JP2779424B2 - α-Tocopherol vitamin A acid ester-cyclodextrin complex - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to α-tocopherol vitamin A acid ester-
The present invention relates to a cyclodextrin complex.

More specifically, α-tocopherol vitamin A acid ester is converted to γ-cyclodextrin or methylated β-
The present invention relates to a complex of α-tocopherol vitamin A acid ester, which is a novel substance obtained by complexing with cyclodextrin, and γ-cyclodextrin or methylated β-cyclodextrin, and a method for producing the same.

That is, the present invention combines α-tocopherol vitamin A acid ester, which is a highly viscous liquid and thus can be formulated only in a specific dosage form, with γ-cyclodextrin or methylated β-cyclodextrin. This is to provide a powdery complex, which facilitates preparation of α-tocopherol vitamin A ester, that is, preparation of various solid preparations, tapes, suppositories, etc.

BACKGROUND OF THE INVENTION α-Tocopherol vitamin A acid ester is an esterification product obtained by the reaction of α-tocopherol with vitamin A acid or a reactive derivative thereof, which has a very clear yellow color. It is a candy-like liquid which is almost insoluble in highly viscous water [JP-A-49-26632]. Therefore, the compound, various solid preparations or oral solution, injection,
It is difficult to apply it to liquid preparations such as eye drops and drops, and even in the preparation of applicable dosage forms, there are often difficulties in handling operations. For example, when this compound is used by dispersing it in water as a liquid, certain surfactants (for example, hydrogenated castor oil (HCO-60) (manufactured by Nikko Chemicals Co., Ltd.)), polysorbate 80 (trade name: TO-1OM)
(Such as Nikko Chemicals Co., Ltd.), but the use of such a surfactant is not always preferred since it may have side effects on the living body.

[Problems to be Solved by the Invention] As described above, α-tocopherol vitamin A ester is a candy-like liquid which is almost insoluble in highly viscous water. Since there is a difficulty in handling operation and it is necessary to use an undesired surfactant when dispersing in water, it is desired to convert this into a shape that can be easily handled and to improve the solubility in water. It was.

[Means for Solving the Problems] The idea that the difficulty in handling due to such properties of α-tocopherol vitamin A ester can be solved by powdering it by any means is considered. The present inventors have intensively studied powdering means for α-tocopherol vitamin A ester. As a result, α-tocopherol vitamin A ester forms a complex with γ-cyclodextrin or methylated β-cyclodextrin. This complex was found to exhibit a thermally stable powder state, and α-tocopherol vitamin A acid ester was successfully formed into a powder.

And surprisingly, the α thus obtained
The complex of tocopherol vitamin A acid ester with γ-cyclodextrin or methylated β-cyclodextrin shows considerable solubility in water, and
It has been found that water-insoluble α-tocopherol vitamin A ester can be solubilized in water by complexing tocopherol vitamin A ester with γ-cyclodextrin or methylated β-cyclodextrin. .

That is, α-tocopherol vitamin A acid ester readily forms complexes with γ-cyclodextrin or methylated β-cyclodextrin, and the complex thus obtained is a solid powder, The present invention was found to be easy to handle as well as to be thermally stable and to maintain a solid powder state even in a heated state.

Thus, the complex of α-tocopherol vitamin A acid ester obtained in this way and γ-cyclodextrin or methylated β-cyclodextrin is used even when α-tocopherol vitamin A acid ester is insoluble in water. Regardless, it has a considerably high solubility in water and expands the freedom of selecting a dosage form when formulating α-tocopherol vitamin A acid ester. It is possible to select a wide range of dosage forms ranging from those to be formulated via the process to those in the form of a solution which is made into a solution by adding water.

The structure of the complex of the α-tocopherol vitamin A acid ester of the present invention and γ-cyclodextrin or methylated β-cyclodextrin is not necessarily clear, but each component constituting the complex is described below. ,
From the analysis of the infrared absorption spectrum (1R) with the complex itself, the X-ray diffraction pattern of the complex, differential thermal analysis, etc., α-tocopherol vitamin A acid ester showed that γ-cyclodextrin or methylated β -Can be considered to be included in the cyclodextrin host molecule.

