CN103202803B - Imiquimod vesicle gel and preparation method for same - Google Patents
Imiquimod vesicle gel and preparation method for same Download PDFInfo
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- CN103202803B CN103202803B CN201310141128.5A CN201310141128A CN103202803B CN 103202803 B CN103202803 B CN 103202803B CN 201310141128 A CN201310141128 A CN 201310141128A CN 103202803 B CN103202803 B CN 103202803B
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Abstract
The invention relates to an imiquimod vesicle gel and a preparation method for the same. The vesicle gel is obtained by preparing a vesicle suspension by using imiquimod and the nonionic surfactants of Brij, Span, Poloxamer and the like via self-assembly, then reacting with the mixed gel matrix of carbomer and povidone, and used for treating the diseases of exophytic genital warts, actinic keratosis, skin basal cancer, melanoma and the like via local application on the skin; and by adding povidone in the carbomer gel matrix, the in-vitro medicine release amount can be increased by 42.1%, thus being beneficial to promote the entrance of medicines in the skin to exert the functions. According to the imiquimod vesicle gel and the preparation method for the same disclosed by the invention, the intradermal retention volume of the medicines in 24 hours can be remarkably increased and is 2.1 times that of the commercially available emulsifiable pastes, and the dose of the medicines penetrating through the skin is reduced by 48.7%; and the equivalent intradermal retention volume can be achieved only by a half of the dose of the commercially available emulsifiable pastes, so that the effectiveness of the medicine effect of the medicated parts can be remarkably enhanced, the dose of the medicines entering in the body can be greatly reduced, and the toxic and side effects of the whole body can be reduced.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of medicine vesicle gel and preparation method thereof.
Background technology
Imiquimod (Imiquimod, S-26308 or R-837), chemistry 1-(2-methyl-propyl)-1H-imidazo [4 by name, 5-C] quinolin-4-amines, it is a kind of non-nucleoside different ring imidazole quinoline amine drug, for white or off-white color crystalline powder, odorless, tasteless, almost insoluble or insoluble in water or ether, dissolve atomic in ethanol, methanol or acetone, dissolve in glacial acetic acid, slightly soluble in 0.1mol/L hydrochloric acid solution, almost insoluble or insoluble in 0.1mol/L sodium hydroxide solution.Imiquimod is the external Novel immune regulating drug for the treatment of external genitalia wart at first, plays immunoregulation effect mainly through induction body produces the cytokines such as interferon (IFN), tumor necrosis factor (TNF), interleukin (IL).
The imiquimod dosage form of current listing has the external preparation such as cream and 5%, 3.75% emulsifiable paste, is mainly used in treating external genitalia and the dermatosis such as crissum condyloma acuminatum, actinic keratosis, basal cancer and melanoma that human papilloma virus infection causes.Imiquimod external preparation is easy to use, dosage is controlled, compared with the methods such as excision, cold therapy, chemotherapy, and the advantages such as have skin histology destructiveness little, good effect, relapse rate is low, and compliance is good.But, current clinical preparation is low at the drug level at dermatologic position, and dosage is large, considerable part Drug Percutaneous Absorption enters in body, thus there is the local toxic and side effects such as pruritus, erythema, burn feeling, tenderness, ulcer, erosion, pain, and accidentally have the system untoward reaction such as fatigue, heating, influenza-like symptom, headache, diarrhoea and myalgia, thus limit the clinical practice of imiquimod.
Vesicle be non-ionic surface active agent (can alone, share, or coordinate other lipid to use), self assembly formation in the solution, similar, in biomembranous Novel Drug Delivery Systems, have good histocompatibility and cellular affinity.Its structure, composition and inside and outside character are similar to liposome, hydrophilic core and hydrophobic lipid bilayer to hydrophilic medicament, hydrophobic drug even insoluble drug all can wrap and carry, and owing to not containing oxidizable rotten phospholipid in its structure composition, and more stable than liposome, be the very promising Novel Drug Delivery Systems of a class.
Keratodermatitis is the important protective barrier of body, and medicine is directly applied almost can not be through.Be difficult to after the drugs through skin of ordinary preparation be detained in skin and enter in body, often through increase dose to maintain effective local concentration, thus bring general toxicity.And after medicine is made vesicle, because of good biocompatibility, and be easy to enter skin, and drug depot can be formed at Intradermal, and then continue, to site of action release medicine, to there is slow releasing function, the bioavailability of medicine can be increased, improve curative effect, also can reduce the dose entering whole body, reduce the toxicity of medicine.Further, as vesicle particle diameter < 300nm, vesicle is easier to enter skin through horny layer.But vesicle suspension, to the poor adherence of skin, directly uses, and medicine easily runs off.
