JPS62120324A - Solubilization of organic substance in water - Google Patents

Abstract

PURPOSE:To make a water-insoluble or hardly soluble organic substance soluble in water, by using a specific beta-cyclodextrin oligomer as a solubilizing agent and clathrating the organic substance in the agent. CONSTITUTION:A water-insoluble or hardly soluble organic substance (e.g. indomethacin, ibuprofen, etc., which are nonsteroidal anti-inflammatory agent useful as a poultice, various fat-soluble vitamins, water-insoluble local anesthetics, etc.) is clathrated in a beta-cyclodextrin oligomer (preferably having an average molecular weight of 2,000-10,000) produced by crosslinking beta- cyclodextrin to modify its pyranose ring structure. The amount of the organic substance to be clathrated is 0.1-2mol, especially about 1mol per 1mol of beta- cyclodextrin. The solubilized substance can be easily dissolved in water to form an aqueous solution.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method of making an organic substance that is insoluble or sparingly soluble in water soluble in water.

[Conventional technology]

Organic substances that are insoluble or poorly soluble in water are present in many substances used in various industrial fields, and because of their insolubility or sparse solubility, they are difficult to treat and often prevent improvements in efficiency. I'm reading.

For example, many anti-inflammatory drugs used as patches are water-insoluble or sparingly soluble, and these are made using water-soluble organic solvents.
For example, it is used as a composition that is kneaded in an alcohol such as propylene glycol and dispersed in water, and then spread on a base fabric. There may be cases where the drug's efficacy is not achieved.

In addition, some drugs that are orally administered as pharmaceuticals are not easily absorbed from the digestive system due to poor solubility in water, even if they are originally effective against diseases.
When taken, the drug's efficacy may be diminished without actually reaching an effective blood concentration.

Various methods have been attempted to solubilize such organic substances, one of which is to include the organic substance with cycloa;1-string.

Cyclodextrin has a cyclic structure in which α-D-glucobylanose is bonded at the 1.4 position, and the number of constituent unit molecules is α for 6 and 8.6 for 7. Eight of them are called T-cyclodextrin, and are produced by allowing special enzymes to act on starch or dextrin.

Cyclodextrin has a hydrophobic space within one molecule due to its unique cyclic molecular structure.
Various compounds are incorporated into this space to form clathrate compounds.

In many cases, the inclusion is carried out in an aqueous solution, but the more hydrophobic the encapsulating substance is, the more likely it is to be included, and there are existing applications that take advantage of this feature. In addition to being used as a solubilizer for various insoluble or poorly soluble substances as mentioned above, it is also effectively used for oxidation of various substances, prevention of dispersion, etc.

However, when used as a solubilizing agent in water, the solubility of cyclodextrin itself in water is not necessarily excellent, so the amount of dissolved encapsulated proboscis that is insoluble or poorly soluble in water is limited. It has not yet been as effective as it should have been.

In order to solve this problem, it has been proposed to use methylated cyclodextrin in which part or all of the cyclodextrin molecule is methylated. (For example, JP-A-57-4914, JP-A-59-47202) [Problems to be Solved by the Invention] The solubilization with the methylated cyclodextrin is for pharmaceuticals that are insoluble or poorly soluble in water.

For example, methylated cyclodextrin is effective in solubilizing drugs for oral administration, injections, etc., but the production of methylated cyclodextrin itself is generally complicated and costly. I can't escape it.

The inventor of the present invention has conducted intensive studies on a method that is easy to produce and can achieve excellent solubilization comparable to that of the methylated cyclodextrin, and has finally completed the present invention.

Means for Solving Problem c] That is, the method of the present invention adds a water-insoluble or sparingly soluble material to a β-cyclodextrin oligomer obtained by crosslinking β-cyclodextrin to change the pyranose ring structure. It is characterized by inclusion of organic substances.

In this invention, in the β-cyclodextrin oligomer, the structure of the pyranose ring is changed by cross-linking β-cyclodextrin with epichlorohydrin, etc., thereby increasing the affinity for water and significantly increasing the solubility in water. It is something.

In this invention, the β-cyclodextrin oligomer is used as a solubilizing agent for an organic substance that is insoluble or poorly soluble in water, and the organic substance is included therein.

