Sorbent for a dialysis device

Abstract

There is provided a sorbent for removing metabolic waste products from a dialysis liquid, the sorbent comprising a layer of immobilized uremic toxin-treating enzyme particles intermixed with cation exchange particles.

Claims

1. A fixed bed sorbent for removing metabolic waste products from a dialysis liquid, the sorbent comprising a primary layer of uremic toxin-treating enzyme particles covalently immobilized on a biocompatible material intermixed with cation exchange particles and anion exchange particles, wherein a pressure drop of the dialysis liquid across the primary layer is dependent on the size of said cation exchange particles; wherein said uremic toxin-treating enzyme particles and said cation exchange particles are, when in use, in direct contact with the dialysis liquid; and wherein the anion exchange particles and cation exchange particles are selected to create pH buffering conditions when in direct contact with the dialysis liquid.

2. The fixed bed sorbent as claimed in claim 1 further comprising a secondary layer of organic compounds absorber particles.

3. The fixed bed sorbent as claimed in claim 2, wherein the direction of the dialysis liquid flow is from said primary layer to said secondary layer.

4. The fixed bed sorbent as claimed in claim 2, wherein said organic compounds absorber particles are activated carbon particles.

5. The fixed bed sorbent as claimed in claim 4, wherein said activated carbon particles have an average particle size in the range of from 10 microns to 1000 microns.

6. The fixed bed sorbent as claimed in claim 1, wherein said uremic toxin-treating enzyme particles convert urea to ammonium carbonate.

7. The fixed bed sorbent as claimed in claim 6, wherein said uremic toxin-treating enzyme is urease.

8. The fixed bed sorbent as claimed in claim 7, wherein said urease is immobilized on at least one of cellulose, nylon, polycaprolactone and chitosan.

9. The fixed bed sorbent as claimed in claim 7, wherein said urease particles have an average particle size in in the range of from 10 microns to 1000 microns.

10. The fixed bed sorbent as claimed in claim 1, wherein said cation exchange particles are zirconium phosphate particles.

11. The fixed bed sorbent as claimed in claim 10, wherein said zirconium phosphate particles have an average particle size in the range of from 10 microns to 1000 microns.

12. The fixed bed sorbent as claimed in claim 1, wherein said anion exchange particles are zirconium oxide particles.

13. The fixed bed sorbent as claimed in claim 12, wherein said zirconium oxide is hydrous zirconium oxide.

14. The fixed bed sorbent as claimed in claim 12, wherein said zirconium oxide particles have particle size in the range of from 10 microns to 1000 microns.

15. The fixed bed sorbent as claimed in claim 1, wherein said cation exchange particles are ammonia absorbers.

16. The fixed bed sorbent as claimed in claim 1, wherein said cation exchange particles comprise ions of a metal whose phosphate is poorly soluble in water.

17. A fixed bed sorbent for removing metabolic waste products from a dialysis liquid, the sorbent comprising a layer of uremic toxin-treating enzyme particles covalently immobilized on a biocompatible material intermixed with cation exchange particles having an average particle size in the range of 50 microns to 200 microns and anion exchange particles; wherein said uremic toxin-treating enzyme particles and said cation exchange particles are, when in use, in direct contact with the dialysis liquid; and wherein the anion exchange particles and cation exchange particles are selected to create pH buffering conditions when in direct contact with the dialysis liquid.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) The accompanying drawings illustrate disclosed embodiments and serve to explain the principles of the disclosed embodiments. It is to be understood, however, that the drawings are designed for purposes of illustration only, and not as a definition of the limits of the invention.

(2) FIG. 1a shows the layout of one embodiment of the sorbent for a dialysis device.

(3) FIG. 1b-1g shows the layout of other different embodiments of the sorbent for a dialysis device.

(4) FIG. 2a is an isometric view of a CAD of the sorbent cartridge and FIG. 2b is a cross sectional view of the sorbent cartridge of FIG. 2a.

(5) FIG. 2c is a cross sectional view of a CAD of another embodiment of the sorbent cartridge having partitions to demarcate the different layers of the sorbent.

(6) FIG. 3 shows a polycarpolactone (PCL) scaffold for use as a biocompatible substrate for the immobilization of urease as disclosed herein.

(7) FIG. 4 shows a polycarpolactone (PCL) scaffold for use as a biocompatible substrate for the immobilization of zirconium phosphate as disclosed herein.

DETAILED DESCRIPTION

(8) Referring to FIG. 1a, there is shown one embodiment of the sorbent (100) used in the disclosed dialysis device. The first layer (1a-1) of the sorbent (100) comprises an activated carbon pad (1).

(9) The second layer (1a-2) of the sorbent (100) is arranged in series, adjacent to the first layer (1a-1), and comprises of a mixture of immobilized urease (2) and zirconium phosphate particles (3). Purified urease obtained from Jack Bean, crude Jack Bean powder or other sources (such as bacterial, recombinant, thermostable urease mutants, etc.) is covalently immobilized. The solid support material or substrate used is cellulose. The immobilized urease (2) is in the form of particles with particle sizes in the range of 25 microns to 200 microns. The total weight range of the immobilized urease particles used is in the range of from 0.5 grams to 30 grams. The zirconium phosphate particles (3) have sizes from 25 microns to 250 microns, obtained from MEI, New Jersey, United States of America. The total weight range of the zirconium phosphate particles (3) is from about 100 grams to 1000 grams.

