JPH05213763A - Readily absorbable activated calcium preparation - Google Patents

Abstract

PURPOSE:To obtain a preparation for supplying calcium, rich in readily absorbable property and functional activation and having high safety. CONSTITUTION:The objective calcium pharmaceutical preparation has a preparation composition characterized by blending a non-toxic calcium salt with vitamin D2 or D3, vitamin A, vitamin C and vitamin E as a readily absorbing calcium salt and is used mainly as an oral agent. The preparation has effect on supplying calcium as well as effect on improving a cerebral function as synergic action. The preparation is effective as a preventing and treating agent for hangover and nerve function disorder and also as a preventing and treating agent for osteoporosis. Since the preparation is high in safety and can be administered for a long period, it is expected also as a treating and preventing agent effective on senile dementia and Alzheimer syndrome.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a non-toxic calcium salt, anhydrous calcium hydrogen phosphate and vitamin D ₂ or D.
_The present invention provides a pharmaceutical composition comprising calcium, vitamin A, vitamin C, and vitamin E, which has enhanced absorption and activity of calcium, and its use.

[0002]

2. Description of the Related Art The required daily amount of calcium for an adult is 6
It is said to be around 00 mg, and in elderly people, the ability to absorb calcium from foods is 2/3 due to metabolic abnormality with aging.
It is said that the calcium level in the bone is eluted to maintain a normal blood calcium level, resulting in fractures and osteoporosis. (Am.J.Clin.Nutr.35.783 ~
803.1982)

As a reason why calcium absorption in breast milk and bioavailability are higher than calcium in general foods, it has been reported that there is a relation between absorption inhibitory factors and sugars. (J.Da
iry Sci., 70, 2429.1987)

[0004] Furthermore, although the existence form of calcium in fresh milk has been extensively studied, the details have not been elucidated. (J. Dairy Sci., 65, 17.1982) Calcium preparations have recently been attracting attention, but there is a problem with absorption when taken as a single product, and their relationship with hormonal regulators such as calcitonin, sugars, minerals, proteins, Vitamin D
Various studies have been conducted on the relationship between groups and ultraviolet rays. (Japanese Patent Laid-Open No. 2-69419)

Regarding the effect of improving brain function, thrombolytic agents and DHA (docosahexaenoic acid) have been reported, but there is no report relating to calcium and vitamins. Regarding vitamins, similar effects are expected, but the effects are not clear. Furthermore, vitamins C, D ₂ , D ₃
Since it is unstable in such cases, preparations using various formulation auxiliaries such as high molecular weight polymers such as cellulose, starch and hydroxypropylcellulose (Japanese Patent Publication No. 1-37).
No. 377, etc.) is disclosed, but there is a problem in stability when compounded with a calcium agent.

[0006]

It is known that calcium induces various diseases due to caries, osteoporosis, stones, hypercalcemia, etc., due to abnormal absorption, abnormal metabolism, and it is considered desirable to ingest an appropriate amount daily. However, there is a problem in its absorbability and activity after absorption, and it has been desired to develop a drug having a reliable effect and high safety.

[0007] Since it is generally considered that the combination of vitamins and calcium agents may impair the absorbability of calcium, it has been devised to increase the amount of calcium, and as a result, it is necessary to take a large amount of calcium. However, it was inconvenient in many cases as large-scale preparations. In addition, it has been pointed out that injection preparations with enhanced absorbability and mixed administration of vitamin D group and calcium preparations are associated with stones in the organs associated with transient hypercalcemia, and are safe to promote appropriate absorption and metabolism. The development of highly effective preparations has been desired.

[0008]

[Means for Solving the Problems] As a result of intensive studies on the above-mentioned problems regarding the method of administering calcium by oral administration, which is highly safe, the present inventors have found that vitamins such as vitamin D ₂ or D ₃ , The combination with Vitamin A, Vitamin C, and Vitamin E has been found to be more effective than the combination with Vitamin D group in improving the absorption of calcium, and the conventional oral administration calcium preparation has almost no effect. The inventors have found that the present invention has a brain function improving agent effect against hangovers and the like, and have completed the present invention.

The non-toxic calcium salt of the present invention is selected from calcium lactate, calcium carbonate, calcium gluconate, anhydrous calcium hydrogen phosphate, beef bone powder, keel bone and the like, which are stable in vitamins and absorbable in calcium. Therefore, it is preferable to use anhydrous calcium hydrogen phosphate. It is necessary that the vitamins have a composition form consisting of vitamins D ₂ , D ₃ , vitamin A, vitamin C, and vitamin E. A preferable composition amount for enhancing the absorbability and activity of calcium is 2000 I as vitamin A per 300 mg of calcium. ． U. , 500 mg as vitamin C,
300 I. as vitamin D ₂ . U. , 400 I. as vitamin D ₃ . U. , About 100 mg is selected as vitamin E.

The present invention is based on the discovery of the easy absorption of calcium by complex vitamins and the effect of reducing toxicity to the organs (stones, etc.) in the process of absorption and excretion, and further improvement of brain function by interaction between calcium and vitamins. It is the discovery of the effect.

