CN104490785B - A kind of ceftiaoxline sodium for injection liposome composition and preparation method thereof - Google Patents
A kind of ceftiaoxline sodium for injection liposome composition and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of ceftiaoxline sodium for injection liposome composition and preparation method thereof, the ceftizoxime sodium liposome includes ceftizoxime sodium, phosphatide, cholesterol and citrate buffer, wherein, phosphatide: cholesterol mass ratio is 1.5 2: 1.The present invention provide ceftizoxime sodium liposome composition, with stability it is excellent, envelop rate is high, the low advantage of seepage, is suitable for industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to arrived a kind of ceftiaoxline sodium for injection liposome composition and
Its preparation method.
Technical background
Ceftizoxime sodium, chemical name is：[6R- [6a, 7b (Z)]] -7 [[2,3- dihydro -2- imino group -4- thiazolyls)
(methoxyimino) acetyl group] amino] -8- oxo -5- thia -1- azabicyclic [4.2.0] oct-2-ene -2- carboxylic acid sodium salts, point
Minor C13H12N5NaO5S2, molecular weight 405.38.
Ceftizoxime sodium belongs to third generation cephalosporin, has broad-spectrum antibacterial action, to various gram positive bacterias and Grain-negative
Bacterium produce wide spectrum lactamase (including penicillase and cephalosporinase) stabilization, to EHEC, Klebsiella Pneumoniae,
The enterobacteriaceae lactobacteriaceaes such as proteus mirabilis have the pseudomonas such as powerful antibacterial action, pseudomonas aeruginosa and acinetobacter
It is poor to this product sensitiveness.Ceftizoxime sodium is to the effect of staphylococcus aureus and MRSE compared with first, second generation head
Spore rhzomorph is poor, and, to this product resistance, various streptococcus are to the equal height of this product for methicillin-resistant staphylococcus aureus and enterococcus spp
Degree is sensitive.The anaerobic bacterias such as peptococcus, peptostreptococcus and part Bacteroides are in sensitivity, clostridium difficile is to this product more than this product
Resistance.Ceftizoxime sodium mechanism of action reaches bactericidal action for the biosynthesis by suppressing bacteria cell wall mucopeptide, is applicable
ALRI, urinary tract infections, abdominal cavity infection, pelvic infection, septicemia, skin soft-tissue infection caused by sensitive bacteria,
Bone and the infection of joint, streptococcus pneumonia or meningitis caused by haemophilus influenzae and Simple gonorrhea.
Chinese patent application CN201010125855.9 discloses a kind of ceftizoxime sodium liposome injection, comprising following
Component：Ceftizoxime sodium, buffer salt system, liposome matrix, freeze-dried excipient, antioxidant, it is characterised in that wherein institute
The phosphate solution that the buffer salt system stated is made up of 5%mg/ml sodium dihydrogen phosphates and 15%mg/ml disodium hydrogen phosphates, delays
It is 6.5~8.0 to rush the pH value of salt system, and described liposome matrix is phosphatide: cholesterol mass ratio is 1: 1 mixture.Should
Ceftizoxime sodium liposome injection is obtained by the following method：1) sodium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injection
In, phosphate buffer is made into, it is 6.5~8.0 to adjust pH value with pH value regulator；2) phosphatide and cholesterol in organic solvent
Middle melting, the phosphate buffer for adding pH value to be 6.5~8.0, is uniformly mixed, and treats that organic solvent volatilization is complete, transfer
10~30min, filtering, sterilizing are stirred to tissue mincer's high speed；3) to step 2) add in resulting material ceftizoxime sodium,
Newborn even grinding is carried out after freeze-dried excipient and antioxidant, is filtered, it is filling in cillin bottle, freezed, obtain cephalo azoles
Oxime sodium lipidosome freeze-dried preparation finished product.
The ceftizoxime sodium liposome has envelop rate higher, can reach 92%, and average grain diameter is 94nm, but through this hair
Person of good sense's research finds that the percolation ratio of the ceftizoxime sodium liposome is also high, also unstable.
