CN100448443C - Nanometer antifungal econazole nitrate emulsion medicine and its prepn process - Google Patents
Nanometer antifungal econazole nitrate emulsion medicine and its prepn process Download PDFInfo
- Publication number
- CN100448443C CN100448443C CNB2006101046205A CN200610104620A CN100448443C CN 100448443 C CN100448443 C CN 100448443C CN B2006101046205 A CNB2006101046205 A CN B2006101046205A CN 200610104620 A CN200610104620 A CN 200610104620A CN 100448443 C CN100448443 C CN 100448443C
- Authority
- CN
- China
- Prior art keywords
- econazole nitrate
- antifungal
- nanometer
- oil
- medicine
- 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.)
- Expired - Fee Related
Links
Abstract
The nanometer antifungal econazole nitrate emulsion medicine consists of econazole nitrate, surfactant, oil and distilled water. Its preparation process includes the following steps: weighing the materials; mixing the surfactant and oil and dissolving econazole nitrate in dimethyl sulphoxide; mixing the solution of econazole nitrate with the surfactant and oil; and final adding distilled water slowly while stirring to form stable homogeneous transparent nanometer antifungal econazole nitrate emulsion medicine. The medicine is used in treating candidal tinea corporis, tinea cruris and tinea pedis, aural mycosis, seborrheic dermatitis, etc. The medicine is absorbed through skin to enter into blood circulation, and this avoids the first pass effect of liver, prolongs the medicine release and prevents stimulation to gastrointestinal tract. The preparation process is simple and low in power consumption.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of novel form of antifungal drug econazole nitrate, particularly a kind of nanometer antifungal econazole nitrate emulsion medicine and preparation method thereof.
Background technology
Econazole nitrate is an imidazoles external broad-spectrum antifungal medicine, all there is antibacterial activity in deep and superficial fungi, chemical name 1-[2,4-two chloro-β (4-chlorine benzyloxy) phenethyl] imidazole nitrate, be white or yellowish crystallization or crystalline powder, odorless, atomic water-soluble.Econazole nitrate is metabolism in liver, is mainly discharged by bile, and is all effective to dermatophytosis, yeast and mycete, for the part gram-positive bacteria antibacterial action also arranged; Be applicable to the treatment of tinea corporis, tinea cruris, tinea pedis, gill fungus, seborrheic dermatitis etc.Econazole nitrate is by the dependent 14-α of interference cell pigment P-450-demethyl enzyme, thereby the biosynthesis that suppresses the main steroid-ergosterol of fungal cell membrane, the damage fungal cell membrane also changes its permeability, so that important intracellular matter leaks outside, and it is synthetic to suppress ribonucleic acid, also can suppress the triacylglycerol of fungus and the biosynthesis of phospholipid, the activity of inhibited oxidation enzyme and peroxidase, causing that the cell hydrogen peroxide is gathered causes degeneration of cell submicroscopic structure and necrocytosis, thereby influence metabolism, stop the somatic cells growth and cause cell death, reach antibacterial, sterilization effects is widely used clinically antifungal drug.
Econazole nitrate is evident in efficacy, but also exists many weak points: oral absorption is poor, and oral 1g bleeding from anus peak concentration of drug only is 1mg/L; The blood system cloth half-life, (T1/2 α) was about 0.4 hour, and blood elimination half-life (T1/2 β) is about 2.1 hours, and t1/2 (T1/2) is 20～24 hours, and the serum albumin combination rate is 90%; Concentration is all very low in cerebrospinal fluid, sputum, aqueous humor, and is poor to the penetrance of blood brain barrier; Main is the metabolite of non-activity through the liver metabolism deactivation, and 14%～22% of oral dose is discharged from urine, is mainly the metabolite of non-activity, is the original shape thing less than 1% wherein, and 50% of oral dose is discharged from feces with original shape.Untoward reaction is many, digestive tract reaction such as nausea,vomiting,diarrhea and loss of appetite; Skin pruritus, erythra, dizziness can take place, feel cold in small number of patients, heating etc., and anaphylactic shock can take place idol; Normocytic anemia, granulocyte and thrombocytopenia, hyperlipemia (as the rising of cholesterol and triacylglycerol) can take place in idol, but clear aminotransferase one property crossed of idol hyperamization slightly raises.There is interaction can increase drug toxicity with multiple medicine.
Summary of the invention
At the shortcoming and defect of existing dosage form, the objective of the invention is to the object of the present invention is to provide a kind ofly be evenly distributed, viscosity is little, transparent, good stability excellent adsorption, bioavailability height, long half time, the little econazole nitrate antifungal drug of side effect.
