CN104000783B - Cefquinome liposome - Google Patents
Cefquinome liposome Download PDFInfo
- Publication number
- CN104000783B CN104000783B CN201410202865.6A CN201410202865A CN104000783B CN 104000783 B CN104000783 B CN 104000783B CN 201410202865 A CN201410202865 A CN 201410202865A CN 104000783 B CN104000783 B CN 104000783B
- Authority
- CN
- China
- Prior art keywords
- cefquinome
- liposome
- preparation
- acid
- polyethylene glycol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229950009592 cefquinome Drugs 0.000 title claims abstract description 128
- YWKJNRNSJKEFMK-PQFQYKRASA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-3-(5,6,7,8-tetrahydroquinolin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 YWKJNRNSJKEFMK-PQFQYKRASA-N 0.000 title claims abstract description 127
- 239000002502 liposome Substances 0.000 title claims abstract description 106
- 238000002360 preparation method Methods 0.000 claims abstract description 73
- 239000007788 liquid Substances 0.000 claims abstract description 60
- -1 isoflavone glucoside Chemical class 0.000 claims abstract description 29
- 239000000654 additive Substances 0.000 claims abstract description 21
- 239000007787 solid Substances 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 17
- 235000010469 Glycine max Nutrition 0.000 claims abstract description 14
- 244000068988 Glycine max Species 0.000 claims abstract description 13
- URRZRRQMNMZIAP-UHFFFAOYSA-N Kudzusapogenol C Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)C(O)CC3(C)CCC21C URRZRRQMNMZIAP-UHFFFAOYSA-N 0.000 claims abstract description 6
- VNGUCOGHCJHFID-FLZFTVBESA-N Soyasapogenol C Chemical compound C([C@@]12C)C[C@H](O)[C@](C)(CO)[C@@H]1CC[C@]1(C)[C@@H]2CC=C2[C@@H]3CC(C)(C)C=C[C@]3(C)CC[C@]21C VNGUCOGHCJHFID-FLZFTVBESA-N 0.000 claims abstract description 6
- 229930182478 glucoside Natural products 0.000 claims abstract description 6
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 claims abstract description 6
- 235000008696 isoflavones Nutrition 0.000 claims abstract description 6
- 229930189104 soyasapogenol Natural products 0.000 claims abstract description 6
- 150000002632 lipids Chemical class 0.000 claims description 17
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims description 14
- 229920001223 polyethylene glycol Polymers 0.000 claims description 14
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical group CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 11
- 239000012736 aqueous medium Substances 0.000 claims description 11
- 239000000787 lecithin Substances 0.000 claims description 11
- 235000010445 lecithin Nutrition 0.000 claims description 11
- 229940067606 lecithin Drugs 0.000 claims description 11
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 9
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 8
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 229940083466 soybean lecithin Drugs 0.000 claims description 6
- 229930003427 Vitamin E Natural products 0.000 claims description 5
- 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 claims description 5
- 235000019165 vitamin E Nutrition 0.000 claims description 5
- 239000011709 vitamin E Substances 0.000 claims description 5
- 229940046009 vitamin E Drugs 0.000 claims description 5
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 4
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 claims description 4
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 claims description 4
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 4
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 4
- 239000005642 Oleic acid Substances 0.000 claims description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 4
- 235000021355 Stearic acid Nutrition 0.000 claims description 4
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 230000003078 antioxidant effect Effects 0.000 claims description 4
- 235000006708 antioxidants Nutrition 0.000 claims description 4
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[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 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 4
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 4
- 235000011187 glycerol Nutrition 0.000 claims description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 4
- 229920001983 poloxamer Polymers 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 4
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 4
- 235000010265 sodium sulphite Nutrition 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- 239000008117 stearic acid Substances 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- 239000000473 propyl gallate Substances 0.000 claims description 3
- 235000010388 propyl gallate Nutrition 0.000 claims description 3
- 229940075579 propyl gallate Drugs 0.000 claims description 3
- 235000000346 sugar Nutrition 0.000 claims description 3
- 239000004094 surface-active agent Substances 0.000 claims description 3
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 2
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims description 2
- 239000004380 Cholic acid Substances 0.000 claims description 2
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 2
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 2
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- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound 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 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 2
- 229960003964 deoxycholic acid Drugs 0.000 claims description 2
- BIABMEZBCHDPBV-UHFFFAOYSA-N dipalmitoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-UHFFFAOYSA-N 0.000 claims description 2
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
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- WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 claims description 2
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Landscapes
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Abstract
Cefquinome liposome, belongs to art of pharmacy, and the particle diameter of the liposome is less than 1000nm, is mainly made up of the raw material of following weight parts：1 part of Cefquinome, phosphatidase 1~40 part, sterol or soybean isoflavone glucoside or 0~15 part of soyasapogenol, 0~15 part of additives.Liquid preparation can be made in the Cefquinome liposome, can also add appropriate caffolding agent and solid pharmaceutical preparation is made.Cefquinome liposome or Cefquinome long circulating liposome produced by the present invention are free of pungent, can eliminate allergic reaction, gained better stability of preparation, and liposome average grain diameter is more than 80% in below 1000nm, envelop rate.It is its preparation method technical maturity, simple and easy to do, it is easy to industrialized production.
