Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2002-04-26
2003-11-18
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S017200, C536S018700, C536S055300
Reexamination Certificate
active
06649755
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates in general to a process for preparing acarbose with high purity useful as medicine for the treatment of diabetes. More particularly, it relates to a process for preparing acarbose with high purity represented by the formula (I), which comprises prepurifying an acarbose-containing solution using a synthetic adsorbent to produce a prepurified acarbose having an acarbose content of a predetermined level or more; and contacting the prepurified acarbose with a monodispersed, strong acid cation exchanger, in one step, to adsorb acarbose.
2. Description of the Prior Art
Acarbose as a glucosidase inhibitor reduces the glucose level in human blood by delaying the absorption of glucose in the human small intestine and thus widely used in medicine for the treatment of diabetes. The inhibitor is obtained by fermentation of Actinoplanes species (see German Patent No. 2,209,832; German Patent No. 2,209,834; and German Patent No. 2,064,092). Many methods for isolating acarbose from this fermentation broth are known in the art.
As disclosed in U.S. Pat. No. 4,062,950, the fermentation broth containing acarbose is centrifuged and the resulting supernatant is decolorized with active charcoal or nonspecific adsorption resins under acid condition, and adsorbed onto active charcoal under neutral condition to separate off ionic materials. After the adsorbed material is eluted with an alcoholic solution or an acetone-containing solution under acidic condition, the eluate is bound to a strong acid cation exchanger or a weak acid cation exchanger. The resulting exchanger is then eluted with an acidic or basic aqueous solution. The eluted solution is then neutralized with an ion exchanger resin and concentrated in vacuo. Then, the concentrate is lyophilized or crystallized by precipitation in organic solvents. At this time, the content of acarbose is 85% in the dry matter(by HPLC method). To prepare acarbose in the more pure state, the crystalline acarbose is then redissolved in distilled water and chromatographed on an ion exchanger resin using cellulose as a substrate. Then, the resulting active fractions are collected and concentrated, followed by lyophilization or precipitation in organic solvents. However, the method disclosed in the latter patent is disadvantageous in that it includes the use of active charcoal and the use of expensive ion exchangers in several steps and thus involves a complicated process and a large economical burden.
Meanwhile, as disclosed in U.S. Pat. No. 4,174,439, the fermentation broth containing mycelium is introduced with the strong acid cation exchanger and the anion exchanger to adsorb acarbose on the exchangers. The mixed ion exchange resin is then separated off from the mycelium by a sieve screw. The mixed ion exchange resin is rinsed with distilled water, and introduced into a first column. Then, the acarbose mixture adsorbed on the column is eluted with a diluted hydrochloric acid. The resulting eluate is passed through a second column whose lower layer portion is packed with an anion exchanger and whose upper layer portion is packed with a highly crosslinked, strong acid cation exchanger. The eluate from the second column is further adsorbed on a strong acid cation exchanger which is then rinsed with a small amount of distilled water. The cation exchanger is fractionally eluted with a diluted hydrochloric acid. The active fractions are neutralized with an anion exchanger, concentrated in vacuo, sterilized by filtration and freeze-dried or spray-dried to afford acarbose at a yield of 52% to 58% in the dry matter.
Meanwhile, as disclosed in U.S. Pat. Nos. 4,666,776 and 4,767,850, the acarbose-containing eluate recovered from the steps 1-5 of U.S. Pat. No. 4,174,439 is adsorbed on a strong acid cation exchanger which is then rinsed with a small amount of distilled water. The resulting eluate is chromatographed using a diluted hydrochloric acid. Then, the active fractions are neutralized with an anion exchanger and lyophilized to give acarbose at an interval yield of 79 to 82%. The obtained acarbose is 78 to 88% pure (by HPLC method).
The prior purification methods as described above utilize complex process in which a step using a combination of the cation exchanger and the anion exchanger is repeatedly performed and a chromatographic step using the cation exchanger is further conducted. Nevertheless, acarbose purified according to these prior methods show an acarbose content unsuitable for use in human medicine.
U.S. Pat. No. 4,904,769 discloses a method of preparing highly pure acarbose from an acarbose-containing solution prepurified according to known methods. The disclosed method utilizes as packing material an expensive, weak acid cation exchanger which has carboxyl groups and is based on dextran, agarose and cellulose. Also, this method maintains the pH of equilibration of the packing material and the constant temperature during the chromatography. This method provide acarbose having a content of not less than 90% by weight at an interval yield of 82% or more. However, this method is disadvantageously more complex in purification process by using the acarbose-containing solution prepurified according to the known methods and further using the weak acid cation exchanger. In addition, this method disadvantageously involves a large economical burden due to the use of the expensive ion exchanger.
PCT Publication WO 99/07720 discloses a method which includes prepurifying an acarbose in fermentation broth by methods discribed in U.S. Pat. Nos. 4,062,950, 4,767,850 and 4,904,769 and then recovering acarbose having a content of not less than 98% using a non-aromatic, strong acid cation exchanger. However, such a method is likewise complex in purification process since it utilizes an acarbose-containing solution prepurified according to the known technologies. Also, this method involves a high economical burden upon its industrial application as it utilizes the expensive, non-aromatic strong acid cation exchanger.
SUMMARY OF THE INVENTION
We have conducted a study on purification method in an attempt to overcome problems of the process complexity and thus the large economical burden. As a result, we have found that an acarbose-containing solution is prepurified using a synthetic adsorbent to obtain a prepurified acarbose having a content of a predetermined level or more, and then highly pure acarbose useful as medicine for the treatment of diabetes is recovered from the prepurified acarbose with only a monodispersed, strong acid cation exchanger, instead of the use of an expensive, weak acid cation exchanger. On the basis of this discovery, we have completed the present invention.
The present invention is a method capable of omitting the use of active charcoal and the five to six steps-exchanger resin process as carried out in the prior method. This method produces highly pure acarbose by prepurifying an acarbose-containing solution with a synthetic adsorbent and then contacting the prepurified acarbose with a monodispersed, strong acid cation exchanger, in one step, to adsorb acarbose.
Generally, due to cation materials other than acarbose present in a filtrate obtained by filtration of mycelium from a fermentation broth, the adsorption of acarbose to a cation exchanger does not easily occur. For this reason, instead of the use of active charcoal and a large amount of ion exchangers as in the prior, the method of the present invention utilizes a synthetic adsorbent to remove coloring materials and impurities other than acarbose and analogues thereof in an acarbose-containg solution. The synthetic adsorbent used in the method of the present invention is selected from the group consisting of a highly porous styrene polymer, a highly porous styrene polymer having bromine chemically bound thereto, a highly porous styrene/divinyl polymer, a crosslinked macroporous aliphatic polymer, a crosslinked macroporous aromatic polymer, a metacrylic acid-based synthetic adsorbent, a carbonaceous syn
Choi Byoung Taik
Choi Gang Sun
Choi Yong Rack
Hong Chung Il
Kim Kyung Hwan
Chong Kun Dang Pharmaceutical Corp.
Krishnan Ganapathy
Webb Ziesenheim & Logsdon Orkin & Hanson, P.C.
Wilson James O.
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