The technical scheme that realizes the foregoing invention purpose is: nanometer antifungal econazole nitrate emulsion medicine mainly is made up of following raw materials by weight:
Econazole nitrate 0.2%～2.0%
Surfactant 40%～45.0%
Oil 5.0%～10%
Dimethyl sulfoxide 5.0%～7.5%
Distilled water 40.5%～44.8%
Total component is 100%
Glass or plastic containers polyoxyethylene ether (40) castor oil hydrogenated (RH40) that the present invention selects for use, castor oil polyoxyethylene ether (EL40) are to skin safe, non-stimulated.
The oil that the present invention selects for use is iso-octyl palmitate, almond oil, Adeps Serpentis, different monooctyl ester, and is safe, nontoxic, and skin is had certain moist effect.
In order to improve the permeability of econazole nitrate nano-emulsion to skin, the present invention has selected for use dimethyl sulfoxide as penetrating agent, skin is had well urge to ooze effect, and dimethyl sulfoxide also is the good solvent as econazole.
Another object of the present invention has provided a kind of preparation method of nanometer antifungal econazole nitrate emulsion medicine, specifically may further comprise the steps:
1) accurately take by weighing each raw material: econazole nitrate, surfactant, oil, dimethyl sulfoxide are standby;
2) with surfactant and oily stirring and evenly mixing;
3) econazole nitrate is added dissolving fully in the dimethyl sulfoxide;
4) will be dissolved with in the dimethyl sulfoxide adding of econazole nitrate
In the surfactant and oil that stirs;
5) distilled water slowly is added drop-wise to 4) in, stir while dripping, until forming stable, even, transparent nanometer antifungal econazole nitrate emulsion medicine.
Nanometer antifungal econazole nitrate emulsion medicine of the present invention detects through transmission electron microscope, and droplet diameter distribution is between 10～100nm.
Whether the mensuration of nanometer antifungal econazole nitrate emulsion medicine stability is to see its stability by centrifugal test, light stability test, temperature stability test, have layering, muddiness and crystal to separate out.
1. high speed centrifugation test
Get the nanometer antifungal econazole nitrate emulsion medicine for preparing in right amount in centrifuge tube, seal, carry out with the rotating speed of 10000r/min centrifugal, behind centrifugal 20min, the econazole nitrate nano-emulsion still keeps clear, has not seen that econazole nitrate is crystalline separates out and lamination.
2. light stability test
The nanometer antifungal econazole nitrate emulsion medicine for preparing is in right amount packed in the vial, and sealing places under the illumination, and light at room temperature is according to 10d, in 1d, 3d, 5d, 7d, 10d sampling.The result shows that nanometer antifungal econazole nitrate emulsion medicine still keeps clear, does not have muddy, lamination.
3. temperature stability test
The nanometer antifungal econazole nitrate emulsion medicine for preparing is in right amount packed in the vial, sealing, placing keeps sample under 4 ℃ of refrigerators, 25 ℃ and 37 ℃ three kinds of temperature conditions of room temperature investigates 30d, observes every the 5d sampling.The result shows that this nanometer antifungal econazole nitrate emulsion medicine all keeps clear under these three kinds of temperature conditions, do not see the phenomenon that layering, muddiness and crystallization are separated out, and temperature stability is good.
Econazole nitrate antifungal nano-emulsion of the present invention is compared with prior dosage form, has the following advantages:
1. econazole nitrate antifungal nano-emulsion particle diameter of the present invention is 10～100nm, be that econazole nitrate is dissolved in the enhancer of cutaneous penetration dimethyl sulfoxide, stir with surfactant, oil again, the water titration is up to even, transparent, the nanometer antifungal econazole nitrate emulsion medicine that is prepared from, appearance transparent, surface tension is low, viscosity is little, good fluidity, have opalescence.
2. econazole nitrate nano-emulsion appearance transparent of the present invention, colourless, little band opalescence, the nano-emulsion surface tension of O/W is little, viscosity is little, good fluidity, and macroscopic property is stable, external preparation for skin is salubriouser, be easy to soak into skin, have the good skin permeability, directly enter blood circulation.
3. econazole nitrate antifungal nano-emulsion of the present invention also can be avoided the contingent liver first-pass effect of oral administration by transdermal administration, improve the econazole nitrate oral administration biaavailability, keep constant blood drug level or pharmacodynamics effect, prolong action time, reduce amount of drug and medication number of times, percutaneous drug delivery can also avoid medicine that gastrointestinal is stimulated, and reducing untoward reaction must take place.