Description
Technical field
The invention belongs to art of pharmacy, and in particular to a kind of new Cefquinome preparation --- Cefquinome liposome.
Background technology
Cefquinome（English name：Cefquinome）It is animal specific forth generation cephalosporin analog antibiotic, character：White, class
White is characterized in pale yellow powder：1）It is highly stable to beta-lactamase；2）It is better than third generation head in antibacterial activity in it
Spore rhzomorph Ceftiofur, compared with third generation cephalo, the plasma half-life length of four generation cephalos, no renal toxicity；3）There is very strong resist
Bacterium activity, to S. aureus L-forms, streptococcus, pseudomonas aeruginosa, enterobacteria section（Escherichia coli, salmonella, Klebsiella, lemon
Lemon acid bacterium, serratia marcesens）There is extremely strong killing action, the staphylococcus and enterobacteria to many methicillin-resistants also have good
Good killing action；4）Has a broad antifungal spectrum, antibacterial activity is strong, suitable for parenterai administration.
However, solubility of the Cefquinome in water is extremely low, therefore certain difficulty be present when being prepared into preparation.On at present
The Cefquinome in city, it is that Cefquinome is dissolved in organic solvent（Dimethylformamide, phenmethylol, Emulsifier EL-60, Malaysia
Acid and ethanol）And the preparation formed, it can cause serious allergic reaction after injecting use, be mainly shown as shiver with cold, heating, aroused in interest
Overrun, bronchial spasm, expiratory dyspnea and low blood pressure.This allergic reaction is probably that Cefquinome is poly- in itself or in solvent
Caused by oxygen ethylene castor oil.Therefore, there is an urgent need to change the formulation of Cefquinome, to increase the water solubility of Cefquinome, drop
The low Cefquinome toxic reaction of itself.
The content of the invention
The purpose of the present invention aims to provide a kind of new Cefquinome preparation.
Based on above-mentioned purpose, this invention takes following technical scheme：Cefquinome liposome, mainly by following weight parts
Raw material be made：1 part of Cefquinome, phosphatidase 1~40 part, sterol or soybean isoflavone glucoside or 0~15 part of soyasapogenol, add
0~15 part of agent.
The phosphatide is selected from lecithin, soybean lecithin, hydrogenated soya phosphatide, hydrolecithin, cephalin, cuorin, phosphorus
Acyl inositol, phosphatidylserine, phosphatidyl glycerol, phosphatidic acid, phosphatidyl-ethanolamine, DLPC, two meat
Beans bandit phosphatidyl choline, DPPC, DPPG, DPPA, two palms
Acyl phosphatidyl-ethanolamine, DSPG, DSPC, DOPC and dioleoyl
Phosphatidyl-ethanolamine.
The sterol is selected from cholesterol, beta-cholestanol and ergosterol.
The additives include antioxidant, surfactant and stabilizer.
The antioxidant is selected from vitamin E, vitamin-e ester, sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, thio sulphur
Sour sodium, propylgallate, the tert-butyl group are to hydroxyl fennel ester, BHT, cysteine and methionine；The surface
Activating agent is selected from dexycholate, cholate, deoxycholic acid, taurocholate, cholic acid, Tween 80, poloxamer and sapn；Institute
State stabilizer and be selected from stearic acid, phosphatidic acid, tetradecylic acid, oleic acid and glycerine.
Phosphatidase 2~30 part, sterol or soybean isoflavone glucoside or 1~10 part of soyasapogenol, 1~10 part of additives.
