WO1979000115A1

WO1979000115A1 - Method for extracting urea from blood washing effluents or from blood liquids

Info

Publication number: WO1979000115A1
Application number: PCT/DE1978/000016
Authority: WO
Inventors: H Lehmann
Original assignee: Gambro Dialysatoren; H Lehmann
Priority date: 1977-08-30
Filing date: 1978-08-05
Publication date: 1979-03-08
Also published as: DE2856941D2; JPS5493900A; SE7709703L; GB2020996B; GB2020996A; FR2401664A1; SE407515B

Abstract

Method for extracting urea from blood washing effluents or from blood liquids, whereby the liquids are treated with a solid organic material which is then separated therefrom, said method utilizing as organic material at least a compound which comprises at least an aldehyd group per molecule, in which the aldehyd groups are activated or masked at the intramolecular or intermolecular scale by a substituant bearing a proton, i.e., as applicable, -COOH, -CHO or -SO3H. The method is applicable to dialysis or ultrafiltration with semi-permeable membranes and allows a rapid and significant elimination of urea, while using a relatively small amount of organic material, without producing harmful substances.

Description

Technical field

Kidney sufferers are subjected to so-called "blood washing" in order to remove the urea, which is the most important metabolic product of the human protein metabolism in terms of quantity, from the blood. This is done by dialysis or diafiltration with the aid of semi-permeable membranes, in one case the urea from the blood passing through the membrane into a washing liquid, while in the other case blood flow. liquid with the urea dissolved therein passes through the membrane, leaving the proteins and blood cells behind. With both methods one is

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^• - - strives to get a closed cycle, in which in one case the blood washing liquid is used again after removing the urea from it and in the other case the blood liquid is added back to the blood after removing the urea from it. Closed circulation of the washing liquid is the prerequisite for dialysis that the artificial kidneys can be kept small.

Urea is difficult to eliminate from aqueous solution under physiological conditions which must be observed with the blood washing liquid and the blood liquid. Various methods have been investigated in order to remove the urea from the washing liquid or blood fluid in a closed circuit, but these have so far not been satisfactory.

State of the art

First of all, attempts have been made to remove the urea from the washing liquid of a dialysis using activated carbon. At ambient temperature, however, this only absorbs about 2 to 3 g of urea per kilogram, while the body has to excrete about 30 g during dialysis. This would require about 10 to 15 kg of adsorption carbon, which in turn requires a large apparatus and thus eliminates the advantages of reducing the size of the artificial kidney itself. According to another known method, the urea is cleaved enzymatically with the aid of urease to ammonia, and the ammonium cations are adsorbed in a cation exchanger. This method has the disadvantage that

Ion exchange, the pH value and electrolyte balance in the organism is disturbed if the process is carried out with blood liquid or recycled blood washing liquid. leads, so that an additional reinfusion of calcium, potassium and magnesium ions is required. The sensitivity of the enzyme used for urea cleavage also prohibits sterilization of the ion exchange column. Finally, a further disadvantage is that the urease has different cleavage quality, so that a non-reproducible cleaning efficiency is obtained.

Other known processes use oxy starch, oxycelulose or polyacrolein for reaction with urea. The disadvantage of this process is that these substances only react relatively slowly with urea under physiological conditions, so that dialysis or diafiltration with a closed circuit would take a long time. When using the oxypolysaccharides, there is also the disadvantage of slow depolymerization.

Finally, for the elimination of urea from blood washing liquids, it has also been proposed to oxidize the urea with nitrites or hypochlorites. With this method, however, there is a risk of carcinogenic nitrosamines or N-chloramines.

Description of the invention

The object on which the invention is based was now to obtain a process for removing urea from blood washing liquids or blood liquids with the aid of a solid, in which the disadvantages described above for the prior art are eliminated, the fastest and most extensive possible Elimination of the urea takes place, the one for the elimi- nation required amount of solids as small as possible

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OMPI, - W1P0, Λ *> 1 can be kept and no dangerous reaction products arise for the organism.

The process according to the invention for removing urea from blood washing liquids or blood liquids 5 by treating these liquids with an organic solid having at least one aldehyde group per molecule and subsequently separating this solid from the liquids is characterized in that little is used as the organic solid with aldehyde groups - 10 least used a compound in which aldehyde groups are activated and masked by a proton-containing substituent of the second order.

Second-order substituents are those which exert an electron-withdrawing effect on the adjacent groups 15, the effect increasing from the group -C00NH ₂ via ■ ^* the group -COOH and the group -CHO to the group -S0 ₃ H. With regard to the definition and examples of second-order substituents, reference is made to Klages "Textbook of Organic Chemistry", 1957, Volume II, page 323 ff. 20.

