CN106389331B - A kind of luliconazole alcohol plastid and preparation method thereof - Google Patents
A kind of luliconazole alcohol plastid and preparation method thereof Download PDFInfo
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- CN106389331B CN106389331B CN201610799123.5A CN201610799123A CN106389331B CN 106389331 B CN106389331 B CN 106389331B CN 201610799123 A CN201610799123 A CN 201610799123A CN 106389331 B CN106389331 B CN 106389331B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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Abstract
The invention belongs to pharmaceutical technology fields, specifically, being related to a kind of luliconazole alcohol plastid and preparation method thereof.The luliconazole alcohol plastid of the present invention, composition includes luliconazole, lecithin, absolute ethyl alcohol and water, wherein：The luliconazole alcohol plastid further includes vitamin E, and the mass ratio of the vitamin E and luliconazole is 0.1~0.5：1, preferably 0.3：1.Not only encapsulation rate is high for luliconazole alcohol plastid provided by the present invention, and particle diameter distribution is uniform, and has good stability, and is still milky suspension under illumination and high temperature experiment, consistency is suitable, and stretchability is good, and be evenly distributed exquisiteness.
Description
Technical field
The invention belongs to pharmaceutical technology fields, specifically, being related to a kind of luliconazole alcohol plastid and preparation method thereof.
Background technology
Luliconazole (luliconazole) be initially researched and developed by Japanese pesticide (Nihon Nohyaku) pillar commercial firm it is new
Type azole antifungal preparation is listed on July 20th, 2005 in Japan, trade name Lulicon, for treating dermatophyte sense
Dye.Hainan Hailing Chemical Pharmaceutical Co., Ltd introduced the medicine and listed at home on June 27th, 2012, trade name Lu Lite.
The luliconazole emulsifiable paste listing that U.S. FDA approval on November 14th, 2013 Medicis drugmakers develop, for treat tinea pedis,
The dermatophytid infections such as jock itch, trade name Luzu.
The Chinese chemical name of luliconazole：(-)-(E) -4 (R) -4- (2,4- dichlorophenyl) -1,3- dithiolanes -2-
Asia substitution (1H- imidazoles -1- substitutions) acetonitrile；Molecular formula：C14H9Cl2N3S2；Molecular weight：354.28；CAS registration numbers：187164-
19-8.The medicine mainly by blocking the biosynthesis of ergosterol, plays antifungic action.Lot of experiments the result shows that,
Luliconazole shows the antibacterial action of broad spectrum high-effect in antibacterial activity, fungi animal model and clinical trial in vitro.
Alcohol plastid is the research hotspot in transdermal absorption formulation in recent years.It is a kind of novel flexible lipidosome, because it contains
There is the ethyl alcohol (30%-45%) of high concentration and gains the name.Alcohol plastid is multi-layer vesicles structure, and bilayer mobility is higher, easily
In deformation so as to penetrate cuticula, assists Medicated Permeation to skin layers, increase the accumulation of drug in skin.It with it is common
Liposome is compared, and grain size is small, stable structure, and drugloading rate is high, and skin-tolerant is good, there is better flexibility, easily deformable to enter skin
Skin deep layer can assist Medicated Permeation, be detained dose to significantly improve percutaneous rate and skin.These feature energy of alcohol plastid
Enough drugs that further carries enter cell and microorganism, this has received widespread attention in percutaneous dosing field.Newtype drug Lu Li
The ethosome preparation of health azoles can become the ideal chose for expanding dept. of dermatology's antifungal drug percutaneous dosing.
" development of luliconazole alcohol plastid and local pharmacodynamic study "【Lin Biwen, doctoral thesis】Disclose a kind of Lu Li
Health azoles alcohol plastid, and its stability and local pharmacodynamics are studied.The result shows that the alcohol prepared using film law technology
Plastid has the advantages that encapsulation rate is high, skin permeation rate is good, and optimized prescription is shown, is 5% (w/v), ethyl alcohol 45% in lecithin
(v/v), under 8 minutes prescriptions of ultrasonic time proportioning, luliconazole ethosome preparation grain size is smaller, encapsulation rate is high.And with thorn
Swash the features such as property is small, stability is good.Pharmacodynamic result shows that alcohol plastid is saturating compared with liposome, water-alcohol solution and the ointment that will list
Skin performance is good, and experiment in vitro shows that the anti-microbial property of luliconazole alcohol plastid is better than liposome and water-alcohol solution.