(10) The third layer (1a-3) of the sorbent (100) is arranged in series, adjacent to the second layer (1a-2). The third layer (1a-3) comprises zirconium phosphate particles (3) of sizes from 25 microns to 250 microns. The total weight range of the zirconium phosphate particles (3) is from about 100 grams to 1000 grams.

(11) The fourth layer (1a-4) of the sorbent (100) is arranged in series, adjacent to the third layer (1a-3). The fourth layer (1a-4) comprises a mixture of hydrous zirconium oxide particles (4) and activated carbon particles (5). The zirconium oxide particles (4) have sizes from 10 microns to 250 microns, obtained from MEI, New Jersey, United States of America. The total weight range of the zirconium oxide particles (4) is from about 10 grams to 100 grams. The activated carbon particles (5) have sizes from 50 microns to 300 microns, obtained from Calgon Carbon Corporation of Pittsburgh, Pa., United States of America. The total weight range of the activated carbon particles (5) is from about 20 grams to 200 grams.

(12) When in use, the sorbent (100) is arranged in the dialysis device such that the direction of the dialysate flow is from the first layer (1a-1) to the fourth layer (1a-4) as shown by the arrow. As the dialysate passes into the first layer (1a-1), the activated carbon pad (1a-1) removes enzyme inhibiting substances, such as oxidants and/or heavy metals, thus maintaining the activity and stability of the uremic toxin-treating enzyme. Furthermore, this layer also removes toxic organic compounds, such as uremic toxins from the spent dialysate.

(13) As the dialysate passes into the second layer (1a-2), the mixture of immobilized urease (2) and zirconium phosphate particles (3) removes urea and ammonium ions from the dialysate. In addition, as the zirconium phosphate particles (3) not only exchange ions but also act as a buffer, the pH conditions around the urease (2) are kept stable, thereby protecting the urease activity and extending its life time. When the dialysate passes through the second layer (1a-2) and enters the intermediate third layer (1a-3), the zirconium phosphate particles (3) present in this layer, quantitatively remove all ammonium ions formed in the second layer (1a-2). After which, the dialysate passes into the fourth layer (1a-4). The mixture of hydrous zirconium oxide particles (4) and activated carbon particles (5) removes any phosphate ions produced by the patient or leached from the zirconium phosphate particles (3) in the second (1a-2) and/or third (1a-3) layer. The mixture also removes creatinine, uric acid and other uremic toxins present in the dialysate. The combination of the different layers in the sorbent (100) improves the overall efficacy of toxin removal and reduces the overall size of the sorbent (100).

(14) Referring now to FIG. 1b, there is shown a second embodiment of the sorbent (102) used. The immobilized urease (2), zirconium phosphate particles (3), hydrous zirconium oxide particles (4), activated carbon particles (5) and the respective substrates used for the following layers are the same as those described above for FIG. 1a.

(15) The first layer (1b-1) of the sorbent (102) comprises immobilized urease (2). The urease (2) used is in the form of particles with particle sizes in the range of 25 microns to 200 microns. The total weight of the urease particles used is in the range of from 0.5 grams to 30 grams.

(16) The second layer (1b-2) of the sorbent (102) is arranged in series, adjacent to the first layer (1b-1). The second layer (1b-2) comprises zirconium phosphate particles (3) of sizes from 25 microns to 250 microns. The total weight range of the zirconium phosphate particles (3) is from about 100 grams to 1000 grams.

(17) The third layer (1b-3) of the sorbent (102) is arranged in series, adjacent to the second layer (1b-2). The third layer (1b-3) comprises hydrous zirconium oxide particles (4) of sizes from 10 microns to 250 microns. The total weight range of the zirconium oxide particles (4) is from about 10 grams to 100 grams.

(18) The fourth layer (1b-4) of the sorbent (102) is arranged in series, adjacent to the third layer (1b-3). The fourth layer (1b-4) comprises activated carbon particles (5) of sizes from 25 microns to 300 microns. The total weight range of the activated carbon particles (5) is from about 20 grams to 200 grams.

(19) When in use, the sorbent (102) is arranged in the dialysis device such that the direction of the dialysate flow is from the first layer (1b-1) to the fourth layer (1b-4) as shown by the arrow.

