SE512349C2 - Multi-chamber container for medical solution, procedure for preparation of medical solution for peritoneal dialysis and use of such container for preparation of medical solution - Google Patents

Abstract

Container for medical solution, particularly for peritoneal dialysis. A large compartment (10) contains the majority of the medical solution, such as sodium bicarbonate, sodium lactate and sodium chloride. In addition, a plurality of small compartments (14, 15) are provided which contain partial quantities of the medical solution which are not compatible for long term storage with the contents of the large compartment, such as calcium ions and glucose. By mixing the contents of the first (14) or second (15) of the small compartments with the contents of the large compartment (10), a solution is obtained having 1.5 % or 2.5 % glucose and 1.0 mM or 1.6 mM calcium. By mixing the contents of both the small compartments with the contents of the large compartment, a solution is obtained having 4.0 % glucose and 2.5 mM calcium. Due to the increased ultrafiltration at high glucose concentration, these medical solutions are calcium-neutral during use as peritoneal dialysis solutions.

Description

SUMMARY OF THE INVENTION The object of the present invention is to adapt the container according to WO 97/05852 for peritoneal dialysis where the lactate buffer is completely or partially replaced by a buffer consisting of bicarbonate.

As is known, however, bicarbonate cannot be combined with calcium or magnesium in the large chamber because there is a risk of precipitation of, for example, carbonates.

Therefore, bicarbonate and calcium / magnesium must be separated. It would then be natural to arrange calcium in the small chambers containing glucose. This is entirely possible as glucose and calcium / magnesium are compatible despite the fact that the divalent ions to some extent catalyze glucose degradation. When mixing the contents of the small chamber with the contents of the large chamber, there is no risk of precipitation of carbonates as the pH of the total solution is kept well below pH = 7.4.

Such a peritoneal dialysis solution conventionally contains a calcium ion concentration of 1.75 mM (mmol / l) and a magnesium ion concentration between 0.25-0.50 mM. The buffer may be bicarbonate only, which then normally occurs in a concentration of 30-40 mM or a combination of bicarbonate and lactate, for example 25 mM bicarbonate and 15 mM lactate.

Below, only calcium ions continue to be discussed because they are of the greatest clinical importance, but the reasoning is of course equally applicable to magnesium ions.

However, if the above solution is to be used in a three-chamber container of the type described in WO 97/05852, a problem arises. When the content in one small chamber is mixed with the content in the large chamber, a concentration of 1.5% glucose and eg 1.75 mM calcium arises, which is regulated by the amount of glucose and the concentration of calcium in the first small chamber. . If the contents of the second small chamber are mixed with the contents of the large chamber, a concentration of 2.5% glucose and 1.75 mM calcium arises, which is regulated by the amount of glucose and the concentration of calcium in the second small chamber. LU C) KU (_11. 512 349 3 chamber. However, if the third glucose concentration of 4% is to be obtained, the chamber and the second small chamber with the contents of it are mixed with the contents of both the first small large chamber, whereby a glucose concentration of 4 .0% arises, but the calcium concentration becomes too high, in this case about 3.4 mM. It does not seem possible to provide a three-chamber container of this type with the possibility of three different glucose concentrations due to the very high calcium concentration which arises at the highest glucose concentration, but the concept seems to need to be expanded to a four-chamber container.

A further object of the present invention is to propose a three-chamber container of the above-mentioned type, in which the above-mentioned problems are eliminated.

The calcium problem in peritoneal dialysis, as well as in is complicated when dialysis patients normally eat Some of the calcium carbonate that is ingested together with the food absorber-dialysis, calcium carbonate to bind phosphate that is present in the food. is carried in the intestinal tract and raises the calcium concentration in the blood.

At the same time, the calcium carbonate binds phosphate so that the patient's phosphate load is reduced. Phosphate is a molecule that is difficult to remove from the body via dialysis because it does not easily pass through membranes, neither synthetic membranes nor peritoneal membranes.