The Cefquinome liposome is liquid preparation, is prepared using any one following method：（1）Film disperses
Method：Cefquinome, phosphatide, sterol and fat-soluble additives are dissolved in organic solvent, depressurizes and has flung at 20~60 DEG C
Solvent, film is formed, then adds in the aqueous media dissolved with water soluble agents and is hydrated, produced after ultrasonic or high-pressure homogeneous
Cefquinome liposome liquid body preparation；Or（2）Injection method：Cefquinome, phosphatide, sterol and fat-soluble additives, which are dissolved in, to be had
Lipid soln is made in solvent, draws the aqueous media dissolved with water soluble agents that the lipid soln injects 20~60 DEG C
In, injection, which finishes, continues stirring removal organic solvent, then carries out ultrasonic or high-pressure homogeneous handle and produces Cefquinome liposome
Liquid preparation；Or（3）Reverse evaporation：Cefquinome, phosphatide, sterol, fat-soluble additives are dissolved in organic solvent, then
The aqueous media dissolved with water soluble agents is added, ultrasound or high speed shear are allowed to form stable w/o type colostrum, then depressurized
Organic solvent is boiled off, produces Cefquinome liposome liquid body preparation；Or（4）Fusion method：Weigh in proportion Cefquinome, phosphatide,
Sterol, fat-soluble additives add the aqueous media mixing dissolved with water soluble agents, Ran Houjing in 60~80 DEG C of heating meltings
Ultrasonic or high-pressure homogeneous handle produces Cefquinome liposome liquid body preparation；The aqueous media is pure water, physiological saline, sweet dew
The phosphate buffer, Chinese holly edge phthalate buffer, acetate buffer that alcohol solution, D/W either pH are 4~8
Or Tris-HCl buffer solutions, organic solvent are selected from ethanol, methanol, acetic acid, acetone, ethyl acetate, chloroform and dichloromethane.Gained
Cefquinome liposome liquid body preparation can use as oral formulations, also can be with appropriate water for injection, physiological saline or glucose
Parenteral solution vibration hydration, forms Cefquinome lipidosome injection.
The raw material also includes the decorative material of 1~2 times of Cefquinome weight, with aqueous media addition system during preparation
Or together added with other lipid components；The decorative material is selected from polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, poly-
Acrylamide, chitosan and PEG-DSPE derivative, wherein, PEG-DSPE derivative is selected from polyethylene glycol-two
It is stearyl phosphatidyl monoethanolamine, polyethylene glycol DPPC, DPPE-PEG5000, poly-
Ethylene glycol hydrogenated soya phosphatide acyl monoethanolamine and polyethylene glycol-DSPC, the mean molecule quantity of polyethylene glycol
For 200~20000.Decorative material is added, long circulating liposome is made in Cefquinome, can further extend Cefquinome fat
The blood circulation time of plastid, the targeting and bioavilability of Cefquinome liposome are improved, the poison for reducing Cefquinome is secondary
Effect.
Described polyethylene glycol mean molecule quantity is 2000~5000.
The Cefquinome liposome is solid pharmaceutical preparation, and caffolding agent is added in the Cefquinome liposome liquid body preparation
Or when preparing liquid preparation with aqueous media add caffolding agent, then gained liposome liquid body preparation is freeze-dried or
It is spray-dried and produces.Glycine, serine, sucrose, lactose, mannitol, glucose, trehalose, wheat may be selected in the caffolding agent
Bud sugar, Arabic gum, xylitol, sorbierite, fructose, dextran or one kind or any combination in albumin, its dosage are pressed
Phosphatide weight ratio meter is calculated adds 0.1~1000 part of caffolding agent for 1 part of phosphatide.Solid pharmaceutical preparation is made in Cefquinome liposome, can be prolonged
The resting period of long Cefquinome liposome, and be readily transported.
Liposome belongs to ultra micron pharmaceutical carrier, and there is lymphatic system to walk tropism, and the one kind for belonging to targeting drug delivery system is new
Formulation.It has class eucaryotic cell structure, or enters lysosome by endocytosis, is then rapidly digested by an enzyme in a body release medicine, or logical
Cross cell fusion, i.e. lipid membrane material is similar with cell membrane construct and merge into intracellular, is then digested release medicine
Thing, medicine is maintained higher concentration in being organized in target area, and change and be encapsulated being distributed inside medicine, make medicine mainly liver,
Accumulated in the histoorgans such as spleen, lung and marrow, so as to improving the therapeutic index of medicine, reducing the dosage of medicine and reducing medicine
The toxicity of thing；After liposome carries, pharmaceutical activity group can be protected not to be degraded in interior environment, can also extended in medicine blood
Circulation time
Cefquinome is encapsulated in class lipid bilayer by the present invention, and a kind of spherical liposome of ultra micro is made, adds medicine
The water solubility and stability of thing, medicine can be prevented to separate out crystal, reduce the toxic reaction of Cefquinome itself.Meanwhile by fat
The Cefquinome of plastid parcel has targeting, can selectively reach diseased region, tissue and cell, and tieed up within the longer time
Hold effective blood drug concentration, there is provided lasting therapeutic effect, the effect of so as to increase Cefquinome and bioavilability, reduce bad
Reaction.The Cefquinome long circulating liposome for modifying to obtain to Cefquinome liposome, delay Slow release, can escape in vivo
Hide MPS capture, extend the circulation time of liposome in blood, have the function that sustained release, targeting, long-acting.
Cefquinome liposome or Cefquinome long circulating liposome produced by the present invention are free of pungent, can eliminate
Allergic reaction, gained better stability of preparation, liposome average grain diameter are more than 80% in below 1000nm, envelop rate.Its preparation method
It is technical maturity, simple and easy to do, it is easy to industrialized production.
Embodiment
With reference to specific embodiment, the invention will be further described.
