WO2020133198A1

WO2020133198A1 - Stabilized aqueous hemofiltration basic solution, dialysis solution and corresponding kit

Info

Publication number: WO2020133198A1
Application number: PCT/CN2018/124806
Authority: WO
Inventors: Taoe LIU; Aaron Lu; Gene Ma; Frank Gong
Original assignee: Fresenius Medical Care R&D (Shanghai) Co., Ltd.; Fresenius Medical Care Deutschland Gmbh
Priority date: 2018-12-28
Filing date: 2018-12-28
Publication date: 2020-07-02
Also published as: CN113597311A

Abstract

A stabilized aqueous hemofiltration basic solution for preparation of a hemofiltration solution or medical substitution fluid comprising · 69-128 mmol/L Sodium ions, · 0-4.8 mmol/L Potassium ions, · 1.1-2.7 mmol/L Calcium ions, · 0.27-1.6 mmol/L Magnesium ions, · 96-128 mmol/L Chloride ions, · 0-27 mmol/L Glucose, and · 0.1-0.3 mmol/L Phosphate ions. A dialysis solution and a corresponding kit for preparing an aqueous hemofiltration solution or medical substitution fluid are provided; it will be more safe and convenient than current clinical practice.

Description

Stabilized aqueous hemofiltration basic solution, dialysis solution and corresponding kit

Technical field

The present invention is to provide a Hemofiltration Basic Solution (HBS) which can be premixed with a 5%sodium bicarbonate solution and used for hemofiltration and hemodiafiltration. The present invention also relates to a dialysis solution and a kit for preparing an aqueous hemofiltration solution or medical substitution fluid.

Background

Acute renal failure is the sudden loss of kidney function. The cause of this is in most patients not associated with the organ kidney itself. Common causes of acute renal failure in intensive care units are severe shock, trauma, the loss of large amounts of blood, and extensive surgical procedures such as in cardiac and vascular surgery.

The treatment of acute renal failure differs from the treatment of chronic renal failure. The latter is usually performed on an outpatient basis for a few hours three to four times a week. In contrast, patients with acute renal failure are always receiving intensive care. For this reason, treatment of these patients can be continuous over several days, which is considered a gentler procedure. The treatment of acute renal failure by hemofiltration is also referred to as continuous renal replacement therapy (CRRT) .

For use in hemofiltration a dialysis solution must be provided which is as physiological as possible, i.e. has a pH of about 6.4 to 7.4, and contains important electrolytes. Furthermore, the dialysis solution must have a buffer system which is physiological and suitable for setting the desired pH. This is preferably achieved by buffer or buffer systems, which themselves can contribute to the total content of electrolytes. The buffers are usually bicarbonate or lactate. Bicarbonate or hydrogen carbonate acts directly as a buffer, while lactate acts as a buffer indirectly, as it must be metabolized in the body of the patient first to bicarbonate. A bicarbonate buffer is preferred in clinical practice.

In clinical practice, the hemofiltration solutions are either prepared in a hospital pharmacy or purchased as a ready-for-use solution. The ready-for-use substitution solution contains Calcium and Hydrogen carbonate ions in concentration ranges that may lead to precipitation of Calcium carbonate under certain circumstances. In general, the higher the pH-value and the temperature of the solution, the higher is the risk for precipitation to occur. If the pH-value is too high, a safe use of the solution cannot be guaranteed anymore. This is especially critical when the product is used as a substitution fluid on a dialysis machine in an intensive care unit environment.

In the current clinical practice in China a Hemofiltration Basic Solution (HBS) is available, which cannot be premixed with bicarbonate. The bicarbonate buffer solution is supplied in a separate bag. The bicarbonate solution requires an extra pump and an independent path to the body which is inconvenient and brings additional risks for the clinical use.

