JPS62198675A - Inclusion compound of vitamin e ester or such - Google Patents

Abstract

NEW MATERIAL:Heptakis(2,6-di-o-methyl)-beta-cyclodextrin inclusion compound of vitamin E ester. EXAMPLE:Heptakis(2,6-di-o-methyl)-beta-cyclodextrin inclusion compound of nico tinic acid tocopherol. USE:A vitamin E ester having high water solubility and improved vioavailability. PREPARATION:For example, a vitamin E ester and dimethyl-cyclodextrin are weighed in a molar ratio of 1:1-1:3, blended with purified water in an amount approximately to make the blend in a sol state, sufficiently kneaded until it becomes a pasty state and dried by vacuum drying, etc., to give a powdery inclusion compound.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel cyclodextrin clathrate compound of vitamin E esters, and more specifically, tocopherol nicotinate Caz-2-(4,8,12- Trimethyltridecy/I/) -21517@8-tetramethyl-
6-chromanol nicotinate], tocopherol acetate [:dA-2-(4,8,12-trimethyltridecyl)-2,5,7,8-tetramethyl-6-chromanol acetate], amber ll) Tips Two rolls 1t-2-
(4,8,12-trimethyltridecyl) -2,5,
7,8-tetramethyl-6-chromanol succinate].
, 6-di-0-methyl)-β-cyclodextrin inclusion compound.

These vitamin m esters are widely used as circulatory drugs and vitamin E drugs.

For example, tocopherol nicotinate is used as a vitamin E drug to treat hypertension, arteriosclerosis, stroke, abnormal lipid metabolism caused by coronary insufficiency, and various symptoms caused by impaired blood circulation in peripheral blood vessels. It is being

(Prior art) Fat-soluble vitamin E esters are fat-soluble in water, so they can be applied to liquid preparations such as oral solutions, injections, and drips.
The absorption rate (
It is known that bioavailability (bioavailability) is low. In general, vitamin E esters are number 11! It is known that most of the body is absorbed through the lymphatic system, and the amount of bile and pancreatic juice greatly influences absorption. This is suggested by the fact that the absorption of these vitamin E esters is affected by meals, and the K absorption rate becomes extremely poor during fasting. For example, in the case of tocopherol nicotinate, the absorption rate when administered in a fasting state is less than 20 times larger than that when administered after a meal (Entern, TII O11neP).
harmaco'1. ThereToxl,,19.
p, p, 216-219), vitamin E esters, in order to increase their water solubility and improve the absorption rate (bioavailability) after administration, they were added to heptaki δ (2
, 6-di-0-methyl)-β-cyclodextrin to obtain preparations (liquids, powders, capsules, etc.) whose absorption is promoted without being affected by meals. It wasn't.

(Problems to be Solved by the Invention) The present invention aims to improve the water solubility and bioavailability of vitamin E esters. An object of the present invention is to provide a β-cyclodextrin clathrate compound. The present invention also aims to provide clathrate compounds of vitamin E esters with increased stability against heat and light,
Thereby, oily vitamin E esters (e.g.
This makes it possible to avoid drug non-uniformity caused by temperature changes and light during the production of solid preparations (tocopherol nicotinate, tocopherol acetate, tocopherol succinate) or during the distribution process as pharmaceuticals.

(Means for Solving the Problems) The present inventors have discovered that vitamin E esters such as tocopherol nicotinate, copherol acetate, tocopherol succinate, etc.
- When clathrated with β-cyclodextrin (hereinafter referred to as dimethyl-β-cyclodextrin or DM-β-0yD), the water solubility of vitamin E esters is improved and the absorption rate after administration is dramatically improved. Furthermore, he discovered that it is stable against physical changes such as heat and light, and was busy completing the invention.

The clathrate compound of vitamin E esters of the present invention is a compound consisting of vitamin E esters, usually called a guest molecule, and dimethyl-β-cyclodextrin, usually called a host molecule. The molar ratio of guest molecules to host molecules is generally between 1:1 and 1:1 to achieve the objectives of the present invention.
0, preferably 1:1 to 1:3, most preferably 1:2
It is the rank. The vitamin E esters used as guest molecules can be synthesized from vitamin E and nicotinic acid, acetic acid, succinic acid, etc., respectively.

