JP2013528103A - Urea adsorbent - Google Patents

Abstract

  An adsorbent polymer is provided that interacts or reacts with an aqueous urea solution to promote dialysis fluid regeneration. One or more specific functional groups can be attached to the adsorbent polymer. Such specific functional groups are selected from carboxylic acids, carboxylic acid esters, carboxylates, amides, dicarboxylic acids, dicarboxylic acid esters, and dicarboxylates to produce the desired urea adsorbent.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a US Patent Application No. 12 / 479,513 filed on June 5, 2009 entitled "Urea Adsorbent", which is a patent cooperation treaty application, Claims the benefit of US Provisional Patent Application No. 61 / 059,610, filed June 6, 2008, entitled “Urea Adsorbent”.

  The following disclosure describes an adsorbent material for separating and / or removing urea from a dialysis solution in an adsorbent-based dialysis treatment, or for separating and / or removing urea from an aqueous solution or liquid in a medical-related process or environment. About.

  Hemodialysis is a process in which toxins such as urea and other molecules are removed from the blood using a semipermeable filtration membrane. Typically, the patient's blood and aqueous solution (ie, dialysate) are pumped in and around hollow semipermeable fibers in opposite directions. In FIG. 1 a known structure of a dialyzer is shown. In general, blood enters from one end of the dialyzer and flows through a hollow semiporous or semipermeable fiber toward the blood outlet side of the dialyzer. On the other hand, dialysate enters the dialysate inlet and flows in the opposite direction with respect to blood flow by flowing near or around the semi-porous hollow fiber through which blood is flowing. The dialysate then exits from the dialysate outlet. While blood flows through the fiber and dialysate flows outside the fiber, toxins in the blood are removed from the blood by a combination of diffusion, convection, and osmosis processes. Generally, a dialyzer is composed of a number of semipermeable hollow fibers that are joined together and placed in a cylindrical jacket as shown. Current dialysis processes can be classified as 1) single pass and 2) adsorbent based. Single pass processes require a continuous supply of large amounts of fresh process water. Treated water can be purified, for example, by reverse osmosis or distillation. A large amount of fresh treated water is used to make the dialysis fluid, which is discarded in a single pass of the dialyzer after flowing through the dialyzer and collecting toxins.

  FIG. 2 shows a cross-sectional schematic / diagram of a single semipermeable fiber that can be used in a dialyzer. Blood flows through a hollow lumen in the semipermeable wall of fibers. The membrane wall has a thickness that is the difference of radius R2 minus radius R1. The membrane is semi-permeable and the dialysate flows in the opposite direction on the outside of the semi-permeable fibers as shown.

  Adsorbent dialysis differs from single pass dialysis in that the dialysate is regenerated using a series of chemical powders to remove toxins from the dialysis solution. Typically, spent dialysate from the dialyzer is pumped through a first chemical layer of an enzyme called “urease”. Urease catalyzes the decomposition of urea into ammonia and carbon dioxide. Next, the dialysate passes through a cation exchange layer (zirconium phosphate) that absorbs ammonia and other positively charged ions, which is a second chemical layer, and then phosphorous that is a third chemical layer. It passes through an anion exchange layer (hydrous zirconium oxide) where anions such as acids and fluorides are absorbed. Finally, the dialysate is pumped through the fourth activated carbon layer where organic metabolites such as creatinine are absorbed. At some point, the filtered dialysate may be passed through a deaerator to remove air, carbon dioxide and other bubbles that may be formed or found in the dialysate.

  The ability of the zirconium phosphate cation exchange layer to absorb ammonia is limited by the number of sites available for binding ammonia. When the zirconium phosphate layer is exhausted, ammonia will remain in the dialysate when recycled to the dialyzer. In this case, the patient may be at risk of ammonia toxicity. As a result, the filtered dialysate must be periodically tested or monitored for ammonia concentration.

  A typical dialysis patient produces about 24 to about 60 grams of excess urea per day that must be removed from the blood to avoid uremia. Thus, what is needed is an adsorbent for use in dialysis that has the ability to remove this amount of urea in a reasonable time frame. Thus, a suitable adsorbent must be capable of removing about 2.5 grams (gm / dl / hour) from the dialysate per deciliter of dialysate per hour.