(20) When the dialysate enters the first layer (1b-1), the immobilized urease (2) breaks down urea present in the dialysate to ammonium carbonate, hence releasing ammonium and bicarbonate ions into the dialysate. As the dialysate passes into the second layer (1b-2), the zirconium phosphate particles (3) absorb ammonium cations arising from the decomposition of urea by the first layer (1b-1). The zirconium phosphate particles (3) act as a cation exchanger to absorb other cations such as calcium, potassium and magnesium, releasing sodium and hydrogen in exchange. As the size of the zirconium phosphate particles (3) used is in the range of 25 microns to 250 microns, the absorption of the unwanted cations and the flow resistance of the sorbent is in the optimum range. This ensures that the dialysate exiting from the layer of zirconium phosphate particles (3) is essentially free of any unwanted cations. The dialysate then passes into the third layer (1b-3) and the hydrous zirconium oxide particles (4) remove any phosphate ions produced by the patient or leached from the zirconium phosphate particles (3) in the second layer (1b-2). In summary, the hydrous zirconium oxide particles (4) act as an anion exchanger by binding anions such as phosphate and fluoride and releases acetate and hydroxide ions in exchange. In addition, the hydrous zirconium oxide particles (4) are also good binders for iron, aluminum and heavy metals. After passing the layer of hydrous zirconium oxide particles (4), the dialysate enters the fourth layer (1b-4) and the activated carbon (5) resident in the fourth layer (1b-4) absorbs organic metabolites such as creatinine, uric acid and other small or medium sized organic molecules from the dialysate without releasing anything in exchange.

(21) Referring now to FIG. 1c, there is shown another embodiment of the sorbent (104) used. The activated carbon particles (5), immobilized urease particles (2), zirconium phosphate particles (3), hydrous zirconium oxide particles (4) and the respective substrates used for the following layers are the same as those described above for FIG. 1a.

(22) The first layer (1c-1) comprises activated carbon particles (5) of sizes from 25 microns to 300 microns. The total weight range of the activated carbon particles (5) is from about 20 grams to 200 grams.

(23) The second layer (1c-2) of the sorbent (104) contains immobilized urease and is arranged in series, adjacent to the first layer (1c-1). The immobilized urease (2) is in the form of particles with particle sizes in the range of 25 microns to 200 microns. The total weight of the urease particles is in the range of from 0.5 grams to 30 grams.

(24) The third layer (1c-3) of the sorbent (104) is arranged in series, adjacent to the second layer (1c-2). The third layer (1c-3) comprises zirconium phosphate particles (3) of sizes from 25 microns to 250 microns. The total weight range of the zirconium phosphate particles (3) is from about 100 grams to 1000 grams.

(25) The fourth layer (1c-4) of the sorbent (104) is arranged in series, adjacent to the third layer (1c-3). The fourth layer (1c-4) comprises hydrous zirconium oxide particles (4). The zirconium oxide particles (4) have sizes from 10 microns to 250 microns. The total weight range of the zirconium oxide particles (4) is from about 10 grams to 100 grams.

(26) The optional fifth layer (1c-5) of the sorbent (104) is arranged in series, adjacent to the fourth layer (1c-4). When present, the fifth layer (1c-5) comprises activated charcoal (5). The activated carbon particles (5) have sizes from 25 microns to 300 microns. The total weight range of the activated carbon particles (5) is from about 20 grams to 200 grams.

(27) When in use, the sorbent (104) is arranged in the dialysis device such that direction of the dialysate flow is from the first layer (1c-1) to the fourth layer (1c-4) as shown by the arrow. As the dialysate passes into the first layer (1c-1), this layer removes enzyme inhibiting substances and toxic organic compounds, including uremic toxins, same as the activated carbon pad described above (FIG. 1a).

(28) As the dialysate passes into the second layer (1c-2), the immobilized urease (2) degrades urea to ammonium ions and carbonate/bicarbonate ions. When the dialysate passes through the second layer (1c-2) and enters the third layer (1c-3), the zirconium phosphate particles (3) remove ammonium ions from the dialysate. When the dialysate moves forward and enters the fourth layer (1c-4), the hydrous zirconium oxide particles (4) remove any phosphate ions produced by the patient or leached from the zirconium phosphate particles (3) in the third layer (1c-3). As the dialysate moves forward and leaves the fourth layer (1c-4), it may enter a fifth layer (1c-5) of activated carbon particles (5). Where present, this fifth layer (1c-5) removes creatinine, uric acid and other uremic toxins present in the dialysate.

(29) Referring now to FIG. 1d, there is shown another embodiment of the sorbent (106) used. The activated carbon pad (1), immobilized urease (2), zirconium phosphate particles (3), hydrous zirconium oxide particles (4), activated carbon particles (5) and the respective substrates used for the following layers are the same as those described above for FIG. 1a.

(30) Arranged in series, an activated carbon pad (1) in the first layer (1d-1), a mixture of the immobilized urease particles (2) and zirconium phosphate particles (3) in the second layer (1d-2) of the sorbent (106) are the same as those of the first two layers (1b-1 and 1b-2) elaborated in the description for FIG. 1a.

(31) The third layer (1d-3) of the sorbent (106) is arranged in series, adjacent to the second layer (1d-2). The third layer (1d-3) comprises a mixture of zirconium phosphate particles (3) and hydrous zirconium oxide particles (4). The total weight range of the zirconium phosphate particles (3) is from about 100 grams to 1000 grams. The total weight range of the hydrous zirconium oxide particles (4) is from about 10 grams to 100 grams.

