DIALYSIS CONCENTRATE

Abstract

The invention provides a first concentrate comprising lactate and calcium ions, said first concentrate having increased stability against precipitation at temperatures around +4 C., said first concentrate being useful for preparing a ready-to-use dialysis fluid by mixing said first concentrate with water and optionally a second concentrate comprising glucose, wherein that the lactate concentration L.sub.conc (expressed in moles per litre, M) of the concentrate fulfills the conditions:

[00001]$a)L_{\mathrm{conc}}>0.8M;\mathrm{and}$$b)L_{\mathrm{conc}}<\left(1.9-0.4{\mathrm{Ca}}_{\mathrm{ready}}\right)M;$

and wherein Ca.sub.ready is the calcium concentration of the ready-to-use dialysis fluid expressed in millimoles per litre (mM).

Claims

1. A first concentrate comprising lactate and calcium ions, said first concentrate having increased stability against precipitation at temperatures around +4 C., said first concentrate being useful for preparing a ready-to-use dialysis fluid by mixing said first concentrate with water and a optionally a second concentrate comprising a glucose preparation, characterized in that the lactate concentration L.sub.conc (expressed in moles per litre, M) of the first concentrate fulfills the conditions: $a)L_{\mathrm{conc}}>0.75M;\mathrm{and}$ $b)L_{\mathrm{conc}}<\left(1.9-0.4{\mathrm{Ca}}_{\mathrm{ready}}\right)M;$ and wherein Ca.sub.ready is the calcium concentration of the ready-to-use dialysis fluid expressed in millimoles per litre (mM).

Description

BRIEF DESCRIPTION OF THE FIGURES

[0043] FIG. 1 is a diagram showing lactate concentration in the aqueous first concentrate as a function of the calcium concentration of the final ready-to-use dialysis fluid.

[0044] FIG. 2 provides a graphical overview of how to produce a ready-to-use dialysis fluid starting from the kit of parts of the second embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0045] The present invention generally relates to dialysis solutions. In particular, the present invention relates to concentrates for manufacturing ready-to-use dialysis solutions. Such ready-to-use dialysis solutions can be used in a variety of suitable applications. Preferably, the dialysis solutions are used during peritoneal dialysis, such as during automated peritoncal dialysis.

[0046] However, it should be appreciated that the present invention can be used in a variety of different and suitable dialysis therapies to treat kidney failure. Dialysis therapy as the term or like terms are used throughout the text is meant to include and encompass any and all suitable forms of therapies that utilizes the patient's blood to remove waste, toxins and excess water from the patient. Such therapies, such as hemodialysis, hemofiltration and hemodiafiltration, include both intermittent therapies and continuous therapies used for continuous renal replacement therapy (CRRT). The continuous therapies include, for example, slow continuous ultrafiltration (SCUF), continuous venovenous hemodiafiltration (CVVH), continuous venovenous hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CCVHDF), continuous arteriovenous hemodialysis (CAVHD), continuous arteriovenous hemodiafiltration (CAVHDF), continuous ultrafiltration periodic intermittent hemodialysis or the like. Preferably, the dialysis solutions are used during peritoneal dialysis, such as automated peritoneal dialysis, continuous ambulatory peritoneal dialysis, continuous flow peritoneal dialysis and the like. Further, although the present invention, in an embodiment, can be utilized in methods providing dialysis therapy for patients having chronic kidney failure or disease, it shall be appreciated that the present invention can be used for acute dialysis needs, for example in an emergency room setting. Lastly, as one skilled in the art appreciates, the intermittent forms of therapy (i.e., hemofiltration, hemodialysis, peritoneal dialysis, and hemodiafiltration) may be used in the in center, self/limited care as well as the home settings.

[0047] Hemodialysis involves withdrawing blood from the body and cleaning it in an extracorporeal blood circuit and then returning the cleansed blood to the body. The extracorporeal blood circuit includes a dialyzer which comprises a semipermeable membrane. The semipermeable membrane has a blood side and a dialysate side, and waste substances and excess fluid are removed from the blood passing on the blood side of the semipermeable membrane through the semipermeable membrane over to the dialysate side of the semipermeable membrane.

[0048] Hemodialysis may be performed in three different treatment modes, hemodialysis, hemofiltration, and hemodiafiltration. Common to all three treatment modes is that the patient is connected by a blood line to the dialysis machine, which continuously withdraws blood from the patient. The blood is then brought in contact with the blood side of the semipermeable membrane within the dialyzer in a flowing manner.

