• 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:
    Die Erfindung betrifft neue, wasserlösliche und stabile Polyenantibiotikum-Derivate und ein Verfahren. zu ihrer Herstellung. Die neuen Derivate von Polyenantibiotika sind ihre mit γ-Cyclodextrin gebildeten Einschlußkomplexe. Die wasserlöslichen Derivate der Polyenantibiotika werden hergestellt, indem man wasserunlösliche oder in Wasser beschränkt lösliche Polyenantibiotika in Gegenwart von Wasser unter Rühren mit γ-Cyclodextrin umsetzt.
    公开号:SU1428208A3
    申请号:SU843835600
    申请日:1984-12-28
    公开日:1988-09-30
    发明作者:Сейтли Йожеф；Викмон Мариа；Штадлер Агнеш；Пиукович Шандор；Инцефи Иштван；Кулчар Габор；Яраи Миклош；Златош Габриелла
    申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    The invention relates to a method for the preparation of new water-soluble and stable formpolyene antibiotics, namely, to a method for the preparation of complexes of a pslyenovy antibiotic-X - -cyclodextrin (J-CZ).
    The purpose of the invention is to obtain new derivatives of polyene antibiotics, which are more soluble in water while maintaining chemical and biological stability, compared to the original antibiotic.
    The method is carried out as follows.
    Example 1. Obtaining a complex of flavofungin. with J-cyclodextrin in the homogeneous phase.
    22 g of f-cyclodextrin (content 130DY 1.5%) at 30 ° C are dissolved in 500 ml of distilled water and 2.5 g (3.85 mmol of solid flavofungin) is added to the solution. The solution is stirred vigorously for 3 hours, then the filtrate is filtered and the resulting intense yellow color is lyophilized to give 21 g of a product, the spectrophotometrically measured flavofungin content of which is 9.3%. This corresponds to approximately 80% of the amount of flavofungin used. The complex is a loose yellow powder 100 mg of the complex dissolves 2.5m
    distilled water at 50 ° C.
    with the formation of a clear solution. This solution contains 3.5 mg / ml of flavofungin and, when stored for 6 days at room temperature and in diffused light, does not undergo any changes chemically or physically. . Maximum solubility occurs at a content of approximately 4% (flavofungin concentration 4 mg / ml), therefore, by lyophilization of this solution, a complex of the most preferred composition is obtained (9-10 wt.% Of biologically active substance).
    Thermogravimetric measurements, studies using a differential scanning calorimeter (DSC) and thermo-destructive analysis (TDA) - (Tmermal Evolution Analyze) show the characteristic difference between flavofungine, flavofungin complex with y-tsTs, and mixtures of flavofungin-TsTs, flavofungin at 100 ° C loses
    Q
    five
    0 5 o
    five
    Q C 0

    7% of its mass (based on the TDA curve, organic substances are released), above 100 ° C it begins to decompose and loses 24% of its mass up to 300 ° C. The lyophilized sample from flavofungin and γ-CD is obtained as a complex due to the fact that it does not lose any organic matter even in the DSC curve between 100 and there is no exothermic change characteristic of the oxidation of flavofungin, however, at 263 ° C is a characteristic peak for the exothermic process, which indicates the oxidation of a flavofungin derived from the complex.
    The DF of the thermostability of the flavofungin complex with the J-PQ of the substance of a 1 mm thickening layer was placed on watch glasses and, not protected from light, was stored at room temperature and at 60 ° C in an oven. Samples taken at various time points were analyzed spectrophotometrically.
    Based on chemical measurements, it was found that flavofungin not included in the complex. After 24 h at 60 C, it undergoes a strong decomposition (this is also confirmed by removing the full UV spectrum). The content of biologically active substance in the complex of flavofungin with y-CD after 50 days becomes approximately 75%. A physical mixture containing 10% flavofungin prepared with glucose loses 50% of the biologically active substance at 14-day storage at room temperature. The content of the biologically active substance in the complex after 50 days is more than 95%. When stored in a closed vessel at + 4 ° C for 7 months, the sample did not show the loss of the biologically active substance.
    The measurement results are presented in Table. 1 (heat resistance expressed as a percentage of the initial content of the biologically active substance),
    The microbiological evaluation also confirmed that flavofungin in the form of the J -CTC complex is much more stable. The flavofungin complex with Y-CD was stored at room temperature and under, antifungal. the action was exactly the same as the original (M1C-value stored in a nitrogen atmosphere in the refrigerator
    Flavofungin µg / ml samples were tested on test microorganisms. S. cerevLsial, p. albicans, s. pseu- dotropicals and c. orusei.
