CN102631544A - Chinese and western anti-fungal liposome and preparation method thereof - Google Patents
Chinese and western anti-fungal liposome and preparation method thereof Download PDFInfo
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- CN102631544A CN102631544A CN2012101241256A CN201210124125A CN102631544A CN 102631544 A CN102631544 A CN 102631544A CN 2012101241256 A CN2012101241256 A CN 2012101241256A CN 201210124125 A CN201210124125 A CN 201210124125A CN 102631544 A CN102631544 A CN 102631544A
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Abstract
The invention discloses a Chinese and western anti-fungal liposome and a preparation method of the Chinese and western anti-fungal liposome. The Chinese and western anti-fungal liposome mainly consists of radix sophorae flavescentis and rhizoma polygonati extractive, voriconazole powder, hydrogenated soya bean lecithin, cholesterol and the like. The preparation method of the Chinese and western anti-fungal liposome comprises the following steps of: coating the radix sophorae flavescentis and rhizoma polygonati extractive in water phase of liposome, leading the voriconazole to be positioned on a phospholipid film, and combining the Chinese medicinal herb with the western medicine due to the preparation of the liposome. The Chinese and western anti-fungal liposome can play a part in slow release, wherein the Chinese medicinal herb immediately-dissolved medicine voriconazole is exposed after effecting to continuously play the medicine effect, and the slow-release effect is more obvious, and the Chinese medicine rhizoma polygonati has a certain repair function in vivo, so that the effects of treating and repairing can be achieved. The voriconazole is prepared into the liposome, and can be embedded with the phospholipid, so that the dissolubility of the voriconazole can be increased, and the Chinese and western anti-fungal liposome has a certain protection function, therefore, the stability of the voriconazole can be greatly improved, and the Chinese and western anti-fungal liposome plays a certain part in slow release.
Description
Technical field
The present invention discloses a kind of antifungal Chinese and Western bound drug liposome and preparation method thereof, relates to Chinese and Western and combines the pharmaceutical technology field.
Background technology
Fungus (Fungus) is a kind of eukaryote.Modal fungus is all kinds of Mushrooms, and fungus also comprises mycete and yeast in addition.The position that fungal infectious disease is invaded human body according to fungus is divided into 4 types: superficial fungi disease, dermatomycosis, subcutaneous mycosis and systemic mycoses; The former two closes and is called superficial mycosis, and the latter two are called deep mycosis again.
Voriconazole was gone on the market by drugs approved by FDA in May, 2002; It is the synthetic triazole antifungal agent of the second filial generation; Has has a broad antifungal spectrum, the advantage that antibacterial efficacy is strong, treatment aggressive aspergillin infection; Treatment is dyed the microbial bad attack sexuality of the drug-fast beads of fluconazol and is comprised Candida krusei, the severe infections that treatment is caused by Scedosporium and Fusarium.
The plant that Radix Sophorae Flavescentis belongs to for the pulse family Radix Sophorae Flavescentis.Function cures mainly: heat clearing and damp drying, parasite killing, diuresis.Be used for hematodiarrhoea, swelling of the vulva pudendal pruritus, eczema, eczema, skin pruritus, scabies leprosy; External treatment trichomonal vaginitis.Radix Sophorae Flavescentis water logging agent has inhibitory action to trichophyton, Trichophyton concentricunm, trichophyton, Du's big belly budlet spore tinea bacterium difficult to understand etc.
Rhizoma Polygonati has another name called Rhizoma Polygonati Cirrhifolii, Caput Gallus domesticus ginseng.Rhizoma Polygonati is used as medicine with rhizome, has boosting qi and nourishing yin, spleen invigorating, lung moistening, kidney benefiting functions.Be used to treat weakness of the spleen and stomach, fatigue and asthenia, xerostomia lack of appetite, deficiency of the lung cough caused by dryness, asthenia of essence and blood, interior-heat disease such as quench one's thirst.In vitro tests shows, Rhizoma Polygonati water proposes liquid, Bacillus typhi, staphylococcus aureus, acid-fast bacilli are had inhibitory action, and 2% Rhizoma Polygonati has inhibitory action in various degree to common pathomycete in sabouraud culture medium.
Voriconazole dissolubility in water is extremely low, and its chemical property is unstable under solution state.
Summary of the invention
The Chinese and Western that the purpose of this invention is to provide the bonded treatment fungal infection of a kind of Chinese medicine and western medicine combines medicine, and good effect has improved stability of drug, and has slow release, long lasting effect, and dosage reduces greatly.