The comparative example of Chinese patent application CN201010125855.9 also discloses that a kind of spore ceftizoxime sodium liposome note
Agent is penetrated, by ceftizoxime sodium 5g, lecithin 23g, cholesterol 7g, citric acid 8g, sodium citrate 15g, sorbierite 18g, vitamin
E7g, ether 200ml are constituted.The liposome uses sodium citrate buffer, and liposome encapsulation is low, and only 55%, under Electronic Speculum
Observation, arranges disorderly and unsystematic, and basis of microscopic observation is placed on after 12h, has crystalline material to separate out.
The content of the invention
It is an object of the invention to provide a kind of encapsulation ratio high, the ceftiaoxline sodium for injection lipid combination of hypotonic leak rate
Thing.The liposome composition has that envelop rate is high, percolation ratio is low, and stability is high, proterties is regular, and particle diameter is small, and distribution collection is medium
Advantage.
The present invention provide a kind of ceftiaoxline sodium for injection liposome, including following weight portion component：Ceftizoxime
2~4 parts of 2~6 parts of the mixed phosphatide of 1~3 part of sodium, soybean lecithin and egg yolk lecithin, 1~3 part of cholesterol and mannitol, with
And citrate buffer that pH value is 6.5~7.5 is appropriate, wherein, the weight ratio of soybean lecithin and egg yolk lecithin for 1~
2：1, preferably 1：1.
The ceftiaoxline sodium for injection liposome of the invention described above, further includes antioxidant, and the antioxidant is selected from dimension
One or more in raw element E, sodium sulfite and sodium hydrogensulfite, preferred vitamin E and sodium sulfite.
The ceftiaoxline sodium for injection liposome of the invention described above, it is preferable that wherein, the total amount and cholesterol of mixed phosphatide
Weight ratio be 1.5~2：1.
Preferably, a kind of component of ceftiaoxline sodium for injection liposome of the invention, including following weight portion：Cephalo azoles
2 parts of 2 parts of the mixed phosphatide of 1 part of oxime sodium, soybean lecithin and egg yolk lecithin, 1 part of cholesterol and mannitol, and pH value is
6.5~7.5 citrate buffer is appropriate.
The ceftiaoxline sodium for injection liposome of the invention described above, the citrate buffer refers in right amount citrate
It is 6.5~7.5 that the consumption of buffer solution is enough to make the pH value of lyophilized preceding solution.
The ceftiaoxline sodium for injection liposome of the invention described above, further includes antioxidant, and the antioxidant is selected from dimension
One or more in raw element E, sodium sulfite and sodium hydrogensulfite, preferred vitamin E and sodium sulfite, consumption is for routinely
Consumption.
The ceftiaoxline sodium for injection liposome of the invention described above, is prepared as follows, and the method is comprised the following steps：
1) soybean lecithin, egg yolk lecithin and cholesterol are dissolved in volatile organic solvent, are uniformly mixed,
It is complete that intensification makes organic solvent volatilize, and obtains immobilized artificial membrane；
2) to step 1) immobilized artificial membrane in add pH value be 6.5~7.5 citrate buffer, if necessary, adjusted with pH
Section agent adjusts pH value to 6.5~7.5, and stirring makes immobilized artificial membrane aquation, then high speed homogenization emulsification, and micro-pore-film filtration obtains filtrate；
3) to step 2) filtrate in add ceftizoxime sodium, mannitol, antioxidant, high-speed stirred emulsifying, filtering,
The lyophilized packing of filtrate, or it is filling in cillin bottle, freezed, obtain ceftizoxime sodium liposome lyophilized formulations finished product.
Method described above, step 1) described in volatile organic solvent be selected from ethanol, isopropanol and chloroform in
One or two mixing, the pH adjusting agent is sodium hydroxide solution, hydrochloric acid, phosphoric acid or citric acid, and preferably NaOH is molten
Liquid or hydrochloric acid.
In the above method, step 2) in so-called " if necessary ", refer to after adding citrate buffer, if the pH of solution
, it is necessary to adjust the pH value of solution to 6.5~7.5 with pH adjusting agent when value is not 6.5~7.5, if the pH value of solution does not become
Change or occur deviation, then without the pH value with pH adjusting agent regulation solution.
Citrate buffer refers to the compound method that American Pharmacopeia records and is obtained, and can also be bought by commercial sources.
