CN102018661B - External preparation for resisting funguses and preparation method of external preparation - Google Patents
External preparation for resisting funguses and preparation method of external preparation Download PDFInfo
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- CN102018661B CN102018661B CN2011100203248A CN201110020324A CN102018661B CN 102018661 B CN102018661 B CN 102018661B CN 2011100203248 A CN2011100203248 A CN 2011100203248A CN 201110020324 A CN201110020324 A CN 201110020324A CN 102018661 B CN102018661 B CN 102018661B
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- acid
- microemulsion
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- pseudolarix
- water
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- 235000019698 starch Nutrition 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses an external preparation for resisting funguses and a preparation method of the external preparation, relating to the field of pharmaceutical preparations. The external preparation is a pseudolaric acid B micro emulsion gel or pseudolaric acid B micro emulsion cream prepared from the following raw materials in percentage by weight: 15-50% of pseudolaric acid B micro emulsion, 40-80% of gel matrix or cream matrix and 5-10% of humectant, wherein the content of the pseudolaric acid B accounts for 0.05-0.4% in the external preparation in percentage by weight; and the pseudolaric acid B micro emulsion is prepared from 0.3-0.8% of pseudolaric acid B, 2-8% of oil, 20-30% of surfactant, 5-15% of cosurfactant and the balance of water in percentage by weight. The external preparation in the invention is convenient for use, does not pollute clothes and has exact curative effect; the diameters of the bacterial inhibition rings of the external preparation on trichophyton rubrums, trichophyton mentagrophytes and candida albicans are obviously larger than that of compound pseudolarix kaempferi tincture; the bacteriostasis of the external preparation on the candida albicans is superior to that of micnazole cream and econazole spray, and the bacteriostasis of the external preparation on the trichophyton mentagrophytes is superior to that of the micnazole cream; and the external preparation has the characteristics of small side effect, no obvious irritation and no anaphylactic reaction on healthy guinea pig skin.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to external preparation of processing with Pseudolarix acid B and preparation method thereof.
Background technology
Cortex Pseudolaricis is dry root bark or the near root bark of pinaceae plant golden larch (Pseudolarix kaempferi Gorden), has parasite killing, itching relieving effect, is usually used in treating ringworm.Pseudolarix acid B (Pseudolaric Acid B; PAB) be from Cortex Pseudolaricis, to separate the novel diterpenoid acid chemical compound that obtains; It is main component in the Chinese medicine Cortex Pseudolaricis; Have effects such as antitumor, antifertility, antifungal, especially to read the strain bacterium, the torulopsis bacterium has remarkable result, Candida albicans is had bactericidal action.But the formulation products that does not still have Pseudolarix acid B at present.Being used for antifungal Chinese medicine medicine for external use at present has econazole, and it mainly is to be used as medicine with the Cortex Pseudolaricis medical material, and there be big, volatile crystallization, the poor stability of separating out of skin irritation in econazole, has limited its use.And other antifungal external chemistry medicines have miconazole nitrate ointment, econazole spray, ketoconazole ointment etc.; These chemicals preparation determined curative effects; But have hepatotoxicity, local excitation and cause side effect such as allergy, so be necessary to develop determined curative effect, safe antimycotic medicine for external application.
Summary of the invention
The objective of the invention is to develop a kind of efficient, antifungal external preparation that side effect is little of percutaneous dosing and its preparation method is provided.
For reaching the object of the invention, the technical scheme of employing is Pseudolarix acid B micro emulsion gels or the Pseudolarix acid B microemulsion ointment of being processed by following raw materials by weight percentage:
Pseudolarix acid B microemulsion 15 ~ 50%
Gel-type vehicle or emulsifiable paste matrix 40 ~ 80%
Wetting agent 5 ~ 10%
The mass percentage content of Pseudolarix acid B in preparation is 0.05 ~ 0.4%,
The Pseudolarix acid B microemulsion is to be 0.3 ~ 0.8% Pseudolarix acid B, 2 ~ 8% oil, 20 ~ 30% surfactants and 5 ~ 15% cosurfactants by mass percent, and all the other are processed for water.
Gel-type vehicle can add water and wetting agent is processed with polymer substances such as tragcanth, gelatin, starch, cellulose derivative, carbomer or sodium alginates; Preferred employing is 0.5 ~ 5% carbomer by mass percent; 0.675 all the other process ~ 6.75% organic base for water, organic base is diethanolamine or triethanolamine or triethylamine; Or be 10 ~ 20% cellulose derivatives by mass percent, all the other are processed for water, and cellulose derivative is any one in hydroxypropyl emthylcellulose or sodium carboxymethyl cellulose or hyprolose or the methylcellulose;
Emulsifiable paste matrix is with mixed with water after the solid oil phase heat fused, under the effect of emulsifying agent, forms Emulsion, and then becomes semisolid substrate under the room temperature.Oil phase majority commonly used mainly contains stearic acid, tristerin, paraffin, Cera Flava, hexadecanol or octadecanol etc. for solid, adds liquid paraffin, vaseline or plant wet goods for regulating denseness sometimes; Emulsifying agent commonly used has newborn soap, sodium lauryl sulphate, Tween 80, paregal O and the polyoxyethylene nonylphenol ether etc. of organic base such as hydroxide, borate or triethanolamine, the Tris(isopropylamine). of monovalent metallic ion and stearic acid effect formation, is preferably processed by following raw materials by weight percentage:
Stearic acid 5 ~ 10%
Hexadecanol or octadecanol 5 ~ 10%
Vaseline 5 ~ 10%
Liquid paraffin 3 ~ 15%
Glyceryl monostearate 3 ~ 10%
Triethanolamine or Tween 80 or sodium lauryl sulphate 1 ~ 5%
All the other are water;
Described wetting agent can be used propylene glycol, glycerin, sorbitol etc., preferably adopts propylene glycol or glycerin.
