JPH05155776A - Therapeutic agent for hyperphosphatemia - Google Patents

Abstract

PURPOSE:To obtain the subject therapeutic agent, containing iron hydroxide as an active ingredient, having high adsorptivity for in vivo phosphoric acid and capable of fixing the phosphoric acid and treating hyperphosphatemia. CONSTITUTION:The objective therapeutic agent contains iron hydroxide obtained by dropping, e.g. a 1M NaOH solution into 1M Fecl3, regulating pH to 7, providing a gelatinous precipitate, washing the formed precipitates, acidifying the washed precipitate with sulfuric acid, then adding a silver nitrate solution, waiting for the time of causing no clouding, washing the precipitate and subsequently drying the precipitate as an active ingredient. Furthermore, this therapeutic agent is administered in a daily dose of 10-100mg per kg body weight in 1-4 divided portions.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a therapeutic agent for hyperphosphatemia, more specifically, a new pharmaceutical preparation capable of treating hyperphosphatemia by adsorbing and fixing phosphoric acid, particularly phosphoric acid present in biological fluids. Regarding

[0002]

2. Prior Art Secondary hyperparathyroidism (2 ° HP
T) and renal osteodystrophy (Renal Osteody-strophy: ROD)
Indicates advanced chronic renal failure (CRF)
Is a common complication in. Although the mechanism of occurrence of these complications is diverse, one of the important factors is hyperphosphatemia, which is caused by the decrease in glomerular filtration capacity due to the decreased renal function and the accumulation of phosphate in the body. Are known. The hyperphosphatemia (hyperphosphatemia) is also known to cause bone metabolism disorders through various mechanisms. That is, when the glomerular filtration capacity is decreased, serum phosphate is increased and calcium is decreased, the secretion of parathyroid hormone is stimulated, and the serum phosphate concentration is returned to the normal value, but this is repeated. Causes chronic sequelae hyperparathyroidism.

[0003] In addition, when the renal function is lowered, active vitamin D ₃ synthesis is directly reduced, and hyperphosphatemia also reduces active vitamin D ₃ synthesis through various mechanisms. The active vitamin D ₃ is involved in the absorption of calcium from the intestinal tract and the absorption / formation of bone, and the decrease in its synthesis contributes to the disorder of bone metabolism.

From this background, 2 ° in CRF
For the prevention and treatment of HPT and ROD, the treatment of hyperphosphatemia is indispensable, and at present, for the treatment of hyperphosphatemia,
Aluminum hydroxide, which suppresses the absorption of phosphorus from the intestinal tract,
Aluminum preparations such as aluminum carbonate, calcium preparations such as calcium carbonate, magnesium preparations, keto acid / amino acid mixtures, phosphoric acid binders such as zirconium compounds are used.

[0005]

The above-mentioned aluminum preparation is currently most frequently used as a phosphate binder,
The daily dose is as high as 3 to 16 g, and it has a bad taste and is extremely difficult to take. In addition, as the number of long-term survivors due to artificial dialysis increases, the administration and administration of the above aluminum (Al) formulation causes osteomalacia due to accumulation of Al, A
Many side effects such as encephalopathy have been reported. These side effects are caused by the fact that the Al preparation is partially dissolved in the stomach having a low pH, and the dissolved Al is absorbed from the digestive tract and reaches the bone and other tissues from the blood. Calcium preparations are also used as a phosphate binder in place of the above Al preparations, but their use has problems such as causing side effects such as hypercalcemia and difficulty in taking them. Magnesium preparations also have the same problems as the above calcium preparations. The keto acid / amino acid mixture does not have a clear serum phosphate lowering effect. Zirconium compounds, etc. have not been clinically used and their safety has not been confirmed. Against this background, there is a strong demand for the development of new phosphate binders that are clinically effective and safe.

[0006]

SUMMARY OF THE INVENTION In view of the above circumstances, the present inventors have found that a new preparation, which has all the drawbacks of known phosphoric acid binders, has a high adsorption capacity for phosphoric acid. ,
For the purpose of providing a new adsorbent that is safe and adaptable to the living body, we have conducted intensive studies on the selective adsorption of phosphoric acid in vivo and the elution of metals. As a result, it was found that iron hydroxide can be an extremely useful phosphate binder in terms of efficacy and safety, as compared with known phosphate binders,
This led to the present invention.

