CN101756886A - Imiquimod micro emulsion gels for local skin and preparation method thereof - Google Patents
Imiquimod micro emulsion gels for local skin and preparation method thereof Download PDFInfo
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- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 229960002751 imiquimod Drugs 0.000 title claims abstract description 76
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
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- IJCWFDPJFXGQBN-UHFFFAOYSA-N 2-[4-Hydroxy-3-(octadecanoyloxy)oxolan-2-yl]-2-(octadecanoyloxy)ethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)C1OCC(O)C1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-UHFFFAOYSA-N 0.000 description 2
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- NWGKJDSIEKMTRX-MDZDMXLPSA-N Sorbitan oleate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(O)C1OCC(O)C1O NWGKJDSIEKMTRX-MDZDMXLPSA-N 0.000 description 2
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Abstract
局部皮肤用咪喹莫特微乳凝胶剂，按质量百分比计，至少包括0.1～2.5％的咪喹莫特，1～24％的溶剂，1～16％的表面活性剂，1～12％的助表面活性剂，1～20％的胶凝剂，其余为水。其中咪喹莫特为1-异丁基-1H-咪唑[4，5-C]喹啉-4-胺。其制法是：将咪喹莫特溶解在溶剂中；将表面活性剂、助表面活性剂加入到溶解了咪喹莫特的溶剂中，分散均匀；加适量水形成微乳液；另用水将胶凝剂溶胀，配制成一定浓度的溶液，将此胶凝剂溶液逐滴加入到上述咪喹莫特微乳液，边加边搅拌，加三乙醇胺调节pH值，制成咪喹莫特微乳凝胶剂。本发明的优点：集中了微乳对药物的彻底分散性，凝胶对皮肤的粘合性、在外力作用下的变形流动性，使药物能理想地均匀涂于患处。顺利经皮进入体内到达靶点，持续发挥药效。
Imiquimod microemulsion gel for local skin, by mass percentage, at least includes 0.1-2.5% imiquimod, 1-24% solvent, 1-16% surfactant, 1-12% co-surfactant, 1-20% gelling agent, and the rest is water. Wherein imiquimod is 1-isobutyl-1H-imidazo[4,5-C]quinolin-4-amine. The preparation method is: dissolving imiquimod in a solvent; adding surfactant and co-surfactant into the solvent in which imiquimod is dissolved, and dispersing evenly; adding an appropriate amount of water to form a microemulsion; The coagulant is swelled and prepared into a solution with a certain concentration, and the gelling agent solution is added dropwise to the above-mentioned imiquimod microemulsion, stirred while adding, and triethanolamine is added to adjust the pH value to prepare the imiquimod microemulsion Glue. The invention has the advantages of the complete dispersibility of the microemulsion to the medicine, the adhesiveness of the gel to the skin, and the deformation fluidity under the action of external force, so that the medicine can be ideally evenly applied to the affected part. Smoothly enter the body through the skin to reach the target, and continue to exert the drug effect.
Description
Technical field:
The present invention relates to local skin administration micro emulsion gels and preparation method thereof, belong to the preparation for external application to skin field.
Background technology:
Imiquimod, chemistry is by name: 1-isobutyl group-1H-imidazoles [4,5-C] quinoline-4-amine, it is an immunomodulator, also is interferon inducers.Riker Labs by the U.S. develops at first, and 3M company and Japanese first drugmaker are transferred the possession of in the back.The new drug application of 3M company proposition in 1997 is by drugs approved by FDA, and go on the market in the U.S. October, and traded commodity is called Aldara, is 5% imiquimod cream of 250mg unit dose package, is used for the treatment of viral infection, herpes-ness progenitalis infection and genital wart.The side effect that takes place during this medicine uses is to produce erythema, toxigenicity when high dose.Report imiquimod as antiviral agent and interferon inducers at U.S.Pat No 4,689,338, and introduced the multiple dosage form of this chemical compound topical.In EP.0 376 534 A1, mainly introduced imiquimod and directly made through skin administration medicament, comprise ointment, ointment, patches etc., the weak point of above-mentioned dosage form are that the storage dose of local skin is few, and Transdermal absorption amount height causes whole body to absorb the side effect that brings.
