CN102091073B - Ceftazidime and tazobactam sodium medicine composition liposome injection - Google Patents
Ceftazidime and tazobactam sodium medicine composition liposome injection Download PDFInfo
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- CN102091073B CN102091073B CN2010105781428A CN201010578142A CN102091073B CN 102091073 B CN102091073 B CN 102091073B CN 2010105781428 A CN2010105781428 A CN 2010105781428A CN 201010578142 A CN201010578142 A CN 201010578142A CN 102091073 B CN102091073 B CN 102091073B
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- China
- Prior art keywords
- ceftazidime
- sodium
- liposome
- hours
- tazobactam
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 44
- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical compound COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 229960000373 tazobactam sodium Drugs 0.000 title claims abstract description 37
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- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 description 1
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- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 210000003677 hemocyte Anatomy 0.000 description 1
- 229940000351 hemocyte Drugs 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- ZUVCYFMOHFTGDM-UHFFFAOYSA-N hexadecyl dihydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(O)=O ZUVCYFMOHFTGDM-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- GTDHYNXLIKNVTJ-UHFFFAOYSA-N n-(1-hydroxy-2-methylpropan-2-yl)octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NC(C)(C)CO GTDHYNXLIKNVTJ-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001095 phosphatidyl group Chemical group 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
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- 229940007046 shigella dysenteriae Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 229960005256 sulbactam Drugs 0.000 description 1
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- MEYZYGMYMLNUHJ-UHFFFAOYSA-N tunicamycin Natural products CC(C)CCCCCCCCCC=CC(=O)NC1C(O)C(O)C(CC(O)C2OC(C(O)C2O)N3C=CC(=O)NC3=O)OC1OC4OC(CO)C(O)C(O)C4NC(=O)C MEYZYGMYMLNUHJ-UHFFFAOYSA-N 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a ceftazidime and tazobactam sodium medicine composition liposome injection which comprises the following components in parts by weight: 3 parts of ceftazidime, 1 part of tazobactam sodium, 3-20 parts of liposome membrane material, 2.2-15 parts of additive, 5-20 parts of freeze-drying proppant and 1-3 parts of antioxidant. The ceftazidime and the tazobactam sodium are prepared into liposome, thus the stability of the preparation is greatly improved, the medicine quality is increased, and the toxic and side effects are reduced; and the ceftazidime and tazobactam sodium medicine composition liposome injection has a targeting property, so that the treatment effect is improved.
Description
Technical field
The present invention relates to a kind of ceftazidime and tazobactam sodium medicinal composition liposome injection and method for making thereof, belong to field of medicine preparations.
Background technology
Ceftazidime (Ceftazidime CAZ) has another name called ceftazidime, fortum etc., is semi-synthetic third generation cephalosporin class antibiotic, and antibiotic vigor is stronger, and antimicrobial spectrum is wider, Grain-positive or negative bacterium is all had pretend usefulness.The beta lactamase that gram positive bacteria, negative bacterium are produced has the stability of height; Bacillus pyocyaneus, escherichia coli, klebsiella bacillus, Bacillus proteus, enterococcus, salmonella, shigella dysenteriae, NEISSERIA GONORRHOEAE, Neisseria meningitidis, golden Portugal bacterium, Hemolytic streptococcus, streptococcus pneumoniae and aerobacteria etc. had strong antibacterial activity, particularly for the strongest antibiotic of bacillus pyocyaneus effect.
The antibacterial action mechanism of ceftazidime can suppress the transpeptidation of transpeptidase in the synthetic final step interconnection of cell wall for influencing the synthetic of bacteria cell wall, interconnection can not be formed, thereby it is synthetic to influence cell wall, causes the antibacterial bacteriolyze dead.
Sodium-tazobactam is the novel penicillanic acid sulfones beta-lactamase inhibitor after sulbactam sodium and clavulanic acid, and its structural formula increases a triazole ring on the basis of sulbactam sodium, presses down enzymatic activity to improve.The enzyme effect that presses down of sodium-tazobactam is better than sulbactam; And stability is because clavulanic acid; Especially extended spectrum (ESBLs) being had stronger inhibitory action, is the beta-lactamase inhibitor that market prospect is arranged at present very much, and have toxicity low, press down advantages such as enzymatic activity is strong, good stability.
