JP6360415B2 - Lanthanum low absorption type oral phosphorus adsorption agent - Google Patents

Description

  The present invention relates to a lanthanum 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 a lanthanum compound and effectively suppressing absorption of lanthanum derived from the lanthanum compound into the living body.

  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. Oral phosphorus adsorbents include inorganic preparations containing metal salts such as calcium salts and lanthanum compounds 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, lanthanum compounds such as lanthanum carbonate are biliary excretion type, so even in patients with impaired renal function, organ accumulation is low, and there are few side effects. Is growing. Regarding the pharmacokinetics of lanthanum compounds, orally administered lanthanum compounds dissociate lanthanum ions by contact with gastric fluid (pH about 1.2) and adsorb phosphorus in the gastrointestinal tract to form poorly soluble substances. Thus, it is known that phosphorous excretion into the stool is promoted to exert an action of inhibiting phosphorus absorption into the body.

  However, although the lanthanum compound is a biliary excretion type, excess lanthanum ions existing in the digestive tract can be absorbed in the small intestine including the duodenum (pH around 5.0) and accumulate in the living body. Are known. In fact, it has been reported that lanthanum is accumulated in the body of patients with reduced renal function receiving lanthanum compounds, and there is concern about the effects of accumulation in the gastrointestinal tract, liver, and bone tissue during long-term use. (Non-Patent Document 1).

  Therefore, in order to enhance safety when administering a lanthanum compound as an oral phosphorus adsorbent, development of an oral phosphorus adsorbent that can effectively suppress lanthanum absorption in vivo is desired.

  On the other hand, alginic acid is a polysaccharide contained in dry algae and is a kind of dietary fiber. Alginate is composed of D-mannuronic acid and L-guluronic acid, 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. Is a salt of a block copolymer in which blocks randomly connected (MG blocks) are bonded arbitrarily. 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.

  Alginates are easily dissolved in water and have a thickening action, and are easily gelled by coexistence with calcium ions. As a thickener, gelling agent, stabilizer, etc., it has long been used in the food field. It is also used as a food additive. Due to the above properties, alginates were feared to have an inhibitory effect on calcium absorption. However, in administration studies with humans and rats, it has been reported that alginate does not inhibit calcium absorption in vivo (non-patented). References 2 and 3).

  In these prior documents, there is no report on the interaction when an alginate and a lanthanum compound are administered, and that the alginate suppresses the absorption of lanthanum.

Calc Tissue Int. 2006; 78 (4): 241-247. 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

  Therefore, an object of the present invention is to provide an oral phosphorus adsorbent capable of adsorbing phosphorus in the body by a lanthanum compound and effectively suppressing absorption of lanthanum derived from the lanthanum compound.

  As a result of diligent studies to solve the above problems, the present inventors have used an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less when administering a lanthanum compound as an oral phosphorus adsorbent, It has been found that lanthanum compounds can effectively suppress the absorption of lanthanum into the living body while effectively exhibiting the phosphorus adsorption ability of the lanthanum compound. The present invention has been completed by further studies based on such knowledge.

That is, this invention provides the invention of the aspect hung up below.
Item 1. An oral phosphorus adsorbent comprising (i) a pharmaceutically acceptable lanthanum compound and (ii) an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less.
Item 2. The oral phosphorus adsorbent according to Item 1, wherein the alkali metal salt of alginic acid has an average molecular weight of 550,000 or less.
Item 3. Item 3. The oral phosphorus adsorbent according to Item 1 or 2, comprising an alkali metal salt of alginic acid in a total amount of 200 parts by weight or less with respect to 100 parts by weight of the lanthanum compound in terms of lanthanum atomic weight.
Item 4. Item 4. The oral phosphorus adsorbent according to any one of Items 1 to 3, wherein the alkali metal salt of alginic acid has a mannuronic acid / guluronic acid molar ratio of 0.1 or more.
Item 5. Item 5. The oral phosphorus adsorbent according to any one of Items 1 to 4, wherein the alkali metal salt of alginic acid has a ratio of mannuronic acid-guluronic acid bonds to total glycosidic bonds of 50% or less.
Item 6. Item 6. The oral phosphorus adsorbent according to any one of Items 1 to 5, wherein the lanthanum compound is at least one selected from the group consisting of lanthanum carbonate, lanthanum hydroxide carbonate, lanthanum chloride, and lanthanum hydroxide.
Item 7. Item 7. The oral phosphorus adsorbent according to any one of Items 1 to 6, which is a tablet, granule, powder, or capsule.
Item 8. Any one of Items 1 to 7, which is a one-agent type preparation comprising a composition containing (i) a pharmaceutically acceptable lanthanum compound, and (ii) an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less. Oral phosphorus adsorption agent as described in 2.
Item 9. a two-agent type combination preparation comprising (i) a first agent comprising a pharmaceutically acceptable lanthanum compound and (ii) a second agent comprising an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less. The oral phosphorus adsorption agent in any one of claim | item 1 -7.
Item 10. An alginic acid preparation for suppressing lanthanum absorption by an oral phosphorus adsorbent containing a pharmaceutically acceptable lanthanum compound, comprising an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less.

