CN1931163A - Nanometer clotrimazole emulsion medicine and its prepn process - Google Patents
Nanometer clotrimazole emulsion medicine and its prepn process Download PDFInfo
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- CN1931163A CN1931163A CNA2006101046084A CN200610104608A CN1931163A CN 1931163 A CN1931163 A CN 1931163A CN A2006101046084 A CNA2006101046084 A CN A2006101046084A CN 200610104608 A CN200610104608 A CN 200610104608A CN 1931163 A CN1931163 A CN 1931163A
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Abstract
The nanometer clotrimazole emulsion medicine consists of surfactant, oil, clotrimazole and distilled water. Its preparation process includes the following steps: weighing surfactant with or without co-surfactant; calculating HLB value and selecting oil for reaching emulsifying HLB value near that of the surfactant phase; dissolving clotrimazole into surfactant; changing the ratio between the surfactant phase and the oil phase regularly; adding distilled water slowly at 20-25 deg.c to form clear and flowing O/W type stable nanometer emulsion liquid. The nanometer clotrimazole emulsion has high skin permeability, no contamination to clothing, high dissolubility of clotrimazole, raised bioavailability of clotrimazole, delayed metabolism time and wide medicine market foreground.
Description
Technical field
The invention belongs to drug world, relate to a kind of novel form of external broad-spectrum antifungal medicine clotrimazole, particularly a kind of nanometer clotrimazole emulsion medicine and preparation method thereof.
Background technology
Clotrimazole is a kind of broad-spectrum antifungal agent, and coccus novel four is joined coccus, thick ball spore bacterium, bud bacterium, capsule histoplasma capsulatum infects all stronger inhibitory action as reading to shallow epidermis skin fungus such as various tinea bacterium, cryptococcus fungal infection and deep fungal.Therefore be commonly used for skin, fingernail, toenail infection and angular cheilitis, external otitis and the vaginal infection that causes by dermatophytes clinically.Because clotrimazole is insoluble to water, so influenced its bioavailability.It is a lot of to treat dermopathic medicine in the market, but mostly is that water preparation reaches or unguentum, wipe easy pollution clothes when the affected part, and action effective is short.
Summary of the invention
At the shortcoming and deficiency of above-mentioned prior art, the invention reside in provides a kind of dissolubility height, the high nanometer clotrimazole emulsion medicine of bioavailability.
The technical scheme that realizes the foregoing invention purpose is mould azoles nanoemulsions medicine, and it is made up of the following weight proportion raw material
Surfactant 40.0%～55.0%
Oil 4.4%～15.0%
Clotrimazole 0.1%～2.0%
Distilled water 35%～50.0%
Total component is 100%.
In the selection of surfactant, the present invention selects the nonionic surfactant of avirulence and good biocompatibility for use.Nonionic surfactant is more stable in solution, is not subject to the influence of strong electrolyte, inorganic salts, also is not subject to the influence of soda acid, and good with the compatibility of other surfactants, and haemolysis is less.In theory, the preparation of 0/W type nanometer emulsion needs the HLB value of surfactant between 8～18, consider preparation technology's simplicity, be the stability of the easy formation of nano-emulsion and the nano-emulsion for preparing, the present invention selects the liquid nonionic surfactant of HLB between 10～15 for use, and is perhaps composite with the non-ionic surface active agent of a kind of HLB＜10.Available surfactant has: lauric acid polyoxyethylene ether, castor oil polyoxyethylene ether (as EL-40), alkylphenol polyoxyethylene are (as TX-8, TX-10), any or several mixture among castor oil hydrogenated polyoxyethylene ether (as RH-40), tween-80 and the span-80.
The present invention is according to when the HLB of the required surfactant of emulsifying oil phase is close with surfactant, the principle that formed emulsion is stable, the oils and fats of selecting for use have any or several mixture of isopropyl myristate, isopropyl palmitate, Adeps Serpentis, almond oil, olive oil, Oleum Ricini and liquid paraffin wet goods.Be in a liquid state, do not have bad abnormal smells from the patient under these oily room temperature.
In order to adjust HLB VALUE OF SURFACTANTS (HLB), can further reduce interfacial tension, increase the compliance and the rigidity of film, be inserted in the interfacial film, promote the formation of the film that radius of curvature is very little, enlarge nano-emulsion and form the zone, the present invention selects bland cosurfactant, mainly contain ethanol, 1,3 butylene glycol, 1, any in the 2-propylene glycol or several mixture.