Such β-cyclodextrin oligomer has an average molecular weight as an oligomer of 2,000 to 10.00.
Those with an average molecular weight of 15 are preferably used.
, 300 is particularly preferred.

Generally, when this average molecular weight becomes too large or too low, the ability of the oligomer to dissolve the organic substance clathrate in water tends to decrease.

Inclusion of organic substances that are insoluble or poorly soluble in water into β-cyclodextrin can be carried out in advance by adding β-cyclodextrin to water or other aqueous solutions.
- A cyclodextrin oligomer is dissolved, a water-insoluble or poorly soluble organic substance to be included is added thereto, and the mixture is stirred at a predetermined temperature (often under moderate heating);
It is clathrated by cooling.

Conversely, the encapsulated proboscis (the water-insoluble or sparingly soluble organic substance) is dispersed and suspended in water or other aqueous solvent, and the β-cyclotextrin oligomer is added thereto, and the predetermined amount is similarly dispersed. The clathrate can also be obtained by stirring at a temperature of 200 ml, or the solubilizing agent and the organic substance may be added to water at the same time and stirred.

The amount of inclusion in this case varies depending on the type of encapsulated proboscis, so it is difficult to generalize, but approximately 0.00% of the organic substance to be included per molecule of β-cyclodextrin, which is the constituent unit of the oligomer. By adding in the range of 1 to 2 molecules, especially at a rate of around 1 molecule, y is effectively included.

It can be applied to the method of this invention. There is no particular restriction on the type of the water-insoluble or poorly soluble organic substance as long as it is a water-insoluble or water-a-soluble organic substance that can be included in the β-cyclodextrin oligomer.

Such organic substances include many medical drugs, such as indomethacin, ketoprofen, diclofenac, and flurbiprofen, which are non-steroidal anti-inflammatory drugs useful as drugs.

Glycol salicylate, methyl salicylate, acetyl salicylate, etc., various fat-soluble vitamins such as vitamins A, B, D, E, and various steroids such as hydrocortiscin or 1,2-devidrocortiscin, As base, water-insoluble local anesthetics, such as 2-(dimethylamino-methyl)-1-ethyl-cyclohexynone-benzoate, or 2-(diethylamino)-N-(2,6-syntylphenyl)-acetamide, water-insoluble Prostanoidens, such as prostacyclin, can be mentioned.

[For production]

In general, among the α-2β-2γ-cyclodextrins, β-cyclodextrin is relatively inexpensive and easily available compared to other cyclodextrins, but its solubility in water is not necessarily good. .

That is, the solubility of cyclodextrin in water is 1, for example, 100 m7 of water at a temperature of 25°C! The amount dissolved in the solution is expressed in grams.

α-Cyclodextrin 14°5 g β-cyclodextrin 1.85 g γ-cyclodextrin 23.2 g, and β-cyclodextrin shows an overwhelmingly lower solubility than other α- or γ-cyclodextrins. There is.

However, the solubility of β-cyclodextrin oligomer (average degree of polymerization 4.7) in water, which is a low polymer of β-cyclodextrin, is about 60 g/100
It shows high solubility in ml water.

Thus, β-cyclodextrin has a fairly low solubility in water, which is due to its bound OH
5, so in the inventions such as the above-mentioned JP-A No. 57-4914, this OH group is replaced with a methyl group to form a methylated cyclodextrin, thereby achieving solubilization. .

On the other hand, in this invention, it has been discovered that scales can be solubilized by lowering and crosslinking β-cyclodextrin and changing the structure of the pyranose ring, and it is a simple methylated derivative of cyclodextrin. This is a fundamental difference from the above-mentioned methylated cyclodextrin.

Generally, inclusion compounds (Inclusion Compounds)
What is called nd) is a three-dimensional skeletal structure made up of a series of atoms or molecules, and the spaces in the lattice made up of this, with other atoms or molecules in a certain organization and a specific crystal structure. It is said that it was formed.

The β-cyclodextrin oligomer used in the present invention has the above-mentioned high dissolution performance as well as an excellent function for forming clathrate compounds, and also has an excellent function for forming clathrate compounds. The effect of preventing consecutive losses is also excellent.