However, since luliconazole drug itself is to light sensitive, destructible so that above-mentioned luliconazole alcohol plastid is in light
According to occurring as soon as the sticky phenomenon of drug after 5 days；And 60 DEG C of high temperature influences are also larger in appearance for above-mentioned luliconazole alcohol plastid, there is ethyl alcohol
Vesica is unstable through high temperature, rupture, volatilization phenomenon generates.
In view of this special to propose the present invention.
Invention content
The technical problem to be solved in the present invention is to overcome the deficiencies of the prior art and provide a kind of preferable Lu Li of stability
Health azoles alcohol plastid, the luliconazole alcohol plastid are still milky suspension under illumination and high temperature experiment, and consistency is suitable, Tu Zhan
Property is good, and be evenly distributed exquisiteness.
To achieve the purpose of the present invention, the present invention adopts the following technical scheme that：
A kind of luliconazole alcohol plastid, composition includes luliconazole, lecithin, absolute ethyl alcohol and water, wherein：Described
Luliconazole alcohol plastid further includes vitamin E, wherein the mass ratio of the vitamin E and luliconazole is 0.1~0.5：1.
" development of luliconazole alcohol plastid and local pharmacodynamic study "【Lin Biwen, doctoral thesis】Disclose a kind of Lu Li
Health azoles alcohol plastid, composition includes luliconazole, lecithin, absolute ethyl alcohol and water.However, since luliconazole drug itself is right
Light sensitive, destructible so that above-mentioned luliconazole alcohol plastid occurs as soon as the sticky phenomenon of drug after 5 days in illumination；And above-mentioned Lu
60 DEG C of high temperature influences are also larger in appearance for vertical health azoles alcohol plastid, there is ethyl alcohol vesica unstable through high temperature, rupture, volatilization phenomenon production
It is raw.
The present inventor has further carried out a large amount of research on the basis of the above, surprisingly finds when in luliconazole
Not only encapsulation rate is high for luliconazole alcohol plastid obtained after adding a certain amount of vitamin E in preparation process, and particle diameter distribution is uniform,
And have good stability, it is still milky suspension under illumination and high temperature experiment, consistency is suitable, and stretchability is good, and distribution is equal
It is even and fine greasy, overcome the defect of the prior art.
It is preferred that the mass ratio of the vitamin E and luliconazole is 0.3：1.
Further, the mass ratio of the luliconazole and lecithin is 1：3~8, preferably 1：5.
Further, the mass volume ratio of the luliconazole and water is 1g：3~8ml.
It is preferred that the mass volume ratio of the luliconazole and water is 1g：5.5ml.
Further, the volume ratio of the absolute ethyl alcohol and water is 3~8：4~9.
It is preferred that the volume ratio of the absolute ethyl alcohol and water is 4.5：5.5.
The present invention also provides the preparation methods of the luliconazole alcohol plastid, and this method comprises the following steps：
1) luliconazole and lecithin are completely dissolved with suitable chloroform, solution A is obtained after stirring evenly；
2) absolute ethyl alcohol and water are mixed, forms solution B；
3) the solution A evaporation obtained by step 1) is removed into chloroform, step 2) is then added and is formed by solution B, then
Vitamin E is added, stirring is to forming uniform dispersion liquid；
4) dispersion liquid obtained by step 3) is ultrasonically treated, then uses miillpore filter whole grain, obtain the Lu Li
Health azoles alcohol plastid.
In above-mentioned preparation method, wherein the supersound process described in step 4) is to be ultrasonically treated 5~10 minutes, ultrasonic work(
Rate is 280~320W.
It is preferred that the supersound process described in step 4) is to be ultrasonically treated 8 minutes, ultrasonic power 300W.
