CN1269476C - Composite liposome of vitaminaacid as well as preparation method and application - Google Patents
Composite liposome of vitaminaacid as well as preparation method and application Download PDFInfo
- Publication number
- CN1269476C CN1269476C CN 200410006003 CN200410006003A CN1269476C CN 1269476 C CN1269476 C CN 1269476C CN 200410006003 CN200410006003 CN 200410006003 CN 200410006003 A CN200410006003 A CN 200410006003A CN 1269476 C CN1269476 C CN 1269476C
- Authority
- CN
- China
- Prior art keywords
- complex liposome
- retinoic acid
- liposome
- complex
- surfactant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- JBQATDIMBVLPRB-UHFFFAOYSA-N isoliquiritigenin Natural products OC1=CC(O)=CC=C1C1OC2=CC(O)=CC=C2C(=O)C1 JBQATDIMBVLPRB-UHFFFAOYSA-N 0.000 description 1
- YNWXJFQOCHMPCK-LXGDFETPSA-N isoliquiritin Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC(C=C1)=CC=C1\C=C\C(=O)C1=CC=C(O)C=C1O YNWXJFQOCHMPCK-LXGDFETPSA-N 0.000 description 1
- 230000003780 keratinization Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- FURUXTVZLHCCNA-AWEZNQCLSA-N liquiritigenin Chemical compound C1=CC(O)=CC=C1[C@H]1OC2=CC(O)=CC=C2C(=O)C1 FURUXTVZLHCCNA-AWEZNQCLSA-N 0.000 description 1
- DEMKZLAVQYISIA-ZRWXNEIDSA-N liquiritin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C([C@H]2OC3=CC(O)=CC=C3C(=O)C2)C=C1 DEMKZLAVQYISIA-ZRWXNEIDSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910052756 noble gas Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940055019 propionibacterium acne Drugs 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000002374 sebum Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 230000036548 skin texture Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000003746 surface roughness Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
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- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
Abstract
The present invention mainly relates to a compound liposome containing vitamin A acid and liquorice flavonoid, a preparation method thereof and the application thereof, which belong to the field of pharmacy. The specific method comprises: the vitamin A acid and the liquorice flavonoid under the action of a surface active agent are simultaneously wrapped in phosphatidyl choline to form the compound liposome. The compound liposome of vitamin A acid, which is prepared with the method, can reduce side effects in the using process of the vitamin A acid, and the compound liposome of vitamin A acid can be used for preparing medicines or cosmetics for preventing and treating skin diseases, such as chromatodermatosis, photoaging, etc., of epithelial cell abnormality.
Description
[technical field]
The present invention relates to pharmaceutical field, relate generally to the complex liposome that contains retinoic acid and licoflavone, and the preparation method of this complex liposome and application.Complex liposome provided by the invention can reduce the side effect in the retinoic acid use, can be used for preparation prevention and dermopathic medicine of epithelial cell abnormity or cosmetics such as treatment chromatopathy and photoaging.
[background technology]
Chromatopathy be since in the body pigment suffer damage, excessively calmly cause in skin, mainly comprise after chloasma, freckle, day sunburn, senile plaque and the inflammation dermatosis such as pigmentation.Wherein common with chloasma, principal character is that the pigment symmetry is excessively calm, easily occurring in YANG part of the body rayed position.This class disease does not have effective medicine, mainly adopts external medication, as hydroquinone, phenolic compounds, vitamin C and E, retinoic acid, the ninth of the ten Heavenly Stems two capric acid etc.Though these medicines have certain effect, certain toxic and side effects is arranged, as atrophoderma, permanent decolouring etc.
The skin photoage phenomenon mainly is because long-term caused epidermis of ultraviolet radiation and corium characteristic change.Mainly show as epidermis and corium attenuation, skin texture coarse, form wrinkle, pigment alteration, hair cell vasodilation and some day photosensitiveness keratinization etc.Many external preparation are used for outward or study in the photoaging that improves skin, and wherein the research with retinoic acid is the most extensive.The external retinoic acid can obviously improve the clinical manifestation of skin photoage, eliminates or reduce wrinkle to form, and reduces pigmentation, reduces skin surface roughness etc.