But nanometer clotrimazole emulsion medicine of the present invention also solubilising other have the treatment mycotic medicine.
Nanometer clotrimazole emulsion medicine of the present invention is an oil-in-water type rice emulsion.
Another object of the present invention provides a kind of preparation method of nanometer clotrimazole emulsion medicine, and step is as follows:
(1) preparation of surfactant phase takes by weighing surfactant by formula proportion, use separately or with help surface activity composite in proportion, calculate the HLB value of this system, stir.The HLB value of common emulsifying agent can be found in some chemical industry handbooks, as " the chemical products handbook of chemical industry publishing house.Because hydrophile-lipophile balance (HLB) value of surfactant has additive properties, the available quality averaging method is obtained the HLB value of surfactant.For example, after two kinds of surfactant A, B mixed, the hydrophile-lipophile balance HLBAB value of its mixed surfactant was
HLBAB＝(WAHLBA+WBHLBB)/(WA+WB)
WA in the formula, WB---the quality of blend surfactants A, B;
HLBA, the HLB value of HLBB---surfactant A, B.
(2) preparation of oil phase is selected one or more oil according to the HLB value of surfactant phase, transfers its ratio, makes the required HLB value of its emulsifying close with surfactant HLB mutually.
(3) clotrimazole is dissolved in the cosurfactant, add surfactant again, change the ratio of surfactant phase and oil phase in 9: 1～1: 9 rule, fully stir at 20 ℃～25 ℃, slowly add distilled water again and stir, be the oil type nanometer clotrimazole emulsion medicine until forming clear, viscosity is little and has mobile colourless or faint yellow O/W emulsion.
The present invention shows the nanometer microscopy through transmitted electron and surveys, and droplet diameter distribution is between 10～100nm, and outward appearance is transparent faint yellow or colourless liquid, has good stability:
1, ageing stability
Ageing stability is meant when nanoemulsions is preserved under room temperature nature change condition, and the nanoemulsions outward appearance prolongs and the degree that changes in time.This nanometer clotrimazole emulsion medicine is transparent lastingly, does not find muddy or precipitation, illustrates that then ageing stability is good.This is an important indicator estimating nanoemulsions.
2, heat storage stability
This nanometer clotrimazole emulsion medicine places test tube, and sealing places 37 ℃ of constant water bath box to store 14 days, and this liquid heat storage back outward appearance is still transparent.
3, anti-freeze-stable
With this nanometer clotrimazole emulsion medicine in refrigerator-4 ℃ preserve a week after.Return to room temperature.If nanoemulsions becomes solids at-4 ℃, return to room temperature, return to transparent, and place one week the back continue transparently, think that then freezing-resistance is good.
4, accelerated stability
This nanometer clotrimazole emulsion medicine places test tube, and sealing under the rotating speed of 15000r/min centrifugal 20 minutes, does not have layering, still clear.
A kind of broad-spectrum antifungal agent of nanometer clotrimazole emulsion medicine of the present invention, coccus novel four is joined coccus, thick ball spore bacterium, bud bacterium, capsule histoplasma capsulatum infects all stronger inhibitory action as reading to shallow epidermis skin fungus such as various tinea bacterium, cryptococcus fungal infection and deep fungal.Therefore be commonly used for the treatment of the skin, fingernail, toenail infection and angular cheilitis, external otitis and the vaginal infection that cause by dermatophytes clinically.Sooner or later each was applied in the affected part 1 time on 1st, should continue medication behind the transference cure 7 days, in case recurrence.
Clotrimazole of the present invention is received the nanoemulsions medicine compared with prior art, has the following advantages:
1) thermodynamic stability height, during preparation operation fairly simple, not phase-splitting, do not precipitate, bin stability improves;
2) light transmission is good, and any inhomogeneities or sedimentary existence easily are found, and sensible quality improves;
3) antiseptic property improves, because decentralized photo liquid is smaller, can prevent the intrusion of antibacterial, increases the dissolubility of some active ingredients simultaneously;
4) have good solubilization, can effectively improve the dissolubility of insoluble drug, can improve the dissolubility of clotrimazole, delay the regression time of clotrimazole, thereby improved the bioavailability of clotrimazole;
5) method technology is simple, is fit to large-scale production.
The specific embodiment
Below further set forth the better quality and the beneficial effect of clotrimazole nanoemulsion medicine of the present invention by testing example, these are tested examples and have comprised that medicine of the present invention tests and the comparative efficacy test animal irritation test, antibacterial activity.