The molar ratio of the former to the latter in the complex of the α-tocopherol vitamin A ester of the present invention and γ-cyclodextrin or methylated β-cyclodextrin is appropriately selected generally in the range of 1: 1 to 1:10. It is practically preferable that the ratio is about 1: 2 to 1: 5, particularly preferably about 1: 3. When the molar ratio is less than 1: 1, the physical properties of the liquid α-tocopherol vitamin A acid ester show superiority,
As a result, it is difficult to obtain a smooth powder.

Heptakis- (2,3-di-o-methyl) -β-cyclodextrin, heptakis- (2,6-di-o-methyl) -β-cyclomethylated β-cyclodextrin used in the present invention can be used. Dextrin, Heptakis-(2,3,6
-Tri-o-methyl)-[beta] -cyclodextrin, and the like.

The method of forming a complex may be a method generally used for preparing an inclusion compound of cyclodextrin having cyclodextrin as a host molecule, such as a kneading method, a solution method, and a freeze-drying method. The body is preferably prepared by a kneading method.

In preparing a complex of α-tocopherol vitamin A acid ester and γ-cyclodextrin or methylated β-cyclodextrin by a kneading method, α-tocopherol vitamin A ester is almost completely dissolved in water. Without
In addition, since it has a property of being hardly soluble in alcohols, it is dissolved in a solvent such as acetone in advance, and the resulting α-tocopherol vitamin A acid solution is converted into a γ-cyclodextrin powder or a methylated β-cyclodextrin powder. In addition, an operation step of removing the solvent while stirring, then adding water, kneading the mixture sufficiently until it becomes a paste, and then removing the moisture by drying under reduced pressure and drying to obtain a powdery composite is employed. . As the water used in this kneading method, an amount of purified water sufficient to turn the kneaded material into a paste is sufficient, and kneading is preferably performed in a cool dark room at room temperature or lower. The kneading time depends on the volume of the sample to be prepared, but 15-30
A minute is enough.

As a modification of this kneading method, the above ratio of α-tocopherol vitamin A acid ester and γ-cyclodextrin or methylated β-cyclodextrin are mixed,
There is also a method in which a solvent and water are added and kneaded, and the solvent is azeotropically removed to obtain a powdery composite in the same manner as described above.

Further, the paste-like mixture obtained as described above may be dried by removing water by means of freeze-drying in some cases to obtain a powdery composite.

As the solvent used in this kneading method, in addition to the above-mentioned acetone, dioxane, acetonitrile and the like which are soluble in both water and an organic solvent can be preferably used.

The complex of α-tocopherol vitamin A acid of the present invention and γ-cyclodextrin or methylated β-cyclodextrin can also be prepared by a solution method, in which case both components are dissolved or suspended in an organic solvent. The complex can be prepared by turbidity, combining the obtained solution or suspension, and thoroughly stirring and then removing the organic solvent from the formed suspension, but the production efficiency of the complex is higher than that of the kneading method. Is also inferior.

The complex of α-tocopherol vitamin A acid ester and γ-cyclodextrin or methylated β-cyclodextrin obtained by the above method is a yellow powder.

The powdery substance itself can be used as an α-tocopherol vitamin A acid ester preparation, but if necessary, various carriers, excipients, binders, lubricants, disintegrants, tablets, The preparation can be prepared in the form of powders, granules, capsules, suppositories and the like.

Further, since the complex of the present invention has extremely high water solubility as compared with the α-tocopherol vitamin A acid ester precursor, an aqueous solution thereof can be prepared. While the drug substance alone does not dissolve in water at all, the complex with cyclodextrin generally has a high solubility in water, and the tendency is that α-cyclodextrin (hereinafter α-CyD) and β-cyclodextrin (hereinafter β-CyD). ), Dimethyl-β-cyclodextrin (hereinafter referred to as DM-β-CyD), and γ-cyclodextrin (hereinafter referred to as γ-CyD).
Complexes with cyclodextrin show the highest solubility.

