WO2006069386A1 - Method of purifying tacrolimus - Google Patents
Method of purifying tacrolimus Download PDFInfo
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- WO2006069386A1 WO2006069386A1 PCT/US2005/047264 US2005047264W WO2006069386A1 WO 2006069386 A1 WO2006069386 A1 WO 2006069386A1 US 2005047264 W US2005047264 W US 2005047264W WO 2006069386 A1 WO2006069386 A1 WO 2006069386A1
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- tacrolimus
- less
- hplc
- area percent
- bed
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
- B01J20/282—Porous sorbents
- B01J20/285—Porous sorbents based on polymers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/42—Selective adsorption, e.g. chromatography characterised by the development mode, e.g. by displacement or by elution
- B01D15/424—Elution mode
- B01D15/426—Specific type of solvent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/22—Eight-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/18—Eight-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
Definitions
- the present invention relates to pure tacrolimus and to a method of purifying the macrolide tacrolimus, using sorption resins.
- Macrolides are multi-membered lactone rings having one or more deoxy sugars as substituents.
- Tacrolimus FK 506
- FK 506 is a macrolide antibiotic that is also an immunosuppressive agent. More potent than cyclosporin, tacrolimus reportedly has a selective inhibitory effect on T-lymphocytes.
- Tacrolimus is typically obtained by fermentation. Tacrolimus, as obtained, typically contains several impurities that can be detected by various means, for example high-pressure liquid chromatography (HPLC).
- HPLC high-pressure liquid chromatography
- the presence of impurities in a pharmaceutical compound is undesirable, and health authorities in many jurisdictions, e.g. the Food and Drug Administration in the United States, have established guidelines relating to acceptable levels of impurities in pharmaceuticals.
- the need for, and commercial utility of, methods of reducing the level of impurities in any pharmaceutical are self-evident.
- PROGRAF® Tablets were analyzed and found to contain several impurities. The tablet impurity profile is summarized in table 1.
- the present invention is directed to tacrolimus having a total impurities content of less than about 0.50 area percent, and, preferably, less than about 0.16 area percent by HPLC.
- the present invention is directed to tacrolimus having less than about 0.06 area percent, and, preferably, less than about 0.02 area percent by HPLC of ascomycin.
- the present invention is directed to tacrolimus having less than about 0.07 area percent, and, preferably, less than about 0.05 area percent by HPLC of dihydrotacrolimus.
- the present invention is directed to tacrolimus having less than about 0.02 area percent by HPLC of the impurity RRT 1.19.
- the present invention is directed to tacrolimus having less than about 0.12 area percent, and, preferably, less than about 0.02 area percent by HPLC of the impurity RRT 0.60.
- the present invention is directed to tacrolimus having less than about 0.12 area percent, and, preferably, less than about 0.02 area percent by HPLC of the impurity RRT 0.83.
- the present invention is directed to tacrolimus having less than about 0.08 area percent, and, preferably, less than about 0.02 area percent by HPLC of the impurity RRT 1.45.
- the present invention is directed to tacrolimus having less than about 0.06 area percent, and, preferably, less than about 0.02 area percent by HPLC of any individual impurity.
- the present invention provides a method for purifying tacrolimus.
- the method comprises providing a loading charge of tacrolimus, loading the loading charge of the tacrolimus onto a bed of sorption resin, eluting the loading charge and bed with an eluent that contains THF and/or acetonitrile and water, to obtain an effluent, collecting the main fraction of the effluent, recovering the tacrolimus from the main fraction, crystallizing the tacrolimus and further recrystallizing it.
- the tacrolimus obtained in the above process has a level of impurities as described above.
- the tacrolimus can be from any source.
- the present invention relates to the tacrolimus prepared according to the method described above..
- ambient temperature refers to a temperature of about 0° to about 40°C, preferably of about 10° to about 35°C.
- reduced pressure refers to a pressure of less than about 760 mm Hg.
- anti-solvent refers to a substance, normally liquid at ambient temperature, in which tacrolimus is at best sparingly soluble.
- impurity relates to any compound having a retention time that differs from that of tacrolimus by at least the detection limit of the chromatography apparatus used to determine the retention time.
- the different retention time may be measured, for example, by the HPLC method described herein below.