  In one embodiment, a urea adsorbent suitable for use in an adsorbent-based dialysis process is provided. The adsorbent absorbs urea from the dialysate without generating ammonia or carbon dioxide, thereby eliminating the need to monitor the concentration of ammonia in the dialysate and the need to degas the dialysate Is also reduced or eliminated. In one variation, the adsorbent is insoluble or substantially insoluble in water and removes urea from the dialysate at a pH range between 4-12, more particularly between about 6-8. It is effective for. In another embodiment, the adsorbent is soluble or substantially soluble and is effective to bind to urea and remove or limit urea from a dialysate solution or other aqueous solution.

  In another aspect, the filter for regenerating dialysate removes urea from an aqueous solution by interacting with or reacting with urea at a pH between 4-12, more particularly between 6-8. It includes an adsorbent layer that includes a polymer having specific functional groups attached thereto. Exemplary polymers can be any one of soluble in water, substantially soluble, insoluble and substantially insoluble. Exemplary polymers further react or interact with urea, but do not release ammonia or generate carbon dioxide near room temperature or in a defined temperature range between about 50 ° F. and 110 ° F. . The reaction product of the polymer and urea can also be any one of soluble in water, substantially soluble, insoluble and substantially insoluble. A second filter layer may be used with an exemplary polymer adsorbent. The second filter layer includes activated carbon for absorbing organic metabolites from dialysate or other aqueous solutions. In one variation, the filter further includes an anion exchange layer for removing anions from the dialysate.

  In another aspect, a filter for removing urea from an aqueous solution or liquid is provided. The filter includes an adsorbent layer or coating. The adsorbent layer or coating includes a polymer having specific functional groups attached thereto. Exemplary polymers with specific functional groups attached are at a pH between 4-12 or a predetermined limited pH range between them (ie 3-7, 5-9, 6-8, etc.). ) Interact or react with urea. Upon interacting with or possibly reacting with urea, urea is bound to the exemplary adsorbent polymer and removed from the aqueous solution. Exemplary polymers can be soluble in water, substantially soluble, insoluble, or substantially insoluble. In addition, exemplary polymers react with urea near room temperature or other predetermined temperature range without releasing ammonia or generating carbon dioxide. In various embodiments, exemplary polymers react or interact with urea to produce a single reaction product. The filter can also include activated carbon for adsorbing and removing other molecules from the aqueous solution. The reaction product produced by the reaction or interaction of an exemplary polymer and urea can be soluble, substantially soluble, insoluble, or substantially insoluble in water.

  For a more complete understanding, reference is now made to the following description, taken in conjunction with the accompanying drawings.

A schematic diagram of a dialyzer is shown. Figure 3 shows a cross-sectional view of a fiber lumen in a dialyzer.

  Referring now to the drawings, various illustrations and embodiments of exemplary urea adsorbents are described and described, and other possible embodiments are described. The drawings are not necessarily drawn to scale, and in some cases, the drawings are exaggerated and / or simplified in some places for illustrative purposes only. Those skilled in the art will recognize a number of possible uses and variations based on the following examples of possible embodiments.

Preparation of adsorbent:
1. Preparation of MPS-IV-048 (polyvinylglyoxalate)

1.1 Reagent

1.2 Procedure Glyoxylic acid monohydrate in distilled water and EDC. Polyvinyl alcohol was added to a stirred solution of HCl and the solution was stirred for 24 hours. Water was evaporated under reduced pressure to give a viscous material, which was used for urea capture experiments from the dialysis solution.

2. Preparation of MPS-IV-054 (polyvinylglyoxalate)

2.1 Reagents

2.2 Procedure Cooling polyvinyl alcohol in dry DMF (0 ° C., ice bath) Sodium hydride was added to the stirred suspension and stirring was continued for 2-3 minutes. Glyoxylic acid monohydrate was added to the mixture and stirred at 0 ° C. for 2 hours, after which the mixture was allowed to reach room temperature. Stirring was continued overnight. The resulting solid was washed with DCM and used for urea capture experiments from the dialysis solution.

2.3 Characteristics Weight of MPS-IV-054 = 3.691 g
Melting point of MPS-IV-054 = 290 does not melt to 0 ° C. Mn = 75540, Mw = 79736, ρ = 1.555 g / cm 3

3. Preparation of MPS-V-003 (bis (polyvinyloxalate))

3.1 Reagent

3.2 Procedure Oxalic acid and EDC in distilled water. Polyvinyl alcohol was added to a stirred solution of HCl and the solution was stirred for 24 hours. Water was evaporated under reduced pressure to give a viscous material, which was used for urea capture experiments from the dialysis solution.