Ceftiaoxline sodium for injection liposome of the invention solves the use citrate buffer of prior art disclosure
(comparative example of CN201010125855.9) and sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution envelop rate is low and unstable asks
Topic, and unexpected technique effect is produced, such as encapsulation ratio is high, and percolation ratio is low, has good stability.
Ceftizoxime sodium liposome of the invention, has advantages below relative to prior art：
Ceftizoxime sodium liposome prepared by the present invention, encapsulation ratio is high, and percolation ratio is low, has good stability, with targeting
Property, rate of release ideal, bioavilability is high, solubility is good, and Clinical practice is safer and more effective.
Specific embodiment
Following examples are used to further elucidate and understand essence of the invention, but with this do not limit the scope of the present invention.
Interpellation is needed, the weight of ceftizoxime sodium is with head in ceftizoxime sodium liposome of the invention and following examples
Spore azoles oxime meter.
Embodiment 1
Prescription
Preparation technology：
1) soybean lecithin, egg yolk lecithin and cholesterol are dissolved in 800ml isopropanols, are uniformly mixed, heated up
Evaporation removes isopropanol completely, obtains immobilized artificial membrane；
2) to step 1) immobilized artificial membrane in add citrate buffer 1500ml, if necessary, with sodium hydroxide solution and
To 7.0, stirring makes immobilized artificial membrane aquation to salt acid for adjusting pH, and then high speed homogenization emulsification, micro-pore-film filtration, obtain filtrate, add injection
It is 2000ml with water to filtrate；
3) to step 2) filtrate in add ceftizoxime sodium, mannitol, vitamin E, high-speed stirred emulsifying, mistake
Filter, sterilizing, the lyophilized packing of filtrate, or filtrate are filling in cillin bottle, are freezed, and obtain ceftizoxime sodium liposome and freeze
Finished dosage form, every bottle of ceftizoxime sodium 0.5g/.
Embodiment 2
Prescription
Preparation technology：
1) soybean lecithin, egg yolk lecithin and cholesterol are dissolved in 1800ml chloroforms：Ethanol is 1：3 mixed solvent
In, it is uniformly mixed, the evaporation that heats up removes chloroform and ethanol completely, obtains immobilized artificial membrane；
2) to step 1) immobilized artificial membrane in add citrate buffer 3000ml, if necessary with sodium hydroxide solution and salt
To 7.0, stirring makes immobilized artificial membrane aquation to acid for adjusting pH, then high speed homogenization emulsification, micro-pore-film filtration,
Filtrate is obtained, it is 4000ml to add water for injection to filtrate；
3) to step 2) filtrate in add ceftizoxime sodium, mannitol, sodium sulfite, high-speed stirred emulsifying, mistake
Filter, sterilizing, the lyophilized packing of filtrate, or filtrate are filling in cillin bottle, are freezed, and obtain ceftizoxime sodium liposome and freeze
Finished dosage form, every bottle of ceftizoxime sodium 1.0g/.
Embodiment 3
Prescription
Preparation technology：
1) soybean lecithin, egg yolk lecithin and cholesterol are dissolved in 6000ml absolute ethyl alcohols, are uniformly mixed, risen
Temperature evaporation removes ethanol completely, obtains immobilized artificial membrane；
2) to step 1) immobilized artificial membrane in add citrate buffer 1500ml, if necessary, with sodium hydroxide solution and
To 6.5, stirring makes immobilized artificial membrane aquation to salt acid for adjusting pH, and then high speed homogenization emulsification, micro-pore-film filtration, obtain filtrate, add injection
It is 2000ml with water to filtrate；
3) to step 2) filtrate in add ceftizoxime sodium, mannitol, sodium sulfite, high-speed stirred emulsifying, mistake
Filter, sterilizing, the lyophilized packing of filtrate, or filtrate are filling in cillin bottle, are freezed, and obtain ceftizoxime sodium liposome and freeze
Finished dosage form, every bottle of ceftizoxime sodium 0.5g/.
