WO2011048097A1

WO2011048097A1 - Bismuth-containing composition for reducing the phosphate concentration in fluids

Info

Publication number: WO2011048097A1
Application number: PCT/EP2010/065724
Authority: WO
Inventors: Hans Von Baeyer; Jens Beckmann
Original assignee: Freie Universität Berlin
Priority date: 2009-10-21
Filing date: 2010-10-19
Publication date: 2011-04-28
Also published as: DE102009045899B4; DE102009045899A1

Abstract

The present invention relates to a bismuth-containing composition for reducing the concentration of inorganic phosphate in fluids, in particular body fluids or dialysis fluids.

Description

Bismuth-containing composition for reducing the phosphate concentration in liquids

The present invention relates to a bismuth-containing composition according to claim 1 and its use according to one of claims 9 or 10.

Phosphates play an important role in human metabolism and are essential to the function of the human organism. Phosphates are usually supplied through the diet and absorbed in the intestine. Up to 70% of the dietary phosphates (about 1400 mg) are excreted through the kidneys and urine. The remainder is utilized in the organism. In people with healthy kidneys, the amount of phosphate excreted in the urine per day is 900 mg on average.

However, if the normal phosphate levels in the blood are exceeded, due to the low solubility of calcium phosphate, its deposition in the vascular systems and the associated calcification occur.

With a deficient kidney excretion capacity, e.g. In the case of renal insufficiency, phosphate accumulates in the patients in the organism in an undesirable amount, so that there is an increased phosphate level in the blood (hyperphosphatemia).

Chronic renal failure patients are usually treated by dialysis. In dialysis patients, however, only substantially lower phosphate levels are tolerated in relation to other retention values. Only a 1, 3-fold excess of phosphate over the normal value is acceptable in dialysis patients. This value can e.g. can be achieved over a prolonged dialysis time, which usually takes between 4 to 6 hours.

For this reason, various approaches have been developed to bind the dietary phosphate in the gastrointestinal tract, thus preventing absorption and the associated transfer into the blood.

For example, in recent decades aluminum compounds such as aluminum hydroxide have been used for intestinal phosphate binding in dialysis patients. DE 4239442 A1 discloses the use of adsorption materials modified with metal oxide hydroxides, eg iron (III) oxide hydroxide. For the selective elimination of inorganic phosphate from a body fluid such as whole blood or plasma, the same is passed over the adsorbent, resulting in the binding of the phosphate to the modified adsorbent material.

DE 19528524 C2 describes the use of a Caiciumhaltigen means for intestinal phosphate binding. In this case, a water-soluble calcium salt, such as calcium acetate is surrounded by a shell of calcium alginate. The calcium alginate dissolves predominantly only in the presence of phosphate and thus allows the release of calcium ions and the associated formation of insoluble calcium phosphate in the intestine. This is done especially in the presence of an elevated phosphate level.

Furthermore, the use of calcium salts of naturally or chemically modified polymers of anionic carboxylic acids or of a sulfuric acid ester for regulating the phosphate level in chronic uremia is known from DE 3402878 A1.

Further compounds which have hitherto been used are calcium carbonate, calcium acetate, magnesium acetate, lanthanum carbonate and 1-chloro-2,3-epoxypropane-allylamine polymer (sevelamer), the latter being converted into the active form by protonation by hydrochloric acid from a prodrug.

However, these compounds currently used have disadvantages that can be effective depending on the constellation of the patient.

One of the most efficient phosphate binders to date is aluminum chloride hydroxide (Phoshonorm). With 3 tablets of 300 mg theoretically 6.3 mmol of phosphate can be bound daily, wherein the phosphate in the form of AIP0 ₄ or AI ₂ (HP0 ₄ ) _{3 is} bound. However, the administered aluminum compounds have not negligible central nervous and bone marrow toxicity. With an elevated aluminum (III) level in the serum, aluminum may therefore no longer be prescribed.

Serious disadvantages of long-term therapy with calcium salts are the development of hypercalcaemia due to the absorption of excess calcium ions, which promotes vascular and connective tissue calcifications. Lanthanum carbonate is based on an expensive raw material. In addition, increased toxicity of lanthanum is likely, as active removal mechanisms such as biomethylation in the case of lanthanum are chemically excluded. The costs for 500 g La (NO ₃ ) ₃ ^* 6H ₂ 0 are currently around 366.00 EUR.

The polymer 1 -chloro-2,3-epoxypropane-allylamine is at sub-acidity, which is due to a reduced secretion of protons from parietal cells into the gastric juice and an associated increased gastric pH between 1, 8 and 4 (normal physiological pH - Value is 1) is not effective.