3.3 Characteristics Weight of MPS-V-003 = 6.20 g

4). Preparation of MPS-V-004 (polyvinyl pyruvate)

4.1 Reagent

4.2 Procedure Pyruvate and EDC in distilled water. Polyvinyl alcohol was added to a stirred solution of HCl and the solution was stirred for 24 hours. Water was evaporated under reduced pressure to give a viscous material, which was used for urea capture experiments from the dialysis solution.

4.3 Characteristics Weight of MPS-V-004 = 6.42 g

5. Preparation of MPS-V-005 (polyvinyl benzoate 0.33 polyvinyl alcohol 0.66)

5.1 Reagent

5.2 Procedure To a stirred and cooled (0 ° C., ice bath) solution of polyvinyl alcohol in dry pyridine (17 ml), a solution of benzoyl chloride in dry pyridine (8 ml) was added dropwise over 10 minutes to bring the reaction temperature to Stirring was continued for 24 hours while gradually increasing to room temperature. After 24 hours, pyridine was removed by co-evaporation with toluene under reduced pressure to give a viscous material that was used in the next step. The viscous material (MPS-V-005) swelled when contacted with solvents such as ethyl acetate, dichloromethane (DCM), chloroform and methanol.

6 Preparation of MPS-IV-009 (polyvinylbenzoate 0.33 polyvinylglyoxalate 0.66)

6.1 Reagent

6.2 Procedure Glyoxylic acid monohydrate in distilled water and EDC. A solution of HCl was added to MPS-V-005 and the suspension was stirred at room temperature for 48 hours. The resulting white precipitate was filtered and dried and used for urea capture experiments from dialysis solutions.

6.3 Characteristics Weight of MPS-V-009 = 1.543 g

7). Preparation of MPS-V-027 (polyvinyl glyoxalate-ethylene copolymer)

7.1 Reagent

7.2 Procedure Glyoxylic acid monohydrate was dissolved in thionyl chloride and the mixture was refluxed for 48 hours. Excess thionyl chloride was removed under vacuum to give a viscous material (glyoxaloyl chloride). Polyvinyl alcohol-co-ethylene was dissolved in dry DMF (by warming to 100 ° C.) and this solution was added to the already obtained viscous material (after cooling to about 40 ° C.). The mixture was stirred in an ice bath for about 30 minutes and NaH was added. Stirring was continued overnight after removal of the ice bath to give a sticky solid that was used for urea capture experiments from the dialysis solution.

7.3 Characteristics Weight of MPS-V-027 = 4.763 g

8). Preparation of MPS-V-036 (polyacrylic acid _0.9 polyvinyl polyacrylic acid _0.1 )

8.1 Reagent

8.2 Procedure Poly (acrylic acid) in EDC. To a stirred solution of HCl. Polyvinyl alcohol was added to the stirred suspension and the solution was stirred overnight. The resulting gel is filtered under suction (vacuum pump), washed with water, methanol, dichloromethane (DCM), acetone and ether, respectively, and dried at room temperature for 1 week to give a glassy solid, which is dialyzed Used for urea capture experiments from solution.

8.3 Characteristics Weight of MPS-V-036 = 3.361 g

9. Preparation of MPS-V-037 (polyvinylpyrulate-ethylene copolymer)

9.1 Reagent

9.2 Procedure Polyvinyl alcohol-co-ethylene was dissolved in DMF (15 ml) by heating the mixture to 100 ° C. This solution (after cooling to 40 ° C.) was added to a mixture of pyruvic acid, dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) in dry DMF (15 ml) and the reaction mixture was stirred at room temperature overnight. . The resulting solid was filtered, washed with water, methanol, dichloromethane (DCM), acetone and ether, respectively, dried and used for urea capture experiments from dialysis solution.

9.3 Characteristics Weight of MPS-V-037 = 6.305 g

10. Preparation of MPS-V-038 (polyvinyl glyoxalate-ethylene copolymer)

10.1 Reagent

10.2 Procedure Polyvinyl alcohol-co-ethylene was dissolved in DMF (15 ml) by heating the mixture to 100 ° C. This solution (after cooling to 40 ° C.) is added to a mixture of glyoxylic acid monohydrate, dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) in dry DMF (15 ml) and the reaction mixture is allowed to cool at room temperature. Stir overnight. The resulting solid was filtered, washed with water, methanol, dichloromethane (DCM), acetone and ether, respectively, dried and used for urea capture experiments from dialysis solution.