- impurity RRT 1.19 relates to an impurity appearing at an RRT of about 1.19, in an HPLC chromatogram. This impurity is an isomer of tacrolimus.
- impurity RRT 0.60 relates to an impurity appearing at an RRT of about 0.60, in an HPLC chromatogram.
- impurity RRT 0.83 relates to an impurity appearing at an RRT of about 0.83, in an HPLC chromatogram.
- impurity RRT 1.45" relates to an impurity appearing at an RRT of about 1.45, in an HPLC chromatogram.
- ascomycin and dihydrotacrolimus refer to
- volume percent and “percent-by- volume” (vol-%) refer to a volume fraction calculated as follows (illustrated for species A):
- VO1-%A Wt A x PA / (Wt A x PA + Wt B x p B )
- Wt A and Wt ⁇ are the weights in grams of species A and B, respectively, and P A and P B are the densities, in g/ml. of species A and B, respectively.
- the present invention is directed to tacrolimus having a total impurities content of less than about 0.50 area percent, and, preferably, less than about 0.16 area percent by HPLC.
- the present invention is directed to tacrolimus having less than about 0.06 area percent, and, preferably, less than about 0.02 area percent by HPLC of ascomycin.
- the present invention is directed to tacrolimus having less than about 0.07 area percent, and, preferably, less than about 0.05 area percent by HPLC of dihydrotacrolimus.
- the present invention is directed to tacrolimus having less than about 0.02 area percent by HPLC of the impurity RRT 1.19.
- the present invention is directed to tacrolimus having less than about 0.12 area percent, and, preferably, less than about 0.02 area percent by HPLC of the impurity RRT 0.60.
- the present invention is directed to tacrolimus having less than about 0.12 area percent, and, preferably, less than about 0.02 area percent by HPLC of the impurity RJRT 0.83.
- the present invention is directed to tacrolimus having less than about 0.08 area percent, and, preferably, less than about 0.02 area percent by HPLC of the impurity RRT 1.45.
- the present invention is directed to tacrolimus having less than about 0.06 area percent, and, preferably, less than about 0.02 area percent by HPLC of any individual impurity.
- the present invention provides a method for purifying tacrolimus, i.e. reduction of the impurities content in tacrolimus.
- the method comprises providing a loading charge of tacrolimus, loading the loading charge of the tacrolimus onto a bed of sorption resin, eluting the loading charge and bed with an eluent that contains THF and/or acetonitrile and water to obtain an effluent, collecting the main fraction of the effluent, recovering the tacrolimus from the main fraction, crystallizing the tacrolimus and further recrystallizing it.
- the tacrolimus obtained in the above process has a level of impurities as described above.
- the tacrolimus can be from any source.
- sorption resins useful in the practice of the present invention are well-known in the art, and are preferably cross- linked, non-ionic styrene-divinyl benzene materials, which can be chemically modified.
- Acrylic-type sorption resins are also known.
- the sorption resins have highly porous structures, having surfaces that can absorb, and then desorb, various chemical species. The absorption and desorption are influenced by the environment, for example the solvent used. In the presence of polar solvents (e.g.
- the sorption resins exhibit hydrophobic behavior.
- non-polar solvents e.g. hydrocarbons
- the sorption resins can exhibit some polar behavior.
- sorption resins have a macroreticular structure, and have surface areas of at least about 300 m 2 /g.
- Sorption resins useful in the practice of the present invention include the
- AMBERLITE® XAD resins available from Rohm and Haas; XAD 4, XAD 7 HP, XAD 16 HP, XAD 761, and XAD 1180, to mention just a few. Also useful are the Diaion sorption resins available from Mitsubishi; HP 10, HP 20, HP 21, HP 30, HP 40, HP 50, SP 800, SP 825, SP 850, SP 875, SP 205, SP 206, SP 207, HPlMG and HP2MG, to mention just a few.
- AMBERLITE® XAD 1180 is an example of a preferred sorption resin for use in the practice of the present invention.
- AMBERLITE® XAD 1180 is a macroreticular cross-linked aromatic polymer.
- the loading charge can be provided as a solution of the tacrolimus in an organic solvent, or in an organic solvent combined with water, or as tacrolimus-loaded loading portion that is a tacrolimus which is adsorbed onto a loading portion of sorption resin.