Embodiment 4
Prescription
Preparation technology：
1) soybean lecithin, egg yolk lecithin and cholesterol are dissolved in 8000ml chloroforms：Ethanol is 1：3 mixed solvent
In, it is uniformly mixed, the evaporation that heats up removes chloroform and ethanol completely, obtains immobilized artificial membrane；
2) to step 1) immobilized artificial membrane in add citrate buffer 3500ml, if necessary with sodium hydroxide solution and salt
To 7.0, stirring makes immobilized artificial membrane aquation to acid for adjusting pH, and then high speed homogenization emulsification, micro-pore-film filtration, obtain filtrate, add injection
Water to filtrate is 4000ml；
3) to step 2) filtrate in add ceftizoxime sodium, mannitol, sodium sulfite, high-speed stirred emulsifying, mistake
Filter, sterilizing, the lyophilized packing of filtrate, or filtrate are filling in cillin bottle, are freezed, and obtain ceftizoxime sodium liposome and freeze
Finished dosage form, every bottle of ceftizoxime sodium 1.0g/.
Embodiment 5
Prescription
Preparation technology：
1) soybean lecithin, egg yolk lecithin and cholesterol are dissolved in 4000ml isopropanols, are uniformly mixed, heated up
Evaporation removes isopropanol completely, obtains immobilized artificial membrane；
2) to step 1) immobilized artificial membrane in add citrate buffer 1500ml, if necessary, with sodium hydroxide solution and
To 7.5, stirring makes immobilized artificial membrane aquation to salt acid for adjusting pH, and then high speed homogenization emulsification, micro-pore-film filtration, obtain filtrate, add injection
It is 2000ml with water to filtrate；
3) to step 2) filtrate in add ceftizoxime sodium, mannitol, vitamin E, high-speed stirred emulsifying, mistake
Filter, sterilizing, the lyophilized packing of filtrate, or filtrate are filling in cillin bottle, are freezed, and obtain ceftizoxime sodium liposome and freeze
Finished dosage form, every bottle of ceftizoxime sodium 0.5g/.
Embodiment 6
Prescription
Preparation technology：
1) soybean lecithin, egg yolk lecithin and cholesterol are dissolved in 2000ml isopropanols, are uniformly mixed, heated up
Evaporation removes isopropanol completely, obtains immobilized artificial membrane；
2) to step 1) immobilized artificial membrane in add citrate buffer 1500ml, if necessary with sodium hydroxide solution and salt
To 7.0, stirring makes immobilized artificial membrane aquation to acid for adjusting pH, and then high speed homogenization emulsification, micro-pore-film filtration, obtain filtrate, add injection
Water to filtrate is 2000ml；
3) to step 2) filtrate in add ceftizoxime sodium, mannitol, vitamin E, high-speed stirred emulsifying, mistake
Filter, sterilizing, the lyophilized packing of filtrate, or filtrate are filling in cillin bottle, are freezed, and obtain ceftizoxime sodium liposome and freeze
Finished dosage form, every bottle of ceftizoxime sodium 0.5g/.
After testing, the liposome of embodiment 6 in terms of shape, particle size, envelop rate, percolation ratio and stability with implementation
Example 1 is suitable.
Comparative example 1
Spore azoles oxime sodium lipidosome freeze-dried preparation is prepared for comparative example 1 by the embodiment 1 of CN201010125855.9.
Comparative example 2~10
Prescription is shown in Table 1
The prescription of the comparative example 2~10 of table 1
Preparation method：Prepared with reference to the method for embodiment 6.
The outward appearance of embodiment 7 and particle diameter are tested
The liposome of embodiment 1~6 and comparative example 1~10 is placed in particle diameter with 0.1% normal saline into solution
In the sample cell of tester, distribution and the size of particle diameter are determined, meanwhile, use electron microscope observation outward appearance.
The liposome microballoon of embodiment 1~6 is in ball or ellipse, and average grain diameter is in 92~95nm.Particle diameter distribution is uniform, and
Scope is narrow.
The liposome microballoon of comparative example 1~10 is in ball or ellipse, and average grain diameter is in 95~110nm, and particle diameter distribution is wider.
Measurement result is shown in Table 2 and table 3.