Retinoic acid has another name called all-trans-retinoic acid, retinoic acid, is the metabolic in vivo intermediate product of vitamin A.Retinoic acid has effects such as the differentiation of the epithelial cell of promotion, inhibition sebum secretion, inhibition propionibacterium acnes, and its external preparation is widely used in the treatment of epithelial cell abnormal diseases such as psoriasis, acne, pigmentation, skin aging.But inflammation sample allergic symptom such as rubescent, twinge, edema in various degree in use can appear usually.Since therapeutic effect, side reaction occurrence degree all with the proportional relation of working concentration, so side reaction is from having limited the clinical use of retinoic acid to a great extent.
Comparing effective method in the research of reduction retinoic acid side reaction at present is to carry out enclose, perhaps cooperates 17-hydroxy-11-dehydrocorticosterone antiallergic therapy.Wherein enclose mainly contains the cycloheptaamylose enclose and the lecithin enclose is two kinds of liposomees.In the cycloheptaamylose enclose, retinoic acid slowly discharges from the molecule cavity of cycloheptaamylose, and this slow release process can reduce the side effect of retinoic acid.In the retinoic acid liposome with the lecithin enclose, constitute the phospholipid and formation human body epithelial cell membrane Main Ingredients and Appearance similar of liposome membrane, can directly be transported in the cell by engulfing effect by the retinoic acid of lecithin enclose, promote the Transdermal absorption of retinoic acid, retinoic acid is concentrated in the epithelial tissue cell, thereby form the targeting accumulation and improved bioavailability of drugs, a kind of retinoic acid flexible lipidosome and preparation thereof are disclosed as Chinese patent application CN02104247.0, this liposome comprises lecithin, cholate, retinoic acid and solvent thereof, its preparation are mainly by the retinoic acid flexible lipidosome, antioxidant and solvent composition.Compare with enclose retinoic acid preparation not, institute's retinoic acid concentration of using is lower when reaching identical curative effect, because of side reaction occurrence degree and the proportional relation of working concentration, so it is also lower to have side effects.Cooperating the 17-hydroxy-11-dehydrocorticosterone treatment is at present than effective method, and external moderate strength 17-hydroxy-11-dehydrocorticosterone such as betamethasone just can be eliminated the inflammation in the retinoic acid use rapidly.But epithelial cell abnormal diseases treatment cycle is longer usually, and the life-time service hormone dependency can occur, can cause serious problems such as atrophoderma.Generally speaking, no matter retinoic acid is to adopt inclusion technique, and still cooperating the 17-hydroxy-11-dehydrocorticosterone therapy to reduce side reaction all has its limitation.
Licoflavone is a compounds that extracts the root, stem from Radix Glycyrrhizae, comprises liquiritin, liquiritigenin, isoliquiritin unit etc.Can obtain glycyrrhizic acid and potassium salt thereof, sodium salt, calcium salt, ammonium salt after this compounds hydrolysis, glycyrrhizic acid and salt thereof further hydrolysis obtain enoxolone and salt thereof.Glycyrrhizic acid, enoxolone and salt thereof also can directly extract from the Radix Glycyrrhizae rhizome and obtain.In actual applications, glycyrrhizic acid and salt thereof, enoxolone and salt thereof are the final active ingredients of liquorice flavonoids compound.This compounds has the effect of 17-hydroxy-11-dehydrocorticosterone sample, but its mechanism of action difference, its antiinflammatory anti-allergic effects does not rely on human body hypophysis-interrenal system, does not produce side reactions such as skin dependency and atrophoderma.But because human body absorbs non-constant to it, the external desired concn generally is not less than 5% and can only produce low intensive antiphlogistic effects, and only effective to light inflammation, clinical value is little.Licoflavone utilizes the liposome special construction it can be transported in the cell after being formed liposome by the lecithin enclose, increases absorption of human body, produces the antiinflammatory anti-allergic effects with the equivalence of moderate strength 17-hydroxy-11-dehydrocorticosterone.