(32) The fourth layer (1d-4) of the sorbent (106) is arranged in series, adjacent to the third layer (1d-3). The fourth layer (1d-4) comprises activated carbon particles (5) which is same to that (1b-4) of FIG. 1b. The total weight range of the activated carbon particles (5) is from about 20 grams to 200 grams.

(33) When in use, the sorbent (106) is arranged in the dialysis device such that direction of the dialysate flow is from the first layer (1d-1) to the fourth layer (1d-4) as shown by the arrow. As the dialysate passes through the first layer (1d-l), this layer removes enzyme inhibiting substances and toxic organic compounds, including uremic toxins, same as the description of the activated carbon pad above (FIG. 1a). When the dialysate enters the second layer (1d-2), the mixture of the urease particles (2) and zirconium phosphate particles (3), same to those descriptions in the section of FIG. 1a, remove urea, ammonium ions and other cations, i.e. calcium, magnesium and potassium in the same way. When the dialysate moves into the third layer (1d-3), the mixture of zirconium phosphate particles (3) and hydrous zirconium oxide particles removes said cations escaping from the second layer (1d-2) as well as phosphate and other unwanted anions. The spatial proximity of zirconium phosphate particles (3) and hydrous zirconium oxide particles (4) may facilitate the re-absorption of leaked phosphate. More advantageously, mixing of both types of ion exchangers in one combined layer significantly improves the performance of both particles as a buffer, thus producing more consistent pH conditions in the dialysate throughout the sorbent's use. Meanwhile this mixture also reduces the size of the sorbent (106) without compromising the toxin removal capability. When the dialysate passes into the final layer (1d-4) of the sorbent (106), the activated carbon (5) further absorbs creatinine, uric acid and other uremic toxins present in the spent dialysate.

(34) Referring now to FIG. 1e, there is shown another embodiment of the sorbent (108) used. The activated carbon pad (1), immobilized urease (2), zirconium phosphate particles (3), hydrous zirconium oxide particles (4), activated carbon particles (5) and the respective substrates used for the following layers are the same as those described above for FIG. 1a.

(35) An activated carbon pad (1) in the first layer (1e-1) is same to that of FIG. 1a elaborated above.

(36) In the second layer (1e-2) of the sorbent (108) is arranged in series, adjacent to the first layer (1e-1). The second layer (1e-2) comprises a mixture of immobilized urease particles (2), zirconium phosphate particles (3) and hydrous zirconium oxide particles (4). The total weight range of urease particles (2) is from 0.5 to 30 grams. The total weight of the zirconium phosphate particles (3) is from about 100 grams to 1000 grams. The total weight range of the hydrous zirconium oxide particles (4) is from about 10 grams to 100 grams. The third layer (1e-3) of the sorbent (108) is arranged in series, adjacent to the second layer (1e-2). The third layer (1e-3) comprises activated carbon particles (5) which is same to that (1b-4) of FIG. 1b. The total weight range of the activated carbon particles (5) is from about 20 grams to 200 grams.

(37) When in use, the sorbent (108) is arranged in the dialysis device such that direction of the dialysate flow is from the first layer (1e-1) to the third layer (1e-3) as shown by the arrow. As the dialysate passes into the first layer (1e-1), this layer removes enzyme inhibiting substances and toxins, same as in the description above (FIG. 1a). When the dialysate enters into the second layer (1e-2), the mixture of the urease particles (2), zirconium phosphate particles (3) and hydrous zirconium oxide particles (4) removes urea, cations such as ammonium ions, calcium, magnesium and potassium and anions such as phosphate and fluoride. Advantageously, mixing of immobilized urease and both types of ion exchangers in one combined layer significantly improves the performance by facilitating immediate toxin absorption and producing more consistent pH conditions in the dialysate throughout the sorbent's use. Meanwhile this mixture also reduces the size of the sorbent (108) without compromising the toxin removal capability. When the dialysate passes into the final layer (1e-3) of the sorbent (108), the activated carbon particles (5) absorb creatinine, uric acid and other uremic toxins present in the dialysate.

(38) Referring now to FIG. 1f, there is shown another embodiment of the sorbent (110) used. The immobilized urease (2), zirconium phosphate particles (3), hydrous zirconium oxide particles (4), activated carbon particles (5) and the respective substrates used for the following layers are the same as those described above for FIG. 1a.

(39) A first layer of activated carbon particles (5) is the same to that described above (FIG. 1c).

(40) The second layer (1f-2) of the sorbent (110) is arranged in series, adjacent to the first layer (1f-1). The second layer (1f-2) comprises a mixture of immobilized urease particles (2), zirconium phosphate particles (3) and hydrous zirconium oxide particles (4). The total weight range of urease particles (2) is from 0.5 to 30 grams. The total weight of the zirconium phosphate particles (3) is from about 100 grams to 1000 grams. The total weight range of the hydrous zirconium oxide particles (4) is from about 10 grams to 100 grams.

