CN101642434B - Levofloxacin lactate liposome sodium chloride injection and preparation method thereof - Google Patents
Levofloxacin lactate liposome sodium chloride injection and preparation method thereof Download PDFInfo
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- CN101642434B CN101642434B CN2009101469491A CN200910146949A CN101642434B CN 101642434 B CN101642434 B CN 101642434B CN 2009101469491 A CN2009101469491 A CN 2009101469491A CN 200910146949 A CN200910146949 A CN 200910146949A CN 101642434 B CN101642434 B CN 101642434B
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Abstract
The invention provides a levofloxacin lactate liposome sodium chloride injection and a preparation method thereof. The levofloxacin lactate liposome sodium chloride injection is characterized by being prepared with the following components according to parts by weight: 1 part of levofloxacin lactate, 5-15 parts of phospholipid, 0.5-1.5 parts of cholesterol, 0.5-2 parts of deoxycholate, 2-10 parts of sodium chloride and 0.5-1.5 parts of antioxidant. The invention adopts specific auxiliary materials to proportion with the original auxiliary materials and adopts the reverse phase evaporation method to prepare the levofloxacin lactate liposome sodium chloride injection of the invention, solving problems of unqualified levofloxacin lactate injection clarity and insoluble particles, and yellowing of solution color in the prior art. The invention provides a stable levofloxacin lactate liposome sodium chloride injection featuring long-time laying aside.
Description
Technical field
The present invention relates to a kind of Liposomal formulation, be specifically related to levofloxacin lactate liposome sodium chloride injection and preparation method thereof, belong to medical technical field.
Background technology
Levofloxacin lactate, chemical name is: its chemical name is: (-)-(s)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxygen-7h-pyrido [1,2,3 ,-de]-[1,4] benzoxazinyl-6-carboxylic acid lactate semihydrate, molecular formula: C
18H
20FN
3O
4C
3H
6O
31/2H
2O, molecular weight: 460.41, structural formula is:
Levofloxacin lactate is the levo form of ofloxacin, and its antibacterial activity is about 2 times of ofloxacin, and its main mechanism suppresses bacterium DNA replication for suppressing DNA of bacteria gyrase activity.Have has a broad antifungal spectrum, characteristics that antibacterial action is strong, to most enterobacteriaceae lactobacteriaceaes, stronger antibacterial activity is arranged as kerekou pneumonia diphtheria, Proteus, salmonella typhosa, Shigella, hemophilus influenza, part escherichia coli, bacillus pyocyaneus, gonococcus etc.; Gram positive bacterias such as part staphylococcus, streptococcus pneumoniae, micrococcus scarlatinae, Hemolytic streptococcus and legionella, mycoplasma, chlamydia also there are good antibacterial action, but relatively poor to anaerobe and enterococcal effect.
At present, existing injection of levofloxacin lactate injection and injectable powder approval listing, but all exist long-term the placement to have clarity and the underproof problem of particulate matter, and the solution colour flavescence, do not meet the quality standard requirement, had a strong impact on the safety of clinical use.Chinese patent CN101292985A discloses a kind of preparation method of levofloxacin Lactate freeze-dried injection, and it does not fundamentally change the problem of above-mentioned existence.
The inventor is through research, beyond thought discovery is applied to a kind of novel form liposome of targeting drug delivery system in the levofloxacin lactate ejection preparation, not only obtained the Liposomal formulation effect, but also solved the clarity of levofloxacin lactate injection and particulate matter is defective, the problem of solution colour flavescence, obtain unexpected invention effect, thereby finished the present invention.
Liposome (liposomes) is dispersed in phospholipid by Britain scholar Bangham and Standish at first and finds when carrying out electron microscopic observation in the water.Phospholipid is dispersed in and forms multilamelar vesicles, every layer of bilayer that is lipid in the water naturally; Separated by water between vesicle central authorities and each layer, the about 4nm of bilayer thickness, the bimolecular folliculus with this similar biofilm structure became liposome afterwards.