The common preparation method of liposome is that filmogens such as lecithin and fat-soluble medicine composition are dissolved in chloroform or the ether, solvent is concentrated into dried by noble gas such as nitrogen purging or drying under reduced pressure mode, after the buffer solution immersion, the reuse ultrasonic Treatment obtains the liposome of required particle diameter.This class preparation method is only applicable to the laboratory small-scale production, a lot of problems will occur in case amplify large-scale production.Harmful solvent such as divisible chloroform not when concentrating; Be sticky solid after concentrating, take out difficulty from container; The container volume of ultrasonic Treatment is limited; Liposome after the processing has the trend of condensing again, influences drug release etc.
Simultaneously, be not used in prevention and the dermopathic retinoic acid complex liposomes of epithelial cell abnormity such as treatment chromatopathy and skin photoage on the market.
At the problems referred to above, the present inventor proposes to add the technical scheme of licoflavone through intensive big quantity research in liposome, and the retinoic acid compound recipe liposome that this technical scheme is made can strengthen the curative effect of retinoic acid and reduce its side effect greatly; The inventor also improves existing liposome preparation technology simultaneously, has found a kind of operation control easy, is easy to the method for preparing lipidosome of suitability for industrialized production.The preparation that this compound recipe liposome is made through animal experiment confirm with the retinoic acid Liposomal formulation with contain retinoic acid and compare with the compound formulation of licoflavone, the skin irritation that causes is lower, thereby has finished the present invention.
[summary of the invention]
[technical problem to be solved]
The technical problem to be solved in the present invention is that the retinoic acid inclusion technique is combined together with cooperating the 17-hydroxy-11-dehydrocorticosterone therapy, and better efficacy, the lower retinoic acid complex liposome of side reaction are provided, and the preparation method of this complex liposome and application.
Retinoic acid complex liposome of the present invention is meant the complex liposome of retinoic acid and licoflavone, utilize liposome structure can increase the characteristic of human body exactly to retinoic acid and licoflavone absorption, realize both strengthening the retinoic acid curative effect, the generation of side reaction be can reduce simultaneously again, prevention and epithelial cell abnormity dermatosiss such as treatment chromatopathy and photoaging can be used for.
[technical scheme]
The invention provides a kind of complex liposome that contains retinoic acid, licoflavone, lecithin, surfactant.By weight percentage, complex liposome contains: retinoic acid 0.01%～2%; Licoflavone 0.01%～2%; Lecithin 0.05%～5%; Surfactant 0.1%～1%; All the other are pharmaceutically acceptable lysate and excipient.
The weight percent content of retinoic acid is preferably 0.02%～0.1% in the complex liposome of the present invention.
Contain licoflavone in the complex liposome of the present invention, described licoflavone comprises glycyrrhizic acid and pharmaceutically acceptable salt or enoxolone and pharmaceutically acceptable salt thereof.
Lecithin is the filmogen of liposome in the complex liposome of the present invention, and described lecithin is meant soybean lecithin.The phosphocholine content of the soybean lecithin of selecting for use is 60%～99%, is preferably 75%～90%.
Owing to have cohesion trend simultaneously in the complex liposome generative process, its cohesion speed final decision the particle diameter of liposome.The inventor adds surfactant and can prevent the cohesion of complex liposome, and can control the particle diameter of complex liposome by the consumption of reconciliation statement surface-active agent through a large amount of studies show that in complex liposome.It is more little to add the big more complex liposome particle diameter of surface activity agent dose, and transdermal effect is strong more, can cause the fat-soluble medicine of lecithin enclose to leak out from complex liposome but amount of surfactant surpasses a certain amount of its excessive solubilization.Among the present invention, it is good and stable that complex liposome will reach transdermal effect, and its particle diameter is controlled at 100nm～300nm.The inventor determines relatively that through a large amount of tests surfactant is a water soluble nonionic surfactant, as brejs, poloxamer class and Tweens.Preferred Tweens.Described Tweens surfactant comprises polysorbas20, polysorbate40, polysorbate60, Tween 80, polysorbate85.
The preparation method of complex liposome of the present invention is: under the effect of above-mentioned surfactant, with retinoic acid and licoflavone simultaneously enclose in lecithin, form described complex liposome.
