CN103585318A - Compound levofloxacin hydrochloride liposome and preparation method thereof - Google Patents
Compound levofloxacin hydrochloride liposome and preparation method thereof Download PDFInfo
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- CN103585318A CN103585318A CN201310592827.1A CN201310592827A CN103585318A CN 103585318 A CN103585318 A CN 103585318A CN 201310592827 A CN201310592827 A CN 201310592827A CN 103585318 A CN103585318 A CN 103585318A
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- levofloxacin hydrochloride
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- fructus mume
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Abstract
The invention relates to a compound liposome of an antibacterial medicine levofloxacin hydrochloride and a preparation method thereof. By virtue of synergy of levofloxacin hydrochloride and dark plum, effects of the levofloxacin hydrochloride and the dark plum are significantly enhanced through the compound liposome; escherichia coli is a Gram-negative bacterium, an outer leaf layer of an outer membrane mainly comprises LPS (lipopolysaccharide), and the internal mobility is extremely low, so that some antibiotics can be effectively excluded; after the levofloxacin hydrochloride and the dark plum are prepared into the compound liposome, the liposome can be effectively adhered to a cell wall of the escherichia coli to break the formation of the cell wall, penetrates into the outer cell membrane, and further enters the interior of the bacterium by being combined with the outer membrane, thereby achieving a relatively good antibacterial effect.
Description
Technical field
The invention provides a kind of levofloxacin hydrochloride complex liposome, also disclose its preparation method simultaneously, belong to medical technical field.
Background technology
In China's medical market, it is the first that the sales volume of anti-infectives occupy all the time, annual sales amount is about more than 300 hundred million yuan, account for 30% left and right of national drug market, at present in anti-infectives market, quinolones consumption has clinically surpassed penicillins, becomes second largest antibacterials.According to estimates, in the novel antibacterial drug products coming into the market, have 1/3 for fluoroquinolones.World's fluoroquinolones is mainly taken as the leading factor with levofloxacin and ciprofloxacin at present, both summations account for 65% left and right of fluoroquinolones global marketing volume, wherein levofloxacin at home the consumption sum of 2003 be 18.83 hundred million yuan, rank first of quinolone antibiotic medicine.The market sales revenue of levofloxacin still keeps the impetus of rapid growth at present, and therefore the better Levaquin of exploitation has huge market prospect.
Infected by microbes is the important diseases of harm humans life and health, and levofloxacin is that Japanese Daiichi Pharmaceutical Co., Ltd. developed in 1986, within 1994, pushes the fluoroquinolone antibacterial agent of Japanese market to.It demonstrates excellent effect to the infection compared with position, deep intractable, complexity especially, is mainly used in clinically that responsive microbial breathing, urinary system, reproduction, skin soft tissue etc. are light, severe infection.But also there are many untoward reaction simultaneously, as gastrointestinal reaction, abdominal discomfort or pain, diarrhoea, n or V; Reaction of central nervous system can have giddy, headache, drowsiness or insomnia; Anaphylaxis has erythra, skin pruritus, occasionally hebra's disease and vasodilation can occur.The dosage form that levofloxacin hydrochloride goes on the market at home at present mainly contains the ordinary preparations such as tablet, capsule, injection and eye drop, temporarily without having slow release, short new formulation appearance of oozing effect.
And liposome is a kind of novel drug-loading system that development in recent years is got up, by phospholipid and cholesterol, formed, can seal water soluble drug, can seal fat-soluble medicine again.The liposome that the ammonium sulphate gradient of take is prepared as the long-range drug delivery technologies on basis, has not easy to leak, and the liposome of preparing compared with traditional method is stable.Liposome also has affinity, slow-releasing, attenuating drug toxicity, increases the advantages such as medicine stability.Therefore, as drug delivery system, there is very large advantage.