That is, the solubility of a complex of α-tocopherol vitamin A ester with various cyclodextrins or methylated cyclodextrins in water was investigated. Each of the above complexes is a complex of α-tocopherol vitamin A acid ester containing 25% w / w of α-tocopherol vitamin A acid ester and cyclodextrin or methylated cyclodextrin. After adding each of the composites to water and dispersing with ultrasonic waves, the mixture was stirred in a water bath at 20 ° C. for 3 hours while being shielded from light, and then subjected to filtration using paper. After extraction with high-performance liquid chromatography (HP
LC). Table 1 shows the results.

Since the solubility in water is high as described above, the complex of the present invention can be used also as a liquid preparation such as a liniment, a drop, an eye drop, an injection, a liquid for internal use, and the like. In addition, considering that cyclodextrin used in preparing the complex of the present invention has less cytotoxicity and local irritation than a conventional solubilizing agent such as a surfactant, application to such a liquid agent is not considered. It expands the application range of α-tocopherol vitamin A acid ester as a medicine, and its significance is extremely large.

The complex of the α-tocopherol vitamin A ester of the present invention and γ-cyclodextrin or methylated β-cyclodextrin is not merely a physical mixture and the presence of α-tocopherol vitamin A ester in the complex The infrared absorption spectrum, X-ray diffraction pattern, and differential thermal analysis pattern of each of α-tocopherol vitamin A acid ester, cyclodextrin or methylated cyclodextrin, and a complex of both were examined to verify the following. The results are shown below.

FIG. 1 shows the infrared absorption spectrum of each of α-tocopherol vitamin A acid ester, γ-cyclodextrin, and the complex of the present invention, and the difference spectrum between the complex and γ-cyclodextrin. FIG. 1A is γ-cyclodextrin alone, FIG. 1B is α-tocopherol vitamin A acid ester-γ-cyclodextrin complex, 1C
The figure is a difference spectrum between FIGS. 1A and 1B, that is, a spectrum corresponding to α-tocopherol vitamin A acid ester in the complex, and FIG. 1D is a spectrum of α-tocopherol vitamin A acid ester alone. . Looking at the spectrum of FIG. 1C, it can be seen that the absorption derived from α-tocopherol vitamin A ester (2970, 1720, 1580, 1460, 1230, 112
0, 960 cm ^-1 ), which is consistent with the spectral pattern in FIG. 1D.

FIG. 2 shows a powder X-ray diffraction pattern of γ-cyclodextrin and α-tocopherol vitamin A ester-γ-cyclodextrin complex. Since α-tocopherol vitamin A acid ester is a candy-like liquid as described above, its own X-ray diffraction analysis is impossible. Therefore, when the X-ray diffraction patterns of γ-cyclodextrin alone and the present complex are compared, disappearance of the peak derived from γ-cyclodextrin and appearance of a new peak are observed.

FIG. 3 shows a complex of α-tocopherol vitamin A ester and dimethyl-β-cyclodextrin (A),
1 shows the powder X-ray diffraction patterns of the physical mixture (B) and dimethyl-β-cyclodextrin alone (C). The physical mixture shown here means a simple mixture of α-tocopherol vitamin A acid ester and cyclodextrin in a state of no crystal structure showing any interaction in a constant weight ratio of both components. . Complex (A)
In the case of, the characteristic peak of each component disappeared, and the appearance of a new peak and the broadening of the peak occurred, indicating that the complex was amorphized. In the case of the physical mixture (B), Dimethyl-β-cyclodextrin.

The results in FIGS. 2 and 3 support that α-tocopherol vitamin A ester and cyclodextrin form a complex having a structure different from the crystal structure of each component. .

FIG. 4 shows the differential thermal analysis (DSC) patterns of α-, β-, γ-cyclodextrin and methyl-β-cyclodextrin alone and their complex with α-tocopherol vitamin A ester. Each complex gave a different pattern compared to the DSC pattern of cyclodextrin alone. Since α-tocopherol vitamin A acid ester itself is a candy-like liquid, no peak corresponding to its melting point appears, but each of the present composites has an endothermic peak at 100 ° C. or higher. It can be seen that the emulsification gives a thermally stable powder.

