Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-06-13
2001-11-27
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06323182
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a concentrate for preparing a medical solution, such as a dialysis solution intended for hemodialysis, hemodifiltration, hemofiltration or peritoneal dialysis. More particularly, the present invention relates to a concentrate comprising glucose and an acid.
BACKGROUND OF THE INVENTION
A concentrate may be a solution in water of one or more substances, which solution is intended to be diluted with water in a desired ratio, such as 1:35.
A concentrate may alternatively be in powder form, for example comprising sodium bicarbonate in powder form, which concentrate is intended to be dissolved in water, and then diluted. Such dissolution may take place in a separate process, so that all of the powder is dissolved before dilution. The dissolution may also take place on-line by passing water through a bed of powder in order to produce a solution to then be diluted. The powder can be a single component, such as sodium bicarbonate or sodium chloride, or a mixture of components, such as sodium chloride, potassium chloride, magnesium chloride, calcium chloride, etc.
It is conventional during hemodialysis to prepare the dialysis solution in situ by mixing one or more concentrates with water in a dialysis machine. The dialysis machine controls the mixing so that the correct composition of the prepared dialysis solution is attained.
A dialysis machine is described in European Application No. 278,100 for the preparation of a dialysis solution starting from one or more concentrates in powder form and one or more concentrates in liquid form. The concentrates are diluted with pure water obtained from a water purifier, such as an RO-unit (reverse osmosis unit)
The dialysis machine prepares a dialysis solution comprising sodium, bicarbonate, potassium, calcium, magnesium, chloride and acetate ions in suitable concentrations, as well as possibly glucose and other ions, all being dissolved in water. The concentrations of the ions in the dialysis solution are generally mirror images of the corresponding concentrations in blood, where the mirror line is the normal concentration of the ions in blood. Thus, if an ion concentration is increased in the blood over the normal concentration, the ion concentration in the dialysis solution is decreased in relation to the normal concentration. The pH of the solution is adjusted to about 7.1 to 7.4. A typical composition of the dialysis solution is the following:
sodium ions
130-150 mM
bicarbonate ions
20-40 mM
potassium ions
2-5 mM
calcium ions
0-5 mM
magnesium ions
0-5 mM
glucose
0-0.2%
acetate ions
3-4 mM
(as well as chloride ions)
As is apparent from the above table, in addition to pure water, there are two substances which are present in the prepared dialysis solution in large quantities, namely sodium ions and bicarbonate ions. In the above-mentioned publication, European Application No. 280,100, at least one of these bulk substances is provided by the machine, starting from powder concentrate provided in one or more columns.
The remaining substances are supplied from a fluid concentrate which primarily comprises potassium, calcium and magnesium ions, and possibly glucose. This concentrate further comprises an acid to balance the pH value for the bicarbonate so that the final dialysis solution has a physiological pH value of about 7.1 to 7.4. Normally, acetic acid (acetate ions) is used. Since these substances are present in relatively small quantities, the solution can be very concentrated.
A concentrate is described in European Application No. 613,688 having a degree of concentration of between about 1:120 and 1:250, i.e. it is intended to be diluted with water in that ratio. It is said to comprise sodium chloride, potassium chloride, calcium chloride, magnesium chloride, hydrochloric/acetic acid and glucose. The concentrate is to be combined with a basic concentrate, which comprises the two substances which are present in large quantities, namely sodium and bicarbonate ions, derived from sodium chloride, and sodium bicarbonate. Moreover, the basic concentrate comprises sodium acetate. Sodium acetate is described as being mixed in the basic concentrate because the addition of sodium acetate prevents precipitation of bicarbonate by complex formation between acetate and bicarbonate ions. The highly concentrated concentrate is used as a treatment individualisation concentrate. This is possible since the concentrate is used in small quantities, normally less than about one liter per treatment. Many different compositions of the individualisation concentrate can be stored in a limited storage space. The highly concentrated concentrate has a very high salt concentration (ionic strength) and is viscous.
During experimentation with a highly concentrated concentrate having a degree of concentration of 1:400, comprising, among other things, glucose and 1200 mM (mmole/liter) acetic acid (undiluted), we discovered that, after one week's storage, the acetate ion concentration was reduced markedly; i.e., by more than 5%. Accordingly, the concentrate did not comply with the information on the label that it contained 3 mM (mmol/l) acetate after dilution in the ratio of 1:400 and with a margin of error of ±5%. In addition, the reduction in the acetic concentration indicated that some other substance had formed, probably by reaction with, or through decomposition of, glucose. Such substance may have an influence upon the patient who is undergoing dialysis.
During continued experiments, it appeared that there is probably an interaction or reaction between acetic acid and glucose causing the reduction in acetate concentration and also of glucose concentration. Accordingly, the concentration of acid was reduced during storage, which may result in raising the pH value of the final prepared solution to an unacceptable level.
The concentration values which are present in the concentrate are about 1.2 M acetic acid (or another acid) and about 2.2-4.4 M glucose at a concentration of 1:400, which results in 3 mM acetic acid and 0.1-0.2% glucose in the finally prepared dialysis solution.
One object of the present invention is to provide a concentrate for dilution with a medical solution, in which the acid concentration is not reduced during storage.
Another object of the present invention is to provide a concentrate for a medical solution which lacks acetate ions, since a great number of patients have developed intolerance to acetate ions.
Yet another object of the present invention is to provide a concentrate for a medical solution, comprising a physiologically acceptable aid for replacing the conventionally used acetic acid.
SUMMARY OF THE INVENTION
In accordance with the present inventions, these and other objects have now been realized by the invention of a concentrate for use in the preparation of an infusion solution comprising gluconic acid and glucose in amounts such that upon dilution with an aqueous solution in a ratio of at least about 1:150 the concentration of the gluconic acid is at least about 600 mmol/l and the concentration of the glucose is at least about 150 g/l. In a preferred embodiment, the gluconic acid and glucose are present in amounts such that upon dilution with an aqueous solution in a ratio of at least about 1:200 the concentration of the gluconic acid is at least about 800 mmol/l and the concentration of the glucose is at least about 200 g/l. In a most preferred embodiment, the gluconic acid and glucose are present in amounts such that upon dilution with an aqueous solution in a ratio of at least about 1:400, the concentration of the gluconic acid is at least about 1600 mmol/l and the concentration of the glucose is at least about 400 g/l.
In accordance with a preferred embodiment of the concentrate of the present invention, the infusion solution comprises a dialysis solution for use in hemodialysis, hemodiafiltration, hemofiltration or peritoneal dialysis.
In accordance with another preferred embodiment of the concentrate of the present invention, the concentrate is
Jonsson Lennart
Knutsson Stefan
Linden Torbjörn
Picard Robert
Gambro AB
Lerner David Littenberg Krumholz & Mentlik LLP
Peselev Elli
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