JPH07258082A - Vitamin e preparation composition - Google Patents

Abstract

PURPOSE:To obtain a vitamin E preparation composition excellent in absorption through the intestinal tube, stable with time and free from occurrence of turbidity. CONSTITUTION:This vitamin E preparation composition contains (a) 35 to 54wt.% vitamin E, (b) 45 to 60wt.% unsaturated fatty acid and (c) 0.8 to 5wt.% hydrophilic nonionic surfactant having >=10 HLB.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a vitamin E pharmaceutical composition which, when orally administered, absorbs vitamin E well into the human body and has excellent storage stability.

[0002]

BACKGROUND OF THE INVENTION Vitamin E is an effective antioxidant,
It is an important drug that prevents the increase of lipid peroxide and stabilizes the biological membrane. Vitamin E (hereinafter referred to as V.E.) has a natural type (d form) and a synthetic type (dl form), and each has a free form and an ester form. The strength of the potency (bioactivity)
Natural free form> Natural ester form> Synthetic free form>
It is said to be the order of synthetic ester form. What is actually used as a preparation is V. It is prepared as a soft capsule containing a large amount of E-acetic acid ester as an excipient and a tablet powder containing mannitol as an excipient. These V. As for E, the free form was left as it was, and the ester form was hydrolyzed by bile and pancreatic juice to become the free form. E is dispersed in micelles and absorbed from the intestinal tract to exert a medicinal effect.

However, the lipophilic drug V. E
Is known as a poorly absorbable drug, and its absorption is not sufficient even if a natural free form (d-α-tocopherol) having high physiological activity is used.

Therefore, various preparations have been made to promote absorption. An example of this is the V. There is a preparation in which oleic acid and lecithin are blended with E (Japanese Patent Laid-Open No. HEI 2-
No. 4712), high absorption is recognized. However, this formulation was unstable because turbidity occurred over time when the free form was used. On the other hand, a technique for enhancing absorption promotion by blending a surfactant (Japanese Patent Laid-Open No. 1-128921,
JP-A-1-238526, JP-A-1-279829
No.) was also reported, but this also had the drawback that turbidity occurred over time when the free body was used. As described above, it is difficult to obtain a stable and transparent soft capsule with these conventional techniques.

From this viewpoint, the present inventors have made various studies,
V. By blending unsaturated fatty acid and a hydrophilic surfactant in E.V. It was found that a preparation having good absorption and stability of E can be obtained, and a patent application was previously filed (JP-A-5-3).
2547).

[0006]

However, this preparation also has V.I. In terms of the absorbency of E, the V.E. Development to E formulation was desired. Therefore, it is an object of the present invention that the stability of V.I. E-formulation is to be provided.

[0007]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that V. The amount of E is 3
5 to 54% by weight, and the unsaturated fatty acid content is 45 to 6
If it is 0% by weight, which is more than the conventional formulation, HLB
Even if the blending amount of the hydrophilic nonionic surfactant having a ratio of 10 or more is 0.8 to 5% by weight, the V. The present invention has been completed by finding that a transparent pharmaceutical composition in which the absorbability of E is remarkably improved and which is stable and does not cause turbidity with time is obtained.

That is, the present invention provides the following component (a),
(B) and (c): (a) Vitamin E 35 to 54 wt%, (b) Unsaturated fatty acid 45 to 60 wt%, (c) Hydrophilic nonionic surfactant having HLB of 10 or more 0.8 to A vitamin E formulation composition containing 5% by weight is provided.

Component (a) vitamin E used in the present invention
May be any of d-α-tocopherol, dl-α-tocopherol and ester forms thereof. It is necessary that the composition of vitamin E be contained in the composition in an amount of 35 to 54% by weight, more preferably 40 to 54% by weight, and particularly preferably about 50% by weight. If it is less than 35% by weight, the V. The content of E becomes small, which is not preferable in the preparation. When it exceeds 54% by weight, the blending amounts of the components (b) and (c) become insufficient, so that the absorbency improving and stabilizing effects cannot be sufficiently obtained.

The unsaturated fatty acid as the component (b) is, for example, an unsaturated fatty acid having 14 to 22 carbon atoms, more preferably tzunic acid, oleic acid, elaidic acid, erucic acid, brassic acid, linoleic acid, Examples thereof include linolenic acid and arachidonic acid. Of these, oleic acid is V. Particularly preferred from the viewpoint of improving the absorbency of E. The blending amount of the component (b) is 45 to 60% by weight, more preferably 45 to 55% by weight, and particularly preferably about 50% by weight. 45% by weight
Is less than V. E Absorbency improvement effect cannot be obtained,
If it exceeds V. It is not preferable in terms of formulation because the amount of E to be blended becomes small.

Examples of the hydrophilic nonionic surfactant having a HLB of 10 or more as the component (c) include polyoxyethylene sorbitan fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil and polyoxy having HLB within this range. Examples thereof include ethylene alkyl ether, and polyoxyethylene sorbitan fatty acid ester is particularly preferable. Examples of such preferable polyoxyethylene sorbitan fatty acid ester include polysorbate 80, such as TO-10M (manufactured by Nikko Chemicals Co., Ltd.), OT-221 (manufactured by NOF Corporation), Tw.
A commercially available product such as een 80 can be used. The blending amount of the component (c) is 0.8 to 5% by weight, but about 1% by weight is particularly preferable. If it is less than 1% by weight, V. The effect of improving the absorbency of E is not sufficient, and V.E. The effect of improving the absorbency of E is reduced. Further, it is not preferable for a pharmaceutical product to blend a large amount of the component (c).

