CN101780052A - Ceftizoxime sodium liposome injection - Google Patents
Ceftizoxime sodium liposome injection Download PDFInfo
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- CN101780052A CN101780052A CN 201010125855 CN201010125855A CN101780052A CN 101780052 A CN101780052 A CN 101780052A CN 201010125855 CN201010125855 CN 201010125855 CN 201010125855 A CN201010125855 A CN 201010125855A CN 101780052 A CN101780052 A CN 101780052A
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- sodium
- liposome
- ceftizoxime
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Abstract
The invention relates to ceftizoxime sodium liposome injection and a preparation method therof. The ceftizoxime sodium liposome freezing-drying preparation comprises ceftizoxime sodium, buffer salt system, liposome matrix, freezing-drying excipient and antioxidant. By selecting particular buffer salt system and the liposome matrix, the ceftizoxime sodium liposome injection has good formation and parcel rate as well as good stability.
Description
Technical field
The present invention relates to medical technical field, related to a kind of ceftizoxime preparation of sodium, related in particular to the method for preparing ceftizoxime sodium liposome injection with specific supplementary material and preparation technology.
Technical background
Ceftizoxime sodium, chemical name is: [6R-[6 (, 7 ((Z)]]-7[[2,3-dihydro-2-imino group-4-thiazolyl) (methoxyimino) acetyl group] amino]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-carboxylic acid sodium salt, molecular formula C
13H
12N
5NaO
5S
2, molecular weight 405.38, structural formula is:
Ceftizoxime sodium belongs to third generation cephalosporin, the tool broad-spectrum antibacterial action, wide spectrum lactamase (comprising penicillinase and cephalosporinase) to multiple gram positive bacteria and gram-negative bacteria generation is stable, enterobacteriaceae lactobacteriaceaes such as escherichia coli, Klebsiella Pneumoniae, proteus mirabilis are had powerful antibacterial action, and Rhodopseudomonas such as Pseudomonas aeruginosa and acinetobacter are poor to this product sensitivity.Ceftizoxime sodium has good antibacterial action to hemophilus influenza and Neisseria gonorrhoeae.Ceftizoxime sodium to the effect of staphylococcus aureus and staphylococcus epidermidis than first, second in generation cephalosporin for poor, methicillin-resistant staphylococcus aureus and Enterococcus are to this product drug resistance, various streptococcus are all extremely sensitive to this product.Anaerobe such as dyspepsiacoccus, peptostreptococcus and part Bacteroides are responsive to this product more, and clostridium difficile is to this product drug resistance.The ceftizoxime sodium mechanism of action is for reaching bactericidal action by the biosynthesis that suppresses the bacteria cell wall mucopeptide.Be applicable to meningitis and simple property gonorrhea due to lower respiratory infection, urinary tract infection, abdominal cavity infection, pelvic infection, septicemia, skin soft-tissue infection, bone and the infection of joint, streptococcus pneumoniae or the hemophilus influenza due to the sensitive organism.
The ceftizoxime preparation of sodium of list marketing is a directly aseptic subpackaged powder of raw material, and poor stability is placed with related substance for a long time and obviously increases, and redissolves badly, and bioavailability is low.
Summary of the invention
Purpose of the present invention aims to provide a kind of encapsulation ratio height, ceftizoxime sodium liposome lyophilized formulations that toxic and side effects is little.In the face of this prepared kind of prior art, bioavailability is low, and solubility is relatively poor, and drug safety can not get ensureing that the inventor advances an idea, and utilizes liposome substrate that principal agent is wrapped up, improves medicine stability.By consulting documents and materials and a large amount of Test Summary improvement, realized the present invention.
Technical scheme of the present invention is as follows:
The invention provides a kind of ceftizoxime sodium liposome lyophilized formulations, comprise following component: ceftizoxime sodium, buffer salt system, liposome substrate, freeze-dried excipient, antioxidant, it is characterized in that wherein said buffer salt system is made up of sodium dihydrogen phosphate and sodium hydrogen phosphate, described liposome substrate is the mixture of phospholipid and cholesterol.