Summary of the invention:
Purpose of the present invention is intended to overcome above-mentioned the deficiencies in the prior art part, and a kind of local skin imiquimod microemulsion gel and preparation method thereof is provided.More above-mentioned preparation, microemulsion can increase its content in substrate, help transdermal penetration.Improve drug effect, reduce transdermal amount and whole body and absorb the side effect that brings.Reduce transdermal amount and whole body and absorb the side effect that brings.
The present invention is insoluble in common organic solvents at imiquimod, easily be dissolved in the fat-soluble solvents such as oleic acid, isostearic acid, be made into microemulsion, the medicine dispersion package is in the emulsion droplet of particle diameter less than 100nm, and the particle diameter of the drug molecule aggregation in the usual cream agent is greater than 1000 μ m, so microemulsion helps percutaneous penetration of drugs, improve drug effect.In gel, can make microemulsion form thin film at skin surface the microemulsion redispersion, similar shape becomes drug depot, makes to keep long drug osmotic.And good with skin-friendliness, be easy to coating.To increase the local skin dose, reduce transdermal amount and whole body and absorb the side effect that brings.
Realize that the technical scheme that the object of the invention adopted is: a kind of imiquimod micro emulsion gels by mass percentage, this imiquimod micro emulsion gels comprises 0.1～2.5% imiquimod at least, 1～24% solvent, 1～16% surfactant, 1～12% cosurfactant, 1～35% gellant, 0.01～5% triethanolamine, all the other are water; Wherein imiquimod is 1-isobutyl group-1H-imidazoles [4,5-C] quinoline-4-amine; Solvent is one or more the mixture in oleic acid, isostearic acid, isopropyl myristate, the fatty acid methyl ester; Surfactant is one or more the mixture in polysorbas20, tween 21, polysorbate40, polysorbate60, tween 61, polysorbate65, Tween 80, sorbimacrogol oleate100, polysorbate85, span 20, span 40, sorbester p18, sorbester p38, sorbester p17, span 83, sorbester p37, the castor oil polyoxyethylene ether; Gellant is one or more the mixture in husky female, the cross-linking sodium carboxymethyl cellulose of carbomer, gelatin, pool Lip river; Cosurfactant is a kind of or or the two or more mixture in isopropyl alcohol, ethanol, propylene glycol, the glycerol.
The preparation method of described imiquimod micro emulsion gel may further comprise the steps:
1) take by weighing 0.1～2.5% imiquimod by weight percentage, 1～24% solvent, 1～16% surfactant, 1～12% cosurfactant, 0.1～35% gellant, 0.01～5% triethanolamine, all the other are water; Wherein said imiquimod is 1-isobutyl group-1H-imidazoles [4,5-C] quinoline-4-amine; Solvent is one or more the mixture in oleic acid, isostearic acid, isopropyl myristate, the fatty acid methyl ester; Surfactant is one or more the mixture in polysorbas20, tween 21, polysorbate40, polysorbate60, tween 61, polysorbate65, Tween 80, sorbimacrogol oleate100, polysorbate85, span 20, span 40, sorbester p18, sorbester p38, sorbester p17, span 83, sorbester p37, the castor oil polyoxyethylene ether; Gellant is carbomer, gelatin, the husky mother in pool Lip river, the mixture of one or more in the cross-linking sodium carboxymethyl cellulose; Cosurfactant is one or more the mixture in isopropyl alcohol, ethanol, propylene glycol, the glycerol;
2) imiquimod is dissolved in the solvent;
3) surfactant, cosurfactant are joined in the above-mentioned solvent that dissolves imiquimod, add water and be prepared into Water-In-Oil and water oil-packaging type micro-emulsion liquid;
4) water is mixed with solution with the gellant swelling;
5) above-mentioned gellant solution is dropwise added in the imiquimod microemulsion of step 3), the limit edged stirs, and adds triethanolamine, regulates pH value; Obtain milky gel (oil-water type microemulsion) or colorless transparent gel (oil-water type microemulsion) at last.