Compared with prior art, the invention has the advantages that：
Luliconazole alcohol plastid encapsulation rate provided by the present invention is high, and particle diameter distribution is uniform, has good stability, in illumination and
It is still milky suspension under high temperature experiment, consistency is suitable, and stretchability is good, and be evenly distributed exquisiteness, and to no skin irritation
Reaction.
Specific implementation mode
In order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below in conjunction with the embodiment of the present invention,
Technical scheme of the present invention is clearly and completely described, following embodiment is not limited to this for illustrating the present invention
The range of invention.
Embodiment 1
1) luliconazole powder 0.1g and lecithin 0.5g are weighed, is completely dissolved, is stirred evenly with suitable chloroform
After obtain solution A；
2) 4.5ml absolute ethyl alcohols and the mixing of 5.5ml water are measured, solution B is formed；
3) the solution A evaporation obtained by step 1) is removed into chloroform, step 2) is then added and is formed by solution B, then
Vitamin E 0.03g is added, stirring is to forming uniform milky dispersion liquid；
4) dispersion liquid obtained by step 3) be ultrasonically treated 8 minutes, then ultrasonic power 300W uses miillpore filter
Whole grain obtains the luliconazole alcohol plastid.It is 197.35nm that laser particle size analyzer, which measures alcohol plastid grain size, and encapsulation rate is
75.36%.
Embodiment 2
1) luliconazole powder 0.1g and lecithin 0.3g are weighed, is completely dissolved, is stirred evenly with suitable chloroform
After obtain solution A；
2) 3ml absolute ethyl alcohols and the mixing of 4ml water are measured, solution B is formed；
3) the solution A evaporation obtained by step 1) is removed into chloroform, step 2) is then added and is formed by solution B, then
Vitamin E 0.05g is added, stirring is to forming uniform milky dispersion liquid；
4) dispersion liquid obtained by step 3) be ultrasonically treated 5 minutes, then ultrasonic power 280W uses miillpore filter
Whole grain obtains the luliconazole alcohol plastid.It is 199.85nm that laser particle size analyzer, which measures alcohol plastid grain size, and encapsulation rate is
74.51%.
Embodiment 3
1) luliconazole powder 0.1g and lecithin 0.8g are weighed, is completely dissolved, is stirred evenly with suitable chloroform
After obtain solution A；
2) 8ml absolute ethyl alcohols and the mixing of 9ml water are measured, solution B is formed；
3) the solution A evaporation obtained by step 1) is removed into chloroform, step 2) is then added and is formed by solution B, then
Vitamin E 0.01g is added, stirring is to forming uniform milky dispersion liquid；
4) dispersion liquid obtained by step 3) be ultrasonically treated 10 minutes, then ultrasonic power 320W is filtered with micropore
Film whole grain obtains the luliconazole alcohol plastid.It is 199.91nm, encapsulation rate that laser particle size analyzer, which measures alcohol plastid grain size,
It is 74.47%.
Embodiment 4
1) luliconazole powder 0.1g and lecithin 0.4g are weighed, is completely dissolved, is stirred evenly with suitable chloroform
After obtain solution A；
2) 6ml absolute ethyl alcohols and the mixing of 7ml water are measured, solution B is formed；
3) the solution A evaporation obtained by step 1) is removed into chloroform, step 2) is then added and is formed by solution B, then
Vitamin E 0.02g is added, stirring is to forming uniform milky dispersion liquid；
4) dispersion liquid obtained by step 3) be ultrasonically treated 7 minutes, then ultrasonic power 310W uses miillpore filter
Whole grain obtains the luliconazole alcohol plastid.It is 198.83nm that laser particle size analyzer, which measures alcohol plastid grain size, and encapsulation rate is
74.53%.