How ceftazidime and sodium-tazobactam are processed compound formulation at present, can improve the antibacterial activity of ceftazidime greatly, reduce bacterial drug resistance.
This series products ceftazidime and the Tazobactam Sodium sodium injection of existing listing, the ubiquity active constituents of medicine is unstable, and the long-term storage related substance is produced more, and content reduces, and this has not only reduced drug effect, and brings drug risk, the harm patients ' interest.
CN 1418632 A disclose ceftazidime for inj and with the compound preparation of sodium-tazobactam, ceftazidime and with the weight ratio of sodium-tazobactam be 3: 1.Form compound preparation by ceftazidime and sodium-tazobactam by 3: 1 (weight ratio) proportionings.At first prepare sodium-tazobactam; Process mixing suspension by Tazobactam Sodium 150g and water for injection; Add sodium bicarbonate solution adjusting pH value to 6.3 ± 0.1 and obtain the Tazobactam Sodium sodium solution; Obtain the Tazobactam Sodium sodium freeze dry through injection activated carbon decolorizing, degerming filtration, lyophilization, obtain the sodium-tazobactam powder after the pulverizing; With ceftazidime 450g and sodium-tazobactam mix homogeneously, 1000 bottles of packing promptly get ceftazidime and sodium-tazobactam and form compound preparation by 3: 1 (weight ratio) proportionings again.Though the document has disclosed ceftazidime and sodium-tazobactam by the best of breed proportioning on 3: 1 therapeutics meanings, its preparation method causes the stability of its pharmaceutics but to be difficult to satisfy the needs of clinical application.
People's such as Huang Hongqian document " study on the stability of ceftazidime for inj/sodium-tazobactam " is introduced after influence factor's experiment, accelerated tests, long-term experiment; Variations such as ceftazidime for inj/sodium-tazobactam outward appearance, pH value, moisture, content, catabolite prove that the stability of ceftazidime for inj/sodium-tazobactam of the prior art is difficult to accept.
According to the inventor's further research, find existing ceftazidime and sodium-tazobactam by 3: 1 (weight ratio) though the combination very extensive at clinical application, adopt the preparation technology of present prior art to amplify after the production; Still there is muddiness in solution after lyophilized powder redissolves, the underproof phenomenon of visible foreign matters, and also stability of solution is very poor; Require to use up at short notice; Otherwise active component is very easily rotten, causes drug quality to descend, and is inappropriate for injection.
Liposome (Liposome) is dispersed in phospholipid by Britain scholar Bangham and Standlish at first and finds when carrying out electron microscopic observation in the water.Phospholipid is dispersed in the water and forms multilamellar vesicle naturally, every layer of equal bilayer of lipid not; Separated by water between vesicle central authorities and each layer, bilayer thickness is about 4nm.Afterwards, this bimolecular folliculus with similar biofilm structure was called liposome.Liposome can be divided into multilamelar liposome and courage and insight liposome.Unilamelar liposome is divided into small unilamellar vesicle and large unilamellar vesicle again.What Bangham and Standlish found at first is exactly multilamelar liposome, and their are prone to preparation, and size is generally the 0.5-5 micron.Small unilamellar vesicle is spherical, and size is generally the 20-50 nanometer; Large unilamellar vesicle is of a size of the micron number magnitude.People such as Britain Lai Men began liposome is used for pharmaceutical carrier in 1971; The main mechanism of action is that drug powder or solution are wrapped in the aqueous phase that the liposome bilayer lipid membrane sealed or embed in the liposome bilayer lipid membrane; This microgranule type of having cellularity; Get into that principal agent is activated the autoimmune function of body in the human body by reticuloendothelial system phagocytic, and change and distributed in the body of entrapped drug, drug main will be put aside in histoorgans such as liver, spleen, lung and bone marrow; Thereby improve the therapeutic index of medicine, reduce the therapeutic dose and the toxicity that reduces medicine of medicine.Mostly liposome as pharmaceutical carrier is large unilamellar vesicle at present, and particle diameter is generally between the 100-1000 nanometer.