Best way to carry out the invention:

Among the proton-containing substituents of second order, the groups -COOH, -CONH ₂ , -S0_H and -S0 ₂ NH _{2 come} into consideration according to the invention, for example. The groups -COOH, -CHO and -SO ^ H are preferred as 25 second-order substituents. Among them, the carboxyl group and the aldehyde group are particularly preferred.

Of course, in the compounds used according to the invention, the. Second order substituents consist of 30 different groups that fall under this term, and some of the substituents can also consist of first order substituents. So it is enough for example in the preferred embodiment of the carboxyl groups that the second-order substituents at least partially consist of such carboxyl groups. The aldehyde used in this invention enthal¬ Tenden compounds may cycloaliphatic shear, aromatic όäer heteroaromatic nature aliphatic, ^{^"be"} wobei.olefinische, aromatic and heteroaromatic compounds are preferred ,, since they have the Mesomerie the double bonds of the electron withdrawing effect of the secondary substituent favor on the aldehyde group. It is therefore expedient to use organic compounds in which the second-order substituent is separated from an aldehyde group by a carbon-carbon bond or an even number of carbon atoms which are bonded by one or more conjugated double bonds.

Since the mesomerism effect decreases with the removal of the second-order substituent from the aldehyde group, it is expedient that in the compound used the

Second order substituent is separated from an adjacent aldehyde group only by two carbon atoms which are connected by an olefinic double bond or are part of an aromatic or heteroaromatic ring.

Examples of such compounds are glyoxylic acid, maleicaldehyde acid and its derivatives, such as mucohalic acid, phenylogens of maleic aldehyde acid and the derivatives thereof, such as phthalaldehyde acid, o-phthalaldehyde acid and pyromellitic dialdehyde acid and its derivatives, and heterophenylogens of maleic aldehyde acid, such as nicotine and their derivatives. Phthalaldehyde acid and pyromellitic dialdehyde acid and their derivatives are preferred,

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OMPI ^~ 1 especially phthalaldehyde acid. However, the compounds may also be polymeric in nature ^'and several Aldehydgrup- pqn in the molecule.

These compounds, in which the aldehyde group and the second-order substituent, particularly a carboxyl group or aldehyde group, are located on adjacent carbon atoms, intramolecularly mask the aldehyde group by the second-order substituent by forming a hydroxylactone, which is obtained by adding the protonhal -

10 second-order substituents on the aldehyde group and formation of a ring, especially a five-membered ring, - arises. For the phthalaldehyde acid of the following formula I, the hydroxylactone has the following formula II.

However, the masking of the aldehyde group by addition of the second-order proton-containing substituent need not be carried out intramolecularly, but can also take place intermolecularly if intramolecular 25th hydroxylactone formation would only be possible with the formation of ring systems, which for steric reasons are unstable.

The activity of the compounds used according to the invention having at least one aldehyde group in the molecule is further increased by the simultaneous use of an acidic, preferably a strongly acidic, cation exchange agent. For example, a strongly acidic cation exchanger based on divinylbenzene-crosslinked polystyrene sulfonic acid can be used.

OMPI, ^< W1P0 1 The acidic cation exchanger β is expediently used in an amount of 0.01 to 10 g, preferably in an amount of 0.1 to 1 g, per gram of the organic compounds with aldehyde groups.

5, it is particularly expedient that Ver¬ above-described compounds in carrier-fixed form to be used, so that they can be held in a column, ^"through which the washing liquid blood or blood liquid for Eliminie¬ tion of urea may be performed.

10 These compounds can be fixed to the carrier on adsorbents, e.g. Activated carbon. If the compounds used according to the invention with aldehyde groups and proton-containing substituents of second order are themselves polymeric in nature, e.g. Vinyl polymers or polypheny-

^'15 -lenoxide, no further support fixation is required.

Commercial usability

It is surprising that the use of compounds with aldehyde groups by a

2θ proton-containing substituents of the second order are activated and masked, urea, specifically selective towards amino acids, such as glycine, from aqueous media, such as dialysis fluid and diafiltrate, rapidly and completely eliminated under approximately physiological conditions

^• 25 and only have to be used in relatively small volumes, so that the dialysis or diafiltration devices can be kept small in a closed circuit of dialysis fluid or blood fluid. Because of this surprising usefulness

30 compounds with activated and masked aldehyde groups, the method according to the invention is particularly suitable for the dialysis or diafiltration of human or animal blood or hemofiltrate.

embodiments

I.

example 1

For a fixation of the compound o-phthalaldehyde acid (2-carboxybenzaldehyde), a solution of 10 g of o-phthalaldehyde acid in 2 1 dialysis solution at 40 was obtained from a storage vessel by means of an acid with adsorption carbon which had been prewashed, dried and sterilized ° C and at a rate of 100 ml / min. pumped through the circuit until no more o-phthalaldehyde acid could be detected in the stock solution.