Gel is that medicine mixes with carbomer (CP), polyvidone (PVP), hydroxypropyl methylcellulose isogel substrate, the glop made or semi-solid preparation, is widely used in delaying, the Novel Drug Delivery Systems such as controlled release and pulse release.Gel is used for local skin treatment, can be closely adhered to skin surface, have good biocompatibility, medicine easily absorbs, and its macromole is wound around and produces slow releasing function to drug molecule, and drug treating time is extended, improve curative effect, and not pollution clothes, good stability.But gel can not form drug depot in skin, be thus difficult to increase local drug concentration in skin.By the vesicle gel that gel-type vehicle and medicine carrying vesicle are mixed, the cohesiveness of gel can be utilized, avoid vesicle in use from skin surface landing, but the winding of its macromole enters skin obstruction to vesicle will be overcome as far as possible.
Summary of the invention
The present invention is directed to the deficiency that existing external preparation exists in the treatment of clinic skin disease, a kind of imiquimod vesicle gel being different from ordinary preparation is provided, it can form drug depot in skin, thus increases the drug level of local skin, reduces the dose entered through skin in body.The present invention also provides the preparation method of this vesicle gel.
For achieving the above object, the present invention adopts following technical scheme:
Imiquimod vesicle gel of the present invention wraps the vesicle suspension carrying imiquimod, be prepared from gel-type vehicle, every gram of this vesicle gel comprises: imiquimod 1 ~ 100mg, prepare the surfactant 5 ~ 200mg of vesicle, gel matrix material 10 ~ 120mg, triethanolamine 1 ~ 80mg, buffer solution is appropriate.
Wherein, described prepare vesicle surfactant comprise 1.5 ~ 20mg polyoxyethylene fatty acid ethers, 2 ~ 40mg polyoxyethylene polyoxypropylene class and 1.5 ~ 180mg be selected from the smooth class of fatty acid Pyrusussuriensis, Polysorbate apoplexy due to endogenous wind one or more.
Wherein, described polyoxyethylene aliphatic alcohol ether class is selected from osmanthus base alcohol polyoxyethylene 23 months ethers (Brij30), spermol polyoxyethylene 2 ether (Brij52), stearyl alcohol polyoxyethylene 2 ether (Brij72), stearyl alcohol polyoxyethylene 20 (Brij78); Described polyoxyethylene polyoxypropylene class is selected from Poloxamer124, Poloxamer188, Poloxamer237, Poloxamer407; The smooth class of described fatty acid Pyrusussuriensis is selected from mono laurate Pyrusussuriensis smooth (Span20), single Palmic acid Pyrusussuriensis smooth (Span40), monostearate Pyrusussuriensis smooth (Span60), sorbitan monooleate (Span80), Sorbitan Trioleate (Span85); Described poly yamanashi esters is selected from polyoxyethylene 20 sorbitan monolaurate (Tween20), polyoxyethylene 20 sorbitan monopalmitate (Tween40), polyoxyethylene 20 sorbitan monostearate (Tween60), polyoxyethylene 20 sorbitan monooleate (Tween80), the smooth trioleate of polyoxyethylene 20 Pyrusussuriensis (Tween85).
Wherein, described gel matrix material comprises 2.5 ~ 40mg carbomer (CP), 2.5 ~ 80mg polyvidone (PVP) and 5 ~ 20mg cellulose derivative.Described carbomer be selected from CP934, CP940, CP941 or CP980 one or more; Described polyvidone be selected from PVP K25, PVP K30, PVP K60 or PVP K90 one or more; Described cellulose derivative be selected from hyprolose, hyetellose, hypromellose or hymetellose one or more.