Liposome technology has following advantage as a new medicinal preparation: (1) increases the dissolubility of medicine; (2) toxicity of reduction medicine; (3) give medicine organ targeting property, liver, lung, spleen, lymphoid tissue are had stronger affinity, make the contained medicine of liposome keep high concentration, thereby play the effect of medicine organ targeting property in these internal organs parts; (4) slow releasing function of increase medicine; (5) raising is to the protective effect of medicine.
The present invention is directed to the ceftazidime instability, it is big that the long-term storage related substance becomes, shortcomings such as content reduction, and examination combines ceftazidime and tazobactam sodium with liposome technology, medicine stability and toxic and side effects are had beyond thought effect.
Summary of the invention
The present invention is intended in the face of the restriction of existing these article of listing because of the technology of preparing means; Consult numerous related datas and a large amount of experimental summaries; Discovery can solve a series of problem after with particular excipient and preparation technology's liposome preparation technology principal agent being wrapped up, and the present invention is realized the content statement as follows at present:
One of the object of the invention provides a kind of ceftazidime and tazobactam sodium lipidosome injection, mainly comprises following component: ceftazidime, sodium-tazobactam, liposome membrane material and additives.Based on the weight portion meter, 3 parts of ceftazidimes, 1 part of sodium-tazobactam, liposome membrane material 3-20 part, additives 2.2-15 part.
Preferably, based on the weight portion meter, 3 parts of ceftazidimes, 1 part of sodium-tazobactam, liposome membrane material 5-12 part, additives 3.6-8 part.
Wherein, the weight ratio of ceftazidime and sodium-tazobactam 3: 1, specification are 2.4g (ceftazidime 1.8g and sodium-tazobactam 0.6g) and 1.2g (ceftazidime 0.9g and sodium-tazobactam 0.3g).
Further, also comprise frozen-dried supporting agent 5-20 part and antioxidant 1-3 part in the preparation.
Preferably, based on the weight portion meter, injection of the present invention comprises, 3 parts of ceftazidimes, 1 part of sodium-tazobactam, liposome membrane material 5-12 part, additives 3.6-8 part, frozen-dried supporting agent 5-20 part and antioxidant 1-3 part.
Preparation lipidosome injection membrane material commonly used is phospholipid and additives; Wherein phospholipid can be selected natural phospholipid and synthetic phospholipid for use usually, and said natural phospholipid is one or more in Ovum Gallus domesticus Flavus lecithin, hydrogenation egg yolk lecithin, EPG, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, soybean lecithin, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, soy phosphatidylserine, the soybean phospholipid acyl inositol; Said synthetic phospholipid is one or more in dioleoyl phospholipid phatidylcholine, distearyl acid phosphatidylcholine, dipalmitoyl phosphatidyl choline, dimyristoyl phosphatidyl choline, two Laurel phosphatidyl cholines, DOPG, distearyl acid phosphatidyl glycerol, two palmityl phosphatidyl glycerols, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, the two lauroyl phosphatidyl glycerols.
The membrane material of additives commonly used has cholesterol, 18-amine., phosphatidic acid, sodium deoxycholate and poloxamer 188.The membrane material that is used to prepare lipidosome injection also has PHOSPHATIDYL ETHANOLAMINE, cholesterol acetyl fat, paddy to carry alcohol, natrii tauroglycocholas, phosphatidyl silk amino acid, stearmide, single stearoyl phosphatidic acid, single stearoyl PHOSPHATIDYL ETHANOLAMINE, two cetyl phosphate (DCP), two palmityl PHOSPHATIDYL ETHANOLAMINEs, single palmityl PHOSPHATIDYL ETHANOLAMINE, two myristoyl PHOSPHATIDYL ETHANOLAMINEs.Additives generally are used for regulating membrane structure, change charged character, like cholesterol liposome bimolecular tunic are solidified, thereby reduce the generation of free radical, have reduced oxidation level, and liposome stability is significantly strengthened.