Now 4 g of urea were dissolved in the stock solution and again at 40 ° C. and at a speed of 100 ml / min. Pumped through the column: The urea concentration of the solution was measured. The volume-corrected initial concentration was 244 mg% urea and had dropped to 105 mg% after 1/2 hour. From then on, the urea concentration decreased only slightly. It was 1O3.8 mg% after 1 hour, 101.4 mg% after 1 1/2 hours and 95.5 mg% after 2 hours.

From this experiment it can be seen that the amount of urea eliminated from the dialysis solution was largely eliminated after only 1/2 hour, which is in contrast to known means for this purpose which require several hours for a corresponding urea elimination.

Example 2

In this example, four compounds according to the invention (A, D, E, F) with three of similar construction were not 1 compounds (C, G, H) falling under the subject matter of the invention with regard to the usability in the removal of urea from aqueous electrolyte-containing solutions, such as dialysis fluids, at one temperature

5 of 40 C examined. The compounds examined were as follows:

A: 2-carboxybenzaldehyde (o-phthalaldehyde acid) B: 2-carboxyacetophenone C: 2-carboxybenzophenone 10 D: o-phthalaldehyde E: mucochloric acid F: mucobromic acid G: c (-angelicalactone H: xanthydrol

15 Since some a balance between heterocyclic and open form consists substances to be tested, that is, free carboxylic acid is present, the change of the pH value was checked and attempts to correct it on activated carbon to ^'by adsorption of the substance.

20 100 ml dialysis fluid (concentrate, diluted 1 + 34) were heated to 40 ° C. After 10 mmol of reagent had been added, stirring was continued for 10 minutes. After taking a sample (a} for pH measurement, 10 mmol (= 600 mg) of urea was added, and the mixture was stirred

25 3 hours at 40 ° C.

After taking a further sample (b), the pH was immediately measured therein. After buffing with phosphate buffer to a pH value of 6.6, the Berthelot urea content was determined.

-30 Then 20 g of dry activated carbon was added and it was kept at 40 ° C. for 2 hours. After standing overnight at room temperature in the supernatant

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OMPI. S ^A , W1P0 _ Solution (c) again checked pH and urea content. - In the case of non-homogeneous reaction mixtures, the samples were centrifuged.

Result ;

Rehearsal. a a b b c

Reagent pH Appearance pH Urea content pH

(mg%) without 7.6 clear 7.9 573 8.7

A 4.0 slightly cloudy 4.3 2887 6.3 279 ^{J +}

B 3.7 clear 3.7 528 6.1

C 4.6 partly undissolved 4.7 554 5.8

D -7.2 partly. undissolved 7.5 ³ 3 ⁵³ 1 ₊ 7.9 54J

- E 3.7 clear 3.7 385 5.5

F 3.8 clear 3.8 439 5.4

G 6.2 partly undissolved 5.7 552 5.8

H 7.6 hardly dissolved 7.8 560 7.3 +) double determination The table shows that the urea content of the solution is only for the compounds 2-carboxybenzaldehyde (A), o-phthalaldehyde (D) and the compounds used according to the invention Mucohalogen acids (E, F), noticeably decreased. This decrease was greater for mucochloric acid (F) than for mucobromic acid (F). It was strongest in the case of 2-carboxybenzaldehyde (A). The compounds of similar structure not covered by the subject matter of the invention, 2-carboxybenzphenone (C), angelic lactone (G) and xanthydrol (H), did not cause any significant change in the urea content of the solution. The mixtures with A, E and F are acidic. In contrast to the mucohalogenic acids, the pH value when mixing

OM with 2-carboxybenzaldehyde (A) increased considerably by adding the activated carbon (up to 6.3}.

When using high concentrations (10 mmol each) of reagent and urea in a molar ratio of 1: 1, the urea concentration was reduced to approx. 50% by reaction with 2-carboxybenzaldehyde.

Example 3

The following adsorbents were added to a solution of 0.9 g NaCl and 0.3 g urea in 100 ml water: 1. 0.5 g acidic cation exchanger LAB I

2. 0.5 g LAB I + 2.5 g activated carbon (granules)}

3. 0.5 g LAB I + 0.75 g phthalaldehyde acid

4. 0.5 ^" g LAB r + 1.5- g phthalaldehyde acid

5. 0.5 g LAB I + 2.5 g activated carbon + 1.5 g phthalaldehyde acid

6. 0.5 g LAB I + 3.0 g phthalaldehyde acid

7. 0.5 g LAB I + 1.1 g pyromellitic dialdehyde acid

8. 0.5 g LAB r + 2.2 g pyromellitic dialdehyde acid

9. 0.5 g LAB I + 2.2 g pyromellitic dialdehyde acid +) LAB I strongly acidic cation exchanger based on divinylbenzene cross-linked polystyrene sulfonic acid