4. econazole nitrate antifungal nano-emulsion preparation method of the present invention is simple, power consumption is low, do not need just energy mass production of special installation.
Below further specify the anti-mycotic efficiency of nanometer antifungal econazole nitrate emulsion medicine by test examples.Comprise econazole nitrate antifungal pharmacodynamics test and clinical pharmacodynamic observation.
Test example 1 econazole nitrate nano-emulsion of the present invention is to the dermopathic clinical observation of fungal infection
1. clinical data
Case is selected:
120 routine superficial mycosis patients, wherein male 75 examples, women 45 examples; 25～65 years old age, average 34.5 years old; Course of disease March～1 year, average 6 months.
(1) case inclusion criteria: light to moderate struvite fungal infection dermatosis (comprising) with bacterial infection; Typical clinical manifestation is arranged, and make a definite diagnosis through the direct microscopy positive of fungus; There are no restrictions on age or sex;
(2) inclusion criteria not: once external corticosteroid or antifungal drug person in preceding 2 weeks of medication; Corticosteroid, antibacterium or antifungal drug person are taken in medication in preceding 4 weeks; Incretion metabolism disease is arranged; The anemia of pregnant woman; To Pevisone frost allergy sufferers.
(3) reject the case standard: patient or its guardian no longer agree to accept this researcher; Suffer from other disease during the treatment again, add and use other medicines, uncomplaisance medication or be late for further consultation person.If but therapy discontinued is because treatment itself, as untoward reaction or do not tolerate and cause, then will not rejects, and note.
2, medicine and method
Nitric acid nano-emulsion antifungal drug of the present invention is applied in the affected part and gently rubs a moment, early, each medication 1 time in evening.Treated altogether 14 days, and checked respectively and kept a record at the 1st, 14,21 day that goes to a doctor.
3. efficacy determination:
(1) curative effect scoring: 7 kinds of symptoms such as erythema, pimple, vesicle, erosion, incrustation, desquamation, pruritus do not have by following standard: the 0=that marks, and 1=is light, among the 2=, and the 3=weight.
(2) therapeutic index: scoring * 100% before therapeutic index=(scoring-treatment back scoring before the treatment)/treatment
(3) evaluation of clinical curative effect: judged curative effect in 21 days after the medication, be divided into recovery from illness, produce effects, invalid 4 grade standards.Recovery from illness: sings and symptoms complete obiteration, therapeutic index are 100%; Produce effects: sings and symptoms is clearly better, and therapeutic index is 〉=60%; Take a turn for the better: sings and symptoms take a favorable turn, and therapeutic index is 20%～60%; Invalid: sings and symptoms does not have obvious improvement, therapeutic index≤20%.Recovery from illness is an effective percentage with the produce effects sum.
(4) mycology evaluation: eliminate and be the microscopy feminine gender, eliminate and be the microscopy positive.
4. result
Nitric acid nano-emulsion antifungal drug treatment superficial mycosis curative effect sees Table 1
Table Spectazole nano-emulsion antifungal drug treatment superficial mycosis curative effect
The result shows: the econazole nitrate antifungal drug has excellent curative to the skin infection mycosis, and up to 94% and 95%, untoward reaction is few respectively for average effectiveness level, clearance rate, shows that the econazole nitrate antifungal drug is good antifungal drug.
Below logical embodiment further sets forth the preparation method of this medicine
Embodiment 1
Accurately take by weighing castor oil polyoxyethylene ether 4.5g, dimethyl sulfoxide 0.5g (wherein dissolving econazole nitrate 0.02g), iso-octyl palmitate 0.5g, under 20 ℃ of conditions, stirring and evenly mixing is then to wherein slowly adding distilled water, the limit edged stirs, the system viscosity is less during beginning, and with the increase of rate of water added, it is sticky that system becomes, continue to drip distilled water and constantly stirring, unexpected when thinning when system, what produced this moment promptly is O/W type water white transparency econazole nitrate nanoemulsions, claims that its weight is 10.0g.
Embodiment 2
Accurately take by weighing castor oil polyoxyethylene ether 4.0g, dimethyl sulfoxide 0.5g (wherein dissolving econazole nitrate 0.07g), almond oil 1.0g, under 20 ℃ of conditions, stirring and evenly mixing is then to wherein slowly adding distilled water, the limit edged stirs, the system viscosity is less during beginning, and with the increase of rate of water added, it is sticky that system becomes, continue to drip distilled water and constantly stirring, unexpected when thinning when system, what produced this moment promptly is O/W type water white transparency econazole nitrate nanoemulsions, claims that its weight is 10.0g.
