CN102138925B - Tigecycline composition and preparation method thereof - Google Patents
Tigecycline composition and preparation method thereof Download PDFInfo
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- CN102138925B CN102138925B CN201010107061.XA CN201010107061A CN102138925B CN 102138925 B CN102138925 B CN 102138925B CN 201010107061 A CN201010107061 A CN 201010107061A CN 102138925 B CN102138925 B CN 102138925B
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- tigecycline
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- threonine
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940011861 tigecycline injection Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a tigecycline composition belonging to the field of medicament preparations, in particular to a tigecycline composition suitable for injection and a preparation method thereof. The composition provided by the invention is prepared by adding one or more selected from Vitamin C or pharmaceutically acceptable salts thereof and amino acids. The tigecycline composition disclosed by the invention not only effectively restricts oxidative degradation, but also remarkably decreases the epimerization of tigecycline and improves the stability of the tigecycline.
Description
Technical field
The compositions that the present invention relates to a kind of tigecycline, belongs to field of pharmaceutical preparations, relates in particular to a kind of tigecycline composition and method of making the same of applicable injection.
Background technology
Tigecycline (tigecycline) is the first glycylcycline class antibiotic that is approved for clinical vein administration, and structure is similar to tetracycline medication, shown in I, is developed and is gone on the market by Hui Shi, is used for the treatment of the complicated skin of adult and skin histology
Infect and the interior infection of the complicated abdomen of being grown up.Tigecycline is stable not in solution, and main degradation pathway is oxidative degradation and epimerization, and the two exists simultaneously.Be embodied under weak basic condition, oxidative degradation easily occurs; And under acid condition, especially pH is less than at 6.0 o'clock, epimerization becomes main degradation pathway.Tigecycline is followed and degradation pathway identical in solution under lyophilised state, and just degradation speed is relatively slow.
In order to increase the stability of tigecycline, Chinese patent application CN200810234680.8 discloses the lyophilized injectable powder being made up of tigecycline, dextran, anhydrous sodium sulfite and sodium citrate; CN200610096514.7 discloses the compositions containing tigecycline and antioxidant.These two sections of patent documentations are all by under alkali condition, select suitable antioxidant to reduce the oxidative degradation of tigecycline, thereby increase its stability.The patent CN200680006447.3 of Wyeth discloses the compositions containing tigecycline and suitable carbohydrate, the aqueous solution that this application contains tigecycline and suitable carbohydrate by lyophilizing under acid pH, thus obtain oxidative degradation and the more stable tigecycline compositions of epimerization.
In addition,, in order to strengthen patient to the resistance infecting, antibiosis usually uses with vitamin C or amino acid whose injection compatibility clinically.As " Accelerated stability test of ceftazidime for inj and Vitamin C Glucose Injection compatibility ", Lu Miao, Li Tao, drug research, the 15th the 21st phase of volume in 2006, the 34th page; " study on the stability of Gatifloxacin for Injection and vitamin C injection compatibility ", Zheng Hailan, Li Shuifu, drug identification, the 14th the 5th phase of volume in 2005,44-45 page; " stability analysis of lomefloxacin hydrochloride glucose injection and vitamin C injection compatibility ", Li Hongyue, Li Rongzhen, Chinese medicine and clinical, the 4th the 7th phase of volume of July in 2004,558-559 page; " stability of Clindamycin hydrochloride injection and Vitamin C Glucose Injection compatibility ", Xue Guoju, Qian Wenjing, Shi Tao, Tian Jie, Chinese pharmacists, the 8th the 4th phase of volume in 2005,302-304 page; " Prescriptions Investigation of Combined Use with Vitamin C Injection ", Xiao Yongxin, Yang Huifen, Jiang great Yi, pharmaceutical organization, the 16th the 13rd phase of volume in 2007,37-38 page; " research of ceftiaoxline sodium for injection stability in Amino Acid Compound Injection ", Guo Jing, Zhou Xueqin, modern hospital, the 9th the 9th phase of volume of JIUYUE in 2009, a professional technique section, 60-61 page; " there is incompatibility in sodium fusidafe as injection and Amino Acid Compound Injection ", smooth extra large cloud tints, MODERN NURSING, July 2007, Vol.13, No.21, the 2024th page.As can be seen here, vitamin C or aminoacid, as nutrient, have been widely used in the auxiliary treatment of various infection, for reducing the repeatedly misery of medication of patient, often various injections are done to quiet with being mixed in transfusion clinically.Applicant is in the time that the compatibility of research tigecycline uses, unexpected discovery, in tigecycline, add after vitamin C or its pharmaceutically acceptable salt or aminoacid, can significantly suppress the epimerization of tigecycline under sour environment, increase its stability, applicant has completed the present invention on this basis.On the one hand, can strengthen patient to the resistance infecting, increase the curative effect of tigecycline; Preparation aspect in addition, has overcome the unsettled shortcoming of tigecycline, has increased the stability of tigecycline, meets the requirement of clinical use.