  According to the present invention, since the absorption of lanthanum into a living body can be effectively suppressed while effectively exhibiting the phosphorus adsorption ability of the lanthanum compound, an oral phosphorus adsorbent of low lanthanum absorption type can be provided. Therefore, according to the present invention, it becomes possible to effectively prevent or treat hyperphosphatemia and the like while suppressing the accumulation of lanthanum due to long-term or excessive doses of lanthanum compounds.

In Experiment 1, it is a figure which shows the result of having measured the residual amount of lanthanum (La) and phosphorus (P). In Experiment 2, it is a figure which shows the result of having measured the residual amount of lanthanum (La) and phosphorus (P). In Experiment 3, it is a figure which shows the result of having measured the residual amount of lanthanum (La) and phosphorus (P). In Experiment 4, it is a figure which shows the result of having measured the residual amount of lanthanum (La) and phosphorus (P).

1. Oral phosphorus adsorbent The oral phosphorus adsorbent of the present invention is characterized by containing a pharmaceutically acceptable lanthanum compound and an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less. Hereinafter, the oral phosphorus adsorbent of the present invention will be described in detail.

Containing Components The oral phosphorus adsorbent of the present invention uses a lanthanum compound as a component that adsorbs phosphorus in vivo.

  The type of lanthanum compound used in the present invention is not particularly limited as long as it is pharmaceutically acceptable and can release lanthanum ions in the digestive tract, and is pharmaceutically acceptable. For example, lanthanum carbonate, Examples thereof include lanthanum hydroxide carbonate, lanthanum chloride, lanthanum hydroxide, lanthanum citrate, lanthanum sulfate, lanthanum nitrate, lanthanum acetate, lanthanum oxide, lanthanum acetylacetate, lanthanum octanoate, lanthanum glycolate, and lanthanum tartrate. Further, these lanthanum compounds may be anhydrides or hydrates. These lanthanum compounds may be used individually by 1 type, and may be used in combination of 2 or more type.

  Among these lanthanum compounds, lanthanum carbonate, lanthanum hydroxide carbonate, lanthanum chloride, and lanthanum hydroxide are preferable. In particular, lanthanum carbonate and lanthanum chloride are preferable, and lanthanum carbonate is more preferable from the viewpoint of high phosphorus adsorption capacity and low elution of lanthanum ions.

  The oral phosphorus adsorbent of the present invention contains an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less. In this way, by using an alkali metal salt of alginic acid having a specific average molecular weight, it is possible to effectively suppress the absorption of lanthanum carbonate derived from lanthanum carbonate in vivo while effectively exhibiting the phosphorus adsorption action by lanthanum carbonate. It becomes possible.

  In the present invention, the average molecular weight of the alkali metal salt of alginic acid is not particularly limited as long as it is 1.1 million or less, but preferably 550,000 or less from the viewpoint of further effectively improving the lanthanum absorption suppressing action. More preferably, 100,000 or less is mentioned. Further, the lower limit of the average molecular weight of the alkali metal salt of alginic acid is not particularly limited, but is usually 1,000 or more, preferably 10,000 or more. In addition, in this invention, the said average molecular weight is a weight average molecular weight of pullulan conversion calculated | required by GPC method.

  Further, in the alkali metal salt of alginic acid used in the present invention, the ratio (molar ratio) of mannuronic acid to gluronic acid is not particularly limited. For example, the ratio of mannuronic acid to glulonic acid (M / G ratio) 0.1 or more. The upper limit value of the M / G ratio of the alkali metal salt of alginic acid is not particularly limited, and examples thereof include 11 or less. In particular, from the viewpoint of more effectively suppressing lanthanum absorption, the M / G ratio of the alkali metal salt of alginic acid is preferably 0.15 to 2, and more preferably 0.25 to 2.

