PACKAGE FOR AN ACIDIC DIALYSIS FLUID CONCENTRATE CONTAINING CITRATE AND GLUCOSE

Abstract

The present invention concerns a package comprising an acidic citrate containing concentrate, an acidic citrate containing concentrate (or acidic citrate containing solution), and a system wherein the acidic citrate containing concentrate is included for providing a dialysis treatment. The acidic citrate containing concentrate contains citric acid and citrate in a molar ratio of 75:25 to 85:15, and has a pH of between 2 and 3.

Claims

1. A package comprising: an acidic citrate containing concentrate comprising a total concentration of citrate of at least 28 mM and less than 35 mM; glucose; and citric acid and citrate in a (mole) ratio between 75:25 to 85:15, wherein the acidic citrate containing concentrate has a pH between 2 and 3; and a plastic material container having an oxygen permeation rate more than 2 g/m.sup.2/24 h at 25° C./90% RH, the acidic citrate containing concentrate sealed in the plastic material container, wherein the acidic citrate containing concentrate in the container, after storage for 14 days at 55° C. and 40% RH, is not more intensely colored than the standard reference solution Y7 according to the standard test for “Appearance of Solution” as set forth in the Hemodialysis Solution of European Pharmacopeia 8.4.

2. The package according to claim 1, wherein the oxygen permeation rate is more than 2.5 g/m.sup.2/24 h at 25° C./90% RH.

3. The package according to claim 1, wherein acidic citrate containing concentrate comprised the citric acid and citrate in a (mole) ratio of 80:20.

4. The package according to claim 1, wherein the acidic citrate containing concentrate has a pH between 2.2 and 2.4.

5. The package according to claim 1, wherein the acidic citrate containing concentrate comprises calcium (Ca.sup.2+) in a concentration of 49-85.5 mM.

6. The package according to claim 1, wherein the acidic citrate containing concentrate comprises potassium (K.sup.+) in a concentration of 0-180 mM.

7. The package according to claim 1, wherein the plastic material container comprises polyolefins.

8. The package according to claim 1, wherein the acidic citrate containing concentrate comprises 3.5-495 mM glucose.

9. An acidic citrate containing concentrate for mixing with water and a bicarbonate solution into a ready to use dialysis fluid, the acidic citrate containing concentrate comprising: a total concentration of citrate of at least 28 mM and less than 35 mM; a glucose; and citric acid and citrate in a (mole) ratio between 75:25 to 85:15, wherein the acidic citrate containing concentrate has a pH of between 2 and 3, and the acidic citrate concentrate is sealed in a container having an oxygen permeation rate of more than 2 g/m.sup.2/24 h at 25° C./90% RH, wherein the acidic citrate containing concentrate in the container, after storage for 14 days at 55° C. and 40% RH, is not more intensely colored than the standard reference solution Y7 according to the standard test for “Appearance of Solution” as set forth in the Hemodialysis Solution of European Pharmacopeia 8.4.

10. The acidic citrate containing concentrate according to claim 9, wherein the oxygen permeation rate is of more than 2.5 g/m.sup.2/24 h at 25° C./90% RH.

11. The acidic citrate containing concentrate according to claim 9 comprising the citric acid and citrate in a (mole) ratio of 80:20.

12. The acidic citrate containing concentrate according to claim 9, wherein the acidic citrate containing concentrate has a pH between 2.2 and 2.4.

13. The acidic citrate containing concentrate according to claim 9, wherein the acidic citrate containing concentrate comprises calcium (Ca.sup.2+) in a concentration of 49-85.5 mM.

14. The acidic citrate containing concentrate according to claim 9, wherein the acidic citrate containing concentrate comprises potassium (K.sup.+) in a concentration of 0-180 mM.

