Dialysis solution, formulated and stored in two parts, comprising phosphate

Abstract

The present invention relates to a medical solution. According to the invention the ready-for-use solution comprises phosphate in a concentration of 1.0-2.8 mM, is sterile and has a pH of 6.5-7.6. The present invention further relates to a method for producing the medical solution and the use thereof.

Claims

1. A ready-for-use dialysis solution obtained by mixing a first single solution with a second single solution, wherein said first single solution comprises phosphate ions and at least one buffer chosen from the group comprising bicarbonate and lactate and wherein said first single solution has a pH of 7.4-8.3; wherein said second single solution comprises calcium, magnesium and HCl and has a pH of 1.3-2.2; wherein said mixing of said first and second single solutions is performed after terminal sterilization and upon use to form the ready-for-use dialysis solution; wherein the ready-for-use dialysis solution comprises phosphate in a concentration of 1.2-2.6 mM, calcium, magnesium, and chloride; wherein said ready-to-use dialysis solution is sterile and has a pH of 6.5-7.6; wherein the ready-for use dialysis solution is a hemodialysis solution, a hemofiltration solution, or a hemodiafiltration solution; and wherein within 24 hours of mixing the ready-for-use dialysis solution is stable and particles of 10 μm are less than 25 counts/ml.

2. A ready-for-use dialysis solution according to claim 1, wherein said first single solution further comprises potassium.

3. A ready-for-use dialysis solution according to claim 1, wherein said second single solution further comprises glucose or glucose-like compounds.

4. A method for producing a ready-for-use dialysis solution according to claim 1, said method comprising the steps of: providing said first and second single solutions in separate compartments, and terminally sterilizing said first and second single solutions.

5. A ready-for-use dialysis solution according to claim 1, wherein the pH of the ready-for-use dialysis solution is 6.5-7.0 or 7.0-7.6.

6. A ready-for-use dialysis solution obtained by mixing a first single solution with a second single solution, wherein said first single solution comprises phosphate ions, carbonate, and bicarbonate; wherein said second single solution comprises calcium, magnesium and HCl and has a pH of 1.0-1.5; wherein said mixing of said first and second single solutions is performed after terminal sterilization and upon use to form the ready-for-use dialysis solution; wherein the ready-for-use dialysis solution comprises phosphate at a concentration of 1.3-2.6 mM, carbonate, bicarbonate, calcium, magnesium, and chloride; wherein said ready-to-use dialysis solution is sterile and has a pH of 7.0-7.6; wherein the ready-for use dialysis solution is a hemodialysis solution, a hemofiltration solution, or a hemodiafiltration solution; and wherein within 24 hours of mixing the ready-for-use dialysis solution is stable and particles of 10 μm are less than 25 counts/ml.

7. A ready-for-use dialysis solution according to claim 6, wherein said second single solution has a pH of 1.3.

8. A ready-for-use dialysis solution according to claim 6, wherein said first single solution further comprises potassium.

9. A ready-for-use dialysis solution according to claim 6, wherein said second single solution further comprises glucose or glucose-like compounds.

10. A method for producing a ready-for-use dialysis solution according to claim 6 said method comprising the steps of: providing said first and second single solutions in separate compartments, and terminally sterilizing said first and second single solutions.

Description

BRIEF DESCRIPTION OF THE DRAWING(S)

(1) FIGS. 1A-C are graphs showing the relationship between pH value in the final ready-for-use solution and the amount produced particles 24 hours after mixing for a solution containing 1.3 mM phosphate.

(2) FIGS. 2A-C are graphs showing the relationship between pH value in the final ready-for-use solution and the amount produced particles 24 hours after mixing for a solution containing 2.6 mM phosphate.

(3) FIGS. 3A-C are graphs showing the relationship between phosphate concentration and the amount of produced particles 24 hours after mixing for a solution having a pH of 7.6.

DETAILED DESCRIPTION OF THE INVENTION

(4) The inventors of the present invention have found that during specific circumstances, concentrations, pH ranges and packaging, a sterile, stabile phosphate containing medical solution could be provided, and it is this which constitute the base for the present invention.