Test example 1 animal irritation test
8 of New Zealand tower rabbits, divide 2 groups, one group is carried out the skin irritation test, adopt each 0.3ml of clotrimazole microemulsion of 0.5%, 1%, 1.5%, 2% that one group eye dripping is observed respectively, tangible zest does not appear behind the 24h, adopt each 3ml of clotrimazole microemulsion of 0.5%, 1%, 1.5%, 2% that another group is carried out the skin irritation test more respectively, 24h sloughs back part of animal spinal column diamond wool before test, the depilation scope is 3cm * 3cm, one side is tested, one side tangible zest do not occur with control sides for contrast behind the 24h.
The test of test example 2 antibacterial activities
Get the New Zealand tower rabbit of 6 body weight no significant differences, on skin, infect achorion, Candida albicans, malassezia furfur, trichophyton, pityrosporum furfur and Microsporum ferrugineum (above strain provides by my school Microbiological Lab) respectively, nanometer clotrimazole emulsion medicine with 0.5%, 1%, 1.5%, 2% carries out external antibacterial activity contrast test, and result of the test is as shown in table 1:
The test of table 1 antibacterial activity in vitro
| Test strain | The effect of the nanometer clotrimazole emulsion medicine of variable concentrations | 2％ | ||
| 0.5％ | 1％ | 1.5％ | ||
| Achorion Candida albicans malassezia furfur trichophyton | Invalid | Effectively | Effectively | Effectively |
| The pityrosporum furfur Microsporum ferrugineum | Invalid | Enabledisable | Effectively | Effectively |
The result of table 1 clearlys show effective Mlc of nanometer clotrimazole emulsion medicine 1%～2%, and above bacterium all is antibiotic preferably vigor, and the high more antibacterial effect of concentration is good more.
The pharmacodynamics contrast test of test example 3 nanometer clotrimazole emulsion medicines and other preparations
Choose female patient 21 examples that have vulvovaginal to infect clinically, be equally divided into three groups, first group with clotrimazole nano-emulsion treatment of the present invention, and external is coated with the affected part of putting on the skin in clean, 1 time every night; The second group of accurate word H21020717 of traditional Chinese medicines clotrimazole cream with 3% (the containing clotrimazole 0.3g) that Shenyang Hongqi Pharmaceutical Co., Ltd. produces treated, and is applied to clean affected part, 1 time every night; The 3rd group of accurate word H31020396 of the traditional Chinese medicines clotrimazole bolt of producing with the medical company limited of the male connection of Fujian Province's Putian City (every piece contains clotrimazole 0.15 gram), clean pudendum before using earlier, get one of aseptic plastic fingerstall, be enclosed within on the forefinger, take out suppository, hold the suppository lower end, fill in vagina gently, suppository is pushed the vagina deep with band cover forefinger.1 time every night, 1 time one piece.Through the treatment of 4d, first group of cure rate is that to be 57%, the three group be 71% to 100%, the second group of cure rate.Obviously visible nanometer clotrimazole emulsion medicine drug treatment is short, and curative effect is better than clotrimazole ointment and clotrimazole bolt.
The concrete experimental example and the embodiment that provide below in conjunction with the applicant describe in further detail.
Embodiment 1
Accurately take by weighing castor oil hydrogenated polyoxyethylene ether 4.5g, ethanol 1.0g (wherein dissolving clotrimazole 0.2g), olive oil 0.5g, under 20 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, then to wherein slowly adding distilled water, the limit adds the waterside manually stirs, and the system viscosity is less during beginning, with the increase of rate of water added, it is sticky that system can become, this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, when system unexpected when thinning, what produced this moment promptly is O/W type water white transparency nanometer clotrimazole emulsion medicine, claims that its weight is 10.0g.
Embodiment 2
Accurately take by weighing castor oil polyoxyethylene ether 4.5g, ethanol 0.5g (wherein dissolving clotrimazole 0.1g), iso-octyl palmitate 0.5g, under 22 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, then to wherein slowly adding distilled water, the limit adds the waterside manually stirs, and the system viscosity is less during beginning, with the increase of rate of water added, it is sticky that system can become, this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, when system unexpected when thinning, what produced this moment promptly is the faint yellow transparent nanometer clotrimazole emulsion medicine of O/W type, claims that its weight is 10.00g.