Liposome research is that liposome is meant that the earliest the natural grease compounds is suspended in the vesicle with double seal structure that forms in the water, now also can be prepared by the phosphatide cpd of synthetic when previous very active field.People such as late 1960s Rahman at first use liposome as pharmaceutical carrier, liposome is fit to vivo degradation, avirulence and non-immunogenicity, particularly great number tested data proof liposome can improve the Drug therapy index, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier, and reduces advantage such as drug dose.
Summary of the invention
Defective at prior art levofloxacin lactate injection clarity and particulate matter, and the problem of solution colour flavescence, the object of the present invention is to provide a kind of levofloxacin lactate liposome sodium chloride injection stable, that can place for a long time, specifically, by specific adjuvant and supplementary material proportioning, with making levofloxacin lactate liposome sodium chloride injection of the present invention, solved the problem of above-mentioned existence by reverse phase evaporation.
The technical scheme that the present invention solves is as follows:
The invention provides a kind of levofloxacin lactate liposome sodium chloride injection, it is characterized in that making: 1 part of levofloxacin lactate, phosphatidase 15～15 part by following parts by weight of component, 0.5～1.5 part in cholesterol, 0.5～2 part of NaTDC, 2～10 parts in sodium chloride, 0.5～1.5 part in antioxidant.
As the preferred embodiment for the present invention, above-mentioned described levofloxacin lactate liposome sodium chloride injection, it is characterized in that making: 1 part of levofloxacin lactate by following parts by weight of component, phosphatidase 16～13 part, 0.5～1 part in cholesterol, 0.85～2 part of NaTDC, 3～9 parts in sodium chloride, 0.5～1 part in antioxidant.
Above-mentioned described levofloxacin lactate liposome sodium chloride injection, if necessary, it can also comprise makes pH value be adjusted to 4.6～5.0 pharmaceutically acceptable buffer salt solution, and for example buffer salt solution is selected from one or more in phosphate buffer, citrate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer.
The above-mentioned described levofloxacin lactate liposome sodium chloride injection of the present invention, phospholipid wherein, can be selected from natural phospholipid or synthetic phospholipid, natural phospholipid for example 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 phospholipid, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, soy phosphatidylserine or the soybean phospholipid acyl inositol; Synthetic phospholipid for example 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 or the two lauroyl phosphatidyl glycerols.
The above-mentioned described levofloxacin lactate liposome sodium chloride injection of the present invention, wherein said antioxidant, be not particularly limited, can be antioxidant pharmaceutically commonly used, for example be selected from sodium sulfite, sodium pyrosulfite, L-cysteine, thiourea, formaldehyde and close in sodium sulfite, vitamin E, ascorbyl palmitate, the butylated hydroxyarisol one or more.
The above-mentioned described levofloxacin lactate liposome sodium chloride injection of the present invention, it is by comprising the steps to make: (1) be dissolved in phospholipid, cholesterol, NaTDC and antioxidant and become oil phase in the organic solvent; (2) levofloxacin lactate is become water in or the buffer salt solution water-soluble with sodium chloride; (3) above-mentioned oil phase and water are mixed, stir and form water/oil type (w/o type) Emulsion, the heated and stirred evaporation, when reaching the thickness state, add entry or buffer salt solution again, continue the heated and stirred evaporation and remove residual organic solvent, ultrasonic, be transferred in the at a high speed even matter blender, stir even matter, promptly get the levofloxacin lactate liposome sodium chloride injection.
Wherein, above-mentioned described organic solvent for example can be selected from chloroform, ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane one or more.
As the most preferred specific embodiments of the present invention, above-mentioned described levofloxacin lactate liposome sodium chloride injection, it is characterized in that making 100 bottles of levofloxacin lactate liposome sodium chloride injection: levofloxacin lactate 10g by following component, soybean lecithin 60g, cholesterol 5g, NaTDC 15g, ascorbyl palmitate 10g, sodium chloride 90g, the potassium dihydrogen phosphate of pH value 5.0-dipotassium hydrogen phosphate buffer 10L.