The features such as the contained antibiotic substance of Chinese herbal medicine has the generation of being difficult for drug resistance, and toxic and side effects is little, safety height, wherein, Fructus Mume can be restrained and be promoted the production of body fluid, relieving colic caused by ascaris anthelmintic. control chronic cough, deficiency-heat excessive thirst, chronic malaria, chronic diarrhea, dysentery, has blood in stool, hematuria, metrorrhagia, ascariasis of biliary tract stomachache, vomiting, ancylostomiasis, psoriasis, bulbar conjunctiva polyp etc.Its contained organic acid has very strong killing action to the pathogen such as mycete of invading in gastrointestinal tract.
summary of the invention:
The invention discloses a kind of levofloxacin hydrochloride complex liposome, it is characterized in that by following raw materials by weight portion than making:
Levofloxacin hydrochloride: 1 ~ 2, phospholipid: 10 ~ 20, cholesterol: 10, surfactant: 1 ~ 2, Fructus Mume extract 0.01 ~ 2.
Wherein, Fructus Mume extract obtains by following preparation technology:
Water soaking 2 ~ the 3h that adds 5 times of amounts in Fructus Mume, strong fire is heated to boil with slow fire boiling 40 ~ 60min again, filters, and collects filtrate, is placed in 4 ℃ of preservations, and residue adds 3 times of water gagings, soaks 2 ~ 3h, then decocts 30 ~ 60min, filters, and merges filtrate 2 times, and spraying is dry.
Levofloxacin hydrochloride complex liposome provided by the invention obtains by following preparation technology:
Said mixture is added to 17 times of amounts (g/ml) ethanol, and carry out supersound process and make it fully be dissolved to clarification; The alcoholic solution that this is dissolved with to medicine is injected in 35 ℃ of aqueous solutions that contain 3% ammonium sulfate fast, rotating speed is 500rpm simultaneously, stir 3min, solution is light blue opalescence, the bag filter that this solution is housed is placed in to PH7.4, and temperature is in the PBS buffer solution of 37 ℃, dialysis 24h, remove ammonium sulfate, both obtained liposome turbid liquor.
The invention also discloses the application of this complex liposome suspension in preparation antibacterials, make the oral formulations such as tablet, capsule, powder, granule, oral liquid, be used for the treatment of that responsive microbial breathing, urinary system, reproduction, skin soft tissue etc. are light, severe infection.
good effect of the present invention is:
Utilize the synergism of levofloxacin hydrochloride and Fructus Mume, by complex liposome, levofloxacin hydrochloride and Fructus Mume action effect are significantly strengthened, because escherichia coli are gram negative bacterias, adventitia siphonal lobe layer mainly contains LPS and forms, internal liquidity is extremely low, can effectively repel part antibiotic, the husky star of the left oxygen method of hydrochloric acid and Fructus Mume are made after complex lipid body preparation, liposome can effectively stick on Bacillus coli cells wall, destroy the generation of cell wall, invade on epicyte, and then enter antibacterial inside by being combined with adventitia, reach good fungistatic effect.
The specific embodiment
Below in conjunction with embodiment, the present invention is further explained.Should be understood that, following examples are only for explaining the present invention, rather than limit the scope of the invention.
embodiment 1
The present embodiment is the preparation of Fructus Mume extract.
Get Fructus Mume 50g, add the water soaking 2h of 250ml, strong fire is heated to boil with slow fire boiling 40min again, filters, and collects filtrate, is placed in 4 ℃ of preservations, and residue adds 3 times of water gagings, soaks 2h, then decocts 30min, filters, and merges filtrate 2 times, and spraying is dry.
embodiment 2
Liposome turbid liquor prepared by the present embodiment, it consists of levofloxacin hydrochloride, phospholipid (soybean lecithin), cholesterol, sorbester p17, Fructus Mume extract.
Get the water soaking 2.5h that Fructus Mume 100g adds 500ml, strong fire is heated to boil with slow fire boiling 40min again, filters, and collects filtrate, is placed in 4 ℃ of preservations, and residue adds 3 times of water gagings, soaks 2h, then decocts 30min, filters, and merges filtrate 2 times, and spraying is dry.