[0049] In hemodialysis, an aqueous solution called dialysis fluid is brought in contact with the opposite membrane surface, the dialysate side, in a flowing manner. Waste substances (toxins) and solutes are removed/controlled mainly by diffusion. Excess fluid is removed by applying transmembrane pressure over the semipermeable membrane. Solutes and nutrients may diffuse in the opposite direction from the dialysis fluid, through the semipermeable membrane and into the blood.

[0050] In hemofiltration, no dialysis fluid is brought in contact with the dialysate side of the semipermeable membrane. Instead only a transmembrane pressure is applied over the semipermeable membrane thereby removing fluid and waste substances, from the blood through the semipermeable membrane wall and into the dialysate side thereof (convective flow). Fluid and waste substances are then passed to drain. To replace some of the removed fluid, a correctly balanced electrolyte/buffer dialysis fluid (also named infusion fluid, replacement fluid, or substitution fluid) is infused into the extracorporeal blood circuit. This infusion may be done either pre the dialyzer (pre-infusion mode) or post the dialyzer (post-infusion mode) or both.

[0051] Hemodiafiltration is a combination of hemodialysis and hemofiltration, a treatment mode that combines transport of waste substances and excess fluids through the semipermeable wall by both diffusion and convection. Thus, here a dialysis fluid is brought in contact with the dialysate side of the semipermeable membrane in a continuously flowing manner, and a dialysis fluid (also named infusion fluid or replacement fluid) is used for infusion into the extracorporeal blood circuit in pre-infusion mode, post-infusion mode or both.

[0052] For many patients, hemodialysis is performed for 3-5 hours, three times per week. It is usually performed at a dialysis centre, although home dialysis is also possible. When home dialysis is performed patients are free to perform dialysis more frequently and also in more gentle treatments with longer treatment times, i.e. 4-8 hours per treatment and 5-7 treatments per week. The dose and treatment times may be adjusted due to different demand of the patients. In the case of patients suffering from acute renal insufficiency, a continuous treatment, throughout a major portion of the entire day for up to several weeks, a continuous renal replacement therapy (CRRT), or intermittent renal replacement therapy (IRRT) is the indicated treatment depending on the patients' status. Also here the removal of waste substances and excess fluid from the patient is effected by any or a combination of the treatment modes hemodialysis, hemofiltration and hemodiafiltration.

[0053] In a peritoneal dialysis treatment a hypertonic dialysis fluid is infused into the peritoneal cavity of the patient. In this treatment solutes and water is exchanged in the capillary vessels of a patient's peritoneal membrane with said hypertonic dialysis fluid. The principle of this method is diffusion of solutes transferred according to the concentration gradient and water migration due to the osmotic differences over the peritoneal membrane.

[0054] The dialysis fluids used in all the above dialysis techniques contain mainly electrolytes like sodium, magnesium, calcium, potassium, an acid/base buffer system and optionally glucose or a glucose-like compound. All the components in dialysis fluids are selected to control the levels of electrolytes and the acid-base equilibrium within the blood and to remove waste materials from the blood.

[0055] The daily consumption of dialysis fluids for patients on automated peritoneal dialysis is much lower than for patients on hemodialysis, but it is still quite large. Typically, a patient on automated peritoneal dialysis consumes about 12-15 liters of dialysis fluid each treatment session. Such a large consumption creates a lot of problems. Firstly, it is neither easy nor convenient for the patients or their care givers to carry around heavy containers of dialysis liquids. Secondly it is quite expensive to transport and distribute these heavy containers from manufactures or distributors to patients and clinics. Hence, there is a clear incentive to find ways of facilitating handling by patients and care givers as well as reducing the transportation need.

[0056] One way of facilitating handling as well as reducing the need for transportation is to develop concentrates which can be diluted with optionally purified and/or sterilized water in order to produce a reconstituted ready-to-use dialysis fluid. Suitable containers for such concentrates are much smaller, less heavy, and consequently easier to handle. As a concentrate lasts much longer compared to an equivalent amount of a ready-to-use solution, the transportation need is also reduced. The environmental impact of manufacturing as well as transporting concentrates is also reduced.

[0057] It is important that such concentrates are stable at all reasonable storage temperatures, such as from +4 C. to +40 C. In particular, it is important that no precipitations are formed at such storage conditions. In concentrates comprising both lactate as well as calcium ions, there is a risk that precipitations are formed, especially at temperatures close to +4 C. and at high lactate and calcium ion concentrations. It has, however, turned out that it is possible to mathematically express whether precipitations will form in a particular concentrate.