(5) One of the more important matters searching for the most favorable circumstances, concentrations, pH ranges and packaging is the formation of particles during production, storage and preparation for a ready-for-use solution. The amount of particles has to stay in between specific ranges both concerning the size of the particles as well as the amount of particles. This is specified within the European Pharmacopoeia, and for particles in the size of 10 μm the limit is 25 counts/ml. It is very important that the particle formation is kept to a minimum, otherwise the immune system could get triggered, which could lead to start of the inflammatory cascade. A further problem with the presence of particle is the risk of clogging the filters, which are used during the dialysis treatment.

(6) The main components that give rise to the problem of particle formation are calcium ions in combination with either carbonate and/or phosphate.

(7) The first instant thought to solve the problem is of course to keep calcium ions separated from carbonate and phosphate during production and storage, but the problem is still there when preparing the ready-for-use solution, whereby the formation of solid calcium carbonate and calcium phosphate still could be formed during mixing.

(8) The present inventors have found that, with a phosphate concentration of up to about 2.8 mM in the ready-for-use solution, the amount of formed particles are within the allowed limits if the pH value in the ready-for-use solution is kept to at most 7.4, preferably at most 7.2.

(9) If the phosphate concentration is up to about 1.3 mM in the ready-for-use solution an allowed amount of particles are formed if the pH value in the ready-for-use solution is kept to at most 7.6, preferably at most 7.4.

(10) The present inventors have also found that calcium and phosphate could be kept together during preparation and storage if these two components are kept in a compartment with a pH below 2.5, preferably below 1.5, and most preferably below or equal to 1.3.

(11) In one embodiment of the invention the medical solution is before use divided into at least two single solutions, a first single solution and a second single, wherein said first and second single solutions, after terminal sterilization and up on use, are to be mixed to form a final solution with a pH of 6.5-7.6.

(12) Said first single solution comprises at least one buffer chosen from the group comprising acetate, lactate, citrate, pyruvate, carbonate and bicarbonate and said second single solution comprises an acid.

(13) In another embodiment of the invention said first single solution comprises bicarbonate and carbonate in such proportions that the partial pressure of carbon dioxide, CO.sub.2, in the first single solution is of the same order of magnitude as the partial pressure of carbon dioxide, CO.sub.2, of the atmosphere. Bicarbonate and carbonate are preferably mixed as sodium bicarbonate and sodium carbonate, and in one embodiment said first single solution has a pH within the range of 10.1-10.5, preferably 10.3.

(14) By adjusting the partial pressure of carbon dioxide, CO.sub.2, in the first single solution in the same order of magnitude as the partial pressure of carbon dioxide, CO.sub.2, in the atmosphere, the carbon dioxide in the compartment for the first single solution stays within the bag compartment and does not enter out of the bag material out into the atmosphere, as the partial pressure of CO.sub.2 within the liquid is in equilibrium with the partial pressure of CO.sub.2 in the atmosphere.

(15) After having mixed said first and second single solutions in this embodiment into a ready-for-use solution, said ready-for-use solution has a pH within the range of 7.0-7.6. Further, said ready-for-use solution preferably has a bicarbonate concentration of at least 25 mM, preferably at least 30 mM, and at most 45 mM, preferably at most 40 mM.

(16) However, the combination of bicarbonate/carbonate in said first single solution could in another embodiment, as stated above, be exchanged to or supplemented by one or more of the buffers chosen from the group comprising acetate, lactate, citrate and pyruvate. In one embodiment, the buffer is bicarbonate in a concentration of 25-35 mM with optionally 0-15 mM lactate added, wherein the concentration given is the concentration in the ready-for-use solution.

(17) In one embodiment said second single solution preferably has a pH within the range of 1.0-1.5, most preferably a pH of 1.3. In one embodiment of the invention said second single solution comprises HCl.