Embodiment 1
Cefquinome liposome, mainly it is made up of the raw material of following weight parts：Cefquinome 50mg, lecithin 500mg, courage
Sterol 40mg.It is liquid preparation, is prepared using film dispersion method：Take Cefquinome, lecithin, cholesterol input eggplant shape
In bottle, 20ml ethanol is added：Acetone volume ratio=2:1 mixed solvent, ultrasound make raw material fully dissolve；Eggplant-shape bottle is placed in 40
Decompression rotary evaporation flings to organic solvent in DEG C water bath with thermostatic control, and one layer of lipid membrane is formed on bottle inwall；It is slowly added to 10ml
Phosphate buffer（pH7.0）, hydration, vortex oscillation, make the lipid membrane on eggplant-shape bottle be completely dissolved；Mixed liquor is through room
Warm ultrasonic disperse（Ultrasonic power 600W) 30min, that is, Cefquinome liposome liquid body preparation is made.
After testing, the average grain diameter of liposome is 257nm in the liquid preparation, and particle diameter is in below 500nm, particle diameter
It is distributed narrow, shows that liposome size is more homogeneous.The liposome liquid body preparation can be stablized storage a couple of days at room temperature, at 4 DEG C
It can stablize storage at least three moon, precipitation or lamination not observed during storage.
Embodiment 2
Cefquinome liposome, mainly it is made up of the raw material of following weight parts：Cefquinome 50mg, soybean lecithin 200mg,
Cephalin 50mg, soybean isoflavone glucoside 20mg, vitamin E（Additives）10mg, sodium taurocholate（Additives） 0.15mg.It is
Liquid preparation, it is prepared using injection method：It is accurate weigh Cefquinome, soybean lecithin, cephalin, soybean isoflavone glucoside with
And vitamin E, add 10ml ethanol to dissolve it, lipid soln is made；The lipid soln, which is drawn, with syringe slowly injects 30ml
Physiological saline containing 0.5% sodium taurocholate（Aqueous media, 40 DEG C）In, injection is finished with electronics constant speed stirrer with 2000r/min's
Rotating speed is stirred to ethanol and eliminated, then high-pressure homogeneous（Homogenization pressure 10000psi) handle 5 times, produce Cefquinome liposome
Liquid preparation, put in 4 DEG C of refrigerators and save backup.
After testing, the average grain diameter of liposome is 50nm in the liquid preparation, and particle diameter is in below 150nm, grain
Footpath distribution is narrow, shows that liposome size is more homogeneous.The liposome liquid body preparation can be stablized storage a couple of days at room temperature, 4 DEG C
Under can stablize storage at least three moon, do not observe during storage precipitation or lamination.
Embodiment 3
Cefquinome liposome, mainly it is made up of the raw material of following weight parts：Cefquinome 100mg, hydrolecithin
2000mg, cuorin 50mg, soyasapogenol 800mg, stearic acid（Additives）50mg, PLURONICS F87（Additives）100mg、
Glycerine（Additives）400mg, vitamin C（Additives）100mg.It is liquid preparation, is prepared using fusion method：It is accurate to claim
Cefquinome, hydrolecithin, cuorin, soyasapogenol and stearic acid are taken, adds in conical flask and is heated to 75 DEG C of meltings,
Lipid fused solution is obtained, it is standby；100mg PLURONICS F87s, 400mg glycerine, 100mg vitamin Cs is taken to be dissolved in the grapes of 20ml 5%
In sugar juice, 75 DEG C are heated to, is added in lipid fused solution, high speed shear mixing, through high-pressure homogeneous（Homogenization pressure
15000psi) handle 3 times, produce Cefquinome liposome liquid body preparation.
After testing, the average grain diameter of liposome is 47nm in the liquid preparation, and particle diameter is in below 140nm, particle diameter
It is distributed narrow, shows that liposome size is more homogeneous.The liposome liquid body preparation can be stablized storage a couple of days at room temperature, at 4 DEG C
It can stablize storage at least three moon, precipitation or lamination not observed during storage.
Embodiment 4
Cefquinome liposome, mainly it is made up of the raw material of following weight parts：Cefquinome 100mg, hydrogenated soybean lecithin
Fat 1500mg, DSPC 200mg, ergosterol 300mg, oleic acid（Additives）50mg, Tween 80（It is additional
Agent）100mg, sodium pyrosulfite（Additives）100mg.It is liquid preparation, is prepared using reverse evaporation：Take cephalo quinoline
Oxime, hydrogenated soy phosphatidyl choline, DSPC, ergosterol, oleic acid are dissolved in 30ml chloroform/methanols (volume ratio 1:
1）In the mixed solvent, obtain organic phase；Separately weigh 100mg Tween 80s, 100mg sodium pyrosulfites are dissolved in 10ml acetate buffers
（pH6.0）（Aqueous media）In, obtain aqueous phase；It is again that organic phase is mixed with water, high speed shear（12000rpm) 5min makes system
Stable w/o type colostrum is formed, then in removing organic solvent is evaporated under reduced pressure on Rotary Evaporators, produces Cefquinome liposome
Liquid preparation.
