• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Amorphous solid formed by lyophilization or cosolvent precipitation of an aqueous solution of 7-[ alpha -(2-aminothiazol-4-yl)- alpha -(Z)-methoximinoacetamido]-3-[(1-methyl-1-pyrrolidinio)-methyl[-3-ceph em-4-carboxylate zwitterion and a salt or mixture of salts from a selected particular group is a broad spectrum antibiotic composition and has better temperature stability at least up to 45 DEG C. than the zwitterion. The salt is one wherein the cation is selected from the group consisting of sodium, lithium, calcium, and magnesium and the anion is selected from the group consisting of chloride, bromide, and iodide. The molar ratio of zwitterion to salt ranges from about 0.5:1 to about 2:l.
    公开号:SU1575942A3
    申请号:SU884355050
    申请日:1988-01-08
    公开日:1990-06-30
    发明作者:Артур Каплан Муррей；Баллард Богардус Джозеф；Р.Палепу Нагесвара
    申请人:Бристоль-Мейерз Компани (Фирма)；
    IPC主号:
    专利说明:

    intravenous infections without the use of buffers or bases,
    The examples below illustrate the invention.
    Example 1. Preparation and testing of a 1: 1 complex zwitterion: sodium chloride complex.
    To a vessel equipped with a stirrer, 800 ml of an aqueous solution containing 250 g of zwitterion is introduced, with stirring at a medium speed, 30.41 g of sodium chloride is added to ensure a molar ratio of zwitterion: sodium chloride 1: 1. Water for injection, meeting the requirements of the United States Pharmacopoeia (USP), is added to 1 liter. Continue to mix the solution for 15 minutes, then with intervals of 5-10 minutes until the samples taken between intervals with stirring show a significant amount of undissolved particles. The resulting solution is transferred to a stainless steel autoclave to operate at elevated pressure. The solution is discharged from the autoclave, using compressed nitrogen, through an installation with a sterilized filter equipped with a pre-filter and a filter for sterilization into a clean sterilized collector. Then, 4 ml portions (1 g of the active HOCTHJ due to the zwitterion) are aseptically filled into glass flasks with 10 ml. After filling, the flasks are sealed with stoppers used for freeze-drying. The flasks are placed in lyophilization trays, which are placed in a lyophiliser, where the product is frozen for 4 hours at (-30) - (-iO) ° C. Then, the temperature in the condenser connected to the lyophilizer is kept at (-60) ± 3 ° C and the freezing unit is turned off. When the temperature in the condenser reaches -50 C, the vacuum pump is turned off. When the vacuum level reaches 200 µP, the temperature on the shelf is set at -13 ± 3 ° C and maintained for 16-13 hours. Then the temperature on the shelf is adjusted to + 25 ° C. The temperature of + 25 ± 2 ° С is maintained for 48 hours. The lyophilizer is discharged and the flasks removed. The product, an amorphous solid, is characterized as a complex of zwitterion: sodium chloride 1: 1.
    Calculated,%: C 42.34; H 4.49; N 15.59; S 11.60; HaO (KF) absence; Na (sulphated ash) 4.27; C1 6.58.
    0 «5 п е
    five
    Cfg H24NC 0.5-52ClNa.
    Found (correction for water),%: C 41.96; H 4.57; N 14.73; S 12.28; H2O (KF) 1.80; Na (sulphated ash) 3.15; C1 6.85.
    In the infrared analysis, there were no significant differences between this product and the zwitterion. However, the point of decomposition determined by the differential scanning calorimetry method was measured exothermically at 197.4 ° C, which is noticeably different from that of the zwitterion (173.84 ° C). This indicates that this product is a compound different from the zwitterion.
    The same product is obtained by adding 10–20 volumes of isopropanol to a collector containing an aqueous solution of zwitterion and sodium chloride to form a precipitate 3 separating it using vacuum filtration, washing the precipitate with isopropanol and drying under high vacuum. The product is obtained in dry form.
    To assess the broad spectrum of activity, minimal inhibitory concentrations (MIC) of this product and zwitterion are determined by the method of twofold serial dilution of agar (Muller-Hinton agar). The data obtained are given in table. 1 (Bristol A N corresponds to a special type of microorganism).