That is, the present invention relates to a therapeutic agent for hyperphosphatemia characterized by containing iron hydroxide as an active ingredient.

The therapeutic agent for hyperphosphatemia of the present invention utilizes iron hydroxide as an active ingredient as described above, and therefore, the active ingredient has a high adsorptivity for phosphoric acid. The formulation itself is safe to apply to living organisms.

In particular, the therapeutic agent of the present invention is extremely sparingly soluble within the pH range of 2 to 8 shown in the digestive system of the living body and blood, does not disturb the balance of necessary electrolytes, and is far superior to known Al preparations. It has the property of showing a large phosphate adsorption capacity.

This is as shown in the embodiments described later. That is, the amount of iron hydroxide adsorbed on phosphoric acid is not known as A at
The amount of phosphoric acid adsorbed by the preparation 1 exceeds the amount, and a remarkable difference is observed especially in strong acidity. Furthermore, in the Al preparation, there is concern that phosphoric acid adsorbed in the stomach at pH 2 is desorbed in the intestine at pH 6 to 7, but iron hydroxide is strongly acidic and a large amount of adsorption is irreversible. Very unlikely to be desorbed and absorbed by the living body to cause side effects. In fact, the elution of iron (Fe) from this iron hydroxide and the elution of Al from the Al preparation were
When e and Al are compared at pH 2 where they are most soluble, iron hydroxide hardly elutes Fe, but about 1
0% Al was eluted. This suggests that iron hydroxide dissolves in the stomach and is less likely to be absorbed through the digestive tract.

In any case, it is clear that the therapeutic agent for hyperphosphatemia of the present invention is very effective as a pharmaceutical.

The therapeutic agent for hyperphosphatemia of the present invention essentially comprises iron hydroxide as an active ingredient. The ferric hydroxide also includes a hydrate. The iron hydroxide gel can be advantageously used in the present invention in a commonly available powder form. The iron hydroxide sol is usually preferably added to a polysaccharide such as dextran and can be advantageously used in the present invention in the form of powder.

The pharmaceutical preparation of the present invention is usually put into practical use in the form of a general pharmaceutical preparation composition using a pharmaceutical carrier together with the above-mentioned active ingredient compound. As the pharmaceutical carrier, a filler, a bulking agent, a binder which is usually used, depending on the use form of the pharmaceutical,
Diluents and excipients such as moisturizers, disintegrants, surfactants, lubricants and the like can be exemplified, and these are appropriately selected and used according to the dosage unit form of the obtained preparation.

Various forms can be selected as the dosage unit form of the drug of the present invention according to the purpose of treatment, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, Examples thereof include capsules. In the case of molding in the form of tablets, as the pharmaceutical carrier, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid,
Water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone and other binders, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose,
Disintegrants such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate and calcium carbonate, polyoxyethylene sorbitan fatty acid esters,
Sodium lauryl sulfate, stearic acid monoglyceride and other surfactants, sucrose, stearin, cocoa butter, hydrogenated oil and other disintegration inhibitors, glycerin, starch and other moisturizers, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Adsorbents, purified talc, stearates, boric acid powders, and lubricants such as polyethylene glycol can be used. Further, the tablets may be tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multi-layer tablets. In the case of molding into a pill form, as a pharmaceutical carrier, for example, an excipient such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, a binder such as ethanol, laminaran , Disintegrating agents such as agar and the like can be used. Capsules are usually prepared by mixing the active ingredient compound of the present invention with various pharmaceutical carriers exemplified above and filling hard gelatin capsules, soft capsules and the like. Further, in the drug of the present invention, a colorant, a preservative, a fragrance, a flavoring agent, a sweetening agent and the like and other pharmaceuticals can be contained, if necessary.

The amount of the active ingredient compound to be contained in the drug of the present invention is not particularly limited and is appropriately selected from a wide range, but it is usually about 30 to 100% by weight in the pharmaceutical preparation. Is good.

The administration method of the above-mentioned pharmaceutical preparation is not particularly limited, and it is determined according to various preparation forms, patient's age, sex and other conditions, degree of disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered.