(18) In one embodiment said ready-for-use solution further comprises one or more electrolytes. The electrolytes are one or more of the ions of sodium, calcium, potassium, magnesium and/or chloride. The arrangement of the electrolytes in the different compartments is dependent on the different electrolytes co-behavior with the other substances present in said single solutions, i.e. whether some sort of reaction could occur between one or more of the electrolyte(s) and the other substances present in a specific single solution. Usually, the electrolytes are contained in said second single solution. For example, calcium ions and magnesium ions are preferably provided in any of the other single solutions, but said first single solution when said first single solution comprise the combination of bicarbonate/carbonate, only bicarbonate and/or phosphate. The reason for this is that calcium and magnesium and bicarbonate/carbonate, bicarbonate and/or phosphate together could cause precipitation of calcium carbonate, magnesium carbonate, calcium phosphate and magnesium phosphate. However, calcium ions and magnesium ions could be kept with bicarbonate under certain circumstances, such as specific pH ranges and so on, this is for example disclosed in EP 0 437 274, which hereby is enclosed by reference. Further calcium and magnesium could be kept with phosphate also under certain circumstances, see above of this.

(19) Sodium ions and/or chloride ions, on the other hand, are usually arranged in both said first and said second single solutions.

(20) Said medical solution could further comprise glucose or glucose-like compounds, and in one embodiment the glucose or glucose-like compounds is arranged in said second single solution. During sterilization and storage glucose or glucose-like compounds should be kept at a low pH value in order to ensure that the formation of glucose degradation products (GDPs) are kept to a minimum. In one embodiment the pH in the second single solution is below 2.5.

(21) In the method for producing a medical solution according to above, said single solutions are provided in separate compartments. Thereafter said single solutions are terminally sterilized. Preferably, the terminal sterilization is heat sterilization and/or radiation sterilization, (see also European Pharmacopoeia 1977 for a review of different sterilization techniques). In one embodiment of the method according to the invention, the terminal sterilization is heat sterilization at a temperature of at least 100° C., preferably at least 121° C.

(22) The sterilization time may vary depending on the sterilization temperature, the type of container and the contents therein to be sterilized.

(23) The radiation sterilization may be either ionising or non-ionising sterilization. Examples of ionising sterilization are gamma and beta radiation. Examples of non-ionising radiation sterilization is UV radiation.

(24) The medical solution according to the present invention has the advantage of ensuring good stability and good biocompatibility.

(25) Said single solutions could be provided in different compartments in a multi-compartment bag, and the mixing could be provided by having the different compartments coupled by frangible pins, which pins could be broken in order to mix the content in the different compartments within the multi-compartment bag. The mixing could further be provided by having a peal seal in-between the different compartments, which peal seals could be pealed in order to mix the content in the different compartments.

EXAMPLES

(26) Below you will find different examples of solutions according to the present invention.

Example 1

(27) The following pairs of single solutions were prepared according to the table 1-5 below. The volume relationship between the first single solutions and the second single solutions are 1:20.

(28) TABLE-US-00001 TABLE 1 (solution 1) First single solution Second single solution (basic part) (acid part) (mM) (mM) Na.sup.+ 1461.0 70.5 Cl.sup.− — 113.6* Ca.sup.2+ — 1.8 Mg.sup.2+ — 0.5 HCO.sub.3.sup.− 139.0 — CO.sub.3.sup.2− 661.0 — H.sub.2PO.sub.4.sup.− — — *Chloride ions have been added as NaCl, CaCl.sub.2, MgCl.sub.2, and HCl.

(29) TABLE-US-00002 TABLE 2 (solution 2) First single Second single solution solution (basic part) (acid part) (mM) (mM) Na.sup.+ 1487.0 70.5 Cl.sup.− — 113.6* Ca.sup.2+ — 1.8 Mg.sup.2+ — 0.5 HCO.sub.3.sup.− 139.0 — CO.sub.3.sup.2− 661.0 — H.sub.2PO.sub.4.sup.− 26 — *Chloride ions have been added as NaCl, CaCl.sub.2, MgCl.sub.2, and HCl.

