JPH07116037B2 - Vitamin E formulation composition - Google Patents

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, an important drug that prevents the increase of lipid peroxide and stabilizes biological membranes. 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 (potency) is said to be in the order of natural free body> natural ester body> synthetic free body> synthetic ester body. 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. Therefore, it is excellent in absorption from the intestinal tract, is stable over time, and does not cause turbidity. Formulation E was desired.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that V. When a certain amount of an unsaturated fatty acid and a hydrophilic surfactant having an HLB of 10 or more is added to E, an excellent absorption promoting effect is obtained, and a transparent pharmaceutical composition which is stable and does not cause turbidity with time is obtained. We have found this and completed the present invention.

That is, the present invention provides the following component (a),
(B) and (c) (a) Vitamin E (b) Unsaturated fatty acid 10% by weight or more (c) Hydrophilic surfactant having HLB of 10 or more 1-1
A vitamin E formulation composition containing 0% 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. Although the content of vitamin E is not particularly limited, it may be 10 to 10 in the composition.
It is preferable to contain 80% by weight.

Examples of the unsaturated fatty acid as the component (b) include unsaturated fatty acids having 14 to 22 carbon atoms, and more preferred are tzunic acid, oleic acid, elaidic acid, erucic acid, brassic acid, linoleic acid, Examples thereof include linolenic acid and arachidonic acid. These may be used alone or in combination of two or more, and the compounding amount is 10% by weight or more.

Examples of the hydrophilic 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 polyoxyethylene alkyl having HLB within this range. Examples include ether. These may be used alone or in combination of two or more, and the compounding amount is 1 to 10% by weight. If it is less than 1% by weight, the effect of promoting absorption is small, and if it exceeds 10% by weight, the absorption is suppressed, and neither is preferable.

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.

[0012]

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.

[0013]

EXAMPLES The present invention will be specifically described below with reference to test examples and examples. Reference Example 1 V. of the composition of the present invention As a premise for testing the absorption effect of E, an appropriate dose was examined. V. Absorption of E from the gastrointestinal tract is said to be passive diffusion, but there are many unclear points, and it is reported that the amount increased in plasma and blood cells does not exceed three times the normal standard value even when administered in large doses. (Mino Makoto, Vitamin, 63, (1989), 429-434,
Makoto K., J. Nutr. Sci. Vitaminol 35, 133-
142 (1989)). This time, using SD male rats, V. E.E. with the same amount of medium-chain fatty acid triglyceride as the basic formulation. As E, 100 mg / kg and 200 mg / kg were orally administered to 3 animals in each group. After administration,
Blood was collected from the orbital venous plexus over time, and the blood concentration was measured by the following method. The endogenous V. Since E was present, a non-administration group was prepared and subtracted when calculating the area under the blood concentration curve (AUC). The results are shown in Fig. 1. V. in blood Measurement of E: 0.1 ml of purified water and 1 ml of ethanol are added to 0.2 ml of plasma and shaken for 1 minute. 5 ml of n-hexane
Is added, the mixture is shaken for 5 minutes, and then centrifuged at 3000 rpm for 10 minutes. Take 4 ml of n-hexane, distill off in a nitrogen stream, and add 0.3 ml of an n-hexane solution containing 10 μg / ml of 2,2,5,7,8-pentamethyl-6-hydroxycoumar as an internal standard substance to dissolve it. , 20 μl thereof is measured by HPLC under the following conditions. Column packing material: NUCLEOSIL NH ₂ mobile phase: n-hexane: isopropyl ether (3: 1) Detection: Fluorescence detector Excitation wavelength 298 nm Measurement wavelength 325 nm From the results of FIG. 1, AUC of 100 mg / kg and 200 mg / kg administration groups (~) 24h) is 99.8 μg · h / ml, 105.7 μg ·
When the dose is 100 mg / kg or more, the absorption seems to be saturated as described by Mino et al. Therefore, this time, in order to examine the absorption promoting effect from the saturated state, the absorption promoting effect at 100 mg / kg administration (absorption in the basic formulation is saturated) was examined.

Example 1 The content formulation was V.I. E (free form) 50% by weight, oleic acid 40% by weight, Tween 805 5% by weight, medium chain triglyceride 100% by weight, mixed and dissolved at room temperature,
After forming a transparent solution, it was filled in a soft capsule according to a conventional method. The filling amount was 200 mg in a No. 4 oval. Example 2 V.V. was carried out in the same manner as in Example 1 except that oleic acid was replaced by linoleic acid. An E formulation composition was obtained. Example 3 V.V. was carried out in the same manner as in Example 1 except that Tween 80 of Example 1 was replaced with polyoxyethylene hydrogenated castor oil (HCO-60). An E formulation composition was obtained. Example 4 The V. V.E. in the same manner except that E was replaced by 10% by weight. An E formulation composition was obtained. Example 5 The content formulation is V.I. E 80% by weight, oleic acid 10% by weight, Tween 805 5% by weight, medium chain fatty acid triglyceride 100% by weight.
An E formulation composition was obtained.

Comparative Example 1 A composition was prepared by removing oleic acid and Tween 80 from Example 1. Comparative Example 2 A product obtained by removing oleic acid from Example 1 was prepared. Comparative Example 3 Example 1 was prepared by removing Tween 80 from Example 1. Comparative Example 4 The oleic acid of Example 1 was prepared in an amount of 5% by weight. Comparative Example 5 Tween 80 of Example 1 was prepared in an amount of 0.5% by weight. Comparative Example 6 Tween 80 of Example 1 was prepared in an amount of 20% by weight. Comparative Example 7 Purified soybean lecithin 10 except for Tween 80 of Example 1
It was prepared to be blended in a weight percentage.

Test Example 1 From the results of Reference Example 1, V. AUC was examined in the same manner as in Reference Example 1 with respect to the samples administered with the compositions of Examples 1 to 5 and Comparative Examples 1 to 7 with the dose of E being 100 mg / kg. The results are shown in Table 1.

[0017]

[Table 1]

Test Example 2 20 ml of the contents of Examples 1 to 5 and Comparative Example 7 were placed in a glass bottle and stored in an open state and a sealed state at 40 ° C. and a humidity of 75%, and the properties were observed. The results are shown in Table 2.

[0019]

[Table 2]

From the results of Test Examples 1 and 2, it was found that the addition of the surfactant alone did not show an absorption promoting effect, and the addition of the unsaturated fatty acid alone did not show a sufficient effect. Further, when the amount of the surfactant added was 0.5% by weight, the effect was weak, and when it was 20% by weight, it tended to be suppressed. In Comparative Example 7, the absorption promoting effect was observed, but turbidity occurred over time. In Examples 1 to 3, that is, when the unsaturated fatty acid and the surfactant were combined, there was also an absorption promoting effect and it was transparent over time.

[Brief description of drawings]

FIG. It is a figure which shows the time-dependent change of the blood level by the dose of E.

Continuation of front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical display location A61K 47/12 J 47/34 G 47/44 EJ (72) Inventor Katsumi Imamori Shimo Shizu, Yotsukaido, Chiba Prefecture Nitta 2521-86 (72) Inventor Yo Iwasa 886-16 Shiratsuwa, Yotsukaido, Chiba (56) References JP-A-2-4712 (JP, A) JP-A-61-5011 (JP, A)

Claims (1)

[Claims] 1. The following components (a), (b) and (c) (a) Vitamin E (b) Unsaturated fatty acid 10% by weight or more (c) Hydrophilic surfactant having HLB of 10 or more 1-1
A vitamin E formulation composition containing 0% by weight.