The above-mentioned described ceftizoxime sodium liposome lyophilized formulations of the present invention, it is characterized in that described buffer salt system is the phosphate solution that contains the sodium hydrogen phosphate of 1～10% (mg/ml) sodium dihydrogen phosphate and 5～30% (mg/ml), the pH value of buffer salt system is 6.5～8.0; As preferably, above-mentioned described buffer salt system is the phosphate solution that contains the sodium hydrogen phosphate of 5% (mg/ml) sodium dihydrogen phosphate and 15% (mg/ml), and the pH value of buffer salt system is 6.5～8.0.
Preferably, the above-mentioned described ceftizoxime sodium liposome lyophilized formulations of the present invention, it is characterized in that described liposome substrate is phospholipid: the cholesterol mass ratio is 1～3: 2 mixture; More preferably, above-mentioned described liposome substrate is phospholipid: the cholesterol mass ratio is 1: 1 a mixture.
Preferably, above-mentioned described ceftizoxime sodium liposome lyophilized formulations is characterized in that described phospholipid is Ovum Gallus domesticus Flavus lecithin and/or soybean lecithin.
Preferably, above-mentioned described ceftizoxime sodium liposome lyophilized formulations, it is characterized in that described freeze-dried excipient can be selected from one or more in mannitol, trehalose, sorbitol, glycine, sodium chloride, D-glucose, the lactose, most preferably, described freeze-dried excipient is selected from mannitol, sodium chloride, lactose.
Preferably, above-mentioned described ceftizoxime sodium liposome lyophilized formulations, it is characterized in that described antioxidant can be selected from one or more in thiourea, vitamin E, sodium sulfite, sodium sulfite, the dibenzylatiooluene, most preferably, described antioxidant is selected from thiourea or vitamin E.
As preferred version of the present invention, above-mentioned described ceftizoxime sodium liposome lyophilized formulations is characterized in that calculating by weight, 10 parts of ceftizoxime sodiums, 18～92 parts of liposome substrate, 8～36 parts of freeze-dried excipients, 3～14 parts of antioxidants.
As another goal of the invention of the present invention, the preparation method of above-mentioned described ceftizoxime sodium liposome lyophilized formulations also is provided, it comprises the steps:
1) sodium dihydrogen phosphate and sodium hydrogen phosphate are dissolved in the water for injection, are made into phosphate buffer, regulating pH value with the pH value regulator is 6.5～8.0;
2) fusion in organic solvent phospholipid and cholesterol, the adding pH value is 6.5～8.0 phosphate buffer, mixes, and treats the organic solvent volatilization fully, is transferred to tissue mincer's high speed and stirs 10～30min, filters, and sterilizes;
3) to step 2) add in the gained material and carry out that breast is even to be ground behind ceftizoxime sodium, freeze-dried excipient and the antioxidant, to filter, fill is carried out lyophilizing in cillin bottle, obtained ceftizoxime sodium liposome lyophilized formulations finished product.
Wherein, above-mentioned described preparation method, described organic solvent is selected from ether or isopropyl alcohol.
As preferably, above-mentioned described preparation method, wherein said pH value regulator can be selected from sodium hydroxide, potassium hydroxide, hydrochloric acid, phosphoric acid, sodium carbonate, sodium bicarbonate, citric acid, sodium citrate, ethylenediamine, diethylamine, ethanolamine, triethanolamine, three hydramine, preferably, described pH value regulator is sodium hydroxide or phosphoric acid.
The present invention is in research process, find unexpectedly, select the phosphate-buffered liquid system for use, preparation-obtained liposome, on shaping and encapsulation ratio, has good effect, and other buffer salt solutions, as citron salt buffer, borate buffer solution, carbonate buffer solution, acetate buffer, but the shaping of liposome and encapsulation ratio are obviously not as phosphate.