After testing, the average grain diameter of liposome is 45nm in the liquid preparation, and particle diameter is in below 180nm, particle diameter
It is distributed narrow, shows that liposome size is more homogeneous.The liposome liquid body preparation can be stablized storage a couple of days at room temperature, at 4 DEG C
It can stablize storage at least three moon, precipitation or lamination not observed during storage.
Embodiment 5
Cefquinome liposome, mainly it is made up of the raw material of following weight parts：Cefquinome 100mg, two nutmeg acyl phosphorus
Phosphatidylcholine 1800mg, DPPA 100mg, beta-cholestanol 400mg, tetradecylic acid（Additives）100mg, deoxidation courage
Sour sodium（Additives）500mg, sodium sulfite（Additives）100mg.It is liquid preparation, is prepared using reverse evaporation：
Cefquinome, two nutmeg phosphatidyl cholines, DPPA, beta-cholestanol, tetradecylic acid is taken to be dissolved in 30ml dichloros
In methane, organic phase is obtained；Separately NaTDC, sodium sulfite is taken to be dissolved in 10ml citrate buffers（pH6.2）（Aqueous phase is situated between
Matter）In, obtain aqueous phase；It is again that organic phase is mixed with water, 8min is ultrasonically treated through water-bath type, makes the stable W/O of System forming
Type emulsion（Bath temperature is controlled at 20 DEG C）, then it is evaporated under reduced pressure in Rotary Evaporators and removes organic solvent, after reaches colloidal state
5ml citrate buffers, aquation is added dropwise, continuation is evaporated under reduced pressure in short-term, after sonicated 20min, produces Cefquinome fat
Plastid liquid preparation.
After testing, the average grain diameter of liposome is 55 nm in the liquid preparation, particle diameter in 150 below nm,
Narrow particle size distribution, show that liposome size is more homogeneous.The liposome liquid body preparation can be stablized storage a couple of days at room temperature, and 4
It can stablize storage at least three moon at DEG C, precipitation or lamination not observed during storage.
Embodiment 6
Cefquinome liposome, mainly it is made up of the raw material of following weight parts：Cefquinome 100mg, lecithin 1000mg,
DSPG 100mg, cholesterol 100mg, butylated hydroxyarisol 50mg.It is liquid preparation, is used
Film dispersion method is prepared：Cefquinome, lecithin, DSPG, cholesterol, the tert-butyl group are taken to hydroxyl fennel
Fragrant ether puts into pear shape bottle, adds 10ml ethyl acetates to dissolve, and then removes organic solvent, vacuum drying 2~3 in 30 DEG C of vacuum rotary steams
It obtains constant weight film.10ml is added containing 10% sucrose, the tris-HCl buffer solutions of 10 % mannitol（20mmol/L, pH7.0, contain
0.15mol/L NaCl）, pear shape bottle is shaken in rotation makes film scattered wherein, then high-pressure homogeneous processing（Homogenization pressure
12000psi) 5 times, that is, Cefquinome liposome liquid body preparation is made.
Gained liquid preparation is placed in pre-freeze 24 hours at 40 DEG C, lyophilized in freeze drier (freezing program is：40
DEG C, 8 hours；30 DEG C, 6 hours；20 DEG C, 6 hours；10 DEG C, 5 hours；0 DEG C, 5 hours；15 DEG C, 5 hours), obtain cephalo quinoline
Oxime lipidosome solid preparation.
Average grain diameter is 136 ± 31nm after gained Cefquinome lipidosome solid preparation adds water redissolution, and all particles exist
Below 300nm.
Embodiment 7
Cefquinome liposome, mainly it is made up of the raw material of following weight parts：Cefquinome 100mg, soybean lecithin
1500mg, polyethylene glycol（Mean molecule quantity 4000）- DSPE（PEG4000-DSPE）150mg, do not eat
Sub- propyl propionate 50mg, natrium taurocholicum（Additives）0.15mg.It is liquid preparation, is prepared using injection method：It is accurate to claim
Take Cefquinome, soybean lecithin, PEG2000-DSPE（PEG4000-DSPE）, propylgallate,
Add 10ml ethanol to dissolve it, lipid soln is made；The lipid soln is drawn with syringe slowly inject 30ml contain 0.5% cow-bezoar
Sodium taurocholate（60℃）The aqueous solution in, injection is finished to be stirred to ethanol with 1000r/min rotating speed with electronics constant speed stirrer and removed
To the greatest extent, it is then high-pressure homogeneous（Homogenization pressure 10000psi) handle 5 times, produce Cefquinome liposome liquid body preparation.
