JPH06271465A - Long acting ascorbic acid preparation - Google Patents

Abstract

PURPOSE:To provide a preparation capable of sufficiently exhibiting its medicinal effect by a less number of administration in comparison with the conventional preparation and of keeping the concentration in blood for a long time, having a high biological utility value and further capable of also reducing troublesomeness in intake. CONSTITUTION:There is provided a long acting ascorbic acid preparation containing ascorbic acid or its salt, one or more kinds of materials selected from hydrogenated vegetable oils and sucrose fatty acid esters and corn protein. This long acting ascorbic acid preparation can quickly increase the concentration in blood in the same manner as the conventional ascorbic acid preparation whereas the disappearance is far slower. This preparation, consequently, exhibits an excellent long acting property and the rate of dissolution can also be controlled corresponding to the mixture ratio of the corn protein. Preparation is, therefore, possible according to the symptom, the object, etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a sustained-release ascorbic acid preparation.

[0002]

The action and effect of ascorbic acid or its salts are well known, and for example, (1) activate the functions of enzymes in the living body, and also corticosteroids and thyroid hormones. , (2) densify and strengthen the blood vessel wall, promote the production of platelets, activate thrombin action, and maintain biological homeostasis such as preventing bleeding and participating in hemostasis,
(3) Preventing pigment deposition by suppressing melanin production,
The cosmetic effect is also known.

On the other hand, when ascorbic acid or its salt is insufficient in the body due to various causes, for example, scurvy,
Diseases such as hormonal insufficiency such as Merrell-Barrow disease, Addison's disease, malnutrition and weakness occur in children. In addition, it causes weakening of the blood vessel wall, delay of growth of bones and teeth, and reduction of immunity, antibody production ability, resistance to infection, and wound healing ability.

Specific use symptoms include inflammation and bleeding such as stomatitis, gingivitis, nephritis, renal bleeding, gastric bleeding, intestinal bleeding, illness such as pulmonary tuberculosis, pneumonia, colds, encephalitis, rheumatism, and cancer. Is for allergic poisoning, minor infectious diseases, etc.
Spans many areas. Other recovery from illness, fatigue, pregnancy,
It is also widely used during lactation.

However, ascorbic acid or a salt thereof does not remain in the body at a high concentration for a long time and is excreted outside the body without being absorbed even when administered at a certain concentration or more.
In particular, administration by injection is generally orally administered with respect to the administration of ascorbic acid or a salt thereof, because the residual time in the body is shorter than that of oral administration and the administration method is complicated, except when rapid-acting is expected. However, even when administered orally, when the dose reaches a certain concentration, further absorption cannot be expected, and its bioavailability decreases. For this reason, it is effective to administer an appropriate amount in small doses in order to increase the bioavailability of ascorbic acid or a salt thereof, but most conventional ascorbic acid preparations are immediate release. However, the duration of blood concentration is low, and the number of administrations must be increased for this reason, and there was a problem in terms of compliance when actually taking the drug. Therefore, there has been a demand for the development of a sustained-release ascorbic acid preparation having high bioavailability without such drawbacks.

The present invention has been made in order to meet the above-mentioned needs, and provides a long-acting ascorbic acid preparation having a high bioavailability and an excellent long-lasting property, the dissolution rate of which can be adjusted according to the medical condition, purpose and the like. The purpose is to provide.

[0007]

Means for Solving the Problems As a result of extensive studies to achieve the above object, the present inventor has found that one or more hydrogenated vegetable oils and sucrose fatty acid esters are added to ascorbic acid or a salt thereof. It is possible to control the elution time by using and corn protein together with the corn protein. While the blood concentration is rapidly increased as in the conventional formulation, the elimination process is much slower, resulting in excellent sustainability. The inventors have found that an ascorbic acid preparation to be retained can be obtained, and completed the present invention.

The present invention will be described in more detail below. The ascorbic acid preparation of the present invention comprises ascorbic acid or a salt thereof, one or more selected from hydrogenated vegetable oil and sucrose fatty acid ester, and corn protein. It contains.