The present invention is therefore based on the problem to provide a drug for reducing the phosphate content in the plasma, which does not have the disadvantages mentioned above.

This object is achieved by a composition having the features of claim 1.

Thus, a bismuth-containing composition is used to reduce the concentration of inorganic phosphate in liquids, particularly body fluids or dialysis fluids.

The use of bismuthaltigen compounds as a drug is known. Thus, a preparation containing bismuth nitrate oxide and di-bismuth tris (tetraoxodialuminate) with the trade name Angass is used for the treatment of gastric ulcers. The use of bismuth for the use of gastric ulcers has been known for more than 100 years. Toxicity studies have shown that only very small amounts of bismuth are absorbed by the blood. Active excretion via respiration and urine occurs after biomethylation of bismuth to Me ₃ Bi (Boertz, J., et al., Drug Metab. Dispos. 2009, 37 (2): 352-358).

The use of this preparation to reduce the phosphate content in liquid as a further indication has not been described yet.

Bismuth, especially in the trivalent form, has a much higher affinity for phosphate compared to the calcium used so far, so that in comparison to calcium with far smaller molar amounts, a similar effect is achieved in the phosphate binding. This can be proven by the different saturation concentrations for different phosphate compounds. Thus, the saturation concentration of phosphate is in the case of aluminum phosphate AIP0 ₄ 9.9 ^* 10 ^"11 mol / l, calcium phosphate Ca ₃ (P0 ₄₎ ² 5.0 ^* ^{10" 9} mol / l and magnesium phosphate Mg ₃ (P0 ₄₎ ₂ 7,5 ^* 10 ^"7 mol / l, while the phosphate saturation concentration in the case of Bismutphosphat BiP0 ₄ 1, 8 ^* 10 mol / l and is thus much lower compared to the other phosphates. the values prove to that Bismutphosphat compared the other phosphates is a sparingly soluble salt and precipitates even at lower bismuth and phosphate concentrations.

The composition is particularly suitable for the prevention and treatment of hyperphosphatemia in chronically renal patients with and without dialysis treatment.

Another advantage of the use of bismuth-containing compounds for reducing phosphates, especially in blood plasma, is that the dialysis times usually required for phosphate reduction can be reduced, in particular halved.

Since the affinity of bismuth to phosphate ions is higher than that of calcium ions by at least one to three powers of 10, it is possible to use correspondingly lower dosages.

Another advantage of using a bismuth-containing composition is the very good dialysis properties of bismuth. The normal kidney usually does not function as a potent excretory agent for bismuth, as a significant portion of the filtered bismuth is tubular reabsorbed. This effect is missing during dialysis. The bismuth present in the serum, which was not previously precipitated in the intestine in the form of bismuth phosphate and was therefore absorbed, is removed from the plasma on the next dialysis and thus removed from possible deposition in organs.

Preferably, the bismuth-containing composition comprises a bismuth compound selected from the group consisting of bismuth oxides, bismuth nitrates, bismuth subnitrate, bismuth subcitrate and bismuth aluminates. Advantageously, bismuth nitrate oxide and / or dibismuth tris (tetraoxodialuminate) is used. In a preferred embodiment, the bismuth-containing composition contains 100 to 300 mg, preferably 100 to 200 mg, particularly preferably 150 mg of bismuth nitrate oxide and 10 to 150 mg, preferably 20 to 100 mg, particularly preferably 50 mg of di-bismuth tris (tetraoxodialuminate) * 10 H ₂ 0.

The daily absorbed amount of bismuth (Bi ³⁺ ) is advantageously between 50 to 850 mg / d, preferably 100 to 600 mg / d, in particular 200 to 500 mg / d. The daily intake of bismuth can be divided into several portions. Thus, the Bi ³⁺ administration can take place 3 to 4 times with partial amounts in each case between 50 and 350 mg Bi ³⁺ , preferably between 100 and 300 mg Bi ³⁺ , particularly preferably between 120 and 280 mg Bi ³⁺ . The amount of bismuth administered varies in particular depending on the pH of the liquid, such as the pH of the gastric juice. This is the so-called bioavailability of the bismuth compound, which may vary somewhat from patient to patient.

The bismuth-containing composition can be used to reduce the concentration of inorganic phosphate in the intestinal fluid, blood and / or plasma of humans.

In a preferred embodiment, the bismuth-containing composition is used to reduce the concentration of inorganic phosphate in the plasma, in particular in the context of hemodialysis or peritoneal dialysis.