Pseudolarix acid B microemulsion ointment is to be 15 ~ 50% Pseudolarix acid B microemulsion by mass percent, and 40 ~ 80% emulsifiable paste matrix and 5 ~ 10% wetting agent are formed; The mass percentage content of Pseudolarix acid B in the microemulsion ointment is 0.05 ~ 0.4%.If emulsifiable paste matrix can prepare Pseudolarix acid B microemulsion ointment equally with other ointment base such as greasing base or water-soluble base replacement.
The oily common available oleic acid of preparation Pseudolarix acid B microemulsion, soybean oil, Oleum Arachidis hypogaeae semen, olive oil, ethyl oleate, isopropyl palmitate, isopropyl myristate etc. preferably adopt oleic acid, any one in ethyl oleate or the isopropyl myristate; The common available lecithin of surfactant, tween, poloxamer, polyoxyethylene castor oil, sad capric acid polyethyleneglycol glyceride etc. preferably adopt tween, any one in polyoxyethylene castor oil or the sad capric acid polyethyleneglycol glyceride; The common available short chain alcohol of cosurfactant such as ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutanol, n-amyl alcohol, isoamyl alcohol, 1-hexanol, 2-hexanol, 1-capryl alcohol, sec-n-octyl alcohol, Polyethylene Glycol or TC etc.; Preferred ethanol, any one in Polyethylene Glycol or the TC of adopting.
Another technical problem to be solved by this invention provides the method for preparing of above-mentioned Pseudolarix acid B micro emulsion gels and ointment.
The preparation of Pseudolarix acid B micro emulsion gels or ointment comprises the following steps:
The preparation of A, Pseudolarix acid B microemulsion
Be 0.3 ~ 0.8% Pseudolarix acid B, 2 ~ 8% oil, 20 ~ 30% surfactants and 5 ~ 15% cosurfactants by mass percentage; All the other are the water preparation; Take by weighing oil, surfactant and cosurfactant mix homogeneously and be prepared into concentrated breast; Add the Pseudolarix acid B stirring in concentrated Ruzhong and make dissolving, under agitation splash into distilled water then, make the Pseudolarix acid B microemulsion; Prepared microemulsion is spheroid or nearly spheroid through transmission electron microscope observing, is 18.5 ± 2.5nm through the particle diameter of laser particle size analysis microemulsion;
The preparation of B, gel-type vehicle or ointment substrate
Be 0.5 ~ 5% carbomer, 0.675 ~ 6.75% organic base by mass percentage, all the other take by weighing raw material for the dosage of water; Carbomer water swelling; It is transparent to drip organic base to gel then, and pH value is 6 ~ 7 promptly to get gel-type vehicle, or is 10 ~ 20% cellulose derivatives by mass ratio; All the other are distilled water, take by weighing cellulose derivative and promptly get gel-type vehicle with the distilled water swelling;
Be respectively 5 ~ 10% stearic acid, 5 ~ 10% hexadecanol or octadecanol by mass percentage; 5 ~ 10% vaseline, 3 ~ 15% saxols and 3 ~ 10% glyceryl monostearates take by weighing; Process oil phase in 60 ~ 90 ℃ of water-bath fusions; Triethanolamine by 1 ~ 5% or Tween 80 or sodium lauryl sulphate take by weighing makes emulsifying agent, and all the other are mixed and made into water for water; With water and oil phase mix homogeneously, after the emulsifying evenly, put the cold emulsifiable paste matrix that promptly gets;
The preparation of C, Pseudolarix acid B micro emulsion gels or Pseudolarix acid B microemulsion ointment
Be the proportioning raw materials preparation of the wetting agent of 15 ~ 50% Pseudolarix acid B microemulsion, 40 ~ 80% gel-type vehicle or emulsifiable paste matrix and 5 ~ 10% by mass percentage; Pseudolarix acid B microemulsion and wetting agent that steps A is made add gel-type vehicle or the ointment substrate that B makes; Stirring and evenly mixing; And remove bubble through evacuation, promptly get micro emulsion gels or Pseudolarix acid B microemulsion ointment.
When preparation Pseudolarix acid B microemulsion in the available oleic acid of said oil, ethyl oleate, the isopropyl myristate any one be raw material, and it is raw material that surfactant can be used in tween, polyoxyethylene castor oil, the sad capric acid polyethyleneglycol glyceride any one; Cosurfactant can use in ethanol, Polyethylene Glycol, the TC any one for raw material;
The cellulose derivative of preparation during gel-type vehicle can use in hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, hyprolose or the methylcellulose any one to be raw material;
Preferably propylene glycol or glycerin are raw material to said wetting agent when preparation Pseudolarix acid B micro emulsion gels or Pseudolarix acid B microemulsion ointment.