That is, the present invention provides a readily absorbable active calcium preparation which is easy to use, lightweight, efficient in actual production, and effective as a brain function improving agent.

The dose of the composition of the present invention to an adult is about 30 to 600 mg, preferably about 200 to 500 mg as calcium per day for an adult. Hereinafter, the present invention will be described in more detail with reference to Examples (formulation examples, pharmacological pharmacological test examples).

[0013]

【Example】

Formulation Example 1 Ingredients were weighed according to the following formulation and made into granules according to a standard method. Vitamin C (ascorbic acid) 500 mg Vitamin A (retinol palmitate) 4000I. U vitamin _{D 3} (cholecalciferol) 400I. U Vitamin E (acetate d over α over-tocopherol) (300 mg as calcium) 100 mg calcium hydrogen phosphate 1017mg anhydrous D over mannitol q.s. hydroxypropylcellulose 150mg Perfume fine amount Total 3000mg

Formulation Example 2 The ingredients are weighed according to the following formulation and the diameter is 8.0 m according to the standard method.
m tablets. Vitamin C (sodium ascorbate) 281 mg (250 mg as ascorbic acid) Vitamin A (retinol acetate) 3000I. U Vitamin D ₂ (Ergocalciferol) 300I. U Vitamin E (succinate dl over α over-tocopherol) 50mg calcium hydrogen phosphate 644 mg (as 150mg calcium) crystalline cellulose q.s. Hydroxypropylcellulose 50mg Magnesium stearate 15mg Perfume fine amount Total 1600 mg (of 8 tablets)

Formulation Example 3 The ingredients were weighed according to the following formulation and prepared into capsules (No. 4) according to a standard method. Vitamin C (calcium ascorbate) 60 mg (50 mg as ascorbic acid) Vitamin A (retinol acetate) 2000I. U vitamin _{D 3} (cholecalciferol) 200I. U Vitamin E (d-α-tocopherol) 10 mg Vitamin B ₁ (bisbentamine) 57 mg (25 mg as thiamine hydrochloride) Calcium lactate 230 mg (30 mg as calcium) D-mannitol proper amount magnesium stearate 14 mg Total 420 mg (in 3 capsules)

Reference formulation example The ingredients were weighed according to the following formulation and prepared into granules according to a standard method. Vitamin C (ascorbic acid) 1000 mg Vitamin _{B 2} (riboflavin butyrate) 12 mg Vitamin E (acetate d over α over-tocopherol) 300 mg D over mannitol q.s. hydroxypropylcellulose 150mg Perfume fine amount Total 6000mg

Test Example 1 (Stability over Time) The contents (relative to 0 day) of each component after storing Formulation Examples 1, 2 and 3 at 60 ° C. for 3 weeks are shown below. The content of each component after storage at 60 ° C for 3 weeks was 90% or more and stable. Content Content after storage for 3 weeks at 60 ° C (% relative to 0 day) Formulation Example 1 Formulation Example 2 Formulation Example 3 Ascorbic acid 97.8-Ascorbic acid Na-96.3-Ca ascorbic acid-97. 2 Retinol palmitate 91.3-Retinol acetate-92.0 92.4 Cholecalciferol 95.2-94.9 Ergocalciferol-93.7-acetic acid d-α tocopherol 101.2-succinic acid dl -Α-tocopherol-99.6-d-α-tocopherol-91.5 Bisbentiamine-99.3 anhydrous calcium hydrogen phosphate 99.6-calcium hydrogen phosphate-99.1-calcium lactate- 98.4

Test Example 2 (Effect of activating easy absorption of calcium) [Test method] Female SD rats (body weight 90 g) were divided into 3 groups of 6 rats each, and after ovariectomy, low calcium and vitamin B ₆
After being fed a deficient diet (hereinafter referred to as deficient diet) for 30 days, the first
The group of the present invention formulation (Formulation Example 1) was allowed to freely feed in a form of 3% mixed with a deficient diet, and the second group had 100 deficient diets.
400 I. of vitamin D ₃ per g. U and anhydrous calcium hydrogen phosphate were mixed freely with 1% of purified water, and each group was bred for 30 days and subjected to urinary calcium excretion, renal biopsy, and femoral fracture test.

[Test Results] The amount of excreted calcium in urine was measured by atomic absorption spectrometry after collecting urine for 48 hours 2 days after drug administration and 3 days before the end of the experiment. The results are shown below. Urinary calcium excretion (mg / day) 2 days after drug administration 3 days before the end of the experiment Group 1 0.51 ± 0.01 1.32 ± 0.11 Group 2 0.29 ± 0.01 0.94 ± 0.14

The fracture test of the femur is carried out by a conventional method with a plunger speed of 100 cm / min and a full scale of 50 k.
g, the central portion of the left and right femurs was broken at a chart speed of 120 cm / min, and the breaking force and energy were measured.
The results are shown below. Breaking test Breaking force (10 ⁶ dyn) Energy (10 ⁵ erg) 1st group 14.3 ± 0.2 21.0 ± 1.3 2nd group 12.2 ± 0.3 19.3 ± 1.1

In the group using the preparation of the present invention, the excretion of calcium in the urine is high, but it is also high in the bone rupture test. Therefore, this result is not due to bone elution, but is due to the promotion of calcium absorption from the intestinal tract. I was able to judge that there was. In the renal biopsy, no abnormality was found in the first group, but in the second group, Ca deposits were found in a large number of Ca deposits at the boundary between the medulla and cortex. From the above results, it was found that the preparation of the present invention is a highly safe calcium preparation.

