HK1097459B - Peritoneal dialysis solution - Google Patents

Description

The invention relates to a solution for peritoneal dialysis as defined in claim 1.

In addition to a buffer system and an osmoticum, a peritoneal dialysis solution generally contains electrolytes, usually calcium, sodium and magnesium salts, often in the form of chlorides.

During dialysis treatment, many blood components, including sodium ions from the patient's blood, pass through the peritoneum into the dialysate. e amount of sodium removed from the blood depends, among other things, on the sodium concentration gradient between the blood side and the dialysis side.

It is well known that patients with hypertension are advised against consuming saline (NaCl). Blood pressure reduction is achieved by a low saline diet on the one hand and by effective sodium uptake during dialysis on the other. To reduce the sodium content of the extracellular space during dialysis to achieve blood pressure reduction, it has been proposed to use a low sodium peritoneal dialysis solution (Clin. Neph. Vol. 416) (1994) pp. 357-363, Nakayama et al.). The peritoneal solution known from this pressure reading shows a sodium diffusion of 120 mmol/l. Further significantly increased concentration of sodium concentrates (usually called magnesium anion) is achieved by the use of calcium and calcium chloride, which can only be significantly reduced by the transport of calcium and sodium anion, and by the use of this peritoneal solution.

However, the use of the known peritoneal dialysis solution has undesirable side effects due to a lack of dehydration in the patients and hyponatremia. e use of the said peritoneal dialysis solution alone with a sodium concentration of 120 mmol/ l is associated with significant adverse effects (hyponatremia) and therefore unacceptable, especially in patients with low oral sodium intake.

U.S. Patents 5,589,197, 5,629,025, and 5,631,025 identify peritoneal dialysis solutions containing various osmotics with sodium levels in the range of 35 to 125 mmol/l. The preferred concentration range is a sodium ion concentration of ≤ 120 mmol/l. Clinically, such peritoneal dialysis solutions have also been shown to reduce blood pressure and increase the ultrafiltration volume at the same osmolarity compared to standard known solutions with normal sodium concentrations in the range of 134 mmol/l. However, the use of the US patents also results in the sodium levels described above being reduced to clinically acceptable levels.

In the case of pre-known peritoneal dialysis solutions, the problem is either hypertension (at a sodium ion concentration of about 134 mmol/ l) or clinical side effects (at a sodium ion concentration ≤ 120 mmol/ l). In the case of current peritoneal dialysis, sodium ion concentrations are usually set to 134 mmol/ l, as this avoids the side effects described in low sodium dialysis solutions.

The purpose of the present invention is to provide a solution for peritoneal dialysis which has a blood pressure lowering effect and does not have the side effects known from the use of low sodium peritoneal dialysis solutions.

This is achieved by a solution for peritoneal dialysis with the characteristics of claim 1, according to which the sodium ion concentration of the peritoneal dialysis solution is 125 mmol/l.

Sodium is usually used as a salt (NaCl), i.e. as a chloride. A reduction in the sodium ion concentration can therefore lead to an equimolar reduction in the chloride ion concentration. A synergistic effect cannot be excluded because the chloride ion concentration will necessarily also be reduced if sodium is used as a chloride.

The solution of the invention for peritoneal dialysis provides an effective blood pressure lowering effect, while avoiding side effects, with effects occurring at a natrium ion level in the claimed range and particularly pronounced at 125 mmol/l and 91-94 mmol/l chloridione levels. The solution of the invention for peritoneal dialysis leads to an increase in salt excretion and is used to support the oral salt diet. Antihypertensive agents can be saved in more than 50% of patients with peritoneal dialysis due to the blood pressure lowering effect of the solution of the invention.

The further development of the invention provides that the solution for peritoneal dialysis also contains an osmotic, additional electrolytes and a buffer.

It is known from EP 0 935 967 A2 to provide a peritoneal dialysis solution consisting of two individual solutions, the first containing calcium ions, further electrolyte salts and glucose and acidified with a physiologically acceptable acid to a pH below 3,2 and the second containing bicarbonate with a content ≤ 10 mmol/l and the salt of a weak acid with pka < 5. Such a peritoneal dialysis solution has the advantage of preventing the degradation of glucose during heat sterilisation and of not imposing special requirements on the bag material due to the low CO2 partial pressure.

Such a solution consisting of two individual solutions for peritoneal dialysis is also possible for the present invention.

Accordingly, it may be expected that the solution consists of two individual solutions, the first containing the osmotic and a physiologically compatible acid and the second containing a buffer.

If the peritoneal dialysis solution consists of two individual solutions, it may be provided that each of the individual solutions contains sodium ions, and the mixture ratio shall be set so that the sodium ions concentration of the peritoneal dialysis solution is 125 mmol/l.

In further development of the present invention, it is intended that the pertionedialysis solution contains calcium ions, magnesium ions, H+ superfluids, chloride ions, lactates, hydrogen carbonates and glucose in addition to sodium ions.

If two individual solutions are used, it can be assumed that in the first individual solution, in addition to calcium ions, there are other electrolytes, the osmotic (e.g. glucose) and a physiologically compatible acid. In a second individual solution, the buffer system can be provided. This can be, for example, bicarbonate and the salt of a weak acid (e.g. lactate).

If the peritoneal dialysis solution consists of two single solutions, the first single solution may be provided with the following components:

Natriumionen [mmol/l]:	172-200
Calciumionen [mmol/l]:	2-4
Magnesiumionen [mmol/l]:	0,8-1,2
0,9-1,1
Chlorid [mmol/l]:	176-210
Glucose [mmol/l]:	100-500.