Comparative example
1) luliconazole powder 0.1g and lecithin 0.5g are weighed, is completely dissolved, is stirred evenly with suitable chloroform
After obtain solution A；
2) 4.5ml absolute ethyl alcohols and 5.5ml water are measured, solution B is mixed to form；
3) the solution A evaporation obtained by step 1) is removed into chloroform, step 2) is then added and is formed by solution B, stirs
It mixes to the uniform milky dispersion liquid of formation；
4) dispersion liquid obtained by step 3) be ultrasonically treated 8 minutes, then ultrasonic power 300W uses miillpore filter
Whole grain obtains the luliconazole alcohol plastid.It is 267.95nm that laser particle size analyzer, which measures alcohol plastid grain size, and encapsulation rate is
69.43%.
Test example 1, stability test
This test example has investigated the stability test of luliconazole alcohol plastid made from the present invention and comparative example.
1, illumination experiment
A collection of luliconazole alcohol plastid is continuously prepared according to embodiment 1 and the method for comparative example respectively, is taken respectively prepared
Same batch luliconazole alcohol plastid, be separately added into 10ml volumetric flasks, sealed membrane sealing.It is placed under clarity detecting apparatus and carries out
Illumination experiment measured medicament contg (mg) with HPLC methods, and observes cosmetic variation situation on the 10th day at the 0th day, the 5th day.As a result
It is shown in Table 1：
Assay after table 1, luliconazole alcohol plastid illumination experiment (n=5,)
2, high temperature is tested
A collection of luliconazole alcohol plastid is continuously prepared according to embodiment 1 and the method for comparative example respectively, is taken respectively prepared
Same batch luliconazole alcohol plastid, be separately added into 10ml volumetric flasks, sealed membrane sealing.It is placed in insulating box and carries out 60 DEG C of height
Temperature experiment measured medicament contg (mg) with HPLC methods, and observes cosmetic variation situation on the 10th day at the 0th day, the 5th day.As a result see
Table 2：
Assay after table 2, luliconazole alcohol plastid illumination experiment (n=5,)
From above-mentioned experimental result can be seen that the present invention be added to luliconazole alcohol plastid made from vitamin E in light
According to and high temperature experiment under still be milky suspension, consistency is suitable, and stretchability is good, and be evenly distributed exquisiteness.It can be seen that its alcohol plastid
Stability is preferable.
Above-mentioned experiment is also carried out to the luliconazole alcohol plastid obtained by other embodiments of the present invention, the result obtained
It is similar.
Test example 2
Skin irritation test is to evaluate drug tolerance and an important indicator of safety.This test example has investigated this
Variation of the luliconazole alcohol plastid made from invention and comparative example in erythema test and dermal pathology structure.
1, experiment material
1.1 laboratory apparatus
Microscope (BH2 Japan OLYMPUS)
Hair clipper for children (Panasonic Japan)
1.2 drugs and reagent
Luliconazole alcohol plastid (is prepared Following the procedure of Example 1)
Luliconazole alcohol plastid (made from the method according to comparative example)
1.3 experimental animal
SD rats 4, male, weight 250-300g, (Military Medical Science Institute's Experimental Animal Center, SPF grades, animal is closed
Lattice card number：SCXK- (army) 2012-0004)
2, experimental method and result
2.1 method
Rat is tested into preceding 24 hours back shavings, back is divided into two regions without hair skin, is carried respectively with filter paper
Different pharmaceutical dosage form (luliconazole alcohol plastid made from embodiment 1, luliconazole alcohol plastid made from comparative example) is fixed on mouse
Skin of back.It throws off within 24 hours, is cleaned with warm water, see result within 24,48 hours.Remove within 48 hours the inspection of different zones skin row pathology
It looks into, and normal mice skin of back is taken to compare.
2.2 evaluation method
Every rat back experimental result according to the form below is subjected to stimulate the reaction scoring, calculate mean scores by table 3, table 4 into
Row evaluation.
Table 3, skin wound repair grade form
Table 4, skin wound repair evaluation index
| Intensity | Score value |
| It is nonirritant | 0-0.49 |
| Slight stimulation | 0.5-2.99 |
| Severe irritation | 3.0-5.99 |
| Strong stimulation | >6.0 |
2.3 experimental result
Skin irritatin the results are shown in Table 5 after the administration of the luliconazole alcohol plastid of the present invention and comparative example：
Table 5, skin irritation result
Above-mentioned experiment is also carried out to the luliconazole alcohol plastid obtained by other embodiments of the present invention, the result obtained
It is similar.
