JPH09157174A - Calcium preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation capable of exhibiting high absorption, excellent in durability and transferability to bones after absorption and having high bioavailability by compounding ascorbic acid in a specified range. SOLUTION: This preparation contains calcium ascorbate corresponding to >=8% in terms of calcium based on the total of the compound calcium. Further, the preparation optionally contains about 10-40% total calcium salt including calcium ascorbate, furthermore 1-10% binding agent such as gum arabic, 2-10% disintegrator such as lowly substituted hydroxypropyl cellulose and 0.5-2% lubricant such as magnesium stearate, each based on the total weight of the preparation.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a calcium preparation containing calcium ascorbate and provides a calcium preparation excellent in absorbability and bioavailability.

[0002]

2. Description of the Related Art It is now widely known that calcium is not only an essential component for the formation of bones and teeth of mammals including humans, but also one of the important nutrients that support various life phenomena. . In particular, low intake and absorption of calcium has become a major cause of osteoporosis in recent years.In addition, calcium deficiency is a cause of diseases such as high blood pressure, arteriosclerosis, arthralgia, diabetes, immune disease and obesity. It has been pointed out that However, calcium has an extremely low absorption rate into the human body when not ingested at the same time as a component having an absorption promoting action such as vitamin D or protein,
It is difficult to obtain the required amount of calcium by taking it alone. Normally, it is said that the amount of calcium required for an adult per day is 600 mg, but not all of the calcium contained in foods and drinks is absorbed by the human body by ingestion, and the amount of calcium required. To supplement the above with only a daily diet, a large amount of calcium-containing food must be taken.

However, the amount of calcium intake from foods has decreased with the changes in modern dietary habits. Particularly in women, the above-mentioned diseases such as mental irritability, insomnia, and osteoporosis caused by calcium deficiency increase. Tend to do. For this reason, calcium preparations and pharmaceuticals as nutritional supplements capable of positively supplementing calcium from other than foods, such as tablets or granules containing calcium salts, have been developed and marketed. In these preparations intended to reinforce calcium, the absorption of calcium is enhanced by incorporating vitamins such as vitamin D and amino acids as an absorption promoter of calcium. However, active vitamin D assists absorption of calcium from the intestinal tract, and at the same time releases calcium from bone in cooperation with parathyroid hormone. Therefore, when vitamin D is ingested excessively, hypercalcemia and uremia are caused. It is known to cause dysfunction and further disorders such as osteomalacia. In addition, a large amount of amino acids may cause side effects such as hyperuricemia, so that the range of compounding amount is limited. On the other hand, there are many calcium compounds used in these medicines and dietary supplements,
Some of them have a high absorption rate, but it is generally said that there is no difference in the absorption rate of calcium (10 to 32% in adults), and one with a higher calcium absorption rate is required. Has been. Although the calcium agent has a problem of calcium absorption rate as described above, it has a problem that if it is not taken for a long period of time, the effect on the bone such as increase in bone amount cannot be seen. That is, even if the calcium agent is taken, the effect is not felt at an early stage, which makes it difficult to take the calcium agent patiently.

[0004]

DISCLOSURE OF THE INVENTION The present invention is intended to provide a calcium preparation having high bioavailability.

[0005]

[Means for Solving the Problems] For the above reasons, a calcium agent which has a high absorption rate of calcium by searching for a calcium compound which itself has high absorbability and high bioavailability, and which is effective when taken As a result of various studies for development, it was found that calcium ascorbate, which is usually used as a vitamin C agent, exhibits a surprisingly high calcium absorption rate, and further studies have completed the present invention. That is, in the present invention, 8% of the total calcium content is calculated in terms of calcium.
It is a calcium preparation characterized by containing calcium ascorbate corresponding to the above. It is already known that calcium ascorbate also works as ascorbic acid (vitamin C), and the effect as vitamin C (stain, freckle, relief of pigmentation due to sunburn / rash, etc.) is already known. In addition to the good bioavailability of calcium, the vitamin C effect has the advantage of increasing the motivation for taking the drug and improving the compliance of drug intake. According to the guidelines for manufacturing pharmaceutical products, it is recommended to take a calcium preparation with a daily dose of 300 to 700 mg as a guide. As shown in the experimental examples below, calcium ascorbate exhibits high absorbability (double that of calcium carbonate), has good sustainability, and has high transferability to bone after absorption. The purpose of supply can be reached.
However, calcium ascorbate, which also acts as ascorbic acid, may cause urinary tract stones in some users due to excess, so the maximum daily amount of the vitamin C main drug standard (2,000 m ascorbic acid)
g, calcium ascorbate 2,420.66m
g) is the maximum daily dose, and the maximum amount of vitamin-based adjuvant that is expected to be effective as vitamin C (500 mg ascorbic acid, 605.16 mg as calcium ascorbate) is the minimum daily dose. The range may be appropriately selected and used. That is, the dose may be set so that calcium is in the range of about 56.7 mg to 227 mg / day. Therefore, daily dose of calcium 3
Other calcium compounds are blended so as to satisfy 00 to 700 mg, but the amount of calcium ascorbate in the formulation is 8% or more of the total amount of calcium incorporated in the formulation in terms of calcium amount, preferably, About 8-76
%, And more preferably, an amount corresponding to about 10 to 40% is appropriately selected.

The calcium compound used in the present invention is usually used as calcium, for example, calcium carbonate, calcium hydrogen phosphate, calcium lactate, calcium gluconate or the like, or shell calcium, crab derived from oyster shells, shellfish, coral and the like. , Shellfish such as shrimp,
Examples of the raw material include algae such as kelp, hijiki and wakame, bones of mammals, and egg shells. In addition, the amount of the compound in the formulation is generally about 1 to 60 of the formulation weight as a total calcium salt containing calcium ascorbate in consideration of the compoundability and taste of the calcium salt.
The amount may be appropriately selected from the weight%, preferably about 10 to 40% by weight, but it is not strictly limited, and when it is used as a capsule or a coated preparation, it may be prepared in an amount of more than 60% by weight. . In the case of the compounding agent, vitamin D may be compounded to increase the absorption rate of the calcium compound compounded with calcium ascorbate, or Eucommia ulmoides, which is said to increase bone density, may be compounded.

The preparation of the present invention is prepared according to a conventional method into powders, granules,
It is appropriately prepared as a solid oral preparation such as pills, tablets, capsules, chewable tablets, or liquid oral preparation such as liquid preparation, syrup, etc. When the preparation of the present invention is manufactured as a chewable tablet, it is preferable to use, for example, the method described in JP-A-5-306229. In addition to the above-mentioned calcium essential components, various additives generally used in the formulation technology can be added to the formulation of the present invention, if necessary. Examples of such additives include excipients, binders, disintegrants, lubricants, coating agents, preservatives, stabilizers, coloring agents, flavoring agents, etc. that are acceptable in terms of formulation technology. . Here, the excipient may be one that is used in ordinary formulation techniques, for example, corn starch, microcrystalline cellulose, lactose, sucrose, glucose,
Powdered reduced maltose starch syrup, fructose, D-sorbitol and D-
Mannitol is mentioned.

As the binder, for example, acacia powder, gum arabic, gelatin, tragacanth gum, partially pregelatinized starch, polyvinylpyrrolidone and the like can be used.
The amount used is generally about 1 to
It can be 10% by weight. As the disintegrant, for example, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium (actizol), starch, crystalline cellulose, hydroxypropyl starch and the like are used. The amount used can usually be about 2-10% by weight of the total weight of the formulation. Examples of the lubricant include magnesium stearate, talc, light anhydrous silicic acid, hydrogenated vegetable oil, and the like, but magnesium stearate, light anhydrous silicic acid, and hydrogenated vegetable oil can be preferably used. The amount used is not strictly limited and may be an amount usually used in the formulation technology, but generally about 0.2 to 3% by weight, preferably about 0.5% by weight based on the total weight of the formulation. Can be up to 2% by weight. As the coating agent, for example, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl acetal diethylaminoacetate, cellulose acetate trimellitate (CAT), polyvinyl acetate phthalate, shellac and the like are used.

Examples of colorants include tar dyes, lake dyes, red iron oxide, copper chlorophyll, riboflavin,
Examples include coffee, cocoa and carmine. The amount used is not strictly limited, but can be about 0.05 to 0.3% by weight, based on the total weight of the formulation.
As the corrigent, a sweetener, an acidulant, a flavoring agent and the like can be appropriately combined and used. Here, examples of the sweetener include aspartame, saccharin, stevia, and the like, and aspartame is preferably used. Although the amount used is not strictly limited,
It can be about 0.01 to 3% by weight, based on the total weight of the formulation. Examples of the acidulant include citric acid, malic acid, tartaric acid, lactic acid, adipic acid, maleic acid and the like, and adipic acid and citric acid are preferably used. The amount used is not strictly limited, but is about 0.01-based on the total weight of the preparation.
It can be 10% by weight. Furthermore, examples of the flavoring agent include lemon flavor, orange flavor, apple flavor, strawberry flavor, melon flavor, peppermint flavor, and the like.
Preferably, lemon flavor can be used. The amount used is not strictly limited, but can be about 0.05 to 2% by weight, based on the total weight of the formulation.

The formulation of the present invention may contain metal salts other than calcium salt and various vitamins other than ascorbic acid. As the metal salt that can be blended here, ferrous fumarate, ferrous sulfate, sodium ferrous citrate,
Organic or inorganic iron salts such as ferrous succinate, ferrous glucuronic acid, ferrous orotonic acid, ferrous aminoacetate, ferric polymaleate, soluble ferric pyrophosphate, and dried ferrous hydroxide gel; carbonic acid Although magnesium, magnesium salts such as magnesium oxide can be exemplified, preferably, ferrous fumarate and soluble ferric pyrophosphate as the iron salt, magnesium carbonate can be used as the magnesium salt,
One or two or more of these metal salts can be appropriately combined and blended. Examples of vitamins include vitamin A, vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , cyanocobalamin, vitamin D, vitamin E, nicotinic acid amide, calcium pantothenate, folic acid and the like, or derivatives thereof, Preferably, vitamin D and vitamin E or derivatives thereof can be used.
These vitamins may be used alone or in combination of two or more kinds as appropriate. The amount of each of the above metal salts and vitamins is not strictly limited and can be appropriately selected according to the purpose of blending, but in general, about 0.05 to 10 wt% based on the total weight of the formulation. Can be%.

When the preparation of the present invention is manufactured as a tablet, it can be prepared according to a usual formulation technique. For example, the following preparation methods are available. After uniformly mixing all the constituents, the tablet of the present invention is obtained by directly tableting according to a conventional method. Alternatively, the other components other than the flavoring agent and the lubricant to be blended are uniformly mixed, and then a part of the binder is dissolved in water to form an aqueous solution, which is then granulated according to a conventional method. The obtained granules are dried and then pulverized, and a flavoring agent is added to the obtained powder, if necessary, and mixed. A tablet of the present invention can be produced by adding a lubricant to the obtained mixture and further mixing and tableting according to a conventional method. When the preparation of the present invention is manufactured as a chewable tablet, the binder is
It is preferable to use low-viscosity hydroxyalkyl cellulose. According to this method, it is possible to satisfactorily chew without finely powdering the calcium salt or adjusting the particle size, and without causing a tableting failure such as capping or lamination. A lock is obtained. The size of the tablet obtained by the above is not particularly limited and can be appropriately selected depending on the dose of the calcium compound and the dose amount at the time of one dose, for example, one dose at a time In the case of a chewable tablet, the diameter can be about 10 to 24 mm, preferably about 10 to 22 mm, particularly preferably about 10 to 20 mm, and the weight of one tablet is about 0.4 to 3 g, preferably about 10 mm. It can be from 0.6 to 2 g, particularly preferably from about 1 to 2 g.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below with reference to Reference Examples, Examples and Experimental Examples, but it goes without saying that the present invention is not limited to these descriptions. Reference Example 1 Preparation of calcium carbonate ( ⁴⁵ CaCO ₃ ) 2.775 g of calcium chloride (CaCl ₂ ) was weighed and 0.1N
-The total volume was made up to 100 ml with hydrochloric acid. This solution (10 mg Ca
/ A ⁴⁵ CaCl ₂ solution corresponding to 40μCi in 40ml of ml) was added 21.22Myueru. To this, an excess amount (40 ml) of 10% sodium carbonate solution was added, and after standing for 15 minutes, the precipitated ⁴⁵ CaCO ₃ was centrifuged at 3000 rpm for 10 minutes,
The obtained residue was dried overnight in a desiccator, and further dried in a dryer (100 ° C.) for about 30 minutes. By this method, about 10 μCi / 250 mg of ⁴⁵ CaCO ₃ (100 mg as Ca amount) was prepared. The reaction equivalence relationship follows the following formula.

Reference Example 2 Calcium ascorbate (
Preparation of ⁴⁵ CaAs A) 1 g of ascorbic acid was suspended in 1 ml of deionized water, 0.28 g of ⁴⁵ CaCO ₃ powder prepared in Reference Example 1 was added, and water was added so that the whole was dissolved and stirred at 40 ° C. Dissolved. The solution was washed, filtered with a small amount of deionized water as washing water, and concentrated under reduced pressure to about 2 ml. While the same amount of methanol was added dropwise to the concentrated liquid, the mixture was gradually cooled to 10 ° C. or lower, and seed crystal 1 mg was added before the end point to precipitate ⁴⁵ CaAsA. The crystals were filtered through a glass filter equipped with a sinter filter, washed with cold methanol, and then vacuum dried at 50 ° C. or lower to give powder, which was used as ⁴⁵ CaAsA. cold
The NMR spectrum of CaAsA synthesized using CaCO ₃ of Co., Ltd. was completely in agreement with that of the standard product (sold by Takeda Pharmaceutical Co., Ltd.).
In this way, about 10 μCi / 1066 mg of ⁴⁵ CaAsA (Ca
An amount of 100 mg) was prepared.

Experimental Example (1) Administration and Treatment of Animals Using the calcium compounds prepared in Reference Examples 1 and 2 above, the following 6 types of administration solutions were prepared. The experimental group corresponding to each administration solution is shown in (). In addition, ⁴⁵
As the CaCl ₂ solution, a commercially available ⁴⁵ CaCl ₂ solution was diluted with water and used. 1. ⁴⁵ CaAsA solution 0.5 μCi / 5 mg Ca / ml (low dose group) 1.0 μCi / 10 mg Ca / ml (high dose group) 2. ⁴⁵ CaCl ₂ solution 0.5 μCi / 5 mg Ca / ml (low dose group) 1.0 μCi / 10 mg Ca / ml (high dose group) 3. ⁴⁵ CaCO ₃ solution 0.5 μCi / 5 mg Ca / ml (low dose group) 1.0 μCi / 10 mg Ca / ml (high dose group) Male Wistar rats aged 10 weeks with a body weight of about 250 g were used as one group of 5 rats. Each dosing solution was administered. The rats were fasted one day and night (16 to 17 hours) before the start of the experiment, and were kept in a state of impaired water intake two hours before the administration. ^{For 45} CaCl ₂ group and ⁴⁵ CaAsA group, exactly 1 ml of the above-mentioned administration solution was orally administered using a gastric sonde, and immediately lightly restrained in a Ballman cage (to the extent that a fence was formed around the rat with a stainless rod). . ^{As for the 45} CaCO ₃ group, it was prepared in Reference Example 1 because it was hardly dissolved in water.
2.5 mg and 25 mg of ⁴⁵ CaCO ₃ (0.5 μC each)
(i / 5 mg Ca and 1.0 μCi / 10 mg Ca) were accurately weighed in small test tubes and suspended in 0.8 ml of deionized water, and the whole amount was taken with a syringe and rapidly orally administered. After that, ⁴⁵ Ca remaining in the small test tube and syringe
CO ₃ was washed with 0.2 ml deionized water and this was orally administered again. After the administration was completed, it remained in the small test tube and syringe.
⁴⁵ CaCO ₃ was measured and the net dose was calculated.

(2) Pharmacokinetic properties
analysis of properties) 1. ^{Based on} the blood kinetics of ⁴⁵ Ca, it was considered that the in vivo absorbability of each calcium compound could be evaluated, and this analysis was performed by a computer based on the following calculation formula. Apparent absorption rate (%) = (total radioactivity during administration-radioactivity in feces) / total radioactivity during administration x 100 Retention rate in body (%) = (total radioactivity during administration-in feces and urine) Radioactivity) / total radioactivity upon administration × 100 The results at high and low doses of each calcium compound are shown in [FIG. 1] and [FIG. 2], respectively. As shown in [Fig. 1], at high doses, the blood concentrations of all three compounds reached maximum one hour after administration, and calcium ascorbate and calcium chloride had almost the same values, but the maximum value of calcium carbonate was It was less than half that of both compounds. Calcium chloride rapidly disappeared from the blood from 1 hour after administration, and calcium carbonate gradually decreased, and after 10 hours, both values remained at a low level until 34 hours after the administration. on the other hand,
With calcium ascorbate, there was almost no change from 1 to 3 hours after administration, then it gradually decreased until the 10th hour, and reached almost the same values as calcium chloride and calcium carbonate at 24 hours. As shown in [Fig. 2],
Even at low doses, all three compounds reached the maximum value 1 hour after administration, but calcium ascorbate showed the highest blood concentration and persistence. On the other hand, the maximum blood concentrations of calcium chloride and calcium carbonate were almost the same, and the subsequent blood concentration transitions were also almost the same. From these results, it was suggested that among the three compounds, calcium ascorbate is the compound having the highest absorbability regardless of the dose and the high persistence in blood. Calcium chloride was highly absorbed when administered at high doses, but not as high as calcium ascorbate at low doses.