Frozen-dried supporting agent commonly used has mannitol, glycine, sorbitol, xylitol, glucose, lactose, trehalose, and frozen-dried supporting agent is used for supporting the formability after the lyophilizing, plays the effect of skeleton.
Antioxidant commonly used has sodium sulfite, sodium sulfite, sodium pyrosulfite, vitamin E, vitamin C, glutathion, propyl gallate; Antioxidant is used for playing the effect that the protection active component is avoided oxidation, and very big effect is played in the raising of stability.
According to ceftazidime sodium and tazobactam sodium medicament composition liposome injection recited above, wherein the liposome membrane material is preferably the combination of dioleoyl phospholipid phatidylcholine and soy phosphatidylserine, most preferably is preferred 3: 1 combination.
According to ceftazidime and tazobactam sodium medicinal composition liposome injection recited above, wherein additives are preferably the combination of cholesterol acetyl fat and 18-amine., most preferably are 2: 1 combinations.
According to ceftazidime and tazobactam sodium medicinal composition liposome injection recited above, it is that frozen-dried supporting agent is preferably the combination of mannitol and glycine, most preferably is 3: 2 combination.
According to ceftazidime and tazobactam sodium medicinal composition liposome injection recited above, wherein antioxidant is preferably the combination of vitamin C and sodium sulfite, most preferably is 1: 1 combination.
Though; The preparation technology of liposome becomes routine techniques already; But the selection of different preparation technologies and excipient is also non-obvious; The inventor adopts the Liposomal formulation of the excipient preparation of above special component and content proportioning to have unforeseeable technique effect through secular creative work acquisition, has improved envelop rate and has redissolved dissolubility and syringeability afterwards.
Another object of the present invention provides the ceftazidime and tazobactam sodium medicinal composition liposome injection, and wherein preparation process is:
(1) at first prepares blank liposome, active component has been dissolved in the blank liposome, produced parcel, had technological means to form envelop rate preferably.
(2) will and be made into sterile solution, be sub-packed in the cillin bottle, carry out conventional lyophilizing by loading amount by the principal agent of liposome membrane material parcel and frozen-dried supporting agent and antioxidant.
According to ceftazidime and tazobactam sodium medicinal composition liposome injection recited above, its described liposome preparation can be chosen as following several different methods:
Membrane process: by Rotary Evaporators liposome membrane material solution is used for preparing liposome membrane behind the organic solvent, then principal agent, frozen-dried supporting agent, antioxidant is dissolved in preparation medicine lipid liquid solution in the film solution;
Alcohol injection: the liposome membrane material is dissolved in the ethanol, slowly will be dissolved in the buffer salt that contains principal agent, frozen-dried supporting agent, antioxidant with micro-transfusion device and injects, preparation medicine lipid liquid solution;
Freeze-drying: directly dispose liposome membrane material solution and drug solution and mix, the insulation supersound process, the back obtains the medicine lipid liquid solution by high-speed tissue mashing machine's shaken.
Another object of the present invention provides the method for preparing of ceftazidime and tazobactam sodium medicinal composition liposome injection, and wherein preparation process comprises:
(1) liposome membrane material and additives are dissolved in the organic solvent, organic solvent is removed in decompression on rotary film evaporator, has obtained phospholipid membrane;
(2) citric acid-sodium citrate buffer solution of adding pH value 6.2 in phospholipid membrane, jolting is stirred and is made the complete aquation of phospholipid membrane, prepares blank liposome with high-quality homogenizer;
(3) ceftazidime, sodium-tazobactam, antioxidant are dissolved in the water for injection through filtering with microporous membrane, add blank liposome and mix 55 ℃ of supersound process 30min; Even with the aqueous solution that is dissolved with frozen-dried supporting agent again;
(4) be sub-packed in the cillin bottle by the regulation loading amount, place and carry out lyophilizing in the freezer dryer, detect qualified back packing warehouse-in.