Embodiment 3
Accurately take by weighing castor oil polyoxyethylene ether 3.0g, 1,3-butanediol 1.0g (wherein dissolving clotrimazole 0.05g), Semen Myristicae isopropyl ester 0.44g, under 23 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, to wherein slowly adding distilled water, the limit adds the waterside and manually stirs then, the system viscosity is less during beginning, with the increase of rate of water added, it is sticky that system can become, and this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, unexpected when thinning when system, what produced this moment promptly is the faint yellow transparent nanometer clotrimazole emulsion medicine of O/W type, claims that its weight is 10.0g.
Embodiment 4
Accurately take by weighing castor oil hydrogenated polyoxyethylene ether 4.0g, 1,2-propylene glycol 0.5g (wherein dissolving clotrimazole 0.01), almond oil 1.0g, under 24 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, to wherein slowly adding distilled water, the limit adds the waterside and manually stirs then, the system viscosity is less during beginning, with the increase of rate of water added, it is sticky that system can become, and this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, unexpected when thinning when system, what produced this moment promptly is O/W type water white transparency nanometer clotrimazole emulsion medicine, claims that its weight is 10.00g.
Embodiment 5
Accurately take by weighing castor oil hydrogenated polyoxyethylene ether 4.5g, ethanol 0.8g (wherein dissolving clotrimazole 0.15g), Adeps Serpentis 0.5g, under 22 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, then to wherein slowly adding distilled water, the limit adds the waterside manually stirs, and the system viscosity is less during beginning, with the increase of rate of water added, it is sticky that system can become, this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, when system unexpected when thinning, what produced this moment promptly is O/W type water white transparency nanometer clotrimazole emulsion medicine, claims that its weight is 10.0g.
Embodiment 6
Accurately take by weighing alkylphenol polyoxyethylene 3.0g, 1,3-butanediol 1.0g (wherein dissolving clotrimazole 0.07g), Semen Myristicae isopropyl ester 0.44g, under 25 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, to wherein slowly adding distilled water, the limit adds the waterside and manually stirs amount of water for then, the system viscosity is less during beginning, with the increase of rate of water added, it is sticky that system can become, and this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, unexpected when thinning when system, what produced this moment promptly is the faint yellow transparent nanometer clotrimazole emulsion medicine of O/W type, claims that its weight is 10.00g.
Embodiment 7
Accurately take by weighing castor oil hydrogenated polyoxyethylene ether 4.0g, ethanol 0.9g (wherein dissolving clotrimazole 0.13g), isopropyl palmitate 1.0g, under 20 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, then to wherein slowly adding distilled water, the limit adds the waterside manually stirs, and the system viscosity is less during beginning, with the increase of rate of water added, it is sticky that system can become, this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, when system unexpected when thinning, what produced this moment promptly is the faint yellow transparent nanometer clotrimazole emulsion medicine of O/W type, claims that its weight is 10.0g.
Embodiment 8
Accurately take by weighing lauric acid polyoxyethylene ether 4.0g, ethanol 1.0g (wherein dissolving clotrimazole 0.18g), Adeps Serpentis 1.0g, under 22 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, then to wherein slowly adding distilled water, the limit adds the waterside manually stirs, and the system viscosity is less during beginning, with the increase of rate of water added, it is sticky that system can become, this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, when system unexpected when thinning, what produced this moment promptly is O/W type water white transparency nanometer clotrimazole emulsion medicine, claims that its weight is 10.00g.
Embodiment 9
By the tween 80 3.0g that takes by weighing accurate in scale in embodiment 6 prescriptions, span-80 1.5g, ethanol 0.4g (wherein dissolving clotrimazole 0.03g), paraffin oil 1.5g, under 24 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, to wherein slowly adding distilled water, the limit adds the waterside and manually stirs then, the system viscosity is less during beginning, with the increase of rate of water added, it is sticky that system can become, and this moment, liquid crystal state or water-in-oil type microemulsion may appear in system, continue to drip and constantly stir, unexpected when thinning when system, what produced this moment promptly is the faint yellow transparent clotrimazole microemulsion of O/W type, claims that its weight is 10.00g.
Claims (10)
1, a kind of nanometer clotrimazole emulsion medicine, it is characterized in that it is made up of the following weight proportion raw material: surfactant 40.0%～55.0%, oil 4.4%～15.0%, clotrimazole 0.1%～2.0%, distilled water 35%～50.0%, total component is 100%.
2, nanometer clotrimazole emulsion medicine according to claim 1 is characterized in that: described surfactant is a nonionic surfactant.
3. nanometer clotrimazole emulsion medicine according to claim 2 is characterized in that: described nonionic surfactant is any or several mixture among lauric acid polyoxyethylene ether, castor oil polyoxyethylene ether, castor oil hydrogenated polyoxyethylene ether, alkylphenol polyoxyethylene, tween-80, the span-80.
