CN1422611A - Albendazole lipid and method for preparing said lipid by neutralization method - Google Patents
Albendazole lipid and method for preparing said lipid by neutralization method Download PDFInfo
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- CN1422611A CN1422611A CN 02152519 CN02152519A CN1422611A CN 1422611 A CN1422611 A CN 1422611A CN 02152519 CN02152519 CN 02152519 CN 02152519 A CN02152519 A CN 02152519A CN 1422611 A CN1422611 A CN 1422611A
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Abstract
The present invention relates to an albendazole diposome, its composition contains (wt%) 0.50-1.00% of albendazole powder, 1.00-3.00% of lecithin, 0-0.30% of sodium benzoate, 0-0.02% of antioxidant and the rest is 0.7-0.9% of sodium chloride solution. Said invention can improve solubility of albendazole, raise biological utilization coefficient of albendazole, raise target property and its medicinal clinical therapeutic effect. Said invention provides a neutralization method to prepare liposome, which can be used for preparing liposome of other similar substances. Said invention does not use chloroform, acetone, ethyl ether and other organic solvent.
Description
One, technical field:
The present invention relates to liposome and preparation method thereof, is a kind of albendazole liposomes and neutralisation preparation method thereof, is applied to the parasite of human control especially.
Two, background technology:
When being dispersed in lipoids materials such as phospholipid in the water, can form multilamellar vesicle, every layer of bilayer that is lipid.Separated by water between vesicle central authorities and each layer, this vesicle with similar biomembrane bimolecular structure is called liposome (liposomes) (referring to " the potential method on the cancer chemotherapy-seal the actinomycin D of liposome " experiment biomedicine field journal of people such as Rahman Y E, 1974,146 (4): 1173).By certain method and technology, can be in the bilayer of liposome with drug encapsulation, making liposome is that pharmaceutical carrier is used as the instrument of delivery medicine.Liposome has characteristics such as biodegradable in vivo, avirulence and non-immunogenicity as pharmaceutical carrier, particularly its natural targeting, characteristics such as long-lasting are in the research that targeting vector is widely used in medicines such as antitumor, parasiticide, biovaccine.
Prepare at present that liposome is commonly used to be had with main method; Membrane process is (referring to Rahman Y E, " steroid compound and streptolysin S are to the infiltrative effect of cationic phospholipid structure " molecular biology magazine Deng the people, 1965,13:238), reverse phase evaporation is (referring to Szoka F, the academic journal 1978 of " process of water and high envelop rate liposome in the reverse phase evaporation preparation " U.S. science country Deng the people, 75:4194.), injection method is (referring to Deamer D, " the ether evaporation prepares big unilamellar liposome " biochemistry biophysics journal 1976 Deng the people, 443:629), freeze-drying (the biology techniques of writing referring to people such as Kirby C, the 2979th page 1984), the pro-liposome method is (referring to " pro-liposome: a kind of new departure that solves old problem " medicament science magazine 1986 of people such as Payne NI, 75:325) etc.
These methods adopt chloroform, ether or ethanol etc. that lipoids such as phospholipid dissolving back redispersion is formed liposome at aqueous phase more.Albendazole (Albendazole) belongs to benzimidazoles derivative, chemistry [5-(rosickyite base)-1H-benzimidazolyl-2 radicals-yl] methyl carbamate by name, it is not only a kind of broad-spectrum anti-parasite medicine, also being a kind of medicine of comparatively ideal treatment echinococcosis, is one of main medicine of the The World Health Organization (WHO) anti-Echinococcus hydatid cyst of recommending.Because albendazole is insoluble in water, slightly soluble in acetone, ether or chloroform, almost insoluble in ethanol (referring to two ones of Pharmacopoeia of People's Republic of China .2000 versions. the 333-334 of Chemical Industry Press page or leaf) therefore, limited the performance of absorption in vivo such as albendazole prior dosage form such as tablet, capsule and drug effect.Albendazole is prepared into albendazole liposomes, can improves its dissolubility, improve bioavailability, the clinical efficacy of intensifier target tropism and raising medicine.But reported method is difficult to it is prepared into the albendazole liposomes preparation because the slightly solubility of albendazole makes now.
Three, summary of the invention:
The invention solves a difficult problem of albendazole being made albendazole liposomes, and provide a kind of neutralisation to prepare the new method of liposome, be particularly useful for making albendazole liposomes, also available neutralisation prepares the liposome of other allied substances.
The present invention is achieved by the following measures:
A kind of albendazole liposomes, percent by volume is made of following composition by weight: A. has 0.50 to 1.00% albendazole powder; B., 1.00 to 3.00% lecithin is arranged; C., 0 to 0.30% sodium benzoate is arranged; D.0 to 0.02% antioxidant; E. surplus is 0.7 to 0.9% sodium chloride solution.