In addition, although the adjuvant of the tigecycline injection of the listing of FDA approval is at present lactose,, in Chinese Pharmacopoeia version in 2005, lactose quality standard is only the excipient standard of pro ore preparation, the unsuitable direct excipient as injection preparation.There is certain risk as injection supplementary material in lactose, may bring potential safety hazard.And in Aisan, the ratio of lactose intolerance is higher, may increase the probability that is caused untoward reaction by lactose intolerance.In addition, in clinical practice field, the adjuvant with lactose as injection, especially when large usage quantity, while needing a large amount of medication as some patients with severe symptoms, may mean patient has been increased to pressure aspect the energy balance, for the treatment of diabetics especially like this.
In order to increase the curative effect of tigecycline, expand the applicable crowd of product, reduce clinical safety in utilization risk, overcome the unsettled shortcoming of tigecycline, the invention provides a kind of new tigecycline compositions, thereby solved the problems referred to above.
Summary of the invention
The object of this invention is to provide a kind of stable tigecycline for injection compositions.
Another object of the present invention is to provide a kind of method of preparing above-mentioned tigecycline for injection compositions.
The invention provides a kind of composition for injection, comprise tigecycline and proppant, wherein proppant is selected from one or more in vitamin C or its pharmaceutically acceptable salt or aminoacid, and the pH value of said composition is 3.0～6.0.
Described pharmaceutically acceptable salt comprises alkali metal salt, alkali salt or ammonium salt etc., as sodium salt, potassium salt, calcium salt, magnesium salt etc., is preferably sodium salt.Described aminoacid comprises glycine, arginine, threonine, proline, methionine, lysine, tryptophan, valine, leucine, isoleucine, aspartic acid, agedoite, cystine, cysteine, histidine, glutamic acid, serine, alanine, phenylalanine, the natural amino acids such as tyrosine and alpha-non-natural amino acid, also comprise above-mentioned amino acid whose pharmaceutically acceptable salt, as alkali metal salt, alkali salt, ammonium salt, inorganic acid salt (example hydrochloric acid salt) or acylate (as acetate) etc., be preferably threonine or serine.
In above-mentioned composition for injection, wherein proppant is preferably one or more in vitamin C, ascorbic sodium salt, threonine or serine, and described pH is preferably 3.5～5.5, is more preferably 4.0～5.0.
In embodiments more of the present invention, the mass ratio 1: 0.5～10 of tigecycline and proppant, be preferably 1: 1～5, most preferably be 1: 1～3.Further, in compositions, can comprise chelating agen, described chelating agen comprises disodium EDTA, EDTA calcium complex disodium salt, 1,2-1,2-diaminocyclohexane tetraacetic acid etc., be preferably EDTA calcium complex disodium salt, wherein the mass ratio of tigecycline and chelating agen is 1: 0～0.1, be preferably 1: 0.01～and 0.05.
Composition for injection of the present invention comprises injection solution and solid dosage forms for injection, is preferably solid dosage forms for injection.
Compositions of the present invention can be prepared by many acceptable methods, and following method is exemplary, does not mean that and limits the invention.