Advantage of the present invention: 1, the compatibility of product of the present invention and skin is good, is easy to coating, and is easy to use, and pollution clothes not can strengthen the compliance of patient's medication.2, can promote the skin of Pseudolarix acid B to see through ability, particularly can improve the local skin drug level, help the local illness of Drug therapy and play a role.3, determined curative effect, to trichophyton, the inhibition zone diameter of alpha fungus and Candida albicans is all significantly greater than the econazole agent; The oidiomycetic bacteriostasis of white is superior to miconazole emulsifiable paste and econazole spray, the inhibition of alpha fungus is superior to the miconazole emulsifiable paste.4, side effect is little, and the intact skin single is smeared administration or repeatedly smeared administration and all do not have obvious irritation; The damaged skin single smeared administration or repeatedly smear administration have slight zest; Healthy guinea pig skin there is not irritated reaction.
Further set forth technical scheme of the present invention and progress through embodiment below.
The specific embodiment
Embodiment 1The preparation of 0.05% Pseudolarix acid B micro emulsion gels
The preparation of A Pseudolarix acid B microemulsion
Take by weighing Pseudolarix acid B 0.2g, oleic acid 1.8g, Tween 80 16g; Dehydrated alcohol 8g and water 40g, at room temperature with oleic acid, tween 80; Dehydrated alcohol obtains concentrating breast after stirring abundant mixing, add Pseudolarix acid B in concentrated Ruzhong again; Stirring is dissolved in Pseudolarix acid B fully and concentrates breast, under stirring condition, slowly splashes into water 40g then, promptly gets transparent about 0.3% Pseudolarix acid B microemulsion.Microemulsion is nearly spheroid through transmission electron microscope observing, is 18.5 ± 2.5nm through the particle diameter of laser particle size analysis microemulsion;
The preparation of B, gel-type vehicle
The 1.4g carbomer with 280mL distilled water swelling, is dripped triethanolamine 1.89g to transparent, promptly get the blank gel-type vehicle of about 0.5% carbomer, pH value is 6.2.
The preparation of C, Pseudolarix acid B micro emulsion gels
With microemulsion 66g, blank gel-type vehicle 283.29g and wetting agent propylene glycol 30g mixing, and to use triethanolamine 0.5g to regulate pH be 6.8, evacuation is removed bubble, promptly gets about 0.05% Pseudolarix acid B micro emulsion gels.
The mass percentage content of Pseudolarix acid B in preparation is 0.053%.
Embodiment 2The preparation of 0.25% Pseudolarix acid B micro emulsion gels
The preparation of A Pseudolarix acid B microemulsion
Take by weighing Pseudolarix acid B 1g, ethyl oleate 5g, polyoxyethylene castor oil 40g; PEG400 20g and water 74g, at room temperature with ethyl oleate, polyoxyethylene castor oil; PEG400 obtains concentrating breast after stirring abundant mixing, add Pseudolarix acid B in concentrated Ruzhong again; Stirring is dissolved in Pseudolarix acid B fully and concentrates breast, under stirring condition, slowly splashes into water 74g then, promptly gets transparent about 0.7% Pseudolarix acid B microemulsion.Microemulsion is nearly spheroid through transmission electron microscope observing, is 18.5 ± 2.5nm through the particle diameter of laser particle size analysis microemulsion;
The preparation of B, gel-type vehicle
The 5.5g carbomer with 207.5mL distilled water swelling, is dripped diethanolamine 7g to transparent, promptly get about 2.5% blank gel-type vehicle, pH value is 6.5;
The preparation of C, Pseudolarix acid B micro emulsion gels
With microemulsion 140g, blank gel-type vehicle 220g and wetting agent glycerin 40g mixing, and to use diethanolamine 0.5gpH be 6. 4, evacuation is removed bubble, promptly gets about 0.25% Pseudolarix acid B micro emulsion gels.
The mass percentage content of Pseudolarix acid B in preparation is 0.25%.
Embodiment 30.4% Pseudolarix acid B micro emulsion gels
The preparation of A Pseudolarix acid B microemulsion
Take by weighing Pseudolarix acid B 2g; Isopropyl myristate 20g, sad capric acid polyethyleneglycol glyceride 60g, TC 20g and water 148g; At room temperature with isopropyl myristate, sad capric acid polyethyleneglycol glyceride and TC after stirring abundant mixing; Obtain concentrating breast, add Pseudolarix acid B in concentrated Ruzhong again, stirring is dissolved in Pseudolarix acid B fully and concentrates breast; Under stirring condition, slowly splash into 148g water then, promptly get 0.8% transparent Pseudolarix acid B microemulsion.Microemulsion is nearly spheroid through transmission electron microscope observing, is 18.5 ± 2.5nm through the particle diameter of laser particle size analysis microemulsion;
The preparation of B, gel-type vehicle
The 11.25g carbomer with 202mL distilled water swelling, is dripped triethylamine 12g to transparent, promptly get about 5% blank gel-type vehicle, pH is 6.8;
The preparation of C, Pseudolarix acid B micro emulsion gels
With microemulsion 250g, blank gel-type vehicle 225.25g and wetting agent glycerin 25g mixing, and to use triethylamine 1g to regulate pH be 6.9, and evacuation is removed bubble, promptly gets 0.4% Pseudolarix acid B micro emulsion gels.
The mass percentage content of Pseudolarix acid B in preparation is 0.4%.