  In the alkali metal salt of alginic acid used in the present invention, the ratio of the binding of mannuronic acid-guluronic acid to the total glycosidic bond (hereinafter sometimes referred to as “MG bond ratio”) is not particularly limited. Preferably, 50% or less is mentioned. Further, the lower limit value of the MG bond ratio of the alkali metal salt of alginic acid is not particularly limited, but is usually 10% or more.

In the present invention, the MG bond ratio is a value determined by NMR analysis, and the specific measurement method is as follows. First, a ¹ H-NMR spectrum of an alkali metal salt of alginic acid was obtained, and a peak derived from a mannuronic acid-mannuronic acid bond (MM bond) (mannuron located on the 1-position side of the 1,4-glycoside bond). Integrated value of the peak of the proton at the 1st position of the acid), integrated value of the peak derived from the bond of mannuronic acid-guluronic acid (MG bond) (peak of the proton at the 1st position of mannuronic acid), mannuronic acid-guluronic acid- Integral value of peak derived from mannuronic acid bond (MGGM bond) (5-position proton peak of gluronic acid), derived from guluronic acid-guluronic acid-guluronic acid bond (G-G-G bond) The integrated value of the peak (the peak of the 5-position proton of guluronic acid located in the center), the peak derived from the bond of mannuronic acid-guluronic acid-guluronic acid (MG bond) (5 of guluronic acid located in the middle) Place (Integral value of proton peak) and the integral value of the peak derived from the bond (G-GM bond) of guluronic acid-guluronic acid-mannuronic acid (the proton peak at the 5-position of guluronic acid located in the center). . Next, the MG bond ratio is calculated according to the following formula.

  The alkali metal salt of alginic acid having the MG bond ratio can be obtained by a known production method. For example, in the alkali metal salt of alginic acid, the MG bond is known to be easily hydrolyzed under high temperature conditions as compared with the MM bond and GG bond. Alkaline metal salt of alginic acid satisfying the above range can be obtained by hydrolyzing alkali metal salt of alginic acid exceeding 50% under high temperature conditions.

  The type of alkali metal salt of alginic acid used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include sodium salt and potassium salt. Among these alkali metal salts of alginic acid, a sodium salt is preferable. These alkali metal salts of alginic acid may be used alone or in combination of two or more.

  In the oral phosphorus adsorbent of the present invention, the ratio of the lanthanum compound and the alkali metal salt of alginic acid may be appropriately set according to the type of lanthanum compound used and the type of alkali metal salt of alginic acid. A range in which the alkali metal salt of alginic acid is 200 parts by weight or less, preferably 100 parts by weight or less per 100 parts by weight of the total amount of lanthanum compound in terms of lanthanum atomic weight. Moreover, the lower limit of the ratio of the alkali metal salt of alginic acid per 100 parts by weight of the lanthanum compound in terms of the lanthanum atomic weight is not particularly limited, and examples thereof include 1 part by weight or more, preferably 5 parts by weight or more.

  Moreover, the oral phosphorus adsorbent of the present invention may contain a derivative of alginic acid, if necessary, in addition to the lanthanum compound and the alkali metal salt of alginic acid. 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 the lanthanum compound within a range not impairing the effects of the present invention. Examples of the component (other than the lanthanum compound) exhibiting such a phosphorus adsorption action include calcium carbonate, calcium acetate, sevelamer hydrochloride, polylysine, and aluminum gel.

  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-agent type preparation comprising a composition containing the lanthanum compound and the alkali metal salt of alginic acid, and the first agent containing the lanthanum compound and the alginic acid. It may be a two-agent type preparation in which the second agent containing an alkali metal salt is separately formulated. 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 alkali metal salt of the lanthanum compound and the alginic acid may be appropriately set according to the dosage form, application, etc. The lanthanum compound content is 10 to 99% by weight, preferably 20 to 90% by weight, and the alkali metal salt content of alginic acid is 1 to 90% by weight, preferably 1 to 80% by weight.

  Further, when providing the oral phosphorus adsorbent of the present invention as a two-drug type preparation, the content of the lanthanum compound in the first preparation and the content of the alkali metal salt of alginic acid in the second preparation are as follows: What is necessary is just to set suitably according to a dosage form, a use, etc. For example, the content of the lanthanum compound in the first preparation is 10 to 100% by weight, preferably 20 to 90% by weight. Moreover, 10 to 100 weight% is mentioned as content of the alkali metal salt of alginic acid in the said 2nd formulation.