The experiment in vitro result of study shows. (see Table 1 and accompanying drawing 1, accompanying drawing 2): compare with micro emulsion gel for preparing with this microemulsion and commercial emulsifiable paste with the imiquimod microemulsion that the prescription of the imiquimod microemulsion among the embodiment 6 prepares, percutaneous accumulation infiltration capacity is carried out regression treatment to time of penetration, and regression equation sees Table 1 and Fig. 1.Transdermal penetration speed＞micro emulsion gel＞the emulsifiable paste that shows microemulsion.Fig. 2 shows the cortex content of imiquimod micro emulsion gel between emulsifiable paste and microemulsion, shows that micro emulsion gel more can keep the content of medicine in cortex than microemulsion, forms similar drug storehouse storage, keeps infiltration for a long time, reduces the medication number of times, alleviates toxicity.
Compared with prior art, the present invention has following advantage:
(1) microemulsion and gel are combined into a kind of novel form micro emulsion gels, it combines the advantage of microemulsion and gel, and microemulsion has medicine and disperses the gained particle diameter little with respect to the regular dosage form ointment, helps transdermal penetration; On the other hand, in order to prevent that medicine is diffused rapidly to the whole body infiltration from local penetration and causes whole body to absorb the side effect that the back is brought, in gel, can make microemulsion form thin film the microemulsion redispersion at skin surface, similar shape becomes drug depot, is to keep long drug osmotic.
(2) micro emulsion gels has better skin-friendliness than ointment, ointment and patch, is easy to coating, and pollution clothes not can strengthen the compliance of patient's coating.
Description of drawings
Fig. 1, cumulative release amount are to the penetration kinetics curve of time
Its Fig. 1 compares with micro emulsion gel for preparing with this microemulsion and commercial emulsifiable paste for the imiquimod microemulsion for preparing with the prescription of the imiquimod microemulsion among the embodiment 6, percutaneous accumulation infiltration capacity is carried out regression treatment to time of penetration, the penetration kinetics curve that obtains.Transdermal penetration speed＞micro emulsion gel＞the emulsifiable paste that shows microemulsion.
Fig. 2, local skin imiquimod micro emulsion gels, imiquimod cream, behind the imiquimod water-in-oil microemulsion in the comparison of skin hold-up.
Fig. 2 shows the cortex content of imiquimod micro emulsion gel between emulsifiable paste and microemulsion, shows that micro emulsion gel more can keep the content of medicine in cortex than microemulsion, forms similar drug storehouse storage, keeps infiltration for a long time, reduces the medication number of times, alleviates toxicity.
The specific embodiment
Further specify the preparation method and the effect of imiquimod micro emulsion gels of the present invention below by embodiment.
One, preparation example:
Embodiment 1
Get imiquimod 100g, add oleic acid 1.5kg stirring and make dissolving, add castor oil polyoxyethylene ether EL603.0kg and isopropyl alcohol 1kg again, mixing also stirs, under constantly stirring, add the about 60kg of water gentle agitation in the homogenizer that above-mentioned solution is housed, promptly form faint yellow in bluish transparent oil-in-water microemulsion A, record mean diameter 30nm; Other takes by weighing carbomer 934 powder 1.5kg, evenly is sprinkling upon in the 50kg distilled water, and abundant swelling is prepared into that to contain carbomer 934 be that 3% carbomer water swelling solution B is standby; Take by weighing B 33.4kg and add among the A, the limit edged stirs, and adds the about 1kg of triethanolamine and regulates pH value, makes the transparent imiquimod micro emulsion gels of 100kg, i.e. 0.1% imiquimod micro emulsion gels.