Summary of the invention

The stabilized Hemofiltration Basic Solution of the present invention comprises three parts including water for injection, electrolyte salts and one or more stabilizers. The electrolytes can be salt of sodium, calcium and magnesium with a concentration close to the electrolytic composition of plasma. Optionally, the solution comprises a potassium salt. The stabilizer used here is phosphate with concentration of 0.1-0.3 mmol/L. Preferably, the phosphate concentration is about 0.2 mmol/L. Glucose may be included in the formulation as supplement. The pH of the solution can be better controlled in an acidity range lower than 6.0. The Hemofiltration Basic Solution of the present invention can be premixed with a bicarbonate buffer solution to form a ready-to-use hemofiltration solution.

In a preferred embodiment the stabilized aqueous hemofiltration basic solution for preparation of a hemofiltration solution or medical substitution fluid comprises 69-128 mmol/L Sodium ions, 0-4.8 mmol/L Potassium ions, 1.1-2.7 mmol/L Calcium ions, 0.27-1.6 mmol/L Magnesium ions, 96-128 mmol/L Chloride ions, 0-27 mmol/L Glucose, and 0.1-0.3 mmol/L Phosphate ions.

In another preferred embodiment the stabilized aqueous hemofiltration basic solution for preparation of a hemofiltration solution or medical substitution fluid comprises 113 mmol/L Sodium ions, 0 mmol/L Potassium ions, 1.6 mmol/L Calcium ions, 0.8 mmol/L Magnesium ions, 118 mmol/L Chloride ions, 10.6 mmol/L Glucose, and 0.2 mmol/L Phosphate ions.

In Table 1 the preferred composition is given for the Hemofiltration Basic Solution (HBS) and for the ready-to-use solution, which is obtained by mixing the HBS with a 5 wt. -%bicarbonate solution.

Table 1: Hemofiltration Basic Solution formulation

In a preferred embodiment, the stabilized aqueous hemofiltration basic solution for preparation of a hemofiltration solution or medical substitution fluid comprises 113 mmol/L Sodium, 0 mmol/L Potassium, 1.6 mmol/L Calcium, 0.8 mmol/L Magnesium, 118 mmol/L Chloride, 10.6 mmol/L Glucose, and 0.2 mmol/L Phosphate.

The present invention also relates to a Kit for preparing a ready-for-use aqueous hemofiltration solution or medical substitution fluid comprising at least one container with a hemofiltration basic solution as described above and a container with a 5 wt. -%bicarbonate solution.

In one embodiment of the Kit the volume of the container containing the hemofiltration basic solution is 4 L and the volume of the container with the bicarbonate solution is 250 mL. The Kit may be useful for preparing a ready-to-use solution for the treatment of acute renal failure. The final mixed solution for clinical use comprises 125-150 mmol/L Sodium, 0-4.5 mmol/L Potassium, 1.0-2.5 mmol/L Calcium, 0.25-1.5 mmol/L Magnesium, 90-120 mmol/L Chloride, 0-25 mmol/L Glucose, 0.1-0.3 mmol/L Phosphate, and 30-60 mmol/L Hydrogen carbonate.

Description of Drawings

Figure 1 exemplarily shows a hemofiltration basic solution (HBS) bag of the present invention.

Figure 2 exemplarily shows a pH-trending in a common precipitation experiment.

Figure 3 exemplarily shows a stability comparison of HBS without phosphate and with phosphate.

Figure 4 exemplarily shows a comparison of different formulation with different concentration of phosphate and also pre-mixed with different pH 5%sodium bicarbonate.

Description of Specific Embodiments

Hemofiltration Basic Solution (HBS) bag of the present invention is depicted in Figure 1.

To this end, according to a first aspect of the present invention, a Hemofiltration Basic Solution (HBS) bag is provided, the HBS bag comprising:

· a single chamber 1 for containing a hemofiltration basic solution;

· a connective tube 2 with an injection port 3, and

· an infusion port 4 for fluidly connecting a second solution bag to the chamber 1 for mixing the hemofiltration basic solution in chamber 1 with a second solution.

The Hemofiltration Basic Solution in the chamber 1 is diluted or dissolved to form a hemofiltration solution suitable for CRRT via the connecting tube.

The hemofiltration basic solution bag of the present invention has a volume of 4 L or 5 L.