A kind of Chinese and Western disclosed by the invention combines the antifungal liposome, it is characterized in that mainly by following raw materials by weight portion than processing:
100 ~ 300 parts of Radix Sophorae Flavescentis Rhizoma Polygonati extracts, 10 ~ 30 parts in voriconazole powder, 800 ~ 1000 parts of hydrogenated soy phosphatidyl cholines, 200 ~ 300 parts in cholesterol.
Chinese and Western according to the invention combines the method for preparing of antifungal liposome, may further comprise the steps:
1) 200 ~ 400 parts of Radix Sophorae Flavescentiss, Rhizoma Polygonati are added 8 ~ 12 times of water gaging mixing decoctings for 600 ~ 800 parts, extract 2 times, each 2h is concentrated to 10 ~ 20% and gets the Radix Sophorae Flavescentis Rhizoma Polygonati extract, is spray dried to dry powder.
2) Radix Sophorae Flavescentis Rhizoma Polygonati extract powder is 100 ~ 300 parts, is dissolved in 10 ~ 20 times the water, as the water of liposome;
3) get 10 ~ 30 parts in voriconazole powder, be dissolved in the chloroform solvent, mix for 200 ~ 300 parts with 800 ~ 1000 parts of hydrogenated soy phosphatidyl cholines, cholesterol again; Rotary evaporation forms thin film, adds step 2) the aqueous solution hydration of Radix Sophorae Flavescentis Rhizoma Polygonati extract, be prepared into liposome, high pressure homogenize 2min, lyophilizing or spray the dried powder that becomes.
Voriconazole is prepared into liposome, can be chimeric with phospholipid, both increased the dissolubility of voriconazole, also have the certain protection effect, improved the stability of voriconazole greatly, play certain slow releasing function simultaneously.Radix Sophorae Flavescentis, Rhizoma Polygonati extract are coated on the aqueous phase of liposome; Can play slow releasing function, Chinese medicine had both come out after the onset of chemical medicine voriconazole and had continued the performance drug effect, and slow release effect is more obvious; The Chinese medicine Rhizoma Polygonati has the certain repairing effect in vivo simultaneously, plays treatment and minors multiple effect.
Good effect of the present invention is:Radix Sophorae Flavescentis, Rhizoma Polygonati extract are coated on the aqueous phase of liposome, and voriconazole is on immobilized artificial membrane, and the preparation through liposome combines Chinese herbal medicine and Western medicine.Can play slow releasing function, Chinese medicine had both come out after the onset of chemical medicine voriconazole and had continued the performance drug effect, and slow release effect is more obvious, and the Chinese medicine Rhizoma Polygonati has the certain repairing effect in vivo simultaneously, plays treatment and minors multiple effect.Voriconazole is prepared into liposome, can be chimeric with phospholipid, both increased the dissolubility of voriconazole, also have the certain protection effect, improved the stability of voriconazole greatly, play certain slow releasing function simultaneously.
Description of drawings
Fig. 1 is that medicine of the present invention is at extracorporeal releasing experiment figure.
The practical implementation method
Embodiment 1:
Get exsiccant Radix Sophorae Flavescentis 200g, Rhizoma Polygonati 600g, add the water of 8000mL, extract 2 times, each 2h merges the water extract.Be concentrated into 10% ~ 20%, spray drying.Get the 10g spray powder and be dissolved in the 100mL water, as aqua liquid, subsequent use.Getting voriconazole 1g is dissolved in the 50mL chloroform.With the mixed of C/PL, use the 300mL dissolved in chloroform with 1:4.The chloroformic solution that will contain voriconazole then is added in the mixed liquor of C/PL mixing.Rotary Evaporators evaporate to dryness chloroform forms thin film, adds the aqua liquid hydration.High pressure homogenize, lyophilization gets lipid freeze-dry powder.
Embodiment 2:
Get exsiccant Radix Sophorae Flavescentis 300g, Rhizoma Polygonati 700g, add the water of 8000mL, extract 2 times, each 2h merges the water extract.Be concentrated into 10% ~ 20%, spray drying.Get the 10g spray powder and be dissolved in the 200mL water, as aqua liquid, subsequent use.Getting voriconazole 1.5g is dissolved in the 50mL chloroform.With the mixed of C/PL, use the 300mL dissolved in chloroform with 1:4.The chloroformic solution that will contain voriconazole then is added in the mixed liquor of C/PL mixing.Rotary Evaporators evaporate to dryness chloroform forms thin film, adds the aqua liquid hydration.High pressure homogenize, lyophilization gets lipid freeze-dry powder.