[0058] Accordingly, a stable first concentrate comprising both lactate and calcium ions has been obtained if the the lactate concentration L.sub.conc (expressed in moles per litre, M) of the concentrate fulfills the conditions:

[00004]$a)L_{\mathrm{conc}}>0.75M;\mathrm{and}$$b)L_{\mathrm{conc}}<\left(1.9-0.4{\mathrm{Ca}}_{\mathrm{ready}}\right)M;$

and [0059] wherein Ca.sub.ready is the calcium concentration of the ready-to-use dialysis fluid expressed in millimoles per litre (mM). It is preferred to use slightly more concentrated solutions wherein L.sub.conc>0.80 M.

[0060] In order to minimize the risk for precipitation, the concentrate composition should also fulfill the condition:

[00005]$c)L_{\mathrm{conce}}<\left(1.85-0.4{\mathrm{Ca}}_{\mathrm{ready}}\right)M$ [0061] wherein Ca.sub.ready has the same meaning as above. Other similar variants of the equation of condition c) could also be considered, such as L.sub.conc<(1.750.4Ca.sub.ready) M, L.sub.conc<(1.70.4Ca.sub.ready) M, L.sub.conc<(1.80.4Ca.sub.ready) M, and L.sub.conc<(1.650.4Ca.sub.ready) M.

[0062] The stability of different variants of the first concentrate are shown in FIG. 1, where the lactate concentration in the first concentrate is shown as a function of the calcium concentration of the ready-to-use dialysis fluid. In the diagram of FIG. 1, first concentrates in which precipitates were formed are indicated with squares and first concentrates without any precipitation are indicated with triangles. The uppermost curve corresponds to condition b) above and the middle curve corresponds to condition c) above.

[0063] The first concentrate of the present invention can include several different components. As already indicated, the first concentrate is buffered by lactate. The buffer pH can include any suitable level effective for formulating and sterilizing the concentrate composition and subsequently formulating a ready-to-use dialysis solution that includes a mixture of the first concentrate, a second concentrate, which is an acidic glucose concentrate and optionally purified water. The pH of the first concentrate should be within the range of 5.5-9.0, and preferably within the range of 6.5-8.0. The first concentrate may contain other electrolytes such as Cl.sup., Na.sup.+, Mg.sup.2+, and K.sup.+ in addition to Ca.sup.2+. Furthermore, a pH adjusting agent can be added to the first concentrate, such as sodium hydroxide, hydrochloric acid, and/or the like. Typical concentrations of electrolytes are:

TABLE-US-00001 Sodium chloride 1.5-3.3 M Calcium chloride 0.025-0.0375 M Magnesium chloride 0-0.008 M

[0064] The first concentrate is intended to be used as one component of a kit of parts for preparing a peritoneal dialysis composition. Said kit also comprises a second concentrate, which is an acidic glucose concentrate. In an embodiment, the acidic concentrate has a pH that ranges from 1.5-4.0, preferably from 2.0-3.2. The second concentrate may also include a pH-adjusting agent. Examples of pH adjusting agents include an inorganic acid, such as hydrochloric acid. Typically, the second concentrate is saturated to a level within the range of 30%-70%. The second concentrate may also be terminal sterilized.

[0065] The first and second concentrates may be stored in a multi-chambered bag for convenience. Then, the first concentrate is stored in a first chamber and the second concentrate in a second chamber. Such a multi-chambered bag may be equipped with connections and conduits for connecting the chambers to a mixing unit, where the concentrates are mixed and diluted.

[0066] The acid glucose concentrate, the concentration composition and the purified water can be formulated, sterilized and admixed in any suitable manner prior to use, such as prior to infusion by peritoneal dialysis. Water should be within limits that are safe from a microbiological and chemical perspective; this water could for example be purified water, highly purified water, ultrapure water, water for injection (WFI), sterile WFI, water for hemodialysis, distilled water, sterile purified water and water for pharmaceutical use. In one embodiment, a mixed solution including specific amounts of the first and second concentrates and purified water are formulated into a desired peritoneal dialysis liquid by mixing.

[0067] FIG. 2 provides a scheme 100 showing one way of how to prepare a desired peritoneal dialysis liquid. A container 10 comprising a first concentrate and a container 12 comprising a second concentrate are each connected to a mixer 16 by conduits. In one embodiment, the containers 10, 12 may be chambers in a multi-chambered bag 50. A source 14 of purified water is also connected to the mixer 16 by a conduit. The mixer 16 is controlled by a controller 18 based on input from a user interface 20. Depending on such user input and control signals from the controller 18, the mixer 16 receives specific amounts of first and optionally second concentrates as well as water from said sources 10,12, 14, and produces a ready-to-use dialysis fluid that is delivered through output/container 22.