The calcium concentration in the peritoneal dialysis solution that is generally recommended today is 1.75 mM. This is considered a suitable compromise, which corresponds to the normal physiological concentration of calcium in the blood, ie free calcium, as calcium is partly free, partly bound to protein, especially albumin. If the calcium concentration in the patient is elevated, there is an outflow of calcium, while if the concentration is too low, calcium is supplied to the body.

If an excess of calcium occurs, hypercalcemia, this results in, among other things, the following symptoms: vomiting, confusion, impaired muscle function, ECG disorders and Tissue calcification. min | u mix .in ..1.

Hypercalcemia is usually treated by the patient avoiding eating calcium carbonate for a few days, with the calcium concentration falling rapidly. On the other hand, hypocalcemia results in the following symptoms, among others: convulsions, hyperreflexia, twitching, ECG changes and hyperparathyroidism.

Hypocalcaemia is usually treated by increasing the intake of calcium carbonate. Therefore, the calcium concentration in the dialysis solution is usually kept constant.

It is realized that the calcium problem is troublesome as the above-mentioned symptoms are difficult to diagnose.

Recently, it has been discussed to lower the calcium concentration in dialysis solution further, to 1.35, 1, 25 or 1.0 mM. The motivation is that it can increase the oral intake of calcium carbonate and further reduce the phosphate load in the patient. The risk of hypocalcaemia increases and increased attention is required to diagnose and remedy this.

There are previous experiments that show that the transport of calcium ions across the peritoneal membrane is affected by the glucose concentration in the peritoneal dialysis solution. However, this effect is rarely discussed. According to the present invention, however, this discovery is used to solve the above-mentioned problem in a three-chamber container of the type described in WO 97/05852 to adapt it to a buffer containing bicarbonate.

Our experiments with simulations of calcium transport across the peritoneal membrane demonstrate the following unexpected results. If a peritoneal dialysis solution is to be neutral (inlet and outflow equal) with respect to calcium transport for 4 hours, it should contain about 1.2 mM calcium at 1.5% glucose, about 1.6 mM at 2.5 glucose and finally about 2.3 mM calcium at 4.0% glucose, ie the calcium concentration should be mainly proportional to the glucose concentration in the finished solution.

This can be obtained in a three-chamber container in that calcium is present in substantially the same concentration in the small glucose chambers and that the final glucose concentration in the mixed solution is determined by the volume in the small chambers as the glucose concentration is the same in the small glucose chambers, This for example 50%. means that the calcium concentration will always be in proportion to the glucose concentration. The higher the glucose concentration (larger volume), the more ultrafiltration and thus also the higher calcium concentration in the mixed solution. The calcium concentration can then be chosen so that the patient either has a net loss, net gain or neutral calcium balance regardless of the ultrafiltration and glucose concentration.

A further object of the present invention is therefore to provide a three-chamber container of the type described above with bicarbonate in the large chamber and glucose together with calcium in the two small chambers, the increase of the calcium concentration at the highest glucose concentration resulting in a better calcium control. than before. This finding is completely different from prior art where the same calcium concentration has always been used regardless of the glucose concentration.

By using a peritoneal dialysis solution where the calcium concentration is proportional to the glucose concentration, it is possible to use the same solution in the small chambers, ie the plant used to fill the three-chamber container only needs to produce solutions with two different compositions, one for the large chamber and one for the two small chambers. As a result, the manufacturing cost can be reduced.

Further objects, problems, solutions and features appear from the following claims and the following detailed description of the invention with reference to the drawings and several embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows a container that can be used in the present invention. 10 15 20 25 30 L.) UI 512 549 6 Figs. 2, 3 and 4 are diagrams showing the calcium balance across a peritoneal membrane in a computer simulation.

DETAILED DESCRIPTION OF EXAMPLES AND EMBODIMENTS Fig. 1 shows a three-chamber container that can be used in the present invention. The container consists of a container 1 sealed at both ends with welds 20 and 21. The container is divided into a large chamber 10 and two smaller chambers 14 and 12 and 13.