The dosage of the above-mentioned pharmaceutical preparation is appropriately selected depending on its usage, age of the patient, sex and other conditions, degree of disease and the like, but usually the amount of the compound of the present invention as an active ingredient is 1.
The amount is preferably about 10 to 100 mg per kg body weight per day, and the preparation can be administered in 1 to 4 divided doses per day.

Further, the therapeutic agent for hyperphosphatemia of the present invention can be prepared by orally administering the preparation to the living body as described above, and further, iron hydroxide as an active ingredient compound of the therapeutic agent is packed in an adsorption column. Extracorporeal circulation of blood, especially artificial kidneys, such as regeneration mechanism in dialysis, and direct blood perfusion (Direct Hemoperf
Usion) system can also be used together.

[0019]

EXAMPLES The effectiveness and safety of the active ingredient compound for treating hyperphosphatemia of the present invention as a phosphate adsorbent will be described in more detail with reference to Examples.

[0020]

Test Example 1 Phosphoric Acid Adsorption Experiment Preparation of Iron Hydroxide Preparation 1M FeCl ₃ aqueous solution is dripped with 1M NaOH aqueous solution to obtain pH 7 and gel precipitate is obtained. The iron hydroxide gel precipitate was added to No. 1 Suction-filter with filter paper and wash with distilled water. The washing was carried out by acidifying the filtrate with sulfuric acid and then adding a silver nitrate solution until white turbidity did not occur, that is, 250 m of a raw material iron chloride solution.
About 10 l of distilled water is used for 1 l. After the above washing, the precipitate is dried at 50 ° C. for about 24 hours (since drying for about 10 hours causes the precipitate to harden into pellets, the steps of crushing and drying again in a mortar are repeated each time). The powder thus obtained contained 50.2% Fe. It is stored on silica gel in a desiccator with internal vacuum.

Comparative Al formulation A commercially available Japanese Pharmacopoeia, dried aluminum hydroxide gel was used for comparison. It contained 52.8% Al.

Test Method As a test solution, a 50 mM 10 mM KH ₂ PO ₄ solution 50 was used.
0 ml of which the pH was adjusted with hydrochloric acid or sodium hydroxide was used. 1 g of the above-mentioned iron hydroxide or dried aluminum hydroxide gel was added to the test solution, stirred, sampled with time, and filtered through a membrane filter having a pore size of 0.45 μm. The phosphoric acid concentration in the filtrate was measured by the phosphorus molybdenum method, and the Fe and Al concentrations were measured by flameless atomic absorption.

Results Time-dependent changes in the phosphate adsorption amount (PBC) of iron hydroxide and dried aluminum hydroxide gel are shown in FIGS. 1 and 2, respectively.
Further, the amount of phosphoric acid adsorbed on the iron hydroxide and the dried aluminum hydroxide gel after 3 hours at various pHs is shown in FIG.

In FIG. 1, the vertical axis represents the phosphate adsorption amount of iron hydroxide (PBC / mmol and PBC / mg), the horizontal axis represents the time (t / min) after the addition of the sample, and the vertical axis in FIG. Phosphoric acid adsorption amount of aluminum hydroxide gel (PBC / mm
ol and PBC / mg), the horizontal axis shows the time (t / min) after addition of the sample, and each graph is a plot of the value at each pH. Further, in FIG. 3, the vertical axis represents the phosphoric acid adsorption amount (PBC / mmol and PBC / mg) of iron hydroxide (expressed as Fe) or dry aluminum hydroxide gel (expressed as Al), and the horizontal axis represents pH.

From each figure, the amount of phosphate adsorbed by iron hydroxide is pH.
It is clear that in 2 to 8, the amount of phosphoric acid adsorbed on the dried aluminum hydroxide gel exceeds the amount, and in particular in the case of strong acidity, a remarkable difference is seen.

Furthermore, in the above test, the molar ratio of the added Fe or Al and the adsorbed phosphoric acid (PO ₄ ^3- / (F
FIG. 4 shows the efficiency of phosphoric acid adsorption by plotting e, Al)) at various pH values.

From the figure, Fe is Al at all pH values.
It is clear that the efficiency of phosphoric acid adsorption is higher, and that it is remarkably higher especially in strong acidity.