EXAMPLES

[0068] Test solutions representing candidate concentrate compositions were prepared by adding different amounts of solid constituents to containers and finally adding purified water up to a desired volume. The test solutions were heat sterilized and incubated for more than two months at +4 C.

[0069] A table of ready-to-use dialysis liquids based on the first and second concentrates of each example is also provided at the end of each example.

Example 1

TABLE-US-00002 First concentrate Sodium chloride 3.22 M Calcium chloride 0.06125 M Magnesium chloride 0.0175 M Sodium lactate 1.40 M Sodium hydroxide Ad. pH 6.5-9.0

TABLE-US-00003 Second concentrate: 50% glucose Glucose 2.775 M Hydrochloric acid Ad. pH 2.0-3.1

TABLE-US-00004 Mixed solution composition example 1 A (mL/L) 0 30 50 80 100 B (mL/L) 25 Na.sup.+ (mM) 132 Mg.sup.2+ (mM) 0.50 Ca.sup.2+ (mM) 1.75 Cl.sup. (mM) 97 Lactate (mM) 40 Glucose (mM) 0 83.3 138.8 222.0 278

[0070] Ca.sub.ready is 1.75 mM for the ready-to-use solution and L.sub.conce is 1.40 M for the first concentrate of example 1. Condition a) above is fulfilled as L.sub.conc is larger than 0.75 M. Condition b) above is not fulfilled as 1.90.41.75 mM=1.2, which is less than L.sub.conc. Precipitations were found in the first concentrate.

Example 2

TABLE-US-00005 First concentrate Sodium chloride 3.22 M Calcium chloride 0.04375 M Magnesium chloride 0.00875 M Sodium lactate 1.40 M Sodium hydroxide Ad. pH 6.5-9.0

TABLE-US-00006 Second concentrate: 50% glucose Glucose 2.775 M Hydrochloric acid Ad. pH 2.0-3.1

TABLE-US-00007 Mixed solution composition example 2 A (mL/L) 0 30 50 80 100 B (mL/L) 25 Na.sup.+ (mM) 132 Mg.sup.2+ (mM) 0.25 Ca.sup.2+ (mM) 1.25 Cl.sup. (mM) 95 Lactate (mM) 40 Glucose (mM) 0 83.3 138.8 222.0 278

[0071] Ca.sub.ready is 1.25 mM for the ready-to-use solution and L.sub.conce is 1.40 M for the first concentrate of example 1. Condition a) above is fulfilled as L.sub.conc is larger than 0.75 M. Condition b) above is not fulfilled as 1.90.41.25 mM=1.4, which is equal to L.sub.conc. Precipitations were found in the first concentrate.

Example 3

TABLE-US-00008 First concentrate Sodium chloride 2.76 M Calcium chloride 0.0525 M Magnesium chloride 0.0075 M Sodium lactate 1.20 M Sodium hydroxide Ad. pH 6.5-9.0

TABLE-US-00009 Second concentrate: 50% glucose Glucose 2.775M Hydrochloric acid ad pH. 2.0-3.1

TABLE-US-00010 Mixed solution composition example 3 A (mL/L) 0 30 50 80 100 B (mL/L) 33.3 Na.sup.+ (mM) 132 Mg.sup.2+ (mM) 0.25 Ca.sup.2+ (mM) 1.75 Cl.sup. (mM) 96 Lactate (mM) 40 Glucose (mM) 0 83.3 138.8 222.0 278

[0072] Ca.sub.ready is 1.75 mM for the ready-to-use solution and L.sub.conce is 1.20 M for the first concentrate of example 1. Condition a) above is fulfilled as L.sub.conc is larger than 0.75 M. Condition b) above is not fulfilled as 1.90.41.75 mM=1.2, which is equal to L.sub.conc. Precipitations were found in the first concentrate.

