CN101623262B - Cephazolin sodium pentahydrate proliposome preparation - Google Patents
Cephazolin sodium pentahydrate proliposome preparation Download PDFInfo
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- CN101623262B CN101623262B CN200910169230XA CN200910169230A CN101623262B CN 101623262 B CN101623262 B CN 101623262B CN 200910169230X A CN200910169230X A CN 200910169230XA CN 200910169230 A CN200910169230 A CN 200910169230A CN 101623262 B CN101623262 B CN 101623262B
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- proliposome
- cephazolin sodium
- sodium pentahydrate
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Abstract
The invention provides a cephazolin sodium pentahydrate proliposome preparation which comprises the following components by weight part: 5-15 parts of cephazolin sodium pentahydrate, 10-50 parts of lecithin phosphatidylserine, 1-20 parts of cholesterol and 5-40 parts of proppant which consists of two or more of mannitol, lactose, glucose, trehalose, sucrose, dextran, sorbitol, sodium chloride, glycine and hydrolyzed gelatin. The cephazolin sodium pentahydrate proliposome has good stability and cannot crack because of dewatering, fusion, ice crystal generation, and the like in a drying process; and after hydrated re-dissolution, the entrapment rate of the cephazolin sodium pentahydrate proliposome cannot be reduced.
Description
Technical field
The present invention relates to a kind of Cephazolin sodium pentahydrate proliposome and method for making thereof, belong to medical technical field.
Background technology
Cephazolin sodium pentahydrate, its chemical name is: (6R, 7R)-the 3-[[(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl) sulfur] methyl]-7-[(1H-tetrazolium-1-yl) acetylamino]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid sodium salt five hydrates, molecular formula is: C
14H
14N
8NaO
4S
35H
2O, molecular weight: 567.56, structural formula is:
Cephazolin sodium pentahydrate is a first generation cephalosporin, has a broad antifungal spectrum, its antibacterial action mechanism be with the bacterial cell membrane inner membrance on target position albumen be that penicillin-binding protein (PBPs) combines (mainly acting on PBP1, PBP3), suppress the bacteria cell wall biosynthesis, thereby play antibacterial action.Except that Enterococcus, methicillin-resistant staphylococcus, this product all has good antibacterial activity to other gram positive coccus, and streptococcus pneumoniae and Hemolytic streptococcus are extremely sensitive to this product.Clinical respiratory tract infection, genito-urinary system, cholecystitis, liver abscess, endocarditis, septicemia and soft tissue due to the sensitive organism and the ear of being mainly used in infects etc., also can be used as preoperative prophylactic.
The Cephazolin sodium pentahydrate of listing is a sterile powder injection at present, and poor stability to the instability of temperature and light, becomes turbid after the redissolution, and needs shady and cool place to preserve.
Chinese patent CN1424039A discloses a kind of pharmaceutical composition that contains cefazolin sodium and beta-lactamase inhibitor and preparation method thereof, and described compositions contains 20: 1-1: the cefazolin sodium of 5 weight ratios or its pharmaceutical salts and beta-lactamase inhibitor (Tazobactam Sodium, clavulanic acid).Said composition has shown the coordination potentiation, has better antibacterial effect when using separately than cefazolin sodium or its pharmaceutical salts or Tazobactam Sodium or its pharmaceutical salts.But this patent is not taked the corresponding protection measure to cefazolin sodium, can not change the problem of poor stability, the very fast hydrolysis oxidation of meeting in the aqueous solution, forfeiture drug effect.
Summary of the invention
The inventor is through research in earnest for a long time, the combination of two or more proppant of certain weight ratio and the egg yolk lecithin acyl serine and the cholesterol of specific proportioning are selected in discovery for use, according to method of the present invention, Cephazolin sodium pentahydrate is made pro-liposome, not only can solve the existing existing variety of issue of cefazolin sodium preparation of sodium, can also improve bioavailability, it is easily absorbed by the body, thereby finish the present invention.
An object of the present invention is to provide a kind of Cephazolin sodium pentahydrate proliposome preparation, it comprises Cephazolin sodium pentahydrate, egg yolk lecithin acyl serine, cholesterol and proppant; Perhaps it is made up of these components.