After testing, the average grain diameter of liposome is 60 nm in the liquid preparation, particle diameter in 180 below nm,
Narrow particle size distribution, show that liposome size is more homogeneous.The liposome liquid body preparation can be stablized storage a couple of days at room temperature, and 4
It can stablize storage at least three moon at DEG C, precipitation or lamination not observed during storage.
Embodiment 8
Cefquinome liposome, mainly it is made up of the raw material of following weight parts：Cefquinome 100mg, lecithin 1000mg,
Polyethylene glycol（Mean molecule quantity 200）- hydrogenated soya phosphatide acyl monoethanolamine（PEG200-HSPE) 100mg, cholesterol 100mg,
Butylated hydroxyarisol 50mg.It is liquid preparation, is prepared using film dispersion method：Weigh Cefquinome, lecithin
Fat, polyethylene glycol-hydrogenated soya phosphatide acyl monoethanolamine（PEG200-HSPE), cholesterol, butylated hydroxyarisol add pears
In shape bottle, after addition 10ml ethyl acetate dissolvings, rotary evaporation, 30 DEG C are removed under reduced pressure organic solvent, and vacuum drying obtains for 2-3 days
Constant weight film；10ml is added to shake pear shape bottle containing 10% sorbierite, 5% dextran, the aqueous solution of 5% albumin, rotation, obtain
Liposomal suspensions, Liposomal suspensions are ultrasonically treated（Ultrasonic power 600W) 20min, that is, Cefquinome long circulating is made
Liposome liquid body preparation.
Gained Cefquinome liposome liquid body preparation is spray-dried using spray dryer, spray drying condition
For：120 DEG C, charging rate 50mL/min of EAT, cyclone separator pressure difference 50mm water, atomizing disk rotating speed 2500r/min.
Collect dried product, as Cefquinome long circulating liposome solid pharmaceutical preparation.The average grain of liposome in the solid pharmaceutical preparation
Footpath is 45nm, and particle diameter is in below 145nm.
Embodiment 9
Cefquinome liposome, mainly it is made up of the raw material of following weight parts：Cefquinome 100mg, hydrolecithin
1600mg, polyethylene glycol（Mean molecule quantity 1000）- DPPC（PEG1000-DPPC) 160mg, thio sulphur
Sour sodium 100mg.It is liquid preparation, is prepared using reverse evaporation：Take Cefquinome, hydrolecithin, polyethylene glycol-
DPPC（PEG1000-DPPC) it is dissolved in 30ml dichloromethane, obtains organic phase；Separately weigh sodium thiosulfate
It is dissolved in 10ml water and obtains aqueous phase；Organic phase is mixed with water, it is ultrasonically treated through water-bath type（Bath temperature is controlled at 20 DEG C）Directly
The w/o type emulsion stable to System forming, then it is evaporated under reduced pressure in Rotary Evaporators and removes organic solvent, obtain Cefquinome
Long circulating liposome liquid preparation.
1000mg lactose, 500mg glucose, 500mg are added into gained Cefquinome long circulating liposome liquid preparation
Trehalose ultrasonic dissolution, is then dried under reduced pressure using Mini Spray-Drier（130~140 DEG C of inlet temperature, outlet temperature
50~60 DEG C, air pressure 1.2Atm, charging rate 60mL/min）, produce Cefquinome long circulating liposome solid pharmaceutical preparation.
After testing, the average grain diameter of liposome is 65nm in the solid pharmaceutical preparation, and particle diameter is narrow in 180 below nm, particle diameter distribution
It is narrow, show that liposome size is more homogeneous.
Embodiment 10
Cefquinome liposome, mainly it is made up of the raw material of following weight parts：Cefquinome 100mg, lecithin 2000mg,
Polyethylene glycol（Mean molecule quantity 4000）- DPPE（PEG4000 DPPE）200mg.It is liquid system
Agent, it is prepared using fusion method：Cefquinome, lecithin, polyethylene glycol-DPPE accurately are weighed,
Add in conical flask and be heated to 80 DEG C of meltings, obtain lipid fused solution, it is standby；Take 1000mg glycine, 500mg maltose,
1000mg mannitol is heated to 80 DEG C in 20ml water, adds in lipid fused solution, high speed shear mixing, through high-pressure homogeneous（
Matter pressure 15000psi) handle 3 times, produce Cefquinome long circulating liposome liquid preparation.
The liquid preparation is placed in pre-freeze 10 hours at 80 DEG C, then freezed by freeze-dryer（Lyophilized program is 40
DEG C, 10 hours；20 DEG C, 8 hours；0 DEG C, 8 hours；20 DEG C, 5 hours）, produce Cefquinome long circulating liposome solid（Freeze
It is dry）Preparation.
After testing, the average grain diameter of liposome is 55nm in the solid pharmaceutical preparation, and particle diameter is in below 150nm, particle diameter
It is distributed narrow, shows that liposome size is more homogeneous.