A kind of neutralisation preparation method of albendazole liposomes, undertaken by following step: percent by volume is dissolved in 0.50 to 1.00% albendazole powder and 1.00 to 3.00% lecithin in the glacial acetic acid at first by weight, secondly with sodium hydroxide solution acid is neutralized, the control pH value is 5 or 6 or 7, obtains containing the albendazole liposomes of sodium acetate; The sodium acetate of removing in the neutralization reaction to be produced through dialysis then, after 0 to 4 ℃ ice-water bath and 0 to 40 minute supersound process, 0.7 to 0.9% sodium chloride solution of sodium benzoate, 0 to 0.02% antioxidant and the surplus of adding 0 to 0.30% obtains albendazole liposomes; Wherein, antioxidant is vitamin E or/and vitamin C, and the amount of glacial acetic acid is equal to or greater than the glacial acetic acid amount that can dissolve albendazole powder and lecithin.
A kind of neutralisation prepares liposome method, undertaken by following step: percent by volume is dissolved in 1.00 to 3.00% lecithin in the glacial acetic acid at first by weight, secondly with sodium hydroxide solution acid is neutralized, the control pH value is 5 or 6 or 7, obtains containing the liposome of sodium acetate; The sodium acetate of removing in the neutralization reaction to be produced through dialysis then after 0 to 4 ℃ ice-water bath and 0 to 40 minute supersound process, adds 0.7 to 0.9% sodium chloride solution of 0 to 0.30% sodium benzoate, 0 to 0.02% antioxidant and surplus, obtains liposome; Wherein, antioxidant be vitamin E or and vitamin C, the amount of glacial acetic acid be equal to or greater than can dissolving lecithin the glacial acetic acid amount.
The present invention is prepared into albendazole liposomes with albendazole, can improve the dissolubility of albendazole, improves the albendazole bioavailability, the clinical efficacy of intensifier target tropism and raising medicine.The invention provides the new method that a kind of neutralisation prepares liposome, be particularly useful for making albendazole liposomes, also available neutralisation prepares the liposome of other allied substances, as: medicines such as benzimidazoles derivative are made liposome.In the method for the invention, do not use organic solvents such as chloroform, acetone, ether, environmental pollution is little in the production, easy operating and suitability for industrialized production.
Five, the specific embodiment:
The present invention is not subjected to the restriction of following embodiment.
Embodiment 1: per 100 milliliters of 0.7% or 0.9% sodium chloride solutions by 1.00 or 3.00% lecithin, 0 or 0.15% or 0.30% sodium benzoate, 0 or 0.01% or 0.02% antioxidant and surplus of the liposome of pastille (blank liposome) are not formed.Its preparation method is as follows: earlier 1.0 grams or 3.0 gram phospholipid etc. are dissolved in the glacial acetic acid, with sodium hydroxide solution acid are neutralized then, the control pH value is 5 or 6 or 7, obtains containing the blank liposome of sodium acetate; Remove sodium acetate through dialysis, ice-water bath (0 or 2 or 4 ℃), ultrasonic 0 or 20 minute or 30 minutes or 40 minutes; Add 0 gram or 0.15 gram or 0.30 gram sodium benzoate and 0 gram or 0.01 gram or 0.02 gram antioxidant, add 0.7% or 0.9% sodium-chloride water solution to 100 and milliliter obtain blank liposome.
Embodiment 2: per 100 milliliters of 0.7% or 0.9% sodium chloride solutions by 0.50% or 1.00% albendazole powder, 1.00% lecithin, 0 or 0.15% or 0.30% sodium benzoate, 0 or 0.01% or 0.02% antioxidant and surplus of albendazole liposomes are formed.Its preparation method is as follows: earlier 0.5 gram or 1.0 gram albendazoles (medicine) and 1.0 gram phospholipid etc. are dissolved in the glacial acetic acid, with sodium hydroxide solution acid are neutralized then, the control pH value is 5 or 6 or 7, must contain the albendazole liposomes of sodium acetate; Remove sodium acetate through dialysis, ice-water bath (0 or 2 or 4 ℃), ultrasonic 0 or 20 minute or 30 minutes or 40 minutes; Add 0 gram or 0.15 gram or 0.30 gram sodium benzoate and 0 gram or 0.01 gram or 0.02 gram antioxidant, add 0.7% or 0.90% sodium-chloride water solution to 100 and milliliter promptly get envelop rate on average at the albendazole liposomes of 29.5 ± 4.8 (%).