The present invention also provides the preparation method of described medicine vesicle gel further, and it comprises the steps:
The first step: prepare vesicle
By the described surfactant preparing vesicle of recipe quantity, with appropriate organic solvent dissolution completely after, ultrasonic with the medicament mixed of recipe quantity, then adopt injection method or film dispersion method and buffer solution mixing and emulsifying, after stirring volatile organic solvent, obtain medicine vesicle suspension;
Second step: prepare vesicle gel
Get the gel matrix material of recipe quantity respectively, add suitable quantity of water, placement makes fully swelling, then adjusts pH5 ~ 9 with appropriate triethanolamine, grind well, obtain gel-type vehicle, medicine vesicle suspension is added in gel-type vehicle, finally add buffer solution to recipe quantity, fully grind well, obtain medicine vesicle gel.
Wherein, described organic solvent be selected from methanol, ethanol, isopropyl alcohol, ethyl acetate, acetone or chloroform one or more.
Wherein, described buffer solution be selected from the borate buffer solution of pH3.6 ~ 9.5, phosphate buffer, carbonate buffer solution or citrate buffer one or more.
After the surfactants such as medicine elder generation and polyoxyethylene fatty acid ethers are made vesicle by the present invention, the gel-type vehicle jointly made with carbomer and polyvidone etc. is again mixed with and forms, applied by local skin, medicine can be strengthened be detained in the skin at medicine position, thus heighten the effect of a treatment, reduce toxic and side effects.
In vesicle gel of the present invention, vesicle particle diameter, gel-type vehicle all have impact to the effect that medicine enters skin.Surfactant (HLB value 1.8 ~ 30 in vesicle prescription, more little more lipophilic, more large more hydrophilic) selection, after use amphipathic property all preferably Brij, can promote that oil loving Span and hydrophilic Poloxamer forms being mutually fitted together in vesicle process in self assembly, be beneficial to and form less emulsion droplet in high-speed stirred emulsion process, and then the little and vesicle of good dispersion of obtained particle diameter.Therefore the obtained vesicle particle diameter of this patent is at about 200nm, and is conducive to vesicle and enters skin.
Gel-type vehicle adopts CP and PVP mixture, more alone CP's, interference preparation of Chinese medicine being entered to skin is few, can increase the cohesiveness of medicine and improve the speed that medicine carrying vesicle enters skin, and then improve the action character of medicine, there is significant slow releasing function in vitro.Permeation test in vitro shows, compared with commercially available emulsifiable paste, gel, the hold-up of vesicle gel energy significantly increasing medicament of the present invention in animal skins, have and impel medicine in site of action enrichment, and the feature reduced through skin dose, it is conducive to reducing the drug effect beyond medication local, thus reduces toxic and side effects, significantly can improve the deficiency of existing preparation, high-efficiency low-toxicity treatment Related Skin Diseases.
Accompanying drawing explanation
Fig. 1 is the medicine carrying vesicle aspect graph (× 400) of observation by light microscope;
Fig. 2 is the grain size distribution of medicine carrying vesicle;
Fig. 3 is the drug release patterns in vitro (n=3) of the vesicle gel prepared by different gel-type vehicle;
Fig. 4 is the drug release patterns in vitro (n=3) of vesicle gel and control formulation;
Fig. 5 is the transdermal dose of accumulation (n=3) of vesicle gel and control formulation Chinese medicine;
Fig. 6 is different time vesicle gel and the hold-up of control formulation Chinese medicine in skin (n=3).
Detailed description of the invention
Following examples are used for further illustrating the present invention, but should not be construed as limitation of the present invention.
The preparation process of the vesicle suspension in vesicle gel of the present invention, first non-ionic surface active agent is dissolved in organic solvent, add the medicine of recipe quantity again, after ultrasonic, adopt injection method to be introduced in organic facies by aqueous phase (buffer solution) to mix, form vesicle suspension by self assembly mode, then mix with the gel-type vehicle for preparing in advance.The imiquimod of vesicle suspension package-contained prepared by the present invention is insoluble drug.Through comparing discovery to part investigation project: the preparation method of medicine carrying vesicle of the present invention, does not have particular requirement to model drug, can adopt same prescription, same preparation method, bag carries medicine of different nature, as retinoic acid, 5-Fu.Obtained vesicle suspension can make vesicle gel further.
The preparation process of the gel-type vehicle in vesicle gel of the present invention, be first host material is added water fully swelling, then regulate pH make formation gel-type vehicle.Its material adopts CP and PVP, also can select to add hypromellose used in combination, be prepared into suitable gel-type vehicle by adjustment ratio.