Here, the proportion of ascorbic acid or a salt thereof incorporated in the sustained-release ascorbic acid preparation of the present invention is preferably 20 to 40% (weight%, the same applies hereinafter), and 20%.
If the amount is less than 40%, the medicinal effect may not be sufficiently exerted, while if it exceeds 40%, a manufacturing problem may occur.

Known hydrogenated vegetable oils may be added to the present invention. For example, as a commercially available product, Lubri Wax-102 (manufactured by Freund Sangyo Co., Ltd.)
Are used. The blending ratio of this hydrogenated vegetable oil is 5
-40% is preferable, and if it is less than 5%, its effect is not sufficiently obtained, and if it exceeds 40%, the hardness may be lowered when formulated into a tablet or the like.

As the sucrose fatty acid ester, those having a fatty acid residue having 10 to 20 carbon atoms are preferable. In this case, the fatty acid may be a single fatty acid or a mixed fatty acid, and edible oil and fat such as hardened beef tallow. Fatty acids from are preferably used. Further, those having a high monoester content are preferable, and for example, DK ester (manufactured by Daiichi Pharmaceutical Co., Ltd.) and the like can be used as commercial products. The content of sucrose fatty acid ester is also preferably 5 to 40%.

On the other hand, known maize protein may be blended, for example, Showa Zein 88 (manufactured by Showa Sangyo Co., Ltd.) is used. The mixing ratio of this corn protein is preferably 0.1 to 10%.

The hydrogenated vegetable oil, corn protein, and sucrose fatty acid ester to be added to the sustained-release ascorbic acid preparation of the present invention are all approved as food additives and have low toxicity to humans.

In addition to the above-mentioned components, it is also possible to add, to the sustained-release ascorbic acid preparation of the present invention, additives which are commonly used at the time of preparation of the preparation, such as lactose, glucose and soluble starch. Like other ascorbic acid preparations, it can be used in combination with other drugs.

The sustained-release ascorbic acid preparation of the present invention can be prepared in a suitable oral administration form such as tablets and granules, and its production method is ascorbic acid or a salt thereof.
One or two of hydrogenated vegetable oil and sucrose fatty acid ester
Seed or more mixed, centrifugal fluidized granulation method of hanging the above mixed powder on a mini pellet using a corn protein solution dissolved in an ethanol / water mixed solution, corn protein dissolved in an ethanol / water mixed solution at the mixed powder. Examples thereof include a fluidized granulation method of spraying and granulating, and a method of kneading the above mixed powder and a corn protein solution with a kneader. Further, the granules can be tableted to obtain tablets.

The ascorbic acid preparation of the present invention can be applied not only to the treatment and prevention of diseases similar to the conventional ascorbic acid preparations, but also to foods which can be expected to have effects such as nourishing tonic and cosmetic effects.

[0017]

The sustained ascorbic acid preparation of the present invention comprises:
As well as conventional ascorbic acid preparations, it not only rapidly raises its blood concentration, but its elimination process is much more gradual, so it has excellent persistence, so its efficacy is reduced with fewer administrations than before. Since it can be sufficiently exerted and the blood concentration can be maintained for a long time, it has high bioavailability and can reduce the troublesomeness of taking it. Moreover, since the elution rate can be controlled by the blending ratio of corn protein, it can be prepared according to the symptoms, purpose and the like. Therefore, it is effective as a therapeutic and prophylactic drug, and further applicable to health foods and the like.

[0018]

EXAMPLES The present invention will be specifically described below by showing Examples and Comparative Examples, but the present invention is not limited to the following Examples.

[Example 1] Ascorbic acid 2,500 g Hydrogenated vegetable oil 2,500 g Corn starch 600 g Powdered sugar 1,700 g Nonpareil 2,500 g Corn protein 200 g Total 10,000 g

Ascorbic acid (Takeda Pharmaceutical Co., Ltd.) 2,5
00 g, hydrogenated vegetable oil (Lovely WAX102, manufactured by Freund Sangyo) 2,500 g, cornstarch (manufactured by Nippon Shokuhin Kako) 600 g, and powdered sugar (manufactured by Nisshin Seito) 1,700
Mix g.