Sifurobukis) 17in, in which 6 and 7.8 D-glucobylanoses, which are its constituent units, are linked in a cyclic manner is commonly called α-9β-9r-cyclodextrin. These are natural schiflov kisses)
Of course, it can also be used as a host molecule for the object of the present invention, but for vitamin esters, dimethyl-β-cyclodextrin is particularly suitable for achieving the above object. This dimethyl-β-cyclodextrin is D- which is a constituent unit of β-cyclodextrin.
The two hydroxyl groups at the 2.6-position of gelcopynose are chemically substituted with methoxy groups, and the melting point is 295-300℃.
It is a compound with a molecular weight of 1331, which has the property of being soluble in both water and organic solvents, and has low hygroscopicity and high surface activity.

Generally, kneading methods, solution methods, etc. are known as clathration methods. The clathrate compound of the present invention can be produced using any method. Examples of the method for producing the clathrate compound of the present invention will be described below.

In the crosstalk method, the molar ratio of vitamin E esters to dimethyl-β-cyclodextrin is weighed so that it is 1 = 1 to 1:3, and after adding purified water to the extent that it becomes a sol in a dark room, The mixture is thoroughly kneaded until it becomes a paste, and then dried under reduced pressure to obtain a powdery clathrate compound. The crosstalk temperature is not particularly limited and room temperature is sufficient, and the crosstalk time depends on the amount of the sample to be prepared, but usually 0.5 to 2 hours is sufficient.

In addition, in the solution method, vitamin E esters, dimethyl-
Mix β-cyclodextrin and water, tightly stopper and stir at room temperature, or add alcohol (methanol, ethanol, etc.) or organic solvent to DM-β-C7D saturated aqueous solution.
A solution of vitamin E esters dissolved in C is added dropwise all at once or gradually at room temperature, stirred for 3 to 5 hours, cooled or concentrated, and the resulting precipitate is collected to obtain a clathrate compound.

The clathrate compound thus obtained can be made into a freeze-dried product, if necessary.

The dimethyl-cyclodextrin encapsulated compound of vitamin E esters obtained by the above method is a white to slightly yellow powder with extremely high solubility in water. The formation of the clathrate compound was confirmed by various means such as solubility phase diagram, powder X-ray diffraction, dissolution rate, electron micrograph, differential thermal analysis (DTA), and infrared absorption spectroscopy. Ta.

Taking tocopherol nicotinate as an example of vitamin E esters, the solubility phase diagram, differential thermal analysis, X-ray diffraction, and dissolution behavior are shown below. The same operation was performed for other vitamin E esters, and it was confirmed that clathrate compounds were formed.

Figure 1 C. Nicotinic acid tocopherol DM-β-0
It is a solubility phase diagram of 7D at 25°C. In the case of vitamin E ester, the shape of the curve as shown in Figure 1 suggests the formation of a higher order water-soluble complex. That is, the solubility of vitamin E esters in water is significantly increased by adding DM-β-0yD. According to the obtained phase diagram, when the composition ratio of the clathrate compound of the present invention is calculated using the nonlinear least squares method, the molar ratio of vitamin E esters to DM-β-07D is 1:2. It is recognized that

Figure 2 shows the nicotine range DM-β-Oy
, D shows differential thermal analysis. As is clear from FIG. 2, the endothermic peak due to melting around 37° C. observed in the IC of tocopherol nicotinate alone disappears in the complex. This is tohanicotinic acid; ferolka;
DM-β-0rD J-indicates the formation of a thermally stable clathrate. Similarly, for tocopherol monosuccinate, the endothermic peak around 77°C disappeared. Furthermore, even when acetic acid ester is heated to 100° C. or higher, no endothermic peak is observed in the clathrate compound.

Sara tocopherol nicotinate-DM-β-CyD (
The powder X-ray diffraction pattern for a molar ratio of 1:2 is shown in FIG. As is clear from Figure 5, the peaks of physical mixtures are simply observed as the sum of the same components, but in the case of clathrate compounds, the peaks of each component disappear, new peaks appear, and the peaks broaden. This shows that the clathrate compound has become amorphous. Similar phenomena were observed for other molar ratios, and it was recognized that clathrate compounds were formed.