Thus, the α-tocopherol vitamin A ester containing cyclodextrin as a guest molecule and the inclusion complex of the present invention have various advantages such as high solubility in water and thermal stability. The inclusion complex according to the present invention is not only suitable for various solid preparations, liquid preparations and the like in the formulation, but also can be expected to improve absorbability after administration.

[Examples] Hereinafter, preparation examples and preparation examples of the complex of the present invention will be described.

Example Preparation Example of Complex 5 g of α-tocopherol vitamin A acid ester was taken in brown spice, and 20 ml of acetone was added to make a solution. γ-
CyD (3 g) was placed in an agate mortar, 4 ml of the above solution was added and mixed by adsorption, acetone was evaporated, 5 ml of distilled water was added, and the mixture was kneaded in a dark room for about 30 minutes until it became a paste. The obtained γ-CyD inclusion complex of α-tocopherol vitamin A ester was dried under reduced pressure for 3 days, and passed through a 100-mesh sieve, and used in Preparation Example 1. Similarly, DM-β-Cy
Complexes with D and β-CyD were prepared, and Formulation Examples 2 and 3, respectively.
Used in

Formulation Example 1 Tablet α-Tocopherol Vitamin A acid ester-γ-CyD
A disintegrant, a binder, and a lubricant were added to the composite, mixed well, and then compression-molded with a tableting machine to produce tablets. The component ratio in the tablet is as follows.

Formulation Example 2 Injection α-Tocopherol Vitamin A acid ester-DM-β-
After ultrasonic dispersion of the aqueous solution of CyD complex,
The mixture was stirred on a water bath for 3 hours and passed using a membrane filter (pore size 0.22 μm). After sterilization of the resulting solution, 10 ml each aseptically dispensed into vials,
Lyophilized. Α-tocopherol vitamin A used
The composition of the acid ester-DM-β-CyD complex aqueous solution is as follows.

Formulation Example 3 cream α-tocopherol vitamin A acid ester-β-CyD
The complex was added to the water-absorbing ointment and kneaded until a pale yellow cream was obtained. The amount of α-tocopherol vitamin A ester-β-CyD complex and the amount and composition of the water-absorbing ointment are as follows.

[Brief description of the drawings]

FIG. 1A shows γ-cyclodextrin, FIG. 1B shows α-tocopherol vitamin A acid ester-γ-cyclodextrin complex, and FIG. 1D shows α-tocopherol vitamin A.
The infrared absorption spectrum (IR) for the acid ester is shown, and FIG. 1C shows the difference spectrum between FIG. 1A and FIG. 1B. FIG. 2 shows α-tocopherol vitamin A acid ester-γ
2 shows a powder X-ray diffraction pattern of -cyclodextrin complex and γ-cyclodextrin. FIG. 3 shows a powder X-ray diffraction of a complex (A) of α-tocopherol vitamin A ester with dimethyl-β-cyclodextrin, a physical mixture thereof (B) and dimethyl-β-cyclodextrin alone (C). Indicates a pattern. In FIG. 4, (A) is an α-tocopherol vitamin A acid ester-γ-CyD complex, (B) is γ-CyD alone, and (C) is α-tocopherol vitamin A acid ester-β-. (D) of β-CyD alone, (E) of α-tocopherol vitamin A ester-α-CyD complex, (F) of α-CyD alone, and (G) of α of CyD complex. -Tocopherol vitamin A acid ester-dimethyl-β-CyD complex, and (H) shows the differential thermal analysis (DSC) pattern of dimethyl-β-CyD alone.

──────────────────────────────────────────────────の Continued on the front page (58) Field surveyed (Int.Cl. ⁶ , DB name) A61K 31/355 A61K 47/40 CA (STN)

Claims (1)

(57) [Claims] 1. A complex of α-tocopherol vitamin A acid ester and γ-cyclodextrin or methylated β-cyclodextrin.