Nonpareil 101 (made by Freund Sangyo)
A liquid in which 2,500 g of corn protein (Showa Zein 88, manufactured by Showa Sangyo Co., Ltd.) was dissolved in 3 liters of a mixed liquid of ethanol and purified water (9: 1) while 2,500 g was put in a centrifugal fluidized granulator CF-750 and rotated. While spraying with, the above mixed powder was applied to obtain granules.

Next, the following tests were carried out using the above granule preparation (containing 250 mg of ascorbic acid in 1 g) and the commercially available granule preparation of ascorbic acid (containing 250 mg of ascorbic acid in 1 g). 1. Test Method From the day 9 days before the start of the test, 6 adult males selected as test subjects were daily administered with 1000 mg / day of ascorbic acid to saturate the ascorbic acid in body tissues. On the day of the test, the subjects were divided into 2 groups of 3 persons each, and 4 g of the above-mentioned product of the present invention (10 g of ascorbic acid)
00 mg) and 2 g of the above commercial product (500 mg as ascorbic acid) were administered to the comparative group after breakfast. Blood was collected immediately before administration and 1, 3, 6, 9, 12 hours after administration. 2. Test Results The average plasma ascorbic acid concentration of each group was as shown in Table 1 and FIG.

[0023]

[Table 1]

In order to facilitate comparison and examination between the two groups, the 0-hour value as a control was subtracted, and each parameter was calculated based on this value. The results are shown in Tables 2 and 3.

[0025]

[Table 2]

[0026]

[Table 3]

As shown by the above parameters, Cmax
There is no difference between the two products in terms of Tmax and Tmax,
A significant difference was observed in AUC and T _1/2 , which reflected the difference in the disappearance process. That is, in the group of the present invention, a half-life that is 3 times or more that of the comparative group was observed, indicating that the elimination process is slow. Further, when the AUC up to infinity time was calculated in order to compare the utilization rates in the living body, the group of the present invention showed a value about 3.4 times that of the comparative group. Considering that the dose of ascorbic acid in the group of the present invention was twice that of the comparative group, the result was remarkably excellent.

Next, assuming continuous administration, a simulation was conducted in the case where the product of the present invention was administered every 12 hours and the commercially available product was administered every 6 hours. That is, as for the product of the present invention, once ascorbic acid was used at 1000 times.
mg, twice a day, and in the case of a commercially available product, ascorbic acid was administered once at 500 mg, four times a day. The results are shown in FIGS. Table 4 shows the parameters in the steady state.

[0029]

[Table 4]

As shown by the above-mentioned parameters, both formulations were administered with 2000 mg / day of ascorbic acid, but a stable concentration transition was observed in the group of the present invention.

Therefore, as shown in the results of Table 1 and FIG. 1, 2 g of the commercial preparation (500 mg as ascorbic acid)
And 4 g of the preparation of the present invention (1000 m as ascorbic acid
When g) was administered, the dose of the product of the present invention was twice that of the commercially available product, but the absorption amount was about 3.4 times. Further, from the results of Table 4 and FIGS. 2 and 3, according to the simulation when 2000 mg of ascorbic acid was administered daily, the product of the present invention had a lower concentration ratio in the steady state than the commercially available product, and the blood concentration at the high concentration was higher. It was revealed that the concentration can be maintained.

From the above, the product of the present invention shows an increase in blood concentration as quickly as the conventional preparation, but the elimination process is gradual. It is recognized that it is used in the body.

Example 2 Ascorbic acid granule preparations A to I having the following formulations were prepared in the same manner as in Example 1 and subjected to a dissolution test. The dissolution test was performed by the rotating basket method of the Japanese Pharmacopoeia, 900 ml of water at 37 ° C. was used as a test solution, and the rotation speed was 100 rpm.