Embodiment 40.05% Pseudolarix acid B microemulsion cellulose gel colloid
The preparation of A Pseudolarix acid B microemulsion
Take by weighing Pseudolarix acid B 0.2g, oleic acid 1.8g, tween 80 16g; Dehydrated alcohol 8g and water 40g, at room temperature with oleic acid, tween 80; Dehydrated alcohol obtains concentrating breast after stirring abundant mixing, add Pseudolarix acid B in concentrated Ruzhong again; Vibration is dissolved in Pseudolarix acid B fully and concentrates breast, under stirring condition, slowly splashes into 40g water then, promptly gets transparent about 0.3% Pseudolarix acid B microemulsion.Microemulsion is nearly spheroid through transmission electron microscope observing, is 18.5 ± 2.5nm through the particle diameter of laser particle size analysis microemulsion;
The preparation of B, gel-type vehicle
With the 30g hydroxypropyl emthylcellulose, be swelling to transparently with the 270mL distilled water, promptly get the blank gel-type vehicle of about 10% hydroxypropyl emthylcellulose;
The preparation of C, Pseudolarix acid B microemulsion cellulose gel colloid
With microemulsion 66g, blank gel-type vehicle 300g and wetting agent propylene glycol 34g mixing, evacuation is removed bubble, promptly gets about 0.05% Pseudolarix acid B microemulsion cellulose gel colloid.
The mass percentage content of Pseudolarix acid B in preparation is 0.05%.
Embodiment 50.25% Pseudolarix acid B microemulsion cellulose gel colloid
The preparation of A Pseudolarix acid B microemulsion
Take by weighing Pseudolarix acid B 1g, ethyl oleate 5g, polyoxyethylene castor oil 40g; PEG400 20g and water 74g, at room temperature with ethyl oleate, polyoxyethylene castor oil; PEG400 obtains concentrating breast after stirring abundant mixing, add Pseudolarix acid B in concentrated Ruzhong again; Stirring is dissolved in Pseudolarix acid B fully and concentrates breast, under stirring condition, slowly splashes into 74g water then, promptly gets transparent about 0.7% Pseudolarix acid B microemulsion.Microemulsion is nearly spheroid through transmission electron microscope observing, is 18.5 ± 2.5nm through the particle diameter of laser particle size analysis microemulsion;
The preparation of B, gel-type vehicle
Be swelling to transparently with the 187mL distilled water with the 33g sodium carboxymethyl cellulose fibre is plain, promptly get about 15% sodium carboxymethyl cellulose blank gel-type vehicle;
The preparation of C, Pseudolarix acid B microemulsion cellulose gel colloid
With microemulsion 140g, blank gel-type vehicle 220g and wetting agent propylene glycol 40g mixing, evacuation is removed bubble, promptly gets about 0.25% Pseudolarix acid B microemulsion cellulose gel colloid.
The mass percentage content of Pseudolarix acid B in preparation is 0.25%.
Embodiment 60.4% Pseudolarix acid B microemulsion cellulose gel colloid
The preparation of A, Pseudolarix acid B microemulsion
Take by weighing Pseudolarix acid B 2g; Isopropyl myristate 20g, sad capric acid polyethyleneglycol glyceride 60g, TC 20g and water 148g; At room temperature with isopropyl myristate, sad capric acid polyethyleneglycol glyceride and TC after stirring abundant mixing; Obtain concentrating breast, add Pseudolarix acid B in concentrated Ruzhong again, stirring is dissolved in Pseudolarix acid B fully and concentrates breast; Under stirring condition, slowly splash into 148g water then, promptly get 0.8% transparent Pseudolarix acid B microemulsion.Microemulsion is that nearly spheroid is 18.5 ± 2.5nm through the particle diameter of laser particle size analysis microemulsion through transmission electron microscope observing;
The preparation of B, gel-type vehicle
40g hyprolose or methylcellulose are swelling to transparent with the 160mL distilled water, promptly get the blank gel-type vehicle of about 20% hyprolose or methylcellulose;
The preparation of C, Pseudolarix acid B microemulsion cellulose gel colloid
With microemulsion 250g, blank gel-type vehicle 200g and wetting agent glycerin 50g mixing, evacuation is removed bubble, promptly gets 0.4% Pseudolarix acid B microemulsion cellulose gel colloid.
The mass percentage content of Pseudolarix acid B in preparation is 0.4%.
Embodiment 70.05% Pseudolarix acid B microemulsion ointment
The preparation of A Pseudolarix acid B microemulsion
Take by weighing Pseudolarix acid B 0.2g, oleic acid 1.8g, tween 80 16g; Dehydrated alcohol 8g and water 40g, at room temperature with oleic acid, tween 80; Dehydrated alcohol obtains concentrating breast after stirring abundant mixing, add Pseudolarix acid B in concentrated Ruzhong again; Stirring is dissolved in Pseudolarix acid B fully and concentrates breast, and then under stirring condition, slowly splashes into 40g water, promptly gets transparent about 0.3% Pseudolarix acid B microemulsion.Microemulsion is nearly spheroid through transmission electron microscope observing, is 18.5 ± 2.5nm through the particle diameter of laser particle size analysis microemulsion;
The preparation of B, emulsifiable paste matrix
Take by weighing stearic acid 33g, hexadecanol or octadecanol 22.5g, glyceryl monostearate 22.5g, liquid paraffin 45g and vaseline 27g, heating makes and is melted into oil phase in 70 ℃ of water-baths.Other takes by weighing triethanolamine 4g and water 150g, and heating makes and becomes water in 70 ℃ of water-baths.Then water is slowly added in the oil phase, it is complete until emulsifying that the limit edged stirs, and puts coldly promptly to get;
The preparation of C, Pseudolarix acid B microemulsion ointment
Through the homogenizer mixing, evacuation is removed bubble, promptly gets 0.05% Pseudolarix acid B microemulsion ointment with microemulsion 66g, blank ointment base 304g and glycerin 30g.