(41) When in use, the sorbent (110) is arranged in the dialysis device such that direction of the dialysate flow is from the first layer (1f-1) to the second layer (1f-2) as shown by the arrow. As the dialysate passes into the first layer (1f-1), this layer removes enzyme inhibiting substances as well as creatinine, uric acid and other uremic toxins present in the dialysate, as in the description above (FIG. 1c). When the dialysate enters into the second layer (1f-2), the mixture of the urease particles (2) and zirconium phosphate particles (3) and hydrous zirconium oxide particles (4) removes urea, cations such as ammonium ions, calcium, magnesium and potassium, and anions such as phosphate and fluoride in the same way as described above (FIG. 1e). The advantage herein is same as the description above (FIG. 1e).

(42) Referring now to FIG. 1g, there is shown another embodiment of the sorbent (112) used. The activated carbon particles (5), immobilized urease particles (2), zirconium phosphate particles (3), hydrous zirconium oxide particles (4) and the respective substrates used for the following layers are the same as those described above for FIG. 1a.

(43) There is one homogenous filling (1g-1) for the sorbent (112). The filling layer (1g-1) is a homogenous mixture of immobilized urease particles (2), zirconium phosphate particles (3), hydrous zirconium oxide particles (4) and activated carbon particles (5). The total weight range of urease particles (2) is from 0.5 grams to 30 grams; the total weight of the zirconium phosphate particles (3) is from about 100 grams to 1000 grams; the total weight range of the hydrous zirconium oxide particles (4) is from about 10 grams to 100 grams; the total weight range of activated carbon particles is from 20 grams to 200 grams.

(44) When in use, the sorbent (112) is arranged in the dialysis device such that direction of the dialysate flow is from the bottom dimension to the top dimension (1g-1) as shown by the arrow. As the dialysate passes through the sorbent (112), the mixture of the immobilized urease particles (2), zirconium phosphate particles (3), hydrous zirconium oxide particles (4) and activated carbon particles (5) removes urea, cations such as ammonium ions, calcium, magnesium and potassium, anions such as phosphate and fluoride, and enzyme inhibiting substances and small to medium size organic metabolites, such as creatinine, uric acid and other uremic toxins. This arrangement gives the benefits of an improved performance of both particles as a buffer, thus producing more consistent pH conditions in the dialysate throughout the sorbent's use. More advantageously, mixing of immobilized urease, both types of ion exchangers and activated carbon in one combined layer gives the benefits of a much more compact size of the sorbent (112) and sufficient toxin removal capability. It also reduces the pressure drop caused by the sorbent to a minimum, and facilitates the production process significantly. It eliminates the risk of having uneven sorbent layers, which would be a cause for premature exhaustion of the sorbent layers.

(45) Referring to FIG. 2a and FIG. 2b, there is shown a cartridge (18), for housing the sorbent (102) as described above. The cartridge (18) is made of polycarbonate. The top (20) of the cartridge (18) and the bottom of the cartridge (28) have flanges for slotting into the dialysis device. The interior of the cartridge (18) is divided into three compartments. The first compartment (26) houses the mixture of immobilized urease (16) and zirconium phosphate particles (14). The first compartment has a height of 27 mm, a length of 113 mm and a breadth of 57 mm. The second compartment (24) houses the zirconium phosphate particles (14). The second compartment (24) has a height of 27 mm, a length of 113 mm and a breadth of 57 mm. The third compartment (22) the mixture of activated carbon particles (10) and hydrous zirconium oxide particles (12). The third compartment (22) has a height of 13 mm, a length of 113 mm and a breadth of 57 mm.

(46) Referring now to FIG. 2c, there is shown a cross sectional view of a cartridge 18′ having a number of technical features that are the same as the cartridge 18 described above which are indicated by the same reference numeral but with a prime symbol (′). The bottom (27) and top (21) of cartridge 18′ do not contain flanges and have reduces the overall external dimensions of the cartridge (18′). The cartridge (18′) can be inserted in the dialysis device and secured by fastening means such as nuts and bolts. The cartridge (18′) also contains separators (19) for a better demarcation of the different layers of the sorbent.

(47) Referring now to FIG. 3, there is shown a PCL scaffold or substrate (30) used for urease immobilization as described above. The PCL scaffold (30) has a diameter of about 7 cm.

(48) Referring to FIG. 4, there is shown a PCL scaffold (32) containing 40% zirconium phosphate. The PCL scaffold (32) has a diameter of about 7 cm.

