CN101249074A - Aztreonam liposomes freeze-dry preparations and method of preparing the same - Google Patents
Aztreonam liposomes freeze-dry preparations and method of preparing the same Download PDFInfo
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- CN101249074A CN101249074A CNA2008100889551A CN200810088955A CN101249074A CN 101249074 A CN101249074 A CN 101249074A CN A2008100889551 A CNA2008100889551 A CN A2008100889551A CN 200810088955 A CN200810088955 A CN 200810088955A CN 101249074 A CN101249074 A CN 101249074A
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- aztreonam
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Abstract
The invention discloses a freeze-dried preparation of aztreonam liposomes, wherein aztreonam is encapsulated in antioxidant-containing liposomes made of neutral phospholipids, negative charge phospholipids and cholesterol. The freeze-dried preparation has stable quality. Additionally, the aztreonam is encapsulated to minimize toxicity and adverse effects without affecting drug effectiveness.
Description
Technical field
The invention belongs to medical technical field, what relate in particular to is aztreonam for injection Liposomal formulation and preparation method.
Background technology
Aztreonam, chemical name is: [2S-[2 α, 3 β (z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo group-3-azetidinyl) amino]-2-oxo ethylidene] amino] oxo]-2 Methylpropionic acid.The antibacterial activity that most of aerobic gram-negative bacterias is had height, comprise enterobacteriaceae lactobacteriaceaes such as the pneumobacillus of escherichia coli, Klebsiella and OKCY holder bacterium, aerobacteria, bacillus cloacae, Proteus, Serratia, citric acid bacterium genus, Shigella, and hemophilus influenza, gonococcus, meningococcus etc., it also has good antibacterial action to Pseudomonas aeruginosa.Aztreonam by with the aerobic gram-negative bacteria cell membrane of sensitivity on penicillin-binding protein 3 (PBP3) height affinity suppress the synthetic of cell wall.Different with most of beta-lactam antibiotics is that it does not induce antibacterial to produce beta-lactamase, highly stable to bacteriogenic most of beta-lactamases simultaneously.Be applicable to the various infection of treatment due to the responsive aerobic gram-negative bacteria, as: skin soft-tissue infections such as urinary tract infection, lower respiratory infection, septicemia, intra-abdominal infection, gynecological infection, postoperative wound and burn, ulcer etc.The above-mentioned type that also is used for the treatment of in the nosocomial infection infects (as immunodeficiency patient's nosocomial infection).
The clinical consumption of this product is big, determined curative effect, and market prospect is good.But aztreonam is less stable in aqueous solution, should not make liquid preparation for example injection carry out long-term storage, therefore limited the clinical practice of aztreonam to a certain extent.
Summary of the invention
Should not make the deficiency of liquid preparation at aztreonam less stable in aqueous solution, the object of the present invention is to provide a kind of stay-in-grade aztreonam for injection Liposomal formulation.
The present invention adopts following technical scheme: a kind of aztreonam liposomes freeze-dry preparations is that aztreonam is sealed the lyophilized formulations that obtains with the plasmalogen that is formed by neutral phospholipid, negative charge phospholipid and cholesterol that contains antioxidant.
The parts by weight of described each composition can for:
100～3000 parts of aztreonam
50～18000 parts in neutral phospholipid
Negative charge phosphatidase 10 .5～12000 parts
2～9000 parts in cholesterol
0.050～100 part of antioxidant
Can also comprise 200～4000 parts of 200～2000 parts of sugar and buffer agents.
Described buffer agent can be selected from one or more in arginine, histidine, glycine, sodium citrate and the sodium glutamate.
Described sugar can be selected from one or more in lactose, maltose, sucrose, glucose, trehalose and the soft plantation white sugar.
Described neutral phospholipid can be selected from one or more in Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, two stearic acid lecithin, soybean lecithin, hydrogenated soy phosphatidyl choline, two palmitic acid lecithin and the two myristic acid lecithin.