The liposome that the present invention is prepared is observed under Electronic Speculum, found uniform particles, present circle or ellipse.Envelop rate is investigated, and it is higher to draw envelop rate, has reached 92.3%, and residual organic solvents is investigated, and the result meets the Chinese Pharmacopoeia regulation.
The prepared ceftizoxime sodium liposome lyophilized formulations of the present invention is carried out influence factor, accelerated test, long term test investigation, have no significant change.
The prepared ceftizoxime sodium liposome preparation of the present invention is carried out acute toxicology, thermal source, particulate matter detect, every inspection index meets the pharmacopeia requirement, has proved the safety of this product.
By comparing, can learn that the present invention has the following advantages with prepared this series products of prior art and prior art:
1 supplementary material involved in the present invention is common to be easy to get, the price cheapness, and preparation process is simple to operate, practical.
The prepared ceftizoxime sodium liposome preparation of 2 the present invention, the encapsulation ratio height has certain targeting, the rate of release ideal.
The prepared ceftizoxime sodium liposome preparation of 3 the present invention, stability has better improved drug safety.
The ceftizoxime sodium liposome preparation that 4 the present invention are prepared, the high solubility of bioavailability is good, more utilizes use clinically.
The specific embodiment
The preparation of embodiment one ceftizoxime sodium liposome lyophilized formulations
Prescription (specification 0.05g)
Ceftizoxime sodium 5g
Soybean lecithin 23g
Cholesterol 23g
Sodium dihydrogen phosphate 5g
Sodium hydrogen phosphate 15g
Sorbitol 18g
Vitamin E 7g
Ether 200ml
Preparation technology:
A is dissolved in 5g sodium dihydrogen phosphate and 15g sodium hydrogen phosphate in the 100ml water for injection, is made into phosphate buffer, and regulating pH value with the sodium hydroxide solution of 0.1mol/L and 1% phosphoric acid solution is 7.0;
B is the 70 ℃ of fusions in the ether of 200ml of the cholesterol of the soybean lecithin of 23g and 23g, and the adding pH value is 7.0 phosphate buffer, mixes, treat the organic solvent volatilization fully, be transferred to tissue mincer's high speed and stir 10～30min, filter, sterilization;
C adds 5g ceftizoxime sodium, 18g sorbitol, 7g vitamin E and fully carry out the even grinding of breast in dispersing emulsification machine in this solution, fill is filtered in cillin bottle, carries out lyophilizing, has obtained ceftizoxime sodium liposome preparation finished product.
The preparation of embodiment two ceftizoxime sodium liposome lyophilized formulations
Prescription (specification 0.1g)
Ceftizoxime sodium 10g
Ovum Gallus domesticus Flavus lecithin 27g
Cholesterol 27g
Sodium dihydrogen phosphate 15g
Sodium hydrogen phosphate 45g
Sodium chloride 32g
Sodium sulfite 9g
Isopropyl alcohol 400ml
Preparation technology:
A is dissolved in 15g sodium dihydrogen phosphate and 45g sodium hydrogen phosphate in the 300ml water for injection, is made into phosphate buffer, and regulating pH with the sodium hydroxide solution of 0.1mol/L and 1% phosphoric acid solution is 6.5;
B is the 70 ℃ of fusions in the isopropyl alcohol of 400ml of the cholesterol of the Ovum Gallus domesticus Flavus lecithin of 27g and 27g, and the adding pH value is 6.5 phosphate buffer, mixes, treat the organic solvent volatilization fully, be transferred to tissue mincer's high speed and stir 10～30min, filter, sterilization;
C adds to be transferred to behind 10g ceftizoxime sodium, 32g sodium chloride, the 9g sodium sulfate in this solution and carries out in the dispersing emulsification machine that breast is even to be ground, and in fill and the cillin bottle, lyophilizing is carried out in filtration, has obtained ceftizoxime sodium liposome preparation finished product.