Example 4

TABLE-US-00011 First concentrate Sodium chloride 1.84 M Calcium chloride 0.035 M Magnesium chloride 0.005 M Sodium lactate 0.80 M Sodium hydroxide Ad. pH 6.5-9.0

TABLE-US-00012 Second concentrate: 50% glucose Glucose 2.775M Hydrochloric acid Ad. pH 2.0-3.1

TABLE-US-00013 Mixed solution composition example 4 A (mL/L) 0 30 50 80 100 B (mL/L) 50 Na.sup.+ (mM) 132 Mg.sup.2+ (mM) 0.25 Ca.sup.2+ (mM) 1.75 Cl.sup. (mM) 96 Lactate (mM) 40 Glucose (mM) 0 83.3 138.8 222.0 278

[0073] Ca.sub.ready is 1.75 mM for the ready-to-use solution and L.sub.conce is 0.80 M for the first concentrate of example 1. Condition a) above is fulfilled as L.sub.conc is larger than 0.75 M. Condition b) above is fulfilled as 1.90.41.75 mM=1.2, which is larger than L.sub.conc. Precipitations were not found in the first concentrate.

Example 5

TABLE-US-00014 First concentrate Sodium chloride 1.84 M Calcium chloride 0.025 M Magnesium chloride 0.005 M Sodium lactate 0.80 M Sodium hydroxide Ad. pH 6.5-9.0

TABLE-US-00015 Second concentrate: glucose 50% Glucose 2.775M Hydrochloric acid Ad. pH 2.0-3.1

TABLE-US-00016 Mixed solution composition example 5 A (mL/L) 0 30 50 80 100 B (mL/L) 50 Na.sup.+ (mM) 132 Mg.sup.2+ (mM) 0.25 Ca.sup.2+ (mM) 1.25 Cl.sup. (mM) 96 Lactate (mM) 40 Glucose (mM) 0 83.3 138.8 222.0 278

[0074] Ca.sub.ready is 1.25 mM for the ready-to-use solution and L.sub.conce is 0.80 M for the first concentrate of example 1. Condition a) above is fulfilled as L.sub.conc is larger than 0.75 M. Condition b) above is fulfilled as 1.90.41.25 mM=1.4, which is larger than L.sub.conc. Precipitations were not found in the first concentrate.

Example 6

TABLE-US-00017 First concentrate Sodium chloride 2.76 M Calcium chloride 0.0375 M Magnesium chloride 0.0075 M Sodium lactate 1.20 M Sodium hydroxide Ad. pH 6.5-9.0

TABLE-US-00018 Second concentrate: 50% glucose Glucose 2.775M Hydrochloric acid Ad. pH 2.0-3.1

TABLE-US-00019 Mixed solution composition example 6 A (mL/L) 0 30 50 80 100 B (mL/L) 33.3 Na.sup.+ (mM) 132 Mg.sup.2+ (mM) 0.25 Ca.sup.2+ (mM) 1.25 Cl.sup. (mM) 96 Lactate (mM) 40 Glucose (mM) 0 83.3 138.8 222.0 278

[0075] Ca.sub.ready is 1.25 mM for the ready-to-use solution and L.sub.conce is 1.20 M for the first concentrate of example 1. Condition a) above is fulfilled as L.sub.conc is larger than 0.75 M. Condition b) above is fulfilled as 1.90.41.25 mM=1.4, which is larger than L.sub.conc. Precipitations were not found in the first concentrate.

Example 7

TABLE-US-00020 First concentrate Sodium chloride 2.3 M Calcium chloride 0.04375 M Magnesium chloride 0.00625 M Sodium lactate 1.00 M Sodium hydroxide ad. pH 6.5-9.0

TABLE-US-00021 Second concentrate: 50% glucose Glucose 2.775M Hydrochloric acid Ad. pH 2.0-3.1

TABLE-US-00022 Mixed solution composition example 3 A (mL/L) 0 30 50 80 100 B (mL/L) 40 Na.sup.+ (mM) 132 Mg.sup.2+ (mM) 0.25 Ca.sup.2+ (mM) 1.75 Cl.sup. (mM) 96 Lactate (mM) 40 Glucose (mM) 0 83.3 138.8 222.0 278

[0076] Ca.sub.ready is 1.75 mM for the ready-to-use solution and L.sub.conce is 1.00 M for the first concentrate of example 1. Condition a) above is fulfilled as L.sub.conc is larger than 0.75 M. Condition b) above is fulfilled as 1.90.41.75 mM=1.2, which is larger than L.sub.conc. Precipitations were not found in the first concentrate.

[0077] While the invention has been described in connection with what is presently considered to be the most practical embodiments, it is to be understood that the invention is not to be limited to the disclosed embodiments, but on the contrary, it is intended to cover various modifications and equivalents included within the spirit and scope of the appended claims.