15. A system for extracorporeal blood treatment in an extracorporeal blood circuit comprising an arterial blood line configured to be connected to a vascular access for withdrawing blood from a patient and a venous blood line configured to be connected to the vascular access for returning blood to the patient, the system comprising: a filtration unit with a dialysate side and a blood side, wherein the blood side is in blood communication with the arterial and venous blood lines; a source of acidic citrate containing concentrate, wherein the acidic citrate containing concentrate is sealed in a container having an oxygen permeation rate of more than 2 g/m.sup.2/24 h at 25° C./90% RH, the acidic citrate containing concentrate comprising a total concentration of citrate of at least 28 mM and less than 35 mM; glucose; and citric acid and citrate in a ratio (mole) between 75:25 to 85:15, wherein the acidic citrate containing concentrate has a pH between 2 and 3; and a source of bicarbonate, wherein the system is configured to mix the acidic citrate containing concentrate with the bicarbonate to provide a ready to use dialysis fluid comprising citrate in a total concentration of at least 0.8 mM and less than 1.0 mM; 130-150 mM sodium (Na+); and 20-40 mM bicarbonate, and wherein the ready to use dialysis fluid has a pH above 7.25, wherein the acidic citrate containing concentrate in the container, after storage for 14 days at 55° C. and 40% RH, is not more intensely colored than the standard reference solution Y7 according to the standard test for “Appearance of Solution” as set forth in the Hemodialysis Solution of European Pharmacopeia 8.4.

16. The system according to claim 15, wherein the ready to use dialysis fluid has a pH above 7.3.

17. The system according to claim 15, wherein the acidic citrate containing concentrate comprises the citric acid and citrate in a (mole) ratio of 80:20.

18. The system according to claim 15, wherein the ready to use dialysis fluid comprises calcium (Ca.sup.2+) in a concentration of 1.4-1.9 mM.

19. The system according to claim 15, wherein the source of acidic citrate containing concentrate comprises a plastic material having an oxygen permeation rate more than 2.5 g/m.sup.2/24 h at 25° C./90% RH.

Description

BRIEF DESCRIPTION OF THE DRAWING(S)

[0038] FIG. 1 shows the amount glucose degradation products dependent on pH. A glucose solution (50%) was heat sterilized and incubated at 40 degrees C. for 30 days. Concentration of 3,4-didexyglucosone-3-ene (3,4-DGE; triangles), 3-deoxyglucosone (3-DG; squares), 5-hydroxymethyl-2 furaldehyde (5-HMF; diamonds) and color (cross; arbitrary unit).

DETAILED DESCRIPTION OF THE INVENTION

[0039] For handling and transporting dialysis fluids, and products related thereto, like acidic concentrate, there are some requirements connected to the package material. For the citrate containing acidic concentrate to be included in the present system there is a desire of package material which reduces the tendency of discoloration of the acidic concentrate.

[0040] Further, there are requirements to replace packages, such as plastic containers, of polyvinyl chloride (PVC), commonly used for different solutions used in the field of dialysis treatment. For example, previously, polyvinyl chloride (PVC) was a commonly used material for the plastic containers for acidic concentrates to be used in dialysis treatment. However, this plastic material has low oxygen permeability and when used in plastic containers for acidic concentrates for dialysis fluid, there has been shown discoloration of the product. An alternative plastic material to polyvinyl chloride is polyolefines. However, also features such as permeability of oxygen shall be considered.

[0041] The package comprising the acidic citrate containing concentrate is of a plastic material comprising polyolefines, preferably a multilayer film of polyolefine.

[0042] The plastic container is made of polyolefines. The group of plastic materials denoted ‘polyolefines’, or with another name ‘polyalkenes’ are polymers produced from olefins as the monomer. Examples of polyolefines are polyethylene, polypropylene, etc.

[0043] The plastic material providing an oxygen permeation rate as herein defined may be a multilayer film. For example, a suitable plastic material comprises polyolefines with the following structure: a first layer of a modified propylene copolymer, a second layer of polyethylene, and, a third layer of copolyester.

[0044] Multilayered films suitable for the acidic citrate containing concentrate are described in EP 0733472 A2 and EP 0738589 A2.

[0045] By the present invention, this has surprisingly been solved by having a plastic material of polyolefines having an oxygen permeability of more than 2 g/m.sup.2/24 h at 25° C./90% RH.