Embodiment 2
Get imiquimod 100g, add oleic acid 1.5kg stirring and make dissolving, add castor oil polyoxyethylene ether EL60 1.5kg and isopropyl alcohol 1kg again, mixing also stirs, under constantly stirring, add the about 10kg of water gentle agitation in the homogenizer that above-mentioned solution is housed, promptly form faint yellow in bluish transparent doubly-linked ideotype microemulsion A, record mean diameter 30nm; Other takes by weighing carbomer 934 powder 300g, evenly is sprinkling upon in the 10kg distilled water, and abundant swelling is prepared into that to contain carbomer 934 be that 3% carbomer water swelling solution B is standby; Take by weighing B 5.78g and add among the A, the limit edged stirs, and adds the about 120g of triethanolamine and regulates pH value, makes the transparent imiquimod micro emulsion gels of 20kg, i.e. 0.5% imiquimod micro emulsion gels.
Embodiment 3
Get imiquimod 100g, add oleic acid 1.5g stirring and make dissolving, add castor oil polyoxyethylene ether EL601.5kg and isopropyl alcohol 1.0kg again, mixing also stirs, under constantly stirring, add the about 3.0kg of water gentle agitation in the homogenizer that above-mentioned solution is housed, promptly form faint yellow transparent water-in-oil microemulsion A, record mean diameter 30nm; Other takes by weighing carbomer 934 powder 300g, evenly is sprinkling upon in the 10kg distilled water, and abundant swelling is prepared into that to contain carbomer 934 be that 3% carbomer water swelling solution B is standby; Take by weighing B 2.84kg and add among the A, the limit edged stirs, and adds the about 60g of triethanolamine and regulates pH value, makes 10kg milky imiquimod micro emulsion gels, i.e. 1% imiquimod micro emulsion gels.
Embodiment 4
Get imiquimod 150g, add isostearic acid 1.5kg stirring and make dissolving, add Tween 80 1.5kg and ethanol 1kg again, mixing also stirs, under constantly stirring, add the about 3.0kg of water gentle agitation in the homogenizer that above-mentioned solution is housed, promptly form faint yellow middle water-in-oil microemulsion A, record mean diameter 30nm; Other takes by weighing carbomer 934 powder 1.5kg, evenly is sprinkling upon in the 50kg distilled water, and abundant swelling is prepared into that to contain carbomer 934 be that 3% carbomer water swelling solution B is standby; Take by weighing B 2.84kg and add among the A, the limit edged stirs, and adds the about 60g of triethanolamine and regulates pH value, makes 10kg milky imiquimod micro emulsion gels, i.e. 1.5% imiquimod micro emulsion gels.
Get imiquimod 200g, add iso stearate 1.5kg stirring and make dissolving, add Tween 80 1.5kg and ethanol 1kg again, mixing also stirs, under constantly stirring, add the about 3kg of water gentle agitation in the homogenizer that above-mentioned solution is housed, promptly form faint yellow transparent water-in-oil microemulsion A, record mean diameter 30nm; Other takes by weighing carbomer 934 powder 300g, evenly is sprinkling upon in the 10kg distilled water, and abundant swelling is prepared into that to contain carbomer 934 be that 3% carbomer water swelling solution B is standby; Take by weighing B 2.84kg and add among the A, the limit edged stirs, and adds the about 60g of triethanolamine and regulates pH value, makes 10kg milky imiquimod micro emulsion gels, i.e. 2.0% imiquimod micro emulsion gels.
Embodiment 6
Get imiquimod 250g, add iso stearate 2.0kg stirring and make dissolving, add Tween 80 1kg and isopropyl alcohol 0.5kg again, mixing also stirs, under constantly stirring, add the about 3kg of water gentle agitation in the homogenizer that above-mentioned solution is housed, promptly form faint yellow transparent water-in-oil microemulsion A, record mean diameter 30nm; Other takes by weighing carbomer 934 powder 300g, evenly is sprinkling upon in the 10kg distilled water, and abundant swelling is prepared into that to contain carbomer 934 be that 3% carbomer water swelling solution B is standby; Take by weighing B 3.19kg and add among the A, the limit edged stirs, and adds the about 60g of triethanolamine and regulates pH value, makes 10kg milky imiquimod micro emulsion gels, i.e. 2.5% imiquimod micro emulsion gels.
