CN1188409A - Antifungal agent - Google Patents

Antifungal agent Download PDF

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Publication number
CN1188409A
CN1188409A CN96194503A CN96194503A CN1188409A CN 1188409 A CN1188409 A CN 1188409A CN 96194503 A CN96194503 A CN 96194503A CN 96194503 A CN96194503 A CN 96194503A CN 1188409 A CN1188409 A CN 1188409A
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China
Prior art keywords
micatin
antifungal
chloride
trichophyton
effect
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CN96194503A
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明石敏
田中重男
杉田喜美子
小比田英机
山岸三千男
小畑清隆
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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Priority to CN96194503A priority Critical patent/CN1188409A/en
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Abstract

An antifungal composition including an imidazole-type antifungal compound and a quaternary ammonium salt is a medicament having a far more potentiated activity of miconazole nitrate and a higher therapeutic effect, and is effective against both Trichophyton and Candida.

Description

Antifungal
The present invention relates to a kind of antifungal.Relate to a kind of being characterised in that in more detail and contain the antifungal compositions that imidazoles is antifungal and quaternary ammonium salt.
Imidazoles as the antifungal main flow is that antifungal is the medicament that has imidazole radicals in its chemical constitution in the world.Mainly be to show antibacterial action by the cell membrane that destroys fungus.
As imidazoles is antifungal, and clotrimazole, micatin, econazole nitrate, bifonazole, Oxiconazole Nitrate, sulconazole nitrate, tioconazole etc. are as the conversion OTC composition of (Switch OTC) and known by people.
Clotrimazole only uses in the medicine for external use field, is effective to Trichophyton, Candida etc.When being used for healthy skin, thinking does not almost have to absorb in the body, but thinks that partial side effect is arranged, as the excitement of skin, rubescent, come out in a rash etc., consider these phenomenons with to the direct stimulation of skin or irritated act on relevant.
Bifonazole demonstrates the effect identical with clotrimazole.It is effective being considered to multiple human pathogenic fungi.With other imidazoles is that antifungal is compared, and thinks that the percutaneous permeability of its outer time spent is good, storing property of the medicament height in skin histology.With clotrimazole the excitement of skin, rubescent, partial side effect such as come out in a rash are arranged equally.
Micatin, econazole nitrate, when Trichophyton, Candida, Cryptococcus etc. were also demonstrated antimicrbial power and are used for healthy skin, thinking did not almost have to absorb in the body; Usually when external is used, do not have the side effect of general, but think and have the side effect same in the part with clotrimazole.
So-called quaternary ammonium salt is meant the material that belongs to quaternary ammonium salt as cationic surfactant.Benzethonium chloride, benzalkonium chloride, dequalinium chloride etc. are for example arranged.Be considered to bring into play bactericidal action because the cation-adsorption of quaternary ammonium salt on the surface of thalline, enters in the cell then so that the protein in the pair cell influences
Benzethonium chloride, benzalkonium chloride demonstrate sterilizing power to gram-bacteria, fungus, but as side effect to the skin life-time service time, can occur stimulating, come out in a rash, allergic symptom such as titillation this be known.
Dequalinium chloride is considered to antibacterial (particularly staphylococcus aureus, the sterilization of haemolysis type streptococcus), fungus are demonstrated sterilizing power.Mainly be engaged in antibacterial in the oral cavity, anti-toothache preparation, the anti-alveolysis agent.
By imidazoles is that antifungal and quaternary ammonium salt cooperate the medicament that forms still not know, and is antifungal and salicylic acid or benzoic example but disclose the cooperation imidazoles in No. the 2208598th, the open communique of British patent.
The general vitamin B1 deficiency that is difficult to healing, necessary long-term coating, winter, beriberic symptom can not be effected a radical cure fully, can only slow down the activity of bacterium, therefore wished to develop the high medicament of therapeutic effect.In addition, beriberic morbidity is microbial by Trichophyton or beads, and the difference between Trichophyton and the candidiasis is use microscopic examination by special doctor, can only differentiate by the cultivation of bacterium since differentiate difficulty so to both sides all efficacious agents be important.As previously mentioned, imidazoles is that antifungal has partial side effect, as the excitement of skin, rubescent, come out in a rash etc., thereby reduce that to work hard aspect side effect also be necessary reducing their use levels in medicament.