Embodiment 1:
1, the preparation of imiquimod vesicle suspension
Getting recipe quantity 10mg Brij78(HLB value is respectively 15.3), 10mg Span85(HLB value is 1.8), 20mg Span40(HLB value is 6.7), 20mg Poloxamer188(HLB value is 29) in cillin bottle, add organic solvent, stir (2000r/min) at 60 DEG C of water bath condition lower magnetic forces to make to dissolve completely, add 10mg imiquimod (≤80 order), after stirring, in 60 DEG C of water-baths, ultrasonic 3min, obtains organic facies.The PBS(pH7.3 in 60 DEG C will be incubated in advance under stirring) pour airtight stirring 10min in organic facies fast into, then be transferred in 37 DEG C of water-baths, open wide at 2000r/min and stir 3h, fling to ethanol and ethyl acetate, obtain imiquimod vesicle suspension (being called for short: vesicle suspension).
Adopt same preparation method, do not add medicine, obtained blank vesicle suspension, for preparation control formulation.
2, the preparation of imiquimod vesicle gel
Get recipe quantity 15mg CP940,15mg PVP K30 respectively, respectively add water appropriate, place make fully swelling after, with triethanolamine, CP solution is adjusted to pH5 ~ 9, then adds PVP solution and grind well, obtain gel-type vehicle.The vesicle suspension made is added in gel-type vehicle, finally adds buffer solution to recipe quantity, fully grind well, obtain fine and smooth uniform milky semi-solid, be i.e. imiquimod vesicle gel (content 0.33%, pH7.2 is called for short: vesicle gel).
Adopt same sample preparation method, but recipe quantity medicine is suspended in fully swelling PVP solution, mix with the PVP mixing up pH, add blank vesicle suspension again, (medicine does not carry with vesicle bag the imiquimod gel of the blank formulation dosing of obtained same content, but completely the same with the component of imiquimod vesicle gel, be called for short: gel), for comparison.
3, the morphologic observation of imiquimod vesicle
Prepare three batches of vesicle suspensions, dip with glass rod and be evenly coated with exhibition on microscope slide, observe under optical microscope (× 400), result: each batch of vesicle is tiny and even, sees Fig. 1.
4, the mean diameter of vesicle and surperficial Zeta potential measure
Prepare three batches of vesicle suspensions, measure its mean diameter and surface potential with particle diameter potentiometric analyzer, result is as table 1.Grain size distribution, is shown in Fig. 2.
From table 1, Fig. 2, the mean diameter of imiquimod vesicle suspension is (197.2 ± 4.6) nm, and particle size distribution comparatively evenly (polydispersity index PDI is less), is not easily assembled with surface potential.
5, the entrapment efficiency determination of imiquimod vesicle
Adopt polydextran gel (G50) chromatography.Take two parts of a certain amount of imiquimod vesicle suspensions (about containing imiquimod 1mg), a copy of it loading, excessively post, with distilled water with 1.0ml/min speed eluting, the follicular eluent 4 ~ 6ml of collecting belt, the vesicle collected in liquid is destroyed with 5% hydrochloric acid-isopropyl alcohol (v/v=1:1), measure absorbance in 320nm place, calculate to obtain the dose m that carries of vesicle bag
1; Another part does not cross the imiquimod vesicle suspension of post, carries out same process and destroys vesicle and measure, obtain total dose m
2.By formula: EE%=(m
1/ m
2) × 100%, computational envelope rate, obtaining envelop rate meansigma methods is 20.4 ~ 60.4%.
6, the screening of gel-type vehicle
With synthetic membrane method tablets in vitro amount for index, vesicle gel prepared by gel-type vehicle is jointly made by CP and PVP by investigating, in the vesicle gel made with CP gel-type vehicle, (namely little on drug-eluting impact) that drug release is many, is defined as gel-type vehicle of the present invention.
Adopt the vertical glass diffusion cell of TK-6A type percutaneous dispersion test instrument, volume is 7.2ml, and diffusion area is 2.46cm
2, be placed in by dialyzer between diffusion cell and reception tank, reception solvent is 0.9% normal saline-isopropyl alcohol=1:1(pH7.4), percutaneous dispersion test instrument temperature is (32.0 ± 0.5) DEG C, and magnetic agitation rotating speed is 300r/min.Get every part of suitable imiquimod 1mg of gel 0.3g() uniform application is on hemodialysis's film, and every part of parallel assay three times, draws receiving liquid 3.0ml respectively at 0.5,1,2,4,6 and 12h, supplements 3.0ml simultaneously and receive solvent in acceptance pool.Measure with ultraviolet visible spectrophotometry, calculate 12h Percutaneous permeability Q, draw Q-t curve, the results are shown in Figure 3.