The mass percentage content of Pseudolarix acid B in preparation is 0.05%.
Embodiment 80.25% Pseudolarix acid B microemulsion ointment
The preparation of A Pseudolarix acid B microemulsion
Take by weighing Pseudolarix acid B 1g, ethyl oleate 5g, polyoxyethylene castor oil 40g; PEG400 20g and water 74g, at room temperature with ethyl oleate, polyoxyethylene castor oil; PEG400 obtains concentrating breast after stirring abundant mixing, add Pseudolarix acid B in concentrated Ruzhong again; Stirring is dissolved in Pseudolarix acid B fully and concentrates breast, under stirring condition, slowly splashes into 74g water then, promptly gets transparent about 0.7% Pseudolarix acid B microemulsion.Microemulsion is nearly spheroid through transmission electron microscope observing, is 18.5 ± 2.5nm through the particle diameter of laser particle size analysis microemulsion;
The preparation of B, ointment substrate
Take by weighing stearic acid 13g, hexadecanol or octadecanol 20g, glyceryl monostearate 8g, liquid paraffin 3g and vaseline 21g, heating makes and is melted into oil phase in 60 ℃ of water-baths.Other takes by weighing sodium lauryl sulphate 3g and water 172g, and heating makes and becomes water in 60 ℃ of water-baths.Then water is slowly added in the oil phase, it is complete until emulsifying that the limit edged stirs, and puts coldly promptly to get;
The preparation of C, Pseudolarix acid B microemulsion ointment
Through homogenizer mixing mixing, evacuation is removed bubble, promptly gets 0.25% Pseudolarix acid B microemulsion ointment with microemulsion 140g, blank ointment base 240g and propylene glycol 20g.
The mass percentage content of Pseudolarix acid B in preparation is 0.25%.
Embodiment 90.4% Pseudolarix acid B microemulsion ointment
The preparation of A Pseudolarix acid B microemulsion
Take by weighing Pseudolarix acid B 2g; Isopropyl myristate 20g, sad capric acid polyethyleneglycol glyceride 60g, TC 20g and water 148g; At room temperature with isopropyl myristate, sad capric acid polyethyleneglycol glyceride and TC after stirring abundant mixing; Obtain concentrating breast, add Pseudolarix acid B in concentrated Ruzhong again, stirring is dissolved in Pseudolarix acid B fully and concentrates breast; Under stirring condition, slowly splash into 148g water then, promptly get 0.8% transparent Pseudolarix acid B microemulsion.Microemulsion is nearly spheroid through transmission electron microscope observing, is 18.5 ± 2.5nm through the particle diameter of laser particle size analysis microemulsion;
The preparation of B, ointment substrate
Take by weighing stearic acid 20g, hexadecanol/octadecanol 12.5g, glyceryl monostearate 25g, liquid paraffin 20g and vaseline 12.5g, heating makes and is melted into oil phase in 90 ℃ of water-baths.Other takes by weighing tween 80 12.5g and water 97.5g, and heating makes and becomes water in 90 ℃ of water-baths.Then water is slowly added in the oil phase, it is complete until emulsifying that the limit edged stirs, and puts coldly promptly to get;
The preparation of C, Pseudolarix acid B microemulsion ointment
Through homogenizer mixing mixing, evacuation is removed bubble, promptly gets 0.4% Pseudolarix acid B microemulsion ointment with microemulsion 250g, blank emulsifiable paste matrix 200g and propylene glycol 50g.
The mass percentage content of Pseudolarix acid B in preparation is 0.4%.
Test Example 1The transdermal penetration contrast test of the ordinary gel agent of Pseudolarix acid B and ointment and Pseudolarix acid B micro emulsion gels and ointment
The ordinary gel agent of Pseudolarix acid B or the preparation of ointment: with 10ml dissolve with ethanol 200mg Pseudolarix acid B, add the corresponding substrate of about 90g then respectively, mixing makes 0.2% ordinary gel agent or ointment 100g.
The transdermal penetration comparative test is carried out in 0.2% micro emulsion gels of the present invention or ointment and 0.2% ordinary gel agent or ointment.