Present inventors have the medicament of fungicidal effectiveness and improve its usability Trichophyton and candidiasis both sides with exploitation is purpose, is that antifungal and the medicament with useful effect have carried out various screenings for selecting imidazoles.Found that certain quaternary ammonium salt has the reinforced effects that multiplies each other aspect sterilizing power, and finished the present invention based on this discovery.
That is to say, the present invention relates to a kind of antifungal compositions, it is characterized in that containing imidazoles is antifungal and quaternary ammonium salt.
Imidazoles is in the antifungal, and preferred material is miconazole, econazole, clotrimazole, bifonazole etc.And the salt of miconazole, econazole also can use.Especially nitrate is widely used.
So-called quaternary ammonium salt is meant the material that belongs to quaternary ammonium salt as cationic surface work agent, and preferred quaternary ammonium salt has benzethonium chloride, benzalkonium chloride, dequalinium chloride etc. among the present invention.
Imidazoles is that the use level of antifungal is 0.2～1 weight %, preferred 0.5～1 weight %.
The use level of quaternary ammonium salt is 0.1～1 weight %, preferred 0.5～1 weight %, and for example the use level of benzethonium chloride is 0.5～1.0 weight %, the use level of benzalkonium chloride is 0.1～1 weight %, preferred 0.5～1 weight %.
Imidazoles with respect to 1 weight portion is an antifungal, preferably cooperates quaternary ammonium salt 0.1～1 weight portion, more preferably cooperates 0.1～0.5 weight portion.
In the effective ingredient of the present invention, can mix known additive etc. as required, available usual method is made external preparation such as liquor, detergent, Emulsion, tincture, ointment, cream, aqueous gel, oil-base gel agent, aerosol.
As water soluble ingredient, can enumerate propylene glycol, 1,3 butylene glycol, glycerol, ethanol, polyethylene glycols etc.
As the oiliness composition, can enumerate diisopropyl adipate, stearoyl alcohol, spermol, three decanes, medium chain triglyceride etc.
As polymer substance, can enumerate carboxy vinyl polymer, methylcellulose etc.
As the pH regulator agent, can enumerate organic amines such as inorganic salt, diisopropanolamine (DIPA) such as sodium hydroxide etc.
As antioxidant, can enumerate dibenzylatiooluene (BHT), Butylated hydroxyanisole (BHA), alpha-tocopherol, arabo-ascorbic acid, sodium pyrosulfite etc.
As coloring agent, can enumerate titanium oxide etc.
As surfactant, for example can enumerate polyoxyethylene hardened castor oil, sorbitan monostearate, sorbitan monopalmitate, glyceryl monostearate, sorbitan list dodecylate, polyoxyethylene polyoxypropylene block copolymer, polysorbate class, sodium lauryl sulfate, sucrose fatty acid ester, lecithin etc.
As stabilizing agent, can enumerate EDTA-2Na etc.
In addition, the particularly preferred antifungal compositions of the present invention is to be that epiphyte pharmaceutical and dequalinium chloride are the antifungal compositions of feature to contain imidazoles.
If further research skin irritation, preparationization etc. from the quaternary ammonium salt of the bactericidal effect of confirming to multiply each other, as shown in table 1, dequalinium chloride is optimum.
Table 1
The chemical compound title is suitable for the preparation skin irritation
Benzalkonium chloride zero △ dequalinium chloride 00
Among the present invention, effective use level of micatin is 0.2～1 weight %, preferred 0.5～1 weight %.
Effective use level of dequalinium chloride is 0.05～0.5 weight %, preferred 0.1～0.5 weight %.
With respect to 1 weight portion micatin dequalinium chloride is 0.1～1 weight portion, preferred 0.1～0.5 weight portion.
Medicament of the present invention is the potent antifungal that a kind of bactericidal effect is enhanced.
Below enumerate the test example and specify effect of the present invention.
Test example 1
(1) strains tested
Strains tested adopts following mushroom.
Trichophyton purpureatum (Trichophyton rubrum)
Trichophyton mentagrophytes (Trichophyton mentagrophytes)
(2) preparation method of spore liquid
On the inclined-plane of the developmental tube that 1/10 Sa Shi agar culture medium is housed, implant for the examination bacterium, cultivated for 3～4 weeks in 28 ℃.Cultivate the back and take out thalline, it is transplanted on bead is housed and 10ml contains in the conical flask (100ml volume) of the normal saline solution of 0.1%Tween80, vibrate after 1 hour,, become spore liquid through the tampon filtration with the sterilization spatula.The spore liquid stored refrigerated was used in 1 month
(composition of 1/10 Sa Shi agar culture medium)
Glucose 4.0g, peptone 1.0g, potassium dihydrogen phosphate (anhydrous) 1.5g, magnesium sulfate (7 hydrate) 1.0g, Chile saltpeter 1.0g, agar 20.0g, distilled water 1000ml.
(3) preparation of reagent agent