- the adsorption includes preparing a solution of the tacrolimus in an organic solvent, optionally containing water and combining the solution with a portion of sorption resin and water.
- the sorption resin can be the same as that used to prepare the bed, or it can be a different sorption resin.
- the loading portion of sorption resin can be about 33 percent to about 50 percent the volume of the bed.
- the organic solvent used to prepare the solution from which the loading charge is loaded or deposited is preferably selected from the group consisting of tetrahydrofuran (THF), acetone, acetonitrile (ACN), methanol, ethanol, n-butanol, n-propanol, iso-propanol, esters (e.g. ethyl acetate), and dipolar aprotic solvents, such as dimethylformamide (DMF). More preferably, the organic solvent is THF, acetone or ACN, and, most preferably, THF and ACN.
- the combination of the loading charge of the tacrolimus solution, loading portion of sorption resin, and water can be in any convenient vessel equipped with an agitator (e.g. a stirred tank reactor).
- an agitator e.g. a stirred tank reactor.
- the loading charge of the tacrolimus solution can be about 100 g/1, and the volume of water can be at least about five times the volume of solution.
- the bulk volume of the loading portion of sorption resin can be approximately equal to the volume of solution. The skilled artisan will know to optimize the proportions by routine experimentation to obtain adsorption of the tacrolimus on the loading portion of the sorption resin.
- the now tacrolimus-loaded loading portion is juxtaposed to a prepared bed of wet sorption resin.
- the bed is confined in a suitable vessel.
- the bed is confined within a column, preferably of circular cross-section.
- the desired amount of sorption resin is slurried with water or a mixture of water and a solvent (e.g. THF or ACN).
- a solvent e.g. THF or ACN
- the separation of tacrolimus and impurities is done by passing an eluent through the loading charge and subsequently through the bed of sorption resin juxtaposed thereto and in fluid communication therewith.
- the eluent comprises an additional organic solvent selected from the group of solvents that are used for dissolving the tacrolimus in the first step of the process.
- the loading charge is provided as a solution of the tacrolimus in an organic solvent, or in an organic solvent combined with water
- the solution is injected into the prepared bed of wet sorption resin, the column is contacted with the flow of tacrolimus solution, the eluent is introduced into the stream of solution flowing through and around the loading portion of sorption resin, whereby the tacrolimus sample is gradually adsorbed onto the loading portion of sorption resin.
- the bed may be placed in fluid communication with a second bed so that effluent from the first bed elutes through the second bed.
- the second bed may be, and, preferably, is decoupled from the first bed (i.e. fluid communication is broken) and elution is continued through the second bed alone.
- the eluent is a mixture of THF and water having about 33 volume percent to 37.
- the eluent fractions may be collected and diluted with water, and thereafter may pass threw a third bed (column).
- additional columns may be connected to the system and are diluted with additional amount of water in order to obtain a purer product.
- additional amount of water is added to the last column in order to increase the adsorption of tacrolimus onto the sorption resin.
- the eluent includes water and an organic solvent, such as THF, can and mixtures thereof.
- a preferred eluent is essentially a mixture of THF and water having about 20 volume percent to about 50 volume percent, most preferably about 31 volume percent to about 40 volume percent, THF.
- an organic solvent such as methanol, acetonitrile, acetone, or n-butanol
- the THF content is less than 38 volume percent, preferably between about 4 and about 38 volume percent.
- Another preferred eluent is a mixture of acetonitrile and water having about 30 volume percent to about 70 volume percent, most preferably about 40 volume percent to about 65 volume percent, acetonitrile.
- the eluent when the eluent is a mixture of acetonitrile and water, the eluent can also include about 0.0005 to about 0.003 parts phosphoric acid to 1 part eluent.
- the eluent is eluted through the loading charge and bed of sorption resin juxtaposed thereto at a rate that depends on the gross cross-sectional area of the bed (measured perpendicular to the flow of eluent).
- the flow rate (relative to the cross-sectional area) is less than about 25 cm/hour, preferably less than about 15 cm/hour.
- Lower elution rates increase the time, but improve the separation efficiency.
- a preferred elution rate for increased separation efficiency is about 9 cm/hour to about 11 cm/hour.