In the time preparing injection solution, one or more proppant and the water that are selected from vitamin C or its pharmaceutically acceptable salt or aminoacid can be mixed to form to solution, add pH adjusting agent to regulate pH value, then add tigecycline to dissolve, optionally regulate pH value, obtain injection solution.In above-mentioned preparation process, optionally, in solution, can add needle-use activated carbon, after stirring, coarse filtration decarburization, then through filtering with microporous membrane, sterilizing.
Through lyophilization, spraying, dry or other method well known in the art can prepare solid dosage forms for injection to above-mentioned injection solution, preferably prepares by lyophilization.
Injection solution of the present invention, also comprises and will in above-mentioned solid dosage forms for injection, add the solution that pharmaceutically acceptable diluent redissolves or further dilution makes.Described diluent comprises water for injection, saline (as 0.9% normal saline), 5% or 10% D/W, sodium lactate ringer's injection etc.
In above-mentioned preparation method, described pH adjusting agent comprises acid, alkali or buffer agent, described acid comprises hydrochloric acid (comprising 1.0N hydrochloric acid), 2,5-resorcylic acid, lactic acid, citric acid, acetic acid or phosphoric acid etc., described alkali comprises sodium hydrate aqueous solution or potassium hydroxide aqueous solution etc., described buffer agent comprises succinate, phosphate, acetate or citrate, is preferably phosphate.The pH value of solution is adjusted to 3.0～6.0, and preferably 3.5～5.5, most preferably 4.0～5.0.
Compositions of the present invention can be deposited or in solution, pass into noble gas in preparation process under as the inert gas environment such as nitrogen, carbon dioxide, with the degradation process that further slows down, but not necessarily.Tigecycline of the present invention comprises any solid forms, comprises tigecycline polymorph, amorphous forms and salt.
The present invention is by under acid pH, taking one or more in vitamin C or its pharmaceutically acceptable salt or aminoacid as proppant, not only effectively suppress oxidative degradation, and significantly reduced the generation of tigecycline epimer, increased the stability of tigecycline.Compared with existing compositions, compositions of the present invention not only can strengthen patient to the resistance infecting, increase the curative effect of tigecycline, the potential safety hazard of avoiding above-mentioned lactose to bring, and significantly increased the stability of tigecycline in production, storage and clinical use procedure, meet the requirement of clinical application.
Detailed description of the invention
To contribute to understand the present invention by following embodiment, but not limit the scope of the invention.
Embodiment 1
(A) 50mg tigecycline is placed in to the sample bottle of 10mL, adds 2mL water to make its dissolving; (B) 50mg tigecycline is placed in the sample bottle of 10mL, adds 2mL water that it is dissolved, and regulates pH to 4.5; (C) vitamin C of 50mg is dissolved in the water of 2mL, adds NaOH aqueous solution to regulate pH to 3.5, adds 50mg tigecycline, and stirring and dissolving, regulates pH to 3.5; (D) vitamin C of 50mg is dissolved in the water of 2mL, adds NaOH aqueous solution to regulate pH to 4.5, adds 50mg tigecycline, and stirring and dissolving, regulates pH to 4.5; (E) vitamin C of 50mg is dissolved in the water of 2mL, regulates pH to 6.0, adds 50mg tigecycline, and stirring and dissolving regulates pH to 6.0; (F) threonine of 100mg is dissolved in the water of 2mL, adds salt acid for adjusting pH to 3.5, adds 50mg tigecycline, and stirring and dissolving regulates pH to 3.5; (G) threonine of 100mg is dissolved in the water of 2mL, adds salt acid for adjusting pH to 4.5, adds 50mg tigecycline, and stirring and dissolving regulates pH to 4.5; (H) threonine of 100mg is dissolved in the water of 2mL, regulates pH to 6.0, adds 50mg tigecycline, and stirring and dissolving regulates pH to 6.0.Respectively the above-mentioned solution preparing is crossed to fill after 0.22 μ m filter membrane, after lyophilization, inflated with nitrogen tamponade.
Lyophilizing sample is placed 10 days under the condition of 40 DEG C/75%RH, HPLC analytic sample, detection method is as follows:
Taking octadecylsilane chemically bonded silica as filler chromatographic column, mobile phase A, B carry out gradient elution, and detection wavelength is 248nm.