(30) TABLE-US-00003 TABLE 3 (solution 3) First single Second single solution solution (basic part) (acid part) (mM) (mM) Na.sup.+ 1513.0 70.5 Cl.sup.− — 113.6* Ca.sup.2+ — 1.8 Mg.sup.2+ — 0.5 HCO.sub.3.sup.− 139.0 — CO.sub.3.sup.2− 661.0 — H.sub.2PO.sub.4.sup.− 52 — *Chloride ions have been added as NaCl, CaCl.sub.2, MgCl.sub.2, and HCl.

(31) TABLE-US-00004 TABLE 4 (solution 4) First single Second single solution solution (basic part) (acid part) (mM) (mM) Na.sup.+ 1461.0 71.8 Cl.sup.− — 113.6* Ca.sup.2+ — 1.8 Mg.sup.2+ — 0.5 HCO.sub.3.sup.− 139.0 — CO.sub.3.sup.2− 661.0 — H.sub.2PO.sub.4.sup.− — 1.3 *Chloride ions have been added as NaCl, CaCl.sub.2, MgCl.sub.2, and HCl.

(32) TABLE-US-00005 TABLE 5 (solution 5) First single Second single solution solution (basic part) (acid part) (mM) (mM) Na.sup.+ 1461.0 73.1 Cl.sup.− — 113.6* Ca.sup.2+ — 1.8 Mg.sup.2+ — 0.5 HCO.sub.3.sup.− 139.0 — CO.sub.3.sup.2− 661.0 — H.sub.2PO.sub.4.sup.− — 2.6 *Chloride ions have been added as NaCl, CaCl.sub.2, MgCl.sub.2, and HCl.

(33) The solutions were sterilized in an autoclave at 121° C. for 40 minutes. After sterilization, the first and second solution in each pair were mixed and the amounts of particles in the sizes 2, 5 and 10 μm, respectively, were measured. The results are presented in table 6 below.

(34) TABLE-US-00006 TABLE 6 Mixed ready-for-use solution (mM) Particles counts/ml Na.sup.+ Cl.sup.− Ca.sup.2+ Mg.sup.2+ HCO.sub.3.sup.− CO.sub.3.sup.2− H.sub.2PO.sub.4.sup.− 2 μm 5 μm 10 μm Solution 1 143.6 108.0 1.7 0.5 6.9 33.0 — 140 59 13 Solution 2 144.8 108.0 1.7 0.5 6.9 33.0 1.3 75 30 5 Solution 3 146.2 108.0 1.7 0.5 6.9 33.0 2.6 75 29 5 Solution 4 144.8 108.0 1.7 0.5 6.9 33.0 1.2 194 84 16 Solution 5 146.2 108.0 1.7 0.5 6.9 33.0 2.5 199 72 11

(35) The particle counts were made by with the help of a HIAC Model 9703 Liquid Particle Counting System (serie No. F08504) with the software version Pharm, Spec. 1,4.

(36) As evident from the results above in table 6, the resulting ready-for-use solutions according to the invention is well under the limits given in the European Pharmacopoeia.

Example 2

(37) In order to find out the optimal pH ranges for the ready-for-use solution in order to keep the formation of particles to a minimum the following pair of single solutions according to table 7 was prepared and mixed. The volume relation between the first single solution and the second single solution is 1:20.

(38) TABLE-US-00007 TABLE 7 First single Second single Mixed ready- solution solution for-use (basic part) (acid part) solution (mM) (mM) (mM) Na.sup.+ 1461.0 70.5 143.6 Cl.sup.− — 113.6* 108.0 Ca.sup.2+ — 1.8 1.7 Mg.sup.2+ — 0.5 0.5 HCO.sub.3.sup.− 139.0 — 6.9 CO.sub.3.sup.2− 661.0 — 33.0 *Chloride ions have been added as NaCl, CaCl.sub.2, MgCl.sub.2, and HCl.

(39) The mixed solution was split in two parts, and 1.3 mM NaH.sub.2PO.sub.4 were added to one part and 2.6 mM NaH.sub.2PO.sub.4 were added to the other part. The two different solutions were pooled in 50 ml glass bottles and in each group of bottles with the two different concentrations of NaH.sub.2PO.sub.4 the pH was adjusted to 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, and 8.2. The amount of particles was measured 24 hours later.