By levofloxacin hydrochloride 2g, phospholipid (soybean lecithin) 20g, cholesterol 10g, sorbester p17: 2g, Fructus Mume extract 2g adds 650ml ethanol, and carries out supersound process and make it fully be dissolved to clarification; The alcoholic solution that this is dissolved with to medicine is injected in 35 ℃ of aqueous solutions that contain 3% ammonium sulfate fast, rotating speed is 500rpm simultaneously, stir 3min, solution is light blue opalescence, the bag filter that this solution is housed is placed in to PH7.4, and temperature is in the PBS buffer solution of 37 ℃, dialysis 24h, remove ammonium sulfate, both obtained liposome turbid liquor.
embodiment 3
Liposome turbid liquor prepared by the present embodiment, it consists of levofloxacin hydrochloride, phospholipid (soybean lecithin), cholesterol, Tween 80, Fructus Mume extract.
Get the water soaking 2h that Fructus Mume 200g adds 1000ml, strong fire is heated to boil with slow fire boiling 60min again, filters, and collects filtrate, is placed in 4 ℃ of preservations, and residue adds 3 times of water gagings, soaks 2h, then decocts 30min, filters, and merges filtrate 2 times, and spraying is dry.
By levofloxacin hydrochloride 2g, phospholipid (soybean lecithin) 20g, cholesterol, Tween 80: 2g, Fructus Mume extract 2g adds 650ml ethanol, and carries out supersound process and make it fully be dissolved to clarification; The alcoholic solution that is dissolved with medicine is injected in 35 ℃ of aqueous solutions that contain 3% ammonium sulfate fast, rotating speed is 500rpm simultaneously, stir 3min, solution is light blue opalescence, the bag filter that this solution is housed is placed in to PH7.4, and temperature is in the PBS buffer solution of 37 ℃, dialysis 24h, remove ammonium sulfate, both obtained liposome turbid liquor.
embodiment 4
Liposome turbid liquor prepared by the present embodiment, it consists of levofloxacin hydrochloride, phospholipid (soybean lecithin), cholesterol, sorbester p17, Fructus Mume extract.
Get the water soaking 3h that Fructus Mume 100g adds 500ml, strong fire is heated to boil with slow fire boiling 60min again, filters, and collects filtrate, is placed in 4 ℃ of preservations, and residue adds 3 times of water gagings, soaks 2h, then decocts 30min, filters, and merges filtrate 2 times, and spraying is dry.
By levofloxacin hydrochloride 2g, phospholipid (soybean lecithin) 10g, cholesterol 10g, sorbester p17 2g, Fructus Mume extract 2g adds 450ml ethanol, and carries out supersound process and make it fully be dissolved to clarification; The alcoholic solution that is dissolved with medicine is injected in 35 ℃ of aqueous solutions that contain 3% ammonium sulfate fast, rotating speed is 500rpm simultaneously, stir 3min, solution is light blue opalescence, the bag filter that this solution is housed is placed in to PH7.4, and temperature is in the PBS buffer solution of 37 ℃, dialysis 24h, remove ammonium sulfate, both obtained liposome turbid liquor.
embodiment 5
Liposome turbid liquor prepared by the present embodiment, it consists of levofloxacin hydrochloride, phospholipid (soybean lecithin), cholesterol, sorbester p17, Fructus Mume extract.
Get the water soaking 2h that Fructus Mume 100g adds 500ml, strong fire is heated to boil with slow fire boiling 50min again, filters, and collects filtrate, is placed in 4 ℃ of preservations, and residue adds 3 times of water gagings, soaks 3h, then decocts 40min, filters, and merges filtrate 2 times, and spraying is dry.