The second individual solution may contain the following components: Other

Natriumionen [mmol/l]:	70-80
Lactat [mmol/l]:	65-75
Hydrogencarbonat [mmol/l]:	4-6

An appropriate mixing ratio of the first and second individual solutions allows the concentration range of the sodium ions in the application solution to be easily adjusted.

If two individual solutions are used, they are usually heat sterilised, then combined to form the application solution and then administered to the patient.

It is also conceivable to provide only a single solution and to present it in these sodium ions in the concentration range of the invention.

The present invention also relates to a solution according to claim 5, where the double chamber belt consists of a plastic bag in which a first chamber containing the first single solution and a second chamber containing the second single solution are adjacent to each other, with both chambers separated by a weld seam, which is dimensioned so that it opens when pressed on one of the liquid-filled chambers so that the contents of the two chambers can mix with each other. In such a double chamber bag, the buffer system of, for example, lactate and bicarbonate can be placed in a bag chamber, while glucose and electrolytes in a second chamber can be placed in a sterile environment. The resulting solution can be used to dissolve the acid and nitrate in a solution that is suitable for the patient.

Further details and advantages of the invention are explained in more detail by the following example: Other

Phase II- Studie	CAPD Niedrig-Natrium Lösung FME, 2003			CAPD Niedrig-Natrium Lösung Nakayama et al, 1994
Zeit (Wochen)	W 0	W +2	W +4	W 0	W +2	W +4
Patienten	N=4	N=4	N=4	N=9	N=8	N=7
D-Natrium (mmol/l)	134	125	125	132	120	120
D-Chlorid (mmol/l)	102.5	93.5	93.5	96	84	84
MAD (mmHg)	116	105	108	123	116	107
KG (kg)	65.5	65.6	64.8	61	61.7	61.6
Mittleres S-Natrium (mmol/l)	138.8	135.5	137.0	137	133	136
Mittleres UF-Volumen (ml/Tag)	1088	n.b.	1068	918	880	890
Mittlere TPN-Ausscheidung (mmol/Tag)	83.2	n.b.	55.1	38	n.b.	85
SUE	Keine			2x 'drop-out':
1x Hvponatriämie, 1x Überwässerung

The table shows the results of a study in which dialysis patients were treated with the peritoneal dialysis solution of the invention (columns 2-4), compared with the results of the study available in Cl. Neph. Vol. 41 (**) (1994) pp. 357-363, Nakayama et al. (columns 5-7).

The second row shows the duration of treatment in weeks (W) and the number of patients participating at the time (N).

As shown in the second and fifth columns, patients were adjusted to 134 mmol/l sodium at the start of the study with the dialysis solution of the invention (W 0) and 132 mmol/l sodium in the Nakayama et al. study.

The sodium ion concentration in the dialysate was then adjusted to 125 mmol/l according to the present invention and compared with the published values of 120 mmol/l according to Nakayama et al.

From row 5 of the table, it can be seen that a significant reduction in blood pressure (MAD) was achieved when using the dialysis solution of the invention. After two weeks of treatment (W+2), despite the higher sodium concentration of the dialysis solution of the invention than in the comparator solution, a strong absolute and relative reduction in blood pressure was obtained than in the comparator test according to Nakayama et al. After four weeks of treatment, despite the higher sodium concentration of the solution of the invention, blood pressure values were comparable to those in the comparator test.

The mean ultrafiltration volume (UV volume) of the solution of the invention was similar to that of the solution used at the beginning of the experiment (134 mmol/l sodium content).

As can be seen from the last line of the table, the use of the peritoneal dialysis solution of the invention did not result in any adverse reactions or serious adverse events. In contrast, in the trials described by Nakayama et al., two patients had to discontinue the study, one of whom was found to be over-hydrated and another who was discontinued due to hyponatremia and the resulting adverse reactions.

The dialysis solution according to the invention thus allows peritoneal dialysis, which avoids the side effects known from pre-existing low sodium dialysis solutions, while achieving effective blood pressure reduction.

Claims (5)

1. A solution for peritoneal dialysis, obtainable by combining two separate solutions, characterized in that the first separate solution comprises an osmotic agent and a physiologically compatible acid and the second separate solution comprises a buffer, the finished solution contains sodium ions in a concentration of 125 mmol/l and chloride ions in a concentration in the range from 91 mmol/l to 94 mmol/l, and in that the finished solution also comprises calcium ions, magnesium ions, H⁺ excess ions, lactate ions, hydrogen carbonate ions and glucose in addition to sodium ions.
2. A solution for peritoneal dialysis in accordance with claim 1, wherein sodium ions are present in each of the separate solutions.
3. A solution for peritoneal dialysis in accordance with one of the preceding claims, wherein the first separate solution includes the following components: Sodium ions [mmol/l]: 172-200 Calcium ions [mmol/l]: 2-4 Magnesium ions [mmol/l]: 0.8-1.2 0.9-1.1 Chloride [mmol/l]: 176-210 Glucose [mmol/l]: 100-500.
4. A solution for peritoneal dialysis in accordance with one of the preceding claims, wherein the second separate includes the following components: Sodium ions [mmol/l]: 70-80 Lactate [mmol/l]: 65-75 Hydrogen carbonate [mmol/1]: 4-6.
5. A solution for peritoneal dialysis in accordance with one of the claims 1 to 4, characterized in that the separate solutions are provided in a double-chambered pouch which consists of a plastic pouch in which a first chamber with the first separate solution and a second chamber with the second separate solution are arranged adjacent to one another, with both chambers being separated by a weld seam dimensioned such that it opens on pressure on one of the chambers filled with liquid so that the content of the two chambers can be mixed with one another.