    The data in Table 1 indicate that the product obtained, i.e. complex ziterion: sodium chloride 1: 1, has equivalent microbiological activity compared with zwitterion.
    The toxicity of the zwitterion complex: sodium chloride 1: 1 is tested on Sprague-Dawley rats by a single intravenous bolus. The LD 50 for combined data from 2 studies is 796 mg / kg with 95% limits, a confidence between 759 and 832 microns / kg. These data are to be compared with THL 50 669 microns / kg and 95% limits. validity between 618 and 732 mg / kg for zwitterion. The response curves were parallel, however, in terms of efficacy, this product was less toxic than zwitterion.
    Stability at elevated temperature is determined after storage of the 1: 1 complex of sodium zwitterionic chloride and zwitterion in a dry powder.
    state of loss of effectiveness through high performance liquid chromatography (HPLC) analysis. Indicators of the loss of effectiveness are presented in Table 2. The limits show extreme values for a variety of experiments.
    The stability of an aqueous solution of a 1: 1 zwitterionic complex of sodium chloride is determined by changing the structure at various concentrations after storage at 25 ° C for fixed periods of time. Structural changes by diluting to 250 mg / ml (nominally) are carried out with sterile injectable water that meets the requirements of the United States Pharmacopoeia (USP). For subsequent dilution, a 0.9% sodium chloride solution is used. The data presented in table 3. The limits show extreme values for a variety of experiments.
    The data table. 3 indicates satisfactory stability of an aqueous solution of the zwitterion complex:: NaCl 1: 1 for at least 24 hours at 25 ° C (room temperature)
    EXAMPLE 2: Preparation and Testing of a Complex from Zwitterion and Calcium Chloride.
    4.6 g of zwitterion is dissolved in 14 ml of water for injection containing 950 mg of calcium chlorine (1 mol-eq.).
    The resulting solution is passed through a 0.22 micron sterile filter.
    The filtrate is added under aseptic conditions and under rapid agitation with an interval of 5 minutes to 400 ml of absolute ethanol. An amorphous precipitate is formed.
    The mixture is stirred up for 0.5 hours.
    The solid is suction filtered and washed with 40 ml of ethanol, which is added to the filtrate (designated as filtrate A).
    The solid, wet from ethanol, is stirred up in 100 ml of absolute ethanol for 0.5 h. The resulting amorphous solid is separated by vacuum filtration, washed with 20 ml of ethanol, 50 ml of ether, then dried in high vacuum at 50 ° C for 4 h, which gives 2.2 g of a product containing cvntterion and calcium chloride in a 2: 1 molar ratio
    Calculated,%: C 42.56; H 4.51; N 15.68; S 11.96; C1 6.6; Ca (in the form of ash) 3.73.
    five
    0
    five
    , 505S2 (CljCa) 0fi. . . Found,%: C 38.4; n 4.85; N 13.76; S 8.82; C1 5.44; Ca (in the form of ash) 3.59; HZ0 (KF) 7.79.
    Found (dry basis),%: C 41.65; N 14.92; S 9.57; C1 5.9, Ca (as ash) 3.89.
    Filtrate A is concentrated under vacuum Q at 35 ° C to 30 ml. Very dense cubic-shaped microparticles are obtained, showing the absence of double refraction.
    The solid solids 5 are suction filtered, washed with 15 ml of absolute ethanol, then 20 ml of ether, and dried to give 2.0 g of an amorphous solid product consisting of calcium chloride in a molar ratio of 1.5: 1 ( sesqui-zwitterion).
    Calculated,%: C 41.1; H 4.5; N 14.7; S 10.8; C1 8.33, Ca (in the form of ash) 4.8.
    (Cf9H N605S) 1iS СаС12. Found,%: C 37.35; H 5.17; N 12.37; S 10.24; C1 7.84; Ca (in the form of ash) 4,47; H20 (KF) 3.24; ethanol O, 5 mol.
    0 Found (NgO and base not containing ethanol),%: C 40.01; H 4.88; N 13.3; S 10.57; C1 8.3; Ca (in the form of ash) 4.7.
    Soluble and insoluble complexes in ethanol do not show a significant difference according to high performance liquid chromatography (HPLC) and ultraviolet spectra from zwitterion.