Described negative charge phospholipid can be selected from one or more in two myristic acid phosphatidyl glycerols, dilaurate phosphatidyl glycerol, two stearic acid phosphatidyl glycerol, two myristic acid phosphatidic acid, two stearic acid phosphatidic acid, dilaurate phosphatidic acid, two palmitic acid phosphatidic acid, two oleic acid Phosphatidylserine or the dilinoleic acid phosphatidylinositols.
Described antioxidant is preferably vitamin E.
The present invention also provides a kind of preparation method of aztreonam liposomes freeze-dry preparations, in turn includes the following steps:
(1) preparation blank liposome: used neutral phospholipid, negative charge phospholipid, cholesterol and antioxidant are dissolved in mix homogeneously in chloroform or the chloroform-methanol mixed solvent, solvent decompression in the solution is removed, form lipid membrane; The organic acid soln of preparation 0.01～0.5mol/L comes the aquation lipid membrane with acid solution, and hydration temperature gets blank liposome suspension between 40 ℃～70 ℃;
(2) homogenize liposome: preparation liposome in back is to the required particle diameter and the uniformity fully for aquation, and the particle diameter of liposome is controlled at 50～300nm;
(3) preparation contains the liposome of aztreonam: the aqueous alkali of preparation 0.1～2.0mol/L, aztreonam is dissolved in the water for injection, be heated to 40 ℃～70 ℃, regulate the blank liposome suspension to alkalescence with the aqueous alkali for preparing, with aztreonam solution and alkaline blank liposome suspension mix homogeneously and 40 ℃～70 ℃ insulations 30 minutes down;
(4) preparation aztreonam liposomes suspension: be 3%～20% sugar aqueous solution and add buffer agent adjusting pH value to 5.0～7.0 by weight compound concentration, the content of buffer agent is 0.2%～10%, get Liposomal dispersion, the liposome that contains aztreonam then with the washing of this dispersion liquid, utilize the dialysis Filtration to make aztreonam liposomes solution be replaced into the Liposomal dispersion of pH value 5.0～7.0, make aztreonam liposomes be dispersed in sugar aqueous solution like the Human Physiology environmental classes in, the aztreonam liposomes suspension;
(5) standardize solution, degerming, packing, lyophilizing: add injection water standardize solution, with the filtering with microporous membrane degerming of aztreonam liposomes suspension, packing, lyophilization gets finished product.
Described organic acid can be selected from citric acid, succinic acid, acetic acid, oxalic acid, Fructus Vitis viniferae acid, lactobionic acid, glucuronic acid or galacturonic acid.
Described alkali can be selected from calcium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate or sodium hydroxide.
Technical scheme of the present invention is the characteristic according to liposome, select the blank liposome of a certain proportion of mixture of phospholipids preparation parcel aztreonam for use, adding cholesterol and antioxidant increase the stability of liposome aztreonam, lipidosome freeze-dried preparation by lyophilizing formation, can pass through intravenously administrable, it has effectively solved the problem of quality stability, and owing to adopt liposome that aztreonam is sealed, toxic and side effects also reduces relatively simultaneously, and drug action does not reduce yet.Aztreonam liposomes preparation provided by the invention carries out acute toxicity test, chronic toxicity test, abnormal toxicity test and heat source check, and is all up to specification, and safety obtains proof.
Preparation method of the present invention adopts the pH value gradient method to promote the medicine parcel, with buffer agent and sugared outside suspension media as aztreonam, the particle diameter of liposome is between 50nm～300nm, the medicine encapsulation ratio can reach 100%, and encapsulation ratio height, cost are low, the suitable suitability for industrialized production of carrying out.
The specific embodiment
The invention will be further described below in conjunction with specific embodiment, to help understanding content of the present invention.