Test method: rat skin exsomatize to see through experiment (after the disconnected neck of male SD rat puts to death, shave hair immediately, peel off skin of abdomen, remove subcutaneus adipose tissue, clean with normal saline flushing, freezing preservation, subsequent use.Face with preceding and thaw naturally, with the normal saline washing, the reuse pure water rinsing gets final product.The integrity of each pretest inspection Corium Mus.Adopt improved Franz diffusion cell, the rat abdomen skin of handling well is fixed in supply pool and accepts between the pond, stratum corneum side is to supply pool, and effectively the transdermal area is 2.27cm
2In the supply pool micro emulsion gels, ordinary gel agent, microemulsion ointment and the common ointment that contains the 10mg Pseudolarix acid B; Acceptable solution is 20% ethanol-normal saline, in 1,2,4,6,8,10,12, and 24h sampling, and the acceptable solution of additional respective volume.Institute's sample thief is measured Cortex Pseudolaricis in the acceptable solution with the filtering with microporous membrane of 0.22 μ m
The content of acetic acid; By formula
calculates the accumulation infiltration capacity of each prescription
C wherein
nRepresent the concentration that n sample point records, C
iExpression the
iThe concentration that individual sample point records, V
0The volume in pond is accepted in expression, and V representes the volume of each sampling, and A representes the release area.Q
n(μ gcm
-2) for the accumulation infiltration capacity, time t is made linear regression with Q, the gained straight slope is steady-state permeation speed constant Js (μ gcm
-2H
-1).After the transdermal test in vitro test stops, from diffusion cell, take out rat skin, the water washing surface, Cotton Gossypii is dried, and shreds, and adds ethanol 5mL, homogenate, 5000rmin
-1Centrifugal 5min gets supernatant, with 0.22 μ m membrane filtration, gets subsequent filtrate, and adopting the content of Pseudolarix acid B in the high effective liquid chromatography for measuring skin is the skin hold-up.Result of the test:
The transdermal penetration of table 1 Pseudolarix acid B ordinary preparation and microemulsion formulation relatively
Conclusion: micro emulsion gels Pseudolarix acid B stable state percutaneous rate is 3.57 times of ordinary gel agent, and transdermal amount is 2.43 times of ordinary gel agent, and the hold-up in skin is 4.72 times of ordinary gel agent.Microemulsion ointment Pseudolarix acid B stable state percutaneous rate is 4.08 times of usual cream agent, and transdermal amount is 2.64 times of ordinary gel agent, and the hold-up in skin is 3.65 times of ordinary gel agent.Show after Pseudolarix acid B is prepared into microemulsion to promote the skin of Pseudolarix acid B to see through ability, particularly can improve the local skin drug level, help the local illness of Drug therapy and play a role.
Test Example 2The bacteriostatic test of Pseudolarix acid B microemulsion formulation
Test method: adopt the K-B disk diffusion method to carry out antibacterial comparative experiments.Cut-off directly is the plate of 9cm, and the husky fort glucose agar medium of impouring 15 mL process flat board after the condensation.The cotton swab of usefulness sterilization dips in respectively gets trichophyton, alpha fungus, Candida albicans test organisms suspension, evenly coats media surface by 3 directions, encloses around edge one at last, processes to contain the bacterium flat board, and room temperature is placed 5 min.Process the round scraps of paper of diameter 6 mm with filter paper, through pressuresteam sterilization and dry for standby.The sample that every scraps of paper drip variable concentrations respectively is affixed on and contains on the bacterium flat board.Cultivate 24 h observed results for 28 ℃, accurately measure the scraps of paper size (mm) of antibacterial circle diameter on every side, survey and average for 3 times with slide calliper rule.
Test specimen: be respectively the Pseudolarix acid B micro emulsion gel, Pseudolarix acid B microemulsion ointment, econazole, Miconazole Nitrate Cream and econazole spray.
Result of the test:
Through to trichophyton, the antifungal experimental result of alpha fungus and Candida albicans shows: micro emulsion gels or ointment to the inhibition zone diameters of this three kinds of funguses all significantly greater than the econazole agent; The oidiomycetic bacteriostasis of white is superior to miconazole emulsifiable paste and econazole spray, the inhibition of alpha fungus is superior to the miconazole emulsifiable paste, see table 2.
The fungistatic effect of table 2 Pseudolarix acid B microemulsion formulation and commercial preparation relatively
Conclusion: prove that Pseudolarix acid B micro emulsion gels or ointment are a kind of promising antifungal novel formulation.
Test Example 3The skin irritation test
With the negative contrast of normal saline, be vehicle control with gel-type vehicle and ointment base, with Pseudolarix acid B micro emulsion gels and ointment for receiving the reagent thing through rabbit intact skin and damaged skin irritation test.
Intact skin irritation test method: get 20 of new zealand rabbits, male and female half and half are divided into negative control group, substrate matched group at random, are tried totally 5 groups of drug group, 4 every group.Test and in the middle of the back, shedded every about 6cm * 6cm of scope in preceding 24 hours.The harmless the wounded of inspection skin of unhairing makes an experiment before the administration.With normal saline, gel-type vehicle, ointment base, Pseudolarix acid B micro emulsion gel and Pseudolarix acid B microemulsion ointment are coated in respectively on the rabbit depilation skin that has divided into groups, single-dose, continuously coating administration 8 hours.Multiple dosing divides into groups and the same single-dose of coating method, but applies every day 1 time, continues 8 hours, continuously coating 14 days at every turn.
Sample: normal saline, gel-type vehicle, emulsifiable paste matrix, Pseudolarix acid B micro emulsion gel, Pseudolarix acid B microemulsion emulsifiable paste.
Result: under available light, observe dermoreaction, all do not have skin erythema and edema.Single-dose 1,24,48 and 72 hours perusal coating parts after removing medicine do not have erythema and edema yet, the situation of pigmentation, petechia, pachylosis and epidermatic atrophy do not occur yet.Multiple dosing is 1 h observation behind each removal medicine, no skin erythema and edema.After the last administration, 1,24,48 and 72 hours perusal coating parts do not have erythema and edema yet after removing medicine, the situation of pigmentation, petechia, pachylosis and epidermatic atrophy do not occur yet.
Conclusion: Pseudolarix acid B micro emulsion gels and ointment are smeared administration or are repeatedly smeared administration and all do not have obvious irritation through the intact skin single.