    Example 2. Obtaining a complex of flavofung with Y-CC, in a heterogeneous phase.
    9g of J-cyclodextrin (water content 1.5%) is homogenized in a porcelain mortar with 1 g of flavofungin at room temperature. The mixture is suspended in 5 ml of 50% ethanol. After a few minutes of stirring, the suspension suddenly becomes solid. The pasty substance is spread across the width to a thin layer and dried in a vacuum desiccator for several hours. Then the solid complex is ground into powder. 10 g of product are obtained with 10% by weight of biologically active substance.
    The product is studied for heat resistance. In this case, it is found that the complex as a lyophilized complex has a high heat resistance and its antifungal effect is not reduced.
    The X-ray diffraction analysis of the complex converted into powder shows characteristic reflection peaks at a significantly deviating (20) angle in a different place than in the case of a physical mixture of similar composition, which indicates a different crystal lattice and confirms the fact of complexation. An X-ray diffraction image of the lyophilized complex of flavofungin with J-CD indicates amorphous structure.
    Example 3. Obtaining a complex of nystatin with in a homogeneous phase.
    10 g of J-CZ (water content 1.5%) at 50 ° C are dissolved in 90 ml of distilled water. To the solution is added
    2 g (2.16 mmol) of nystatin (biological activity 5033 U / mg). The solution is mixed vigorously for 15 minutes. After filtering off the yellow precipitate, the solution is lyophilized. 10 g of product is obtained, the spectrophotometrically determined content of nystatin in which is 8%. Biological activity 399 U / mg. Nystatin C complex is a light yellow friable powder that dissolves quickly in
    eight
    water at room temperature to form a clear solution. The concentration of nystatin in a solution is 8-9 mg / ml, which corresponds to approximately 100 mg of the complex per ml of solution. The biological evaluation definition of the complex indicates that the biological activity of the initial nystatin
    persists.
    Thermogravimetric measurements, studies using a differential scanning calorimeter (DSC) and thermo-destructive analysis (TDA)
    show a characteristic difference between nystatin, a-nestatin complex with X-CD, and a mixture of nystatin with V-CC. Nystatin contains 3% of water, which gives up to (TG-curve).
    The decomposition begins at 150 ° C with an exothermic process (in the DSC krivor peak at 165 ° C, with a weight loss of 8% - the TG curve), then slow decomposition occurs, and
    at 350 ° C, measurable mass loss of 54%, Hot decomposition of nystatin. The X-CC with respect to temperature is the same, but there are some deviations in the thermocyclic curves of the complex in the mixture, which in the lyophilis make the presence of a complex probable. There is no sharp peak in the TDA curve at TbO C, which indicates organic volatilization.
    VE In the DSC, the curve does not exhibit an exothermic peak characteristic of nystatin decomposition (only at a temperature of 200 ° C). In the TG curve, the difference is that the freeze dried sample at 250 ° C decomposes faster than the physical mixture. The complexation of nystatin with X-CD is also confirmed by NMR studies.

    The stability of the solutions prepared from the lyophilized complex of nystatin c) f-im solutions was investigated as follows.
    An aqueous solution with a concentration of 5 mg / ml was prepared from an active substance containing 8%. The solution was stored at room temperature unprotected from light. At different points in time, the content of the biologically active substance in the solutions was monitored spectrophotometrically.
    , daysConcentration of nystatin mg / ml
    05.0
    14.8
    24.75
    54.70
    64.6
    74.55 - 84.5
    104.5
    124.5
    214.1
    Solutions on the second day begin to opalesce. Samples were taken after shaking the solution. The sample was diluted with a 400-fold amount of ethanol and then photometrically. The calculation was carried out from the existing (apparent) at L-d, 304 ± 1 extinction values. After 3 weeks of the aqueous solution, there is still over 80% of the total amount of biologically active substance. High values of the extrication belong to high values of activity,
     Example 4. Preparation of nystatin complex with J-cyclodextrin in a heterogeneous phase.