Embodiment 3: per 100 milliliters of 0.7% or 0.9% sodium chloride solutions by 0.50% or 1.00% albendazole powder, 1.50% lecithin, 0 or 0.15% or 0.30% sodium benzoate, 0 or 0.01% or 0.02% antioxidant and surplus of albendazole liposomes are formed.Its preparation method is as follows: earlier 0.5 gram or 1.0 gram albendazoles (medicine) and 1.5 gram phospholipid etc. are dissolved in the glacial acetic acid, with sodium hydroxide solution acid are neutralized then, the control pH value is 5 or 6 or 7, must contain the albendazole liposomes of sodium acetate; Remove sodium acetate through dialysis, ice-water bath (0 or 2 or 4 ℃), ultrasonic 0 or 20 minute or 30 minutes or 40 minutes; Add 0 gram or 0.15 gram or 0.30 gram sodium benzoate and 0 gram or 0.01 gram or 0.02 gram antioxidant, add 0.7% or 0.90% sodium-chloride water solution to 100 and milliliter promptly get envelop rate on average at the albendazole liposomes of 50.5 ± 5.3 (%).
Embodiment 4: per 100 milliliters of 0.7% or 0.9% sodium chloride solutions by 0.50% or 1.00% albendazole powder, 2.00% lecithin, 0 or 0.15% or 0.30% sodium benzoate, 0 or 0.01% or 0.02% antioxidant and surplus of albendazole liposomes are formed.Its preparation method is as follows: earlier 0.5 gram or 1.0 gram albendazoles (medicine) and 2.0 gram phospholipid etc. are dissolved in the glacial acetic acid, with sodium hydroxide solution acid are neutralized then, obtain containing the albendazole liposomes of sodium acetate, the control pH value is 5 or 6 or 7; Remove sodium acetate through dialysis, ice-water bath (0 or 2 or 4 ℃), ultrasonic 0 or 20 minute or 30 minutes or 40 minutes; Add 0 gram or 0.15 gram or 0.30 gram sodium benzoate and 0 gram or 0.01 gram or 0.02 gram antioxidant, add 0.7% or 0.90% sodium-chloride water solution to 100 and milliliter promptly get envelop rate on average at the albendazole liposomes of 76.4 ± 3.8 (%).
Embodiment 5: per 100 milliliters of 0.7% or 0.9% sodium chloride solutions by 0.50% or 1.00% albendazole powder, 2.50% lecithin, 0 or 0.15% or 0.30% sodium benzoate, 0 or 0.01% or 0.02% antioxidant and surplus of albendazole liposomes are formed.Its preparation method is as follows: earlier 0.5 gram or 1.0 gram albendazoles (medicine) and 2.5 gram phospholipid etc. are dissolved in the glacial acetic acid, with sodium hydroxide solution acid are neutralized then, obtain containing the albendazole liposomes of sodium acetate, the control pH value is 5 or 6 or 7; Remove sodium acetate through dialysis, ice-water bath (0 or 2 or 4 ℃), ultrasonic 0 or 20 minute or 30 minutes or 40 minutes; Add 0 gram or 0.15 gram or 0.30 gram sodium benzoate and 0 gram or 0.01 gram or 0.02 gram antioxidant, add 0.7% or 0.90% sodium-chloride water solution to 100 and milliliter promptly get envelop rate on average at the albendazole liposomes of 80.4 ± 3.4 (%).
Embodiment 6: per 100 milliliters of 0.7% or 0.9% sodium chloride solutions by 0.50% or 1.00% albendazole powder, 3.00% lecithin, 0 or 0.15% or 0.30% sodium benzoate, 0 or 0.01% or 0.02% antioxidant and surplus of albendazole liposomes are formed.Its preparation method is as follows: earlier 0.5 gram or 1.0 gram albendazoles (medicine) and 3.0 gram phospholipid etc. are dissolved in the glacial acetic acid, with sodium hydroxide solution acid are neutralized then, the control pH value is 5 or 6 or 7, obtains containing the albendazole liposomes of sodium acetate; Remove sodium acetate through dialysis, ice-water bath (0 or 2 or 4 ℃), ultrasonic 0 or 20 minute or 30 minutes or 40 minutes; Add 0 gram or 0.15 gram or 0.30 gram sodium benzoate and 0 gram or 0.01 gram or 0.02 gram antioxidant, add 0.7% or 0.90% sodium-chloride water solution to 100 and milliliter promptly get envelop rate on average at the albendazole liposomes of 83.7 ± 4.1 (%).