Preferred concrete scheme is that retinoic acid, licoflavone, lecithin, surfactant and pharmaceutical adjuvant are dissolved in the adequate amount of ethanol, the alcoholic solution that makes is poured in the phosphate buffered saline(PBS), mix and promptly obtain the complex liposome suspension solution, add other pharmaceutically the acceptable excipient obtain liposome of the present invention.When preparing this liposome, adopting highly purified soybean lecithin is the filmogen of liposome, selects for use ethanol as solvent, thereby has avoided the harmful and organic solvent that do not dissolve each other with water with chloroform or ether etc.The alcoholic solution of lecithin adds in the entry, and after ethanol and water dissolved each other, dissolved lecithin was just separated out automatic formation liposome in the ethanol.
Complex liposome of the present invention can be used for preparation prevention and dermopathic medicine of epithelial cell abnormity or cosmetics such as treatment chromatopathy and photoaging.
[beneficial effect]
Retinoic acid complex liposome of the present invention is meant the complex liposome of retinoic acid and licoflavone, utilize liposome structure can increase the characteristic of human body exactly to retinoic acid and licoflavone absorption, realize both strengthening the retinoic acid curative effect, the generation of side reaction be can reduce simultaneously again, prevention and epithelial cell abnormity dermatosiss such as treatment chromatopathy and photoaging can be used for.
Compare with the preparation method of original liposome, the preparation method of retinoic acid and licoflavone complex liposome is simple to operate, is suitable for control, is very suitable for suitability for industrialized production.
In the complex liposome provided by the invention, by retinoic acid and licoflavone while enclose are formed complex liposome in lecithin, utilize liposome structure composition and human body cell film similar, the phase reciprocity adheres to, merges and engulfs effect, liposome institute enclose medicine directly can be transported to intracellular absorption characteristic, improve the pharmacological action of retinoic acid and licoflavone, and reduced the side effect in use of common retinoic acid preparation.Among the present invention, the complex liposome transdermal effect is good and stable, and its particle diameter should be controlled at 100nm～300nm.
Simultaneously, when preparing this liposome, adopting highly purified soybean lecithin is the filmogen of liposome, selects for use ethanol as solvent, thereby has avoided the harmful and organic solvent that do not dissolve each other with water with chloroform or ether etc.The alcoholic solution of lecithin adds in the entry, and after ethanol and water dissolved each other, dissolved lecithin was just separated out automatic formation liposome in the ethanol.The ethanol content of staying in the liposome turbid liquor is lower, and especially content is lower in final preparation, and external can not produce any stimulation and toxicity to skin, need not to remove specially.This method for preparing lipidosome has greatly been simplified the preparation process of liposome owing to the process of having saved the lecithin solvent of removing.
Following specific embodiment further specifies the present invention, but does not limit the present invention with this.
[specific embodiment]
Embodiment 1 retinoic acid and licoflavone complex liposome 1
Prescription: retinoic acid 1g, glycyrrhizic acid 1.5g, soybean lecithin (phosphocholine content 80%) 4g, 0.5g polysorbate60, BHT 0.01g, ethanol (85%) 40g, PBS solution (0.1mol/L, pH7.2) 153g.
Compound method: retinoic acid, glycyrrhizic acid, soybean lecithin, polysorbate60, BHT are added in the ethanol, be stirred to molten entirely; Pour lysate into suspension solution that mixing in the PBS solution promptly obtains complex liposome.
Embodiment 2 retinoic acid and licoflavone complex liposome 2
Prescription: retinoic acid 1g, trisodium glycyrrhetinate 1.5g, soybean lecithin (phosphocholine content 80%) 4g, 0.5g polysorbate60, BHT 0.01g, ethanol (80%) 40g, PBS solution (0.1mol/L, pH7.2) 153g.
Compound method: retinoic acid, trisodium glycyrrhetinate, soybean lecithin, polysorbate60, BHT are added in the ethanol, be stirred to molten entirely; Pour lysate into suspension solution that mixing in the PBS solution promptly arrives liposome.
Embodiment 3 retinoic acid and licoflavone complex liposome 3
Prescription: retinoic acid 1g, enoxolone 1.5g, soybean lecithin (phosphocholine content 85%) 4g, 0.5g Tween-60, BHT 0.01g, ethanol (75%) 40g, PBS solution (0.1mol/L, pH7.2) 153g.