In one embodiment, Cephazolin sodium pentahydrate proliposome of the present invention comprises following component by weight:
Cephazolin sodium pentahydrate 5-15 part
Egg yolk lecithin acyl serine 10-50 part
Cholesterol 1-20 part
Proppant 5-40 part
In another embodiment of the invention, Cephazolin sodium pentahydrate proliposome of the present invention comprises following component by weight:
Cephazolin sodium pentahydrate 7-13 part
Egg yolk lecithin acyl serine 15-40 part
Cholesterol 2-10 part
Proppant 10-40 part
In another embodiment of the invention, Cephazolin sodium pentahydrate proliposome of the present invention comprises following component by weight:
10 parts of Cephazolin sodium pentahydrates
30 parts of egg yolk lecithin acyl serines
6 parts in cholesterol
25 parts of proppant
In the present invention, described proppant is to be selected from mannitol, lactose, glucose, trehalose, sucrose, dextran, sorbitol, sodium chloride, glycine, the gelatin hydrolysate two or more, preferred weight ratio is the combination of the combination of 2: 1 sorbitol and dextran, mannitol that weight ratio is 1: 1 and lactose, the combination of glucose and trehalose that weight ratio is 1: 4, and most preferably weight ratio is the combination of 2: 1 sorbitol and dextran.The present invention finds unexpectedly, with the proppant compositions of certain weight ratio, compares single proppant, and skeleton is better, and in the dry run, powder size is better, easier packing, and the Liposomal formulation after the packing redissolves faster.
Another object of the present invention provides a kind of preparation method of Cephazolin sodium pentahydrate proliposome, and it comprises the steps:
(1) egg yolk lecithin acyl serine, cholesterol are dissolved in the organic solvent, make immobilized artificial membrane after removing organic solvent;
(2) add buffer salt solution in the immobilized artificial membrane that makes, make the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying makes the blank liposome suspension;
(3) Cephazolin sodium pentahydrate is water-soluble, add in the blank liposome suspension, add proppant again, make the Cephazolin sodium pentahydrate liposome solutions;
(4) with above-mentioned solution lyophilization or spray drying, make Cephazolin sodium pentahydrate proliposome.
As preferably, the preparation method of Cephazolin sodium pentahydrate proliposome of the present invention, it comprises the steps:
(1) egg yolk lecithin acyl serine, cholesterol are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) add buffer solution in the immobilized artificial membrane that makes, jolting is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(3) Cephazolin sodium pentahydrate is water-soluble, filtering with microporous membrane, filtrate adds in the blank liposome suspension, under 50-60 ℃ temperature, stirred 30-60 minute, add proppant again, stir and make its dissolving, cool to room temperature gets the Cephazolin sodium pentahydrate liposome solutions then;
(4) with above-mentioned solution lyophilization or spray drying, make Cephazolin sodium pentahydrate proliposome.
After preparing Cephazolin sodium pentahydrate proliposome, also its packing under aseptic condition can be obtained the Cephazolin sodium pentahydrate Liposomal formulation, every bottle of 0.025-0.2g (in cefazolin sodium).
In above-mentioned preparation method, the weight portion content that provides in the consumption of Cephazolin sodium pentahydrate, egg yolk lecithin acyl serine, cholesterol, proppant and the Cephazolin sodium pentahydrate proliposome provided herein is identical.
Above-mentioned described preparation method, described organic solvent can be selected from two or more in ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane, preferred volume ratio is the combination of the combination of 1: 1 n-butyl alcohol and acetone, isopropyl alcohol that volume ratio is 3: 2 and methanol, the combination of ethanol and normal hexane that volume ratio is 2: 1, and most preferably volume ratio is the combination of 1: 1 n-butyl alcohol and acetone.The present invention selects the mixed organic solvents of certain volume ratio for use, compares single organic solvent, and solubility property is better, dissolves sooner, and easier reduction vaporization is removed.
In above-mentioned preparation method, buffer solution is selected from one or more in phosphate buffer that the pH value scope is 5.0-6.0, citrate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer, preferably phosphoric acid salt buffer, acetate buffer, citrate buffer, most preferably phosphate buffer.
In the above-mentioned preparation method, step (2) stirs and can make the complete aquation of immobilized artificial membrane, rotating speed 200-600r/min in 20-40 minute; Tissue mashing machine, rotating speed 12000r/min are adopted at a high speed even matter emulsifying; Microporous filter membrane is selected 0.45 μ m aperture for use.