Reagent agent is used micatin, benzalkonium chloride, dequalinium chloride, benzethonium chloride and salicylic acid; Use DMSO with solvent, and be adjusted to experimental concentration and make 2 times of dilution series as dissolving, dilution.
(4) test method
After will also solidifying through the mixed that the reagent agent and the Sa Shi agar culture medium (Rong Yan) of dilution are pressed 1: 99, inoculate about 10 5The spore liquid of individual/milliliter.In 28 ℃ of cultivations 5 days, confirm to have aseptic growth.
DMSO concentration is defined as does not have below 1% of influence to spore-germination.
(5) judgement and calculating formula
The judgement of the effect that multiplies each other is to confirm that the minimum drug concentration (MIC: minimal inhibitory concentration, μ g/ml) that bacterium no longer grows calculates FIC index (Fractional Inhihltory Concentration indcx) when cultivate finishing
(calculating formula) C index=a/a 0+ b/b 0
A: the MIC of two stupid imidazoles of chlorine of nitric acid and the micatin of reagent agent and time spent:
a 0: the MIC when micatin uses separately;
B: the MIC of the reagent agent of micatin and reagent agent and time spent;
b 0: the MIC when reagent agent is used separately.(judgement) has or not combined effect according to following standard determination
＞2: antagonism
Below 2～and greater than 1: summation action
Below 1: synergism
(6) result
Judge the FIC exponential quantity of the effect that multiplies each other, through consider antibacterial evaluation and 1 screening back setting below 1.0 for having the effect of multiplying each other.Its result is as shown in table 2, confirms that nearly all medicament all has the addition or the effect that multiplies each other:
Table 2
FIC indexation compound title trichophyton purpureatum Trichophyton mentagrophytes
Benzethonium chloride 0.49 0.55 benzalkonium chloride 0.12 0.26 dequalinium chloride 0.47 0.68 salicylic acid 0.44 0.72
Test example 2 (1) strains testeds
Strains tested adopts following mushroom.
Trichophyton purpureatum (Trichophyton rubrum)
The preparation method of Trichophyton mentagrophytes (Trichophyton mentagrophytes) (2) spore liquid
Press the preparation with quadrat method preparation (3) reagent agent with the routine l of test
Reagent agent is used micatin, econazole nitrate, clotrimazole, bifonazole and dequalinium chloride; Use DMSO and be adjusted to experimental concentration as dissolving, retarder thinner and make 2 times of dilution series.(4) test method
By carrying out with quadrat method with test example 1.(5) judgement and calculating formula
By calculating with quadrat method with test example 1 and judging.(6) result
The results are shown in the table 3.
Table 3 imidazoles be antifungal and
The effect that multiplies each other of dequalinium chloride
FIC indexation compound title trichophyton purpureatum Trichophyton mentagrophytes
Micatin 0.32 0.55 econazole nitrate 0.63 0.63 clotrimazole 0.38 1.25 bifonazole 0.25 0.14
Its result is as shown in table 3, except the effect of clotrimazole to Trichophyton mentagrophytes, all demonstrates the strong effect that multiplies each other with dequalinium chloride.
Can be clear that according to above result owing to making up the effect that multiplies each other that causes with dequalinium chloride, not only micatin has, and imidazoles is that antifungal all has this effect.
Test example 3 (1) strains testeds
Strains tested adopts following mushroom.
Trichophyton purpureatum (Trichophyton rubrum)
The preparation method of Trichophyton mentagrophytes (Trichophyton mentagrophytes) (2) spore liquid
By preparing with test example 1 same procedure.(3) preparation of reagent agent
Reagent agent is used micatin (MCZ), salicylic acid, benzalkonium chloride (BAC) and dequalinium chloride (DQ); Use DMSO and be adjusted to experimental concentration as dissolving, retarder thinner and make 2 times of dilution series (4) test method
In 20mM phosphate buffer (pH6.5) 20ml of sterilization after filtration, add each medicament 100 μ l, after mixing according to 10 5The concentration of individual/milliliter adds spore liquid (common 50～200 μ l), and stirs it.In 30 ℃ of insulations and measure the survival spore count of the 1st day, the 2nd day and the 3rd day.In addition, be defined in can be not influential below 1% to spore-germination for DMSO concentration.(5) assay method of survival spore count
Survival spore count in spore liquid and the experimental liquid is by using sterilization normal saline solution or LP diluent (DAIGO) to make 10 times of dilution series, each diluent 50 μ l is spread upon on the previously prepared Sa Shi agar culture medium (Rong Yan), under 28 ℃ of situations, cultivate more than 4 days at trichophyton purpureatum, cultivate under the situation of Trichophyton mentagrophytes more than 3 days, calculate the spore count of surviving in spore liquid or the experimental liquid according to the clump count that occurs.(6) the multiply each other judgement of effect