    . 9 g of J-cyclodextrin (water content 1.5%) and 1 g of nystatin (biological activity 5033 N / mg) are homogenized with each other in a porcelain mortar at room temperature. The resulting mixture is suspended in 6 ml of 50% ethanol. After a few minutes, the suspension suddenly becomes solid. The substance is crushed and dried to remove traces of water and solvent in a desiccator over phosphorus pentoxide. The next day, the solid complex is ground into powder. A product with a content of a biologically active substance of 10% by weight is obtained (the biological activity is 45 U / mg).
    The obtained complex. In thermoanalytical studies compared with the mixture shows the same deviations as prepared in example 3 by lyophilization of the complex. - The solubility of the appropriate amount of the biologically active substance 10 mg / ml of the amount of nystatin complex with y-CD and the main nystatin material in 15 ml of distilled water at 37 ° C was investigated. The solutions were stirred using a magnetic stirrer, making 150
    per minute, at various times, samples were taken, filtered, and their content of the biologically active substance was examined spectrophotometrically.
    rem min
    2
    five
    15
    40
    60
    90
    The complex of nystatin with Y-RC, mg / ml
     -9.0 7.2 7.8
    7.A
    7.2.
    6.0
    50
    0 5 5
    g
    0
    0
    The spectrum of samples taken from the aqueous suspension of the main nystatin material was not evaluated. The spectrum of the sample taken during the first 5 minutes is identical to the spectrum of nystatin, later a progressive spread is observed. At first, the maximum around 290 nm was deformed and then completely disappeared, and in the region of smaller wavelengths, a new maximum was obtained, which makes it possible to conclude that the conjugated amorphous system was damaged.
    Example. Obtaining nystatin complex with jC-Iffl in hetergergenic phase by lyophilization.
    8 g of y-CD (water content 1.5%) at 40 ° C are dissolved in 80 ml of water and 2 g (1.16 mmol) of nystatin is added to the solution. The suspension is stirred for 24 hours at 40 ° C., then the mixture is dried by lyophilization. 10 g of the product are obtained in the form of a yellow, friable powder, the spectrometrically measured content of the biologically active substance in which the composition is | L = 20%. The biological activity is 950 U / mg. .
    In the product, the molar ratio between nystatin and -CC is 1: 3. According to X-ray diffraction studies, the complex has an amorphous structure. Processed in the same way, but without p-CD, the main substance retains its crystalline nature, its X-ray diffraction pattern is completely identical to that of the main substance, and its biological activity is much worse. If a complex with a higher content of biologically active substance is obtained in the manner described above, then an X-ray diffractogram shows a peak characteristic of crystalline nystatin.
    To study the solubility of the complex, 500 mg is stirred for 5 minutes in 10 ml of water at room temperature. A nystatin concentration of 4.5 mg / ml was detected spectrophotometrically.
    Example 6. Obtaining complex of amphotericin B with y-CD.
    10 g of U-cyclodextrin (water content 1.5%) is dissolved in 90 ml of distilled water at 37 ° C. 200 mg of amphotericin B are added to the solution. The mixture is vigorously stirred for 2 hours, then the yellow precipitate is filtered, the filtrate is lyophilized. The product is obtained south, the spectrophotometrically measured content of amphotericin B in which is 0.6-0.8 wt.%. The complex is a yellow loose powder, which quickly dissolves in water to form a clear solution. The resulting solution has a concentration of 0.6-0.8 mg / ml of amphotericin B and can be diluted indefinitely with water or saline sodium chloride without precipitating a solid or turbid solution. The solution is stored at room temperature for 6 days and examined spectroscopically : the content of biologically active substance unchanged.
    Example 7. Determination of the antifungal effect of the obtained complexes both immediately after preparation and after storage under conditions in which the biologically active substance, which is not protected by complex formation, has already undergone significant loss of activity.
    a) Flavofungin complex with g-cyclodextrinMo
    The antifungal effect of an aqueous solution of this complex was studied on 6 bacteria and 13 hyphomycetes.
    The results are presented in table. 2
    In the calculation of flavofungin, the minimum inhibitory concentration in each case was 10–25 cg / ml, which corresponds to the activity of an unrelated complex biologically active substance. It should be especially noted that the substance is also active against phytopathogenic fungi, i.e. application against fungal infections of plants
    0
    0
    five
    five
    0
    five
    0
    five
    0
    five
    justified. The complexed biologically active substance acts in the same concentration as flavofungin. The studies were carried out by the method of diffusion on agar. The complex has the advantage that it does not require any energy solvents (LMF or SS) to prepare the solutions. These solvents act suppressively on some fungi, therefore, when measuring, it is necessary to reduce the solvent concentration by pressurizing with water to a value that does not act as suppressant. In practice, for example, a tolerance of 14 DMSO concentration is below 1%. Some polyenes are prone to precipitation at this kind of dilution, i.e. in preparing the preparation of solutions for solutions often encounter obstacles. The substance is recommended to be pulverized and the preparation of the solution, as well as its dilution. water should always be carried out immediately before measurement.