Damaged skin irritation test method: get 20 of new zealand rabbits, male and female half and half are divided into negative control group, substrate matched group at random, are tried totally 5 groups of drug group, 4 every group.Test and in the middle of the back, shedded every about 6cm * 6cm of scope in preceding 24 hours.No. 400 fine sandpapers that reuse is disinfected cause scratch at the place of shedding; Make skin intensive petechia occur; The degree of being with the oozing of blood, immediately with normal saline, gel-type vehicle; Emulsifiable paste matrix, Pseudolarix acid B micro emulsion gel and Pseudolarix acid B microemulsion emulsifiable paste are coated in respectively on the rabbit skin abrasion position of having divided into groups.Single-dose, continuously coating administration 8 hours.Multiple dosing divides into groups and the same single-dose of coating method, but applies every day 1 time, continues 8 hours, continuously coating 14 days at every turn.
Sample: normal saline, gel-type vehicle, ointment base, Pseudolarix acid B micro emulsion gel, Pseudolarix acid B microemulsion emulsifiable paste.
Result: under available light, observe dermoreaction; After 1 hour and 24 hours, all there is not obvious erythema at the dermatologic position to single-dose, fades away in 48 hours after removing medicine; Skin recovered consistent with the normal saline group in 72 hours, and stimulus intensity is assessed as slight zest.Each group has the point-like blood crusts at the injured skin place; Began to come off to 48 hours, matrix group with tried drug group and normal saline group no significant difference, so blood crusts be abrade due to; Non-medicine causes, and damaged skin treated animal skin gloss intensity, elasticity and intact skin group do not have significant difference.Multiple dosing after removing medicine in first day 1 hour with second day removal medicine after 1 h observation, all there is not obvious erythema at the dermatologic position.Faded away in the 3rd day, skin recovered consistent with the normal saline group in the 4th day, and stimulus intensity also is assessed as slight zest.
Conclusion: Pseudolarix acid B micro emulsion gels and ointment are smeared administration or repeatedly smeared administration the damaged skin single has slight zest.
Test Example 4The skin hypersensitivity reaction test
Test method: 80 healthy albino guinea-pigs of cleaning level are divided into 6 groups at random, receive each 20 of reagent thing Pseudolarix acid B gel and emulsifiable pastes, respectively 10 of all the other positive groups, excipient matched group and normal saline negative control group.Tested preceding 24 hours, the 3cm * 3cm that on the skin of left side, back, sheds earlier, the harmless the wounded of inspection skin of unhairing makes an experiment before the administration.The administration of the 2nd day beginning sensitization contact: positive group applies 1% 2,4-dinitrochlorobenzene on depilation skin, and all the other each groups apply respective sample, apply after 6 hours, removes and is tried drug combination warm water cleaning medicine-feeding part.Every at a distance from 7 days during sensitization, promptly at 0 day, 7 days and 14 days, each applied once at same position.Have a rest after 2 weeks, promptly at 28 days, all Cavia porcelluss are cooked and excite sensitization to attack, and apply 6 hours with local excitation at the rib abdominal part of not administration.Remove back 24 h observation local skins and have or not erythema and edema.Sensitization rate=occur skin erythema and edema animal animal subject number/animal subject number * 100%.
Sample: normal saline (negative control), gel-type vehicle (excipient), ointment base (excipient), Pseudolarix acid B micro emulsion gel (receiving the reagent thing), Pseudolarix acid B microemulsion emulsifiable paste (receiving the reagent thing), 1% 2,4-dinitrochlorobenzene (positive control).
The result: excite remove medicine after 1 hour, 24 hours, 48 hours, observed skin erythema, edema and other abnormal responses respectively in 72 hours, erythema and edema are marked, calculate irritated incidence rate.The result sees table 3.
Table 3 couple guinea pig skin anaphylaxis result
Conclusion: with the negative contrast of normal saline, with gel-type vehicle or emulsifiable paste matrix is vehicle control; With 2; The positive contrast of 4-dinitrochlorobenzene, through the reaction test of healthy guinea pig skin hypersensitivity, the result shows that Pseudolarix acid B micro emulsion gels or ointment do not have irritated reaction to healthy guinea pig skin.
Claims (2)
1. one kind is used for the antifungal external preparation, it is characterized in that: former by following mass percent
Pseudolarix acid B micro emulsion gels or Pseudolarix acid B microemulsion ointment that material is processed:
Pseudolarix acid B microemulsion 15 ~ 50%
Gel-type vehicle or emulsifiable paste matrix 40 ~ 80%
Wetting agent 5 ~ 10%
The mass percentage content of Pseudolarix acid B in preparation is 0.05 ~ 0.4%,
Described Pseudolarix acid B microemulsion is to be 0.3 ~ 0.8% Pseudolarix acid B, 2 ~ 8% oil, 20 ~ 30% surfactants and 5 ~ 15% cosurfactants by mass percent, and all the other are processed for water,
The oil of preparation Pseudolarix acid B microemulsion adopt in oleic acid, ethyl oleate, the isopropyl myristate arbitrarily
A kind of, surfactant adopts any one in tween, polyoxyethylene castor oil, the sad capric acid polyethyleneglycol glyceride; Cosurfactant adopts any one in ethanol, Polyethylene Glycol, the TC,
Described gel-type vehicle is 0.5 ~ 5% carbomer by mass percent, and all the other process 0.675 ~ 6.75% organic base for water, and organic base is diethanolamine or triethanolamine or triethylamine; Or be 10 ~ 20% cellulose derivatives by mass percent, all the other are processed for water, and cellulose derivative is any one in hydroxypropyl emthylcellulose or sodium carboxymethyl cellulose or hyprolose or the methylcellulose;
Described emulsifiable paste matrix is processed by following raw materials by weight percentage:
Stearic acid 5 ~ 10%
Hexadecanol or octadecanol 5 ~ 10%
Vaseline 5 ~ 10%
Saxol 3 ~ 15%
Glyceryl monostearate 3 ~ 10%
Triethanolamine or Tween 80 or sodium lauryl sulphate 1 ~ 5%
All the other are water;
Described wetting agent is propylene glycol or glycerin.