Embodiment 11
Cefquinome liposome, mainly it is made up of the raw material of following weight parts：Cefquinome 50mg, lecithin 1200mg,
Polyethylene glycol（Mean molecule quantity 3350）DSPC（PEG3350-DSPC) 50mg, polyvinylpyrrolidone
（PVP）0.1mg.It is liquid preparation, is prepared using film dispersion method：Take Cefquinome, lecithin, polyethylene glycol-two
DSPC, the dissolving of 10ml ethanol is added, rotary evaporation, 40 DEG C are removed under reduced pressure organic solvent, form film；Add
10ml contains 1% polyvinylpyrrolidone（PVP）The aqueous solution, be ultrasonically treated 30min, be made and Cefquinome long-circulation fat is made
Plastid liquid preparation.The mannitol of the lactose and 8 % that add 8 % makees caffolding agent, freeze-drying, obtains Cefquinome long-circulation fat
Liposome solid preparation.After testing, the average grain diameter of liposome is 55nm in the solid pharmaceutical preparation, particle diameter 130 nm with
Under, narrow particle size distribution, liposome size is homogeneous.
Before use, aqueous vehicles are added into solid preparation to vibrate in short-term, can regain liposome liquid system
Agent.
Embodiment 12
Cefquinome liposome, mainly it is made up of the raw material of following weight parts：Cefquinome 50mg, hydrogenated soya phosphatide
200mg, cholesterol 100mg, polyethylene glycol（Mean molecule quantity 5000）DSPE（PEG-DSPE)
50mg, PEG4000 0.05mg, alpha-tocopherol 20mg.It is liquid preparation, is prepared using film dispersion method：Take cephalo quinoline
Oxime, hydrogenated soya phosphatide, cholesterol, PEG2000-DSPE, alpha-tocopherol are dissolved in 30ml chloroforms, put
In pear shape bottle, rotary evaporation, is removed under reduced pressure solvent under nitrogen flowing, is dried in vacuo 2~3 days, obtains constant weight film.10ml is added to contain
The 0.5% PEG4000 aqueous solution, rotation shake pear shape bottle, obtain Liposomal suspensions.After being purged with nitrogen, sealing is put down at room temperature
Weighing apparatus 1 day, probe sonication 15min, then under 1000psi homogenization pressures it is high-pressure homogeneous processing 3 times, make liposomal particle size by
It is decrescence small, obtain Cefquinome long circulating liposome liquid preparation.Then the % glucose of cumulative volume 5,5 % mannitol, 6 % are added
Trehalose, it is freeze-dried to obtain Cefquinome long circulating liposome solid pharmaceutical preparation.After testing, liposome is averaged in the solid pharmaceutical preparation
Particle diameter is 45nm, and particle diameter is more homogeneous in 120 below nm, narrow particle size distribution, liposome size.
Exemplary embodiments are chosen below and carry out testing experiment, and result of the test is as follows：
Test example 1
The Cefquinome liposome liquid body preparation of Example 1, is observed the form of liposome, and determine lipid
The particle size and distribution situation of body.
Take Cefquinome liposome liquid body preparation appropriate, filling penetrate be diluted with water after with 2 % phosphotungstic acids dyeing, transmission electron microscope
Lower observation particle shape；Take Cefquinome liposome liquid body preparation appropriate, filling penetrate be diluted with water after utilize Zetamaster
Photon correlation spectrometer determines the particle size and distribution, Zeta potential of liposome.
As a result：Spheroidal particle of the Cefquinome liposome in uniformly rule, no aggregation and viscous connection are observed under Electronic Speculum.Experiment is surveyed
Cefquinome liposomal particle size be evenly distributed, average grain diameter is 257 nm, polydispersity index 0.158, and zeta current potentials are
26.4。
Test example 2
The Cefquinome liposome liquid body preparation of Example 1, the envelop rate of liposome is determined using RP-HPLC methods.
The Cefquinome not wrapped up in Cefquinome liposome liquid body preparation is isolated through dialysis, is surveyed with RP-HPLC
Surely free Cefquinome content.Chromatographic condition：It is filler with the base silane bonded silica gel of phenyl-, with second eyeball-water（20:80）
For mobile phase A, alcohol-water（Volume ratio 56:44）For Mobile phase B, flow velocity 1.25mL/min.First tieed up with the % of mobile phase A 100
Hold 4min, Mobile phase B increases to 35.5 % with about 3 % per minute speed, maintains 20min, Mobile phase B again with it is per minute about
2.7 % speed increases to 100 %, maintains 30min, μ l, the 220nm detections of sample size 10, by following equation computational envelope rate.
Envelop rate（%）=（Cefquinome total amount-free Cefquinome amount in liposome）/ Cefquinome total amount
As a result：It is 87.32 % to measure envelop rate.