Two, application examples:
Embodiment 7
68 routine patients are all from the surgery of Huangzhou city institute of traditional Chinese medicine, and all patients all have typical condyloma acuminatum Clinical symptoms, and acetic acid is tested the positive in vain, and the skin lesion diameter is below 5mm.68 routine patients are divided into two groups at random.Treatment group: 34 examples, male 22 examples, women 12 examples; 17 years old～60 years old age, 32.4 years old mean age.Matched group: 34 examples, male 18 examples, women 16 examples; 22 years old～62 years old age, 33.6 years old mean age.The course of disease 15 days～6 months is not just sent out person's 50 examples, recidivist's 18 examples, and two groups of patients' sex, age, the course of disease, there are no significant for clinical manifestation difference (P＞0.05).Treatment group: adopt embodiment 1 0.1% prepared oil-in-water type imiquimod micro emulsion gel to be coated with the wart body outward, the next day 1 time, medication just before going to bed, get the imiquimod micro emulsion gel, evenly be applied in the wart body region, massage up to medicine gently and absorb fully, and reservation 6h～10h, then with clear water and neutral soap with medicine from being that the wart body region is washed off, wart body the fastest 2 week～4 week removes, the wart body comes off and gets final product drug withdrawal during the treatment.Matched group: adopt 5% imiquimod cream of the medical company limited production of the beautiful benefit in Hubei to be coated with the wart body outward, medication just before going to bed every night, the coating method is the same.Two groups of record curative effect and untoward reaction during treating do not re-use the antiviral drugs of any for oral administration or external during treatment.The curative effect judgment criteria is cured: the skin lesion complete obiteration; Produce effects: skin lesion disappears more than 60%; Effectively: skin lesion disappears 20%～59%; Invalid: the skin lesion less than 20% that disappears; Add produce effects example number with healing and calculate total effective rate.After two groups of patients treated through 4 weeks, this treatment group was observed among the 34 routine patients, cure rate 58.8%, and total effective rate 73.5%, treatment treatment group and matched group curative effect credit are by statistics analysed P＞0.05, there was no significant difference.Untoward reaction: local slight red and swollen, pain phenomenon does not appear in the treatment group, and matched group has the local slight prurituss of 5 examples, causalgias, but the patient all can tolerate, and does not influence continuation and treats.
Embodiment 8
70 routine patients are divided into two groups at random still from Huangzhou city institute of traditional Chinese medicine.35 examples are organized in treatment, male 20 examples, women 15 examples.19 years old～65 years old age, 34.8 years old mean age.Matched group: 35 examples, male 18 examples, women 17 examples; 20 years old～57 years old age, 32.8 years old mean age.The course of disease 20 days～6 months is not just sent out person's 50 examples, recidivist's 20 examples, and two groups of patients' sex, age, the course of disease, there are no significant for clinical manifestation difference (P＞0.05).The treatment group adopts embodiment 2 0.5% prepared oil-in-water type imiquimod micro emulsion gels to be coated with the wart body outward, 5% imiquimod cream that matched group adopts Liyi Medicine Science ﹠ Tech. Co., Ltd., Hubei to produce is coated with the wart body outward, coating method and curative effect judging standard are all with Application Example 7, after two groups of patients treated through 4 weeks, this treatment group was observed among the 35 routine patients, cure rate 60.5%, total effective rate 76.2%, treatment treatment group and matched group curative effect credit are by statistics analysed P＞0.05, there was no significant difference.Untoward reaction: local slight red and swollen, pain phenomenon does not appear in the treatment group, and matched group has the local slight prurituss of 3 examples, causalgias, but the patient all can tolerate, and does not influence continuation and treats.