EXAMPLES

Evidence of Improved Urease Activity and Stability by Mixing Immobilized Urease (IU) and Zirconium Phosphate (ZP)

(49) TABLE-US-00001 3 h 5 h 10 h Pure IU (Table 1) PH 8.6 8.6 8.6 Urea removal 94% 98% 86% Pressure drop 20 mmHg 30 mmHg 120 mmHg One layer pure IU, one layer pure ZP (Table 2) PH 7.6 8.22 over-pressure Urea removal 99% 99% over-pressure Pressure drop 70 mmHg 720 mmHg over-pressure IU and ZP, one mixed layer (Table 3) PH 7.6 8.5 8.5 Urea removal 100%  99% 98% Pressure drop 70 mmHg 70 mmHg  70 mmHg

(50) From the above data, it can be seen that when IU and ZP are mixed in one layer, a high level of urea removal can be achieved over a long period of time (10 h), while maintaining a relatively stable pressure drop across the sorbent as shown in Table 3. On the other hand, when IU is used alone, the urea removal efficiency decreases over time and the pressure drop across the sorbent increases significantly over time as shown in Table 1. In the case when IU and ZP are used but in separate layers, although the urea removal efficiency is maintained at a high level, drastic pressure drops occurs over time across the sorbent as shown in Table 2, leading to overpressure and damage to the sorbent and/or the dialysis device.

Study of Absorbance Capacity of Zirconium Phosphate in Dependence of Particle Size

(51) TABLE-US-00002 10 g ZP (batch PP835A-Nov08), 0.3 L/h, 12 mmol/L NH4+ (Table 4) Particle Absorbance Capacity Size Pressure Drop (mmol NH4+ per g ZP) <5 μm 460 - 500 mmHg 0.84 mmol/g 150 - 100 μm  80 - 120 mmHg 0.90 mmol/g

(52) TABLE-US-00003 10 g ZP (batch PP911C-Jan09), 0.3 L/h, 12 mmol/L NH4+ (Table 5) Particle Absorbance Capacity Size Pressure Drop (mmol NH4+ per g ZP) <50 μm 340 - 360 mmHg 0.90 mmol/g  50 - 100 μm 140 - 160 mmHg 0.91 mmol/g 100 - 150 μm 30 - 50 mmHg 0.83 mmol/g 150 - 200 μm 20 - 30 mmHg 0.79 mmol/g

(53) The pressure drop caused by zirconium phosphate particles is shown to be strongly dependent of the particle size of the zirconium phosphate under consideration. Thus, while layers of particles of less than 50 microns size produce unacceptably high pressure drops, particle sizes of 50 to 100 microns already produce significantly lower pressure drops in a favourable range for application in the sorbent cartridge. Increasing the particle size to 100 to 150 microns, and 150 to 200 microns further reduces the pressure drop caused by the particles under consideration. Moreover, it can be seen from above data that the absorbance capacity of the zirconium phosphates under consideration is highest for particles of 50 to 100 microns size. The optimum between ammonia absorbtion capacity and pressure drop is therefore at zirconium phosphate particle sizes of 50 to 100 microns.

Study of Absorbance Capacity of Hydrous Zirconium Oxide in Dependence of Particle Size

(54) TABLE-US-00004 2 g HZO (batch ZrOH 304-AC - Mar09), 0.3 L/h, 1.0 mmol/L P (Table 6) Particle Absorbance Capacity Size Pressure Drop (mmol P per g HZO) <50 μm 30 - 40 mmHg 0.68 mmol/g 50 - 100 μm 20 - 30 mmHg 0.63 mmol/g

(55) The pressure drop caused by hydrous zirconium oxide particles is shown to be significantly lower than that caused by the zirconium phosphate particles, even at particle sizes of smaller than 50 microns. This is partly due to the smaller quantity of hydrous zirconium oxide required for the cartridge functionality. Thus, a layer of hydrous zirconium oxide particles of less than 50 microns (>95% within 10 to 50 microns) size produces an acceptable pressure drop for use in the cartridge, while particles of this size also show improved phosphate absorbance capacity over particles of greater than 50 microns size. The preferred particle size for application in the sorbent cartridge is therefore 10 to 50 microns.

Study of Absorbance Capacity of Activated Carbon in Dependence of Particle Size

(56) The capacity of activated carbon to absorb creatinine is shown to be dependent on the flow rate of dialysate and on the particle size of the carbon under consideration. Crucially, there is a tendency for higher capacity, and increasing pressure drop with smaller particle size. The optimum between acceptable pressure drop and maximum absorbance is at a particle size range of 50-100 μm as shown in the experimental results tabulated below.

(57) Series 1

(58) Activated carbon from Calgon, first batch

(59) Conditions:

(60) Synthetic hemodialysate containing 135 μmol/l creatinine, 37° C.

(61) TABLE-US-00005 TABLE 7 Absorbance Capacity Particle Amount Flow Absorbed (μmol Creatinine Size Carbon Rate Creatinine per g Carbon)  0 - 50 μm 2 g 0.6 Nil (over- l/h pressure)  50 - 100 μm 3 g 0.6 440 μmol 145 μmol/g l/h  100 - 150 μm 4 g 0.6 450 μmol 110 μmol/g l/h  150 - 200 μm 5 g 0.6 460 μmol 100 μmol/g l/h  200 - 300 μm 6 g 0.6 440 μmol  70 μmol/g l/h  300 - 1000 μm 10 g  0.6 450 μmol  60 μmol/g l/h 1000 - 2000 μm 10 g  0.6 300 μmol  30 μmol/g l/h
Series 2
Activated carbon from Calgon, second batch
Conditions:
Synthetic hemodialysate containing 135 μmol/l creatinine, 37° C.