As most preferred another specific embodiments of the present invention, above-mentioned described levofloxacin lactate liposome sodium chloride injection, it is characterized in that making 100 bottles of levofloxacin lactate liposome sodium chloride injection: levofloxacin lactate 20g by following component, distearyl acid phosphatidyl glycerol 200g, cholesterol 20g, NaTDC 40g, sodium sulfite 20g, sodium chloride 90g, the acetic acid of pH value 4.6-sodium-acetate buffer 2L.
As most preferred the 3rd specific embodiments of the present invention, above-mentioned described levofloxacin lactate liposome sodium chloride injection, it is characterized in that making 100 bottles of levofloxacin lactate liposome sodium chloride injection: levofloxacin lactate 30g by following component, egg yolk lecithin acyl serine 400g, cholesterol 15g, NaTDC 25g, vitamin E 15g, sodium chloride 90g, the citric acid of pH value 4.8-sodium citrate buffer 10L.
As another goal of the invention of the present invention, a kind of method for preparing above-mentioned described levofloxacin lactate liposome sodium chloride injection is provided, preparation process is:
(1) phospholipid, cholesterol, NaTDC and antioxidant are dissolved in become oil phase in the organic solvent;
(2) levofloxacin lactate is become water in or the buffer salt solution water-soluble with sodium chloride;
(3) above-mentioned oil phase and water are mixed, stir and form water/oil type (w/o type) Emulsion, the heated and stirred evaporation, when reaching the thickness state, add entry or buffer salt solution again, continue the heated and stirred evaporation and remove residual organic solvent, ultrasonic, be transferred in the at a high speed even matter blender, stir even matter, promptly get the levofloxacin lactate liposome sodium chloride injection.
Above-mentioned described preparation method, wherein said organic solvent for example can be selected from chloroform, ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane one or more.
Levofloxacin lactate liposome sodium chloride injection provided by the invention carries out stability test and investigates, and places 10 days under 60 ℃ of high temperature, illumination 4500Lx condition, and every detection index has no significant change; Accelerated test is 6 months under 40 ℃ of high temperature, relative humidity 75% ± 5% condition, and every detection index does not have significant change; Long term test is 18 months under 25 ℃ of high temperature, relative humidity 60% ± 10% condition, and every detection index does not have significant change.
Levofloxacin lactate liposome preparation provided by the invention carries out acute toxicity test, abnormal toxicity test and heat source check, and is all up to specification, and safety obtains proof.
Levofloxacin lactate liposome sodium chloride injection provided by the invention compared with prior art, has beyond thought effect, and major advantage is as follows:
(1) levofloxacin lactate is wrapped in the liposome, and it is defective to have solved long-term placement particulate matter and clarity, and the problem of solution colour flavescence has guaranteed product quality;
(2) pharmaceutical carrier liposome vivo degradation, avirulence and non-immunogenicity, and can improve the Drug therapy index, reduce drug toxicity and reduce drug side effect;
(3) adopt conventional process equipment, but commercial scale, high efficiency production, and constant product quality is a kind of uniqueness and blanket, the low-cost industrial preparation method.
The specific embodiment
Further specify the present invention by the following examples, but should not be construed as limitation of the present invention.
Embodiment 1
The preparation of levofloxacin lactate liposome sodium chloride injection
Prescription (100 bottles): levofloxacin lactate 10g
Soybean lecithin 60g
Cholesterol 5g
NaTDC 15g
Ascorbyl palmitate 10g
Sodium chloride 90g
Preparation technology
(1) 60g soybean lecithin, 5g cholesterol, 15g NaTDC and 10g ascorbyl palmitate are dissolved in the ethanol of 500ml;
(2) levofloxacin lactate 10g and sodium chloride 90g are dissolved in the potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution of 8000mlpH value 5.0;
(3) with the two mixing, stir, form w/o type Emulsion, the heated and stirred evaporation is when mixture reaches the thickness state, the phosphate buffer that adds 2000mlpH value 5.0 again, continue the heated and stirred evaporation and remove residual ethanol, ultrasonic 30min is transferred in the at a high speed even matter blender, stir even matter 30min, get the levofloxacin lactate liposome sodium chloride injection.