Compound method: retinoic acid, enoxolone, lecithin, polysorbate60, BHT are added in the ethanol, be stirred to molten entirely; Pour lysate into suspension solution that mixing in the PBS solution promptly arrives liposome.
Embodiment 4 retinoic acid and licoflavone complex liposome 4
Prescription: retinoic acid 1g, Monosodium glycyrrhetin 1.5g, soybean lecithin (phosphocholine content 85%) 4g, 0.5g polysorbate60, BHT 0.01g, ethanol (90%) 40g, PBS solution (0.1mol/L, pH7.2) 153g.
Compound method: retinoic acid, Monosodium glycyrrhetin, soybean lecithin, polysorbate60, BHT are added in the ethanol, be stirred to molten entirely; Pour lysate into suspension solution that mixing in the PBS solution promptly arrives liposome.
Embodiment 5 retinoic acid and licoflavone complex liposome solution
Prescription: (in retinoic acid, concentration is 0.025%)
Complex liposome suspension (embodiment 1 gained) 5g
Glycerol 15g
Polyvidone (K90) 10g
Ethyl hydroxybenzoate 0.1g
Sodium benzoate 0.1g
Distilled water adds to 100ml
Compound method: polyvidone, ethyl hydroxybenzoate, sodium benzoate are added in an amount of distilled water after the stirring and dissolving, add glycerol and liposome suspension solution and stir, add distilled water diluting at last, get final product to full dose.
Embodiment 6 retinoic acid and licoflavone complex liposome ointment
Prescription: (in retinoic acid, concentration is 0.025%)
Complex liposome suspension (embodiment 2 gained) 5g
Glycerol 10g
Ethyl hydroxybenzoate 0.1g
Sodium benzoate 0.1g
White oil 6g
Hexadecanol 6g
Monoglyceride 8g
Sorbester p17 2g
Tween 80 3g
Distilled water 59.8g
Be made into 100g
Compound method: will glycerol, sodium benzoate, Tween 80 add in the distilled water and stir, be heated to moltenly entirely, 73 ℃ of insulations are as water.Ethyl hydroxybenzoate, white oil, hexadecanol, monoglyceride, sorbester p17 are mixed and heated to molten entirely, 75 ℃ of insulations are as oil phase.Stir and down water is poured into oil phase insulation 20 minutes, stir adding complex liposome suspension when being cooled to 50 ℃, stirring gets final product.
Embodiment 7 retinoic acid and licoflavone complex liposome gel
Prescription: (in retinoic acid, concentration is 0.025%)
Complex liposome suspension (embodiment 3 gained) 5g
Glycerol 10g
Ethyl hydroxybenzoate 0.1g
Sodium benzoate 0.1g
Carbopol (934 type) 0.6g
Triethanolamine 1.2g
Distilled water 83g
Be made into 100g
Compound method: be stirred to molten entirely in ethyl hydroxybenzoate, the sodium benzoate adding distilled water, stir and slowly add carbopol down, be uniformly dispersed, stir 3～4 hours to the carbopol complete swelling, add the triethanolamine neutralization and obtain clear gel substrate, add complex liposome suspension and glycerol again, stir and just obtain the complex liposome gel.
Experimental example complex liposome skin irritation test of the present invention
1. test objective: by the test of rabbit multiple dosing skin irritation, the relatively skin irritation of retinoic acid and licoflavone complex liposome ointment and the agent of retinoic acid lipidosome cream, retinoic acid and licoflavone compound cream.
2. be subjected to the reagent thing: retinoic acid and licoflavone complex liposome ointment (retinoic acid content is 0.025%, and licoflavone content is 0.0375%) that present embodiment 6 is prepared.
3. experimental animal: healthy, 10 of the qualified one-level new zealand rabbits of growing up, male and female all have, and body weight is 1.5-2.0kg.Test the previous day with nape portion spinal column both sides skin unhairing, each about 50cm of every side
2, account for body surface area about 10%.
