Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
2002-03-04
2004-01-20
Carr, Deborah D. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
C554S080000, C514S114000
Reexamination Certificate
active
06679822
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel and useful polyalkylene oxide-modified phospholipid, the production method thereof, and the uses thereof, and particularly to a polyalkylene oxide-modified phospholipid, which can be used for the modification or the emulsification of a physiologically active substance or for a drug delivery system such as liposome, etc., the production method and the uses thereof.
2. Description of the Related Art
Recently, the investigations of liposome preparations such as an anticancer agent, etc., have been widely carried out and for the purpose of improving the retentivity thereof in blood, the water-soluble high molecular modification of liposome has been actively carried out. As one of the modifications, liposome-modified polyethylene oxide-modified phospholipids have been used. Since they are used for medicines, it is preferred that they contain impurities as less as possible or they contain no impurities.
In the synthesis reaction of a liposome-modified polyethylene oxide-modified phospholipid, a base containing nitrogen, such as triethylamine, etc., is frequently used as the catalyst. In this case, for removing the base excessively existing after the reaction, it is necessary to make the system acidic. However, during the process, the deterioration of the liposome-modified polyethylene oxide-modified phospholipid occurs and it is difficult to obtain a high-pure product.
Also, a base containing nitrogen, such as triethylamine, etc., frequently has an ammonia smell or a specific smell. Thus, it is desirable that such a base is not used for working environment.
Synthetic methods of polyethylene oxide-modified phospholipids are reported by M. C. Woodle (Biochimica et Biophysica Acta, 1105, 193-200(1992)) and S. Zalipsky (Bioconjugate Chem., 4, 296-299(1994)). Practically, they report a method of, after activating the terminal of polyethylene glycol using 1,1′-carbonyl diimidazole or disuccinimidyl carbonate in an organic solvent, the activated terminal of polyethylene glycol is reacted with a phospholipid in the presence of a base such as triethylamine, etc., and thereafter, the product is purified by a reversed-phase silica gel chromatography, etc., to obtained a polyethylene oxide-modified phospholipid.
In the method, immediately after the reaction, for removing the base such as triethylamine excessively existing, the system is similarly made acidic. In the case, monoacyl phospholipid (generally, is called lysophospholipid) is formed. The monoacyl phospholipid has a strong biotoxicity and it gives a problem in the case of using medicines, for example, in the case of being utilized as a drug delivery system.
Also, when after synthesis, a reversed-phase silica gel chromatography or a dialysis is carried out in a purification process, at emerging from the column in the chromatography, the product is deteriorated (the formation of the above-described monoacyl phospholipid, etc.) and during the dialysis, there occurs a problem that the product is hydrolyzed. Accordingly, in such related art methods, it is difficult to obtained high-pure products, which is also a problem from an industrial viewpoint.
As described above, in the related art methods, the products contain a base such as triethylamine, etc., and when it is intended to remove the impurities, lysophospholipid is contained, whereby it is difficult to obtain high-pure products. Also, in the related art methods, from the points that the yields of the products are bad and a large amount of solvent is used, it is difficult to apply these methods to the industrial production of products.
Accordingly, a simple synthetic method of a polyethylene oxide-modified phospholipid having a high purity without containing impurities such as a base having a nitrogen atom, such as triethylamine, etc., or a monoacyl phospholipid has been desired.
Since a phospholipid has excellent effects as an emulsifier and a humectant, many investigations have been made for compounding with not pharmaceuticals alone but cosmetics, and furthermore such a phospholipid has been investigated as liposome or by the addition of another surface active agent. However, especially in the application to emulsions, cosmetics, etc., by increasing the addition amount of the phospholipid, there occurs a problem that the surface active agent is not dissolved well, whereby the addition amount of the other surface active agent than a phospholipid must be increased.
SUMMARY OF THE INVENTION
An object of the invention is to provide a high-pure polyethylene oxide-modified phospholipid having less contents of impurities such as a base having a nitrogen atom, monoacyl phospholipid, etc., and other object of the invention is to provide the production method thereof and the uses thereof.
Furthermore, since the polyalkylene oxide-modified phospholipid of the invention has the effects of phospholipids and can be dissolved in an aqueous solution, the polyalkylene oxide-modified phospholipid can be used as a surface active agent.
The present inventions are the following polyalkylene oxide-modified phospholipid, the production method thereof, and the uses thereof.
(1) A polyalkylene oxide-modified phospholipid represented by following formula (1), wherein the content of a monoacyl phospholipid is not more than 3% by weight and the content of a base having a nitrogen atom is not more than 0.02% by weight.
(In the formula (1), R
1
CO and R
2
CO each independently represents an acyl group having from 4 to 24 carbon atoms; k represents from 1 to 4; R
3
O represents an oxyalkylene group having from 2 to 4 carbon atoms; n is a mean addition mol number of the oxyalkylene group having from 2 to 4 carbon atoms, and represents a number of from 10 to 800; M represents a hydrogen atom, sodium, or potassium; X represents a divalent hydrocarbon group having from 1 to 3 carbon atoms or —C(═O)(CH
2
)
q
— (wherein, q represents from 1 to 4); p represents 0 or 1; and when p is 0, Y is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, and when p is 1, Y is a hydrogen atom, an amino group, a carboxyl group, an aldehyde group, a glycidyl group, or a thiol group.).
(2) The polyalkylene oxide-modified phospholipid described in above-described (1), wherein the content of the monoacyl phospholipid is not more than 2% by weight.
(3) The polyalkylene oxide-modified phospholipid described above-described (1), wherein p is 0, Y is a methyl group, and the content of the monoacyl phospholipid is not more than 0.5% by weight.
(4) A method of producing a polyalkylene oxide-modified phospholipid, comprising following process (A).
Process (A): A process of reacting the activated material of a polyalkylene oxide compound represented by following formula (2) and a phospholipid represented by following formula (3) in an organic solvent in the presence of an alkali metal salt the aqueous solution of which shows alkalinity, which is a solid salt without containing nitrogen.
[In the formula (2), R
3
O represents an oxyalkylene group having from 2 to 4 carbon atoms; n is a mean addition mol number of the oxyalkylene group having from 2 to 4 carbon atoms, and represents a number of from 10 to 800; X represents a divalent hydrocarbon group having from 1 to 3 carbon atoms or —C(═O)(CH
2
)
q
— (wherein, q represents from 1 to 4); p represents 0 or 1; and when p is 0, Y is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, and when p is 1, Y is a hydrogen atom, an amino group, a carboxyl group, an aldehyde group, a glycidyl group, or a thiol group; and Z represents an activating group.)
(In the formula (3), R
1
CO and R
2
CO each independently represents an acyl group having from 4 to 24 carbon atoms and k represents from 1 to 4.).
(5) The production method described in above-described (4), wherein R
1
CO and R
2
CO each is an acyl group having from 12 to 20 carbon atoms.
(6) The production method described in above-described (4) or (5), wherein p is 0 and Y is a methyl group.
(7) The product
Itoh Chika
Kubo Kazuhiro
Ohhashi Syunsuke
Yasukohchi Tohru
Carr Deborah D.
NOF Corporation
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