In the preparation method of pro-liposome of the present invention, the rotary film evaporator that is adopted, be also referred to as scrapper thin film evaporator or turbulent-film evaporator, this area known this class membrane evaporator at present may be used to the present invention, for example can adopt Wuxi City to avenge the centrifugal scrapper thin film evaporator of LG2.5 type that unrestrained fermentation engineering instrument factory is produced, also can adopt the efficient rotary film evaporator of LG-4 type of screen-like mountain peak pharmaceutical equipment factory of Wuxi City army production etc.
Cephazolin sodium pentahydrate proliposome provided by the invention, be granule or powder with good fluidity, stable storage, the liposome that rises such as can disperse or dissolve with the water hydration before using, it carries out stability test and investigates, placed 10 days under 60 ℃ of high temperature, illumination 4500Lx condition, every detection index has no significant change; Accelerated test is 6 months under 40 ℃ of high temperature, relative humidity 75% ± 5% condition, and every detection index does not have significant change; Long term test is 18 months under 25 ℃ of high temperature, relative humidity 60% ± 10% condition, and every detection index does not have significant change.
Cephazolin sodium pentahydrate proliposome preparation provided by the invention is carried out acute toxicity test, abnormal toxicity test and heat source check, and all up to specification, safety obtains proof.
Compared with prior art, Cephazolin sodium pentahydrate proliposome preparation provided by the invention and preparation method thereof has beyond thought effect, and major advantage is as follows:
(1) the present invention is by adopting specific phospholipid material, and specific proppant, prepared Cephazolin sodium pentahydrate proliposome, cefazolin sodium is wrapped in the liposome, not only greatly improved stability, and product liposome in dry run can not break because of dehydration, fusion, ice crystal generation etc., and after aquation was redissolved, the envelop rate of liposome can not reduce;
(2) pharmaceutical carrier liposome vivo degradation, avirulence and non-immunogenicity, and can improve the Drug therapy index, reduce drug toxicity and reduce drug side effect;
(3) adopt conventional process equipment to prepare, but and commercial scale, high efficiency production, and this production cost of products is low.
The specific embodiment
The present invention will adopt following specific embodiment to be described in detail, and should be appreciated that the purpose that these embodiment are only used for setting forth, and also limit protection scope of the present invention never in any form.Those skilled in the art can make multiple modification or change to embodiment of the present invention under spirit of the present invention and purport under the instruction of this description, these all will comprise within the scope of the invention.
The preparation of embodiment 1 Cephazolin sodium pentahydrate proliposome
Prescription: Cephazolin sodium pentahydrate 100g
Egg yolk lecithin acyl serine 300g
Cholesterol 60g
Sorbitol 166.7g
Dextran 83.3g
Preparation technology
(1) 300g egg yolk lecithin acyl serine, 60g cholesterol being dissolved in 1000ml n-butyl alcohol and acetone volume ratio is in 1: 1 the mixed solvent, mix homogeneously, and n-butyl alcohol and acetone are removed in decompression on rotary film evaporator, make immobilized artificial membrane;
(2) add pH value 5.6 phosphate buffered solution 1000ml, jolting was stirred 40 minutes, rotating speed 200r/min makes the complete aquation of immobilized artificial membrane, adopts the even at a high speed matter emulsifying of tissue mashing machine, rotating speed 12000r/min with 0.45 μ m filtering with microporous membrane, makes the blank liposome suspension;
(3) the 100g Cephazolin sodium pentahydrate is dissolved in 1000ml water, filtering with microporous membrane, filtrate adds in the blank liposome suspension, be heated to 50 ℃ and stirred 60 minutes, add 166.7g sorbitol and 83.3g dextran again, stirring and dissolving, cool to room temperature gets the Cephazolin sodium pentahydrate liposome solutions;
(4) with above-mentioned solution lyophilization, make Cephazolin sodium pentahydrate proliposome;
(5) with the Cephazolin sodium pentahydrate proliposome packing under aseptic condition for preparing, every bottle of 0.1g (cefazolin sodium meter) makes the Cephazolin sodium pentahydrate Liposomal formulation.