By levofloxacin hydrochloride 1g, phospholipid (soybean lecithin) 20g, cholesterol 10g, sorbester p17: 2g, Fructus Mume extract 1.5g adds 600ml ethanol, and carries out supersound process and make it fully be dissolved to clarification; The alcoholic solution that is dissolved with medicine is injected in 35 ℃ of aqueous solutions that contain 3% ammonium sulfate fast, rotating speed is 500rpm simultaneously, stir 3min, solution is light blue opalescence, the bag filter that this solution is housed is placed in to PH7.4, and temperature is in the PBS buffer solution of 37 ℃, dialysis 24h, remove ammonium sulfate, both obtained liposome turbid liquor.
embodiment 6
Liposome turbid liquor prepared by the present embodiment, it consists of levofloxacin hydrochloride, phospholipid (soybean lecithin), cholesterol, sorbester p17, Fructus Mume extract.
Get the water soaking 3h that Fructus Mume 100g adds 500ml, strong fire is heated to boil with slow fire boiling 60min again, filters, and collects filtrate, is placed in 4 ℃ of preservations, and residue adds 3 times of water gagings, soaks 3h, then decocts 40min, filters, and merges filtrate 2 times, and spraying is dry.
By levofloxacin hydrochloride 2g, phospholipid (soybean lecithin) 10g, cholesterol 10g, sorbester p17: 2g, Fructus Mume extract 0.5g adds 450ml ethanol, and carries out supersound process and make it fully be dissolved to clarification; The alcoholic solution that is dissolved with medicine is injected in 35 ℃ of aqueous solutions that contain 3% ammonium sulfate fast, rotating speed is 500rpm simultaneously, stir 3min, solution is light blue opalescence, the bag filter that this solution is housed is placed in to PH7.4, and temperature is in the PBS buffer solution of 37 ℃, dialysis 24h, remove ammonium sulfate, both obtained liposome turbid liquor.
following experiment has shown the beneficial effect of compound recipe liposome of the present invention
1. experiment material and method
1.1 experiment material
Escherichia coli (middle inspection institute 140732), peptone (Beijing extensive and profound in meaning star biotechnology Co., Ltd), yeast extract (Beijing extensive and profound in meaning star biotechnology Co., Ltd), sodium chloride (Beijing Chemical Plant), agar powder (Chinese Hui Shi biochemical reagents company limited), levofloxacin hydrochloride (Dong Kang source, Wuhan Science and Technology Ltd.), Fructus Mume extract (above-mentioned experiment gained), levofloxacin hydrochloride complex liposome (gained of the present invention).The reagent that this experiment is used, apparatus all passes through high pressure steam sterilization, and all operations all carries out on the ultra-clean testing stand of sterilizing room.
1.2 experimental techniques:
1.2.1 the preparation of LB culture medium:
LB fluid medium: get peptone 10g, yeast extract 5g, sodium chloride 10g is dissolved in 1L deionized water, in 121 ℃ of sterilizing 20min.LB solid medium: get peptone 10g, yeast extract 5g, sodium chloride 10g, agar powder 15g, is dissolved in 1L deionized water, in 121 ℃ of sterilizing 20min.LB semisolid culturemedium: get peptone 10g, yeast extract 5g, sodium chloride 10g, agar powder 7.5g, is dissolved in 1L deionized water, in 121 ℃ of sterilizing 20min.
1.2.2 bacteriostatic experiment:
The Escherichia coli bacteria liquid (in exponential phase) of cultivating after 6 hours is mixed homogeneously with top-layer agar culture medium after (bacteria containing amount is 1%), be down flat plate and cover plate and cover, room temperature standing a moment.
Get solid medium 20ml as bottom culture medium, get semisolid culturemedium (bacteria containing amount is 1%) 5.5ml as upper strata culture medium, after solidifying, by levofloxacin hydrochloride chemical medicine solution (A), Fructus Mume extracting solution (B), levofloxacin hydrochloride and Fructus Mume extract (weight ratio 1:1) mixed liquor (C), levofloxacin hydrochloride complex liposome suspension (is respectively embodiment 2, embodiment 3, embodiment 4, embodiment 5), each liquid is got same volume and is injected into separately respectively in corresponding dull and stereotyped Oxford cup (50mg/ml), cover plate lid, put in constant incubator, cultivate after 24 hours, observed result, with bacterial colony counting instrument, measure inhibition zone diameter, record data, unit is mm.Experiment repeats 3 times.