The liposome outward appearance and particle size of the embodiment 1~5 of table 2
| Average grain diameter (nm) | Outward appearance | |
| Embodiment 1 | 92 | Spherical in shape, regular shape is uniform in size |
| Embodiment 2 | 92.5 | Spherical in shape, regular shape is uniform in size |
| Embodiment 3 | 93 | In shape ball, regular shape is uniform in size |
| Embodiment 4 | 93 | In ball ball, regular shape is uniform in size |
| Embodiment 5 | 95 | In ball ball, regular shape is uniform in size |
| Embodiment 6 | 93 | In ball ball, regular shape is uniform in size |
The result of table 2 shows that liposome of the invention, face shaping is regular, and uniform in size, particle diameter distribution is good.
60 DEG C of relevant materials of the average grain diameter outward appearance of 3 comparative example of table 1~10 and 10 days high temperature
The result of table 3 shows do not have the ceftizoxime sodium liposome of the comparative example 1-10 of the technology of the present invention feature, though it is in ball
Shape or oval and rule, but size is uneven, and average grain diameter is bigger than normal and particle diameter distribution is wider.
The stability quality investigation of embodiment 8
With reference to Chinese Pharmacopoeia (2010 editions) annex experiment accelerated to prepared in above-described embodiment liposome and long-term
Study on the stability, for proterties, acid-base value, clarity, content, relevant material item-test and statistics.The results are shown in Table 4 Hes
Table 5.
Comparative example 1~10 investigates 60 DEG C of contents for placing 10 days of high temperature and relevant material, the results are shown in Table 3.
The accelerated test result of 4 embodiment of table 1~6
The long-term test results of 5 embodiment of table 1~6
The ceftizoxime sodium liposome that can be seen that embodiment of the present invention preparation by the result of the test with upper table 3,4 and 5 is each
Item is investigated to have no significant change；Relevant material change is little, and clarity meets regulation.Liposome is to cephalo in illustrating the present invention
The parcel of azoles oxime sodium serves protective effect, stabilizes the property of itself, has ensured the up-to-standard and drug safety of preparation.And
Comparative example 1~10 declines in 60 DEG C of contents placed 10 days of high temperature and relevant material rises substantially, hence it is evident that show unstable.
The envelop rate of embodiment 9 is determined with percolation ratio is oozed
Sample obtained in Example 1~5 and comparative example, respectively at room temperature respectively at 0 day, 30 days, 60 days, 90 days,
With 180 days, inspect periodically, determine envelop rate, compare with 0 day dose of envelop rate, calculate percolation ratio, the results are shown in Table 6 and table
7。
The envelop rate of 6 embodiment of table 1~6 and percolation ratio
| Time | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Comparative example 1 |
| Envelop rate | 94% | 93% | 92% | 92% | 91% | 95% | 91% |
| 0 day percolation ratio | 0.32 | 0.35 | 0.36 | 0.38 | 0.37 | 0.31 | 0.35 |
| 30 days percolation ratios | 0.35 | 0.36 | 0.37 | 0.39 | 0.39 | 0.33 | 0.56 |
| 60 days percolation ratios | 0.38 | 0.39 | 0.38 | 0.41 | 0.46 | 0.41 | 1.05 |
| 90 days percolation ratios | 0.40 | 0.43 | 0.45 | 0.46 | 0.48 | 0.45 | 5.38 |
| 180 days percolation ratios | 0.45 | 0.46 | 0.50 | 0.51 | 0.53 | 0.50 | 10.90 |
The envelop rate of 7 comparative example of table 2~8 and percolation ratio
| Time | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | Comparative example 6 | Comparative example 7 | Comparative example 8 |
| Envelop rate | 90% | 91% | 93% | 90% | 92% | 92% | 85% |
| 0 day percolation ratio | 0.31 | 0.35 | 0.33 | 0.34 | 0.31 | 0.31 | 0.31 |
| 30 days percolation ratios | 0.34 | 0.60 | 0.67 | 0.79 | 0.69 | 0.89 | 0.66 |
| 60 days percolation ratios | 1.30 | 1.39 | 1.88 | 2.31 | 2.16 | 3.07 | 9.05 |
| 90 days percolation ratios | 5.40 | 6.43 | 6.45 | 7.46 | 6.48 | 8.48 | 10.38 |
| 180 days percolation ratios | 10.45 | 12.46 | 11.50 | 12.66 | 11.53 | 12.53 | 13.90 |
From table 6 and the result of table 7, the envelop rate of liposome of the invention is suitable with comparative example or slightly excellent, with depositing
The extension of time is put, gained Liposomal formulation percolation ratio change of the invention is little, but comparative example gradually increases.Show this hair
Bright ceftiaoxline sodium for injection liposome composition is more stable, is conducive to long term storage.
