JPS58167613A - Preparation of water-soluble cyclodextrin-containing polymer - Google Patents

Abstract

PURPOSE:To prepare a water-soluble cyclodextrin-containing polymer in high yield suitable for including a slightly soluble drug, having high including ability, by reacting a specific epoxy compound with cyclodextrin. CONSTITUTION:0.1-20g diepoxy compound shown by the formula (R is H or methyl; n is 1-10) and 0.5-5.0g cyclodextrin are dissolved in 10ml solvent (e.g., dimethylformamide, etc.), they are reacted in the presence of a catalyst (e.g., triethylamine, etc.) at 50-150 deg.C for 10-30hr, a cyclodextrin-containing polymer is precipitated in acetone, etc., washed, and dried to give the desired cyclodextrin-containing polymer. The diepoxy compound is obtained by synthesizing an ethylene glycol with epichlorohydrin.

Description

Detailed Description of the Invention The present invention relates to a method for producing a water-soluble cyclodextrin-containing polymer, and more specifically, to a method for producing a water-soluble cyclodextrin-containing polymer suitable for inclusion of a poorly soluble drug with a large molecular size. Regarding manufacturing methods.

Cyclodextrins (hereinafter referred to as "CD") are known to form clathrate compounds as so-called host compounds that incorporate various compounds (dust compounds) into the ring. Utilizing the formation of this clathrate compound, attempts have been made to apply it to medicines, such as making volatile substances non-volatile, protecting oxidized and photodegradable substances, and solubilizing poorly soluble drugs.

However, regarding the solubilization of poorly soluble drugs, although inclusion by CD increases the solubility compared to the poorly soluble drug alone, there is a phenomenon in which the solubility of the clathrate compound decreases compared to CD alone. However, there was a problem in terms of bioavailability.In addition, drugs with large molecules that have two inclusion sites form stable inclusion compounds due to the involvement of two molecules of CD. Conceivable.

Conventionally, regarding the formation of CD-containing polymers.

A method of making a water-insoluble resin by reacting CD with a halomethyloxirane compound represented by epichlorohydrin and a crosslinking agent such as formaldehyde (US Pat. No. 34207)
No. 88) is publicly known. In addition, a method of immobilizing CD on a crosslinked copolymer synthesized using a glycidyl ester of an unsaturated carboxylic acid and a crosslinking agent was disclosed in JP-A-55-754.
It is disclosed in Publication No. 02.

However, the CD-containing polymers obtained by these methods are intended to be water-insoluble and do not have sufficient inclusion ability, so they are not suitable for pharmaceutical applications.On the other hand, water-soluble CD-containing polymers For the synthesis of CD, a method using radical polymerization of an acrylic acid modified product of CD [Macr
Omolecules, 9 (5), 701 (
1976)] and a method of condensing CD and epichlorohydrin under mild conditions [Preliminary Proceedings of the 41st Spring Annual Meeting of the Chemical Society of Japan (April 1980) 3U Special 2] are known. The former method, which involves radical polymerization of a modified acrylic acid product of CD, requires two steps to synthesize the modified acrylic acid product used as a raw material, and the separation operation of the product is complicated, and the yield of the target product is low. Moreover, the latter method was simple but had the disadvantage of low yield.

That is, the present invention solves the problems of the conventional CD and CD-containing polymers described above, and provides a method for producing a water-soluble CD-containing polymer with a high yield and high inclusion ability. The purpose is to provide.

In view of the above points, the present inventors have conducted extensive research and have found the following formula (■): (wherein, R represents a hydrogen atom or a methyl group, and n represents an integer from 1 to 10, respectively. ) It has been discovered that the above-mentioned problems can be solved by using the jepoxy compound shown by the following, and the present invention has been completed.

That is, the present invention provides a water-soluble CD-containing polymer characterized by reacting a jepoxy compound represented by the following formula (I): (wherein R and n have the same meanings as above) with CD. It is a manufacturing method.

The present invention will be explained in detail below.

The structure of CD used in the present invention is one in which D-glucobylanose groups are linked in a cyclic manner through α-1,4-glycosidic bonds. Depending on the degree of polymerization, this CD contains α-CD (
There are three types of isomers: β-CD (polymerization degree 6), β-CD (polymerization degree 7), and β-CD (polymerization degree 8), and in the present invention, these can be used alone or as a mixture of two or more types. It will be done.

As the jepoxy compound represented by the formula (I), commercially available ones or those produced by various known methods can be used. The jepoxy compounds include, for example, ethylene glycol, GefL/nglycol, triethylene glycol, pentaethylene glycol, decaethylene glycol, propylene glycol, dinolobylene glycol, pentazolopylene glycol, decapropylene glycol, etc. It can be easily synthesized by reacting ethylene glycols or propylene glycols represented by the formula (wherein R and n have the same meanings as above) with epichlorohydrin.