- the content and composition of the eluted fractions can be monitored by any convenient means. Detection and quantification of impurities in tacrolimus, in particular ascomycin and dihydrotacrolimus, can be carried-out by the hereinbelow described HPLC method.
- the main fraction is collected, so that the final isolated product has about 0.1 area percent or less by HPLC of ascomycin.
- the tacrolimus separated from impurities and therefore having a reduced level of impurities can be isolated from effluent by any conventional means (e.g. extraction, lyophilization, evaporation, addition of anti-solvent).
- Water, alkanes and cycloalkanes are useful anti-solvents, and others are known in the art. Isolation methods can be combined. For example anti-solvent can be combined with concentrated eluent.
- a preferred method of isolation includes concentration of the main fraction at 70°C or less, preferably 60°C or less, preferably at pressure of 760 mm Hg or less, to about 50 percent of its initial volume, whereby concentrated tacrolimus fraction is obtained.
- Phosphoric acid about 1 to about 10 ml per liter of eluent is preferably added before concentration to stabilize the tacrolimus.
- the concentrated main fraction is maintained at ambient temperature for a holding time.
- a holding time is about 1-4 days.
- Water immiscible solvent such as ethyl acetate or dichloromethane
- a base such as ammonia solution
- the base is added until the pH is of about 9 or less.
- Crystallization of the oily residue of tacrolimus comprises dissolving the oily residue of tacrolimus in ethyl acetate and cyclohexane, adding water to induce crystallization of tacrolimus and recovering the crystallized tacrolimus.
- the oily residue is diluted with ethyl acetate and concentrated again to oily residue.
- the water is added drop-wise.
- the water:tacrolimus ratio is 0.015 kg to 0.3 kg water to 1 kg tacrolimus in the crystallization process.
- Recrystallization of tacrolimus comprises dissolving the tacrolimus in ethyl acetate, concentrating the solution until obtaining an oily residue, dissolving the oily residue in ethyl acetate, adding cyclohexane to the solution, adding water to induce crystallization of tacrolimus and recovering the crystallized tacrolimus.
- dissolution and concentration steps may be repeated.
- the solution is treated with charcoal in order to remove the color and fibers. Concentration is as described above.
- the obtained tacrolimus is further dried.
- the method includes the steps of: preparing a loading charge of tacrolimus comprising a solution of tacrolimus with or without a loading portion of a sorption resin, especially a macroreticular resin, such as AMBERLITE® XAD 1180 and Diaion HP 20; loading the loading charge to wet sorption resin, especially AMBERLITE® XAD 1180 and Diaion HP 20, that can be contained in a vessel, especially a column; eluting the loading portion and sorption resin with an eluent that is a mixture of tetrahydrofuran (THF) and water, about 20 volume percent to about 50 volume percent, especially about 31 volume percent to about 40 volume percent THF, or a mixture of acetonitrile (ACN) and water, about 30 volume percent to about 70 volume percent and
- THF tetrahydrofuran
- ACN acetonitrile
- the obtained tacrolimus has less than 0.50 area percent, most preferably, less than 0.16 area percent by HPLC of total impurities content.
- the obtained tacrolimus has less than about 0.06 area percent, most preferably, less than about 0.02 area percent by HPLC of ascomycin.
- the obtained tacrolimus has less than about 0.07 area percent, most preferably, less than about 0.05 area percent by HPLC of dihydrotacrolimus.
- the obtained tacrolimus has less than about 0.02 area percent by HPLC of the impurity RRT 1.19.
- the obtained tacrolimus has less than about 0.12 area percent, most preferably, less than about 0.02 area percent by HPLC of the impurity RRT 0.60.
- the obtained tacrolimus has less than about 0.12 area percent, most preferably, less than about 0.02 area percent by HPLC of the impurity RRT 0.83.
- the obtained tacrolimus has less than about 0.08 area percent, most preferably, less than about 0.02 area percent by HPLC of the impurity RRT 1.45.
- the obtained tacrolimus has less than about 0.06 area percent, most preferably, less than about 0.02 area percent by HPLC of any individual impurity.
- the present invention provides the tacrolimus obtained by the above process. Chromatofiraphic conditions used for examples
- Eluent A: Measure 200 ml of acetonitrile into a 2000 ml volumetric flask, then dilute to volume with distilled water to 2000 ml total volume.