    To assess the broad spectrum of activity of this product, minimum inhibitory concentrations (MIC) for the product zwitterion: calcium chloride are determined at a molar ratio of 5 and zwitterion using the two-time serial dilution method of agar (Muller-Hinton agar). The data obtained are presented in table 4, where special types of microorganisms are marked as 0 Bristol A N:
    Stability at elevated temperature after storage of the product zwitterion: calcium chloride at a molar ratio of 1.5: 1 and zwitter tag 5 in dry powdered form based on the loss of potential properties by high performance liquid chromatography (HPLC). The loss of potential properties is shown in Table 5, where
    five
    0
    limits indicate extreme values for many experiments,
    PRI me R 3. The study of thermal stability.
    Lyophilized compositions are prepared from zwitterion and sodium chloride or calcium chloride and their stability is determined at different temperatures. In tab. 6 shows the residual activity values as determined by the analysis of such compositions by high performance liquid chromatography (HPLC).
    The complex zwitterion: sodium chloride 1: 1 is suitable for pharmaceutical use, has a wide range of actions characteristic of antibiotics, and is largely equal to that of the zwitterion O As seen from the “test results, this complex has a satisfactory solution stability, less than 24 hours at 25 ° C (at a concentration of 250 mg / ml of zwitterion in sterile water there is less than 10% loss of activity, as determined by analysis using high-performance liquid chromatography) “In contrast to Ariona has a satisfactory stability at elevated temperature for a dry powder form (about 10% loss after 4 weeks of storage at 45 ° C), which is determined by high performance liquid chromatography (HPLC), and exceptional stability for a dry form. powder at normal refrigerator temperatures (not lost at 6 months storage at 4 ° C) during the entire 24-hour period, after which the above complex changes structure, providing an injection-suitable composition (i.e. after restructuring to provide a concentration suitable for injection). Composition suitable
    for injection, maintained at a satisfactory pH, i.e. ranging from 4.2 to 6.2, without the use of buffers or bases. The complex mentioned above is less toxic than zwitterion.
    The compositions in question are converted into compositions suitable for injection by diluting with sterile water and / or saline to provide compositions with zwitterion activity based on concentrations ranging from 1 to 400 mg / ml
    as determined by high performance liquid chromatography (HPLC) analysis, preferably in the range of 2.5 to 250 mg / ml. It is reasonable to carry out dilution to 250 mg / ml,
    Q using sterile water for injection, which meets the requirements of the United States Pharmacopoeia (USP) and if further dilution is needed, take 0.9% sodium chloride solution according to USP. For
    5 for intramuscular or intravenous administration for the purpose of treatment to an adult. Man, the total daily dosage in the range from 750 to 3000 mg is divided into sufficient dosages.
    The compositions are transported and stored in a dry state under the conditions of a conventional refrigerator (for example at 4 ° C), and they must remain active by more than 90% for at least 1-2 years. Such compositions are readily convertible into compositions suitable for injection.
    formula of invention
    The method of preparing in amorphous form thermally stable 7-C2- (2-aminothiazol-4-yl) -2- (g) -methoxyiminoacetamido J-3- (1-methyl-1-pyrrolidinio) methyl-3- complexes cephem-4-carboxate with metal halides of general formula
    N
    C-CONH-T - f
    N och3
    about
    but -
    (nC1) y (CaC12);
    characterized in that (2-aminothiazol-4-yl) -2- (g) -methoxyiminoacetamido} -3- (1-methyl-1-pyrrolidinis) methyl-3-cephem- 4-carboxylate to obtain a concentration of 100 ...
    40 mg / ml and the corresponding molar amount of sodium chloride or calcium chloride and the desired product is isolated from the solution by lyophilization.
    MIC values (mg / ml)
    1.S.pneumoniae
    2.S.pyogenese
    3.S.faecalis
    4.S. aureus
    5.S aureus / + 50%
    6.S.aureus / Pen.
    7.S.aureus / meth.