4. nanometer clotrimazole emulsion medicine according to claim 1 is characterized in that: can also add cosurfactant in the described surfactant.
5. nanometer clotrimazole emulsion medicine according to claim 4 is characterized in that: described cosurfactant is ethanol, 1,3 butylene glycol, 1, any in the 2-propylene glycol or several mixture.
6, nanometer clotrimazole emulsion medicine according to claim 1 is characterized in that: but any or several mixture in described oil isopropyl myristate, isopropyl palmitate, iso-octyl palmitate, Adeps Serpentis, almond oil, olive oil, Oleum Ricini and the saxol.
7, according to described any nanometer clotrimazole emulsion medicine of claim 1～6, it is characterized in that: the particle diameter of described nanometer clotrimazole emulsion medicine is 10nm～100nm.
8, according to described any nanometer clotrimazole emulsion medicine of claim 1～6, it is characterized in that: described nanometer clotrimazole emulsion medicine is the nanoemulsions of oil-in-water type.
9, according to described any nanometer clotrimazole emulsion medicine of claim 1～6, it is characterized in that: but described nanometer clotrimazole emulsion medicine also solubilising other have the treatment mycotic medicine.
10, the preparation method of the described nanometer clotrimazole emulsion medicine of claim 1 is characterized in that, specifically comprises the following steps:
(1) preparation of surfactant phase takes by weighing the surfactant of certain mass, use separately or with help surface activity composite by a certain percentage, calculate the HLB value of this system, stir;
(2) preparation of oil phase is selected one or more oil according to the HLB value of surfactant phase, transfers its ratio, makes the required HLB value of its emulsifying close with surfactant HLB mutually;
(3) clotrimazole is dissolved in the cosurfactant, add surfactant again, change the ratio of surfactant phase and oil phase in 9: 1～1: 9 rule, fully stir at 20 ℃～25 ℃, slowly add distilled water again and stir, be the oil type nanometer clotrimazole emulsion medicine until forming clear, viscosity is little and has mobile colourless or faint yellow O/W emulsion.
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| CNA2006101046084A CN1931163A (en) | 2006-09-20 | 2006-09-20 | Nanometer clotrimazole emulsion medicine and its prepn process |
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| CNA2006101046084A CN1931163A (en) | 2006-09-20 | 2006-09-20 | Nanometer clotrimazole emulsion medicine and its prepn process |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101032507B (en) * | 2007-04-06 | 2010-09-29 | 西北农林科技大学 | Bacteria resisting medicine of erythrocin nanometer-emulsion and the preparing method |
| CN104622805A (en) * | 2015-01-19 | 2015-05-20 | 山西远扬医药科技有限公司 | Econazole nitrate microemulsion and preparation method and application thereof |
| CN104800148A (en) * | 2015-04-20 | 2015-07-29 | 程伟智 | Clotrimazole emulsifiable paste and preparation method thereof |
| CN111388354A (en) * | 2020-03-25 | 2020-07-10 | 瑞希(重庆)生物科技有限公司 | Microemulsion and preparation method thereof |
| WO2023287309A1 (en) * | 2021-07-16 | 2023-01-19 | Uniwersytet Medyczny Im. Piastów Śląskich We Wrocławiu | Pharmaceutical composition in the form of vegetable oil-based nanoemulsion, multiphase composition and method of preparation of these compositions |
-
2006
- 2006-09-20 CN CNA2006101046084A patent/CN1931163A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101032507B (en) * | 2007-04-06 | 2010-09-29 | 西北农林科技大学 | Bacteria resisting medicine of erythrocin nanometer-emulsion and the preparing method |
| CN104622805A (en) * | 2015-01-19 | 2015-05-20 | 山西远扬医药科技有限公司 | Econazole nitrate microemulsion and preparation method and application thereof |
| CN104800148A (en) * | 2015-04-20 | 2015-07-29 | 程伟智 | Clotrimazole emulsifiable paste and preparation method thereof |
| CN111388354A (en) * | 2020-03-25 | 2020-07-10 | 瑞希(重庆)生物科技有限公司 | Microemulsion and preparation method thereof |
| WO2023287309A1 (en) * | 2021-07-16 | 2023-01-19 | Uniwersytet Medyczny Im. Piastów Śląskich We Wrocławiu | Pharmaceutical composition in the form of vegetable oil-based nanoemulsion, multiphase composition and method of preparation of these compositions |
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