[0046] It has been shown that plastic package material of polyolefines has the property to reduce, or even, avoid the drawbacks above. The package containing an acidic citrate containing concentrate, as herein defined, has a defined oxygen permeation rate. It has been shown that with an oxygen permeation rate of more than 2 g/m.sup.2/24 h at 25° C./90% RH; for example more than 2.5 g/m.sup.2/24 h at 25° C./90% RH; or more than 3.5 g/m.sup.2/24 h at 25° C./90% RH.

[0047] The package may, for example, be in form of a bag, such as a bag for 3 to 6 l.

[0048] The acidic citrate containing concentrate comprises the citric acid and citrate in a ratio of between 75:25 to 85:15, for example in a ratio of 80:20. The ratio herein considered is the mole ratio of citric acid to citrate.

[0049] The package comprises an acidic citrate containing concentrate having a total concentration of citrate of between 28 and 45 mM, for example in a total concentration of citrate of 28, 35 or 45 mM.

[0050] The pH of the acidic citrate containing concentrate included in the package is between 2 and 3, for example between 2.2 and 2.4. Examples of suitable pH are 2.2, 2.3 and 2.4.

[0051] The acidic citrate containing concentrate included in the package may also comprise further electrolytes and components suitable for dialysis. One such electrolyte is calcium (Ca.sup.2+). Calcium is present in a concentration that the acidic citrate containing concentrate when diluted to a ready to use dialysis fluid comprises calcium (Ca.sup.2+) in a concentration of 1.4-1.9 mM. Examples of concentrations of calcium in the ready to use are 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, and 1.9 mM.

[0052] Another electrolyte to be included in the acidic citrate containing concentrate is potassium. Potassium is present in a concentration that when the acidic citrate containing concentrate is diluted to a ready to use dialysis fluid, the dialysis fluid comprises potassium (K.sup.+) in a concentration of 0-4 mM, For example, potassium (K+) in the following concentrations 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, and 4 mM.

[0053] Further, the acidic citrate containing concentrate may also comprise magnesium (Mg.sup.2+) as an electrolyte. Magnesium is suitable present in a concentration to provide a concentration of between 0.25 mM and 0.75 mM in the diluted acidic citrate containing concentrate, such as 0.5 mM magnesium. For example, magnesium may be present in a concentration of 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, and 0.75.

[0054] The herein defined package comprises an acidic citrate containing concentrate intended for dilution 1+34, or alternatively 1+44, to form a ready to use dialysis fluid.

[0055] The package comprises an acidic citrate containing concentrate having a pH between 2 and 3, for example a pH of between 2.2 and 2.4. For example the pH is 2.2, 2.3, or 2.4.

[0056] The package herein described, comprises an acidic citrate containing concentrate which have a composition that when diluted provides a dialysis fluid of the following composition:

TABLE-US-00001 sodium 93-113 mM potassium 0.0-4.0 mM magnesium 0.25-0.75 mM calcium 1.25-1.9 mM citric acid 0.75-0.85 mM citrate 0.15-0.25 mM chloride 96-122 glucose 0-11 mM

[0057] Further, the package herein described, comprises an acidic citrate containing concentrate which have a composition that when diluted provides a dialysis fluid of the following composition:

TABLE-US-00002 sodium 93-113 mM potassium 0.0-4.0 mM magnesium 0.25-0.75 mM calcium 1.25-1.9 mM citric acid 0.75-0.85 mM citrate 0.15-0.25 mM chloride 96-122 glucose 0.1-11 mM

[0058] More specifically the acidic citrate containing concentrate may have a composition that when diluted provides a dialysis fluid of the following composition:

TABLE-US-00003 sodium 93-113 mM potassium 0.0-4.0 mM magnesium 0.25-0.75 mM calcium 1.25-1.9 mM citric acid 0.80 mM citrate 0.20 mM chloride 96-122 glucose 0-11 mM

[0059] This composition may in another option contain 0.1-11 mM glucose. For example, the composition may comprise glucose in an amount of 5.5 or 5.6 mM.