Embodiment 9
60 routine patients are divided into two groups at random still from Huangzhou city institute of traditional Chinese medicine.30 examples are organized in treatment, male 20 examples, women 10 examples.18 years old～60 years old age, 32.8 years old mean age.Matched group 30 examples, male 18 examples, women 12 examples; 18 years old～55 years old age, 31.9 years old mean age.The course of disease 20 days～7 months is not just sent out person's 30 examples, recidivist's 30 examples, and two groups of patients' sex, age, the course of disease, there are no significant for clinical manifestation difference (P＞0.05).The treatment group adopts embodiment 3 1.0% prepared water-in-oil type imiquimod micro emulsion gels to be coated with the wart body outward, 5% imiquimod cream that matched group adopts Liyi Medicine Science ﹠ Tech. Co., Ltd., Hubei to produce is coated with the wart body outward, coating method and curative effect judging standard are all with Application Example 7, after two groups of patients treated through 4 weeks, this treatment group was observed among the 30 routine patients, cure rate 63.1%, total effective rate 78.1%, treatment treatment group and matched group curative effect credit are by statistics analysed P＞0.05, there was no significant difference.Untoward reaction: local slight red and swollen, pain phenomenon does not appear in the treatment group, and matched group has the local slight prurituss of 3 examples, causalgias, but the patient all can tolerate, and does not influence continuation and treats.
60 routine patients are divided into two groups at random still from Huangzhou city institute of traditional Chinese medicine.30 examples are organized in treatment, male 15 examples, women 15 examples.20 years old～60 years old age, 33.8 years old mean age.Matched group 30 examples, male 20 examples, women 10 examples; 22 years old～55 years old age, 34.9 years old mean age.The course of disease 25 days～7 months is not just sent out person's 30 examples, recidivist's 30 examples, and two groups of patients' sex, age, the course of disease, there are no significant for clinical manifestation difference (P＞0.05).The treatment group adopts embodiment 4 1.5% prepared water-in-oil type imiquimod micro emulsion gels to be coated with the wart body outward, 5% imiquimod cream that matched group adopts Liyi Medicine Science ﹠ Tech. Co., Ltd., Hubei to produce is coated with the wart body outward, coating method and curative effect judging standard are all with Application Example 7, after two groups of patients treated through 4 weeks, this treatment group was observed among the 30 routine patients, cure rate 64.7%, total effective rate 78.9%, treatment treatment group and matched group curative effect credit are by statistics analysed P＞0.05, there was no significant difference.Untoward reaction: local slight red and swollen, pain phenomenon does not appear in the treatment group, and matched group has the local slight prurituss of 4 examples, causalgias, but the patient all can tolerate, and does not influence continuation and treats.
Embodiment 11
60 routine patients are divided into two groups at random still from Huangzhou city institute of traditional Chinese medicine.30 examples are organized in treatment, male 15 examples, women 15 examples.18 years old～60 years old age, 33.1 years old mean age.Matched group 30 examples, male 18 examples, women 12 examples; 18 years old～55 years old age, 32.9 years old mean age.The course of disease 18 days～5 months is not just sent out person's 30 examples, recidivist's 30 examples, and two groups of patients' sex, age, the course of disease, there are no significant for clinical manifestation difference (P＞0.05).The treatment group adopts embodiment 4 2.0% prepared water-in-oil type imiquimod micro emulsion gels to be coated with the wart body outward, 5% imiquimod cream that matched group adopts Liyi Medicine Science ﹠ Tech. Co., Ltd., Hubei to produce is coated with the wart body outward, coating method and curative effect judging standard are all with Application Example 7, after two groups of patients treated through 4 weeks, this treatment group was observed among the 30 routine patients, cure rate 66.3%, total effective rate 80.3%, treatment treatment group and matched group curative effect credit are by statistics analysed P＞0.05, there was no significant difference.Untoward reaction: local slight red and swollen, pain phenomenon does not appear in the treatment group, and matched group has the local slight prurituss of 4 examples, causalgias, but the patient all can tolerate, and does not influence continuation and treats.