The preparation of embodiment three ceftizoxime sodium liposome lyophilized formulations
Prescription (specification 0.2g)
Ceftizoxime sodium 20g
Soybean lecithin 18g
Cholesterol 18g
Sodium dihydrogen phosphate 5g
Sodium hydrogen phosphate 15g
Mannitol 16g
Thiourea 6g
Ether 200ml
Preparation technology:
A is dissolved in 5g sodium dihydrogen phosphate and 15g sodium hydrogen phosphate in the 100ml water for injection, is made into phosphate buffer, and regulating pH with the sodium hydroxide solution of 0.1mol/L and 1% phosphoric acid solution is 7.8;
B is the 70 ℃ of fusions in the ether of 200ml of the cholesterol of the soybean lecithin of 18g and 18g, and the adding pH value is 7.8 phosphate buffer, mixes, treat the organic solvent volatilization fully, be transferred to tissue mincer's high speed and stir 10～30min, filter, sterilization;
C is transferred to the fully even grinding of breast in the dispersing emulsification machine add 20g ceftizoxime sodium, 16g mannitol, 6g thiourea in this solution after, in fill and the cillin bottle, filters, and carries out lyophilizing, has obtained ceftizoxime sodium liposome preparation finished product.
The quality investigation of test example one ceftizoxime sodium liposome lyophilized formulations
(Chongqing City Qingyutang Pharmaceutical Co., Ltd. produces with the listing sample to this product prepared in the foregoing description with reference to Chinese Pharmacopoeia (2005 editions) appendix, lot number 20080301) carries out influence factor, accelerated test and long-time stability and investigate, at character, acid-base value, clarity, content, the check of related substance project and statistical result.
Table 1 influence factor result
Table 2 accelerated test result
Table 3 long-term test results
From above result of the test as can be seen, each investigation item of the ceftizoxime sodium liposome lyophilized formulations of embodiment of the invention preparation has no significant change; The listing sample is after acceleration June and long-term 18 months test, and basicity descends obviously, content reduces, the related substance increase is a lot, clarity is against regulation.Illustrated that liposome among the present invention has played protective effect to the parcel of ceftizoxime sodium, stablized the character of self, ensured the up-to-standard and drug safety of preparation.
The investigation of test example two ceftizoxime sodium liposomes
Prescription (specification 0.05g)
Ceftizoxime sodium 5g
Soybean lecithin 23g
Cholesterol 23g
Sodium dihydrogen phosphate 5g
Sodium hydrogen phosphate 15g
Sorbitol 18g
Vitamin E 7g
Ether 200ml
Preparation technology:
A is dissolved in 5g sodium dihydrogen phosphate and 15g sodium hydrogen phosphate in the 100ml water for injection, is made into phosphate buffer, and regulating pH value with the sodium hydroxide solution of 0.1mol/L and 1% phosphoric acid solution is 7.0;
B is the 70 ℃ of fusions in the ether of 200ml of the cholesterol of the soybean lecithin of 23g and 23g, and the adding pH value is 7.0 phosphate buffer, mixes, treat the organic solvent volatilization fully, be transferred to tissue mincer's high speed and stir 10～30min, filter, sterilization;
C adds 5g ceftizoxime sodium, 18g sorbitol, 7g vitamin E and fully carry out the even grinding of breast in dispersing emulsification machine in this solution, fill is filtered in cillin bottle, carries out lyophilizing, has obtained ceftizoxime sodium liposome preparation finished product.