4. experimental control medicine:
Retinoic acid lipidosome cream (retinoic acid content is 0.025%) (control drug 1)
Retinoic acid and licoflavone compound cream (retinoic acid content is 0.025%, and licoflavone content is 0.0375%) (control drug 2)
5. test method and observation index: 10 rabbit are divided into 2 groups at random, and 5 every group, wherein first group of every animal left side is coated with trial drug, and the right side is coated with 1, the second group of every animal left side of control drug and is coated with trial drug, and the right side is coated with control drug 2, and dosage is the 1g/ side.Be administered once every day, makes medicine contact 6 hours with animal skin after the administration, uses the warm water flush away then, successive administration 7 days.After each administration, cover reuse immobilization with adhesive tape wrapping with two-layer gauze.Observe before the administration, record is smeared the position and is had or not situations such as erythema, edema.Removed the residual thing that tried with warm water in 24 hours after the last administration, and observe to remove situations such as the erythema that be subjected to behind the reagent thing by reagent thing and removal 1 hour, 24 hours, 48 hours, 72 hours, 96 hours, edema, and the recovery situation of above-mentioned variation and required time.
6. irritant reaction standards of grading
The standards of grading of skin erythema, edema are as follows after the administration:
| Intact skin stimulates classification | |||
| Erythema | Edema | ||
| No erythema | 0 | No edema | 0 |
| Reluctantly as seen | 1 | Reluctantly as seen | 1 |
| Moderate erythema | 2 | The cutaneous protuberance profile is clear | 2 |
| Serious erythema | 3 | The about 1mm of edema protuberance, clear-cut | 3 |
| The aubergine erythema also has eschar to form | 4 | Edema about 1mm of protuberance and expanded range | 4 |
7. skin irritation intensity evaluation
The evaluation criterion of skin irritation intensity is as follows:
| Mean scores | The skin irritation intensity evaluation |
| ＜0.5 | Nonirritant |
| ＜2.09 | Slight zest |
| ＜6.0 | The moderate zest |
| ＜8.0 | Strong and stimulating |
Computational methods:
8. result of the test
Each time point is observed rabbit erythema, edema situation, and the result is as follows:
First group of result of the test statistics of table 1 (n=5)
| Observing time | Group | The skin irritation classification | Stimulate mean scores | Stimulus intensity is estimated | |||||||||
| Erythema | Edema | ||||||||||||
| 0 | 1 | 2 | 3 | 4 | 0 | 1 | 2 | 3 | 4 | ||||
| Administration 1 day | Test group | 5/5 | 0 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0 | Do not have |
| Matched group 1 | 5/5 | 0 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0 | Do not have | |
| Administration 2 days | Test group | 5/5 | 0 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0 | Do not have |
| Matched group 1 | 3/5 | 2/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.4 | Do not have | |
| Administration 3 days | Test group | 4/5 | 1/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.2 | Do not have |
| Matched group 1 | 2/5 | 2/5 | 1/5 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.8 | Slightly | |
| Administration 4 days | Test group | 3/5 | 2/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.4 | Do not have |
| Matched group 1 | 0 | 2/5 | 2/5 | 1/5 | 0 | 4/5 | 1/5 | 0 | 0 | 0 | 2.0 | Slightly | |
| Administration 5 days | Test group | 1/5 | 3/5 | 1/5 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 1.0 | Slightly |
| Matched group 1 | 0 | 1/5 | 3/5 | 1/5 | 0 | 4/5 | 1/5 | 0 | 0 | 0 | 2.2 | Moderate | |
| Administration 6 days | Test group | 0 | 4/5 | 1/5 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 1.2 | Slightly |
| Matched group 1 | 0 | 1/5 | 3/5 | 1/5 | 0 | 4/5 | 1/5 | 0 | 0 | 0 | 2.2 | Moderate | |
| Administration 7 days | Test group | 0 | 5/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 1 | Slightly |
| Matched group 1 | 0 | 1/5 | 4/5 | 0 | 0 | 2/5 | 3/5 | 0 | 0 | 0 | 2.4 | Moderate | |
| Drug withdrawal 1h | Test group | 0 | 5/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 1 | Slightly |
| Matched group 1 | 0 | 1/5 | 4/5 | 0 | 0 | 2/5 | 3/5 | 0 | 0 | 0 | 2.4 | Moderate | |
| Drug withdrawal 24h | Test group | 2/5 | 3/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.6 | Slightly |