  Moreover, when providing the oral phosphorus adsorbent of the present invention as a two-drug type preparation, when blending the aforementioned alginic acid derivative, a component exhibiting a phosphorus adsorption action (other than a lanthanum compound), an additive, etc., It 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 oral administration is possible. For example, solid forms such as tablets, pills, powders, granules, capsules, etc .; syrup And the like. 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 a lanthanum compound and suppress phosphorus absorption, so various diseases caused by excessive intake of phosphorus, etc. It is suitably used as a medicament for the prevention or treatment of symptoms such as phosphateemia, renal failure and osteoporosis. In addition, since the oral phosphorus adsorbent of the present invention can suppress the absorption of lanthanum derived from a lanthanum compound, dialysis patients who need to take a phosphorus adsorbent containing a lanthanum compound continuously for a long period of time and renal failure in conservative phase Even in chronic kidney disease patients such as patients, it is suitably used as a medicine suitable for long-term use with little lanthanum accumulation.

  The dose and frequency of administration of the oral phosphorus adsorbent of the present invention are appropriately set according to the age of the subject and the degree of symptoms. For example, the dose per day of the lanthanum compound in terms of lanthanum atomic weight It is set to be about 0.25 to 3.00 g, preferably 0.75 to 2.25 g, and the number of administrations is usually set three 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, an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less exhibits an action of suppressing lanthanum compound-derived lanthanum absorption in vivo. Therefore, the present invention further suppresses lanthanum absorption by an oral phosphorus adsorbent containing a pharmaceutically acceptable lanthanum compound, which contains an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less. Of alginate preparations.

  The alginic acid preparation of the present invention is used for suppressing absorption of lanthanum derived from the lanthanum compound when an oral phosphorus adsorbent containing the lanthanum compound 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 a lanthanum compound and not containing an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less.

  The composition, type and the like of the alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less used in the alginic acid preparation of the present invention are as described in “1. Oral phosphorus adsorbent”. The content of alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less in the alginic acid preparation of the present invention, other components that can be added, dosage form, application target, administration method, etc. are described in “1. Oral Phosphorus Adsorption”. This is the same as the case of the second agent shown in the column “Agent”.

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

Production Example A lanthanum compound and various sodium alginate were produced or prepared by the method described below.

[Lantern carbonate]
After adding 170.8 g (0.46 mol, Wako Pure Chemical Industries, Ltd.) and purified water to 3 L beaker, lanthanum chloride heptahydrate was made up to 992.6 g, and stirred and dissolved while maintaining at 30 ° C. A lanthanum chloride aqueous solution was obtained. Purified water was added to 115 g of sodium carbonate, and an aqueous sodium carbonate solution having a total amount of 540 mL was added dropwise to the stirred lanthanum chloride aqueous solution, and the addition was stopped when the pH reached 9.7. This reaction product was filtered and washed with water, and the obtained reaction product after washing with water was placed in a dryer and dried at 80 ° C. for 12 hours to obtain lanthanum carbonate tetrahydrate.

[Lanthanum chloride]
As lanthanum chloride, lanthanum chloride heptahydrate (Wako Pure Chemical Industries, Ltd.) was used.

[Sodium alginate 1]
As sodium alginate 1, sodium alginate ("Kimika Argin IL-6", Kimika Co., Ltd.) was used. The sodium alginate 1 had an MG bonding rate of 43%, a GG bonding rate of 21%, an MM bonding rate of 36%, an M / G ratio of 0.8, and an average molecular weight of 1.05 million.

[Sodium alginate 2]
As sodium alginate 2, sodium alginate ("Kimika Algin ULV-5", Kimika Co., Ltd.) was used. The sodium alginate 2 had an MG bond rate of 40%, a GG bond rate of 20%, an MM bond rate of 40%, an M / G ratio of 1.15, and an average molecular weight of 150,000.

[Sodium alginate 3]
As sodium alginate 3, sodium alginate ("Kimika Algin ULV-3", Kimika Co., Ltd.) was used. The sodium alginate 3 had an MG bond rate of 40%, a GG bond rate of 25%, an MM bond rate of 35%, an M / G ratio of 1.21, and an average molecular weight of 130,000.