- Quantification Limit less than 0.02 area percent.
- Retention times of impurities ascomycin (RRT 0.95), dihydrotacrolimus (RRT 1.25) and the impurity RRT 1.19 are relative to tacrolimus and expressed as an area percent relative to the area of all peaks in the chromatogram.
- the detection and quantification limits for typical HPLC equipment available at present are less than 0.01 area percent and less than 0.02 area percent, respectively.
- a tacrolimus starting material was purified by chromatography and several crystallization steps. The purity analysis was conducted using the analytical HPLC method described above under "Chromatographic conditions used for examples.”
- the starting material contained 0.16 area percent ascomycin, 1.56 area percent of the impurity RRT 1.19, and 0.46 area percent dihydrotacrolimus.
- An assay of the starting substance gave a purity of 95 percent by mass.
- the final product contained 0.02 area percent ascomycin, 0.02 area percent of the impurity RRT 1.19, and 0.05 area percent dihydrotacrolimus. The amount of any other impurity present was no more than 0.02 area percent, and the purity of the tacrolimus obtained with the method of the invention was 99.84 area percent.
- AMBERLITE® XAD 1180 sorption resin was used for the chromatography. Three chromatography columns (40 cm diameter, 1 m column height, and ca. 100 liters wet sorption resin) were prepared. The tacrolimus starting material in an amount of 3812g, where 3623 g was active substance, was dissolved in 30 liters of acetone. The resin AMBERLITE® XAD 1180 in an amount of 33 liters was added to the tacrolimus solution. Water in an amount of 180 liters was slowly added, with agitation to the tacrolimus solution:resin mixture. When the addition of water was complete, the loading charge of sorption resin was collected by filtration.
- the collected loading charge was loaded as a layer on the top of the bed of wet sorption resin.
- the total resin volume was ca. 100 liters.
- the column was first eluted with ca. 700 liters of eluent of tetrahydrofuran/water (34 vol -% THF). After the first elution, a second column was connected to the first column. The elution was continued with ca. 1400 liters of eluent of THF/water (34 vol -% THF). The first column was disconnected from the second column, and the elution was continued with ca. 1200 liters of eluent of THF/water (34 vol -% THF).
- preliminary fractions may be combined, e.g., 10 ml from each appropriate fraction, and analyzed with HPLC analysis. If the HPLC analysis of the preliminary combination results in higher than a 0.02 area percent ascomycin concentration and/or higher than a 0.04 area percent dihydrotacrolimus concentration, the number of combined fractions should be modified to provide the desired high purity, as obtaining the desires high purity during the combination of the fractions will provide a high purity final yield.
- the combined main fraction (ca. 500 liters) was mixed with 100 ml of 85 percent phosphoric acid, and concentrated at reduced pressure to a volume of about 200 liters.
- the concentrate was cooled to ambient temperature, and 50 liters of water, 100 liters of ethyl acetate, and 200 ml of concentrated ammonia solution were added to the concentrate.
- the ethyl acetate phase (ca. 75 liters) was separated, and concentrated under reduced pressure to oily residue.
- the oily residue was diluted with 10 liters of ethyl acetate, and concentrated again to an oily residue under reduced pressure.
- the heating temperature was ca. 6O 0 C, and the estimated boiling temperature was 20-40°C.
- the dilution-concentration step was repeated twice.
- the solid content of oily residue was established by evaporation of a small amount of sample under reduced pressure, resulting in a solids content of 1329 g for the oily residue.
- the oily residue was diluted with ethyl acetate to ca. 2525 g, and 7970 ml cyclohexane was added to the solution.
- the temperature was maintained at 25°C using a temperature circulator.
- Tacrolimus in an amount of 1250 g was dissolved in 7.5 liters of ethyl acetate.
- the solution was concentrated to an oily residue under reduced pressure.
- the dissolution-concentration step was repeated twice.
- the oily residue was dissolved in 3750 ml ethyl acetate, and treated with 12.5 g of charcoal.
- the charcoal treatment was carried out at 30 0 C for 30 minutes.
- the suspension was filtered, and the filter cake was washed with 125 ml ethyl acetate.