The mixture was stirred at 40 ° C. take a sample after 1, 2, 3 and 4 hours, filter and adjust to pH 7.2 with phosphate buffer solution. The urea content of the sample was then determined according to Berthelot. Try starting after. after after after

Concentration 1 hour 2 hours 3 hours 4 hours

. 1 300 286 297 288 292

2 300 261 266 264 264 3 300 225 191 168 111

4 300 160 105 84 59

5 300 - 172 145 132 122

6 300 55 32 26 26

7 300 243 185 170 149 8 300 77 43 53 61

9 300 98 88 100 90

It can be seen from the test results that acidic cation exchangers and activated carbon do not result in any significant reduction in the urea content. In contrast, the compounds phthalaldehyde acid and pyromellitic dialdehyde acid used according to the invention lead to a more than 90% removal of the urea content. It is particularly striking that this technical effect of the compounds used according to the invention is not enhanced by activated carbon; but is significantly weakened, as a comparison of tests 4 and 5 or 8 and 9 shows. This result is extremely surprising since it has an additive effect of active. coal with the organic compounds used according to the invention should have been expected.

Example 4 - -

The experiment was carried out as in Example 3, but in each case 100 ml of a 0.9% NaCl solution were used, which contained 5 mmol of the amino acid glyamine instead of 5 mmol (corresponding to 0.3 g) of urea. Samples were taken after 4 hours from the mixtures stirred at 40 ° C. and the glycine content was determined photometrically by means of a ninhydrin reaction.

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- - WIPO Right. The concentration of the starting solution with glycine was 392 mg, that of the starting solution with urea at 300 mg%.

Glycine mg% urea mg% after 4 hours after 4 hours

1. 0.5 g LAB I (H ⁺ form) as a blank. 368 292

2. 0.5 g LAB I (H ⁺ form)

+ 0.75 g phthalaldehyde acid 318 111

3. 0.5 g LAB I (H ⁺ form) + 1.5 g phthalaldehyde acid. ^" - 360 59

4. 0.5 g LAB I (H ⁺ form) + 1.1 g pyromellitic dialdehyde acid 350 149

5. 0.5 g LAB I (H ⁺ form)

+ 2.2 g pyromellitic dialdehyde acid 392 61

Example 5

Fresh bovine blood was adjusted to a hematocrit of 25% with physiological saline solution. With a blood flow of 200 ml / min. and a transmembrane pressure difference of 300 mm Hg were 50 ml / min over a polyamide membrane. Filtered protein-free hemofiltrate. In each case 100 ml thereof were mixed with 300 mg urea and stirred with the following adsorbents at 38 ° C. for 4 hours:

1. 1.5 g phthalaldehyde acid

2. 1.5 g phthalaldehyde acid + 0.5 g strongly acidic cation exchanger as in example 3

The following urea contents were found after 1, 2, 3 and 4 hours:

_0MPI Trial starting after after after no. Conc. 1 hour 2 hours 3 hours 4 hours

318 230 176 120 2 318 209.5 156 120 99

Claims

P a t e n t a n s r u c h e

I 1. Process for removing urea from Blutwasch¬ liquids or blood liquids by treating these liquids with an organic solid with at least one aldehyde group per molecule and subsequent separation of this solid from the liquids, characterized in that at least one organic solid with aldehyde groups Compound used in which aldehyde groups are activated and masked by a proton-containing substituent of the second order.

2. The method according to claim 1, characterized in that one at least one

, Compound containing aldehyde group is used, in which the second-order substituent is a -COOH, -CHO and / or -S0 ₃ H group.

3. The method according to claim 1 and 2, characterized gekennzeich¬ net that one uses at least one aldehyde group per molecule containing compound in which the second order substituent of an aldehyde group by a carbon-carbon bond or an even number of carbon atoms, which are connected by one or more conjugated double bonds.

4. The method according to claim 3, characterized in - that one uses at least one aldehyde group per Mole¬ cool containing compound in which the second order substituent is separated from an adjacent aldehyde group by two carbon atoms which are connected by an olefinic double bond or part of an aromatic or heteroaro- are matical ring.

5. Process according to Claims 1 to 4, characterized in that phthalaldehyde acid, o-phthalaldehyde and / or pyromellitic dialdehyde acid or its hydroxylactones are used as the compound containing at least one aldehyde group.

6. The method according to claim 1 to 5, characterized gekennzeich¬ net that one uses the at least one aldehyde group-containing compound in carrier-fixed form.

7. The method according to claim 1 to 6, characterized gekennzeich¬ net that an acidic cation exchanger is used together with the organic solid with aldehyde groups.