Embodiment 1
Aztreonam 100g
Two stearic acid lecithin 50g
Two stearic acid phosphatidyl glycerol 0.5g
Cholesterol 2g
Vitamin E 50mg
Citric acid 5g
Natrium carbonicum calcinatum 5g
Sucrose 200g
Glycine 200g
Water for injection 5000ml
Preparation technology
(1) according to prescription two stearic acid lecithin, two stearic acid phosphatidyl glycerol, cholesterol and vitamin E are dissolved in mix homogeneously in the chloroform, with Rotary Evaporators solvent decompression in the solution is removed, form lipid membrane, the citric acid soln of preparation 0.25mol/L, come the aquation lipid membrane with citric acid soln, hydration temperature generally between 50 ℃～60 ℃, gets blank liposome suspension.
(2) aquation is controlled at 100～120nm with machine-processed liposome to the mean diameter that is equipped with of the equal grain of high pressure in the back fully, and the liposome particle diameter and the uniformity can detect with multi-angle nanoparticle analyzer.
(3) aztreonam is dissolved in the fresh water for injection, be heated to 50 ℃～60 ℃, regulate blank liposome suspension to 7.6 with the Carbon Dioxide sodium water solution of 0.8mol/L, with aztreonam solution and alkaline blank liposome suspension mix homogeneously and 55 ℃～65 ℃ insulations 30 minutes down.
(4) prepare 9% aqueous sucrose solution and add 1.0% glycine by weight, get Liposomal dispersion, contain the liposome of aztreonam then with the washing of this dispersion liquid, utilize the dialysis Filtration to make aztreonam liposomes solution be replaced into the Liposomal dispersion of pH value 6.0～7.0.
(5) add injection water standardize solution, with the filtering with microporous membrane degerming of aztreonam liposomes suspension, packing, lyophilization gets finished product.
Embodiment 2
Aztreonam 3000g
Hydrogenated soy phosphatidyl choline 18000g
Two myristic acid phosphatidyl glycerol 12000g
Cholesterol 9000g
Vitamin E 100g
Succinic acid 15000g
Sodium hydroxide 21000g
Lactose 2000g
Glycine 4000g
Water for injection 50000ml
Preparation technology: operate with reference to embodiment 1 each step, the succinic acid solution with 0.3mol/L in (1) comes the aquation lipid membrane; (3) regulating blank liposome suspension to pH value with the sodium hydrate aqueous solution of 0.5mol/L in is 7.2; (4) preparation 4.5% lactose aqueous solution and add 1.0% glycine in is as Liposomal dispersion.
Embodiment 3
Aztreonam 500g
Two stearic acid lecithin 3200g
Two stearic acid phosphatidyl glycerol 680g
Cholesterol 950g
Vitamin E 12g
Citric acid 5600g
Natrium carbonicum calcinatum 8000g
Sucrose 1200g
Glycine 1250g
Water for injection 10000ml
Preparation technology: operate with reference to embodiment 1 each step, the citric acid with 0.25mol/L in (1) comes the aquation lipid membrane; (3) the Carbon Dioxide sodium water solution with 0.8mol/L in is regulated blank liposome suspension to 7.6; (4) preparation 9% aqueous sucrose solution and add 1.0% glycine in is as Liposomal dispersion.
Embodiment 4
Aztreonam 100g
Hydrogenated soy phosphatidyl choline 18000g
Two stearic acid phosphatidyl glycerol 12000g
Cholesterol 9000g
Vitamin E 50mg
Citric acid 5g
Sodium hydroxide 5g
Sucrose 200g
Arginase 12 00g
Water for injection 20000ml
Preparation technology: operate with reference to embodiment 1 each step, the citric acid soln with 0.5mol/L in (1) comes the aquation lipid membrane; (3) sodium hydrate aqueous solution of 1.0mol/L is regulated blank liposome suspension to 7.7 in; (4) preparation 9% lactose aqueous solution and add 0.8% arginine in is as Liposomal dispersion.
