound ketoconazole ointment agent paraxylene induced mice ear swelling of the present invention significantly inhibits
Effect shows that antiphlogistic effects are higher than common compound ketoconazole ointment.
Experimental example 4：The extracorporeal bacteria inhibitor test of Compound Ketoconazole Cream agent.
Antibacterial experiment in vitro is carried out using the Compound Ketoconazole Cream agent in embodiment 10 to embodiment 12, and is answered with common
Square ketoconazole ointment (compound ketoconazole ointment, lot number 150901, Jiangsu Ling Bao medicine companies limited company) carries out comparative study.
1. test method：
The dilution of 1.1 drugs：
2g test medicines are dissolved in ethyl alcohol, the solution that mass concentration is 0.1% is made into, is separately added into sabouraud culture medium
In.Each group of 10 culture dishes, each culture dish liquid feeding 10ml, totally 4 groups, be respectively embodiment 10 groups (I), 11 groups of embodiment
(II), embodiment 12 groups (III) and positive control group (IV).Separately with blank control group 10, sabouraud culture medium is only added in.
1.2 inoculation：
3 kinds of dermatophytes (Trichophyton rubrum, alpha fungus and dogs that picking is grown on sabouraud culture medium inclined-plane respectively
Sporidiole bacteria), 0.5ml physiological saline is added in, is fully ground and is made into bacterium colony suspension, its spore 105/ is counted with blood counting chamber
Ml, then various 30 μ l of suspension are seeded in respectively on the culture medium of experimental group and control group, in 27 DEG C of cultures, after inoculation 7
~14d judges result.
1.3 observation：
According to the growth period feature of each bacterium colony, speed, diameter, color, the form of colony growth are observed and recorded daily
Deng.
2. result of the test：
2.1 in vitro culture：
Blank control group 2d after inoculation starts continued propagation, and experimental group colony growthing slow, diameter are substantially small at this time
5d or so colony growth rates are substantially accelerated after blank control group, experimental group inoculation, but, knot slow-growing compared with blank group
Fruit is as shown in table 11.Experimental group and the color of blank control group bacterium colony are without significant difference, but in terms of colonial morphology, experimental group with
Based on graininess, blank control group is based on villiform.
Influence of 11. drug of table to colony diameter (in terms of cm)
12. drug of table starts bacterium colony to grow the influence of number of days (in terms of culture dish number)
From the fungal culture result in table 12, stronger in the initial stage inhibitory action of fungal infection, the middle and later periods is to fungi
Inhibitory action gradually weaken.Compared with positive control, Compound Ketoconazole Cream agent in embodiment 10 to embodiment 12
Bacteriostasis is stronger.
Claims (10)
1. a kind of Compound Ketoconazole Cream agent, by ketoconazole-Evalution of Paeonol Liposomes, oil phase substrate, aqueous phase substrate and emulsifier
It is made, wherein the ketoconazole-Evalution of Paeonol Liposomes is by ketoconazole, Paeonol, lecithin, cholesterol, Tween-80, dimension
Raw element E and pH value are made up of 6.5~7.5 phosphate buffer of film dispersion method.
2. Compound Ketoconazole Cream agent according to claim 1, it is characterised in that：
In parts by weight, 25~35g ketoconazoles-Evalution of Paeonol Liposomes, 1 part of breast are included in every 100 parts of Compound Ketoconazole Cream agent
Agent, 17~20 parts of oil phase substrates, surplus is aqueous phase substrate.
3. Compound Ketoconazole Cream agent according to claim 1, it is characterised in that：
Ketoconazole-the Evalution of Paeonol Liposomes by parts by weight 10~30 parts of ketoconazoles, 10~30 parts of Paeonols, 200~
600 parts of lecithin, 50~200 parts of cholesterol, 5~15 parts of Tween-80s, 5~15 parts of vitamin Es and 10~30 parts of pH value are
6.5~7.5 phosphate buffer is made.