Formulation A (Product of the Invention) Ascorbic acid 2,500 g Hydrogenated vegetable oil 2,500 g Corn starch 600 g Powdered sugar 1,850 g Nonpareil 2,500 g Corn protein 50 g Total 10,000 g

Formulation B (Product of the Invention) Ascorbic acid 2,500 g Hydrogenated vegetable oil 2,500 g Corn starch 600 g Powdered sugar 1,750 g Nonpareil 2,500 g Corn protein 150 g Total 10,000 g

Formulation C (Product of the Invention) Ascorbic acid 2,500 g Hydrogenated vegetable oil 2,500 g Corn starch 600 g Powdered sugar 1,600 g Nonpareil 2,500 g Corn protein 300 g Total 10,000 g

Formulation D (Product of the Invention) Ascorbic Acid 2,500 g Sucrose Hardened Beef Fatty Acid Ester 2,500 g Corn Starch 600 g Powdered Sugar 1,600 g Nonpareil 2,500 g Corn Protein 300 g Total 10,000 g

Formulation E (comparative) Ascorbic acid 2,500 g Corn starch 600 g Powdered sugar 3,600 g Nonpareil 2,500 g Corn protein 800 g Total 10,000 g

Formulation F (Comparative) Ascorbic acid 2,500 g Corn starch 600 g Powdered sugar 3,570 g Nonpareil 2,500 g Corn protein 830 g Total 10,000 g

Formulation G (Comparative) Ascorbic acid 2,500 g Hydrogenated vegetable oil 2,500 g Corn starch 600 g Powdered sugar 1,900 g Nonpareil 2,500 g Total 10,000 g

Formulation H (comparative product) Ascorbic acid 2,500 g Sucrose hardened beef tallow fatty acid ester 2,500 g Corn starch 600 g Powdered sugar 1,900 g Nonpareil 2,500 g Total 10,000 g

Formulation I (comparative product) Commercial product used in Example 1 The results of blood ascorbic acid concentrations of the above Formulations A to I are shown in Table 5.
And shown in FIG.

[0043]

[Table 5]

As is clear from Table 5 and FIG. 4, it is recognized that the sustained ascorbic acid preparation of the present invention can control the elution rate by the mixing ratio of the corn protein in the ethanol / water mixture.

[Example 3] Ascorbic acid 2,500 g Hydrogenated vegetable oil 1,000 g Sucrose fatty acid ester 1,600 g Lactose 4,600 g Corn protein 300 g Total 10,000 g

Ascorbic acid 2,500 g, Lovely W
AX 1,000 g, sucrose fatty acid ester (DK Ester F-20W Daiichi Kogyo Seiyaku Co., Ltd.) 1,300 g and lactose 4,600 g were put in a fluidized granulator (Freund Sangyo) and separately corn protein (Showa Zein 88 Showa Sangyo) Granules are formed by spraying a solution prepared by dissolving 800 g of ethanol / purified water (9: 1) in a mixture of 12 liters, and granulated with 300 g of the remaining sucrose fatty acid ester, and then mixed with a tabletting machine (Kikusui Seisakusho). To obtain tablets. This tablet also showed the same durability as the formulation of Example 1.

[Brief description of drawings]

FIG. 1 is a graph showing blood levels of ascorbic acid in the product of the present invention and a commercial product.

FIG. 2 is a graph showing changes in blood levels of ascorbic acid when the product of the present invention is continuously administered.

FIG. 3 is a graph showing changes in blood levels of ascorbic acid when a comparative product was continuously administered.

FIG. 4 is a graph showing the results of dissolution tests of various preparations.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] August 12, 1993

[Procedure Amendment 1]

[Document name to be corrected] Drawing

[Name of item to be corrected] Figure 4

[Correction method] Change

[Correction content]

[Figure 4]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 47/44 C 7433-4C

Claims (1)

[Claims] 1. A continuous ascorbic acid preparation comprising ascorbic acid or a salt thereof, one or more selected from hydrogenated vegetable oils and sucrose fatty acid esters, and corn protein.