(62) TABLE-US-00006 TABLE 8 Absorbance Capacity Particle Amount Flow Absorbed (μmol Creatinine size Carbon Rate Creatinine per g Carbon)  0 - 100 μm 2 g 0.6 l/h  80 μmol 40 μmol/g 100 - 200 μm 4 g 0.6 l/h 220 μmol 55 μmol/g 200 - 500 μm 4 g 0.6 l/h 140 μmol 35 μmol/g
Series 3
Activated carbon from Sorb
Conditions:
Synthetic hemodialysate containing 110 μmol/l creatinine, 37° C.

(63) TABLE-US-00007 TABLE 9 Absorbance Capacity Particle Amount Flow Absorbed (μmol Creatinine size Carbon Rate Creatinine per g Carbon)  0 - 100 μm 2 g 0.6 l/h 242 μmol 121 μmol/g  100 - 200 μm 4 g 0.6 l/h 320 μmol 80 μmol/g 200 - 500 μm 4 g 0.6 l/h 275 μmol 70 μmol/g 1000 - 2000 μm 37 g  6.0 l/h 275 μmol  7 μmol/g

Layout and Design of Sorbent Cartridge

(64) The Sorbent cartridge disclosed herein is designed to remove urea and other waste materials that are present in the spent dialysate and enable the regeneration of the dialysate for its repeated use in dialysis. This will reduce the amount of dialysate used in conventional modalities of about 120 litres in a 4-hour haemodialysis session or 70 to 100 litres in a week typical peritoneal dialysis. In hemodialysis, the cartridge can be used to regenerate the dialysate that will pass through the hemodialyzer. The dialysate can be regenerated into a reservoir of the dialysate for reconstitution and continued use in dialysis. In peritoneal dialysis, the cartridge can be used to regenerate the dialysate withdrawn from the patient's peritoneal cavity. The regenerated dialysate may then be made available to reconstitution systems allowing its re-introduction into the patient's cavity.

(65) The sorbent cartridge is designed, in terms of size and weight, to be wearable with the carrier disclosed herein when inserted in the dialysis device (collectively known as the wearable peritoneal dialysis machine or WPDM). This enables patients to be more mobile in carrying out their daily activities and to be more economically productive. The dialysis device comprising the disclosed sorbent can remove uremic toxins 24/7, and is effective in removal of the uremic toxins in comparison to any other current modalities available in the market.

(66) From experiment carried out, it is observed that the sorbent disclosed herein is able to absorb 190 mmol of urea (or 5.3 grams of urea-N). The sorbent cartridge is also a sterile, single use unit, used individually or in combination with the prescribed amount of glucose to be incorporated, through the enrichment module in the WPDM. In summary, the preferred sorbent layouts, quantity of the components in each layer and function are represented in the following tables:

(67) TABLE-US-00008 General principle (Table 10) Quantity, g Function Regenerated Removes from Release into Dialysate the Dialysate the Dialysate Flow Direction Hydrous HZO: 10 to 100 Creatinine, uric Acetate Zircinium Oxide AC: 20 to 200 acid, phosphate (HZO) and and organic Activated Carbon molecules (AC) Zirconium ZP: 100 to 1000 Ammonia, Sodium- and Phosphate (ZP) calcium, hydrogen-ions magnesium and potassium Immobilized IU: 0.5 to 30 Urea, Ammonium Urease (IU) and ZP: 100 to 1000 ammonium, carbonate, Zirconium calcium, sodium- and Phosphate (ZP) magnesium and hydrogen-ions potassium Spent Dialysate Flow Direction

In Vitro Test

1. Purpose

(68) The purpose of the in-vitro test is to verify the sorbent cartridge's functionality under conditions simulating its application in the regeneration of patient hemodialysisate. To this end, the patient spent dialysate is replaced by synthetic spent hemodialysate, containing the uremic toxins urea, creatinine and phosphate in the expected concentrations for continuous hemodialysis.

(69) TABLE-US-00009 2. Cartridge composition (Table 11) Quantity, g Regenerated Dialysate Flow Direction Activated Carbon (AC) 55 g Hydrous Zirconium Oxide (HZO) 60 g Zirconium Phosphate (ZP) 335 g  Immobilized Urease (IU) and IU: 6 g Zirconium Phosphate (ZP) ZP: 120 g Activated Carbon (AC) Pad, 3 mm thickness Spent Dialysate Flow Direction

3. In Vitro Test Conditions

(70) The test was conducted at a dialysate temperature of 37° C. and a continuous flow rate of 6.0 L/h. Exhaustion is defined as the point where at least one of the chemical components of the regenerated dialysate is out of the acceptable range (see 3.2 below).

(71) The following tables show the composition of a typical spent hemo-dialysate, the medically accepted ranges for the components of regenerated dialysate and the quantities of the absorbed toxins when spent dialysate is passed through one embodiment of the sorbent disclosed herein (Table 11).