The reaction between CD and the above jepoxy compound can be carried out by heating both in a solvent in the presence of a suitable catalyst. The amount of both used may be as long as the molar ratio of the jepoxy compound to CD is 1 or more, but especially 2 to 2.
It is preferably within the range of 0. The concentration of both in the solvent varies depending on the solvent used, but in general, the concentration of both in the solvent is 10 d.
In contrast, it is preferable that the CD is within the range of 0.5 to 5.0.9, and the jepoxy compound is within the range of 0.1 to 20y.

The reaction temperature is not particularly limited, but generally the reaction rate is higher at higher temperatures, so it is preferably within the range of 50 to 150°C, and more preferably within the range of 90 to 120°C. Any solvent may be used as long as it is sufficient to dissolve the CD and the jepoxy compound, and examples thereof include dimethylformamide (DMF) and dimethylsulfoxide (DMSO). As the catalyst, any catalyst that can serve as a ring-opening polymerization catalyst for epoxy groups can be used, such as tertiary amines such as triethylamine, boron complex salts such as amine-boron trifluoride complexes, Lewis acids, inorganic acids, etc. Can be mentioned. Although it varies depending on the size and type of catalyst used, for example, in the case of using triethylamine, it is generally preferable that it is within the range of 0.05 to 2.0 d relative to CD10F. The reaction is completed by reacting for 10 to 30 hours under the above conditions. After the reaction is completed, the desired CD-containing polymer can be obtained by precipitating the CD-containing polymer in acetone, appropriately washing and drying. At this time, a solvent such as isopropyl alcohol may be used instead of acetone.

The reaction product obtained by the present invention consists of the hydroxyl group of CD (for example, β-CD has 7 -class hydroxyl groups and 14 secondary hydroxyl groups in one molecule) and the terminal carbon atom of the glycidyl group of the jepoxy compound. This is a CD-containing polymer having as a unit a structure in which these are bonded via ether bonds.

Furthermore, the CD-containing polymer obtained by the present invention can be used in the same way as well-known CDs for making volatile substances non-volatile, protecting oxidative and photodegradable substances, adsorbing and separating various compounds, etc. . More importantly, as is clear from the test examples shown below, compared to CD monomer, it has increased water solubility,
This indicates that the inclusion ability was improved. Therefore, by using the water-soluble CD-containing polymer obtained by the present invention to clathrate poorly soluble drugs with large molecular sizes such as vitamin A and various steroid compounds, it becomes possible to use the water-soluble CD-containing polymer widely in medicine. In this respect, the present invention has high industrial value.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Comparative Examples.

Example 1 β-CD6.9 (5°3X10'mol), ethylene glycol diglycidyl ether 9.3.9 (5,3
X10-'''') and 0.3 ml of triethylamine were dissolved in 40 ml of DMF and placed in a 100 ml 40 flask. The reaction was carried out by heating at 110° C. for 21 hours while stirring.

After cooling to room temperature, the reaction solution was poured into about 300 ml of acetone to precipitate a polymer. After thorough washing with acetate, it was dried in a vacuum dryer. The obtained product is a highly hygroscopic pale yellow carmeloid material, and the yield is 10. O11
Met.

Example 2 β-CD 6.9 (5,3X10-'mol), ethyleneglyfur diglycidyl ether 9.3.9 (5,
3 x 10-' mol) and 1.0 ml of triethylamine
was dissolved in DMSO40d and placed in a 100ml 40 flask. The reaction was carried out by heating at 110° C. for 21 hours while stirring. After cooling to room temperature, it was treated in the same manner as in Example 1. The obtained product was a highly hygroscopic pale yellow carmeloid material, and the yield was 10.6 Ii.

Example 3 β-CD 6.9 (5,3XIO"-'mol), nonaethylene glycol diglycidyl ether 27.8II
0.3 ml of (5,3X10-"%le) and )!J-r-+ru7mine was dissolved in DMF40-.Hereinafter, Example 1
processed in the same way. The resulting product was a hygroscopic, highly viscous material with a yield of 12.6 g.

Example 4 β-CD 6 g (5,3X 10-' mol), 9.91 i' of globylene glycol diglycidyl ether
(5,3X10'mol) and triethylamine 0.3
ml was dissolved in 40 ml of DMF. Thereafter, the same treatment as in Example 1 was carried out. The resulting product was a hygroscopic powdery soft material with an iIV amount of 10.0 N.