Test Example 3 (Pharmaceutical Pharmacological Test Example) Memory Disorder Improving Action Using male ddy mice (5 weeks old), whether a test drug improves the suppression of the memory process induced by scopolamine is checked by a dark box. It was examined using the passive avoidance learning test used.

[Experimental equipment] A training box consisting of a light room and a dark room having the same structure is used. The dark room was designed to be able to give a footshock through the floor grid, and used a room with a doorway at which the experimental animals could move freely at the boundary between the two rooms.

[Acquisition test] Put an experimental animal in a light room,
Immediately after moving to the dark room, I continued to give a foot shock until I returned to the bright room.

[Regeneration Test] Twenty-four hours after the memorization test, the experimental animals were placed in the light room again, and the time until moving to the dark room was measured up to 300 seconds.

[Administration of Drug to be Tested] Formulation Example 1 (3 g) was mixed with bait from 1 day before the memory acquisition test, and Formulation Example 2 (16 tablets)
A pulverized product of the preparation of Reference Example (3 g) was mixed with 3% of the feed and freely ingested.

[Preparation of memory impairment model] Scopolamine hydrobromide was dissolved in physiological saline to prepare a memory acquisition test.
0.25 mg / kg was intraperitoneally administered min.

[Data Processing and Results] With respect to each test group to which the test drug was administered and the control group to which the test drug was not administered, the rate of extension of the memory retention time of the test drug-administered group with respect to the control group based on the results of the regeneration test. Was calculated. The extension rate was found to be more significant than that of the vitamin supplement alone. The results are shown below.

Formulation of the present invention Number of animals Lengthening rate of memory retention time Composition of formulation example 18 69 Formulation of formulation example 2 62 62 Formulation of reference example 1 18 37

Test Example 4 A group of 6 persons who were aware of headache and nausea due to a hangover took 1 g of the preparation according to Production Example 1 and Reference Example as a vitamin preparation, and a questionnaire survey was conducted 4 hours after the administration. Almost all responded that the calcium-containing formulation of the present invention has a recovery effect. The results of the aggregation are shown below. Results of aggregation Headache (number of responses) Nausea (number of responses) Manufacturing Example 1 Reference Example Manufacturing Example 1 Reference Example 1) Improved. 3 0 3 0 2) I think it is improving. 2 2 3 2 3) Unknown 1 3 0 3 4) Deteriorated 0 1 0 1

[0031]

The formulation of the present invention is a composition comprising anhydrous calcium hydrogen phosphate, vitamins D ₂ and D ₃ , vitamin A, vitamin C and vitamin E. It is a preparation with enhanced absorption of calcium and has an effect of improving brain function. Not only is it effective in the prevention and treatment of osteoporosis, it is also expected as a cerebral function improving agent for the prevention and treatment of hangover, cerebral dysfunction, and it is highly safe and can be administered for a long time. It is expected as an effective therapeutic and preventive agent for Alzheimer's dementia.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI technical display location A61K 33/06 AAM (72) Inventor Yasuaki Kondo 35 Higashi Sotoboricho, Higashi-ku, Nagoya City San Co., Ltd. Inside the Waseda Institute (72) Inoue Naohisa Ninomiya, 35 Higashi Sotobori-cho, Higashi-ku, Nagoya Sanwa Institute of Research (72) Inventor Yoshimi Tsurumi, 35 Higashi-Tobori-cho, Higashi-ku, Nagoya (72) Inventor Takahiko Mitani 35, Higashi Sotobori-cho, Higashi-ku, Nagoya City Sanwa Chemical Research Institute Co., Ltd. (72) Inventor Takao Sugiyama 35, Higashi-Tohori-cho, Higashi-ku, Nagoya City Sanwa Chemical Lab. (72) Inventor Shunichi An Awa 35 Higashi Sotoboricho, Higashi-ku, Nagoya City Sanwa Chemical Research Institute Co., Ltd.

Claims (2)

[Claims] 1. An easily absorbable activated calcium preparation comprising a non-toxic calcium salt and vitamin D ₂ or D ₃ , vitamin A, vitamin C, and vitamin E as an easily absorbable calcium activator. 2. A brain characterized by using a pharmaceutical composition comprising a non-toxic calcium salt and vitamin D ₂ or ₃ as a calcium absorbable activator, vitamin A, vitamin C and vitamin E as an oral preparation. Function improver