(72) 3.1. Composition of Synthetic Spent Hemo-Dialysate

(73) TABLE-US-00010 TABLE 12 SI units Alternative Units Component Na 140 mmol/L 140 mEq/L Ca 1.50 mmol/L 3.00 mEq/L Mg 0.50 mmol/L 1.00 mEq/L K 2.00 mmol/L 2.00 mEq/L Cl 111 mmol/L 111 mEq/L HCO3 31 mmol/L 31 mEq/L Glucose 11.1 mmol/L 200 mg/dL (anhydrous) 220 mg/dL (dextrose) Toxins Urea 6.00 mmol/L 36.0 mg/dL urea 16.8 mg/dL urea-N Creatinine 203 μmol/L 1.53 mg/dL creatinine Phosphate 720 μmol/L 1.49 mg/dL P

(74) TABLE-US-00011 3.2. Acceptable Range for Regenerated Dialysate (post sorbent cartridge) (Table 13): SI units Alternative Units Component Na 120 - 150 mmol/L 120 - 150 mEq/L Ca 0 mmol/L 0 mEq/L Mg 0 mmol/L 0 mEq/L K 0 mmol/L 0 mEq/L Cl 111 mmol/L 90 - 115 mEq/L HCO3 5 - 37 mmol/L 5 - 37 mEq/L Glucose 0 - 13 mmol/L 0 - 234 mg/dL (anhydrous) 0 - 258 mg/dL (dextrose) Toxins Urea 0 - 0.60 mmol/L 0 - 3.60 mg/dL urea 0 - 1.68 mg/dL urea-N Creatinine 0 - 20 μmol/L 0 - 0.23 mg/dL creatinine Phosphate 0 - 70 μmol/L 0 - 0.22 mg/dL P Ammonia 0 - 1.4 mmol/L 0 - 2 mg/dL N (from urea)

4. Test Results

(75) Exhaustion: The ammonia concentration in the cartridge outflow was greater than 1.4 mmol/L (2.0 mg/dL) after a total of 32 L of synthetic spent dialysate has passed through the sorbent cartridge. All other analytes were still within the acceptable limits.

(76) TABLE-US-00012 4.1. Total Amounts of Absorbed Toxins at the Time of Exhaustion (Table 14) Toxins SI units Alternative Units Urea 190 mmol 11.4 g urea 5.3 g urea-N Creatinine  6.6 mmol 750 mg creatinine Phosphate  23 mmol 710 mg P

(77) TABLE-US-00013 4.2. pH, Sodium and Bicarbonate Balance at time of exhaustion, and Pressure Drop (Table 15) Components SI units Alternative Units pH 6.3 - 7.2 Na 250 mmol total release 250 mEq total release HCO3  70 mmol total release  70 mEq total release Pressure Drop 140 - 170 mmHg

5. Conclusion

(78) The performance of the sorbent cartridge met or exceeded all requirements defined in 3.2 and 3.3 above for use in the regeneration of spent hemodialysate. It had a total capacity of 5.3 g urea-N, 750 mg creatinine and 710 mg phosphate-P.

APPLICATIONS

(79) The disclosed sorbent for a dialysis device may be used for peritoneal dialysis or hemodialysis. Advantageously, the disclosed sorbent when used in a dialysis device is capable of removing protein-bound toxins which is usually not possible with several known dialysis devices.

(80) The disclosed sorbent is a compact and portable sorbent that, when used in the WPDM (wearable peritoneal dialysis machine), is capable of absorbing all of the urea, phosphate, creatinine and other uremic toxins produced by the patient and present in the dialysate providing optimal clearance for uremic toxins. Advantageously, the sorbent is configured in a manner that achieves compactness without compromising on its capacity to remove metabolic waste from the dialysate quickly and effectively. In one preferred embodiment, that is, when the immobilised urease and zirconium phosphate particles coexist in one layer of the sorbent, an optimal working environment is created for the immobilized urease as the zirconium phosphate particles act as buffer to counteract any pH changes. Advantageously, this increases urease activity and prolongs the life of the immobilized urease. More advantageously, as this specific configuration involves the combination of one or more materials in the layers of the sorbent, the overall size of the sorbent is reduced significantly. As a result, the portability of the dialysis device is improved, thereby providing greater patient mobility. At the same time, the zirconium phosphate particles also act as cation exchangers and remove unwanted cations from the dialysate.

(81) In one embodiment, the zirconium phosphate particles provided have an average particle size of 25 microns to 100 microns. Advantageously, this specific particle size range has been found by the inventors to increase the efficacy of the unwanted cation removal capabilities of the zirconium phosphate particles.

(82) While reasonable efforts have been employed to describe equivalent embodiments of the present invention, it will be apparent to the person skilled in the art after reading the foregoing disclosure, that various other modifications and adaptations of the invention may be made therein without departing from the spirit and scope of the invention and it is intended that all such modifications and adaptations come within the scope of the appended claims.