[0060] Depending on the acidity, the low pH, there is a tendency of formation of glucose degradation products. The glucose degradation products include compounds like 5-HMF and FA. Also glucose esters are included in this term. The amount of formed glucose degradation products (GDPs) can be high due to presence of oxygen. Therefore, by having a container of a material having an oxygen permeation, for example, with a rate of more than 2 g/m.sup.2/24 h at 25° C./90% RH the oxygen formed has a possibility to permeate from the solution in a proper way to reduce the amount of glucose degradation products formed, and by that, the discoloration is minimized. Discoloration caused by GDPs has been observed and discussed, for example in ‘Singh. B.; Dean. G. R.; Cantor. S. M. The role of 5-(hydroxymethyl)-furfural in the discoloration of sugar solutions. J. Am. Chem. Soc. 1948. 70. 517-522’ there is a connection made between discoloration and presence of 5-HMF.

[0061] Another embodiment of the invention is the acidic citrate containing concentrate for mixing with a source of bicarbonate into a ready to use dialysis fluid. The said acidic citrate containing concentrate comprises a total concentration of citrate of 28-45 mM; citric acid and citrate in a (mole) ratio of between 75:25 to 85:15; has a pH of between 2.1 and 2.4. The said acidic citrate concentrate is sealed in a container having an oxygen permeation rate of more than 2 g/m.sup.2/24 h at 25° C./90% RH, for example the oxygen permeation rate is of more than 2.5 g/m.sup.2/24 h at 25° C./90% RH, for example more than 3.5 g/m.sup.2/24 h at 25° C./90% RH. For example, the acidic citrate containing concentrate comprises the citric acid and citrate in a (mole) ratio of 80:20. The acidic citrate containing concentrate as above may have a pH of between 2.2 and 2.4.

[0062] Another embodiment of the invention is a composition, an acidic citrate containing concentrate composition comprising a container and an acidic citrate containing concentrate for mixing with a source of bicarbonate into a ready to use dialysis fluid. The said acidic citrate containing concentrate comprises a total concentration of citrate of 28-45 mM; citric acid and citrate in a (mole) ratio of between 75:25 to 85:15; has a pH of between 2.1 and 2.4. The said acidic citrate concentrate is sealed in said container having an oxygen permeation rate of more than 2 g/m.sup.2/24 h at 25° C./90% RH, for example the oxygen permeation rate is of more than 2.5 g/m.sup.2/24 h at 25° C./90% RH, for example more than 3.5 g/m.sup.2/24 h at 25° C./90% RH. For example, the acidic citrate containing concentrate comprises the citric acid and citrate in a (mole) ratio of 80:20. The acidic citrate containing concentrate as above may have a pH of between 2.2 and 2.4.

[0063] The acidic citrate containing concentrate may, when diluted to a ready to use dialysis fluid, comprise calcium (Ca.sup.2+) in a concentration of 1.4-1.9 mM.

[0064] The acidic citrate containing concentrate when diluted to a ready to use dialysis fluid comprises potassium (K.sup.+) in a concentration of 0-4 mM

[0065] The acidic citrate containing concentrate provided is intended for 1+34; or 1+44 dilution.

[0066] A system is also defined herein. The system comprises an arterial blood line configured to be connected to a vascular access for withdrawal of blood from a patient and a venous blood line configured to be connected to the vascular access for returning blood to the patient, and the system comprises: [0067] a filtration unit with a dialysate side and a blood side, which blood side is in blood communication with the arterial and venous blood lines; [0068] a source of acidic citrate containing concentrate, said acidic citrate containing concentrate comprises a total concentration of citrate of 28-45 mM; citric acid and citrate in a ratio (mole) of between 75:25 to 85:15; has a pH of between 2 and 3; [0069] a source of bicarbonate (for example as sodium hydrogen bicarbonate); and which system provides upon mixing of said acidic citrate containing concentrate and said bicarbonate a ready to use dialysis fluid comprising citrate in a total concentration of 0.8-1 mM; 130-150 mM sodium (Na.sup.+); 20-40 mM bicarbonate.