V. From the aspect of absorbency of E, the component (a):
The blending ratio of the component (b): the component (c) is 0.8-by weight.
1.2: 0.8 to 1.2: 0.01 to 0.2 are preferred, and about 1: 1: 0.02 is particularly preferred.

The preferred dosage form of the composition of the present invention is not particularly limited, but soft capsules or hard capsules are preferred. It can also be used as a tablet or powder which is adsorbed on a porous inorganic substance. Above all, soft capsules are particularly preferred.

The composition of the present invention may contain other components in addition to the above essential components as long as the effects of the present invention are not impaired. Examples of this component include fats and oils such as vegetable oils, alcohols such as propylene glycol and ethanol, and other vitamins.

[0015]

EFFECT OF THE INVENTION The E formulation composition was prepared according to V. It is excellent in the absorption of E in the intestinal tract, is stable over time, and does not cause turbidity.

[0016]

EXAMPLES The present invention will be specifically described below with reference to test examples and examples, but the present invention is not limited thereto.

Examples 1 and 2 and Comparative Examples 1 to 4 The contents having the compositions shown in Table 1 were mixed and dissolved at room temperature to give a transparent solution, which was then filled in a soft capsule (No. 4 oval) according to a conventional method.

[0018]

[Table 1]

Test Example 1 (Absorbability Test) As test animals, 10-week-old (290 to 320 g) SD male rats (Japan SLC Co., Ltd.) were used. Rats fasted for about 24 hours were treated with V. 600 mg as E
/ Kg of the formulations of Examples 1 and 2 and Comparative Examples 1 to 3 in Table 1 were orally administered, and further 1 ml of water was administered. Before and after administration of each preparation, the rats were anesthetized with diethyl ether 4, 6, 8, 10, 12, 14 and 24 hours after the administration, and about 0.5 ml of blood was collected from the orbital venous plexus on heparin-containing spits. Blood is 4 ℃, 300
Plasma was obtained by centrifugation at 0 rpm for 10 minutes, stored at -20 ° C, and blood V. The E concentration was measured. Accurately measure 200 μl of the obtained plasma, add 1 ml of 1% sodium ascorbate solution and 1 ml of ethanol to this, stir, add 5 ml of 0.01% BHT / hexane solution, shake for 20 minutes, and then centrifuge. A 4 ml portion of the hexane layer was separated. The solvent was distilled off from the hexane layer under nitrogen gas.
The residue was dissolved in 200 μl of ethanol, and 20 μl of the residue was injected into high performance liquid chromatography under the conditions shown below. From the obtained peak area and the absolute calibration curve obtained from each test animal, V. The E concentration was calculated. In addition, V. E
The calibration curve of 1 showed good linearity in the range of 1 to 50 μg / ml.

<HPLC measurement conditions> Pump: Shimadzu LC-6A Detector: Hitachi F-1050 Automatic sample injection device: Kyowa KSP-600 Data processing device: Shimadzu C-R4A chromatopack guard column: ODS-120T (inner diameter 3. 2mm,
Length 15 mm) Main column: ODS-120T (inner diameter 4.6 mm,
Length 250 mm) Mobile phase: Methanol Flow rate: 1.1 ml / min Wavelength: Excitation wavelength 298 nm Measurement wavelength 325 nm Column temperature: 40 ° C

From the obtained results, the area under the plasma concentration-time curve (AUC _0-24 ) was determined and is shown in Table 2. In the case of the capsule of Comparative Example 4, the data described in JP-A-5-32547 are shown.

[0022]

[Table 2]

From the results shown in Table 2, the V. The E formulation is V. It can be seen that the E absorption is extremely excellent. In particular, it is about 1.2 as compared with the preparation described in JP-A-5-32547.
It was found to have double the absorbency.

Test Example 2 20 ml of the contents of Examples 1 and 2 were placed in a glass bottle and 40
It was stored in an open state and a sealed state under conditions of ° C and a humidity of 75%, and the properties were observed. The results are shown in Table 3.

[0025]

[Table 3]

From Table 3, the invention V. It was found that the E preparation was transparent for a long period of time and had good stability.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Suga Ito 241-48 Miyanogi-cho, Chiba-shi, Chiba (72) Inventor Katsumi Imamori 2521-86 Shimotsushi-shinta, Yotsukaido-shi, Chiba (72) Inventor You Iwasa 886-16 Shikato, Yotsukaido City, Chiba Prefecture

Claims (2)

[Claims] 1. The following components (a), (b) and (c): (a) vitamin E 35 to 54% by weight, (b) unsaturated fatty acid 45 to 60% by weight, (c) HLB of 10 or more. Vitamin E formulation composition containing 0.8 to 5% by weight of the hydrophilic nonionic surfactant. 2. The unsaturated fatty acid is oleic acid, and HL
The vitamin E formulation composition according to claim 1, wherein the hydrophilic nonionic surfactant having B of 10 or more is a polyoxyethylene sorbitan fatty acid ester.