Embodiment 3:
Get exsiccant Radix Sophorae Flavescentis 400g, Rhizoma Polygonati 800g, add the water of 2400mL, extract 2 times, each 2h merges the water extract.Be concentrated into 10% ~ 20%, spray drying.Get the 20g spray powder and be dissolved in the 200mL water, as aqua liquid, subsequent use.Getting voriconazole 2g is dissolved in the 50mL chloroform.With the mixed of C/PL, use the 300mL dissolved in chloroform with 1:4.The chloroformic solution that will contain voriconazole then is added in the mixed liquor of C/PL mixing.Rotary Evaporators evaporate to dryness chloroform forms thin film, adds the aqua liquid hydration.High pressure homogenize, lyophilization gets lipid freeze-dry powder.
Embodiment 4:
Get lipid freeze-dry powder and microcrystalline Cellulose among the embodiment 1 with the mixed of 1:1, dry granulation, fill capsule.
Embodiment 5:
Get lipid freeze-dry powder and cyclodextrin among the embodiment 1, magnesium stearate ratio mixing, dry granulation, tabletting with 2:1:0.1.
Embodiment 6:
Get lipid freeze-dry powder and carbomer isogel substrate mixing among the embodiment 2, be prepared into gel.
Embodiment 7:
Get an amount of stearic acid, glyceryl monostearate, liquid paraffin, white vaseline, Arlacel-60, Tween-60 heat fused, the oil phase temperature is at 70-80 ℃; Other gets an amount of glycerol, sorbitol, water and is heated to 70-80 ℃, under agitation is added in the oil phase, continues to be stirred to about 60 ℃, slowly adds the lipid freeze-dry powder among the embodiment 3, continues to stir molding and promptly gets ointment.
Test Example 1
Gel and the ointment among the embodiment 7 got among the embodiment 6 are an amount of, with miconazole ointment and the positive contrast medicine of voriconazole sheet, carry out extracorporeal bacteria inhibitor test.Test method adopts K-B disk diffusion method to carry out antibacterial comparative experiments.Cut-off directly is the plate of 9cm, and the husky fort glucose agar medium of impouring 15mL processes flat board after the condensation.The cotton swab of usefulness sterilization dips in respectively gets trichophyton, staphylococcus aureus, Candida albicans test organisms suspension, evenly coats media surface by individual direction, encloses around edge one at last, processes to contain the bacterium flat board, and room temperature is placed 5min.Process the round scraps of paper of diameter 6mm with filter paper, through pressuresteam sterilization and dry for standby.The sample that every scraps of paper drip variable concentrations respectively is affixed on and contains on the bacterium flat board.Cultivate the 24h observed result for 28 ℃, accurately measure the scraps of paper size (mm) of antibacterial circle diameter on every side, survey and average for 3 times with slide calliper rule.The result sees table 1.
Table 1 K-B disk diffusion method experimental result
Inhibition zone is big more, and bacteriostasis is obvious more.Through with the commercially available miconazole ointment of antifungal agent preferably and voriconazole sheet relatively, find that the Chinese and Western of this method preparation combines antifungal liposome gel and ointment to have tangible bacteriostasis, and than the better effects if of positive control drug.
Test Example 2
Adopt the plate punch method, the impact effect that the Chinese and Western of research variable concentrations combines the antifungal liposome medicament that fungus is suppressed.
The preparation of bacterium liquid: get Aspergillus flavus and the trichophytons of cultivating for 2 weeks and put the sterilization mortar, add normal saline a little, grind and be emulsion, adding normal saline again, to regulate bacterial concentration be (1～5) * 10
6/ ml mycelia fragment.Candida albicans directly dilutes.
Bacterium basigamy method for making: each plate culture medium 20 ml contains bacterium liquid 0. 5 ml, and the punching diameter is 0. 5 cm.
Liquor strength: get the lipid freeze-dry powder among the embodiment 1, be made into the medicinal liquid of variable concentrations: 0.5%, 1.00%, 2.00%, 3.00%, 4.00%.Every hole adds variable concentrations medicinal liquid 40 ul respectively, puts 25 ℃ of incubators and cultivates.The result sees table 2.
The Chinese and Western of table 2 variable concentrations (%) combines the observation of antifungal liposome medicament to the fungus inhibition zone
| Strain name | 4.00% | 3.00% | 2.00 | 1.00 | 0.5 |
| Trichophyton | 2.0 | 1.8 | 1.5 | 1.0 | 0.6 |
| Aspergillus flavus | 2.2 | 1.9 | 1.5 | 1.2 | 0.7 |
| Candida albicans | 2.5 | 2.4 | 2.1 | 1.8 | 1.2 |
Different with drug level, the inhibition zone difference in size is obvious.Concentration is big more, and it is good more to suppress effect.
Test Example 3
Chinese and Western to embodiment 5 ~ 7 preparations combines antifungal liposome tablet, gel and emulsifiable paste to carry out extracorporeal releasing test.