[Sodium alginate 4]
As sodium alginate 4, sodium alginate ("Kimika Algin ULV-1", Kimika Co., Ltd.) was used. The sodium alginate 4 had an MG bond rate of 39%, a GG bond rate of 25%, an MM bond rate of 36%, an M / G ratio of 1.19, and an average molecular weight of 110,000.

[Sodium alginate 5]
As sodium alginate 5, sodium alginate ("Kimika Algin ULV-L3", Kimika Co., Ltd.) was used. The sodium alginate 5 had an MG bonding rate of 33%, a GG bonding rate of 35%, an MM bonding rate of 32%, an M / G ratio of 1.15, and an average molecular weight of 60,000.

[Sodium alginate 6]
As sodium alginate 6, sodium alginate (“sodium alginate 80-120”, Wako Pure Chemical Industries, Ltd.) was used. The sodium alginate 6 had an MG bond rate of 49%, a GG bond rate of 15%, an MM bond rate of 36%, an M / G ratio of 1.25, and an average molecular weight of 2,050,000.

[Sodium alginate 7]
Sodium alginate (“Kimika Algin IL-6M”, Kimika Co., Ltd.) was dissolved in purified water to 1% by weight, and an aqueous hydrochloric acid solution was added to convert it into an alginate gel. The obtained alginate gel solution was heat-treated at 95 ° C. for about 120 minutes. After completion of the heat treatment, the mixture was cooled to room temperature and the alginic acid was washed with water, followed by dehydration, drying and pulverization to obtain alginic acid. The obtained alginic acid had an MG bond rate of 20%, a GG bond rate of 27%, an MM bond rate of 53%, an M / G ratio of 1.7, and an average molecular weight of 40,000. This alginic acid was suspended in purified water so as to be 1.25% by weight, and the pH was adjusted to 7 with an aqueous sodium hydroxide solution to obtain sodium alginate 7.

[Sodium alginate 8]
Non-swellable alginic acid (“Wako primary alginic acid”, Wako Pure Chemical Industries, Ltd.) was heated at 80 ° C. for 13 days to obtain alginic acid. The obtained alginic acid had an MG bond ratio of 43%, a GG bond ratio of 14%, an MM bond ratio of 43%, an M / G ratio of 1.4, and an average molecular weight of 50,000. This alginic acid was suspended in purified water so as to be 1.25% by weight, and the pH was adjusted to 7 with an aqueous sodium hydroxide solution to obtain sodium alginate 8.

[Sodium alginate 9]
Sodium alginate (“Kimika Argin I-3”, Kimika Co., Ltd.) was dissolved in purified water to 1 wt%, and an aqueous hydrochloric acid solution was added to convert it into an alginate gel. Next, alginic acid was recovered and washed with water, followed by dehydration, drying and pulverization to obtain alginic acid. The obtained alginic acid had an MG bond ratio of 49%, a GG bond ratio of 18%, an MM bond ratio of 33%, an M / G ratio of 0.8, and an average molecular weight of 410,000. This alginic acid was suspended in purified water so as to be 1.25% by weight, and the pH was adjusted to 7 with an aqueous sodium hydroxide solution to obtain sodium alginate 9.

[Sodium alginate 10]
Alginic acid was obtained by operating under the same conditions as in the case of sodium alginate 9 except that “Kimika Algin IL-6G” (Kimika Co., Ltd.) was used as the sodium alginate. The obtained alginic acid had an MG bond rate of 32%, a GG bond rate of 49%, an MM bond rate of 19%, an M / G ratio of 0.15, and an average molecular weight of 510,000. This alginic acid was suspended in purified water so as to be 1.25% by weight, and the pH was adjusted to 7 with an aqueous sodium hydroxide solution to obtain sodium alginate 10.

[Sodium alginate 11]
Alginic acid was obtained by operating under the same conditions as in the case of sodium alginate 9 except that “Kimika Algin IL-6M” (Kimika Co., Ltd.) was used as the sodium alginate. The obtained alginic acid had an MG bond ratio of 45%, a GG bond ratio of 10%, an MM bond ratio of 45%, an M / G ratio of 1.6, and an average molecular weight of 530,000. This alginic acid was suspended in purified water so as to be 1.25% by weight, and the pH was adjusted to 7 with an aqueous sodium hydroxide solution to obtain sodium alginate 11.

  The MG bond rate, GG bond rate, MM bond rate, M / G ratio, and average molecular weight were measured by the methods described below.