Whether or not the adsorption of phosphoric acid by iron hydroxide was irreversible with respect to pH change was determined after adsorption of phosphoric acid at pH 2 for 60 minutes in the same manner as above using iron hydroxide. , The pH was increased by 1 and the amount of adsorption was measured after 20 minutes.

The obtained results are shown in FIG.

From the figure, p of phosphoric acid adsorbed at pH 2
The desorption amount associated with the increase in H was smaller than that expected from the pH characteristics of the adsorption amount, which indicates that the phosphate adsorption capacity of iron hydroxide is irreversible regardless of the pH increase.

Finally, the elution of Fe from iron hydroxide at pH 2, which is the most soluble, was compared with the elution of Al from dry aluminum hydroxide gel.

The results are shown in FIG. 6 [vertical axis: Fe or Al elution amount from iron hydroxide or dried aluminum hydroxide gel (Fe
Or Al / mmol), horizontal axis: time after sample addition (t /
Minutes)].

According to FIG. 6, Fe was hardly dissolved in iron hydroxide, but about 10% of Al was eluted in the dried aluminum hydroxide gel.

[0034]

Example 1 Preparation of Capsules L-HPC (low-substituted hydroxypropyl cellulose, manufactured by Shin-Etsu Chemical Co., Ltd.) 60 g, lactose 28 g per 500 g of iron hydroxide.
And 6 g of corn starch are added and mixed. After adding 6 g of magnesium stearate to this mixed powder, 2
No. capsules are filled to obtain capsules.

The composition per capsule is as follows.

[0036]

[0037]

Example 2 Preparation of Tablets L-HPC (low-substituted hydroxypropylcellulose, manufactured by Shin-Etsu Chemical Co., Ltd.) 60 g, lactose 32 g per 500 g of iron hydroxide.
And Aerosil (light anhydrous silicic acid, Nippon Aerosil) 2
g and mix. 6 g of magnesium stearate was added to this mixed powder, and the mixture was compressed with a 10 mmφ punch to obtain tablets.

The composition per tablet is as follows.

[0039]

[0040]

[Example 3] Preparation of gastric retentive agent 400 g of iron hydroxide was mixed with 25 g of microcrystalline cellulose (Avicel, manufactured by Asahi Kasei Corporation) containing 75 g of carboxymethyl cellulose as a binder, and the obtained powder was kneaded with water. Combined and extruded, diameter 1.2-1.4m
A columnar granulated product having m and a length of about 2 to 15 mm was obtained. This granulation product is processed with a spheronizer (Marumerizer, etc.),
It was a sphere having a diameter of 1.2 to 1.4 mm. The spheres were dried (pellet having a density of 3.2 to 3.6 g / ml) and filled in a No. 2 capsule.

The composition per capsule is as follows.

[0042]

[Brief description of drawings]

FIG. 1 shows the amount of phosphate adsorption (PB) of iron hydroxide according to Test Example 1.
It is a graph which calculated | required the time-dependent change of C).

FIG. 2 is a graph showing changes with time of a phosphoric acid adsorption amount (PBC) of a dried aluminum hydroxide gel according to Test Example 1.

FIG. 3 is a graph showing the amount of phosphoric acid adsorbed on iron hydroxide and dried aluminum hydroxide gel after 3 hours at various pHs according to Test Example 1.

FIG. 4 shows a molar ratio of the amount of added Fe or Al and the amount of adsorbed phosphoric acid according to Test Example 1 (PO ₄ ^{3 −} / (Fe, A
1) is a graph in which the efficiency of phosphoric acid adsorption is obtained by plotting l)) at various pH values.

FIG. 5: The phosphoric acid adsorption by iron hydroxide according to Test Example 1 is p.
It is a graph which investigated whether it was irreversible to H change.

6 is the elution property of Fe from iron hydroxide at pH 2 and A from dried aluminum hydroxide gel according to Test Example 1. FIG.
It is a graph which contrasted with the elution property of 1.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Takao Sugano 20 Agarikawa, Takahagi-shi, Ibaraki Domitori Hayakawaryo 3-8

Claims (1)

[Claims] 1. A therapeutic agent for hyperphosphatemia, which comprises iron hydroxide as an active ingredient.