Next, the dissolution behavior at 37°C of the clathrate compounds prepared at each molar ratio was determined as tocopherol nicotinate-DM-β-C! 7
D (molar ratio 1:1 to 1:5) was measured as an example, and the results are shown in FIG. These are the results measured by the powder method using 6.8 (2nd liquid of the 10th revised Japanese Pharmacopoeia disintegration test method) as the test liquid. Nicotinic acid; ferol alone does not dissolve at all, but clathrate compounds with various molar ratios dissolve 1
It shows fast dissolution reaching equilibrium in ~2 minutes. % to molar ratio 1:
It is observed that the clathrate compound No. 2 increases the supersaturation concentration the most.

As described above, it has been recognized that vitamin E esters become the most preferable clathrate compound at a molar ratio of 1:2, and the solubility is improved. Next, we conducted an administration experiment using Peagle-sized tablets and found that in a fasted state, its absorption rate significantly improved the blood concentration compared to conventional preparations. Other esters show a similar tendency, and this suggests that it is not possible to expect the same efficacy at doses lower than those used in conventional formulations, but instead promotes absorption without being affected by food. It becomes possible to create a formulation that

The vitamin E esters-Dn-β-0yD clathrate compound of the present invention has excellent characteristics both physiologically and physicochemically. It can be applied to liquid preparations such as drugs and drops, and it can also be applied to blood by improving absorption during oral administration! A one-degree increase makes it possible to enhance the effect or reduce the dosage, and at the same time, if the clathrate compound of the present invention is used, solids and liquids can be resistant to temperature changes and light during manufacturing as solid preparations or during distribution. It eliminates phase changes during the process, maintains an extremely stable state, and maintains uniformity. The clathrate compound according to the present invention has enabled the diversification of various dosage forms such as oral preparations, tablets, capsules, liquid preparations, and granules.

(Example) Next, production examples and formulation examples of the clathrate compounds of the present invention will be shown.

Using tocopherol nicotinate, copherol (IrF acid), and tocopherol succinate as vitamin E esters, DM-β-C7
Put each of D into a mortar, add an appropriate amount of distilled water to make a sol, and knead for about 50 minutes to obtain a DM-β-07D clathrate of vitamin E esters. Ta. After drying this under reduced pressure for 3 days, it was passed through a 100 mesh sieve and used in the following formulation examples. An example of its formulation is shown below using tocopherol nicotinate as an example.

Formulation Example 1 (Tablet) Crystalline cellulose 41.2 m Corn starch 60. O#Hydroxypropylcellulose 25. CD9 Calcium-carboxymethyl cellulose 73.0η Magnesium stearate 2.0 ■ 500.0 Immediate clathration compound Compression molded.

Formulation Example 2 (Capsules) Corn starch 196.2 Magnesium stearate 5゜031g50α0IIF Excipients are added to the clathrate, and the mixture is left in powder form or granulated. A lubricant is added and the mixture is packed into hard capsules. Filled.

Formulation example 3 (granules) Corn starch 10α0 lactose 571,2 recommended 9 Hydroxyglobil cellulose 30,0 g10
An excipient, a disintegrant, and a binder were added to the 0α0119 clathrate compound and mixed evenly, and then granulated with a granulator and dried and sieved to produce granules.

Formulation example 4 (syrup) White sugar
75α00?10chi (v/v) ethanol
Appropriate amount A Proper amount 000m White sugar was added to the clathrate compound, 1o* (v/v) ethanol and purified water were added and dissolved by heating, and after cooling, 1.000mK was prepared with purified water.

[Brief explanation of drawings]

Figure 1 is a solubility phase diagram of tocopherol nicotinic acid with l-β-CYD, Figure 2 is a differential thermal analysis curve diagram of the clathrate of the present invention, etc., and Figure 3 is a diagram of the differential thermal analysis curve of the clathrate of the present invention. FIG. 4 is a diagram showing the dissolution behavior of the clathrate compounds (various molar ratios) of the present invention.

Claims (2)

[Claims] (1) Heptakis(2,6-di-O-methyl)-β-cyclodextrin clathrate of vitamin E esters. (2) The clathrate compound according to claim (1), wherein the vitamin E ester is tocopherol nicotinate, tocopherol acetate, or tocopherol succinate.