According to document (Antimicrobial Agents and Chemotherapy Feb.1977, p.225-228), if separately the time and and the difference of the survival spore count of time spent be about 2 more than the order of magnitude then be judged as the effect that multiplies each other
The killing curve of (result of the test) (1) micatin
Confirmed the micatin sterilizing power in sterilization normal saline solution (pH) separately.Its result as shown in Figure 1, sterilizing power increases along with concentration.The easy 3.13 μ g/ml concentration of judging the bactericidal effect that multiplies each other are selected in the test of combined effect.(2) killing curve of medicament and time spent
Table 4 illustrates the interior maximum proportioning of border standard of each medicament and micatin.
Table 4
The chemical compound title Proportioning *
Salicylic acid benzalkonium chloride dequalinium chloride ????10 ????1 ????0.5
*) use level of micatin is defined as under 1 the situation
And the sterilizing power of time spent is confirmed by add each medicament by maximum proportioning separately in the micatin of 3.13 μ g/ml.
As shown in Figure 2, and the sterilizing power of time spent is except salicylic acid, and all being confirmed to be has enhancing when using separately compared with micatin.
Below the effect of each medicament is gone through.
Salicylic result shown in Fig. 3.
Can't see sterilizing power when salicylic acid uses separately fully, and the sterilizing power of time spent when also just using separately with micatin about equally or below it.According to the exponential result of FIC of 1 screening, salicylic acid also can be inferred the bacteriostatic combined effect.
Fig. 4 illustrates the result of benzalkonium chloride
When benzalkonium chloride uses separately, confirm identically with the micatin effect under the situation of trichophyton purpureatum, under the Trichophyton mentagrophytes situation, have the sterilizing power higher than micatin, and the time spent two kinds of bacterium all detecting below the boundary at the 1st day.
Fig. 5 illustrates the result of dequalinium chloride
Sterilizing power when dequalinium chloride uses separately equates with micatin, in case and usefulness, at the 2nd day promptly in that to detect boundary as follows
The multiply each other judgement of effect of sterilizing power, according to document (Antimicrobial Agents andChemotherapy, Feb 1977, p. 225～228), if in the time of separately and and the difference of the survival spore count of time spent be 2 more than the order of magnitude then be judged as and produce effect, therefore benzalkonium chloride and dequalinium chloride are judged as and have the sterilizing power that multiplies each other.
Test example 4 (1) strains testeds
Strains tested adopts following mushroom
Candida albicans (Candida albicans)
The preparation method of staphylococcus aureus (Staphylococcus aureus) (2) bacterium liquid
Candida albicans was cultivated 24 hours in 28 ℃ in Sa Shi agar culture medium (Rong Yan), according to about 10 6Individual/milliliter be suspended in like that the sterilization normal saline solution in, with it as bacterium liquid.Staphylococcus aureus was cultivated 18 hours in 37 ℃ in sulfa drug sensitization test culture medium (Rong Yan), according to about 10 6Individual/milliliter be suspended in like that the sterilization normal saline solution in, with it as bacterium liquid.(3) preparation of reagent agent
Reagent agent is used micatin and dequalinium chloride; Use DMSO and be adjusted to experimental concentration as dissolving, retarder thinner and make 2 times of dilution series.(4) test method
After will also solidifying through the mixed that the reagent agent and the Sa Shi agar culture medium (Rong Yan) of dilution are pressed 1: 99, the bacterium liquid of inoculation Candida albicans.In 30 ℃ of cultivations 2 days, confirm to have aseptic growth.
After will also solidifying through the mixed that the reagent agent and the Mueller-Hinton agar culture medium (Rong Yan) of dilution are pressed 1: 99, inoculate full Staphylococcus aureus.In 30 ℃ of cultivations 24 hours, confirm to have aseptic growth (5) to judge and calculating formula
By calculating with quadrat method and judgement (6) result with test example 1
Table 5 illustrates its result
Table 5
Strains tested FIC index
Candida albicans 0.11
Staphylococcus aureus 0.75
Owing to micatin and dequalinium chloride cooperate the effect that multiplies each other that produces, even also can obtain affirmation to Candida albicans and staphylococcus aureus.
Test example 5
Carried out and the same test of test example 3 about the influence of micatin and the match ratio of dequalinium chloride and time spent (1: 0.12～1.00), Fig. 6 illustrates its result of the test.
Consequently, and the sterilizing power of time spent when match ratio be that 1～0.12 sterilizing power when using separately than micatin and dequalinium chloride when above is stronger, confirm also to have the effect of multiplying each other.
Test example 6: the influence of lecithin