Mobile phase A: 4.35g dipotassium hydrogen phosphate and 0.93g sodium sulfite are dissolved in the EDTA solution of 950ml, adjusts pH value to 6.4 with phosphoric acid, adds the abundant mix homogeneously of 50ml acetonitrile, and filtering with microporous membrane is degassed.
Mobile phase B: 4.35g dipotassium hydrogen phosphate and 0.93g sodium sulfite are dissolved in the EDTA solution of 500ml, adjusts pH value to 6.4 with phosphoric acid, adds the abundant mix homogeneously of 500ml acetonitrile, and filtering with microporous membrane is degassed.
The disodiumedetate of EDTA solution: 3.7g is dissolved in the water of 950ml, adds 50ml acetonitrile mix homogeneously.
Diluent: 4.35g dipotassium hydrogen phosphate and 0.5g sodium sulfite add in 1000ml water, with 1M potassium hydroxide solution adjust pH to 8.0.
The results are shown in Table 1, therefrom can find out, under different pH, add after a certain amount of vitamin C or its pharmaceutically acceptable salt or aminoacid, not only reduce the generation of oxidative breakdown product, and significantly having suppressed the epimerization of tigecycline, epimer significantly reduces, and has significantly increased the stability of tigecycline.
Table 1
| Total impurities | Isomer | Oxide | Tigecycline | |
| Tigecycline (not adjusting pH) | 7.8％ | 4.2％ | 1.40％ | 92.2％ |
| Tigecycline pH4.5 | 9.3％ | 8.4％ | 0.19％ | 90.7％ |
| VC+pH3.5 | 1.18％ | 1.02％ | 0.01％ | 98.8％ |
| VC+pH4.5 | 1.16％ | 0.96％ | 0.03％ | 98.8％ |
| VC+pH6.0 | 1.42％ | 1.08％ | 0.08％ | 98.6％ |
| Threonine+pH3.5 | 1.20％ | 1.11％ | 0.02％ | 98.8％ |
| Threonine+pH4.5 | 1.22％ | 1.08％ | 0.03％ | 98.8％ |
| Threonine+pH6.0 | 1.50％ | 1.21％ | 0.11％ | 98.5％ |
Embodiment bis-
The vitamin C of (A ') 25mg is dissolved in the water of 2mL, adds NaOH aqueous solution to regulate pH to 4.5, adds the tigecycline of 50mg, and stirring and dissolving, regulates pH to 4.5; The vitamin C of (B ') 50mg is dissolved in the water of 2mL, adds NaOH aqueous solution to regulate pH to 4.5, adds the tigecycline of 50mg, and stirring and dissolving, regulates pH to 4.5; The vitamin C of (C ') 100mg is dissolved in the water of 2mL, and NaOH regulates pH to 4.5, adds the tigecycline of 50mg, and stirring and dissolving regulates pH to 4.5; The vitamin C of (D ') 250mg is dissolved in the water of 2mL, and NaOH regulates pH to 4.5, adds the tigecycline of 50mg, and stirring and dissolving regulates pH to 4.5; The threonine of (E ') 25mg is dissolved in the water of 2mL, and salt acid for adjusting pH to 4.5 adds the tigecycline of 50mg, and stirring and dissolving, regulates pH to 4.5; The threonine of (F ') 50mg is dissolved in the water of 2mL, and salt acid for adjusting pH to 4.5 adds the tigecycline of 50mg, and stirring and dissolving, regulates pH to 4.5; The threonine of (G ') 100mg is dissolved in the water of 2mL, and salt acid for adjusting pH to 4.5 adds the tigecycline of 50mg, and stirring and dissolving, regulates pH to 4.5; The threonine of (H ') 250mg is dissolved in the water of 2mL, and salt acid for adjusting pH to 4.5 adds the tigecycline of 50mg, and stirring and dissolving, regulates pH to 4.5; The serine of (I ') 25mg is dissolved in the water of 2mL, and salt acid for adjusting pH to 4.5 adds the tigecycline of 50mg, and stirring and dissolving, regulates pH to 4.5; The serine of (J ') 50mg is dissolved in the water of 2mL, and salt acid for adjusting pH to 4.5 adds the tigecycline of 50mg, and stirring and dissolving, regulates pH to 4.5; The serine of (K ') 100mg is dissolved in the water of 2mL, and salt acid for adjusting pH to 4.5 adds the tigecycline of 50mg, and stirring and dissolving, regulates pH to 4.5; The serine of (L ') 250mg is dissolved in the water of 2mL, and salt acid for adjusting pH to 4.5 adds the tigecycline of 50mg, and stirring and dissolving, regulates pH to 4.5; (M ') 50mg tigecycline is placed in the sample bottle of 10mL, adds 2mL water that it is dissolved, and regulates pH to 4.5 (contrast with).Respectively the above-mentioned solution preparing is crossed to fill after 0.22 μ m filter membrane, lyophilization, inflated with nitrogen tamponade.