Embodiment 5 quality researches are investigated
The sample that makes among above four embodiment is carried out quality testing, and carried out under 40 ℃ of high temperature, relative humidity 75% ± 5% condition accelerated test simultaneously 6 months and 25 ℃ of temperature, relative humidity 60% ± 10% condition under long term test 18 months, it is as follows to obtain data result:
0 day quality testing result of table 1
| Sample | Character | Acidity | Clarity | Related substance (%) | Content (%) |
| Embodiment 1 | The white block | 6.8 | Up to specification | 1.22 | 98.7 |
| Embodiment 2 | The white block | 6.7 | Up to specification | 1.30 | 99.6 |
| Embodiment 3 | The white block | 6.9 | Up to specification | 1.15 | 102.7 |
| Embodiment 4 | The white block | 6.6 | Up to specification | 1.24 | 99.0 |
Table 2 quickens the quality testing result
The long-term quality testing result of table 3
By above data result as can be seen, the sample quality conformance with standard requirement that the present invention makes, and every quality index does not have significant change after quickening June and long-term 18 months, all meets quality standard, and the good quality stability of sample of preparation of the present invention has been described effectively.
Claims (10)
1. aztreonam liposomes freeze-dry preparations is that aztreonam is sealed the lyophilized formulations that obtains with the plasmalogen that is formed by neutral phospholipid, negative charge phospholipid and cholesterol that contains antioxidant.
2. aztreonam liposomes freeze-dry preparations as claimed in claim 1 is characterized in that the parts by weight of described each composition are:
100～3000 parts of aztreonam
50～18000 parts in neutral phospholipid
Negative charge phosphatidase 10 .5～12000 parts
2～9000 parts in cholesterol
0.050～100 part of antioxidant
3. aztreonam liposomes freeze-dry preparations as claimed in claim 2 is characterized in that: also comprise 200～4000 parts of 200～2000 parts of sugar and buffer agents.
4. aztreonam liposomes freeze-dry preparations as claimed in claim 3 is characterized in that: described buffer agent is selected from one or more in arginine, histidine, glycine, sodium citrate and the sodium glutamate.
5. aztreonam liposomes freeze-dry preparations as claimed in claim 3 is characterized in that: described sugar is selected from one or more in lactose, maltose, sucrose, glucose, trehalose and the soft plantation white sugar.
6. aztreonam liposomes freeze-dry preparations as claimed in claim 1 is characterized in that: described neutral phospholipid is selected from one or more in Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, two stearic acid lecithin, soybean lecithin, hydrogenated soy phosphatidyl choline, two palmitic acid lecithin and the two myristic acid lecithin.
7. aztreonam liposomes freeze-dry preparations as claimed in claim 1 is characterized in that: described negative charge phospholipid is selected from one or more in two myristic acid phosphatidyl glycerols, dilaurate phosphatidyl glycerol, two stearic acid phosphatidyl glycerol, two myristic acid phosphatidic acid, two stearic acid phosphatidic acid, dilaurate phosphatidic acid, two palmitic acid phosphatidic acid, two oleic acid Phosphatidylserine or the dilinoleic acid phosphatidylinositols.
8. aztreonam liposomes freeze-dry preparations as claimed in claim 1 is characterized in that: described antioxidant is vitamin E.