    8.E.coli
    9.E.edi
    10.K. pneuraoniae
    11.K. pneumoniae
    12.E.cloacae
    13.E.cloacae
    14.P.mirabilis
    15.P.vulgaris
    16.M.morganii
    17.P.rettgeri
    18.S.marceseens
    19.P.S.aeruginosa
    20.P.S.aeruginosa
    Dry product stability
    or solution resolution, followed, if necessary, by vacuum drying.
    Table 1
    9585 9604 20688 9537 9537 9606 20699 15199 20341-1 9664 20468 9659 9656 9900 21559 15153 22424 20019 9843a 21628
    0.016 0.008 16 0.5 1 1
    More than 0.16 0.016 0.016 0.5 0.016 0.03 0.008 0.03 0.008 0.13 0.03 0.5 2
    125
    0.016 0.008 16 0.5 1 1
    125 0.16 0.003 0.06 1
    0,016 0,06 0,016 0,03 0,016 0,25 0,03 1 3
    Table 2
    Table3 Stability in aqueous solution
    Table 4 The values of the minimum inhibitory concentration (MIC) (mg / ml)
    Dry product stability
    Formulations and percentage of residual activity
    1 D
    3D
    1n
    2n
    4n 8 n
    1n
    2n n 8 n
    3 n
    4 n
    n
    3 n
    3 n
    70 ° С 70 ° С 56 ° С 56 ° С 56 ° С 56 ° С 45 ° С 45 ° С 45 ° С 45 ° С 45 ° С 37 ° С 37 ° С 37 ° С 25 ° С
    66 54
    45-58 39-43
    70 79 39
    69
    85.2 76.6 81.9 73.9 67.7 55.9 91.7 87.5 84.2 76.2 67.4 90.4 85.4 80.9 93.7
    Table3
    Table

    88.7 80.7 86.6 78.4 71.5 62.5 94.3 89.2 85.8 80.4 75.3 92.0 87.3 85.8 95.6
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining thermally stable complexes of 7- [2- (2-aminothiazol-4-yl) -2- (Ζ) methoxyiminoacetamido] -3- (1-methyl-1-pyrrolidinio) methyl-3-cefem-4 in amorphous form -carboxylate with metal halides of the general formula (maCl) at (CaCl 2 ) 2 characterized in that, dissolved in sterilized water
    7- [2- (2-aminothiazol-4-yl) -2- (Ζ) methoxyiminoacetamido 3-3- (1-methyl-1-pyrrolidinio) methyl-3-cefem-4-carboxylate to give a concentration of 100. ..
    40 mg / ml and the corresponding molar or cosolvent precipitation with after the amount of sodium chloride or chloramide, if necessary, dried calcium and from the solution isolated in vacuo.
    the target product is lyophilized;
    Table 1
    MIC values (mg / ml) Microorganism Bristol Zwitterion Complex, color A n Therion: IAa1 1: 1 1. Z. rpeitopiae A 9585 0.016 0.016 2. 5. ruogepeze A 9604 0.008 0.008 3. Z. Taesa Nz A 20688 16 16 4. 3. aigeez A 9537 0.5 0.5 5.8 aigeez / + 50% zegig A 9537 1 1 6. 3.aigeiz / Rep. Kez .. A 9606 1 1 7. 8.aigeiz / teRTS. Kez. 28 ° C A 20699 More than 125 • 125 8. E.soY A 15199 0.16 0, 16 9. E.esN A 20341-1 0.016 0.003 10. K. rpeitop gae A 9664 0.016 0.06 11. K. rpeitopgae A 20468 0.5 1 12. E.s1oasae A 9659 0.016 0.016 13. E.s1oasae A 9656 0,03 0.06 14. R. A 9900 0.008 0.016 15. R.chi1§aggs A 21559 0,03 0,03 16. M. Gogodapy A 15153 0.008 0.016 17. R.geRRegeg1 A 22424 0.13 0.25 18. Z. tagsezepes A 20019 0,03 0,03 19. R.5.aegi§1 pose A 9843a 0.5 1 20. P. 8. Aegi §1 pose / Cl. Kez A 21628 2 3