- the filtered solution was concentrated under reduced pressure, and diluted with ethyl acetate to 2375 g.
- Cyclohexane in an amount of 6.25 liters was added to the tacrolimus solution for 1.5 hours. Water in an amount of 27.5 ml was added to the solution for 2 hours. Water in an amount of 246 ml was added to the solution for 2 hours, initiating crystallization.
- the suspension was cooled to 8°C, and cyclohexane in an amount of 1.25 liters was added to the suspension for 1 hour at 8°C. Then, the suspension was stirred at 8°C for 12 hours. The crystals were filtered, and suspended twice with cyclohexane. The volume of cyclohexane used for the suspensions was 2.5 liters.
- Drying was carried out under reduced pressure at 40°C for 12 hours, and at ca. 25°C for 24 hours. A nitrogen inlet was used during the whole drying process.
- the crystallization steps efficiently reduce the impurity RRT 1.19 content of the product.
- the mass of the final product was 1180 g.
- the purity of the obtained tacrolimus was 99.84 area percent by HPLC, i.e.: total impurity content of 0.16 area percent by HPLC.
- the final product contained: 0.02 area percent by HPLC of ascomycin, 0.05 area percent by HPLC of dihydrotacrolimus and 0.02 area percent by HPLC of the impurity RRT 1.19, 0.02 area percent by HPLC of the RRT 0.83, less than 0.02 area percent by HPLC of the RRT 0.60, less than 0.02 area percent by HPLC of the RRT 1.45, 0.02 area percent by HPLC of the RRT 0.25 and less than 0.02 area percent by HPLC of any individual impurity.
- the impurity profile is summarized in table 2. Table 2
- one or more additional crystallization steps may be performed to remove the impurity.
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Abstract
Description
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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JP2006554356A JP2007523201A (en) | 2004-12-22 | 2005-12-22 | Method for purifying tacrolimus |
MX2007005868A MX2007005868A (en) | 2004-12-22 | 2005-12-22 | Method of purifying tacrolimus. |
EP05855772A EP1828205A1 (en) | 2004-12-22 | 2005-12-22 | Method of purifying tacrolimus |
CA002586700A CA2586700A1 (en) | 2004-12-22 | 2005-12-22 | Method of purifying tacrolimus |
IL183241A IL183241A0 (en) | 2004-12-22 | 2007-05-15 | Method for purifying tacrolimus |
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US63862804P | 2004-12-22 | 2004-12-22 | |
US60/638,628 | 2004-12-22 | ||
US63881504P | 2004-12-23 | 2004-12-23 | |
US60/638,815 | 2004-12-23 |
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WO2006069386A1 true WO2006069386A1 (en) | 2006-06-29 |
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PCT/US2005/046856 WO2006069333A1 (en) | 2004-12-22 | 2005-12-22 | Method of purifying macrolides |
PCT/US2005/047264 WO2006069386A1 (en) | 2004-12-22 | 2005-12-22 | Method of purifying tacrolimus |
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EP (2) | EP1828204A1 (en) |
JP (2) | JP2007523201A (en) |
CA (2) | CA2586700A1 (en) |
IL (2) | IL183240A0 (en) |
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WO2008059516A2 (en) * | 2006-08-21 | 2008-05-22 | Concord Biotech Limited | Process for purification of macrolides |
WO2008065887A1 (en) * | 2006-11-27 | 2008-06-05 | Terumo Kabushiki Kaisha | Process for producing o-alkylated rapamycin derivative, and o-alkylated rapamycin derivative |
KR101003042B1 (en) * | 2008-03-17 | 2010-12-21 | 종근당바이오 주식회사 | Method for refining of high purity of Tacrolimus |