The above is only presently preferred embodiments of the present invention, is not intended to limit the present invention in any form, though
So the present invention has been disclosed as a preferred embodiment, and however, it is not intended to limit the invention, the technology people of any familiar present invention
Member without departing from the scope of the present invention, when the technology contents using above-mentioned prompt make it is a little change or be modified to
The equivalent embodiment of equivalent variations, it is right according to the technical essence of the invention as long as being the content without departing from technical solution of the present invention
Any simple modification, equivalent change and modification made by above example, in the range of still falling within the present invention program.
Claims (10)
1. a kind of luliconazole alcohol plastid, composition includes luliconazole, lecithin, absolute ethyl alcohol and water, it is characterised in that：Institute
The luliconazole alcohol plastid stated further includes vitamin E, wherein the mass ratio of the vitamin E and luliconazole be 0.1~
0.5：1, the mass ratio of the luliconazole and lecithin is 1：3~8；The luliconazole alcohol plastid is with the following method
It is prepared：
1）Luliconazole and lecithin are completely dissolved with suitable chloroform, solution A is obtained after stirring evenly；
2）Absolute ethyl alcohol and water are mixed, solution B is formed；
3）By step 1）The solution A evaporation of gained removes chloroform, and step 2 is then added）It is formed by solution B, is added
Vitamin E, stirring is to forming uniform dispersion liquid；
4）By step 3）The dispersion liquid of gained is ultrasonically treated, and miillpore filter whole grain is then used, and obtains the luliconazole
Alcohol plastid.
2. luliconazole alcohol plastid according to claim 1, it is characterised in that：The vitamin E and luliconazole
Mass ratio is 0.3：1.
3. luliconazole alcohol plastid according to claim 1, it is characterised in that：The matter of the luliconazole and lecithin
Amount is than being 1：5.
4. according to the luliconazole alcohol plastid described in claim 1-3 any one, it is characterised in that：The luliconazole with
The mass volume ratio of water is 1g：3~8ml.
5. luliconazole alcohol plastid according to claim 4, it is characterised in that：The mass body of the luliconazole and water
Product is than being 1g：5.5ml.
6. according to the luliconazole alcohol plastid described in claim 1-3 any one, it is characterised in that：The absolute ethyl alcohol with
The volume ratio of water is 3~8：4~9.
7. luliconazole alcohol plastid according to claim 6, it is characterised in that：The volume ratio of the absolute ethyl alcohol and water
It is 4.5：5.5.
8. a kind of preparation method of the luliconazole alcohol plastid described in claim 1-7 any one, it is characterised in that：Described
Preparation method includes the following steps：
1）Luliconazole and lecithin are completely dissolved with suitable chloroform, solution A is obtained after stirring evenly；
2）Absolute ethyl alcohol and water are mixed, solution B is formed；
3）By step 1）The solution A evaporation of gained removes chloroform, and step 2 is then added）It is formed by solution B, is added
Vitamin E, stirring is to forming uniform dispersion liquid；
4）By step 3）The dispersion liquid of gained is ultrasonically treated, and miillpore filter whole grain is then used, and obtains the luliconazole
Alcohol plastid.
9. preparation method according to claim 8, it is characterised in that：Step 4）Described in supersound process be ultrasonically treated
5~10 minutes, ultrasonic power was 280~320W.
10. preparation method according to claim 9, it is characterised in that：Step 4）Described in supersound process be ultrasound at
Reason 8 minutes, ultrasonic power 300W.
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Effective date of registration: 20171204 Address after: 100853 General Hospital of PLA, Fuxing Road, Beijing, Haidian District 28, China Applicant after: General Hospital of Chinese PLA Address before: 100853 Department of Dermatology, No. 28, Fuxing Road, Beijing, Department of Dermatology, General Hospital of PLA Applicant before: Lin Biwen |
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