Test example 3
The solid dried frozen aquatic products of Example 6 is appropriate, sealing, in 4 DEG C of placements of refrigerator, is sampled 0,1,2,3, June, to grain
The indexs such as footpath, envelop rate, percolation ratio, content are measured, and evaluate the stability of the lipidosome freeze-dried product of Cefquinome.
As a result show, the lipidosome freeze-dried product of Cefquinome are placed 6 months for 4 DEG C in refrigerator, its particle diameter, envelop rate, content etc.
Quality index is basically unchanged, and shows that the lipidosome freeze-dried product stability of Cefquinome is good.
Test example 4
The Cefquinome lipidosome solid lyophilized formulations of Example 10 are dissolved in distilled water, and the molten of 1 mg/ml is made
Liquid, surrounding is placed at 4 DEG C, 25 DEG C and 36 DEG C, precipitation is collected in 8,12,16,20,24 and 28 days high speed centrifugations, with HPLC methods
Determine Cefquinome content.As a result show, 4 DEG C of placement basic ne-leakages of surrounding；25 DEG C of storages, two weeks basic ne-leakages；35 ℃
Place 8 days, concentration only declines 3 % or so, places 12 days, the % of change in concentration 10；In the case where environment temperature is not higher than 35 DEG C,
The lipid physical efficiency keeps the stability of more than 8 days, shows that Cefquinome liposome stability is good.
Claims (3)
1. Cefquinome liposome, it is characterised in that be mainly made up of the raw material of following weight parts：1 part of Cefquinome, phosphatidase 2
1~10 part of~30 parts, soybean isoflavone glucoside or soyasapogenol, 1~10 part of additives；The additives include anti-
Oxidant, surfactant and stabilizer；The antioxidant is selected from vitamin E, vitamin E ester, sodium sulfite, bisulfite
Sodium, sodium pyrosulfite, sodium thiosulfate, propylgallate, butylated hydroxyarisol, BHT, half Guang
Propylhomoserin and methionine；The surfactant is selected from dexycholate, cholate, deoxycholic acid, taurocholate, cholic acid, told
Temperature 80, poloxamer and sapn；The stabilizer is selected from stearic acid, phosphatidic acid, tetradecylic acid, oleic acid and glycerine；The raw material is also
Include the decorative material of 1~2 times of Cefquinome weight, during preparation with aqueous media addition system or with other lipids into
Divide and together add；The decorative material gathers selected from polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide and shell
Sugar, the mean molecule quantity of polyethylene glycol is 200~20000；The phosphatide is selected from lecithin, soybean lecithin, hydrogenated soybean phosphorus
Fat, hydrolecithin, cephalin, cuorin, phosphatidylinositols, phosphatidylserine, phosphatidyl glycerol, phosphatidic acid, phosphatidyl
Monoethanolamine, DPPG, DPPA, DPPE and dioleoyl phospholipid acyl second
Hydramine.
2. the Cefquinome liposome as described in claim 1, it is characterised in that described polyethylene glycol mean molecule quantity is
2000~5000.
3. Cefquinome liposome as claimed in claim 1 or 2, it is characterised in that the Cefquinome liposome is solid
Preparation, caffolding agent is added in the Cefquinome liposome liquid body preparation or is added when preparing liquid preparation with aqueous media
Caffolding agent, is then freeze-dried or is spray-dried to gained liposome liquid body preparation and produced.
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| CN104983695B (en) * | 2015-07-17 | 2018-01-09 | 江西博莱大药厂有限公司 | A kind of Ceftiofur Hydrochloride liposome freeze-drying agent and preparation method thereof |
| CN108236604A (en) * | 2018-02-07 | 2018-07-03 | 中国药科大学 | Eliquis flexible lipidosome |
| CN108434101A (en) * | 2018-04-08 | 2018-08-24 | 武汉迈德森医药科技股份有限公司 | A kind of novel Tivozanib liposomes for anticancer, preparation and its preparation method and application |
| CN109463751B (en) * | 2018-12-25 | 2022-02-08 | 江苏艾兰得营养品有限公司 | Preparation method of coenzyme Q10 liposome health food |
| CN111228243B (en) * | 2019-12-24 | 2022-02-18 | 珠海亿胜生物制药有限公司 | Tobramycin liposome for aerosol inhalation and preparation method thereof |
| CN112516076B (en) * | 2020-12-16 | 2024-05-03 | 郑州百瑞动物药业有限公司 | In-situ gel for ceftiofur injection and preparation method thereof |
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| CN103637933A (en) * | 2013-11-11 | 2014-03-19 | 聂克德 | Traditional Chinese medicine formula of acne-removing mask |
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| CN102335133A (en) * | 2011-07-14 | 2012-02-01 | 海南美大制药有限公司 | Cefaclor lipidosome solid preparation |
| CN103585109A (en) * | 2013-11-20 | 2014-02-19 | 河南牧翔动物药业有限公司 | Cefquinome liposome and preparation method thereof |
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