9. the preparation method of the described aztreonam liposomes freeze-dry preparations of claim 1 is characterized in that in turn including the following steps:
(1) preparation blank liposome: used neutral phospholipid, negative charge phospholipid, cholesterol and antioxidant are dissolved in mix homogeneously in chloroform or the chloroform-methanol mixed solvent, solvent decompression in the solution is removed, form lipid membrane; The organic acid soln of preparation 0.01～0.5mol/L comes the aquation lipid membrane with acid solution, and hydration temperature gets blank liposome suspension between 40 ℃～70 ℃;
(2) homogenize liposome: preparation liposome in back is to the required particle diameter and the uniformity fully for aquation, and the particle diameter of liposome is controlled at 50～300nm;
(3) preparation contains the liposome of aztreonam: the aqueous alkali of preparation 0.1～2.0mol/L, aztreonam is dissolved in the water for injection, be heated to 40 ℃～70 ℃, regulate the blank liposome suspension to alkalescence with the aqueous alkali for preparing, with aztreonam solution and alkaline blank liposome suspension mix homogeneously and insulation under 40 ℃～70 ℃;
(4) preparation aztreonam liposomes suspension: be 3%～20% sugar aqueous solution and add buffer agent adjusting pH value to 5.0～7.0 by weight compound concentration, the content of buffer agent is 0.2%～10%, get Liposomal dispersion, the liposome that contains aztreonam then with the washing of this dispersion liquid, utilize the dialysis Filtration to make aztreonam liposomes solution be replaced into the Liposomal dispersion of pH value 5.0～7.0, make aztreonam liposomes be dispersed in sugar aqueous solution like the Human Physiology environmental classes in, the aztreonam liposomes suspension;
(5) standardize solution, degerming, packing, lyophilizing: add injection water standardize solution, with the filtering with microporous membrane degerming of aztreonam liposomes suspension, packing, lyophilization gets finished product.
10. the preparation method of aztreonam liposomes freeze-dry preparations as claimed in claim 9, it is characterized in that: described organic acid is selected from citric acid, succinic acid, acetic acid, oxalic acid, Fructus Vitis viniferae acid, lactobionic acid, glucuronic acid or galacturonic acid, and described alkali is selected from calcium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate or sodium hydroxide.
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| CNB2008100889551A CN100548295C (en) | 2008-04-09 | 2008-04-09 | Aztreonam liposomes freeze-dry preparations and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101912356A (en) * | 2010-08-02 | 2010-12-15 | 王明 | Aztreonam/arginine medicinal composition lipid microsphere injection |
| CN102068413A (en) * | 2010-12-31 | 2011-05-25 | 石药集团中诺药业（石家庄）有限公司 | Biapenem lyophilized preparation and preparation method thereof |
| CN102119924A (en) * | 2011-01-24 | 2011-07-13 | 山东鲁抗立科药物化学有限公司 | Monodisperse nano aztreonam liposome preparation and preparation method thereof |
| CN104856958A (en) * | 2014-02-21 | 2015-08-26 | 海南灵康制药有限公司 | Special aztreonam ultra-fine powder preparation and preparation method thereof |
| CN109310735A (en) * | 2016-05-13 | 2019-02-05 | 我希望增效剂公司 | New cationic peptide SPR741 is to the active synergistic effect of antibiotic |
-
2008
- 2008-04-09 CN CNB2008100889551A patent/CN100548295C/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101912356A (en) * | 2010-08-02 | 2010-12-15 | 王明 | Aztreonam/arginine medicinal composition lipid microsphere injection |
| CN102068413A (en) * | 2010-12-31 | 2011-05-25 | 石药集团中诺药业（石家庄）有限公司 | Biapenem lyophilized preparation and preparation method thereof |
| CN102068413B (en) * | 2010-12-31 | 2013-01-02 | 石药集团中诺药业（石家庄）有限公司 | Biapenem lyophilized preparation and preparation method thereof |
| CN102119924A (en) * | 2011-01-24 | 2011-07-13 | 山东鲁抗立科药物化学有限公司 | Monodisperse nano aztreonam liposome preparation and preparation method thereof |
| CN102119924B (en) * | 2011-01-24 | 2012-09-05 | 山东鲁抗立科药物化学有限公司 | Monodisperse nano aztreonam liposome preparation and preparation method thereof |
| CN104856958A (en) * | 2014-02-21 | 2015-08-26 | 海南灵康制药有限公司 | Special aztreonam ultra-fine powder preparation and preparation method thereof |
| CN104856958B (en) * | 2014-02-21 | 2016-07-20 | 海南灵康制药有限公司 | A kind of aztreonam preparation and preparation method thereof |
| CN109310735A (en) * | 2016-05-13 | 2019-02-05 | 我希望增效剂公司 | New cationic peptide SPR741 is to the active synergistic effect of antibiotic |
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| CN100548295C (en) | 2009-10-14 |
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