The preparation of embodiment 2 Cephazolin sodium pentahydrate proliposomes
Prescription: Cephazolin sodium pentahydrate 50g
Egg yolk lecithin acyl serine 285g
Cholesterol 15g
Mannitol 120g
Lactose 120g
Preparation technology
(1) 285g egg yolk lecithin acyl serine, 15g cholesterol being dissolved in 1000ml isopropyl alcohol and methanol volume ratio is in 3: 2 the mixed solvent, mix homogeneously, and isopropyl alcohol and methanol are removed in decompression on rotary film evaporator, make immobilized artificial membrane;
(2) add pH value 5.0 acetate buffer solution 1000ml, jolting was stirred 30 minutes, rotating speed 600r/min makes the complete aquation of immobilized artificial membrane, adopts the even at a high speed matter emulsifying of tissue mashing machine, rotating speed 12000r/min with 0.45 μ m filtering with microporous membrane, makes the blank liposome suspension;
(3) the 50g Cephazolin sodium pentahydrate is dissolved in 800ml water, filtering with microporous membrane, filtrate adds in the blank liposome suspension, be heated to 60 ℃ and stirred 40 minutes, add 120g mannitol and 120g lactose again, stirring and dissolving, cool to room temperature gets the Cephazolin sodium pentahydrate liposome solutions;
(4) with above-mentioned solution lyophilization, make Cephazolin sodium pentahydrate proliposome;
(5) with the Cephazolin sodium pentahydrate proliposome packing under aseptic condition for preparing, every bottle of 0.05g (cefazolin sodium meter) makes the Cephazolin sodium pentahydrate Liposomal formulation.
The preparation of embodiment 3 water cefazolin sodium sodium proliposomes
Prescription: Cephazolin sodium pentahydrate 25g
Egg yolk lecithin acyl serine 50g
Cholesterol 100g
Sorbitol 60g
Dextran 30g
Preparation technology
(1) 50g egg yolk lecithin acyl serine, 100g cholesterol being dissolved in 800ml n-butyl alcohol and acetone volume ratio is in 1: 1 the mixed solvent, mix homogeneously, and n-butyl alcohol and acetone are removed in decompression on rotary film evaporator, make immobilized artificial membrane;
(2) add pH value 6.0 citrate buffer solution 800ml, jolting was stirred 20 minutes, rotating speed 500r/min makes the complete aquation of immobilized artificial membrane, adopts the even at a high speed matter emulsifying of tissue mashing machine, rotating speed 12000r/min with 0.45 μ m filtering with microporous membrane, makes the blank liposome suspension;
(3) the 25g Cephazolin sodium pentahydrate is dissolved in 500ml water, filtering with microporous membrane, filtrate adds in the blank liposome suspension, be heated to 55 ℃ and stirred 30 minutes, add 60g sorbitol and 30g dextran again, stirring and dissolving, cool to room temperature gets the Cephazolin sodium pentahydrate liposome solutions;
(4) with above-mentioned solution lyophilization, make Cephazolin sodium pentahydrate proliposome;
(5) with the Cephazolin sodium pentahydrate proliposome packing under aseptic condition for preparing, every bottle of 0.025g (cefazolin sodium meter) makes the Cephazolin sodium pentahydrate Liposomal formulation.
The preparation of embodiment 4 Cephazolin sodium pentahydrate proliposomes
Prescription: Cephazolin sodium pentahydrate 200g
Egg yolk lecithin acyl serine 450g
Cholesterol 240g
Glucose 70g
Trehalose 280g
Preparation technology
(1) 450g egg yolk lecithin acyl serine, 240g cholesterol being dissolved in 2000ml ethanol and normal hexane volume ratio is in 2: 1 the mixed solvent, mix homogeneously, and ethanol and normal hexane are removed in decompression on rotary film evaporator, make immobilized artificial membrane;
(2) add pH value 5.4 phosphate buffered solution 1500ml, jolting was stirred 30 minutes, rotating speed 400r/min makes the complete aquation of immobilized artificial membrane, adopts the even at a high speed matter emulsifying of tissue mashing machine, rotating speed 12000r/min with 0.45 μ m filtering with microporous membrane, makes the blank liposome suspension;
(3) the 200g Cephazolin sodium pentahydrate is dissolved in 2000ml water, filtering with microporous membrane, filtrate adds in the blank liposome suspension, be heated to 50 ℃ and stirred 50 minutes, add 70g glucose and 280g trehalose again, stirring and dissolving, cool to room temperature gets the Cephazolin sodium pentahydrate liposome solutions;
(4) with above-mentioned solution lyophilization, make Cephazolin sodium pentahydrate proliposome;
(5) with the Cephazolin sodium pentahydrate proliposome packing under aseptic condition for preparing, every bottle of 0.2g (cefazolin sodium meter) makes the Cephazolin sodium pentahydrate Liposomal formulation.