Embodiment 12
60 routine patients are divided into two groups at random still from Huangzhou city institute of traditional Chinese medicine.30 examples are organized in treatment, male 20 examples, women 10 examples.18 years old～60 years old age, 32.8 years old mean age.Matched group 30 examples, male 18 examples, women 12 examples; 18 years old～55 years old age, 31.9 years old mean age.The course of disease 20 days～7 months is not just sent out person's 40 examples, recidivist's 30 examples, and two groups of patients' sex, age, the course of disease, there are no significant for clinical manifestation difference (P＞0.05).The treatment group adopts embodiment 3 2.5% prepared water-in-oil type imiquimod micro emulsion gels to be coated with the wart body outward, 5% imiquimod cream that matched group adopts Liyi Medicine Science ﹠ Tech. Co., Ltd., Hubei to produce is coated with the wart body outward, coating method and curative effect judging standard are all with Application Example 7, after two groups of patients treated through 3 weeks, this treatment group was observed among the 30 routine patients, cure rate 72.3%, total effective rate 81.2%, treatment treatment group and matched group curative effect credit are by statistics analysed P＜0.05, there was no significant difference.Untoward reaction: local slight red and swollen, pain phenomenon does not appear in the treatment group, and matched group has the local slight prurituss of 3 examples, causalgias, but the patient all can tolerate, and does not influence continuation and treats.
The table 1 in-vitro percutaneous penetration kinetics equation of respectively writing out a prescription
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102755283A (en) * | 2012-07-13 | 2012-10-31 | 浙江大学 | Water-in-oil medicament nanodispersion compound thermosensitive hydrogel and preparation method thereof |
| CN103202803A (en) * | 2012-12-18 | 2013-07-17 | 苏州大学 | Imiquimod vesicle gel and preparation method for same |
| CN105030671A (en) * | 2015-07-14 | 2015-11-11 | 哈尔滨医科大学 | Methimazole microemulsion, methimazole microemulsion-based gel and preparation method and application of methimazole microemulsion |
| EP3347000A4 (en) * | 2015-09-11 | 2019-03-27 | Phio Pharmaceuticals Corp. | Methods for treating skin disorders and conditions utilizing haptens |
| 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 |
| CN110559256A (en) * | 2019-09-19 | 2019-12-13 | 湖北科益药业股份有限公司 | Local imiquimod of skin |
-
2010
- 2010-02-09 CN CN201010112062A patent/CN101756886A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102755283A (en) * | 2012-07-13 | 2012-10-31 | 浙江大学 | Water-in-oil medicament nanodispersion compound thermosensitive hydrogel and preparation method thereof |
| CN102755283B (en) * | 2012-07-13 | 2013-09-04 | 浙江大学 | Water-in-oil medicament nanodispersion compound thermosensitive hydrogel and preparation method thereof |
| CN103202803A (en) * | 2012-12-18 | 2013-07-17 | 苏州大学 | Imiquimod vesicle gel and preparation method for same |
| CN103202803B (en) * | 2012-12-18 | 2015-05-13 | 苏州大学 | Imiquimod vesicle gel and preparation method for same |
| CN105030671A (en) * | 2015-07-14 | 2015-11-11 | 哈尔滨医科大学 | Methimazole microemulsion, methimazole microemulsion-based gel and preparation method and application of methimazole microemulsion |
| CN105030671B (en) * | 2015-07-14 | 2019-01-11 | 哈尔滨医科大学 | Methimazole micro emulsion, methimazole micro emulsion gel and its preparation method and application |
| EP3347000A4 (en) * | 2015-09-11 | 2019-03-27 | Phio Pharmaceuticals Corp. | Methods for treating skin disorders and conditions utilizing haptens |
| 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 |
| CN110559256A (en) * | 2019-09-19 | 2019-12-13 | 湖北科益药业股份有限公司 | Local imiquimod of skin |
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