The investigation of Comparative Examples ceftizoxime sodium liposome
Prescription (specification 0.05g)
Ceftizoxime sodium 5g
Lecithin 23g
Cholesterol 7g
Citric acid 8g
Sodium citrate 15g
Sorbitol 18g
Vitamin E 7g
Ether 200ml
Preparation technology:
A is dissolved in 15g sodium citrate and 8g sodium citrate in the 100ml water for injection, is made into citric acid-sodium citrate buffer, and regulating pH value with the sodium hydroxide solution of 0.1mol/L and 10% citric acid soln is that pH value is 7.0;
B is the 70 ℃ of fusions in the ether of 200ml of the cholesterol of the lecithin of 23g and 7g, and the adding pH value is 7.0 citrate buffer, mixes, and treats the organic solvent volatilization fully, is transferred to tissue mincer's high speed and stirs 10～30min, filters, and sterilizes;
C adds 5g ceftizoxime sodium, 18g sorbitol, 7g vitamin E and fully carry out the even grinding of breast in dispersing emulsification machine in this solution, fill is filtered in cillin bottle, carries out lyophilizing, has obtained ceftizoxime sodium liposome preparation finished product.
Liposomal formulation prepared in top test example two and the Comparative Examples is got respectively in the glucose solution that 0.4g is dissolved in 500ml5%, obtained the suspension solution of 0.8mg/ml, the particle diameter and the envelop rate of liposome are investigated, it is as follows to investigate the result:
Prepared Liposomal formulation in the test example, the how rounded or ellipticalness of character rule, mean diameter is 94nm, and envelop rate reaches 92%, was placed on microscopically and observes after 12 hours, and no crystallization is separated out.
Prepared Liposomal formulation in the Comparative Examples is observed under Electronic Speculum, and character is random, arranges disorderly and unsystematicly, and envelop rate is 55%, was placed on microscopically and observes after 12 hours, has crystalline material to separate out.
This test has illustrated buffer and the prepared liposome encapsulation height of liposome substrate ratio that goes out preferred for this invention, and liposome is more stable.
Claims (9)
1. ceftizoxime sodium liposome injection, comprise following component: ceftizoxime sodium, buffer salt system, liposome substrate, freeze-dried excipient, antioxidant, it is characterized in that wherein said buffer salt system is made up of sodium dihydrogen phosphate and sodium hydrogen phosphate, described liposome substrate is the mixture of phospholipid and cholesterol.
2, ceftizoxime sodium liposome preparation according to claim 1, it is characterized in that described buffer salt system is the phosphate solution that contains the sodium hydrogen phosphate of 1～10% (mg/ml) sodium dihydrogen phosphate and 5～30% (mg/ml), the pH value of buffer salt system is 6.5～8.0; Preferred described buffer salt system is the phosphate solution that contains the sodium hydrogen phosphate of 5% (mg/ml) sodium dihydrogen phosphate and 15% (mg/ml), and the pH value of buffer salt system is 6.5～8.0.
3. according to the described ceftizoxime sodium liposome lyophilized formulations of claim 1-2, it is characterized in that described liposome substrate is phospholipid: the cholesterol mass ratio is 1～3: 2 mixture, and preferred described liposome substrate is phospholipid: the cholesterol mass ratio is 1: 1 a mixture.
4. according to the described ceftizoxime sodium liposome lyophilized formulations of claim 1-3, it is characterized in that described phospholipid is Ovum Gallus domesticus Flavus lecithin and/or soybean lecithin.
5. according to the described ceftizoxime sodium liposome lyophilized formulations of claim 1-4, it is characterized in that described freeze-dried excipient can be selected from one or more in mannitol, trehalose, sorbitol, glycine, sodium chloride, D-glucose, the lactose.
6. according to the described ceftizoxime sodium liposome lyophilized formulations of claim 1-5, it is characterized in that described antioxidant can be selected from one or more in thiourea, vitamin E, sodium sulfite, sodium sulfite, the dibenzylatiooluene.
7. according to the described ceftizoxime sodium liposome lyophilized formulations of claim 1-6, it is characterized in that calculating by weight 10 parts of ceftizoxime sodiums, 18～92 parts of liposome substrate, 8～36 parts of freeze-dried excipients, 3～14 parts of antioxidants.