When the above-mentioned organic substance is included in such a β-cyclodextrin oligomer and this clathrate is dissolved in water, the β-cyclodextrin oligomer is easily dissolved in water while including this organic substance. As a result, the clathrated organic substances that are insoluble or poorly soluble in water can be easily dissolved.

〔Example〕

This invention will be described in more detail below with reference to Examples and Comparative Examples.

! ■ and 2 I, 2 Indomethacin, a non-steroidal anti-inflammatory agent known as a medicinal ingredient of sip medicine, is used as an organic substance that is poorly soluble in water, and β- Cyclodextrin oligomer, conventionally used β-cyclodextrin, and propylene glycol were used, and the amount of these solubilizers added was varied to determine the rate of increase in the concentration of indomethacin relative to the amount of solubilizer added. was measured.

These results are shown in Table 1.

Note that the production of β-cyclodextrin oligomer is
The procedure was as shown in (A) below, the addition of indomethacin to the solubilizer was carried out as shown in (B) below, and the measurement of the dissolved amount and the calculation of the rate of increase were carried out as shown in (C) below.

(A) Formation β of β-cyclodextrin oligomer
- Add 12 mJ' of pure water to 20 g of cyclodextrin and mix to make 18 mJ of 33% sodium hydroxide aqueous solution.
and 100 mg of sodium borohydride were added to form a homogeneous solution.

While stirring and maintaining the temperature at 50°C, epichlorohydrin in an amount 5 times the amount of β-cyclodextrin was added dropwise, and stirring was continued at the same temperature of 50°C for 4 hours.

Next, 20 mA of pure water was added to this to dilute it.

Dialysis was performed in pure water, and the resultant was concentrated and dried to obtain a β-cyclodextrin oligomer.

The average molecular weight of the obtained β-cyclodextrin oligomer was 5,300.

(B) Addition of each solubilizer to 100 ml of water, add 20 mg of indomethacin and the specified amount of each solubilizer, and stir for 10 minutes to clathrate or mix these solubilizers. Each sample was obtained with various amounts of .

In addition, the sample without solubilizer added for calculating the rate of increase in solubility was prepared in the same manner as above, using 100 mj of water! To.

This was obtained by adding only 20 mg of indomethacin and stirring for 10 minutes.

In both cases, the dissolved amount was measured from the absorption spectrum of the liquid using a Jasco UVIDEC-510 (JASCO Model) spectrophotometer.

The increase rate is the amount of increase expressed as a percentage based on the sample without the addition of the solubilizer.

Table 1 The abbreviations for solubilizers in Table 1 have the following meanings. (The same applies below) 0-β-CyD ... β-cyclodextrin oligomer β-Cyro ... β-cyclodextrin P, G
・・・Propylene glycol-, 2, and ″
3,4 The amount of dissolved organic substance relative to the amount of other soluble agents was calculated according to Example 1 and Comparative Example 1.2 above, except that ketoprofen (non-steroidal anti-inflammatory drug) was used as an organic substance poorly soluble in water. The results shown in Table 2 were obtained by measuring the increase rate.

Table 2 [Effects of the Invention] According to the method of the present invention, a β-cyclodextrin oligomer that can be easily produced from β-cyclodextrin is used, and its excellent inclusion function allows it to contain water-insoluble or poorly water-soluble organic compounds. It is possible to clathrate substances at high concentrations, and this clathration also makes the encapsulated proboscis nonvolatile.

Due to the excellent solubility of the β-cyclodextrin oligomer, the clathrate can dissolve the clathrated organic substance in a very simple manner.

By the method of the present invention, it is possible to solubilize water-insoluble or poorly water-soluble organic substances used in various industrial fields, including the above-mentioned medical drugs.

The present invention is extremely advantageous in this respect.

Claims (2)

[Claims] (1) Water-soluble organic substance characterized by including a water-insoluble or poorly soluble organic substance in a β-cyclodextrin oligomer obtained by crosslinking β-cyclodextrin to change the pyranose ring structure. method. (2) The β-cyclodextrin oligomer is
The method for solubilizing an organic substance in water according to claim 1, wherein the average molecular weight is in the range of 2,000 to 10,000.