Embodiment 3
Accurately take by weighing castor oil polyoxyethylene ether 2.5g, dimethyl sulfoxide 0.75g (wherein dissolving econazole nitrate 0.12g), Adeps Serpentis 0.5g, under 20 ℃ of conditions, stirring and evenly mixing is then to wherein slowly adding distilled water, the limit edged stirs, the system viscosity is less during beginning, and with the increase of rate of water added, it is sticky that system becomes, continue to drip distilled water and constantly stirring, unexpected when thinning when system, what produced this moment promptly is O/W type water white transparency econazole nitrate nanoemulsions, claims that its weight is 10.0g.
Embodiment 4
Accurately take by weighing castor oil polyoxyethylene ether 1.0g, dimethyl sulfoxide 0.75g (wherein dissolving econazole nitrate 0.15g), different monooctyl ester 1.0g, under 20 ℃ of conditions, stirring and evenly mixing is then to wherein slowly adding distilled water, the limit edged stirs, the system viscosity is less during beginning, and with the increase of rate of water added, it is sticky that system becomes, continue to drip distilled water and constantly stirring, unexpected when thinning when system, what produced this moment promptly is O/W type water white transparency econazole nitrate nanoemulsions, claims that its weight is 10.0g.
Embodiment 5
Accurately take by weighing castor oil polyoxyethylene ether 4.5g, dimethyl sulfoxide 0.5g (wherein dissolving econazole nitrate 0.2g), Adeps Serpentis 0.5g, under 20 ℃ of conditions, stirring and evenly mixing is then to wherein slowly adding distilled water, the limit edged stirs, the system viscosity is less during beginning, and with the increase of rate of water added, it is sticky that system becomes, continue to drip distilled water and constantly stirring, unexpected when thinning when system, what produced this moment promptly is O/W type water white transparency econazole nitrate nanoemulsions, claims that its weight is 10.0g.
Claims (3)
1. a nanometer antifungal econazole nitrate emulsion medicine is characterized in that, is made by following raw materials by weight percent:
Econazole nitrate 0.2%～2.0%, surfactant 40%～45.0%, oil 5.0%～10%, dimethyl sulfoxide 5.0%～7.5%, distilled water 40.5%～44.8%
In described glass or plastic containers polyoxyethylene ether castor oil hydrogenated, the castor oil polyoxyethylene ether any;
Described oil is any in iso-octyl palmitate, almond oil, Adeps Serpentis, the different monooctyl ester.
2. nanometer antifungal econazole nitrate emulsion medicine according to claim 1 is characterized in that: the particle diameter of described econazole nitrate nano-emulsion is 10nm～100nm.
3. the preparation method of nanometer antifungal econazole nitrate emulsion medicine according to claim 1 is characterized in that, comprises the following steps:
1) accurately take by weighing each raw material: econazole nitrate, surfactant, oil, dimethyl sulfoxide are standby;
2) with surfactant and oily stirring and evenly mixing;
3) econazole nitrate is added dissolving fully in the dimethyl sulfoxide;
4) dimethyl sulfoxide that will be dissolved with econazole nitrate adds in the surfactant and oil stir;
5) distilled water slowly is added drop-wise to 4) in, stir while dripping, until forming stable, even, transparent nanometer antifungal econazole nitrate emulsion medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101046205A CN100448443C (en) | 2006-09-21 | 2006-09-21 | Nanometer antifungal econazole nitrate emulsion medicine and its prepn process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101046205A CN100448443C (en) | 2006-09-21 | 2006-09-21 | Nanometer antifungal econazole nitrate emulsion medicine and its prepn process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1931165A CN1931165A (en) | 2007-03-21 |
| CN100448443C true CN100448443C (en) | 2009-01-07 |
Family
ID=37877288
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006101046205A Expired - Fee Related CN100448443C (en) | 2006-09-21 | 2006-09-21 | Nanometer antifungal econazole nitrate emulsion medicine and its prepn process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100448443C (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009056754A2 (en) * | 2007-10-26 | 2009-05-07 | Galderma Research & Development | Use of econazole or salts thereof for treating acne |
| CN103860566B (en) * | 2014-04-08 | 2015-12-09 | 张绪伟 | A kind of triamcinolone acetonide econazole cream agent and preparation method thereof |