Further, freeze-dry process is:
A, pre-freeze: the medicinal liquid that branch is installed is cooled to-50～-35 ℃ by 1～3 ℃ of/minute speed, is incubated freezing 3 hours;
B, distillation: the medicine evacuation that pre-freeze is good, to 15Pa, in 7～9 hours, at the uniform velocity slowly be warming up to-22～-18 ℃ then, be incubated 1～2 hour, in 4～6 hours, at the uniform velocity be warming up to 10～15 ℃ again;
C, drying: the distillation medicine of stage after finishing that finish at the uniform velocity was warming up to 30 ℃ in 4 hours, heat preservation and dryness 3 hours detects qualified back packing and puts in storage.
Preferably:
A, pre-freeze: the medicinal liquid that branch is installed is cooled to-40 ℃ by 2 ℃ of/minute speed, is incubated freezing 3 hours;
B, distillation: the medicine evacuation that pre-freeze is good, to 15Pa, in 8 hours, at the uniform velocity slowly be warming up to-20 ℃ then, be incubated 2 hours, in 5 hours, at the uniform velocity be warming up to 10 ℃ again;
C, drying: the distillation medicine of stage after finishing that finish at the uniform velocity was warming up to 30 ℃ in 4 hours, heat preservation and dryness 3 hours detects qualified back packing and puts in storage.
In the above-mentioned described method for preparing; Described organic solvent can be methanol, ethanol, ether, acetone, isopropyl alcohol, acetonitrile, chloroform, N; In the dinethylformamide one or more, preferred volume ratio are 1: 3 the isopropyl alcohol and the mixed solvent of acetonitrile.
Ceftazidime and tazobactam sodium lipidosome injection provided by the invention and preparation method thereof has the following advantages:
(1) active component ceftazidime and sodium-tazobactam wrap up through liposome technology, have greatly improved stability, and placing content and related substance does not for a long time almost have significant change, has ensured the quality of medicine;
(2) the liposome preparation technology is simple to operation, is suitable for suitability for industrialized production, and cost is low;
(3) improve drug quality, reduced toxic and side effects.
The specific embodiment
Below can provide the Comparative Examples of specific embodiments and embodiment by preferred version according to the present invention, and carry out experiment exam preparation effect of the present invention is described.Used embodiment, Comparative Examples, Test Example all are further to explain to of the present invention, and not can be used as is the further restriction to invention.
Embodiment 1
The preparation of ceftazidime and tazobactam sodium medicine compound liposome
Prescription (100 bottles):
Ceftazidime 90g
Sodium-tazobactam 30g
Dioleoyl phospholipid phatidylcholine 112.5g
Soy phosphatidylserine 37.5g
Cholesterol acetyl fat 72g
18-amine. 36g
Mannitol 90g
Glycine 60g
Sodium sulfite 15g
Vitamin C 15g
Preparation technology:
(1) 112.5g dioleoyl phospholipid phatidylcholine, 37.5g soy phosphatidylserine, 72g cholesterol acetonyl ester, 36g 18-amine. being dissolved in the 1000ml volume ratio is in 1: 3 the mixed solvent of isopropyl alcohol and acetonitrile; Mixed solvent is removed in decompression on rotary film evaporator, has obtained phospholipid membrane;
(2) citric acid-sodium citrate buffer solution 500ml of adding pH value 6.2 in phospholipid membrane, jolting 10min stirs and makes the complete aquation of phospholipid membrane, prepares blank liposome with high-quality homogenizer;
(3) 90g ceftazidime, 30g sodium-tazobactam, 15g sodium sulfite, 15g vitamin C are dissolved in warp 0.45 μ m filtering with microporous membrane in the 500ml water for injection, add blank liposome and mix 55 ℃ of supersound process 30min; Again with the aqueous solution 500ml mix homogeneously that is dissolved with 90g mannitol and 60g glycine;
(4) be sub-packed in the cillin bottle by the regulation loading amount, place and carry out lyophilizing in the freezer dryer:
A, pre-freeze: the medicinal liquid that branch is installed is cooled to-40 ℃ by 2 ℃ of/minute speed, is incubated freezing 3 hours;
B, distillation: the medicinal liquid evacuation that pre-freeze is good, to 15Pa, in 8 hours, at the uniform velocity slowly be warming up to-20 ℃ then, be incubated 2 hours, in 5 hours, at the uniform velocity be warming up to 10 ℃ again;
C, drying: the distillation medicinal liquid of stage after finishing that finish at the uniform velocity was warming up to 30 ℃ in 4 hours, heat preservation and dryness 3 hours makes cefoperazone sodium and tazobactam sodium medicament composition liposome injection.