Advantageously, the composition is in the form of tablets, suspension or solution, and is administered orally.

The object of the present invention is also achieved by the use of a bismuth-containing composition according to claims 10 and 11.

Accordingly, at least one bismuth-containing composition is used for the manufacture of a medicament for reducing the concentration of inorganic phosphate in plasma for the treatment of hyperphosphatemia.

Further features and advantages of the invention will become apparent from the following description with reference to an embodiment. Working Example

The amount of phosphate absorbed by humans is about 1400 mg (14.75 mmol). Of these, about 80% are absorbed in the intestine, of which in turn 70% are urinary. People with intact kidney function thus excrete on average about 900 mg of phosphate (9.48 mmol) per day. This corresponds to a weekly renal excretion of 66.37 mmol phosphate.

In the context of a dialysis procedure, a partial removal of the urea phosphate by a dialysis filter (dialyzer), wherein the blood flow rates are usually 200-400 ml / min. In this case, about 250 mg of phosphate are removed at a dialysis time of 4 hours.

This value corresponds to a molar phosphate amount of 2.63 mmol per dialysis. If the dialysis treatment takes place 3 times a week, only 7.89 mmol of phosphate per week are removed. This leaves about 58.47 mmol of phosphate per week or 8.35 mmol of phosphate per day, which must be removed in addition to dialysis with phosphate binders.

In the case of an almost completely clogged urine production (oligo-anuria) due to kidney damage (terminal renal insufficiency), the aim is therefore to eliminate the said phosphate amount of 8.35 mmol phosphate per day or 58.47 mmol phosphate per week. But this can so far only be achieved by an additional extension of the dialysis time, which, however, is unreasonable in view of the quite long dialysis times, especially for older patients (> 70 years).

To avoid extended dialysis times and to remove the non-abdialysed phosphate, bismuth (Bi ³⁺ ) is therefore administered orally daily up to 835 mg, which corresponds to a molar amount of about 4 mmol. The result is Bi ₂ (HP0 ₄ ) ₃ . Thus, with this dose of bismuth, 6mM phosphate is bound. The bound, excess phosphate is precipitated in the form of BiP0 ₄ or Bi ₂ (HP0 ₄ ) ₃ and excreted via the stool.

With a daily bismuth total amount of 845 mg to be administered, it is orally administered to the patient in the form of portions a of approximately 21 1 mg of bismuth. For a total daily intake of bismuth 480 mg, 120 mg bismuth aliquots are administered orally. The bismuth will be fed to the main meals at the beginning of the meal.

As already stated, the amount of bismuth administered depends on various factors such as pH or bioavailability and overall patient constitution, and therefore needs to be adjusted accordingly.

Claims

claims

1 . A bismuth-containing composition for reducing the concentration of inorganic phosphate in liquids, especially in body fluids or dialysis fluids.

2. Composition according to claim 1, characterized in that a bismuth compound selected from the group consisting of bismuth oxides, bismuth nitrates and bismuth aluminates are used.

3. Composition according to claim 1 or 2, characterized in that bismuth nitrate oxide and / or dibismuth tris (tetraoxodialuminate) are used as the bismuth compound.

4. Composition according to one of the preceding claims, characterized by 100 to 300 mg, preferably 100 to 200 mg, particularly preferably 150 mg of bismuth nitrate oxide and 10 to 150 mg, preferably 20 to 100 mg, particularly preferably 50 mg of di-bismuth tris (tetraoxodialuminate) * 10 H ₂ 0.

5. Composition according to one of the preceding claims, characterized in that the daily absorbed amount of bismuth between 50 to 850 mg / d, preferably 100 to 600 mg / d, in particular 200 to 500 mg / d.

6. The composition according to any one of claims 1 to 5 for reducing the concentration of inorganic phosphate in the blood, plasma and / or in the intestinal fluid content of humans.

7. A composition according to any one of claims 1 to 5 for reducing the concentration of inorganic phosphate in the blood plasma, in particular in the context of hemodialysis or peritoneal dialysis.

8. The composition according to any one of claims 1 to 5 for the treatment of hyperphosphatemia.

9. Composition according to one of claims 1 to 5, characterized in that the composition is in the form of tablets, suspension or solution.

10. Use of at least one bismuth-containing composition according to one of the preceding claims for the preparation of a medicament for reducing the concentration of inorganic phosphate in liquids, in particular in body fluids or dialysis fluids.

1 1. Use of at least one bismuth-containing composition according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of hyperphosphatemia.