2. one kind like the said method for preparing that is used for the antifungal external preparation of claim 1, it is characterized in that comprising the following steps:
The preparation of A, Pseudolarix acid B microemulsion
Be 0.3 ~ 0.8% Pseudolarix acid B, 2 ~ 8% oil, 20 ~ 30% surfactants and 5 ~ 15% cosurfactants by mass percentage; All the other are the water preparation; Take by weighing oil, surfactant and cosurfactant mix homogeneously and be prepared into concentrated breast, add the Pseudolarix acid B stirring in concentrated Ruzhong and make dissolving, under agitation splash into distilled water then; Make the Pseudolarix acid B microemulsion, the particle diameter of microemulsion is 18.5 ± 2.5nm;
Said oil adopts any one in oleic acid, ethyl oleate, the isopropyl myristate, and surfactant adopts any one in tween, polyoxyethylene castor oil, the sad capric acid polyethyleneglycol glyceride; Cosurfactant adopts any one in ethanol, Polyethylene Glycol, the TC;
The preparation of B, gel-type vehicle or ointment substrate
Be 0.5 ~ 5% carbomer, 0.675 ~ 6.75% organic base by mass percentage, all the other take by weighing raw material for the dosage of water; Carbomer water swelling; It is transparent to drip organic base to gel then, and pH value is 6 ~ 7 promptly to get gel-type vehicle, or is 10 ~ 20% cellulose derivatives by mass ratio; All the other are distilled water, take by weighing cellulose derivative and promptly get gel-type vehicle with the distilled water swelling;
Be respectively 5 ~ 10% stearic acid, 5 ~ 10% hexadecanol or octadecanol by mass percentage, 5 ~ 10% vaseline, 3 ~ 15% saxols and 3 ~ 10% glyceryl monostearates take by weighing, and process oil phase in 60 ~ 90 ℃ of water-bath fusions; Triethanolamine by 1 ~ 5% or Tween 80 or sodium lauryl sulphate take by weighing makes emulsifying agent, and all the other are mixed and made into water for water; With water and oil phase mix homogeneously, after the emulsifying evenly, promptly get emulsifiable paste matrix;
Said cellulose derivative is hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, hyprolose or methylcellulose;
The preparation of C, Pseudolarix acid B micro emulsion gels or Pseudolarix acid B microemulsion ointment
Be the proportioning raw materials preparation of the wetting agent of 15 ~ 50% Pseudolarix acid B microemulsion, 40 ~ 80% gel-type vehicle or emulsifiable paste matrix and 5 ~ 10% by mass percentage; Pseudolarix acid B microemulsion that steps A is made and wetting agent add in the gel-type vehicle or emulsifiable paste matrix that B makes; Equidirectional stirring and evenly mixing; And remove bubble through evacuation, promptly get micro emulsion gels or microemulsion ointment;
Said wetting agent is propylene glycol or glycerin.
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| CN102423293B (en) * | 2011-01-28 | 2013-05-29 | 舒泰神（北京）生物制药股份有限公司 | Microemulsion gel preparation of oxiconazole nitrate |
| CN103830179B (en) * | 2014-03-24 | 2015-11-18 | 段懿玲 | A kind of external preparation and preparation technology thereof containing crotamiton |
| CN103860566B (en) * | 2014-04-08 | 2015-12-09 | 张绪伟 | A kind of triamcinolone acetonide econazole cream agent and preparation method thereof |
| CN105168118A (en) * | 2015-09-30 | 2015-12-23 | 安徽丰乐香料有限责任公司 | Preparation method of natural menthol or peppermint oil hydrogel |
| CN106138034A (en) * | 2016-06-28 | 2016-11-23 | 中国人民武装警察部队后勤学院 | Corter pseudolaricis acetic acid or derivatives thereof prevents and treats the application in ulcerative colitis medicine in preparation |
| CN107441127A (en) * | 2017-09-01 | 2017-12-08 | 骆凌翔 | The compound effacement emulsion of suppression oxygen orientation medicine transdermal chronic disease one again |
| CN110292890A (en) * | 2019-07-02 | 2019-10-01 | 郭恩宇 | A kind of pharmaceutical preparation intelligent agitating device and its application |
| CN113133964B (en) * | 2020-01-17 | 2022-06-14 | 浙江珍珠生活科技有限公司 | Multifunctional nail polish and preparation method thereof |
| CN112294754A (en) * | 2020-11-18 | 2021-02-02 | 浙江得恩德制药股份有限公司 | Triamcinolone acetonide econazole cream and preparation method thereof |
| CN112691075B (en) * | 2020-12-31 | 2023-06-20 | 海南海神同洲制药有限公司 | Sertaconazole nitrate emulsifiable paste and preparation method thereof |
| CN113440477B (en) * | 2021-08-12 | 2022-10-11 | 海南海神同洲制药有限公司 | Low-viscosity ketoconazole cream and preparation method thereof |
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