Lyophilizing sample is placed 10 days under the condition of 40 DEG C/75%RH, HPLC analytic sample, detection method, with embodiment mono-, the results are shown in Table shown in 2.Therefrom can find out, under certain pH, while adding the vitamin C of different proportion or its pharmaceutically acceptable salt or aminoacid, all significantly suppress the generation of epimer and oxidative breakdown product, increase the stability of tigecycline.
Table 2
| Total impurities | Isomer | Oxide | Tigecycline | |
| Tigecycline pH4.5 | 9.3％ | 8.4％ | 0.19％ | 90.7％ |
| pH4.5+VC 25mg | 1.09％ | 0.87％ | 0.03％ | 98.91％ |
| pH4.5+VC 50mg | 1.16％ | 0.96％ | 0.03％ | 98.84％ |
| pH4.5+VC 100mg | 1.19％ | 0.97％ | 0.02％ | 98.81％ |
| pH4.5+VC 250mg | 1.24％ | 1.06％ | 0.04％ | 98.76％ |
| PH4.5+ threonine 25mg | 1.32％ | 1.14％ | 0.04％ | 98.68％ |
| PH4.5+ threonine 50mg | 1.24％ | 1.09％ | 0.02％ | 98.76％ |
| PH4.5+ threonine 100mg | 1.22％ | 1.08％ | 0.03％ | 98.78％ |
| PH4.5+ threonine 250mg | 1.28％ | 1.06％ | 0.04％ | 98.72％ |
| PH4.5+ serine 25mg | 1.67％ | 1.39％ | 0.06％ | 98.33％ |
| PH4.5+ serine 50mg | 1.65％ | 1.37％ | 0.07％ | 98.35％ |
| PH4.5+ serine 100mg | 1.62％ | 1.35％ | 0.05％ | 98.38％ |
| PH4.5+ serine 250mg | 1.72％ | 1.46％ | 0.09％ | 98.28％ |
Embodiment tri-
The vitamin C of (A ") 50mg is dissolved in the water of 2mL, adds NaOH aqueous solution to regulate pH to 4.5, then adds the tigecycline of 50mg, and stirring and dissolving, regulates pH to 4.5; The threonine of (B ") 100mg is dissolved in the water of 2mL, adds aqueous hydrochloric acid solution to regulate pH to 4.5, adds the tigecycline of 50mg, and stirring and dissolving, regulates pH to 4.5.Respectively the above-mentioned solution preparing is crossed to fill after 0.22 μ m filter membrane, after lyophilization, inflated with nitrogen tamponade.
Lyophilizing sample is placed 90 days under the condition of 40 DEG C/75%RH, HPLC analytic sample, detection method, with embodiment mono-, the results are shown in Table shown in 3.Therefrom can find out, add after vitamin C or its pharmaceutically acceptable salt or aminoacid, can significantly increase the stability in tigecycline storage process.