To sum up, compared with prior art, profile is regular, average grain diameter for present invention gained ceftiaoxline sodium for injection liposome
Small, envelop rate is high, percolation ratio is low, liposome is stable.
Any modification is carried out on the basis of essence of the invention or accommodation belongs to protection scope of the present invention.
Claims (7)
1. a kind of component of ceftiaoxline sodium for injection liposome, including following weight portion：1 part of ceftizoxime sodium, soybean lecithin
2~4 parts of 2~6 parts of the mixed phosphatide of fat and egg yolk lecithin, 1~3 part of cholesterol and mannitol, and pH value are 6.5~7.5
Citrate buffer be formulated in right amount, wherein, the weight ratio of soybean lecithin and egg yolk lecithin is 1~2:1, lecithin
The total amount of fat is 1.5~2 with the weight ratio of cholesterol：1, the liposome is prepared as follows, and the method includes following step
Suddenly：
1) soybean lecithin, egg yolk lecithin and cholesterol are dissolved in volatile organic solvent, are uniformly mixed, heated up
Organic solvent is volatilized complete, obtain immobilized artificial membrane；
2) to step 1) immobilized artificial membrane in add citrate buffer, if necessary, with pH adjusting agent adjust pH value to 6.5-7.5,
Stirring makes immobilized artificial membrane aquation, then high speed homogenization emulsification, and micro-pore-film filtration obtains filtrate；
3) to step 2) filtrate in add ceftizoxime sodium, mannitol, antioxidant, high-speed stirred emulsifying, filtering, filtrate
Lyophilized packing, or it is filling in cillin bottle, freezed, obtain ceftizoxime sodium liposome lyophilized formulations finished product.
2. the component of liposome as claimed in claim 1, including following weight portion：1 part of ceftizoxime sodium, soybean lecithin and
2 parts of 2 parts of the mixed phosphatide of egg yolk lecithin, 1 part of cholesterol and mannitol, and the citrate buffer that pH is 6.5~7.5
In right amount.
3. liposome as claimed in claim 1, soybean lecithin is 1 with the weight ratio of egg yolk lecithin:1.
4. liposome as claimed in claim 1, the antioxidant is selected from vitamin E, sodium sulfite and sodium hydrogensulfite
One or more.
5. liposome as claimed in claim 1, the volatile organic solvent is selected from ethanol, isopropanol and chloroform
Plant or various.
6. liposome as claimed in claim 1, the pH adjusting agent is sodium hydroxide solution, hydrochloric acid, phosphoric acid or citric acid.
7. liposome as claimed in claim 6, the pH adjusting agent is sodium hydroxide solution or hydrochloric acid.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101780052A (en) * | 2010-03-17 | 2010-07-21 | 陶灵刚 | Ceftizoxime sodium liposome injection |
| CN102716075A (en) * | 2012-07-03 | 2012-10-10 | 哈药集团制药总厂 | Ceftizoxime sodium-containing pharmaceutical composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009028650A1 (en) * | 2007-08-29 | 2009-03-05 | Yutoku Pharmaceutical Industries Co., Ltd. | Emulsion-type external preparation, and method for production thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101780052A (en) * | 2010-03-17 | 2010-07-21 | 陶灵刚 | Ceftizoxime sodium liposome injection |
| CN102716075A (en) * | 2012-07-03 | 2012-10-10 | 哈药集团制药总厂 | Ceftizoxime sodium-containing pharmaceutical composition |
Non-Patent Citations (1)
| Title |
|---|
| 头抱菌素类抗生素脂质体的包封率测定与渗漏研究;罗云敬等;《中国生化药物杂志》;19991231;第20卷(第1期);全文 * |
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