Comparative Examples 1
The preparation of levofloxacin lactate liposome
Prescription (100 bottles): levofloxacin lactate 10g
Soybean lecithin 45g
Cholesterol 4g
NaTDC 22g
Ascorbyl palmitate 18g
Sodium chloride 90g
Preparation technology
(1) 45g soybean lecithin, 4g cholesterol, 22g NaTDC and 18g ascorbyl palmitate are dissolved in the ethanol of 500ml;
(2) levofloxacin lactate 10g and sodium chloride 90g are dissolved in the potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution of 8000mlpH value 5.0;
(3) with the two mixing, stir, form w/o type Emulsion, the heated and stirred evaporation is when mixture reaches the thickness state, the phosphate buffer that adds 2000mlpH value 5.0 again, continue the heated and stirred evaporation and remove residual ethanol, ultrasonic 30min is transferred in the at a high speed even matter blender, stir even matter 30min, get the levofloxacin lactate liposome injection.
Embodiment 2
The preparation of levofloxacin lactate liposome sodium chloride injection
Prescription (100 bottles): levofloxacin lactate 20g
Distearyl acid phosphatidyl glycerol 200g
Cholesterol 20g
NaTDC 40g
Sodium sulfite 20g
Sodium chloride 90g
Preparation technology
(1) 200g distearyl acid phosphatidyl glycerol, 20g cholesterol, 40g NaTDC and 20g sodium sulfite are dissolved in the isopropyl alcohol of 2000ml;
(2) levofloxacin lactate 20g and sodium chloride 90g are dissolved in the 8000ml water;
(3) with the two mixing, stir, form w/o type Emulsion, the heated and stirred evaporation is when mixture reaches the thickness state, acetic acid-the sodium-acetate buffer that adds 2000mlpH value 4.6 again, continue the heated and stirred evaporation and remove residual isopropanol, ultrasonic 30min is transferred in the at a high speed even matter blender, stir even matter 30min, get the levofloxacin lactate liposome sodium chloride injection.
Comparative Examples 2
The preparation of levofloxacin lactate liposome
Prescription (100 bottles): levofloxacin lactate 20g
Distearyl acid phosphatidyl glycerol 310g
Cholesterol 32g
NaTDC 4g
Sodium sulfite 4.5g
Sodium chloride 90g
Preparation technology
(1) 310g distearyl acid phosphatidyl glycerol, 32g cholesterol, 4g NaTDC and 4.5g sodium sulfite are dissolved in the isopropyl alcohol of 2000ml;
(2) levofloxacin lactate 20g and sodium chloride 90g are dissolved in the 8000ml water;
(3) with the two mixing, stir, form w/o type Emulsion, the heated and stirred evaporation is when mixture reaches the thickness state, acetic acid-the sodium-acetate buffer that adds 2000mlpH value 4.6 again, continue the heated and stirred evaporation and remove residual isopropanol, ultrasonic 30min is transferred in the at a high speed even matter blender, stir even matter 30min, get the levofloxacin lactate liposome injection.
Embodiment 3
The preparation of levofloxacin lactate liposome sodium chloride injection
Prescription (100 bottles): levofloxacin lactate 30g
Egg yolk lecithin acyl serine 400g
Cholesterol 30g
NaTDC 25g
Vitamin E 15g
Sodium chloride 90g
Preparation technology
(1) 400g egg yolk lecithin acyl serine, 30g cholesterol, 25g NaTDC and 15g vitamin E are dissolved in the benzyl alcohol of 2000ml;
(2) levofloxacin lactate 30g and sodium chloride 90g are dissolved in the citric acid-sodium citrate buffer solution of 8000mlpH value 4.8;
(3) with the two mixing, stir, form w/o type Emulsion, the heated and stirred evaporation is when mixture reaches the thickness state, add 2000ml water again, continue the heated and stirred evaporation and remove residual benzene methanol, ultrasonic 30min is transferred in the at a high speed even matter blender, stir even matter 30min, get the levofloxacin lactate liposome sodium chloride injection.