(40) In the enclosed FIGS. 1A-1C the results from this measurements are seen for the solution containing 1.3 mM phosphate. In the enclosed FIGS. 2A-2B the results form this measurements are seen for the solution containing 2.6 mM phosphate.

(41) As evident from the figures, the pH in a ready-for-use solution with a phosphate concentration of 1.3 mM should be below or equal to 7.6, preferably below or equal to 7.4. In a ready-for-use solution with a phosphate concentration of 2.6 mM the pH should be below or equal to 7.4, preferably below or equal to 7.2. Particle formation is normally first observed in the very small size and than they aggregate and form larger particles. The chosen pH upper limits of 7.4 and 7.6, respectively, is based on changes in the particle profile rather than on absolute values. All measured particle sizes where included in the evaluation with some extra focus on the small particles preceding the formation of larger particles.

Example 3

(42) In order to find out the optimal upper limit for the phosphate concentration for the ready-for-use solution in order to keep the formation of particles to a minimum, the following pair of single solutions according to table 8 was prepared. The volume relationship between the first and the second single solution was 1:20.

(43) TABLE-US-00008 TABLE 8 First single Second single Mixed ready- solution solution for-use (basic part) (acid part) solution (mM) (mM) (mM) Na.sup.+ 1461.0 70.5 143.6 Cl.sup.− — 113.6* 108.0 Ca.sup.2+ — 1.8 1.7 Mg.sup.2+ — 0.5 0.5 HCO.sub.3.sup.− 139.0 — 6.9 CO.sub.3.sup.2− 661.0 — 33.0 *Chloride ions have been added as NaCl, CaCl.sub.2, MgCl.sub.2, and HCl.

(44) The first and second single solutions were mixed and split in 5 different parts and phosphate was added in the following concentrations 2.6, 2.8, 3.0, 3.5 and 4.0. pH was adjusted to 7.6 and the amount of particles was measured at 0 hour and 24 hours after mixing.

(45) The results are shown in FIGS. 3A-C, and from the figures it could be concluded that the solution is stable during 24 hours at a phosphate concentration less or equal to 2.8 mM phosphate and a pH of 7.6.

(46) Accordingly, by having a phosphate concentration of 1.0-2.8 in a final ready-for-use solution with a pH of 6.5-7.6 a sterile, stable phosphate containing medical solution could be provided.

Example 4

(47) The following pairs of single solutions were prepared according to the tables 9-11 and constitute different embodiments of the present invention. The volume relationship between the first single solution and the second single solution in these pairs of solutions are 20:1. Accordingly, this time the second single solution has the small volume and the first single solution has the larger volume.

(48) TABLE-US-00009 TABLE 9 First single Second single Mixed ready- solution solution for-use (basic part) (acid part) solution (mM) (mM) (mM) Na.sup.+1) 147.3 140.0 Ca.sup.2+ 25.0 1.25 Mg.sup.2+ 12.0 0.6 K.sup.+ 4.21 4.0 Cl.sup.− .sup.2) 114.3 74.0 115.9 HCO.sub.3.sup.− 34.74 .sup.4) 30.0 Lactate 0 HPO.sub.4.sup.2− .sup.3) 1.26 1.20 Glucose 100.0 5.00 HCl 72.0 pH 7.7-8.2 1.3-1.6 7.0-7.6 .sup.1) Sodium is added as NaCl, NaHCO.sub.3, and Na.sub.2HPO.sub.4. .sup.2) Chloride is added as NaCl, KCl, CaCl.sub.2, MgCl.sub.2 and HCl. .sup.3) Phosphate is added as Na.sub.2HPO.sub.4, but after mixing the two single solutions it will be present mainly as HPO.sub.4.sup.2−. However, H.sub.2PO.sub.4.sup.− and PO.sub.3.sup.3− will also be present due to the equilibrium between these ions. The concentration of each ion will depend on the pH. .sup.4) The amount of bicarbonate is overdosed, since some bicarbonate will convert to CO.sub.2 during mixing and thus leave the solution.