2. experimental result
The antibacterial circle diameter size of the different antibacterial of table 1
From result, simple levofloxacin hydrochloride chemical medicine (A) is more or less the same with the antibacterial circle diameter of simple Fructus Mume extract (B), and in C group, the antibacterial circle diameter of its mixed liquor gained is but obviously greater than drug alone, illustrate after levofloxacin hydrochloride and Fructus Mume form mixture and aspect bacteriostatic activity, there is obvious synergism, and this basis upper according to the present invention prepared levofloxacin hydrochloride complex liposome (embodiment 2, embodiment 3, embodiment 4, embodiment 5) its inhibition zone is apparently higher than simple levofloxacin hydrochloride and Fructus Mume mixture (C), this complex liposome strengthens levofloxacin hydrochloride and Fructus Mume action effect, because escherichia coli are gram negative bacterias, adventitia siphonal lobe layer mainly contains LPS and forms, internal liquidity is extremely low, can effectively repel part antibiotic, the husky star of the left oxygen method of hydrochloric acid and Fructus Mume are made after complex lipid body preparation, liposome can effectively stick on Bacillus coli cells wall, destroy the generation of cell wall, invade on epicyte, and then enter antibacterial inside by being combined with adventitia, reach good fungistatic effect.Separately due to tween, the special chemical structure of span, the liposome of formation can better adhere on the cell wall of antibacterial.Therefore, according to the prepared levofloxacin hydrochloride complex liposome of the present invention, aspect antibacterial activity, be significantly increased.
Claims (2)
1. a levofloxacin hydrochloride complex liposome, it is characterized in that being made by ratio of weight and the number of copies by following medicine:
Levofloxacin hydrochloride: 1 ~ 2, phospholipid: 10 ~ 20, cholesterol: 10, surfactant: 1 ~ 2, Fructus Mume extract 0.01 ~ 2.
2. levofloxacin hydrochloride complex lipid preparation according to claim 1, is characterized in that:
Said mixture is added to 17 times of amounts (g/ml) ethanol, and carry out supersound process and make it fully be dissolved to clarification; The alcoholic solution that this is dissolved with to medicine is injected in 35 ℃ of aqueous solutions that contain 3% ammonium sulfate fast, rotating speed is 500rpm simultaneously, stir 3min, solution is light blue opalescence, the bag filter that this solution is housed is placed in to PH7.4, and temperature is in the PBS buffer solution of 37 ℃, dialysis 24h, remove ammonium sulfate, both obtained liposome turbid liquor;
Described Fructus Mume extract preparation method is as follows:
Water soaking 2 ~ the 3h that adds 5 times of amounts in Fructus Mume, strong fire is heated to boil with slow fire boiling 40 ~ 60min again, filters, and collects filtrate, is placed in 4 ℃ of preservations, and residue adds 3 times of water gagings, soaks 2 ~ 3h, then decocts 30 ~ 60min, filters, and merges filtrate 2 times, and spraying is dry.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104274499A (en) * | 2014-10-21 | 2015-01-14 | 河南牧翔动物药业有限公司 | Oil-in-water type compound minocyline antibacterial medicine |
-
2013
- 2013-11-22 CN CN201310592827.1A patent/CN103585318B/en active Active
Non-Patent Citations (3)
| Title |
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| 宋波等: "苦参、黄芩、乌梅对金黄色葡萄球菌、大肠埃希菌和白假丝酵母菌抗菌活性的研究", 《中国微生态学杂志》 * |
| 张青等: "盐酸左氧氟沙星脂质体的包封率和体外释放研究", 《中国药科大学学报》 * |
| 施洁明等: "表面活性剂在新剂型中的应用", 《中国药房》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104274499A (en) * | 2014-10-21 | 2015-01-14 | 河南牧翔动物药业有限公司 | Oil-in-water type compound minocyline antibacterial medicine |
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