The small chamber 14 and / or 15 can be connected to it by means of welds 11, the large chamber 10 by means of break pins 18, 19, which are normally sealed but can be opened by manual action. When the break pin 18 and / or 19 is opened, the contents of the chamber 14 and / or 15 run down into the large chamber 10 and mix with the contents thereof.

In the manufacture of the container, a suitable solution is filled to the various chambers 10, 14 and 15 via inlet pipes 16, 17 and 22, which pass through the welds 20 and 21. A sampling port or infusion port 23 located through the weld joint 21 enables sampling from and infusion to the chamber 10¿ The solution in the chamber 10 is discharged to a patient via a line 24. The container is suspended in a stand via an opening 25 in the upper weld joint 20. The bag thus described is substantially identical to that shown by WO 97/05852.

The container is preferably of such a size that two liters of peritoneal dialysis solution can be accommodated in the large chamber 10 in a ready-mixed state. Larger or smaller containers are of course possible within the scope of the invention.

We have studied the transport of calcium across the peritoneal membrane as a function of time when installing a peritoneal dialysis solution containing glucose and different concentrations of calcium. Figures 2, 3 and 4 show the results for the glucose concentrations 1.5%, 2.5? or 4.0%. These diagrams show that the calcium transport is partly dependent on the concentration gradient across the membrane, but that the ultrafiltration also has an effect. A normal CAPD treatment means that the patient wears a PD solution for 4 hours and then switches to fresh PD solution. For such a PD solution to result in zero transport of calcium across the peritoneal membrane for 240 minutes, calcium concentrations of 1.2 mM, 1.6 mM and 2.3 mM, respectively, are required.

The calculations assume certain properties of the peritoneal membrane etc., and we believe that a calcium concentration that is mainly proportional to the glucose concentration results in a mainly calcium-neutral treatment, ie the calcium transport across the peritoneal membrane is mainly independent of the glucose concentration.

According to the present invention, this container 1 is to be used for preparing a peritoneal dialysis solution, in which the buffer consists of bicarbonate. The solutions in the different chambers can be as follows.

EXAMPLE 1 Chamber 10 contains 1900 ml with the composition: 40 mM 132 mM sodium bicarbonate sodium chloride Chamber 14 contains 100 ml with the composition: glucose 30% calcium chloride 20 mM magnesium chloride 5 mM sodium chloride 132 mM Chamber 15 contains 100 ml of the composition glucose 50% calcium chloride 8 mM sodium chloride 132 mM By mixing the contents of chamber 14 and chamber 10, a peritoneal dialysis solution is obtained with the following composition: (k) O (J) UT 512 549 8 glucose 1.5% calcium 1.0 mM bicarbonate 38 mM sodium 132 mM magnesium 0.25 mM.

By mixing the contents of chamber 15 and chamber 10, a peritoneal dialysis solution is obtained with the following composition: glucose 2.5% calcium 1.65 mM bicarbonate 38 mM sodium 132 mM - magnesium 0.4 mM. By mixing the contents of chambers 14 and 15 and chamber 10, a peritoneal dialysis solution having the following composition is obtained: glucose 4.0% calcium 2.5 mM bicarbonate 36 mM sodium 132 mM magnesium 0.6 mM.

In a second example of the invention, the contents of the small chambers have the same composition as follows: EXAMPLE 2 Chamber 10 contains 1950 ml of the composition: sodium bicarbonate 25 mM sodium lactate 15 mM sodium chloride 132 mM Chamber 14 contains 60 ml of the composition: 50% 33 mM glucose calcium chloride 5 15 20 25 512 549 8 mM 132 mM magnesium chloride sodium chloride Chamber 15 contains 100 ml of the composition glucose 50% calcium chloride 33 mM magnesium chloride 8 mM sodium chloride 132 mM In a further alternative embodiment of the present invention, solutions having the following compositions are used in the various chambers 10, 14 and 15.