    Taelitsa2
    Dry product stability
    Temperature,° C Time storage Loss of efficiency,% Colortherion Zwitterion complex: TsaS1 1: 1 4 1 month - 0-14 4 month - Lack of 25 1 month - 1-54 5 weeks ·. - 3.0 18 weeks - 6-10% 37 1 month - 9-12.9 5 weeks - 6.0 1 2 weeks - 12.5 4 month - 5-18,0 45 1 week 34.1 5,6 2 weeks - 8.3 4 weeks 71 10.7 56 1 week 45.6 12, 2 weeks - 16 4 weeks - 20 70 1 day 34,4 12.7-23.0 2 days 46.2 21.7 3 days 55,2 34.0 100 1 day 100 92
    Table 3
    Stability in aqueous solution
    Concentration, mg / ml '- Time h The balance,% pH 250 0 -, ·. 5.04-5.22 3 100-102 5.03-5.24 6 100-101 5.03-5.24 24 92.7-96.0 5.14-5.39 fifty 0 - • 5.0-5.17 3 99,4 5.07-5.31 6 97-99.4 5.06-5.31 24 93.2-94.7 5.30-5.60 10 0 - 4.94-5.12 3 99.5-100.1 5.05-5.34 6 99.3-99.4 5.11-5.47 24 95.2-97.0 5.44-5.78 2,5 0 - 5.00-5.19 3 100.0 5.28-5.66 6 99.6-100.0 5.47-5.92 24 96.2-96.8 5.87-6.18
    Table4
    The values of the minimum inhibitory concentration (MIC) (mg / ml)
    Microorganism Bristol Zwitte Zwitterion: A n rion : CaCl1 g , molar correlation 1.5: 1 1. 3.rpeitophe A 9585 0.06 0.016 2. 3. ruo <> ene8 A 9604 0.016 0.016 3. Z. Laesenz A 20688 16 16 4 about Z. aigeez A 9537 1 1 5. Z. aigeez / + 50% Zegiga A 9537 0.5 0.5 6. Z. aigeiz / Rep.-Kez. A 9606 1 3 7. Z. aigeiz / (METN.-RE5.128 ° С) A 20 699 125 63 8. E.coN A 15119 0.016 0.016 9. E.coN A 20341-1 0,03 0.016 10. K. Rpeitoplay A 9664 0,03 0,03 11. K. Rpeitopgai · A 20468 1 1 12. E.s1oasae A 9659 0.016 0.016 13. E.s1oasae A 9656 0.13 0.25 14. R. tNaNZ A 9900 0.008 0.008 15. R.ui1§ag18 A 21559 0,03 0,03 16. h M. toggapn A 15153 0.008 0.008 17. R. geRP ^ eH A 22424 0,03 0,03 18. Z. tagsezseps A 20019 0,03 0.016 19. R. aegi §1 pose A 9843a 0.5 0.5 20. R.aegi§1Pose / Sag. Res. A 21628 2 2
    Table5
    Dry product stability
    Temperature ° C Storage time Loss of properties,% Zwitte -I Zwitterion: CaCl 1 g . rion 1 molar ratio | 1.5: 1 37 2 month - 3,5 45 1 weeks 34, 1 0.4-0 2 weeks - 3.2-5.7 4 weeks 71 56 1 weeks 49.6 0-5.3 2 weeks - 1.7-6.6 4 weeks - 13.7 70 1 day 34,4 2 DAY 46.2 3 DAY 55,2 2.2-6.5 100 1 day 100 20-30,0
    Tableb
    Recipes and the percentage of residual activity