The hemofiltration basic solution bag of the present invention has a length of 380±20 mm and a width of 290±20 mm.

In one embodiment, the hemofiltration basic solution bag of the present invention comprises at least one hole 6 at a corner or an edge of the bag for hanging the bag to an infusion stand, an IV pole or a dialysis machine.

In one embodiment of the present invention, the hemofiltration basic solution bag is made of a PVC-free multi-layer film. Preferably, the bag is made of a polypropylene (PP) containing multi-layer film. One example of a polypropylene (PP) containing multi-layer film is known under the trademark Biofine ^TM.

In one embodiment of the hemofiltration basic solution bag of the present invention is packaged in an overwrap 5 comprising high density polyethylene (HDPE) .

Examples

To show the stabilizing effect of 0.1 to 0.3 mmol/L of phosphate, samples were prepared by mixing the Hemofiltration Basic Solution of the present invention with a 5 wt. -%bicarbonate solution to form a ready-to-use solution. Comparative samples of were prepared without phosphate addition. The composition of all samples is given in Table 2.

Table 2: Formulation design of HBS with and without phosphate

Three test methods were applied to test the stability difference between HBS with phosphate and without phosphate as stabilizing agent. The methods included a Carousel setup, a recirculation setup and a machine setup. CaCO ₃ precipitation was chosen as a parameter to test and monitor the solutions’ stability.

Details are given in Table 3.

Table 3: Test methods of different setups

The start of a CaCO ₃ precipitation can be detected via different analytical methods like, e.g., pH-measurement, turbidimetry and particle measurement. The pH-value at which precipitation occurs is defined as the critical pH-value (pH _crit) and a key parameter for the solution stability. The time point at which the precipitation occurs is called time of germination (t _G) . The t _G values serve only as a guidance because they strongly depend on the adjusted degassing speed. Figure 2 shows a schematic example of the pH-trending in a stress test. CO ₂ constantly evaporates from the solution and the pH-value (black curve) increases over time until the solution reaches a critical state. When the precipitation reaction starts, a significant decrease of the pH-value indicates the initiation of the precipitation reaction (blue arrow) .

The Carousel setup is a modified Rapid-Degassing-Method consisting of a magnetic stirrer with a heating plate unit. It allows in-line measurement via pH-electrodes or turbidimetry sensors. The flasks are open on the top so CO ₂ can escape easily from the solution to bring the pH-value to higher values in a short time. In Carousel test setup study, HBS with 0.1 mmol/L phosphate as stabilizer showed significant higher stability than HBS without phosphate. The mean pH _crit value of HBS with phosphate was increased to 8.58 compared with HBS without phosphate 8.27 (Figure 3) .

Different formulation with different concentration of phosphate from 0.1 mmol/L to 0.3 mmol/L and also pre-mixed with different pH 5%Sodium bicarbonate were designed to further evaluate the stability of the solution. The test results showed that the samples with a higher concentration of phosphate of 0.2 and 0.3 mmol/L, respectively, showed better performance than a formulation with 0.1 mmol/L phosphate during carousel setup testing (cf. Figure 4 and Table 5) .

The Recirculation setup is a setup consisting of a pump and heating unit of the Fresenius CRRT machine. The solution is placed inside a solution bag and pumped in a circle through a tubing system. A sample unit allows in-line measurement e.g. via pH-electrodes or turbidimetry sensors. The solution bag is r opened at the degassing tubes so the CO ₂ can escape more easily to bring the pH-value to higher values in a short time. In recirculation setup, HBS with 0.1 mmol/L phosphate as stabilizer shows significant higher stability than HBS without phosphate. HBS with phosphate can last more than 24 hours without precipitation (t _G=29.25 h with pHcrit 8.51) while HBS without phosphate precipitated within 1 hour (t _G=0.9 h with pH _crit 8.25) .