As shown in Figure 3, after 12h, the tablets in vitro of the vesicle gel of CP and PVP mixed gel substrate, the vesicle gel of CP gel-type vehicle all tends towards stability, the former cumulative release amount is 27%, and the latter's is 19%, after showing to add PVP in CP, can increase by the drug release of 42.1%, that is adding of PVP can reduce the interference of gel to drug release, therefore determine to adopt CP, PVP jointly as gel matrix material of the present invention.
7, extracorporeal releasing test (artificial embrane method)
With commercially available imiquimod cream (commercially available emulsifiable paste), blank vesicle gel dosing (gel), imiquimod vesicle suspension (vesicle suspension) for matched group, investigate the release in vitro of imiquimod vesicle gel (vesicle gel).The each group of preparation containing equivalent medicine is applied on hemodialysis's film, uses percutaneous dispersion test instrument, investigate the release behaviour in vitro of medicine carrying vesicle gel.(32 ± 0.5) DEG C of temperature States Pharmacopoeia specifications, adopt reception solvent, magnetic agitation rotating speed, the every part of sample size in the same " 6 ", and sample time, sample volume, reception solvent make-up and assay method, obtain the preparation of different time medicine.When discharging 12h, although the cumulative release <30% of vesicle gel, matched group discharges >90%, therefore stops experiment at 12h.Drug release patterns in vitro is shown in Fig. 4; 12h cumulative in vitro medicine realeasing rate and by release Equation for Calculating release t1/2 in table 2.
Table 2 cumulative in vitro medicine realeasing rate and release t1/2
As shown in Table 2, vesicle gel tablets in vitro t1/2 similar to vesicle suspension (1.06 times for the latter), being 4.94 times of gel, is 3.83 times of commercially available emulsifiable paste, and slow releasing function Be very effective of the present invention is described.
8, the penetrating absorption of rat skin in vitro
With commercially available imiquimod cream (commercially available emulsifiable paste), blank vesicle gel dosing (gel) for matched group, investigate imiquimod vesicle gel (vesicle gel) the medicine transmission characteristic in Animal skin.Get SD rat (body weight 150 ~ 200g, male), with after the hair on electric shaver removing skin of back after execution, peel off skin, reject subcutaneous fat and tissue, use normal saline rinsed clean.Be fixed on by skin on diffusion cell, stratum corneum side, to giving coyote hole, takes 0.1g vesicle gel and identical gel, the commercially available emulsifiable paste of content of dispersion, is spread evenly across skin surface respectively; Fill it up with reception solvent in acceptance pool: phosphate buffered solution (pH5.8), aerofluxus makes liquid level and skin close contact, temperature (37 ± 0.5) DEG C, rotating speed 400rpm.Stop respectively at 4,8,12 and 24h, under bark fetching, receiving liquid crosses 0.22 μm of filter membrane, and HPLC measures and calculates each time point accumulation agent permeates therethrough amount, obtains accumulating transdermal dose curve (see figure 5).And left drug on skin is clean with normal saline eccysis, collect eluent, destroy vesicle with 5% hydrochloric acid-isopropyl alcohol (v/v=1:1), filter, get filtrate mensuration, calculate left drug amount on skin.And the skin contacted with preparation is cut, centrifugal after adding normal saline homogenate, get 0.2ml and add 5% hydrochloric acid-isopropyl alcohol (v/v=1:1) to 2ml, cross 0.22 μm of filter membrane, HPLC measures and the hold-up (see figure 6) of unit of account area intradermal drug.
As shown in Figure 5, in the vesicle gel of 24h and gel, commercially available emulsifiable paste, the accumulation that drugs through skin enters receiving liquid is respectively through dose: (8.07 ± 0.93), (15.77 ± 1.35), (14.92 ± 1.60) μ g, that is: vesicle gel makes the dose entering receiving liquid through skin reduce 45.8% than gel, reduces 48.7% than commercially available emulsifiable paste.The transmitance of vesicle gel medicine, significantly lower than matched group, is 1.85 times of gel, is 1.95 times of commercially available emulsifiable paste, adopts SPSS17.0 software to carry out t inspection, all there is significant difference (P<0.05).