    The concentration of flavofungin in each case is 10-25 µg / mp. Problems arising from the preparation of a solution from flavofukgin are not objective when using the complex.
    b) Nystatin complex with Y-VD. Biological Estimate ™
    An agar-diffusion method was performed using Candida albicans as a test organism. The complexes were dissolved only in water, nystatin in methanol containing calcium chloride.
    The solutions were diluted with water. The spectrophotometrically measured content of the biologically active substance and the biological activity of some complexes are shown below. 3..
    The main nystatin substance used for complexing has biological activity. 5033 U / mg.
    c) Zmphoteridin B complex with U-CD, Antifungal, then the activity of this complex was investigated using the agar-diffusion method and Candida albicans as a test organism. With respect to amphotericin B, a minimal inhibitory concentration of beta is less than 5 µm / ml, which corresponds to the activity of an unbound com pound.
    plex biologically active substances.
    Example 8. Study of the absorption (absorption) of complexes of polyene-antibiotics with cyclodextrin.
    a) Absorption (absorbability) of nystatin from the nystatin complex administered orally c.
    Absorption of the biologically active substance was investigated in mice, on a model of sepsis caused by intravenous administration of a suspension of Candida albicans. Sepsis within 2-3 days: caused mortality. Experimental animals received orally prepared according to example 3, containing 8% nystatin complex. In a parallel experiment, nystatin was administered intravenously. For both groups, the lengthening of life expectancy was determined based on the untreated control (see tab.4).
    If we compare the doses of nystatin used as an orally complex with intravenous doses of nystatin, which cause approximately equal lengthening of life expectancy (Table 4), the last column, we can conclude that, from an average, the complex enters the bloodstream 6.2. % of biologically active substance. In the case of higher doses (intravenously 1.56 mg / kg, orally 25 mg / kg), the decrease in life expectancy is reduced to the weak toxicity of nystatin.
    b) Absorption of nystatin from the subcutaneously injected nystatin complex with
    j-cc
    Female CFI rats with an average weight of 180 g are treated with nystatin, nystatin c) -CZ complex (content of biologically active substance 8%) and) t -CZ. To this end, suspensions are prepared from the test substances using physiological sodium chloride solution containing tween 8 and injected. subcutaneously. The relationship between dose and mortality is presented in Table. five.
    Of the animals treated with the complex at a dose of 20 mg / kg, 90% die within 48 hours; of the animals treated with free nystatin at a dose of 150 mg / kg, none die during the week of observation. To control 10 animals, so much u-CD was injected subcutaneously to get 0
    five
    0
    five
    0
    five
    0
    five
    0
    five
    90% group with a complex (302 mg / kg). No animals died during the week of observation.
    From tab. 5, it can be seen that a toxic dose is absorbed from the nystatin complex with J-CD when subcutaneously administered, while subcutaneous administration of free nystatin is not absorbed or absorbed only to an insignificant extent.
    Absorbability was also investigated by measuring its blood level, since absorbed nystatin, which entered the bloodstream, is detected in the UV spectrum of blood serum. With subcutaneous administration of free nystatin with a dose of 200 mg / kg, nothing was detected in the blood, while the complex already at a dose of 20 mg / kg gives a well-measured blood level after: 2-4 hours after administration, 6- 10 μg / ml.
    Example 9. Reducing the hemolyzing effect of polyene antibiotics by complexing with y-CD.
    a) Nystatin complex with -1Sh, Hemolytic effect of nystatin, nystatin complex with y-CD (content of biologically active substance 8%) and) p-1SCH were studied on suspensions of red blood cells prepared from human blood by the method of T. Tru et al . (J. Pharm Dyn 6, 408-114, 1983). Results are indicated in the form of a relative 1xC to 50% hemolysis concentration (). The value obtained for free nystatin (EN 57 µg / ml) shows a coincidence with the known EHso value of 50 µg / ml (J. Antibiotus, 22, 1080-1081, 1979). For nisiatina complex with. -CD, based on the biologically active substance, the value of Eneb 115 µg / ml, i.e. Complex reduces the hemolyzing effect of nystatin in half. In the study of the concentrated dependence of the hemolytic effect, it is found that the nystatin c) g-CD complex up to a concentration of 70 µg / ml of nystatin practically does not act hemolytically, while free nystatin in this concentration causes already 70% hemolysis. Also
    investigated the hemolytic effect of the corresponding complex-bound amount (-CC of V-cyclodeistrin. It was found that X-CD, when it coincides with known data, up to a concentration of 1600 µg / ml, does not cause any hemolysis.