| CN104622805B (en) * | 2015-01-19 | 2017-07-21 | 山西远扬医药科技有限公司 | A kind of econazole nitrate microemulsion and preparation method and application |
| WO2016142946A1 (en) * | 2015-03-12 | 2016-09-15 | Sol-Gel Technologies Ltd. | A system for the treatment of dermatological infections |
| CN106963725A (en) * | 2017-04-19 | 2017-07-21 | 赵艳霞 | A kind of dexamethasone nanogel and preparation method thereof |
| CN107455387A (en) * | 2017-07-25 | 2017-12-12 | 佛山市南海建诺鞋业有限公司 | A kind of formula of PU bactericidal creams and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995011676A1 (en) * | 1993-10-29 | 1995-05-04 | Taisho Pharmaceutical Co., Ltd. | Long-acting antifungal o/w preparation |
| JP2000229845A (en) * | 1998-12-10 | 2000-08-22 | Taisho Pharmaceut Co Ltd | Powdery aerosol pharmaceutical preparation containing antifungal agent |
| CN1650860A (en) * | 2004-11-20 | 2005-08-10 | 贵阳高新瑞得科技开发有限公司 | Econazole film agent and its preparation method |
| CN1686136A (en) * | 2005-05-09 | 2005-10-26 | 张文芳 | Vollikongzole preparation and its preparation method |
-
2006
- 2006-09-21 CN CNB2006101046205A patent/CN100448443C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995011676A1 (en) * | 1993-10-29 | 1995-05-04 | Taisho Pharmaceutical Co., Ltd. | Long-acting antifungal o/w preparation |
| JP2000229845A (en) * | 1998-12-10 | 2000-08-22 | Taisho Pharmaceut Co Ltd | Powdery aerosol pharmaceutical preparation containing antifungal agent |
| CN1650860A (en) * | 2004-11-20 | 2005-08-10 | 贵阳高新瑞得科技开发有限公司 | Econazole film agent and its preparation method |
| CN1686136A (en) * | 2005-05-09 | 2005-10-26 | 张文芳 | Vollikongzole preparation and its preparation method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1931165A (en) | 2007-03-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100448443C (en) | Nanometer antifungal econazole nitrate emulsion medicine and its prepn process | |
| Bseiso et al. | Novel nail penetration enhancer containing vesicles “nPEVs” for treatment of onychomycosis | |
| CN101273971A (en) | Ethosomes preparation of antimycotics pharmaceutical and method for preparing the same | |
| CN102302449A (en) | Oil-in-water cinnamic aldehyde nano emulsion medicament | |
| CN102552147A (en) | Bullatacin ethosome gel and preparation method thereof | |
| CN100548285C (en) | A kind of Terbinafine nano milk-like liquid antifungal medicine and preparation method thereof | |
| CN108066342A (en) | A kind of Compound Ketoconazole Cream agent and preparation method thereof | |
| CN102293735A (en) | Antifungal imidazole medicament controlled-release gel and preparation method thereof | |
| CN101756886A (en) | Imiquimod micro emulsion gels for local skin and preparation method thereof | |
| CN102018667B (en) | Imidazoles antifungal skin wiping agent and preparation method thereof | |
| CN102657602A (en) | 3,5-dyhydroxyl-4-isopropyl diphenylethene chitosan gel and preparation method thereof | |
| CN109820814A (en) | A kind of Tacrolimus paste and preparation method thereof | |
| CN108670945A (en) | A kind of nanogel preparation and preparation method thereof with double slow releasing functions | |
| CN101584715B (en) | Spray for preventing and treating skin damnification and resisting infection | |
| CN1931163A (en) | Nanometer clotrimazole emulsion medicine and its prepn process | |
| CN102327273B (en) | Compound clobetasol propionate nano-medicament and preparation method thereof | |
| CN101810640B (en) | Composite nanometer emulsion containing borneol and alum and preparation method thereof | |
| CN104274494B (en) | A kind of American cockroach external preparation and preparation method thereof | |
| CN114432242A (en) | Apremilast nanocrystalline composition and preparation method thereof | |
| CN101396354B (en) | Stable taxabe compound liquid combination and preparation method and use thereof | |
| CN102178649A (en) | Rapamycin liposome eye drops and preparation method thereof | |
| CN110354068B (en) | Supermolecule hydrogel taking ursolic acid/oleanolic acid as raw material, preparation method and application | |
| US9271994B2 (en) | Compositions and methods related to calcitriol | |
| CN102309539A (en) | Spina gleditsiae extract hydrogel patch and preparation method thereof | |
| CN104367636A (en) | Oil-in-water type compound ceftriaxone nanoemulsion antimicrobial medicine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090107 Termination date: 20100921 |