The preparation of Comparative Examples 1 Cephazolin sodium pentahydrate proliposome
Prescription: Cephazolin sodium pentahydrate 100g
Hydrogenated soy phosphatidyl choline 300g
Polyoxyethylene sorbitan monoleate 60g
Mannitol 166.7g
Glucose 83.3g
Preparation technology is with embodiment 1, packing under aseptic condition, and every bottle of 0.1g (cefazolin sodium meter) makes the Cephazolin sodium pentahydrate Liposomal formulation.
The preparation of Comparative Examples 2 water cefazolin sodium sodium proliposomes
Prescription: Cephazolin sodium pentahydrate 50g
Egg yolk lecithin acyl serine 510g
Cholesterol 210g
Mannitol 100g
Lactose 310g
Preparation technology is with embodiment 2, packing under aseptic condition, and every bottle of 0.05g (cefazolin sodium meter) makes the Cephazolin sodium pentahydrate Liposomal formulation.
The mensuration of test example 1 envelop rate
Get the Liposomal formulation of embodiment preparation, the total content that high performance liquid chromatography detects cefazolin sodium is M, selects for use column chromatography to separate liposome.
Get 1.5g sephadex G-50, soak more than the swelling 12h with the pH6.8 phosphate buffer, pack in the chromatographic column (200 * 10mm) into, with above-mentioned phosphate buffer flushing balance, getting the five water cefazolin sodium Liposomal formulations that embodiment 1-3 and Comparative Examples 1-2 obtain respectively is dissolved in water, make every 1ml and contain the about 18mg solution of cefazolin sodium, respectively get solution 1.7ml respectively, add chromatography and live the top, with phosphate buffer 50ml eluting, flow velocity 1.2ml/min, the eluent of collection add rupture of membranes agent (ethanol: 50ml benzyl alcohol=8: 1), mixing, high performance liquid chromatography detects the content M of cefazolin sodium
1
Envelop rate %=M
1/ M * 100%.
Table 1 entrapment efficiency determination result
By above result as can be known, the liposome encapsulation that proportioning makes of writing out a prescription of the embodiment in the scope of the invention is very high, realistic production requirement; And the liposome encapsulation that the outer Comparative Examples prescription proportioning of the scope of the invention makes is very low, has compared tangible gap with embodiment, is not suitable for production requirement.
The detection of test example 2 particle diameters
Get the Liposomal formulation of embodiment 1-3 and Comparative Examples 1-2 preparation, after the adding physiological saline solution mixes, adopt micro-image analyzer to measure the particle size distribution of liposome, the results are shown in Table 2.
Table 2 particle diameter testing result
By above result as can be known, it is spherical that the liposome that embodiment 1-3 makes shows, and particle diameter is even, and scope is 100-200nm; The liposome shape that Comparative Examples 1-2 makes is indefinite, disorderly and unsystematic, not of uniform size, and particle diameter is inhomogeneous, and scope is 400-800nm.
Test example 3 stability tests
With the sample of above each embodiment preparation and (Beijing Taiyang Pharmaceutical Co., Ltd.'s production of the cefazolin sodium sodium injection of listing, lot number 20080106, specification 1.0g/ bottle) under 60 ℃ of high temperature, illumination 4500Lx condition, places and carried out the influence factor in 10 days and test investigation, the results are shown in Table 3; Under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate, the results are shown in Table 4; Under 25 ℃ of high temperature, relative humidity 60% ± 10% condition 18 months, carry out long term test and investigate, detect the variation of every quality index, the results are shown in Table 5.