| Matched group 1 | 0 | 1/5 | 3/5 | 1/5 | 0 | 4/5 | 1/5 | 0 | 0 | 0 | 2.2 | Moderate | |
| Drug withdrawal 48h | Test group | 2/5 | 3/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.6 | Slightly |
| Matched group 1 | 0 | 1/5 | 3/5 | 1/5 | 0 | 4/5 | 1/5 | 0 | 0 | 0 | 2.2 | Moderate | |
| Drug withdrawal 72h | Test group | 4/5 | 1/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.2 | Do not have |
| Matched group 1 | 1/5 | 2/5 | 2/5 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 1.2 | Slightly | |
| Drug withdrawal 96h | Test group | 5/5 | 0 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0 | Do not have |
| Matched group 1 | 3/5 | 2/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.4 | Do not have |
Second group of result of the test statistics of table 2 (n=5)
| Observing time | Group | The skin irritation classification | Stimulate mean scores | Stimulus intensity is estimated | |||||||||
| Erythema | Edema | ||||||||||||
| 0 | 1 | 2 | 3 | 4 | 0 | 1 | 2 | 3 | 4 | ||||
| Administration 1 day | Test group | 5/5 | 0 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0 | Do not have |
| Matched group 2 | 5/5 | 0 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0 | Do not have | |
| Administration 2 days | Test group | 5/5 | 0 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0 | Do not have |
| Matched group 2 | 4/5 | 1/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.2 | Do not have | |
| Administration 3 days | Test group | 3/5 | 2/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.4 | Do not have |
| Matched group 2 | 2/5 | 3/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.6 | Slightly | |
| Administration 4 days | Test group | 3/5 | 2/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.4 | Do not have |
| Matched group 2 | 1/5 | 3/5 | 1/5 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 1.0 | Slightly | |
| Administration 5 days | Test group | 2/5 | 3/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.6 | Slightly |
| Matched group 2 | 0 | 3/5 | 2/5 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 1.4 | Slightly | |
| Administration 6 days | Test group | 0 | 5/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 1.0 | Slightly |
| Matched group 2 | 0 | 2/5 | 2/5 | 1/5 | 0 | 5/5 | 0 | 0 | 0 | 0 | 1.8 | Slightly | |
| Administration 7 days | Test group | 0 | 4/5 | 1/5 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 1.2 | Slightly |
| Matched group 2 | 0 | 2/5 | 3/5 | 0 | 0 | 4/5 | 1/5 | 0 | 0 | 0 | 1.8 | Slightly | |
| Drug withdrawal 1h | Test group | 0 | 5/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 1 | Slightly |
| Matched group 2 | 0 | 2/5 | 3/5 | 0 | 0 | 4/5 | 1/5 | 0 | 0 | 0 | 1.8 | Slightly | |
| Drug withdrawal 24h | Test group | 1/5 | 4/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.8 | Slightly |
| Matched group 2 | 1/5 | 3/5 | 1/5 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 1.0 | Slightly | |
| Drug withdrawal 48h | Test group | 2/5 | 3/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.6 | Slightly |
| Matched group 2 | 2/5 | 3/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.6 | Slightly | |
| Drug withdrawal 72h | Test group | 5/5 | 0 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0 | Do not have |
| Matched group 2 | 4/5 | 1/5 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0.2 | Do not have | |
| Drug withdrawal 96h | Test group | 5/5 | 0 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0 | Do not have |
| Matched group 2 | 5/5 | 0 | 0 | 0 | 0 | 5/5 | 0 | 0 | 0 | 0 | 0 | Do not have |
9. conclusion (of pressure testing)
Can find out that from above result of the test slight the stimulation appearred in retinoic acid and licoflavone complex liposome emulsifiable paste (test group) at the 5th day, be maintained to after the drug withdrawal 48 hours, after drug withdrawal, disappear in 72 hours.The slight stimulation appearred in retinoic acid lipidosome cream (matched group 1) at the 3rd day, moderate occurring on the 5th day stimulates, and was maintained to after the drug withdrawal 48 hours, and drug withdrawal transferred slight stimulation in 72 hours to, disappeared in 96 hours zests of drug withdrawal.The slight stimulation appearred in retinoic acid and licoflavone compound cream (matched group 2) at the 3rd day, be maintained to after the drug withdrawal 48 hours, disappeared in 72 hours after drug withdrawal.