As the base of cream and the lecithin that uses, be that [Shiguan is loyal first-class for the inactivator of antibacterial such as quaternary ammonium salt as everyone knows, No. 91 (1973) are reported by health test institute], so study for its influence that effect that multiplies each other of micatin and dequalinium chloride is brought.
Lecithin concentration is under the situation that micatin uses separately, be adjusted to match ratio (micatin: lecithin=1: 0.5), when using separately, dequalinium chloride reaches and micatin and time spent, lecithin concentration is defined as 1.57 μ g/ml, carries out and the same test of test example 3.
Its result shows that the concentration of these lecithin is not influence fully.
Below enumerate embodiment and specify the present invention
Embodiment 1
(cream prescription example)
Micatin 100g
Lignocaine 200g
Dequalinium chloride 10g
Polyoxyethylene sorbitan monostearate 400g
Sorbitan monostearate 200g
1,3 butylene glycol 1,500g
MCT Oil 1,500g
Glyceryl monostearate 250g
EDTA-2Na??????????????????????10g
Purified Water total amount to 10,000g
(manufacture method)
At water-phase component (1,3-butanediol, EDTA-2Na, dequalinium chloride, Purified Water) the middle oil-phase component (micatin, lignocaine, sorbitan monostearate, MCT Oil, glyceryl monostearate, polyoxyethylene sorbitan monostearate) that adds, after heating, mixture makes cream 10,000g by well-established law.
Embodiment 2
(liquor prescription example)
Nitric acid acid miconazole 100g
Dequalinium chloride 20g
Glycyrrhizic acid dipotassium 50g
BHT??????????????????????????5g
Ethanol 5,000g
Purified Water total amount to 10,000ml
(manufacture method)
After being dissolved in medicament in the ethanol, adding Purified Water, to make its total amount be 10,000ml.
Embodiment 3
(gel cream prescription example)
Micatin 100g
Dequalinium chloride 20g
Lignocaine 200g
Polyoxyethylene sorbitan monostearate 100g
Propylene glycol 1,000g
Liquid paraffin 500g
Stearoyl alcohol 100g
Carboxy vinyl polymer 50g
Diisopropanolamine (DIPA) 100g
Purified Water total amount to 10,000g
(manufacture method)
With oil-phase component (micatin, lignocaine, dequalinium chloride, polyoxyethylene sorbitan monostearate, liquid paraffin, the stearoyl alcohol) dissolving of heating, cool to room temperature.Then carboxy vinyl polymer is dissolved in the propylene glycol, places, make the carboxy vinyl polymer swelling in room temperature.Above-mentioned oil phase and water at room temperature stirred make gel cream.
Embodiment 4
(aerosol prescription)
Stock solution: micatin 50g
Dequalinium chloride 5g
Glycyrrhizic acid dipotassium 25g
Ethanol 2500g
Purified Water 5000ml
Propellant: LPG 5000ml
(manufacture method)
After the stock solution that will dissolve the principal agent composition in the base of ethanol, Purified Water is filled in the container, mounted valve, aerosol is made in the filling spray agent.
Following simple declaration accompanying drawing.
Fig. 1 illustrates the sterilizing power of micatin to trichophyton purpureatum (A) and Trichophyton mentagrophytes (B).Transverse axis represents to preserve natural law, and the longitudinal axis represents to deposit logarithm (1 expression 10 just, of viable count/milliliter 1Individual/milliliter, 2 expressions 10 2Individual/milliliter, 3 expressions 10 3Individual/milliliter, 4 expressions 10 4Individual/milliliter).
Fig. 2 illustrates each medicament and the time spent sterilizing power to trichophyton purpureatum (A) and Trichophyton mentagrophytes (B).Transverse axis represents to preserve natural law, and the longitudinal axis represents to deposit the logarithm of viable count/milliliter
MCZ represents micatin, and BAC represents benzalkonium chloride, and DQ represents dequalinium chloride.
Fig. 3 illustrates salicylic acid and the time spent sterilizing power to trichophyton purpureatum (A) and Trichophyton mentagrophytes (B).Transverse axis represents to preserve natural law, and the longitudinal axis represents to deposit the logarithm of viable count/milliliter.
MCZ represents micatin
Fig. 4 illustrates benzalkonium chloride and the time spent sterilizing power to trichophyton purpureatum (A) and Trichophyton mentagrophytes (B).Transverse axis represents to preserve natural law, and the longitudinal axis represents to deposit the logarithm of viable count/milliliter.
MCZ represents micatin, and BAC represents benzethonium chloride.
Fig. 5 illustrates dequalinium chloride and the time spent sterilizing power to trichophyton purpureatum (A) and Trichophyton mentagrophytes (B).Transverse axis represents to preserve natural law, and the longitudinal axis represents to deposit the logarithm of viable count/milliliter.
MCZ represents micatin, and DQ represents dequalinium chloride.
Fig. 6 illustrates the result who studies for the influence of micatin and the match ratio of dequalinium chloride and time spent.Transverse axis represents to preserve natural law, and the longitudinal axis represents to deposit the logarithm of viable count/milliliter.MCZ represents micatin.