GB201020032D0 (en) * | 2010-11-25 | 2011-01-12 | Sigmoid Pharma Ltd | Composition |
KR101344012B1 (en) | 2012-04-09 | 2013-12-23 | 인하대학교 산학협력단 | Separation method of tacrolimus and ascomycin using simulated moving bed chromatography |
CN103554133B (en) * | 2013-10-31 | 2015-06-24 | 国药集团川抗制药有限公司 | Technology for preparing high-purity tacrolimus |
CN105301159B (en) * | 2015-10-29 | 2017-01-18 | 无锡福祈制药有限公司 | High performance liquid chromatography analysis method of sirolimus |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030168409A1 (en) * | 1999-09-08 | 2003-09-11 | Fujisawa Pharmaceutical Co., Ltd. | Method for separating lactone-containing high-molecular weight compounds |
WO2005010015A1 (en) * | 2003-07-24 | 2005-02-03 | Teva Gyogyszergyar Reszvenytarsasag | Method of purifying macrolides |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3244592A (en) * | 1962-06-09 | 1966-04-05 | Arai Tadashi | Ascomycin and process for its production |
US3993749A (en) * | 1974-04-12 | 1976-11-23 | Ayerst Mckenna And Harrison Ltd. | Rapamycin and process of preparation |
US4160861A (en) * | 1977-10-03 | 1979-07-10 | Merck & Co., Inc. | Method for the separation of antibiotic macrolides |
US4894366A (en) * | 1984-12-03 | 1990-01-16 | Fujisawa Pharmaceutical Company, Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
US5182207A (en) * | 1984-09-14 | 1993-01-26 | American Cyanamid Company | Strains of streptomyces thermoarchaensis |
US4874843A (en) * | 1987-12-03 | 1989-10-17 | Eli Lilly And Company | Chromatographic purification process |
JP2639737B2 (en) * | 1990-01-23 | 1997-08-13 | 寳酒造株式会社 | New R106 compounds |
US5194378A (en) * | 1991-01-28 | 1993-03-16 | Merck & Co., Inc. | Process for producing fk-506 |
US5116756A (en) * | 1991-01-28 | 1992-05-26 | Merck & Co., Inc. | Process for producing FK-506 |
US5091389A (en) * | 1991-04-23 | 1992-02-25 | Merck & Co., Inc. | Lipophilic macrolide useful as an immunosuppressant |
US5227295A (en) * | 1991-11-08 | 1993-07-13 | Dowelanco | Process for isolating A83543 and its components |
CA2132457C (en) * | 1992-03-02 | 1998-06-16 | Kevin Koch | Fluorosugar derivatives of macrolides |
JPH07500613A (en) * | 1992-03-02 | 1995-01-19 | ファイザー・インコーポレーテッド | Desosamin derivatives of macrolides as immunosuppressive and antifungal agents |
US5264355A (en) * | 1992-07-02 | 1993-11-23 | Merck & Co., Inc. | Methlating enzyme from streptomyces MA6858 |
UA41884C2 (en) * | 1993-11-05 | 2001-10-15 | Амерікан Хоум Продактс Корпорейшн | method for the isolation of rapacimin from acid, basic and non polar neutral admixtures being present in the concentrate of extract of fermentation broth of mother liquors |
US5622866A (en) * | 1994-06-23 | 1997-04-22 | Merck & Co., Inc. | Expression cassettes useful in construction of integrative and replicative expression vectors for Streptomyces |
GB9618952D0 (en) * | 1996-09-11 | 1996-10-23 | Sandoz Ltd | Process |
US5616595A (en) * | 1995-06-07 | 1997-04-01 | Abbott Laboratories | Process for recovering water insoluble compounds from a fermentation broth |
DE69934242T2 (en) * | 1998-10-02 | 2007-09-20 | Kosan Biosciences, Inc., Hayward | POLYCETIDE SYNTHASE ENZYME AND RECOMBINANT DNA CONSTRUCTS THEREOF FOR THE PREPARATION OF COMPOUNDS RELATED TO FK-506 AND FK-520 |
WO2000023070A1 (en) * | 1998-10-20 | 2000-04-27 | Ben Venue Laboratories, Inc. | Process for purification of solvents useful in the preparation of pharmaceutical compositions |