Comparative Examples 1
The preparation of ceftazidime and tazobactam sodium medicine compound liposome (commonsense method)
Prescription (100 bottles):
Ceftazidime 90g
Sodium-tazobactam 30g
Dioleoyl phospholipid phatidylcholine 112.5g
Soy phosphatidylserine 37.5g
Cholesterol acetyl fat 72g
18-amine. 36g
Mannitol 90g
Glycine 60g
Sodium sulfite 15g
Vitamin C 15g
Preparation technology:
(1) 112.5g dioleoyl phospholipid phatidylcholine, 37.5g soy phosphatidylserine, 72g cholesterol acetonyl ester, 36g 18-amine. being dissolved in the 1000ml volume ratio is in 1: 3 the mixed solvent of isopropyl alcohol and acetonitrile; Mixed solvent is removed in decompression on rotary film evaporator, has obtained phospholipid membrane;
(2) citric acid-sodium citrate buffer solution 500ml of adding pH value 6.2 in phospholipid membrane, jolting 10min stirs and makes the complete aquation of phospholipid membrane, prepares blank liposome with high-quality homogenizer;
(3) 90g ceftazidime, 30g sodium-tazobactam, 15g sodium sulfite, 15g vitamin C are dissolved in the 500ml water for injection through 0.45 μ m filtering with microporous membrane; Add blank liposome and mix, again with the aqueous solution 500ml mix homogeneously that is dissolved with 90g mannitol and 60g glycine;
(4) be sub-packed in the cillin bottle by the regulation loading amount, place and carry out lyophilizing in the freezer dryer: the medicinal liquid that branch is installed is cooled to-30 ℃ by 2 ℃ of/minute speed, in 8 hours, at the uniform velocity slowly is warming up to 30 ℃ then; Heat preservation and dryness 2 hours makes cefoperazone sodium and tazobactam sodium medicament composition liposome injection.
Embodiment and Comparative Examples are relativelyThe comparison of preferred ratio of adjuvant of the present invention and freeze-dry process
Be each embodiment and the Comparative Examples of empirical factor below having designed with adjuvant that the present invention was screened and consumption and preparation technology in the following form; Wherein embodiment 1-4 adopts preparation technology of the present invention to carry out; Used adjuvant and consumption are within preferable range of the present invention; Used adjuvant or supplementary product consumption are outside preferable range of the present invention among the Comparative Examples 1-4, and the common freeze-dry process of the employing that perhaps has carries out, and in Test Example, investigate the result advantage of the present invention is compared explanation.
The comparison of table 1 embodiment and Comparative Examples
Test Example 1
The mensuration of envelop rate
Get the liposome turbid liquor 10ml that embodiment 1-4 and Comparative Examples 1-4 make and place the bag filter of having handled; Bag filter is immersed among dialysis solution (the aquation medium that promptly the prepares liposome) 100ml; Put on the magnetic stirring apparatus and stir, regularly change dialysis solution, behind the 12h content taking-up in the dialysis solution is put in the 100ml measuring bottle; Add the alcoholic solution 10ml breakdown of emulsion of 5% polyoxyethylene nonylphenol ether, water is settled to scale.Get each 20 μ l of solution of the embodiment 1-2 that states and Comparative Examples 1-3 respectively, the sample introduction analysis calculates the amount W of parcel ceftazidime and sodium-tazobactam in the liposome
Bag, according to formula: envelop rate=(W
Bag/ W
Always) * 100% computational envelope rate.
Table 2 entrapment efficiency determination result
Can know that by above result the liposome encapsulation that the present invention makes is very high, meet the actual production requirement basically; 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.