Test example 1
The mensuration of envelop rate
Get the Liposomal formulation of embodiment preparation, the total content that high performance liquid chromatography detects levofloxacin lactate is M, selects for use column chromatography to separate liposome.
Get 1.5g sephadex G-50, soak more than the swelling 12h with the pH6.8 phosphate buffer, pack in the chromatographic column (200 * 10mm) into, with above-mentioned phosphate buffer flushing balance, get the levofloxacin lactate liposome preparation 1.1ml that embodiment 1-2 and Comparative Examples 1-2 obtain respectively, add chromatography and live the top, with phosphate buffer 50ml eluting, flow velocity 1.3ml/min, the eluent of collecting adds rupture of membranes agent (ethanol: 50ml benzyl alcohol=6: 1), mixing, high performance liquid chromatography detects the content M of levofloxacin lactate
1
Envelop rate %=M
1/ M * 100%.
Table 1 entrapment efficiency determination result
By above result as can be known, the liposome encapsulation that proportioning makes of writing out a prescription of the embodiment in the scope of the invention is very high, meets the actual production requirement substantially; 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
The detection of particle diameter
Get the Liposomal formulation of embodiment 1-3 and Comparative Examples 1-2 preparation, adopt micro-image analyzer to measure the particle size distribution of liposome, result such as table 2:
Table 2 particle diameter testing result
By above result as can be known, it is spherical that the liposome that embodiment 1-3 makes shows, and particle diameter is even, and scope is 100-200nm; The liposome shape that Comparative Examples 1-2 makes is indefinite, disorderly and unsystematic, not of uniform size, and particle diameter is inhomogeneous, and scope is 300-900nm.
Study on the stability
With the sample of above each embodiment preparation and (Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.'s production of the levofloxacin lactate injection of listing, lot number 20081116) under 60 ℃ of high temperature, illumination 4500Lx condition, places and carried out the influence factor in 10 days and test investigation, the results are shown in Table 1; Under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate, the results are shown in Table 2; Under 25 ℃ of high temperature, relative humidity 60% ± 10% condition 18 months, carry out long term test and investigate, detect the variation of every quality index, the results are shown in Table 3.
Table 1 influence factor result
Table 2 accelerated test result
Table 3 long-term test results
Quicken March, June by above found that, the levofloxacin lactate injection its colour changed into yellow of long-term December, listing 18 months the time, clarity is against regulation, and pH value descends bigger, and content reduces obviously, and related substance raises; And the sample appearance character of the present invention's preparation does not have significant change, is colourless clear liquid, and clarity, pH value, content and related substance do not have obvious variation yet.The sample stable quality after long time storage that the present invention's preparation is described is better.
The present invention is described according to preferred embodiment.Should be understood that the description of front and embodiment are just to illustrating the present invention.Under prerequisite without departing from the spirit and scope of the present invention, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (9)
1. levofloxacin lactate liposome sodium chloride injection, it is characterized in that making: 1 part of levofloxacin lactate by following parts by weight of component, phosphatidase 15～15 part, 0.5～1.5 part in cholesterol, 0.5～2 part of NaTDC, 2～10 parts in sodium chloride, 0.5～1.5 part in antioxidant, by what comprise the steps to make: (1) is dissolved in phospholipid, cholesterol, NaTDC and antioxidant and becomes oil phase in the organic solvent; (2) levofloxacin lactate is become water in or the buffer salt solution water-soluble with sodium chloride; (3) above-mentioned oil phase and water are mixed, stir and form water/oil type Emulsion, the heated and stirred evaporation, when reaching the thickness state, add entry or buffer salt solution again, continue the heated and stirred evaporation and remove residual organic solvent, ultrasonic, be transferred in the at a high speed even matter blender, stir even matter, promptly get the levofloxacin lactate liposome sodium chloride injection.