    b) Amphotericin B complex
    1-1Ч,
    The hemolytic effect of this complex (obtained according to example 5, the content of the biologically active substance is 0.6%) was investigated as indicated in p. A). For free amphotericin B, an EHj value of 4.8 µg / ml is given, which coincides with the known data (ЕН5о 5 µg / ml). The complex of amphotericin B and V-CD causes only 2-, 6% hemolysis in a 25 biogram / ml concentration calculated for a biologically active substance, while free amphotericin b in this concentration causes 92.4% hemolysis.
    Production of drugs containing complexes of the polyene antibiotic i) cyclodextrin and plant protection products.
    250 kg of the nystatin cY-cyclodextrin complex is supplemented with talc to 1 g (the complex has a biological activity of 400 U / mg).
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    A method for preparing polyene antibiotic complexes, α-cyclodextrin, characterized in that a practically insoluble polyene antibiotic, such as flavofungin, nystatin or A1 | 1tericin B, is reacted with dried (1 .5% water) J - cyclodextrin at a molar ratio of 1: (2.8-34.5), respectively, in an aqueous or aqueous-alcoholic medium, and the amount of water lies in the range of 1.6-409 ml / 1 mmol of the antibiotic with stirring at 20-50 C. IT a b and c
    100
    The remaining active substance, 100100
    100
    table 2
    Minimum inhibitory concentrations of € And (M1C) flavofungin with vitro
    Test organism
    M1C, mcg / ml
    co neoform cerevisiae albicans tropical crusce pseud tr.
    Yeast and yeast 5-10
    78 / К-16 ОК-1 1282 CBS 562 CBS 430 79 / К 47
    ten
    ten
    25
    10-25
    5-10
    Mushrooms Cryptococe Asperg niger CBS 12648
    Sacchar cerevisiae Asperg fumigatus
    Penicillium digitatum Penicillium chrysogen

    Sporotr, schenku
    Trichoph. rubrum
    Trichoph. mentagroph Trichoph (keratomyc a
    Epiderm.floccosum
    Microsp gypseum
    Microsp. persic
    Plant Fungal Fusarium moniliform DSM-IMB-11778 10-25
    Fusarium oxysporum
    DSM-IMB 10975 10-25
    burnt 5-10


    ten
    ten
    25
    10-25
    5-10
    25
    25 25 25-50
    25
    25
    25
    25
    25
    10-25
    25
    15
    VNIIPI Order 4870/59 Circulation 348
    Random polygons pr-tie, Uzhgorod, st. Project, 4
    142820816
    Table 3
    Table 4
    Table 5
    Subscription
    类似技术:
    公开号 | 公开日 | 专利标题
    DE2902297C2|1989-02-09|
    EP0078820B1|1987-12-09|Inclusion complexes of n-|-3,3-diphenylpropylamine respectively the hydrochloride thereof with cyclodextrin, a process for thepreparation of these inclusion complexes as well as pharmaceutical preparations containing these inclusion complexes
    DE3901527A1|1990-07-26|ALKYLATED POLYETHYLENE IMIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AS MEDICINAL PRODUCTS AND PHARMACEUTICAL PREPARATIONS
    SU1428208A3|1988-09-30|Method of producing complex of polyene antibiotic-gamma-cyclodextrin
    DE2239891C2|1983-03-03|Polyene macrolides substituted on the amino group of their amino sugar residue and their use
    EP0806955B1|2004-03-17|Enrofloxacine injection or infusion solutions
    DE2604481C2|1988-04-21|
    Aloisio et al.2014|Solubility and release modulation effect of sulfamerazine ternary complexes with cyclodextrins and meglumine
    DE2226338A1|1973-01-04|POLYENE MACROLIDE ANTIBIOTIC ACID ADDITION SALTS AND METHOD FOR THE PREPARATION OF THEIR ESTERS
    DD208549A5|1984-04-04|PROCESS FOR PREPARING GAMMA-CYCLODEXTRIN-INTEGRATED INCLUSION COMPOUNDS OF STEROID COMPOUNDS