To mimic the real-life stress condition of a HBS as closely as possible, machine simulation studies were performed in a lab environment with an ambient temperature of approximately 20℃ and a heating temperature around 50℃ to ensure a temperature of 37℃ at the end of the tubing line (where solutions reaches the patient) . In machine simulation study, HBS with 0.1 mmol/L phosphate as stabilizer showed significant higher stability than HBS without phosphate when pre-mixed with fresh 5%sodium bicarbonate (pH ～8.0) . HBS with phosphate can be stable for 72 hours treatment without precipitation in the treatment simulation on FMC CRRT machine. HBS with Phosphate 0.2 mmol/L even pre-mixed with high pH Sodium Bicarbonate (pH 8.5) could also keep stable without precipitation during 72h simulation study on FMC CRRT machine (Table 5) .

Table 4: Machine simulation study test results

Different formulation with different concentration of phosphate from 0.15 mmol/L to 0.25 mmol/L with different pH from 4.1 to 5.2 and pre-mixed with different pH 5%Sodium bicarbonate (pH 8.0 and 8.5) were designed to further evaluate the stability of the solution. HBS without phosphate was used as control. The test results showed that pH of the HBS from 4.1 to 5.2 had no much difference. The pH of bicarbonate, heating temperature and the concentration of phosphate play an important role for the stability of ready-to-use HF solution. Current test result showed phosphate concentration at 0.2 mmol/L was the best choice to improve solution stability when admixed with Bicarbonate. The lower pH of bicarbonate pre-mixed with the HBS, the better performance of ready to use solution to prevent the precipitation (Table 5) .

Table 5: Carousel and machine simulation study result of different HBS formulations

This new designed Hemofiltration Basic Solution (HBS) which can be premixed with 5%sodium bicarbonate provides a stable solution for clinical use to lower down the risk of precipitation on a dialysis or CRRT machine in an intensive care unit environment. It can also avoid the case of off-label use of CRRT machine with extra pump for bicarbonate pumping. It will be more safe and convenient than current clinical practice.

Claims

Stabilized aqueous hemofiltration basic solution for preparation of a hemofiltration solution or medical substitution fluid comprising

· 69-128 mmol/L Sodium ions,

· 0-4.8 mmol/L Potassium ions,

· 1.1-2.7 mmol/L Calcium ions,

· 0.27-1.6 mmol/L Magnesium ions,

· 96-128 mmol/L Chloride ions,

· 0-27 mmol/L Glucose, and

· 0.1-0.3 mmol/L Phosphate ions.
Stabilized aqueous hemofiltration basic solution for preparation of a hemofiltration solution or medical substitution fluid according to claim 1 comprising 113 mmol/L Sodium ions, 0 mmol/L Potassium ions, 1.6 mmol/L Calcium ions, 0.8 mmol/L Magnesium ions, 118 mmol/L Chloride ions, 10.6 mmol/L Glucose, and 0.2 mmol/L Phosphate ions.
Dialysis solution comprising 125-150 mmol/L Sodium, 0-4.5 mmol/L Potassium, 1.0-2.5 mmol/L Calcium, 0.25-1.5 mmol/L Magnesium, 90-120 mmol/L Chloride, 0-25 mmol/L Glucose, 0.1-0.3 mmol/L Phosphate, and 30-60 mmol/L Hydrogen carbonate.
Dialysis solution comprising 125-150 mmol/L Sodium, 0-4.5 mmol/L Potassium, 1.0-2.5 mmol/L Calcium, 0.25-1.5 mmol/L Magnesium, 90-120 mmol/L Chloride, 0-25 mmol/L Glucose, 0.1-0.3 mmol/L Phosphate, and 30-60 mmol/L Hydrogen carbonate.
Kit for preparing an aqueous hemofiltration solution or medical substitution fluid comprising a) at least one container with a hemofiltration basic solution according to claim 1 or 2, and b) at least one container with a bicarbonate solution.
Kit according to claim 5 wherein the volume of the container with the hemofiltration basic solution is 4 L or 5 L.
Kit according to claim 5 or 6 wherein the volume of the container with the bicarbonate solution is 250 mL.
Kit according to claim 5 for the treatment of acute renal failure.