2. levofloxacin lactate liposome sodium chloride injection according to claim 1, it is characterized in that making: 1 part of levofloxacin lactate by following parts by weight of component, phosphatidase 16～13 part, 0.5～1 part in cholesterol, 0.85～2 part of NaTDC, 3～9 parts in sodium chloride, 0.5～1 part in antioxidant.
3. levofloxacin lactate liposome sodium chloride injection according to claim 1 and 2, it is characterized in that described buffer salt solution is selected from one or more in phosphate buffer, citrate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer, makes pH value be adjusted to 4.6～5.0.
4. levofloxacin lactate liposome sodium chloride injection according to claim 1 and 2, it is characterized in that described phospholipid is selected from natural phospholipid or synthetic phospholipid, wherein natural phospholipid is an Ovum Gallus domesticus Flavus lecithin, the hydrogenation egg yolk lecithin, EPG, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, soybean phospholipid, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, in soy phosphatidylserine or the soybean phospholipid acyl inositol one or more, synthetic phospholipid is the 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, in GLYCEROL,DIMYRISTOYL PHOSPHATIDYL or the two lauroyl phosphatidyl glycerols one or more.
5. levofloxacin lactate liposome sodium chloride injection according to claim 1 and 2 is characterized in that described antioxidant is selected from sodium sulfite, sodium pyrosulfite, L-cysteine, thiourea, formaldehyde and closes in sodium sulfite, vitamin E, ascorbyl palmitate, the butylated hydroxyarisol one or more.
6. levofloxacin lactate liposome sodium chloride injection according to claim 1 and 2 is characterized in that described organic solvent is selected from one or more in chloroform, ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane.
7. levofloxacin lactate liposome sodium chloride injection according to claim 1, it is characterized in that making 100 bottles of levofloxacin lactate liposome sodium chloride injection: levofloxacin lactate 10g by following component, soybean lecithin 60g, cholesterol 5g, NaTDC 15g, ascorbyl palmitate 10g, sodium chloride 90g, the potassium dihydrogen phosphate of pH value 5.0-dipotassium hydrogen phosphate buffer 10L.
8. levofloxacin lactate liposome sodium chloride injection according to claim 1, it is characterized in that making 100 bottles of levofloxacin lactate liposome sodium chloride injection: levofloxacin lactate 20g by following component, distearyl acid phosphatidyl glycerol 200g, cholesterol 20g, NaTDC 40g, sodium sulfite 20g, sodium chloride 90g, the acetic acid of pH value 4.6-sodium-acetate buffer 2L.
9. levofloxacin lactate liposome sodium chloride injection according to claim 1, it is characterized in that making 100 bottles of levofloxacin lactate liposome sodium chloride injection: levofloxacin lactate 30g by following component, egg yolk lecithin acyl serine 400g, cholesterol 15g, NaTDC 25g, vitamin e1 5g, sodium chloride 90g, the citric acid of pH value 4.8-sodium citrate buffer 10L.
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| CN102188395B (en) * | 2011-04-29 | 2012-12-05 | 石药集团中诺药业（石家庄）有限公司 | Stable meropenem injection and preparation method thereof |
| CN106606775A (en) * | 2015-10-27 | 2017-05-03 | 格里菲斯大学 | Liposomal group A streptococcus vaccine |
| CN106491529A (en) * | 2016-12-08 | 2017-03-15 | 广东彼迪药业有限公司 | A kind of levofloxacin hydrochloride sodium chloride injection and preparation method thereof |
| CN115721607B (en) * | 2022-11-19 | 2023-07-21 | 华夏生生药业(北京)有限公司 | Levofloxacin lactate injection and preparation method thereof |
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