ID28381A (en) * | 1998-11-09 | 2001-05-17 | Aventis Pharma Deutscland Gmbh | VANKORESMISIN, A PROCESS TO PRODUCE IT AND USE IT AS A MEDICINE |
DE60013434T2 (en) * | 1999-05-25 | 2005-01-20 | Fujisawa Pharmaceutical Co., Ltd. | METHOD FOR SEPARATING ANALOG ORGANIC COMPOUNDS |
AU3654301A (en) * | 2000-02-24 | 2001-09-03 | Biogal Gyogyszergyar | Method of purifying a fermentation broth |
EP1474404A4 (en) * | 2002-02-13 | 2006-01-11 | Biogal Gyogyszergyar | Method for extracting a macrolide from biomatter |
-
2005
- 2005-12-22 WO PCT/US2005/046856 patent/WO2006069333A1/en active Application Filing
- 2005-12-22 US US11/317,152 patent/US20060149057A1/en not_active Abandoned
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- 2005-12-22 JP JP2006554356A patent/JP2007523201A/en active Pending
- 2005-12-22 JP JP2006554355A patent/JP2007523200A/en active Pending
- 2005-12-22 CA CA002586700A patent/CA2586700A1/en not_active Abandoned
- 2005-12-22 WO PCT/US2005/047264 patent/WO2006069386A1/en active Application Filing
- 2005-12-22 CA CA002586692A patent/CA2586692A1/en not_active Abandoned
- 2005-12-22 EP EP05855421A patent/EP1828204A1/en not_active Withdrawn
- 2005-12-22 TW TW094145958A patent/TW200637834A/en unknown
- 2005-12-22 US US11/317,155 patent/US20060142565A1/en not_active Abandoned
- 2005-12-22 TW TW094145959A patent/TW200637835A/en unknown
- 2005-12-22 MX MX2007005868A patent/MX2007005868A/en not_active Application Discontinuation
- 2005-12-22 EP EP05855772A patent/EP1828205A1/en not_active Withdrawn
-
2007
- 2007-05-15 IL IL183240A patent/IL183240A0/en unknown
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030168409A1 (en) * | 1999-09-08 | 2003-09-11 | Fujisawa Pharmaceutical Co., Ltd. | Method for separating lactone-containing high-molecular weight compounds |
WO2005010015A1 (en) * | 2003-07-24 | 2005-02-03 | Teva Gyogyszergyar Reszvenytarsasag | Method of purifying macrolides |
Non-Patent Citations (3)
Title |
---|
CHRISTIANS U ET AL: "SPECIFIC AND SENSITIVE MEASUREMENT OF FK506 AND ITS METABOLITES IN BLOOD AND URINE OF LIVER-GRAFT RECIPIENTS", CLINICAL CHEMISTRY, AMERICAN ASSOCIATION FOR CLINICAL CHEMISTRY, WASHINGTON, DC, US, vol. 38, no. 10, 1 October 1992 (1992-10-01), pages 2025 - 2032, XP000371776, ISSN: 0009-9147 * |
IWASAKI K ET AL: "ISOLATION, IDENTIFICATION, AND BIOLOGICAL ACTIVITIES OF OXIDATIVE METABOLITES OF FK506, A POTENT IMMUNOSUPPRESSIVE MACROLIDE LACTONE", DRUG METABOLISM AND DISPOSITION, WILLIAMS AND WILKINS., BALTIMORE, MD, US, vol. 21, no. 6, November 1993 (1993-11-01), pages 971 - 977, XP000973280, ISSN: 0090-9556 * |
KINO T ET AL: "FK-506, A NOVEL IMMUNOSUPPRESSANT ISOLATED FROM A STREPTOMYCES", JOURNAL OF ANTIBIOTICS, JAPAN ANTIBIOTICS RESEARCH ASSOCIATION, TOKYO, JP, vol. 40, no. 9, September 1987 (1987-09-01), pages 1249 - 1255, XP002057758, ISSN: 0021-8820 * |
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EP1828205A1 (en) | 2007-09-05 |
CA2586700A1 (en) | 2006-06-29 |
MX2007005867A (en) | 2007-07-04 |
IL183240A0 (en) | 2007-08-19 |
TW200637835A (en) | 2006-11-01 |
CA2586692A1 (en) | 2006-06-29 |
JP2007523200A (en) | 2007-08-16 |
US20060149057A1 (en) | 2006-07-06 |
JP2007523201A (en) | 2007-08-16 |
EP1828204A1 (en) | 2007-09-05 |
WO2006069333A1 (en) | 2006-06-29 |
US20060142565A1 (en) | 2006-06-29 |
IL183241A0 (en) | 2007-08-19 |
MX2007005868A (en) | 2007-07-04 |
TW200637834A (en) | 2006-11-01 |
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