Table 3
| Total impurities | Isomer | Oxide | Tigecycline | |
| VC pH4.5 | 2.02％ | 1.64％ | 0.09％ | 97.98％ |
| Threonine pH4.5 | 1.97％ | 1.58％ | 0.07％ | 98.03％ |
Embodiment tetra-
The vitamin C of (A " ') 100mg is dissolved in the water of 4mL, adds NaOH aqueous solution to regulate pH to 4.5, then adds the tigecycline of 100mg, and stirring and dissolving, regulates pH to 4.5, is divided into two equal portions; The threonine of (B " ') 200mg is dissolved in the water of 4mL, adds aqueous hydrochloric acid solution to regulate pH to 4.5, adds the tigecycline of 100mg, and stirring and dissolving, regulates pH to 4.5, is divided into two equal portions.Respectively the above-mentioned solution preparing is crossed to fill after 0.22 μ m filter membrane, after lyophilization, inflated with nitrogen tamponade is then placed 10 days under the condition of 40 DEG C/75%RH.Get above-mentioned vitamin C and the each portion of lyophilized formulations containing threonine of containing, redissolve also room temperature (25 DEG C) placement after 6 hours, HPLC analytic sample with the normal saline of 5mL 0.9% respectively.Get again above-mentioned vitamin C and the each portion of lyophilized formulations containing threonine of containing, first place 6 hours by normal saline redissolution the room temperature (25 DEG C) of 5mL 0.9% respectively, again with normal saline dilution to 250mL, room temperature (25 DEG C) was placed after 6 hours, HPLC analytic sample.Detection method, with embodiment mono-, the results are shown in Table shown in 4.
Therefrom can find out, containing vitamin C or its pharmaceutically acceptable salt or enough stable in amino acid whose lyophilized formulations a period of time after redissolving and diluting, epimerization and oxidative degradation still can significantly be suppressed, and meet the requirement that tigecycline configures and uses in clinical setting completely.
Table 4
| Total impurities | Isomer | Oxide | Tigecycline | |
| VC redissolves | 1.36％ | 1.11％ | 0.08％ | 98.64％ |
| Threonine redissolves | 1.38％ | 1.17％ | 0.07％ | 98.62％ |
| Redissolve+dilution of VC | 1.43％ | 1.18％ | 0.09％ | 98.57％ |
| Redissolve+dilution of threonine | 1.45％ | 1.22％ | 0.08％ | 98.55％ |
Claims (11)
1. a composition for injection, comprises tigecycline and threonine, and wherein the mass ratio of tigecycline and threonine is 1:0.5～5, and the pH value of said composition is 3.0～6.0.
2. the compositions of claim 1, wherein the mass ratio of tigecycline and threonine is 1:1～5.
3. the compositions of claim 1, wherein the mass ratio of tigecycline and threonine is 1:1～3.
4. the compositions of any one in claim 1-3, wherein pH value is 3.5～5.5.
5. the compositions of claim 4, wherein pH value is 4.0～5.0.
6. the compositions of any one in claim 1-3, also comprises chelating agen.
7. the compositions of claim 6, wherein chelating agen is disodium EDTA, EDTA calcium complex disodium salt or CDTA.
8. the compositions of claim 6, wherein the mass ratio of tigecycline and chelating agen is 1:0-0.1.
9. the compositions of claim 6, wherein the mass ratio of tigecycline and chelating agen is 1:0.01-0.05.
10. the compositions of any one in claim 1-3 is injection solution or solid dosage forms for injection.
The compositions of 11. claim 10 is solid dosage forms for injection.
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| CN101132775A (en) * | 2005-03-14 | 2008-02-27 | 惠氏公司 | Tigecycline compositons and methods of preparation |
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| CN101167732A (en) * | 2007-10-22 | 2008-04-30 | 合肥信风科技开发有限公司 | Method for preparing glycylcycline freezing-dried powder injection |
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| CN101132775A (en) * | 2005-03-14 | 2008-02-27 | 惠氏公司 | Tigecycline compositons and methods of preparation |
| CN101152152A (en) * | 2006-09-28 | 2008-04-02 | 南京华威医药科技开发有限公司 | Lgecycline composition for injection and processes for producing same |
| CN1985835A (en) * | 2006-12-05 | 2007-06-27 | 合肥信风科技开发有限公司 | Prepnaring method for freeze dried tigecycline powder for injection |
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