The Chinese and Western that precision takes by weighing reference substance voriconazole and embodiment 5 ~ 7 preparations combines antifungal liposome tablet, gel and emulsifiable paste an amount of; Pack in the bag filter; With the pH7.4 PBS is release medium; Put into 37 ℃ of constant temperature water baths, take a sample at interval, add fresh release medium simultaneously and keep " sink condition " with certain hour.The employing HPLC detects.
Chromatographic condition is: chromatographic column: and Diamonsil C18 (250mm*4.6mm, 5um); Mobile phase: acetonitrile-water-acetic acid (40:60:0.25, V/V/V), flow velocity 1.0mL/min; Detect wavelength: 256nm; Sample size: 20uL.Theoretical cam curve is not less than 1500.The result sees Fig. 1, wherein, and B: tablet, C: gel: emulsifiable paste, E: voriconazole.
As can beappreciated from fig. 1, voriconazole release in vitro very fast, 120min discharges basically fully.And the Chinese and Western of this method preparation combines the antifungal liposome medicament to discharge slowly, about 200min, just discharges fully, has tangible slow releasing function.
Claims (3)
1. Chinese and Western combines the antifungal liposome, it is characterized in that mainly by following raw materials by weight portion than processing:
100 ~ 300 parts of Radix Sophorae Flavescentis Rhizoma Polygonati extracts, 10 ~ 30 parts in voriconazole powder, 800 ~ 1000 parts of hydrogenated soy phosphatidyl cholines, 200 ~ 300 parts in cholesterol.
2. combine the method for preparing of antifungal liposome according to Chinese and Western described in claims 1, may further comprise the steps:
1) 200 ~ 400 parts of Radix Sophorae Flavescentiss, Rhizoma Polygonati are added 8 ~ 12 times of water gaging mixing decoctings for 600 ~ 800 parts, extract 2 times, each 2h is concentrated to 10 ~ 20% and gets the Radix Sophorae Flavescentis Rhizoma Polygonati extract, is spray dried to dry powder;
2) Radix Sophorae Flavescentis Rhizoma Polygonati extract powder is 100 ~ 300 parts, is dissolved in 10 ~ 20 times the water, as the water of liposome;
3) get 10 ~ 30 parts in voriconazole powder, be dissolved in the chloroform solvent, mix for 200 ~ 300 parts with 800 ~ 1000 parts of hydrogenated soy phosphatidyl cholines, cholesterol again; Rotary evaporation forms thin film, adds step 2) the aqueous solution hydration of Radix Sophorae Flavescentis Rhizoma Polygonati extract, be prepared into liposome, high pressure homogenize 2min, lyophilizing or spray the dried powder that becomes.
3. combine the antifungal liposome to can be used for being prepared into oral formulations or external preparation such as gel, Emulsion such as tablet, capsule according to the Chinese and Western described in claims 1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107969706A (en) * | 2017-12-20 | 2018-05-01 | 吉林大学 | A kind of nanoscale enteral nutrition preparation and preparation method thereof |
| CN114931564A (en) * | 2022-05-31 | 2022-08-23 | 杭州赫贝科技有限公司 | Long-acting antifungal patch |
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| CN1985883A (en) * | 2005-12-24 | 2007-06-27 | 江苏中康药物科技有限公司 | Antifungal medicine composition and its preparing method and use |
| CN102058519A (en) * | 2010-11-19 | 2011-05-18 | 苏州特瑞药业有限公司 | Voriconazole slow-release suppository and preparation method thereof |
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2012
- 2012-04-26 CN CN201210124125.6A patent/CN102631544B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1985883A (en) * | 2005-12-24 | 2007-06-27 | 江苏中康药物科技有限公司 | Antifungal medicine composition and its preparing method and use |
| CN102058519A (en) * | 2010-11-19 | 2011-05-18 | 苏州特瑞药业有限公司 | Voriconazole slow-release suppository and preparation method thereof |
Non-Patent Citations (2)
| Title |
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| 吕小迅，周玉珍，吕华冲，马耀荣，袁敏玲: "黄芩、黄精抗真菌作用活性部位实验研究", 《广东药学院学报》, vol. 11, no. 03, 3 September 1995 (1995-09-03) * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107969706A (en) * | 2017-12-20 | 2018-05-01 | 吉林大学 | A kind of nanoscale enteral nutrition preparation and preparation method thereof |
| CN107969706B (en) * | 2017-12-20 | 2021-07-13 | 吉林大学 | Nano-scale enteral nutrition preparation and preparation method thereof |
| CN114931564A (en) * | 2022-05-31 | 2022-08-23 | 杭州赫贝科技有限公司 | Long-acting antifungal patch |
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