10.3 Characteristics Weight of MPS-V-038 = 6.025 g

11. Preparation of MPS-V-047 (Isopropylamine polyacrylamide)

11.1 Reagents

11.2 Procedure Poly (acrylic acid) in distilled water with EDC. To a stirred solution of HCl. To this stirred suspension was added isopropylamine and the solution was stirred overnight. The resulting gel is filtered under suction (vacuum pump), washed with water, methanol, dichloromethane (DCM), acetone and ether, respectively, and dried at room temperature for 1 week to give a viscous gel (like a glassy solid). Was used for urea capture experiments from dialysis solutions.

11.3 Properties Weight of MPS-V-047 = 2.46 g

  The dialysis solution was analyzed for nitrogen content and the amount of urea in the dialysis solution was calculated. In some cases, additional urea was added to the solution as indicated in the second column of each table (1-5). The amount of polymer reagent shown in the third row was added to the solution. The mixture was stirred at room temperature for 1 hour and filtered. The filtrate was analyzed to determine the amount of urea removed from the dialysis solution. The minus sign (-) indicates that the result is not deterministic.

  In the table below, the title identifies the specific polymer reagent tested. The first column of each table represents the number of experiments or the number of runs. The second column identifies the particular dialysis solution used for the experiment and whether additional urea was added to the solution. The third column shows the amount of polymer reagent used in the experiment. The fourth column gives the reaction conditions, eg time and temperature (Note: rt = room temperature). In addition, the room temperature is between about 60-78 ° F. (about 15.56 ° C. to about 25.56 ° C.) and the reaction is about 50 ° F. to about 110 ° F. (about 10 ° C. to about 43.3 ° C.). It is understood that it occurs in the temperature range. It is also believed that reactions can occur at lower or higher temperatures, but such reactions were not specifically tested. The fifth column identifies the analytical portion (eg, filtrate) of the reaction mixture. In some cases, a neutralizing agent is added to the filtrate. The sixth column (BUN or blood urea nitrogen) provides the concentration of nitrogen in the particular dialysis solution used for the experiment. The seventh column gives the amount of urea in the solution. The eighth column contains the maximum amount of urea in the solution. If additional urea is added as shown in the second column, this number will be higher than the corresponding entry in the sixth column. The ninth column is the amount of urea removed from the dialysis solution. The first row of each table provides the maximum or total amount of nitrogen, urea and urea present in the dialysis solution used in the experiment.

  As will be appreciated from the above, vinyl polymers having specific functional groups selected from carboxylic acids, esters and salts, amides, dicarboxylic acids, and esters and salts can be obtained from aqueous solutions having a pH of about 6-8. It can be formulated to provide an adsorbent suitable for use in removing urea. Other adsorbents suitable for removing urea from aqueous solutions having a pH range of 4 to 12 are known to those skilled in the art having the information contained herein, using a variety of the specific functional groups described above. It is feasible. Such exemplary polymers are substantially insoluble in water and can remove urea from the dialysate at a rate of at least 2.5 mg / dl / hour. Furthermore, such polymers may be soluble in water, substantially soluble or insoluble, depending on variations in their manufacture.

  In some variations of the present invention, vinyl polymers such as polyvinyl alcohol, polyvinyl alcohol-ethylene copolymers, and polyacrylic acid are used as carboxylic acids, carboxylic esters, carboxylates, amides, dicarboxylic acids, dicarboxylic esters, and dicarboxylates. Reacted with specific functional groups selected from the rate to produce the desired exemplary adsorbent. Exemplary polymers can be applied to various substrates for use as dialysis adsorbents. Such substrates can be organic or inorganic and can include filter paper, plastic or glass beads and other particulate materials that are insoluble in water. The polymer may also be applied to various screen and mesh type filter materials formed from wires or plastic strands or fabrics.

  Another advantage of exemplary urea adsorbents is the variety of exemplary adsorptions that result from a wide variety such as soluble, insoluble, liquid, viscous materials, adhesives, flexible materials, coatings, and solids or powders. The use of selective functional groups available to make the agent.