[0070] Another system provided comprises an arterial blood line configured to be connected to a vascular access for withdrawal of blood from a patient and a venous blood line configured to be connected to the vascular access for returning blood to the patient, and the system comprises: [0071] a filtration unit with a dialysate side and a blood side, which blood side is in blood communication with the arterial and venous blood lines; [0072] a source of acidic citrate containing concentrate provided in form of the package as herein defined; [0073] a source of bicarbonate (for example as sodium hydrogen bicarbonate); and which system provides upon mixing of said acidic citrate containing concentrate and said bicarbonate a ready to use dialysis fluid comprising citrate in a total concentration of 0.8-1 mM; 130-150 mM sodium (Na.sup.+); 20-40 mM bicarbonate.

[0074] Another system provided comprises an arterial blood line configured to be connected to a vascular access for withdrawal of blood from a patient and a venous blood line configured to be connected to the vascular access for returning blood to the patient, and the system comprises: [0075] a filtration unit with a dialysate side and a blood side, which blood side is in blood communication with the arterial and venous blood lines; [0076] a source of acidic citrate containing concentrate provided in form of acidic citrate containing concentrate as herein defined; [0077] a source of bicarbonate (for example as sodium hydrogen bicarbonate); and which system provides upon mixing of said acidic citrate containing concentrate and said bicarbonate a ready to use dialysis fluid comprising citrate in a total concentration of 0.8-1 mM; 130-150 mM sodium (Na.sup.+); 20-40 mM bicarbonate.

[0078] By any of these systems, a ready to use dialysis fluid having pH of above 7.25; or pH of between 7.3-7.6, preferably pH of between 7.3-7.4, for example pH of 7.4 is provided.

[0079] The system includes an acidic citrate containing concentrate comprising citric acid and citrate in a (mole) ratio of between 75:25 to 85:15, for example, a (mole) ratio of 80:20.

[0080] Further, the system provides a ready to use dialysis fluid comprising calcium (Ca.sup.2+) in a concentration of between 1.4 and 1.9 mM

[0081] The system may provide a ready to use dialysis fluid comprising potassium (K.sup.+), in a concentration of 0-4 mM.

[0082] The source of acidic concentrate is intended for 1+34; or 1+44 dilution.

[0083] The system herein described, comprises a source of acidic citrate, as the package as herein defined, or as the acidic citrate containing concentrate, thus a composition that when diluted provides a dialysis fluid of the following composition:

TABLE-US-00004 sodium 93-113 mM potassium 0.0-4.0 mM magnesium 0.25-0.75 mM calcium 1.25-1.9 mM citric acid 0.75-0.85 mM citrate 0.15-0.25 mM chloride 96-122 glucose 0-11 mM

[0084] Alternatively, a dialysis fluid of the following composition may be provided:

TABLE-US-00005 sodium 93-113 mM potassium 0.0-4.0 mM magnesium 0.25-0.75 mM calcium 1.25-1.9 mM citric acid 0.75-0.85 mM citrate 0.15-0.25 mM chloride 96-122 glucose 0.1-11 mM

[0085] The system does also include a source of bicarbonate providing a ready to use dialysis fluid comprising citrate in a total concentration of 0.8-1 mM; 130-150 mM sodium (Na.sup.+); 20-40 mM bicarbonate; and has a pH above 7.25.

[0086] In one embodiment the source of citrate containing dialysis concentrate is kept and packaged in a plastic material of polyolefines. The oxygen permeability is defined to be at least 2 g/m.sup.2/24 h at 25° C./90% RH, for example 2.5 g/m.sup.2/24 h at 25° C./90% RH; 3.5 g/m.sup.2/24 h at 25° C./90% RH.

Test Methods and Results

Example 1

[0087] An acidic citrate containing concentrate comprising the following composition:

TABLE-US-00006 Concentrate Ready-to-use sodium chloride 4615 mM 103 mM potassium chloride  180 mM  4.0 mM magnesium chloride  22.5 mM  0.5 mM calcium chloride  78.8 mM 1.75 mM citric acid  38.3 mM 0.85 mM citrate   6.8 mM 0.15 mM glucose  250 mM  5.6 mM

[0088] was prepared. The pH of the concentrate was 2.1.

[0089] The acidic concentrate was included in a package comprising a multilayer film of polyolefines (Sealed Air Nexcel® M312A) having an oxygen permeation rate of 3.5 g/m.sup.2/day.