Test Example 2
Stability study
Sample and listing preparation ceftazidime for inj sodium-tazobactam (Guoruitang Pharmaceutical Co., Ltd., Hainan Prov. with above embodiment 1-4 and Comparative Examples 1-4 preparation; Lot number 20100102); Under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months; Carry out accelerated test and investigate, compare dissolution and stability, the result is following:
Table 3 accelerated test is investigated
Can know by above result; After the accelerated test 6 months; The sample of embodiment of the invention 1-4 dissolves acidity, content and related substance does not have significant change, and the sample of Comparative Examples 1-4 preparation is bigger with the decline of listing formulation content, and related substance raises obviously; Acidity significantly reduces, and explains that the stability of the ceftazidime and tazobactam sodium lipidosome injection that the present invention makes increases.
Test Example 3
External pharmacodynamic study
Adopt the agar doubling dilution, measure the fungistatic effect of ceftazidime and tazobactam sodium lipidosome injection for escherichia coli, pneumonia thunder uncle bacterium and enterobacter cloacae.
At first escherichia coli, pneumonia thunder uncle bacterium and the enterobacter cloacae of clinical separation and evaluation are cultivated 18h respectively in nutrient broth, regulate bacterial concentration with sterile saline before each experiment.The concentration of using bacterium colony to measure the bacterium liquid that tries than turbid appearance is that 0.5 to buy be unit (10
8Individual/mL).Adopt agar doubling dilution preparation ceftazidime and tazobactam sodium medicine compound liposome solution and ceftazidime solution, the pastille MH culture medium of formation finite concentration gradient, use respectively 10 μ L inoculating loops with the dibbling of bacterium liquid in the pastille plate.Bacterium liquid final concentration is every 10
6Individual/ml, in 35 ℃ of cultivation 24h, observed result, the result sees table 4.
The external pharmacodynamics of table 4 ceftazidime and tazobactam sodium medicinal composition liposome injection
Can find out that by above result the fungistatic effect of ceftazidime and tazobactam sodium lipidosome injection obviously strengthens.
Test Example 4
Haemolysis and thrombotest
Test method: get one of rabbit, heart extracting blood 10ml, Glass rod stir and remove micro-proteinogen; Make into defibrinated blood, add the 100ml normal saline and shake up, centrifugal; Remove supernatant, sedimentary erythrocyte reuse normal saline washs 4 times to the apparent redness of supernatant, with gained erythrocyte 3ml; Add normal saline 150ml, it is for use to be prepared into 2% red blood cell suspension.
Get 7 in test tube; Indicate that the according to the form below parallelism adds 2% red blood cell suspension and normal saline successively 1-7 number; Put 30min in 37 ℃ of calorstats; Add the not commensurability ceftazidime and tazobactam sodium medicinal composition liposome injection of embodiment 1 then, the negative control tube of the 6th pipe, the positive haemolysis sample of the 7th pipe.After shaking up, put in 37 ℃ of calorstats and observed successively at a distance from 20 minutes approximately, observe to 6h; The 1-5 pipe is compared with 6 pipes, and the clarity of supernatant is identical, transparent red normal complexion rufous flocky precipitate all do not occur; 7 pipe hemocyte complete hemolysis, the 1-5 pipe is compared with 7 pipes, and phenomenon is opposite fully.Result of the test is seen table 5:
Table 5 haemolysis, agglutination test
The result judges: 1-5 managed in 2-6 hour, and its supernatant is compared basic identical with 6 pipes, the brown flocky precipitate of transparent red normal complexion all do not occur.The 1-5 pipe was compared with 7 pipes in 2-6 hour, and then phenomenon is opposite fully, and whole red haemolysises has appearred in 7 pipes.
Conclusion: the ceftazidime and tazobactam sodium lipidosome injection does not have blood coagulation, no erythroagglutination, and injection is safe and reliable, can supply the clinical injection medication.