    VR volume / temperature Zwitterion Zwitterion / Zwitterion: Zwitterion: CaCl 2 pH 5.1 / NaCl 1: 1 : CaCl 1 2 1: 1 1: 0.5 exact acc pH 4.9, os tivness,% exact acc tivness,% 1 D - 70 ° C 66 85,2 94.2 88.7 3 D - 70 ° C 54 76.6 88.8 80.7 1 n - 56 ° C 45 -58 81.9 92.3 86.6 .2 n - 56 ° C 39 -43 73.9 86.9 78,4 4 n - 56 ° C - 67.7 84,4 71.5 8 n - 56 ° C - 55.9 79.0 62.5 1 n - 45 ° C 70 91.7 96.2 94.3 2 n - 45 ° C 79 87.5 93.0 89.2 4 n - 45 ° C 39 84.2 92.9 85.8 8 n - 45 ° C - 76.2 88.9 80,4 thirteen n - 45 ° C - 67.4 86.3 75.3 4 n - 37 ° C 69 ’90, 4 95.2 92.0 8 n - 37 ° C - 85,4 93.5 87.3 thirteen n - 37 ° C - 80.9 91.1 85.8 thirteen n - 25 ° C - 93.7 96.4 95.6
    Note, n - weeks,. d - days.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1575942A3|1990-06-30|Method of obtaining thermally stable complexes 7/2-aminothiazol-4-il 2-|methoxyiminoacetamido/-3-|methyl-3-cephem-4-carboxylate with metal halogenides in amorphous state
    KR0180798B1|1999-03-20|Crystalline penicillin derivative, and its production and use
    EP2062582B1|2013-04-17|Antibiotic composition comprising beta-lactam antibiotics, aminoglycosides and buffers
    JP2568401B2|1997-01-08|Water-soluble meglumine salt and glucamine salt, production method thereof and pharmaceutical composition containing the same
    ES2356792T3|2011-04-13|PROCEDURES FOR THE PREPARATION OF PHARMACEUTICALLY ACCEPTABLE LIOFILIZED SALTS OF DIAMOND PEMETREXED.
    FI86854C|1992-10-26|FOERFARANDE FOER FRAMSTAELLNING AV KRISTALLINA HYDRAT AV CEFALOSPORINSALT
    HU188181B|1986-03-28|Process for producing salts of naphtiridine and quinoline compounds of antimicrobial activity
    US6624143B1|2003-09-23|Calcium salts of lipopeptide antibiotics, method for producing same and their use
    US5750131A|1998-05-12|Ifosfamide lyophilizate preparations
    CS276717B6|1992-08-12|Process for preparing heat stable crystalline addition salts
    JP2958567B2|1999-10-06|Freeze-dried BMY-28142 dihydrochloride for parenteral use
    WO2006106529A1|2006-10-12|A co-spray dried composition of cefepime with base and process for preparation thereof
    WO2005094800A2|2005-10-13|A co-precipitated cefepime composition and process for preparation thereof
    JP2004269401A|2004-09-30|Lyophilized preparation
    AU615245B2|1991-09-26|Aqueous formulations containing a piperidinylcyclopentylheptenoic acid derivative
    KR930001830B1|1993-03-15|Antibacterial lyophilized preparation of aspoxicillin
    CA1307206C|1992-09-08|Antibacterial agent for mammal use comprising cephalosporin derivatives as an effective ingredient
    HU205857B|1992-07-28|Process for producing liofilized products containing etoposide-2-dimethyl-amino derivative as active component
    KR101121942B1|2012-03-09|Cephalosporin in crystalline form
    US3461161A|1969-08-12|Water-soluble tetracycline derivatives
    NL8403948A|1985-07-16|ANTIBACTERIAL MEDICINAL COMPOSITION.