Test Example 1 Measurement of molecular needle distribution The product obtained in Example 1 (hereinafter referred to as rH-183) and the product obtained in Example 2 (hereinafter referred to as rH-183)
It is called 193j. ), the molecular distribution was measured by liquid chromatography (glupermeation chromatography).

The measurement conditions are as follows.

Measuring device M: Liquid chromatography LC manufactured by Shimadzu Corporation
-3A column. 1 (filler'): 'I1.8 to 14000P
W+5000PWCIIK manufactured by Yosoda Kogyo ■, a type of molecular sieve) Elution solvent: Water Elution rate: 1 ml/rnin.

The results are shown in Figure 1.

In Figure 1, the solid line is H-183, and the broken line is H-19.
The molecular weight distribution curves of 3 are shown, respectively.

Furthermore, a represents the elution position of β-CD and b represents the elution position of ethylene glycol diglycidyl ether. There was very little glycidyl ether, indicating that the main product was a CD-containing polymer.

Test Example 2 Water Solubility Test A water solubility test was conducted for H-183, H-193 and β-CD, and the results are shown in the table.

As is clear from the table, the CD-containing polymer obtained according to the present invention was found to have a water solubility about 40 times that of β-CD.

In order to investigate the inclusion effect between H-193 and dust molecules,
Fluorescent substance (6-(p-)luidino)-2-potassium naphthalenesulfonate; hereinafter referred to as rTNs. ] was investigated by fluorescence measurement.

(1) β-CD or H-
Figure 2 shows the fluorescence spectra of each solution in which 193 was dissolved at a concentration of 2 x 10-'M.

In the TNS aqueous solution alone, only a slight peak exists around 500 nm, but when β-CD is present, the peak position and intensity change due to inclusion.

In the presence of H-193, this tendency became even more remarkable than in β-CD. From this, β-CD and) l-19
It is presumed that the inclusion mode of TNS is different in No. 3.

β-CD, H-1 in lXl0-11 M TNS aqueous solution
Figure 3 shows the shadow of the fluorescence intensity based on the concentration change of each of the 93 samples.

It can be seen that as the concentration of both β-CD and H-193 increases, the fluorescence intensity increases and the number of clathrates increases. This phenomenon was treated quantitatively using the 1oz formula shown below. In the formula, [CD'3 is the concentration of β-CD or H-193, ■ is the actual measured value of relative fluorescence intensity, (iii) oo represents the limit value of I, and Kd represents the dissociation constant.

FIG. 4 shows a plot of the relationship between the reciprocal of the relative fluorescence intensity and the reciprocal of the concentration of β-CD or H-193. Fourth
In the figure, the dashed line indicates the concentration of H-193 indicated by the solid line.
It is written using a 0x scale.

β-CD exhibits two types of linearity under low and high concentrations, 1:
Two types of uptake are occurring: 1 and 2=1. on the other hand,
In H-193, it was shown by one type of straight line, indicating that there was only one type of uptake.

This is also clear from the peak positions (λmax) of the fluorescent wavelengths of β-CD and H-193 shown in FIG. In addition, the uptake of H-193 is thought to be 2:1, similar to that under high concentrations of 1 and β-CD. As a result of determining the dissociation constant of the clathrate from the 1otz formula described above, H-193, which is a β-CD-containing polymer produced according to the present invention,
The dissociation constant of the and TNS clathrate (2:1) is 2.5 x 1
0-' M, while β-CD and TNS clathrate (
2:1) was found to be 2.7 x 10-'M. This suggests that large cast molecules such as TNS, which have two inclusion sites, can form more stable inclusion bodies by using CD-containing polymers than by using CD monomers. became clear.

[Brief explanation of the drawing]

FIG. 1 is a diagram showing a molecular weight distribution curve of a CD-containing polymer produced according to the present invention. FIG. 2 is a fluorescence spectrum diagram of H-193 and β-CD. FIG. 3 is a diagram showing the influence of fluorescence intensity based on changes in the respective concentrations of β-CD and H-193 in a TNS aqueous solution. Figure 4 shows the reciprocal of relative fluorescence intensity and β-CD straddle H-19.
3 is a diagram showing the relationship between the concentration and the reciprocal of the concentration. FIG. 5 is a diagram showing the peak positions of fluorescence wavelengths of β-CD and H-193. 11 rod leaves 1 o fγ pot f! Kano I/[CO3(xi03M') Figure 5 Dark L (M)

Claims (1)

[Scope of Claims] 1. Reacting a jepoxy compound represented by the following formula: (wherein R represents a hydrogen atom or a methyl group, each representing an integer from 1 to 10) and a cyclodextrin. 1. A method for producing a water-soluble IJ-containing polymer, characterized in that: