JP5626698B1 - Calcium low absorption type oral phosphorus adsorbent - Google Patents

Abstract

An object of the present invention is to provide an oral phosphorus adsorbent capable of adsorbing phosphorus in the body with calcium carbonate and / or calcium acetate, and further suppressing absorption of calcium derived from calcium carbonate and / or calcium acetate. While administering calcium carbonate and / or calcium acetate as an oral phosphorus adsorbent, by using alginate other than alginic acid and / or calcium salt, the phosphorus adsorption ability of calcium carbonate and / or calcium acetate is effectively exhibited. , Calcium absorption into the living body can be suppressed. [Selection figure] None

Description

  The present invention relates to a calcium low absorption type oral phosphorus adsorbent. More specifically, the present invention relates to an oral phosphorus adsorbent capable of adsorbing phosphorus in the body with calcium carbonate and / or calcium acetate and suppressing absorption of calcium derived from calcium carbonate and / or calcium acetate.

  In chronic kidney disease, phosphorus excretion is insufficient, so phosphorus accumulates in the body, often resulting in hyperphosphatemia. Hyperphosphatemia causes the development of secondary hyperparathyroidism and associated renal dystrophy, and significantly affects the patient's life prognosis and QOL (quality of life).

  Conventionally, oral phosphorus adsorbents are generally used for the treatment of hyperphosphatemia and the like, both domestically and internationally. Examples of oral phosphorus adsorbents include inorganic preparations containing inorganic compounds such as calcium carbonate, calcium acetate and lanthanum carbonate as active ingredients, and polymer resin preparations containing organic compounds such as sevelamer hydrochloride as active ingredients.

  Among the active ingredients of conventional oral phosphorus adsorbents, calcium carbonate is currently the most active because of its strong phosphorus adsorption capacity, low cost, and high safety because it is composed of many ions present in the body. It is used. In addition, calcium acetate has a strong phosphorus adsorptive power and has been put to practical use as an oral phosphorus adsorbent. Regarding the pharmacokinetics of calcium carbonate and calcium acetate, calcium ions are released from orally administered calcium carbonate and calcium acetate, which binds mainly to phosphate ions derived from food, and is insoluble in the intestinal tract as calcium phosphate or calcium phosphate-like It has been found that by becoming a substance, it promotes phosphorus excretion into feces and exerts an action of inhibiting phosphorus absorption into the body.

  On the other hand, for patients with low compliance, or when it is desired to further enhance the phosphorus absorption inhibitory effect, vitamin D preparations are used to treat excessive amounts of calcium carbonate and calcium acetate or secondary hyperparathyroidism. In some cases, the amount of calcium absorbed is increased, resulting in hypercalcemia. In particular, in chronic kidney disease patients who need to take a phosphorus adsorbent continuously for a long period of time, such as dialysis patients, an increase in the amount of calcium absorbed causes vascular calcification, which causes cardiovascular diseases such as arteriosclerosis. There is a problem of increasing the risk.

  In order to solve these problems, it is considered that the use of lanthanum carbonate or sevelamer hydrochloride as a non-calcium preparation is effective as a phosphorus adsorbent. However, lanthanum carbonate has a problem of safety and high cost due to lanthanum accumulation in the body. In addition, sevelamer hydrochloride has a weak phosphorus adsorption ability compared to calcium carbonate and calcium acetate, and there are problems that gastrointestinal symptoms such as constipation, abdominal pain, and abdominal bloating appear as side effects. Thus, in the prior art, an oral phosphorus adsorbent that has a sufficient phosphorus adsorption effect and can be safely used for a long time has not been found.

  On the other hand, alginic acid is a polysaccharide contained in dry algae and is a kind of dietary fiber. Alginic acid is composed of D-mannuronic acid and L-guluronic acid, and includes a block containing only D-mannuronic acid (MM block), a block containing only L-guluronic acid (GG block), and D-mannuronic acid and L-guluronic acid. This is a block copolymer in which alternately connected blocks (MG blocks) are arbitrarily bonded. L-guluronic acid in the GG block is easily coordinated with a divalent metal ion, forms a cross-linked region called Egg Box Junction, and suppresses movement as a molecule. For this reason, there exists a property of forming a harder gel, so that there are many ratios of GG block.

  Alginic acid salts, such as sodium alginate and potassium alginate, dissolve easily in water and exhibit a thickening action, or gel easily by coexistence with calcium ions. For example, it has been used for a long time in the food field. Due to the property of gelling by reacting with calcium, there was a concern about the inhibitory effect on calcium absorption, but in the administration test with humans and rats, the calcium absorption inhibitory action by alginic acid and alginates was not recognized, It is also designated as a food additive (see Non-Patent Documents 1 and 2).

  Alginic acid and its salts are also used in the fields of medical instruments and pharmaceuticals as dental impression agents, wound dressings, gastric mucosa protecting agents, coating agents, capsules and the like.

  For example, Patent Document 1 discloses a soft capsule having a coating layer containing (1) gelatin, (2) a water-soluble polyhydric alcohol or a water-soluble derivative thereof, and (3) low methoxyl pectin or sodium alginate. Enteric soft capsule that gels low methoxyl pectin or sodium alginate in soft capsule coating layer and does not dissolve even when contacted with water, hot water or gastric juice, but can be easily dissolved when contacted with intestinal fluid It is disclosed that can be provided. However, Patent Document 1 only discloses a technique for gelling sodium alginate in a soft capsule coating layer with a calcium salt in order to make the soft capsule enteric.

  Patent Document 2 discloses a composition containing a calcium salt for phosphate binding in the intestinal tract, wherein the calcium salt is coated with a coating made of calcium alginate. However, Patent Document 2 is also a formulation technique in which entericity is provided by a coating layer of calcium alginate, as in Patent Document 1. That is, in Patent Document 2, the coating layer of calcium alginate is maintained until it passes through the stomach whose pH is around 2, and when the intestinal tract whose pH is increased to about 7 to 8 is reached, the coating layer is dissolved, It discloses a pharmaceutical technology that exhibits a medicinal effect by releasing and dissolving a calcium salt as a main ingredient.

  As described above, a preparation technique for forming an enteric coating by utilizing the gelation property of alginate is conventionally known. However, calcium or calcium acetate is administered using alginic acid for orally administered calcium carbonate or calcium acetate. No formulation technology is known to suppress the absorption of

J Millis, Fay B Reed Biochem. 1947; 41 (2): 273-275. Y Nakamura, Y Tonogai et al. J. et al. Food Hyg. Soc. Japan Vol. 29, no. 4 240-248

JP 58-172313 A Japanese National Patent Publication No. 11-510499

  As described above, calcium carbonate and calcium acetate are very useful as oral phosphorus adsorbents, but have problems due to calcium absorption such as hypercalcemia and vascular calcification. Then, this invention aims at providing the oral phosphorus adsorption agent which can adsorb | suck phosphorus in a body with calcium carbonate and / or calcium acetate, and can suppress absorption of calcium derived from calcium carbonate and / or calcium acetate. .

  As a result of intensive studies to solve the above problems, the present inventors have used alginic acid and / or an alginate other than calcium salt together when administering calcium carbonate and / or calcium acetate as an oral phosphorus adsorbent. Thus, it has been found that calcium absorption into a living body can be suppressed while effectively exhibiting the phosphorus adsorption ability of calcium carbonate and / or calcium acetate. The present invention has been completed by further studies based on such knowledge.

That is, this invention provides the oral phosphorus adsorption agent of the aspect hung up below.
Item 1. An oral phosphorus adsorbent comprising (i) calcium carbonate and / or calcium acetate, and (ii) alginates other than alginic acid and / or calcium salts.
Item 2. Item 2. The oral phosphorus adsorbent according to Item 1, comprising alginate other than alginic acid and / or calcium salt in a ratio of (100) parts by weight or less based on 100 parts by weight of calcium carbonate and / or calcium acetate.
Item 3. Item 3. The oral phosphorus adsorbent according to Item 1 or 2, wherein the alginic acid is non-swellable.
Item 4. Item 4. The oral phosphorus adsorbent according to any one of Items 1 to 3, wherein the ratio of mannuronic acid / guluronic acid of alginic acid is 0.8 or more.
Item 5. Item 5. The oral phosphorus adsorbent according to any one of Items 1 to 4, further comprising a derivative of alginic acid.
Item 6. Item 6. The oral phosphorus adsorbent according to any one of Items 1 to 5, which is a tablet, granule, powder, or capsule.
Item 7. Item 7. The agent according to any one of Items 1 to 6, which is a one-agent type preparation comprising a composition containing (i) calcium carbonate and / or calcium acetate, and (ii) alginic acid and / or an alginate other than a calcium salt. Oral phosphorus adsorbent.
Item 8. Claims 1 to 2, which are a combination preparation of two types including (i) a first agent containing calcium carbonate and / or calcium acetate and (ii) a second agent containing alginic acid and / or an alginate other than calcium salt. 6. The oral phosphorus adsorbent according to any one of 6.
Item 9. An alginic acid preparation for suppressing calcium absorption by an oral phosphorus adsorbent containing calcium carbonate and / or calcium acetate, comprising alginic acid and / or an alginate other than calcium salt.
Item 10. Use of a composition comprising (i) calcium carbonate and / or calcium acetate, and (ii) alginic acid and / or an alginate other than a calcium salt for the production of an oral phosphorus adsorbent.
Item 11. orally administering an oral phosphorus adsorbent containing (i) calcium carbonate and / or calcium acetate and (ii) alginic acid and / or an alginate other than calcium salt to a patient who is required to suppress phosphorus absorption, Phosphorus absorption suppression method.
Item 12. A pharmaceutical composition which is orally administered and used for treatment for suppressing phosphorus absorption, comprising (i) calcium carbonate and / or calcium acetate, and (ii) alginic acid and / or alginates other than calcium salts The pharmaceutical composition characterized by the above-mentioned.

  According to the present invention, calcium absorption into a living body can be suppressed while effectively exhibiting the phosphorus adsorption ability of calcium carbonate and / or calcium acetate, and therefore, a calcium low absorption type oral phosphorus adsorbent can be provided. Therefore, according to the present invention, hyperphosphatemia and the like can be effectively prevented or treated while reducing the risk of hypercalcemia, vascular calcification, cardiovascular disease and the like due to long-term or excessive use of calcium preparations. It becomes possible to do.

In Experiment 1, it is a figure which shows the result of having measured the amount of calcium excretion in urine. In Experiment 2, it is a figure which shows the result of having measured the amount of calcium excretion in urine and the amount of phosphorus excretion in urine. In Experiment 3, it is a figure which shows the result of having measured the amount of calcium excretion in urine and the amount of phosphorus excretion in urine. In Experiment 4, it is a figure which shows the result of having measured the amount of calcium excretion in urine and the amount of phosphorus excretion in urine. In Experiment 5, it is a figure which shows the result of having measured the amount of calcium excretion in urine and the amount of phosphorus excretion in urine. In Experiment 6, it is a figure which shows the result of having measured the amount of calcium excretion in urine and the amount of phosphorus excretion in urine. In Experiment 7, it is a figure which shows the result of having measured the amount of calcium excretion in urine and the amount of phosphorus excretion in urine. In Experiment 8, it is a figure which shows the result of having measured the amount of calcium excretion in urine and the amount of phosphorus excretion in urine.

1. Oral Phosphorus Adsorbent The oral phosphorus adsorbent of the present invention is characterized by containing (i) calcium carbonate and / or calcium acetate, and (ii) alginic acid and / or alginates other than calcium salts. Hereinafter, the oral phosphorus adsorbent of the present invention will be described in detail.

Ingredients The oral phosphorus adsorbent of the present invention uses calcium carbonate and / or calcium acetate (hereinafter sometimes referred to as “component (i)”) as a component that adsorbs phosphorus in vivo.

  The calcium carbonate used in the present invention may be any of precipitated calcium carbonate (heavy calcium carbonate) and light calcium carbonate, or a mixture thereof, but exhibits an excellent phosphorus adsorption effect. From the viewpoint of making it preferable, precipitated calcium carbonate is preferable. Calcium carbonate may be anhydrous or hydrated.

  Moreover, any of hydrates such as anhydrides and monohydrates may be used for calcium acetate used in the present invention.

  In the oral phosphorus adsorbent of the present invention, as the component (i), either one of calcium carbonate and calcium acetate may be used alone, or both of these may be used in combination.

  The oral phosphorus adsorbent of the present invention contains alginic acid salts other than alginic acid and / or calcium salts (hereinafter sometimes referred to as “component (ii)”). In the oral phosphorus adsorbent of the present invention, alginates other than alginic acid and / or calcium salts are derived from calcium carbonate and / or calcium acetate in vivo while effectively exhibiting the phosphorus adsorption action by calcium carbonate and / or calcium acetate. Demonstrates the action of suppressing calcium absorption.

  In addition, the alginic acid used in the present invention may be either swellable or non-swellable, and may be a mixture thereof. From the viewpoint of further enhancing the calcium absorption inhibitory effect, Swellable alginic acid is mentioned. Here, “non-swelling” means that it hardly swells even when water is absorbed, and specifically means that the volume when swollen in water is 80 ml / 2 g or less. To do.

  In the present invention, the ratio of mannuronic acid and guluronic acid constituting the alginic acid to be used is not particularly limited. For example, the ratio of mannuronic acid to guluronic acid (M / G ratio) is about 0.1 to 11 Is mentioned. Among them, alginic acid satisfying an M / G ratio of 0.8 or more, preferably 0.8 to 11, more preferably 1.2 to 11, and particularly preferably 1.6 to 11 is more effective in suppressing calcium absorption. Since it can improve effectively, it is used especially suitably in this invention.

  The salt of alginic acid used in the present invention is a salt other than the calcium salt of alginic acid described above, and is not particularly limited as long as it is pharmaceutically acceptable. For example, a water-soluble salt, specifically, Examples include alkali metal salts such as sodium salts and potassium salts; ammonium salts; transition metal salts such as zinc salts and copper salts. As shown in Test Example 2 to be described later, the calcium salt of alginic acid cannot sufficiently suppress calcium absorption derived from calcium carbonate and / or calcium acetate, and the effects of the present invention cannot be achieved. Then, it has been confirmed that the calcium absorption can be effectively suppressed. Among these alginate salts other than calcium salts, alkali metal salts are preferable. Alginates other than these calcium salts may be used individually by 1 type, and may be used in combination of 2 or more type.

  In the oral phosphorus adsorbent of the present invention, as the component (ii), one kind of alginate other than alginic acid and calcium salt may be used alone, or two or more kinds may be used in combination. May be. In addition, alginates other than calcium salts strongly suppress calcium absorption from calcium carbonate and / or calcium acetate rather than alginic acid, but show a tendency to slightly relax the phosphorus adsorption action by calcium carbonate and / or calcium acetate. From the viewpoint of exhibiting a phosphorus adsorption action by calcium carbonate and / or calcium acetate and a calcium absorption inhibitory action derived from calcium carbonate and / or calcium acetate in a more efficient and balanced manner, the component (ii) is preferably alginic acid. Is mentioned.

  In the oral phosphorus adsorbent of the present invention, the ratio of the component (i) and the component (ii) may be appropriately set according to the type of the component (i) and the component (ii) used. A range in which the total amount of the component (ii) is 100 parts by weight or less, preferably 2.5 to 100 parts by weight per 100 parts by weight of the total component (i). In particular, if calcium carbonate is used as the component (i), from the viewpoint of further enhancing the calcium absorption inhibitory action while further effectively exhibiting the phosphorus adsorption action, per 100 parts by weight of the total amount of calcium carbonate, The total amount of the component (ii) is preferably 100 parts by weight or less, more preferably 2.5 to 100 parts by weight, particularly preferably 2.5 to 11 parts by weight. Further, if calcium acetate is used as the component (i), from the viewpoint of further enhancing the calcium absorption inhibitory action while further effectively exhibiting the phosphorus adsorption action, per 100 parts by weight of the total amount of calcium acetate, The total amount of component (ii) is preferably 100 parts by weight or less, more preferably 22 to 100 parts by weight, and particularly preferably 55 to 100 parts by weight.

  In addition to the components (i) and (ii), the oral phosphorus adsorbent of the present invention may contain a derivative of alginic acid as necessary. The derivative of alginic acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include ester derivatives such as propylene glycol ester.

  The oral phosphorus adsorbent of the present invention may contain other components exhibiting a phosphorus adsorbing action as required in addition to calcium carbonate and / or calcium acetate within the range not impairing the effects of the present invention. Examples of the component exhibiting such a phosphorus adsorption action (other than calcium carbonate and / or calcium acetate) include sevelamer hydrochloride, polylysine, aluminum gel, and the like.

  In addition, the oral phosphorus adsorbent of the present invention may contain additives such as excipients, binders, disintegrants, lubricants and the like as necessary in order to prepare a desired dosage form. . Examples of the excipient include sugars such as lactose, sucrose, sucrose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered koji, reduced lactose; D-mannitol, erythritol, D-sorbitol, multi Examples include sugar alcohols such as tall and xylitol; starches such as corn starch, potato starch, rice starch, and partially pregelatinized starch. Examples of the binder include hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, pullulan, polyvinylpyrrolidone, magnesium aluminate metasilicate, and the like. Examples of the disintegrant include corn starch, potato starch, rice starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, carmellose, carmellose sodium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropylcellulose, etc. Is mentioned. Examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, sucrose fatty acid ester and the like. These additives may be used individually by 1 type, and may be used in combination of 2 or more type.

  Furthermore, the oral phosphorus adsorbent of the present invention may contain additives such as sweeteners, corrigents, colorants, stabilizers and the like, as necessary, in order to improve the feeling of dosing.

Formulation Form The oral phosphorus adsorbent of the present invention may be a one-drug type preparation comprising a composition containing the component (i) and the component (ii), and the first agent containing the component (i) and A two-agent type preparation in which the second agent containing the component (ii) is separately formulated may be used. From the viewpoint of ease of taking, a single-agent type preparation is preferable.

  When providing the oral phosphorus adsorbent of the present invention as a one-drug type preparation, the content of the component (i) and the component (ii) may be appropriately set according to the dosage form, use, etc. For example, the content of the component (i) is 50 to 99% by weight, preferably 70 to 90% by weight, and more preferably 80 to 85% by weight. The content of the component (ii) is 1 to 50% by weight, Preferably 1-30 weight%, More preferably, 2-20 weight% is mentioned.

  Further, when the oral phosphorus adsorbent of the present invention is provided as a two-part preparation, the content of the component (i) in the first preparation and the content of the component (ii) in the second preparation are as follows. May be appropriately set depending on the dosage form, application, and the like. For example, the content of the component (i) in the first preparation is 70 to 100% by weight, preferably 75 to 90% by weight, and more preferably 80 to 85% by weight. Moreover, as content of (ii) component in a said 2nd formulation, 10 to 100 weight% is mentioned.

  In addition, when providing the oral phosphorus adsorbent of the present invention as a two-part preparation, the aforementioned alginic acid derivative, a component exhibiting a phosphorus adsorbing action (other than calcium carbonate and / or calcium acetate), an additive and the like are blended. In this case, these may be contained in either the first agent or the second agent, or may be contained in both of them.

Dosage Form The dosage form of the oral phosphorus adsorbent of the present invention is not particularly limited as long as it can be administered orally, and examples thereof include solid forms such as tablets, pills, powders, granules, capsules and the like. It is done. Among these, Preferably, a tablet, a granule, and a capsule are mentioned. When the oral phosphorus adsorbent of the present invention is made into a tablet, pill, or granule dosage form, a coating such as sugar coating or enteric coating may be applied as necessary.

  In addition, when the oral phosphorus adsorbent of the present invention is provided as a two-drug type preparation, the first agent and the second agent may be in the same dosage form or in different dosage forms. May be.

  Methods for formulating such a dosage form are known, and can be performed, for example, by the methods described in the Japanese Pharmacopoeia General Rules for Preparation.

Applicable object / administration method The oral phosphorus adsorbent of the present invention can adsorb food-derived phosphorus with calcium carbonate and / or calcium acetate and suppress phosphorus absorption. It is suitably used as a medicament for the prevention or treatment of diseases such as symptoms such as hyperphosphatemia, renal failure, osteoporosis and the like. Further, since the oral phosphorus adsorbent of the present invention can suppress calcium absorption derived from calcium carbonate and / or calcium acetate, chronic kidney disease requiring continuous administration of the phosphorus adsorbent for a long period of time such as dialysis patients. It is also preferably used as a medicament for preventing cardiovascular diseases such as hypercalcemia, vascular calcification, and arteriosclerosis in patients.

  The dosage and number of administrations of the oral phosphorus adsorbent of the present invention are appropriately set according to the age of the administration subject, the degree of symptoms, etc., and for example, 1 in terms of the dosage of calcium carbonate and / or calcium acetate. It is set to be about 3 to 20 g per day, preferably 3 to 10 g, and the number of administrations may be usually set 3 times a day at every meal. In addition, when a two-drug type preparation is used as the oral phosphorus adsorbent of the present invention, the first agent and the second agent may be administered simultaneously or in any order.

2. Alginic acid preparation As described above, alginates other than alginic acid and / or calcium salts exhibit an action of suppressing calcium absorption derived from calcium carbonate and / or calcium acetate in vivo. Therefore, the present invention further comprises an alginic acid preparation for suppressing calcium absorption by an oral phosphorus adsorbent containing calcium carbonate and / or calcium acetate, characterized by containing alginic acid and / or an alginate other than calcium salt. I will provide a. In the present invention, the expression “alginate preparation” means a preparation containing alginate other than alginic acid and / or calcium salt, and the concept of “alginate preparation” includes an alginate other than calcium salt. Also included are formulations containing and free of alginic acid.

  The alginic acid preparation of the present invention is used for suppressing calcium absorption derived from calcium carbonate and / or calcium acetate when an oral phosphorus adsorbent containing calcium carbonate and / or calcium acetate is administered. That is, the alginic acid preparation of the present invention is a preparation administered to a patient prescribed an oral phosphorus adsorbent containing calcium carbonate and / or calcium acetate and not containing alginic acid and / or an alginate other than calcium salt. is there.

  The types of alginates other than alginic acid and / or calcium salts used in the alginic acid preparation of the present invention are as described in “1. Oral phosphorus adsorbent”. The content of alginates other than alginic acid and / or calcium salt in the alginic acid preparation of the present invention, other components that can be added, dosage forms, application targets, administration methods, etc. are described in the above “1. Oral phosphorus adsorbent”. This is the same as the case of the second agent shown in the column.

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

Test example 1
For alginic acid, pectin, guar gum, and fructooligosaccharide, the calcium absorption suppression effect by administration of calcium carbonate was evaluated. Pectin is known to bind to calcium ions and gel like alginic acid. Guar gum is also used as a thickening polysaccharide like alginic acid. Fructooligosaccharides have been reported to have the effect of promoting calcium absorption. The specific test method is as shown below.

  Seven-week-old male rats (Crl: CD (SD) Nippon Charles River) were prepared and allowed to freely feed a diet having the composition shown in Table 1. Two days after the start of intake of the feed, urine was collected for 24 hours, and the amount of calcium excreted in urine was measured by a colorimetric method (OCPC method). This test was performed using 3 rats in each group, and the average value of urinary calcium excretion was calculated.

  The obtained results are shown in FIG. From this result, when calcium carbonate and alginic acid were used in combination (Example 1), the amount of calcium excreted in urine was reduced, and calcium absorption was higher than that of calcium carbonate alone (Comparative Example 1-1). It became clear that it can be suppressed. On the other hand, when pectin, guar gum or fructooligosaccharide was used together with calcium carbonate, a tendency that calcium absorption was promoted was observed (Comparative Examples 1-2 to 1-4).

Test example 2
In Test Example 1, since it was confirmed that alginic acid has a calcium absorption inhibitory effect by administration of calcium carbonate, the calcium absorption inhibitory effect and phosphorus adsorption effect by calcium carbonate administration were evaluated using alginic acid and its salt. . The specific test method is as shown below.

  Seven-week-old male rats (Crl: CD (SD) Nippon Charles River) were prepared and allowed to freely ingest the diet shown in Table 2. Two days after the start of intake of the feed, urine was collected for 24 hours, and the amount of calcium excretion and phosphorus excretion in the urine was measured. The amount of calcium excreted in urine was measured by a colorimetric method (OCPC method), and the amount of phosphorus excreted in urine was measured by a colorimetric method (phosphomolybdic acid method). In addition, this test was performed using 5 rats in each group, and the average values of calcium excretion and phosphorus excretion in urine were calculated.

  The obtained results are shown in FIG. From this result, when calcium carbonate and alginic acid were used in combination (Example 2-1), the amount of urinary calcium excretion was the same as that of Test Example 1 (Comparative Example 2-1). In comparison, it was significantly reduced, and absorption of calcium could be suppressed. Moreover, the urinary phosphorus excretion amount was equivalent to the case of calcium carbonate alone (Comparative Example 2-1), and the phosphorus adsorption ability of calcium carbonate could be effectively exhibited.

  In addition, when calcium carbonate and sodium alginate or potassium alginate were used in combination (Examples 2-2 to 2-5), although calcium absorption suppression effect was observed, calcium carbonate alone (Comparative Example 2-1) In comparison, a slight upward trend was observed in urinary phosphorus excretion. The combined use of calcium carbonate and alginic acid was considered more desirable because of the balance between the calcium absorption inhibitory effect and the phosphorus adsorption effect.

In contrast, when calcium carbonate and calcium alginate are used in combination (Comparative Example 2-2)
Then, absorption of calcium was promoted, and no calcium absorption suppression effect was observed.

  From the above results, by selecting a combination of calcium carbonate and alginate other than alginic acid and / or calcium salt, calcium absorption to the living body can be effectively suppressed while effectively exhibiting the phosphorus adsorption ability of calcium carbonate. Was confirmed.

Test example 3
Alginic acid is known to be of swellable and non-swellable types. Therefore, swellable and non-swellable alginic acid was used, and the calcium absorption suppression effect and phosphorus adsorption effect by calcium carbonate administration were evaluated. The specific test method is the same as in Test Example 2 except that the feed having the composition shown in Table 3 was used.

  The obtained results are shown in FIG. From this result, when non-swelling property is used as alginic acid, the amount of urinary calcium excretion is significantly lower than when swelling property is used, and it shows excellent calcium absorption suppression effect. Became clear.

Test example 4
The influence of the ratio of calcium carbonate and alginic acid on the calcium absorption inhibition effect and phosphorus adsorption effect was evaluated. The specific test method is as shown below.

  Seven-week-old male rats (Crl: CD (SD) Nippon Charles River) were prepared and allowed to freely feed a diet having the composition shown in Table 4. Seven days after the start of intake of the feed, urine was collected for 24 hours, and the amount of calcium excretion and phosphorus excretion in the urine was measured by the same method as in Test Example 2. This test was performed using 5 rats in each group, and the average values of calcium excretion and phosphorus excretion in urine were calculated.

  The obtained results are shown in FIG. From this result, when alginic acid is contained in a ratio of 2.5 to 100 parts by weight with respect to 100 parts by weight of calcium carbonate, calcium absorption to the living body is achieved while effectively exerting the phosphorus adsorption ability of calcium carbonate. It was confirmed that it can be suppressed more effectively. Although not shown in FIG. 4, in the case where alginic acid is contained at a ratio of 0.5 part by weight or 1.0 part by weight with respect to 100 parts by weight of calcium carbonate, the calcium absorption suppression effect and the phosphorus adsorption effect However, as compared with the case of Example 4-1, the calcium absorption suppression effect was inferior.

Test Example 5
In Test Example 2, it was confirmed that alginate other than alginic acid and / or calcium salt can effectively suppress calcium absorption while effectively exhibiting the phosphorus adsorption action of calcium carbonate. Therefore, in this test, when calcium acetate was administered, the calcium absorption suppression effect and phosphorus adsorption effect by alginates other than alginic acid and / or calcium salts were evaluated. The specific test method is the same as in Test Example 2 except that the feed having the composition shown in Table 5 was used.

  The obtained results are shown in FIG. From this result, when calcium acetate and alginic acid were used in combination (Example 5-1), the amount of calcium excreted in urine was significantly reduced compared to the case of calcium acetate alone (Comparative Example 5-1). And the absorption of calcium could be suppressed. Moreover, the amount of urinary phosphorus excretion was equivalent to that of calcium acetate alone (Comparative Example 5-1), and the phosphorus adsorption ability of calcium acetate could be effectively exhibited. Furthermore, even when calcium acetate and sodium alginate or potassium alginate are used in combination (Examples 5-2 to 5-5), the amount of urinary calcium excretion is lower than that of calcium acetate alone (Comparative Example 5-1). Was.

  From the above results, even when calcium acetate is used, the alginic acid salt other than alginic acid and / or calcium salt can effectively exhibit the phosphorus adsorption action of calcium acetate, even in the case of the test example 2. However, it has been confirmed that there is an action of effectively suppressing calcium absorption.

Test Example 6
In Test Example 3, when calcium carbonate was administered, when non-swelling property was used as alginic acid, a significant decrease in the amount of calcium excreted in urine was observed compared to when swelling property was used. . Therefore, in this test, swellable and non-swellable alginic acid was used, and the calcium absorption suppression effect and phosphorus adsorption effect by calcium acetate administration were evaluated. The specific test method is the same as in Test Example 2 except that the feed having the composition shown in Table 6 was used.

  The obtained result is shown in FIG. From this result, when non-swelling property is used as alginic acid, the amount of excreted urinary calcium is lower than when swelling property is used, and it shows an excellent calcium absorption inhibition effect. It became clear. Moreover, also in the phosphorus adsorption | suction effect, when non-swelling property was used, it was able to be effectively exhibited compared with the case where swelling property was used. That is, from this result, even when calcium acetate is used, in the case of using non-swelling property as alginic acid, as in the case of Test Example 3, urinary calcium is used as compared with the case of using swelling property. It was confirmed that the excretion amount can be remarkably reduced and an excellent calcium absorption suppression effect is exhibited.

Test Example 7
The influence of the ratio of calcium acetate and alginic acid on the calcium absorption inhibition effect and the phosphorus adsorption effect was evaluated. The specific test method is the same as in Test Example 2 except that the feed having the composition shown in Table 7 was used.

  The obtained results are shown in FIG. From this result, when alginic acid is contained in a ratio of 22 to 100 parts by weight with respect to 100 parts by weight of calcium acetate, calcium absorption to the living body is further enhanced while effectively exerting the phosphorus adsorption ability of calcium acetate. It was confirmed that it can be effectively suppressed.

Test Example 8
As the alginic acid, a Normal type, a High M type, and a High G type are known depending on the M / G ratio. Therefore, in this test, the influence of the M / G ratio of alginic acid on the calcium absorption suppression effect and phosphorus adsorption effect by calcium carbonate administration was evaluated. The specific test method is the same as in Test Example 2 except that the feed having the composition shown in Table 8 was used.

  The obtained result is shown in FIG. From these results, it was confirmed that even if alginic acid was used regardless of the M / G ratio, the calcium absorption inhibitory effect was confirmed, but High M type alginic acid having M / G ratios of 1.2 and 1.6 was used. In some cases, a markedly excellent calcium absorption inhibitory effect was observed.

Claims (9)

An oral phosphorus adsorbent characterized by being a one-part preparation comprising a composition containing (i) calcium carbonate and / or calcium acetate, and (ii) alginic acid and / or an alkali metal salt thereof . The oral phosphorus adsorbent according to claim 1, comprising alginic acid and / or an alkali metal salt thereof in a total amount of 100 parts by weight or less with respect to 100 parts by weight of calcium carbonate and / or calcium acetate.   The oral phosphorus adsorbent according to claim 1 or 2, wherein the alginic acid is non-swellable. The oral phosphorus adsorption agent according to any one of claims 1 to 3, wherein a ratio of mannuronic acid / guluronic acid of alginic acid and / or an alkali metal salt thereof is 0.8 or more. The oral phosphorus adsorbent according to any one of claims 1 to 4 , which is a tablet, granule, powder, or capsule. Oral phosphorus adsorption, characterized in that it is a two-part combination preparation comprising (i) a first agent containing calcium carbonate and / or calcium acetate and (ii) a second agent containing non-swellable alginic acid Agent . (i) a first agent containing calcium carbonate and / or calcium acetate, and (ii) a second agent containing alginic acid and / or an alkali metal salt thereof having a ratio of mannuronic acid / guluronic acid of 0.8 or more , An oral phosphorus adsorbent, which is a two-part combination preparation. An alginic acid preparation for suppressing calcium absorption by an oral phosphorus adsorbent containing calcium carbonate and / or calcium acetate, comprising non-swellable alginic acid. Inhibition of calcium absorption by an oral phosphorus adsorbent containing calcium carbonate and / or calcium acetate, characterized by containing alginic acid and / or an alkali metal salt thereof having a ratio of mannuronic acid / guluronic acid of 0.8 or more Alginate preparation for.