Claims (5)
1. a ceftazidime and tazobactam sodium medicinal composition liposome injection is characterized in that comprising following component, based on the weight portion meter, and 3 parts of ceftazidimes, 1 part of sodium-tazobactam, liposome membrane material 5-12 part, additives 3.6-8 part; Frozen-dried supporting agent 5-20 part and antioxidant 1-3 part; Wherein the liposome membrane material is the combination of 3: 1 weight ratio of dioleoyl phospholipid phatidylcholine and soy phosphatidylserine; Additives are the combination of 2: 1 weight ratio of cholesterol acetyl fat and 18-amine.; Frozen-dried supporting agent is the combination of 3: 2 weight ratio of mannitol and glycine; Antioxidant is the combination of 1: 1 weight ratio of vitamin C and sodium sulfite.
2. method for preparing the described ceftazidime and tazobactam sodium medicinal composition liposome injection of claim 1 is characterized in that may further comprise the steps:
(1) liposome membrane material and additives are dissolved in the organic solvent, organic solvent is removed in decompression on rotary film evaporator, has obtained phospholipid membrane;
(2) citric acid-sodium citrate buffer solution of adding pH value 6.2 in phospholipid membrane, jolting is stirred and is made the complete aquation of phospholipid membrane, prepares blank liposome with high-quality homogenizer;
(3) ceftazidime, sodium-tazobactam, antioxidant are dissolved in the water for injection through filtering with microporous membrane, add blank liposome and mix 55 ℃ of supersound process 30min; Even with the aqueous solution that is dissolved with frozen-dried supporting agent again;
(4) be sub-packed in the cillin bottle by the regulation loading amount, place and carry out lyophilizing in the freezer dryer, detect qualified back packing warehouse-in.
3. the method for preparing the ceftazidime and tazobactam sodium medicinal composition liposome injection according to claim 2 is characterized in that the freeze-dry process in (4) step is:
A, pre-freeze: the medicinal liquid that branch is installed is cooled to-50～-35 ℃ by 1～3 ℃ of/minute speed, is incubated freezing 3 hours;
B, distillation: the medicine evacuation that pre-freeze is good, to 15Pa, in 7～9 hours, at the uniform velocity slowly be warming up to-22～-18 ℃ then, be incubated 1～2 hour, in 4～6 hours, at the uniform velocity be warming up to 10～15 ℃ again;
C, drying: the distillation medicine of stage after finishing that finish at the uniform velocity was warming up to 30 ℃ in 4 hours, heat preservation and dryness 3 hours detects qualified back packing and puts in storage.
4. the method for preparing the ceftazidime and tazobactam sodium medicinal composition liposome injection according to claim 3 is characterized in that the freeze-dry process in (4) step is:
A, pre-freeze: the medicinal liquid that branch is installed is cooled to-40 ℃ by 2 ℃ of/minute speed, is incubated freezing 3 hours;
B, distillation: the medicine evacuation that pre-freeze is good, to 15Pa, in 8 hours, at the uniform velocity slowly be warming up to-20 ℃ then, be incubated 2 hours, in 5 hours, at the uniform velocity be warming up to 10 ℃ again;
C, drying: the distillation medicine of stage after finishing that finish at the uniform velocity was warming up to 30 ℃ in 4 hours, heat preservation and dryness 3 hours detects qualified back packing and puts in storage.
5. according to each described method for preparing the ceftazidime and tazobactam sodium medicinal composition liposome injection of claim 2-4, it is characterized in that described organic solvent is that volume ratio is 1: 3 the isopropyl alcohol and the mixed solvent of acetonitrile.
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| CN100441187C (en) * | 2006-08-30 | 2008-12-10 | 中国人民解放军第三军医大学第一附属医院 | Liposome vitamin A acid aerosol for treating chronic obstructive pulmonary disease |
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| CN100441187C (en) * | 2006-08-30 | 2008-12-10 | 中国人民解放军第三军医大学第一附属医院 | Liposome vitamin A acid aerosol for treating chronic obstructive pulmonary disease |
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| Title |
|---|
| 罗云敬等.紫外分光光度法测定头孢他啶脂质体的包封率与渗漏率.《中国抗生素杂志》.1998,第23卷(第3期),203-204，235. * |
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