    CN108752501B|2021-07-09|Organic acid salt-containing chitosan quaternary ammonium salt and preparation method and application thereof
    US20110046212A1|2011-02-24|Use of oleuropein and derivatives in the treatment of type 2 diabetes mellitus and pathologies associated with protein aggregation phenomena
    DE1768655B2|1974-03-07|
    DE2706156C3|1981-08-20|N, N, N-trimethyl derivatives of amphoteric, antifungal polyene antibiotics and processes for their preparation
    US3065138A|1962-11-20|Therapeutic preparations of elemental iron
    DE2803681C2|1989-03-16|
    BE897980A|1984-01-30|PROCESS FOR THE PREPARATION OF A SOLUTION FOR PHARMACEUTICAL USE CONTAINING A NEW MIXED POLYNUCLEAR IRON | COMPLEX AS ACTIVE INGREDIENT
    US3812099A|1974-05-21|Polymer derivative of 1-methyl-5/5-oxo-4-ethyl-tetrahydrofuryl-|-methyl/imidazole with cellulose glycolic acid
    Spinks1951|Estimation and photolability of some thiosemicarbazones
    DE1129148B|1962-05-10|Process for the production of heparin derivatives with cytostatic substances
    SU1685944A1|1991-10-23|Method for preparation of complex platinum | compound with high-molecular n-dna from spleen of cattle, grade a, showing anticarcinogenic activity
    WO2020009594A1|2020-01-09|A crystalline, zinc-free form of insulin glargine and the method of its preparation
    Haney1952|Browning reaction in baked products
    DE2760203C2|1986-07-24|Antibiotically active oligosaccharide, process for its production and medicinal product containing it
    EP1791528A1|2007-06-06|Lyophilisate containing n-diaminomethylene-2-methyl-4,5-di-|-benzamide
    同族专利:
    公开号 | 公开日
    EP0147851B1|1991-09-11|
    EP0147851A3|1986-12-30|
    HUT35172A|1985-06-28|
    JPS60158188A|1985-08-19|
    DE3485058D1|1991-10-17|
    HU196230B|1988-10-28|
    EP0147851A2|1985-07-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    RU2488590C2|2007-07-03|2013-07-27|Биосерген АС|Derivatives of nystatin and their application as antifungal agents|GB978170A|1961-08-04|1964-12-16|Koninklijke Gist Spiritus|Process for the preparation of water-soluble derivatives of polyene antibiotics|
    HU177081B|1978-12-12|1981-07-28|Chinoin Gyogyszer Es Vegyeszet|Process for preparing the occlusion complex of allicin with cyclodextrin|
    JPS57128610A|1981-02-02|1982-08-10|Sumitomo Chem Co Ltd|Stabilized agricultural and horticultural germicidal composition|
    HU190356B|1981-10-27|1986-08-28|Richter Gedeon Vegyeszeti Termekek Gyara Rt,Hu|Process for preparing steroid-gamma-cyclodextrin inclusion complexes with high water-solubility|
    JPH0336827B2|1982-04-12|1991-06-03|Takeda Chemical Industries Ltd|WO1989010739A1|1988-05-11|1989-11-16|Board Of Regents, The University Of Texas System|Hydroxyalkyl cyclodextrin-antifungal polyene antibiotics complexes|
    CA2044663A1|1990-07-12|1992-01-13|Makoto Tanaka|Water-dispersible polyene antifungal complexes|
    AT176155T|1990-11-16|1999-02-15|Nippon Shinyaku Co Ltd|INJECTABLE AMPHOTERICIN B DISPERSION|
    US5450603A|1992-12-18|1995-09-12|Xerox Corporation|SIMD architecture with transfer register or value source circuitry connected to bus|
    CA2553573A1|2004-01-29|2005-08-11|Eisai R & D Management Co., Ltd.|Method for stabilizing macrolide compound|
    CA2897483C|2013-01-31|2017-08-29|Pepsico, Inc.|Beverage preservative system based on pimaricin and headspace gas|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU834508A|HU196230B|1983-12-29|1983-12-29|Process for producing water-soluble forms of polyene antibiotics and pharmaceutics comprising such active ingredient and plant protective with antifungal effect|
    [返回顶部]