    JPH0782149A|1995-03-28|Stabilized preparation of cephem-based antibiotic
    JPH09104694A|1997-04-22|Acic addition salt of arbekacin with |-cis-1,2-epoxypropylphosphonic acid, its production and antimicrobial agent
    同族专利:
    公开号 | 公开日
    DK577387A|1988-07-10|
    JP2568226B2|1996-12-25|
    CS15888A2|1989-01-12|
    DK166404B1|1993-05-17|
    GB8725875D0|1987-12-09|
    YU46689B|1994-04-05|
    AR243501A1|1993-08-31|
    SE8800036L|1988-07-10|
    LU87102A1|1988-08-23|
    BE1002114A3|1990-07-10|
    FI875122A|1988-07-10|
    PT86157B|1991-02-08|
    NL8800025A|1988-08-01|
    CH676202A5|1990-12-28|
    JPS63208522A|1988-08-30|
    DE3740588A1|1988-07-21|
    KR950010154B1|1995-09-11|
    CA1307464C|1992-09-15|
    FI875122A0|1987-11-19|
    US4808617A|1989-02-28|
    CY1679A|1993-10-10|
    SE467910B|1992-10-05|
    AU606361B2|1991-02-07|
    HK5593A|1993-02-05|
    NL193266C|1999-05-06|
    IL84346A|1992-05-25|
    GB2199746A|1988-07-20|
    ZA88114B|1988-06-27|
    OA08796A|1989-03-31|
    CS265249B2|1989-10-13|
    NL193266B|1999-01-04|
    IT8819013D0|1988-01-07|
    KR880008811A|1988-09-13|
    FI89006B|1993-04-30|
    ES2008951A6|1989-08-16|
    SG114792G|1992-12-24|
    PT86157A|1987-12-01|
    IL84346D0|1988-04-29|
    HUT46223A|1988-10-28|
    YU2388A|1989-10-31|
    HU199686B|1990-03-28|
    IE61238B1|1994-10-19|
    GB2199746B|1990-10-24|
    FR2609396A1|1988-07-15|
    GR871860B|1988-05-10|
    AT388672B|1989-08-10|
    IT1215666B|1990-02-22|
    DK577387D0|1987-11-03|
    IE872970L|1988-07-09|
    FI89006C|1993-08-10|
    SE8800036D0|1988-01-08|
    ATA341687A|1989-01-15|
    AU8085687A|1989-05-11|
    DD264614A5|1989-02-08|
    DE3740588C2|1996-07-11|
    FR2609396B1|1993-01-29|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3953439A|1973-08-01|1976-04-27|Smithkline Corporation|Substituted phenylglycylcephalosporins|
    US4029655A|1975-04-11|1977-06-14|Eli Lilly And Company|Method of preparing stable sterile crystalline cephalosporins for parenteral administration|
    US4406899A|1982-03-04|1983-09-27|Bristol-Myers Company|Cephalosporins|
    CA1213882A|1982-03-04|1986-11-12|Jun Okumura|Cephalosporins|
    JPH0370688B2|1983-08-22|1991-11-08|Shionogi & Co|
    US4604386A|1984-07-09|1986-08-05|Eli Lilly And Company|3- cephalosporins|
    JPH0522688B2|1984-11-28|1993-03-30|Shionogi Seiyaku Kk|
    FR2585705B1|1985-08-05|1989-01-13|Bristol Myers Co|CEPHALOSPORIN SALTS AND INJECTABLE COMPOSITIONS|US4910301A|1985-08-05|1990-03-20|Bristol-Myers Company|Cefepime cephalosporin salts|
    CA2011116C|1989-03-06|1999-11-16|Murray A. Kaplan|Lyophilized bmy-28142 dihydrochloride for parenteral use|
    DE19539574A1|1995-10-25|1997-04-30|Boehringer Mannheim Gmbh|Preparations and processes for stabilizing biological materials by means of drying processes without freezing|
    WO2005094800A2|2004-03-31|2005-10-13|Lupin Ltd.|A co-precipitated cefepime composition and process for preparation thereof|
    WO2006109324A2|2005-04-13|2006-10-19|Lupin Limited|Processes for preparation of amorphous cefepime acid addition salts|
    JP5491119B2|2009-10-02|2014-05-14|日東電工株式会社|Pharmaceutical composition containing drug-containing microparticles and method for producing the same|
    KR102226197B1|2013-03-15|2021-03-11|머크 샤프 앤드 돔 코포레이션|Ceftolozane antibiotic compositions|
    US20140275000A1|2013-03-15|2014-09-18|Cubist Pharmaceuticals, Inc.|Ceftolozane pharmaceutical compositions|
    US9872906B2|2013-03-15|2018-01-23|Merck Sharp & Dohme Corp.|Ceftolozane antibiotic compositions|
    ES2800603T3|2013-09-09|2021-01-04|Merck Sharp & Dohme|Treatment of infections with ceftolozane / tazobactam in patients with renal impairment|
    US8906898B1|2013-09-27|2014-12-09|Calixa Therapeutics, Inc.|Solid forms of ceftolozane|
    US9949982B2|2014-09-04|2018-04-24|Shionogi & Co., Ltd.|Preparation containing cephalosporin having a catechol moiety|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US07/001,945|US4808617A|1985-12-18|1987-01-09|Lyophilized or precipitated cephalosporin zwitterion and salt combination|
    [返回顶部]