Table 3 influence factor result
Table 4 accelerated test result
Table 5 long-term test results
Quickened March, June by above found that, long-term December, the cefazolin sodium powder pin clarity of listing is against regulation 18 months the time, and pH value descends bigger, and content reduces obviously, and related substance raises; And the sample appearance character of the present invention's preparation does not have significant change, redissolves well, and clarity, acidity, content and related substance do not have obvious variation yet.The sample stable quality after long time storage that the present invention's preparation is described is better.
And, obtaining by further routine test, after proliposome powders pin aquation of the present invention was redissolved, envelop rate did not change, and is far superior to the product of prior art.
Test example 4 safety testings
The undue toxicity checks according to version pharmacopeia appendix XI C undue toxicity inspection technique in 2005, the sample of the present invention's preparation is diluted to certain density need testing solution with sodium chloride solution, inject in the mice body of Pass Test requirement, mice did not all have the phenomena of mortality in 48 hours as a result, illustrated that this product undue toxicity is up to specification.
Heat source check checks that according to 2005 editions pharmacopeia appendix XI D heat resource method the result is up to specification.
Claims (10)
1. Cephazolin sodium pentahydrate proliposome, calculate by weight, make by following component: Cephazolin sodium pentahydrate 7-13 part, egg yolk lecithin acyl serine 15-40 part, cholesterol 2-10 part, proppant 10-40 part, and described proppant is that weight ratio is that 2: 1 sorbitol and dextran or weight ratio are that 1: 1 mannitol and lactose or weight ratio are 1: 4 glucose and trehalose.
2. Cephazolin sodium pentahydrate proliposome according to claim 1 is characterized in that described proppant is that weight ratio is 2: 1 sorbitol and a dextran.
3. Cephazolin sodium pentahydrate proliposome according to claim 1, wherein, 10 parts of Cephazolin sodium pentahydrates, 30 parts of egg yolk lecithin acyl serines, 6 parts in cholesterol, 25 parts of proppant.
4. according to each described Cephazolin sodium pentahydrate proliposome of claim 1-3, it is an injectable powder, in cefazolin sodium, and single preparation Cephazolin sodium pentahydrate 0.025-0.2g.
5. a method for preparing each described Cephazolin sodium pentahydrate proliposome of claim 1-4 is characterized in that comprising the steps:
(1) egg yolk lecithin acyl serine, cholesterol are dissolved in the organic solvent, make immobilized artificial membrane after removing organic solvent;
(2) add buffer salt solution in the immobilized artificial membrane that makes, make the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying makes the blank liposome suspension;
(3) Cephazolin sodium pentahydrate is water-soluble, add in the blank liposome suspension, add proppant again, make the Cephazolin sodium pentahydrate liposome solutions;
(4) with above-mentioned solution lyophilization or spray drying, make Cephazolin sodium pentahydrate proliposome.
6. the method for preparing Cephazolin sodium pentahydrate proliposome according to claim 5 is characterized in that comprising the steps:
(1) egg yolk lecithin acyl serine, cholesterol are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) add buffer salt solution in the immobilized artificial membrane that makes, jolting is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(3) Cephazolin sodium pentahydrate is water-soluble, filtering with microporous membrane, filtrate adds in the blank liposome suspension, under 50-60 ℃ temperature, stirred 30-60 minute, add proppant again, stir and make its dissolving, cool to room temperature gets the Cephazolin sodium pentahydrate liposome solutions then;
(4) with above-mentioned solution lyophilization or spray drying, make Cephazolin sodium pentahydrate proliposome.
7. according to claim 5 or the 6 described methods that prepare Cephazolin sodium pentahydrate proliposome, wherein said organic solvent is that volume ratio is that 1: 1 n-butyl alcohol and acetone or volume ratio are that 3: 2 isopropyl alcohol and methanol or volume ratio are 2: 1 ethanol and normal hexane.
8. the method for preparing Cephazolin sodium pentahydrate proliposome according to claim 7, wherein said organic solvent are that volume ratio is 1: 1 n-butyl alcohol and an acetone.
9. according to claim 5 or the 6 described methods that prepare Cephazolin sodium pentahydrate proliposome, wherein said buffer salt solution is selected from one or more in phosphate buffer that the pH value scope is 5.0-6.0, citrate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer.
10. by each described prepared Cephazolin sodium pentahydrate proliposome of method for preparing Cephazolin sodium pentahydrate proliposome of claim 5-9.
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