[0090] The acidic citric containing concentrate was then mixed then mixed with a source of bicarbonate, i.e. a buffered solution comprising bicarbonate in a concentration of 37 mM.

[0091] The pH of the final dialysis solution (at 37° C.) was estimated to 7.22 (as a theoretical value, not taking in account the carbon dioxide formation).

Example 2

[0092] An acidic citric containing concentrate comprising the following composition

TABLE-US-00007 Concentrate Ready-to-use sodium chloride 4615 mM  103 mM potassium chloride  180 mM  4.0 mM magnesium chloride  22.5 mM  0.5 mM calcium chloride  78.8 mM 1.75 mM citric acid  36.0 mM 0.80 mM citrate   9.0 mM 0.20 mM glucose  250 mM  5.6 mM

[0093] was prepared. The pH of the concentrate was 2.2. The pH of the final dialysis solution (at 37° C.) was estimated to 7.25 (as a theoretical value).

Example 3

[0094] An acidic citrate containing concentrate comprising the following composition:

TABLE-US-00008 Concentrate Ready-to-use sodium chloride 4615 mM  103 mM potassium chloride  180 mM  4.0 mM magnesium chloride  22.5 mM  0.5 mM calcium chloride  78.8 mM 1.75 mM citric acid  33.8 mM 0.75 mM citrate  11.3 mM 0.25 mM glucose  250 mM  5.6 mM

[0095] was prepared in the same way as in Example 1. The pH of the concentrate was measured to pH 2.3. The pH of the final dialysis solution (at 37° C.) was estimated to 7.28 (as a theoretical value).

Example 4—Stability Test

[0096] The stability of a package comprising the composition of Example 2 was further investigated, following the European Pharmacopeia 8.4 for Haemodialysis solutions, and the test for “Appearance of solution”. The multilayer film of the package was of Sealed Air Nexcel® M312A.

[0097] The test was performed as a “challenging test”, wherein the acidic citrate containing concentrate was kept at 55° C., and 40% RH, during 14 days.

[0098] The appearance of solution (i.e. the acidic citrate containing concentrate) was checked when test was started, after 3, 7, and 14 days. The solution was not more intensely colored than the reference solution (<Y7).

Example 5—Test of a Package in Dialysis Machine

[0099] A package comprising the acidic citrate containing concentrate of Example 2 was used in a system for extracorporeal blood treatment in an extracorporeal blood circuit as herein defined, as the source of acidic concentrate.

[0100] The system is a dialysis machine of model AK 200S, Gambro Lundia AB.

[0101] The source of acidic citrate containing concentrate was the concentrate as defined in Example 2; and the source of bicarbonate was provided as BiCart™ (Gambro Lundia AB).

[0102] The settings used in the machine were “140/34”, thus the dialysis machine provided a dialysis fluid comprising 140 mM sodium, and 34 mM bicarbonate. The pH was measured almost immediately in the ready to use solution by placing the pH electrode in the drain tubing of the dialysis machine. The pH was measured at different time points after the that the dialysis machine gave the “green line”. It took 30 minutes (after the machine gave the “green line”) to get a stable pH value. pH was measured to 7.31 (measured 30 minutes after “green line”).

Example 6—Comparative Experiment

[0103] Example 5 was repeated with a package containing an acidic citrate containing concentrate having a pH of 1.3.

[0104] The source of acidic concentrate included citric acid in a concentration to provide 1 mM citric acid/citrate in the ready to use dialysis fluid. The pH of the concentrate in the package was pH 1.3. The same settings as of Example 5 were used, and the pH measurements were made in the same way. pH of the final dialysis solution (at 37° C.) was measured to 7.24 (measured 30 minutes after “green line”).

[0105] Thus, comparison can be made of Examples 1-3 and Example 5, and it can be concluded that a dialysis fluid comprising a pH closer to physiological pH (i.e. pH 7.4) can advantageously be obtained with the package comprising an acidic citrate containing concentrate as herein defined, or with the acidic citrate containing concentrate sealed in the herein specified plastic material.

[0106] While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiments, it is to be understood that the invention is not to be limited to the disclosed embodiments, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and the scope of the appended claims.