Claims (4)

1. antifungal compositions, it is characterized in that wherein containing imidazoles is antifungal and quaternary ammonium salt.
2. an antifungal compositions is characterized in that wherein containing (A) miconazole, econazole, clotrimazole or bifonazole, and (B) quaternary ammonium salt
3. an antifungal compositions is characterized in that wherein containing (A) miconazole, econazole, clotrimazole or bifonazole, and (B) benzethonium chloride, benzalkonium chloride or dequalinium chloride.
An antifungal with compositions, to it is characterized in that wherein containing imidazoles be antifungal and dequalinium chloride.
CN96194503A 1995-06-07 1996-06-07 Antifungal agent Pending CN1188409A (en)

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CN96194503A CN1188409A (en) 1995-06-07 1996-06-07 Antifungal agent

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100418536C (en) * 2005-04-06 2008-09-17 河南省眼科研究所 Ophthalmic pharmaceutical composition for resisting fungus
CN104606278A (en) * 2014-12-31 2015-05-13 张洛燕 Preparation method of external Zimiexuan tincture
CN108186639A (en) * 2018-02-28 2018-06-22 扬子江药业集团广州海瑞药业有限公司 A kind of pharmaceutical composition of SS 717

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100418536C (en) * 2005-04-06 2008-09-17 河南省眼科研究所 Ophthalmic pharmaceutical composition for resisting fungus
CN104606278A (en) * 2014-12-31 2015-05-13 张洛燕 Preparation method of external Zimiexuan tincture
CN108186639A (en) * 2018-02-28 2018-06-22 扬子江药业集团广州海瑞药业有限公司 A kind of pharmaceutical composition of SS 717
CN108186639B (en) * 2018-02-28 2019-03-05 扬子江药业集团广州海瑞药业有限公司 A kind of pharmaceutical composition of SS 717

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