In embodiment 1 to 6: antioxidant is vitamin E or/and vitamin C, and the amount of glacial acetic acid is equal to or greater than the glacial acetic acid amount that can dissolve albendazole powder and lecithin.
In embodiment 2 to 6: the assay method of envelop rate adopts the dextran gel filtration method, " modern medicine experiment skill pandect " 493-495 page or leaf that people such as the dextran gel filtration method side of seeing for details Ford chief editor's nineteen ninety-five is published by publishing house of Beijing Medical University.
With embodiment 2 to 6 gained albendazole liposomes with negative staining [referring to the 3rd chapter 140-152 page or leaf in " liposome-paractical research " book of Roger R.C.NEW chief editor) observe down at JEM-100CX (II) ultramicroscope (NEC company) and to take pictures, the present invention can make the form of albendazole liposomes of gained through electron microscope observation, be the multilamellar liposome structure, particle diameter is at 0.07 to 0.16 μ m, do not use organic solvents such as chloroform, acetone, ether in the preparation, environmental pollution is little in the production, easy operating and suitability for industrialized production.
Claims (3)
1. albendazole liposomes, it is characterized in that percent by volume is made of following composition by weight: A. has 0.50 to 1.00% albendazole powder; B., 1.00 to 3.00% lecithin is arranged; C., 0 to 0.30% sodium benzoate is arranged; D.0 to 0.02% antioxidant; E. surplus is 0.7 to 0.9% sodium chloride solution.
2. the neutralisation preparation method of an albendazole liposomes, it is characterized in that being undertaken by following step: percent by volume is dissolved in 0.50 to 1.00% albendazole powder and 1.00 to 3.00% lecithin in the glacial acetic acid at first by weight, secondly with sodium hydroxide solution acid is neutralized, the control pH value is 5 or 6 or 7, obtains containing the albendazole liposomes of sodium acetate; The sodium acetate of removing in the neutralization reaction to be produced through dialysis then, after 0 to 4 ℃ ice-water bath and 0 to 40 minute supersound process, 0.7 to 0.9% sodium chloride solution of sodium benzoate, 0 to 0.02% antioxidant and the surplus of adding 0 to 0.30% obtains albendazole liposomes; Wherein, antioxidant is vitamin E or/and vitamin C, and the amount of glacial acetic acid is equal to or greater than the glacial acetic acid amount that can dissolve albendazole powder and lecithin.
3. a neutralisation prepares liposome method, it is characterized in that being undertaken by following step: percent by volume is dissolved in 1.00 to 3.00% lecithin in the glacial acetic acid at first by weight, secondly with sodium hydroxide solution acid is neutralized, the control pH value is 5 or 6 or 7, obtains containing the liposome of sodium acetate; The sodium acetate of removing in the neutralization reaction to be produced through dialysis then after 0 to 4 ℃ ice-water bath and 0 to 40 minute supersound process, adds 0.7 to 0.9% sodium chloride solution of 0 to 0.30% sodium benzoate, 0 to 0.02% antioxidant and surplus, obtains liposome; Wherein, antioxidant be vitamin E or and vitamin C, the amount of glacial acetic acid be equal to or greater than can dissolving lecithin the glacial acetic acid amount.
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| CN 02152519 CN1222276C (en) | 2001-11-21 | 2002-11-20 | Albendazole lipid and method for preparing said lipid by neutralization method |
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| CN01137699.6 | 2001-11-21 | ||
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| CN 02152519 CN1222276C (en) | 2001-11-21 | 2002-11-20 | Albendazole lipid and method for preparing said lipid by neutralization method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105232465A (en) * | 2015-11-11 | 2016-01-13 | 郑州后羿制药有限公司 | Fenbendazole liposome preparation and preparing method thereof |
| CN108210460A (en) * | 2016-12-13 | 2018-06-29 | 河南后羿实业集团有限公司 | A kind of preparation method of albendazole liposomes preparation |
| CN115429756A (en) * | 2021-11-05 | 2022-12-06 | 烟台药物研究所 | Albendazole lipid compound and preparation method and application thereof |
-
2002
- 2002-11-20 CN CN 02152519 patent/CN1222276C/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105232465A (en) * | 2015-11-11 | 2016-01-13 | 郑州后羿制药有限公司 | Fenbendazole liposome preparation and preparing method thereof |
| CN108210460A (en) * | 2016-12-13 | 2018-06-29 | 河南后羿实业集团有限公司 | A kind of preparation method of albendazole liposomes preparation |
| CN115429756A (en) * | 2021-11-05 | 2022-12-06 | 烟台药物研究所 | Albendazole lipid compound and preparation method and application thereof |
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| CN1222276C (en) | 2005-10-12 |
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