<Measurement method of MG bond ratio, GG bond ratio, MM bond ratio, and M / G ratio>
A spectrum of ¹ H-NMR was obtained for sodium alginate or alginic acid constituting sodium alginate. The MG bond ratio was determined according to the method described above based on the ¹ H-NMR spectrum. Further, the GG bond ratio and the MM bond ratio are values calculated according to the following formula based on the spectrum of ¹ H-NMR.

The M / G ratio is described in “Keiichiro Matsushima et al., Selective Decomposition of Alginic Acid by Supercritical / Subcritical Water Microreaction, Hokkaido Industrial Test Station Report No. 305, 2006, pp. 39-44”. According to the method of ^{1, it} was measured by ¹ H-NMR.

<Measurement method of average molecular weight>
About the average molecular weight of the alginic acid which comprises sodium alginate or sodium alginate, the weight average molecular weight of pullulan conversion was computed using the Shimadzu Corporation GPC system. Specific measurement conditions are as follows.
Preparation of measurement solution : A 0.1% by weight sodium alginate solution was prepared using a 0.1 M aqueous sodium nitrate solution.
Column used : Shodex SB-806M HQ
Reference material : Pullulan (STANDARD P-82, manufactured by Shodex)
Mobile phase : 0.1 M sodium nitrate aqueous solution
Detector : Differential refractometer
Column temperature : 40 ° C
Flow rate : 1.0 mL / min

Test example 1
Using the sodium alginate 1 to 6, the phosphorus adsorption ability by lanthanum carbonate and the lanthanum absorption suppression effect by sodium alginate were evaluated. The specific test method is as follows.

  First, 50 mL of 10 mM phosphoric acid aqueous solution adjusted to pH 1.2 with hydrochloric acid was put into a 100 mL beaker, and an oral phosphorus adsorbent shown in Table 1 was added using a stirrer (RCN-7, manufactured by Tokyo Rika Kikai Co., Ltd.). And stirred for 10 minutes. Thereafter, a 0.5 mol / L sodium hydroxide aqueous solution was dropped at a rate of 1 g / min with a metering pump (MP-2000, Tokyo Rika Kikai Co., Ltd.), and the pH in the beaker was changed over time to adjust the pH to 5 When it reached 0.0, 2 mL sampling was performed. The sampled solution was filtered through a 0.45 μm membrane filter, and the lanthanum and phosphorus concentrations were measured using an inductively coupled plasma (ICP) emission spectroscopic analyzer.

Specific measurement conditions for measurement of lanthanum and phosphorus concentrations are as follows.
1 mL of the sampled solution, 1 mL of dilute nitric acid and 1 mL of yttrium standard solution (100 ppm) are added to make exactly 20 mL with ultrapure water, which is used as a sample solution. By inductively coupled plasma emission spectroscopy, lanthanum in the sample solution, And phosphorus residual amount was computed. The equipment and conditions used are as follows.
ICP emission spectroscopy analyzer : SPECTRO ARCOS (SII Nanotechnology Inc.)
Detection wavelength : phosphorus 177.495 nm, lanthanum 408.672 nm, yttrium 377.433 nm
Standard solution for atomic absorption analysis : Wako Pure Chemical Industries, Ltd.

  The obtained results are shown in FIG. When lanthanum carbonate and sodium alginate having an average molecular weight of 1.1 million or less (Examples 1 to 5) are combined, the phosphorus concentration is reduced to 1 ppm or less as in the case of lanthanum carbonate alone (Comparative Example 1). It has been confirmed that sodium alginate of 1.1 million or less does not reduce the phosphorus adsorption ability of lanthanum carbonate. Further, when lanthanum carbonate and sodium alginate having an average molecular weight of 1.1 million or less (Examples 1 to 5) are combined, the lanthanum concentration can be reduced as compared with the case of lanthanum carbonate alone (Comparative Example 1), and the average molecular weight is reduced. It was confirmed that sodium alginate of 1.1 million or less has lanthanum adsorption ability. In particular, it has also been clarified that the lanthanum adsorption ability of sodium alginate improves as the average molecular weight decreases, even within an average molecular weight of 1.1 million or less. On the other hand, with a molecular weight of 2,050,000 (Comparative Example 2), which is a general sodium alginate, the phosphoric acid concentration was 1 ppm or less, but the lanthanum adsorption capacity was almost the same as that of lanthanum carbonate alone (Comparative Example 1).