4. Compound Ketoconazole Cream agent according to claim 1, it is characterised in that：
Any one or more of the emulsifier in lauryl sodium sulfate, paregal O, glycerin monostearate.
5. Compound Ketoconazole Cream agent according to claim 1, it is characterised in that：
Any one or more of the oil phase substrate in octadecyl alcolol, hexadecanol, albolene, atoleine.
6. Compound Ketoconazole Cream agent according to claim 1, it is characterised in that：
The aqueous phase substrate is glycerine and/or the mixture of propylene glycol and water.
7. Compound Ketoconazole Cream agent according to claim 1, it is characterised in that：
Preservative is also included in the Compound Ketoconazole Cream agent.
8. a kind of preparation method of Compound Ketoconazole Cream agent according to any one of claim 1 to 6, including as follows
Step：
1) ketoconazole-Evalution of Paeonol Liposomes is prepared：
A ketoconazole, Paeonol, lecithin, cholesterol and vitamin E) are weighed, is added in suitable organic solvent and dissolves, obtain
To oily solution, oily solution under 40~55 DEG C of water bath conditions is then depressurized into rotary evaporation, after removing organic solvent, is formed
Homogeneous, transparent oiliness film；
B Tween-80) is weighed, is added in the phosphate buffer that pH value is 6.5~7.5 and dissolves, obtain aqueous solution,
Then use aqueous solution hydration step A) in obtained oiliness film, up to the presence of no insoluble substance, obtain dispersion；
C) by step B) in obtained dispersion in power be 80~130W, under conditions of frequency is 30~60kHz at ultrasound
Reason 5~10 minutes, obtains ketoconazole-Evalution of Paeonol Liposomes suspension；
D) by step C) in obtained ketoconazole-Evalution of Paeonol Liposomes suspension by 0.45 μm of filtering with microporous membrane, obtain ketone
Health azoles-Evalution of Paeonol Liposomes；
2) oil phase is prepared：
Oil phase substrate is weighed, heating melting obtains oil phase after 70~80 DEG C of heat preservations；
3) water phase is prepared：
Emulsifier is weighed, dissolving in aqueous phase substrate is added to and, after 70~80 DEG C of heat preservations, obtains water phase；
4) cream is prepared：
Under agitation, the oil phase obtained in step 2) is added in the water phase obtained in step 3), is dropped after stirring evenly
Temperature adds in the ketoconazole-Evalution of Paeonol Liposomes obtained in step 1), cools down while stirring thereto to 50~60 DEG C, until drop
Until room temperature, Compound Ketoconazole Cream agent is obtained.
9. preparation method according to claim 8, it is characterised in that：
Any one or more of organic solvent described in step 1) in methanol, ethyl alcohol, ether, chloroform；
Oil phase substrate described in step 2) in octadecyl alcolol, hexadecanol, albolene, atoleine any one or it is more
Kind；
Emulsifier described in step 3) in lauryl sodium sulfate, paregal O, glycerin monostearate any one or
It is a variety of；
Aqueous phase substrate described in step 3) is glycerine and/or the mixture of propylene glycol and water.
10. preparation method according to claim 8, it is characterised in that：
Rotary evaporation is depressurized described in step 1) to complete using the Rotary Evaporators equipped with vacuum pump；
Stirring is completed using mechanical stirring device or magnetic stirring apparatus described in step 4).
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| CN113440477A (en) * | 2021-08-12 | 2021-09-28 | 海南海神同洲制药有限公司 | Low-viscosity ketoconazole cream and preparation method thereof |
| CN115381768A (en) * | 2022-07-22 | 2022-11-25 | 山东大学 | Rose essential oil alcohol carrier cream and preparation method and application thereof |
| CN115381768B (en) * | 2022-07-22 | 2024-10-22 | 山东大学 | Rose essential oil alcohol transfer body cream and preparation method and application thereof |
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