As shown in Figure 6, the intradermal drug hold-up of 24h unit are, vesicle gel is (36.4 ± 1.1) μ g/cm
2, be significantly greater than (20.1 ± 3.2) μ g/cm of gel
2and (17.1 ± 3.2) μ g/cm of commercially available emulsifiable paste (P<0.01)
2(P<0.01).That is: the Intradermal hold-up of 24h vesicle gel is 1.8 times of gel, is 2.1 times of commercially available emulsifiable paste.Even if when 4h, the unit are intradermal drug hold-up of vesicle gel, is also respectively 1.4 times of gel and 1.9 times of commercially available emulsifiable paste.Show the Be very effective that vesicle gel of the present invention improves drug transdermal characteristic, can impel drug accumulation in skin, and reduce through dose, be conducive to the local therapeutic effects strengthening medicine, reduce general toxicity.In addition, if reach same Intradermal hold-up, vesicle gel only needs the dose of commercially available emulsifiable paste half (47.2% ~ 51.3%), and now transdermal dose will be less, and the reduction for toxic and side effects will advantageously.
Claims (1)
1. an imiquimod vesicle gel, is characterized in that, prepares by the following method and obtains:
1), the preparation of imiquimod vesicle suspension:
Get recipe quantity 10mg Brij78 respectively, HLB value is 15.3,10mg Span85, HLB value is 1.8,20mg Span40, and HLB value is 6.7,20mg Poloxamer188, and HLB value is 29 in cillin bottle, add organic solvent, stir 2000r/min at 60 DEG C of water bath condition lower magnetic forces to make to dissolve completely, add 10mg ,≤80 order imiquimods, after stirring, in 60 DEG C of water-baths, ultrasonic 3min, obtains organic facies; The PBS in 60 DEG C will be incubated in advance, pH7.3 under stirring, pour airtight stirring 10min in organic facies fast into, be then transferred in 37 DEG C of water-baths, open wide at 2000r/min and stir 3h, fling to ethanol and ethyl acetate, obtain imiquimod vesicle suspension;
2), the preparation of imiquimod vesicle gel:
Get recipe quantity 15mg CP940,15mg PVP K30 respectively, respectively add water appropriate, place make fully swelling after, with triethanolamine, CP solution is adjusted to pH5 ~ 9, then adds PVP solution and grind well, obtain gel-type vehicle; The vesicle suspension made is added in gel-type vehicle, finally adds buffer solution to recipe quantity, fully grind well, obtain fine and smooth uniform milky semi-solid, i.e. imiquimod vesicle gel.
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| CN112438944B (en) * | 2019-09-03 | 2024-07-02 | 苏州百迈生物医药有限公司 | Temperature-sensitive gel pharmaceutical composition for treating tumors |
| CN110559257A (en) * | 2019-09-19 | 2019-12-13 | 湖北科益药业股份有限公司 | Imiquimod vesicle gel and preparation method thereof |
| CN110917345B (en) * | 2019-09-26 | 2021-11-09 | 苏州百迈生物医药有限公司 | Chemotherapy immune combined medicine and preparation method thereof |
| CN116710073A (en) * | 2020-12-30 | 2023-09-05 | 苏州百迈生物医药有限公司 | Self-sustained-release immunoadjuvant suspension, preparation method and application thereof |
| CN114010592B (en) * | 2021-11-05 | 2024-02-06 | 苏州百迈生物医药有限公司 | Imiquimod suspension preparation capable of being injected in tumor or around tumor as well as preparation method and application thereof |
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| CN1923170A (en) * | 2006-10-11 | 2007-03-07 | 北京科信必成医药科技发展有限公司 | Imiquimod turbid liquor and gelling agent thereof |
| CN101756886A (en) * | 2010-02-09 | 2010-06-30 | 华中师范大学 | Imiquimod micro emulsion gels for local skin and preparation method thereof |
| CN101919808A (en) * | 2010-08-19 | 2010-12-22 | 苏州大学 | Topical fluorouracil vesicle gel and preparation method thereof |
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| CN1377648A (en) * | 2002-04-23 | 2002-11-06 | 四川大学 | Imiquimod or its derivative liposome for local skin and its preparing method and use |
| CN1923170A (en) * | 2006-10-11 | 2007-03-07 | 北京科信必成医药科技发展有限公司 | Imiquimod turbid liquor and gelling agent thereof |
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