Test example 2
Except for using the oral phosphorus adsorbent shown in Table 2, the phosphorus adsorption ability by lanthanum carbonate and the lanthanum absorption inhibitory effect by sodium alginate were evaluated under the same conditions as in Test Example 1.

  The obtained results are shown in FIG. In the case of combining lanthanum carbonate and sodium alginate having an average molecular weight of 1.1 million or less (Examples 6 to 10), the lanthanum concentration was reduced compared to the case of lanthanum carbonate alone (Comparative Example 3). It was observed that the lower the average molecular weight, the higher the lanthanum adsorption ability of sodium alginate. In addition, in sodium alginate having an average molecular weight of 1.1 million or less, when the M / G ratio is in the range of 0.15 to 1.7, particularly when the M / G ratio is around 1, the lanthanum absorptive ability is remarkably excellent. confirmed.

Test example 3
Except that the oral phosphorus adsorbent shown in Table 3 was used, the phosphorus adsorption ability by lanthanum carbonate and the lanthanum absorption inhibitory effect by sodium alginate were evaluated under the same conditions as in Test Example 1.

  The obtained results are shown in FIG. In the case of combining lanthanum carbonate and sodium alginate having an average molecular weight of 1.1 million or less (Examples 11 to 15), the lanthanum concentration could be reduced as compared with the case of lanthanum carbonate alone (Comparative Example 4). Further, from this result, it was confirmed that lanthanum can be effectively adsorbed by adding 5 to 200 parts by weight of sodium alginate with respect to 100 parts by weight in terms of lanthanum atomic weight.

Test example 4
Using the sodium alginate 5, the phosphorus adsorption ability by lanthanum chloride and the lanthanum absorption suppression effect by sodium alginate were evaluated. Specifically, the phosphorus adsorption ability by lanthanum chloride and the lanthanum absorption inhibitory effect by sodium alginate were evaluated under the same conditions as in Test Example 1 except that the oral phosphorus adsorbent shown in Table 4 was used.

  The obtained results are shown in FIG. From this result, it was found that even when lanthanum chloride was used as the phosphorus adsorbent, sodium alginate adsorbed lanthanum without inhibiting the lanthanum phosphorus adsorption as in the case of using lanthanum carbonate.

  From the above results, there is provided an oral phosphorus adsorbent that effectively suppresses the bioabsorbability of lanthanum without affecting the phosphorus adsorption ability of the lanthanum compound by using sodium alginate having an average molecular weight of 1.1 million or less. It became clear that it was possible.

Claims (10)

  An oral phosphorus adsorbent comprising (i) a pharmaceutically acceptable lanthanum compound and (ii) an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less.   The oral phosphorus adsorbent according to claim 1, wherein the alkali metal salt of alginic acid has an average molecular weight of 550,000 or less.   The oral phosphorus adsorbent according to claim 1 or 2, comprising an alkali metal salt of alginic acid in a ratio of 200 parts by weight or less based on 100 parts by weight of the total amount of lanthanum compound in terms of lanthanum atomic weight.   The oral phosphorus adsorption agent according to any one of claims 1 to 3, wherein a molar ratio of mannuronic acid / guluronic acid of an alkali metal salt of alginic acid is 0.1 or more.   The oral phosphorus adsorbent according to any one of claims 1 to 4, wherein the alkali metal salt of alginic acid has a ratio of mannuronic acid-guluronic acid bonds to total glycosidic bonds of 50% or less.   The oral phosphorus adsorbent according to any one of claims 1 to 5, wherein the lanthanum compound is at least one selected from the group consisting of lanthanum carbonate, lanthanum hydroxide carbonate, lanthanum chloride, and lanthanum hydroxide.   The oral phosphorus adsorption agent according to any one of claims 1 to 6, which is a tablet, granule, powder, or capsule.   The composition according to any one of claims 1 to 7, which is a one-agent type preparation comprising (i) a pharmaceutically acceptable lanthanum compound and (ii) an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less. An oral phosphorus adsorbent according to claim 1.   a two-agent type combination preparation comprising (i) a first agent comprising a pharmaceutically acceptable lanthanum compound and (ii) a second agent comprising an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less. The oral phosphorus adsorption agent in any one of Claims 1-7.   An alginic acid preparation for suppressing lanthanum absorption by an oral phosphorus adsorbent containing a pharmaceutically acceptable lanthanum compound, comprising an alkali metal salt of alginic acid having an average molecular weight of 1.1 million or less.