In the test of rabbit multiple dosing skin irritation, the zest comparison that retinoic acid and licoflavone complex liposome emulsifiable paste are produced is little according to the zest that medicine retinoic acid lipidosome cream, retinoic acid and licoflavone compound cream are produced.
Claims (15)
1, a kind of complex liposome is characterized in that this complex liposome contains surfactant, retinoic acid by weight percentage 0.01%～2%, licoflavone 0.01%～2%, lecithin 0.05%～5%.
2, complex liposome according to claim 1, by weight percentage, the content of retinoic acid is 0.02%～1%.
3, complex liposome according to claim 1, wherein said licoflavone are glycyrrhizic acid and pharmaceutically acceptable salt or enoxolone and pharmaceutically acceptable salt thereof.
4, complex liposome according to claim 1, wherein said lecithin is soybean lecithin.
5, complex liposome according to claim 4, the phosphocholine content of wherein said soybean lecithin is 60～99%.
6, complex liposome according to claim 5, the phosphocholine content of wherein said soybean lecithin is 75～90%.
7, the arbitrary complex liposome according to claim 1～6, the content that it is characterized in that surfactant is 0.1～1% by weight percentage.
8, complex liposome according to claim 7, wherein said surfactant are water soluble nonionic surfactant.
9, complex liposome according to claim 8, wherein said surfactant are brejs, the husky nurse class of uncle's chromium or Tweens.
10, complex liposome according to claim 9, described surfactant is a Tweens.
11, complex liposome according to claim 10, described surfactant is selected from polysorbas20, polysorbate40, polysorbate60, Tween 80 or polysorbate85.
12, the preparation method of the described arbitrary complex liposome of claim 7 is characterized in that: under the effect of described surfactant, with retinoic acid and licoflavone simultaneously enclose in described lecithin, form described complex liposome.
13, preparation method according to claim 12, wherein, the particle diameter of controlling complex liposome by the consumption of regulating described surfactant is 100nm～300nm.
14, the described arbitrary complex liposome of claim 1～6 is used for preparation prevention and dermopathic medicine of epithelial cell abnormity or cosmetics such as treatment chromatopathy and photoaging.
15, the described complex liposome of claim 7 is used for preparation prevention and dermopathic medicine of epithelial cell abnormity or cosmetics such as treatment chromatopathy and photoaging.
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| CN100441187C (en) * | 2006-08-30 | 2008-12-10 | 中国人民解放军第三军医大学第一附属医院 | A liposomal retinoic acid aerosol for treating chronic obstructive pulmonary disease |
| CN101816632B (en) * | 2010-04-23 | 2012-08-22 | 广东药学院 | Composite functional liposome and preparation method and application thereof |
| CN101843584B (en) * | 2010-06-02 | 2012-05-30 | 北京大学 | A kind of complex of all-trans retinoic acid and liposome and its application |
| CN103181895A (en) * | 2011-12-29 | 2013-07-03 | 南京农业大学 | Glycyrrhetinic acid nano-liposome for improving immune function of livestock and poultry and its preparation method |
| CN103202780A (en) * | 2013-04-16 | 2013-07-17 | 纪艺琼 | Nano essence for cosmetic and preparation method thereof |
| CN104606063B (en) * | 2015-03-04 | 2021-07-16 | 王海龙 | Liposome containing cosmetic active ingredients and preparation method and application thereof |
| CN113350288A (en) * | 2021-06-09 | 2021-09-07 | 山东良福制药有限公司 | All-trans-retinoic acid/betamethasone co-loaded flexible nano-liposome and preparation method of gel thereof |
| CN118576507A (en) * | 2024-05-08 | 2024-09-03 | 山东省食品药品检验研究院 | A glabridin-bosine co-loaded liposome gel and its preparation method and application |
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