EXAMPLE 3 Chamber 10 contains 1850 ml of the composition: sodium bicarbonate 27 mM sodium lactate 16 mM sodium chloride 132 mM Chamber 14 contains 150 ml of the composition: glucose 20% calcium chloride 13 mM magnesium chloride 3.2 mM sodium chloride 132 mM Chamber 15 contains 260 ml of calcium chloride 12.5 mM magnesium chloride 3.1 mM sodium chloride 132 mM Due to the dilution effect, the calcium concentration will be somewhat lower than in the first two examples.

To avoid problems with high pH values, the pH is adjusted to 7.2. the value in the large phase normally to a pH = pH value 10 -15 .512 349 10 the small chambers are usually laid about 3.0 to prevent glucose degradation during autoclaving.

When a patient uses a container according to the present invention, he will receive a calcium influx or outflow which is determined by the content of free calcium in the blood and the concentration of calcium in the reconstituted dialysis solution as well as by the glucose concentration. In the case of the highest glucose concentration, the net effect will be approximately the same as at the two lower degrees of concentration and the use of the container according to the invention will thus be substantially transparent to the patient.

The invention has been described above with reference to preferred embodiments of the invention. One skilled in the art will recognize that further combinations are possible. Such modifications obvious to a person skilled in the art are intended to be accommodated within the scope of the invention. The invention is limited only by the following patent claims.

Claims (6)

íl 10 15 20 25 30 512 349 U PATENTKRAV Container containing medical solution for peritoneal dialysis, consisting of a large chamber (10) with a volume large enough to contain the reconstituted medical solution, and at least two small chambers (14, 15), the solution, while the remaining part of the medical solution containing subsets of the medicinal is in the large chamber, the small chambers being selectively connected to the large chamber for mixing the contents of at least one of the small chambers with the contents of the large chamber for preparing said medical solution, characterized in that a first (14) of the small chambers contains glucose and calcium ions with such a concentration that the glucose concentration in the reconstituted solution becomes a first predetermined value, such as 1.5%, and the calcium ion concentration becomes a second predetermined value, such as 1 , 2 mM, a second (15) of the small chambers contains glucose and calcium ions with such a concentration that glucose concentration in the reconstituted solution becomes a third predetermined value, such as 2.5%, and the calcium ion concentration becomes a fourth predetermined value, such as 1.6 m, and (14) (15) of the small chambers can be mixed with the contents of the large chamber ( 10) higher concentrations of glucose and calcium ions. that the contents of the first and the second to form a ready-made solution with further Container according to Claim 1, characterized in that the glucose concentration is substantially proportional to the calcium ion concentration in the reconstituted medicinal solution. 10 15 20 25 30 512 349 I2 Container according to Claim 2, characterized in that the small chambers (14, 15) contain solutions with the same concentration of glucose and calcium, but with different volumes. Container according to any one of the preceding claims, characterized (14, 15) ions, for example with a concentration such that the result of the small chambers further containing the magnesium concentration in the reconstituted medical solution is about 0.25 - 0.75 mM . A process for preparing a medical solution for peritoneal dialysis, in a container consisting of a first large chamber with a volume large enough to contain the reconstituted medical solution, and at least two small chambers containing subsets of the medical solution. , while the remaining part of the medical solution is in the large chamber, the small chambers being selectively connected to the large chamber for mixing the contents of at least one of the small chambers with the contents of the large chamber for preparing said medical solution, characterized that the large chamber contains bicarbonate ions and the small chambers contain glucose and calcium ions, and that the contents of one or more of the small chambers are mixed with the contents of the large chamber to provide a medical solution where the concentration of glucose is substantially proportional to the concentration of calcium ions. Use of a container according to any one of claims 1 to 4 for the preparation of a peritoneal dialysis solution where the concentrations of glucose and calcium ions are substantially proportional to each other in the reconstituted peritoneal dialysis solution, the glucose concentration being between about 1.5%. and about 4% and the calcium ion concentration is between about 1.0 mM and about 2.5 mM in the reconstituted peritoneal dialysis solution.