8. method for preparing the ceftizoxime sodium liposome lyophilized formulations, it comprises the steps:
1) sodium dihydrogen phosphate and sodium hydrogen phosphate are dissolved in the water for injection, are made into phosphate buffer, regulating pH value with the pH value regulator is 6.5～8.0;
2) fusion in organic solvent phospholipid and cholesterol, the adding pH value is 6.5～8.0 phosphate buffer, mixes, and treats the organic solvent volatilization fully, is transferred to tissue mincer's high speed and stirs 10～30min, filters, and sterilizes;
3) to step 2) add in the gained material and carry out that breast is even to be ground behind ceftizoxime sodium, freeze-dried excipient and the antioxidant, to filter, fill is carried out lyophilizing in cillin bottle, obtained ceftizoxime sodium liposome lyophilized formulations finished product.
9. preparation method according to claim 8 is characterized in that described organic solvent is selected from ether or isopropyl alcohol.
10. preparation method according to claim 8 is characterized in that described pH value regulator can be selected from sodium hydroxide, potassium hydroxide, hydrochloric acid, phosphoric acid, sodium carbonate, sodium bicarbonate, citric acid, sodium citrate, ethylenediamine, diethylamine, ethanolamine, triethanolamine, three hydramine.
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| CN2010101258559A CN101780052B (en) | 2010-03-17 | 2010-03-17 | Ceftizoxime sodium liposome injection |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044449A (en) * | 2012-12-28 | 2013-04-17 | 吴秋萍 | Novel ceftizoxime sodium compound and medicine composition thereof |
| CN104490785A (en) * | 2014-12-20 | 2015-04-08 | 福安药业（集团）股份有限公司 | Ceftizoxime sodium liposome composition for injection and preparation method thereof |
| CN104922679A (en) * | 2015-05-28 | 2015-09-23 | 浙江长典医药有限公司 | Child-type medicinal composition with ceftizoxime sodium and low-sodium carrier |
| CN105232461A (en) * | 2015-11-03 | 2016-01-13 | 浙江永宁药业股份有限公司 | Flomoxef sodium lipidosome freeze-drying preparation and preparation method thereof |
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| CN101461813A (en) * | 2008-12-25 | 2009-06-24 | 海南瑞基药物研究有限公司 | Cefotiam hydrochloride preparation for injection and preparation method thereof |
| CN101584664A (en) * | 2009-06-12 | 2009-11-25 | 海南数尔药物研究有限公司 | A kind of Cefodizime sodium proliposome preparation and preparation method thereof |
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2010
- 2010-03-17 CN CN2010101258559A patent/CN101780052B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101461813A (en) * | 2008-12-25 | 2009-06-24 | 海南瑞基药物研究有限公司 | Cefotiam hydrochloride preparation for injection and preparation method thereof |
| CN101584664A (en) * | 2009-06-12 | 2009-11-25 | 海南数尔药物研究有限公司 | A kind of Cefodizime sodium proliposome preparation and preparation method thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044449A (en) * | 2012-12-28 | 2013-04-17 | 吴秋萍 | Novel ceftizoxime sodium compound and medicine composition thereof |
| CN104490785A (en) * | 2014-12-20 | 2015-04-08 | 福安药业（集团）股份有限公司 | Ceftizoxime sodium liposome composition for injection and preparation method thereof |
| CN104490785B (en) * | 2014-12-20 | 2017-06-06 | 福安药业（集团）股份有限公司 | A kind of ceftiaoxline sodium for injection liposome composition and preparation method thereof |
| CN104922679A (en) * | 2015-05-28 | 2015-09-23 | 浙江长典医药有限公司 | Child-type medicinal composition with ceftizoxime sodium and low-sodium carrier |
| CN105232461A (en) * | 2015-11-03 | 2016-01-13 | 浙江永宁药业股份有限公司 | Flomoxef sodium lipidosome freeze-drying preparation and preparation method thereof |
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