  It will be appreciated by those skilled in the art having the benefit of this disclosure that this urea adsorbent provides a viable replacement for the previously known dialysis adsorbent materials. It should be understood that the drawings and detailed description herein are to be regarded as illustrative rather than restrictive, and are not intended to limit the particular forms and examples disclosed. is there. On the contrary, any further modifications, changes, rearrangements, substitutions, changes, design choices, and implementations that will be apparent to those skilled in the art without departing from the spirit and scope thereof, as defined by the following claims Includes form. Accordingly, the following claims are intended to be construed to include all such further modifications, variations, rearrangements, substitutions, variations, design choices, and embodiments. Is done.

Claims (35)

  A polymer suitable for use as an adsorbent to regenerate dialysate, said polymer interacting with urea in a liquid at a pH between 6 and 8 to remove urea from an aqueous solution The polymer is substantially insoluble in water, reacts with urea without releasing ammonia, and the reaction product of the polymer and urea is substantially insoluble in water. polymer. The polymer is of the formula:

The polymer of claim 1, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 1, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 1, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 1, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 1, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 1, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 1, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 1, comprising a repeating unit having:   The polymer of claim 1, wherein the functional group comprises at least two adjacent carbonyl groups.   The polymer of claim 1, wherein the functional group comprises one of a carboxylic acid, a carboxylic ester, a carboxylate, or an amide.   The polymer of claim 1, wherein the functional group comprises one of a dicarboxylic acid, a dicarboxylic acid ester, or a dicarboxylate.   The polymer of claim 1, wherein the functional group comprises one of oxalate, pyruvate, benzoate or acrylic acid. A filter for regenerating dialysate,
An adsorbent layer comprising a polymer with specific functional groups attached to interact with urea at a pH between 5 and 10 to remove urea from an aqueous solution;
Activated carbon for absorbing organic metabolites from the dialysate, wherein the polymer is substantially insoluble in water and interacts with urea without releasing ammonia in a predetermined temperature range, the polymer and urea The reaction product of is substantially insoluble in water.   The filter of claim 14, further comprising an anion exchange layer for removing anions from the dialysate.   A polymer suitable for use as an adsorbent for regenerating dialysate, said polymer having a specific functional group that reacts with urea at a pH between 4 and 12 to remove urea from an aqueous solution. Bound and the polymer is soluble or substantially insoluble in water and interacts or reacts with urea without releasing ammonia in the temperature range of about 50 ° F to 110 ° F. The polymer, wherein the reaction product of the polymer and urea is soluble in water or substantially insoluble in water. The polymer is of the formula:

The polymer of claim 16, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 16, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 16, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 16, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 16, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 16, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 16, comprising a repeating unit having: The polymer is of the formula:

The polymer of claim 16, comprising a repeating unit having:   17. The functional group of claim 16, wherein the functional group comprises at least one carbonyl group (C = O) as either a ketone, an anhydride, an ester, an amide, or a combination of 2-10 adjacent or remote functional groups. The polymer described.   17. A polymer according to claim 16, wherein the functional group comprises a carboxylic acid, a carboxylic ester, a carboxylate or an amide.   The polymer of claim 16, wherein the functional group comprises one of a dicarboxylic acid, a dicarboxylic ester, a general dicarboxylate moiety, or a combination of the functional groups.   The polymer of claim 16, wherein the functional group comprises one of oxalate, pyruvate, benzoate or acrylic acid.   17. The polymer of claim 16, wherein the functional group reacts with urea at a pH between 6-9.   The polymer of claim 16, wherein the reaction product of the polymer and urea is insoluble in water. A dialysate regeneration filter for removing solids or liquids from dialysate,
An adsorbent layer comprising a polymer to which functional groups that interact or react with urea at a pH between 4 and 12 to limit urea from an aqueous solution are bound;
Activated carbon for absorbing organic metabolites from the dialysate, and the polymer is soluble or substantially insoluble in water and interacts or reacts with urea without releasing ammonia. A filter wherein the polymer-urea interaction or reaction product is soluble in water or substantially insoluble in water.   32. The filter of claim 31, further comprising an anion exchange layer for removing anions from the dialysate.   32. A filter according to claim 31, wherein the functional group interacts or reacts with urea at a pH between 6-9.   32. The filter of claim 31, wherein the polymer is soluble in water.   32. The filter of claim 31, wherein the polymer and urea interaction or reaction product is insoluble in water.