(49) TABLE-US-00010 TABLE 10 First single Second single Mixed ready- solution solution for-use (basic part) (acid part) solution (mM) (mM) (mM) Na.sup.+1) 147.4 140.0 Ca.sup.2+ 30.0 1.5 Mg.sup.2+ 10.0 0.5 K.sup.+ 0 Cl.sup.− .sup.2) 104.8 80.0 107.2 HCO.sub.3.sup.− 40.0 .sup.4) 35.0 Lactate 0 HPO.sub.4.sup.2− .sup.3) 1.26 1.2 Glucose 0 HCl 72.0 pH 7.7-8.3 1.3-1.6 7.0-7.6 .sup.1) Sodium is added as NaCl, NaHCO.sub.3, Na.sub.2HPO.sub.4 and sodium lactate. .sup.2) Chloride is added as NaCl, CaCl.sub.2, MgCl.sub.2 and HO. .sup.3) Phosphate is added as Na.sub.2HPO.sub.4, but after mixing the two single solutions it will be present mainly as HPO.sub.4.sup.2−. However, H.sub.2PO.sub.4.sup.− and PO.sub.3.sup.3− will also be present due to the equilibrium between these ions. The concentration of each ion will depend on the pH. .sup.4) The amount of bicarbonate is overdosed, since some bicarbonate will convert to CO.sub.2 during mixing and thus leave the solution.

(50) TABLE-US-00011 TABLE 11 First single Second single Mixed ready- solution solution for-use (basic part) (acid part) solution (mM) (mM) (mM) Na.sup.+1) 147.4 140.0 Ca.sup.2+ 25.0 1.25 Mg.sup.2+ 12.0 0.6 K.sup.+ 4.2 4.0 Cl.sup.− .sup.2) 149.1 74-0 145.9 HCO.sub.3.sup.− 0 Lactate 36.8 35.0 HPO.sub.4.sup.2− .sup.3) 1.26 1.2 Glucose 100.0 5.0 HCl 12.0 pH 7-4-7.9 1.9-2.2 6.5-7.0 .sup.1) Sodium is added as NaCl,, Na.sub.2HPO.sub.4 and sodium lactate. .sup.2) Chloride is added as NaCl, CaCl.sub.2, MgCl.sub.2 and HCl. .sup.3) Phosphate is added as Na.sub.2HPO.sub.4, but after mixing the two single solutions it will be present mainly as HPO.sub.4.sup.2−. However, H.sub.2PO.sub.4.sup.− and PO.sub.3.sup.3− will also be present due to the equilibrium between these ions. The concentration of each ion will depend on the pH.

Example 5

(51) The following pair of single solutions was prepared according to the table 12 and constitutes an embodiment of the present invention. The volume relationship between the first single solution and the second single solution in this pair is 1:20.

(52) TABLE-US-00012 TABLE 12 First single Second single Mixed ready- solution solution for-use (basic part) (acid part) solution (mM) (mM) (mM) Na.sup.+1) 1256 81.25 140 Ca.sup.2+ 1.32 1.25 Mg.sup.2+ 0.63 0.6 K.sup.+ 4.21 4 Cl.sup.− .sup.2) 121 114.9 HCO.sub.3.sup.− 132 6.6 CO.sub.3.sup.2− 538 26.9 HPO.sub.4.sup.2− .sup.3) 24 1.2 Glucose 5.26 5.00 (0.9 g/l) HCl 31.6 pH 10.3 1.5 7.25 .sup.1) Sodium is added as NaCl, NaHCO.sub.3, Na.sub.2CO.sub.3, and Na.sub.2HPO.sub.4. .sup.2) Chloride is added as NaCl, KCl, CaCl.sub.2, MgCl.sub.2 and HCl. .sup.3) Phosphate is added as Na.sub.2HPO.sub.4, but after mixing the two single solutions it will be present mainly as HPO.sub.4.sup.2−. However, H.sub.2PO.sub.4.sup.− and PO.sub.3.sup.3− will also be present due to the equilibrium between these ions. The concentration of each ion will depend on the pH.

(53) It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be covered by the appended claims.