2. Pharmacokinetic properties and bioavailability of calcium compounds The results of the pharmacokinetic properties and bioavailability of each calcium compound are shown in [Table 1] to [Table 4]. As is clear from [FIG. 1] and [FIG. 2], the AUC of calcium ascorbate (area under the blood concentration curve: reflects the total absorption) is the highest among the three calcium compounds at both doses. Its high absorbency was also confirmed by pharmacokinetic analysis.

[0017]

[Table 1]

[0018]

[Table 2]

[0019]

[Table 3]

[0020]

[Table 4] Blood retention time (MRT) and time to reach maximum blood concentration (T
no significant difference was observed, but the maximum concentration in blood (Cmax) was as high as CaAsA = CaCl ₂ > Ca.
CO ₃ , CaAsA> CaCl ₂ > CaCO ₃ at low doses, and the result shows that calcium ascorbate has an intestinal absorbability equal to or superior to that of calcium chloride. Also,
In terms of bioavailability, both doses were CaAsA> C
It is a result of aCl ₂ > CaCO ₃ , and it is speculated that calcium ascorbate exhibits higher bioavailability than other calcium compounds, especially at high doses.

3. Distribution of ⁴⁵ Ca in femur and kidney and urinary excretion The results of distribution of each calcium compound in femur and kidney and urinary excretion are shown in [Table 5] to [Table 7]. Calcium ascorbate showed high uptake in both high and low doses in the femur, where calcium was actively absorbed and utilized, followed by calcium chloride and calcium carbonate in that order. Almost no difference was observed among the three compounds in the kidney that was not the uptake organ. On the other hand, excretion of calcium in urine was in the order of calcium ascorbate> calcium chloride> calcium carbonate at high dose, and in the order of low dose calcium ascorbate> calcium carbonate> calcium chloride, showing high absorbability. Calcium ascorbate showed the highest amount of excretion, but the amount excreted was not considered abnormal.

[0022]

[Table 5]

[Table 6]

[0023]

[Table 7]

[0024]

Example 1 Precipitated calcium carbonate in 9 tablets 936.5 mg (375 mg as Ca) cholecalciferol 0.005 mg (200 IU) calcium ascorbate 2,420 mg (227 mg as Ca) partially pregelatinized starch 116 mg corn starch 297 mg stearin Magnesium acid 30 mg Crystalline cellulose Appropriate amount 4,230 mg Total from calcium ascorbate to crystalline cellulose 7
Take the ingredients and manufacture plain tablets according to a conventional method. 47 per tablet
Set to 0 mg.

Example 2 Calcium ascorbate in 6 tablets 1,100 mg (103.2 mg as Ca) Precipitated calcium carbonate 1,240.4 mg (496.7 mg as Ca) Cholecalciferol 0.01 mg (400 IU) Partial α-starch 84.6 mg Corn starch 216.4 mg Magnesium stearate 20 mg L-HPC 257.99 mg Hydroxypropyl methylcellulose 68.6 mg Titanium oxide 12.0 mg Total 3,000 mg 7 components from calcium ascorbate to low-substituted hydroxypropyl cellulose (LHPC). Then, an uncoated tablet is produced according to a conventional method, and hydroxypropylmethylcellulose and titanium oxide are used as a coating agent to produce a film-coated tablet by a known method for producing a tablet.
Use 500 mg per tablet.

Example 3 Calcium ascorbate in 6 tablets 605 mg (56.7 mg as Ca) Boley powder 1,474.6 mg (543.2 mg as Ca) Ergocalciferol 0.01 mg (400 IU) Eucommia ulmoides extract 60 mg (raw drug equivalent) 600 mg) Partially pregelatinized starch 79.2 mg Corn starch 202.6 mg Magnesium stearate 20 mg L-HPC suitable amount total 2,820 mg Take 8 components from calcium ascorbate to low-substituted hydroxypropyl cellulose and manufacture plain tablets according to a conventional method. . The dose is 470 mg per tablet.

[Brief description of the drawings]

Figure 1: ⁴⁵ Ca at high doses of each calcium compound
The blood kinetics of is shown.

FIG. 2: ⁴⁵ Ca at low doses of each calcium compound
The blood kinetics of is shown.

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Claims (1)

[Claims] 1. A calcium preparation containing calcium ascorbate equivalent to 8% or more of the total calcium content in terms of calcium equivalent.