EP0077354A1

EP0077354A1 - Dialysis solution containing glucose, amino acids & insulin

Info

Publication number: EP0077354A1
Application number: EP82901271A
Authority: EP
Inventors: Robert K. Ausman
Original assignee: Baxter Travenol Laboratories Inc
Current assignee: Baxter International Inc
Priority date: 1981-04-27
Filing date: 1982-03-25
Publication date: 1983-04-27
Also published as: ZA822608B; IT1151741B; CA1168582A; JPS58500563A; IT8220921A0; WO1982003773A1; EP0077354A4

Abstract

Une solution medicale destinee a etre administree a des patients, et d'une maniere caracteristique une solution de dialyse peritoneale, consiste en une solution aqueuse dans laquelle sont presents des sels physiologiques en concentration suffisante pour avoir une compatibilite osmotique avec le sang. Pour un effet osmotique accru et aussi a des fins de nutrition, un melange d'acides amines, de preference comprenant des acides amines essentiels, de l'insuline et de preference une source de nutrition carbohydratee peut etre present dans des proportions suffisantes pour ameliorer l'assimilation des acides amines et de la source carbohydratee par un patient diabetique, par exemple, ou d'autres patients.A medical solution intended to be administered to patients, and typically a solution for peritoneal dialysis, consists of an aqueous solution in which physiological salts are present in sufficient concentration to have osmotic compatibility with the blood. For an increased osmotic effect and also for nutritional purposes, a mixture of amino acids, preferably comprising essential amino acids, insulin and preferably a source of carbohydrate nutrition may be present in proportions sufficient to improve the assimilation of amino acids and carbohydrate source by a diabetic patient, for example, or other patients.

Description

DIALYSIS SOLUTION CONTAINING GLUCOSE, AMINO ACIDS & INSULIN

Technical Field At the present time thousands of patients who have lost or compromised kidney function from end stage renal disease are being maintained by a dialysis procedure. While many are maintained by hemodialysis/ others are maintained by a medical procedure known as peritoneal dialysis, for example continuous ambulatory peritoneal dialysis (CAPD), disclosed in U.S. Patent No. 4,239,041. This latter technique is rapidly growing in clinical acceptance as the technique of choice for maintaining many patients with lost or compromised kidney function. In the CAPD procedure, peritoneal dialysis solution is inserted into the peritoneal cavity, whereby diffu¬ sion exchange takes place between the solution and the bloodstream across the natural body membranes, to remove by diffusion the waste products which are normally ex- creted through the kidneys, typically solutes such as sodium and chloride ions, and other materials normally excreted by the body such as urea and creatinine, and also water.

The nature and rate of the materials removed from the body by peritoneal dialysis is a function of the sol¬ utes present in the peritoneal dialysis solution. Phy¬ siological salts are present in the peritoneal dialysis solution, such as sodium chloride, sodium lactate, and sodium acetate, generally at slightly hypotonic concen- trations (but for calcium) so that excess concentrations of the ions forming such salts in the bloodstream will diffuse into the peritoneal dialysis solution for removal.

Background Art

To remove water from the patient, as is generally necessary, other solutes may be added to generate the nec¬ essary osmotic pressure. In typical peritoneal dialysis solutions, this solute is a sugar such as glucose, which may normally be present in peritoneal dialysis solutions in a concentration of about 0.5 to 4.25 percent by weight. When it is desired to accelerate the ultrafiltra ion of

10 water from the patient, higher concentrations of sugar in this range are used.

However, as a disadvantage of this system, during the peritoneal dialysis process, as water diffuses into the peritoneal dialysis solution, sugar present in the

3-5 peritoneal dialysis solution diffuses into the bloodstream to a significant extent. Accordingly, while the system is safe and effective for increasing the ultrafiltration dur¬ ing peritoneal dialysis, the patient receives a heavy dose of calories during each peritoneal dialysis procedure from

²⁰ the sugar diffusing into his bloodstream. In many in¬ stances, this high calorie dose is undesired, as it can result in weight gain and fat, as well as increased serum lipids. Particularly in the case of diabetics, the trans¬ port of significant quantities of sugar such as glucose

" from the peritoneal dialysis solution into the patient's bloodstream can create complications in the medical main¬ tenance of the patient.

The ingredients of the solution of this invention are all individually known as ingredients of parenteral

30 solutions, although not all of them have been used as ingredients in dialysis solutions. For example, on page 812 of the October 12, 1968 issue of The Lancet, a preliminary communication from John Jessing reports the addition of amino acids to dialysis fluids in pa¬

35 tients under regular peritoneal dialysis regimens. As

O^FI stated therein, "most amino acids are easily absorbed by the peritoneum". However, difficulties can be encount¬ ered in the assimilation of free amino acids which pass across the peritoneal membrane or some other membrane to enter the bloodstream. It is known that chronically high levels of_amino acids in the bloodstream can be toxic, and persons with end stage renal failure cannot excrete excess serum amino acid concentrations through the kid¬ neys. Accordingly, while it is known that many persons in renal failure have a chronically negative nitrogen balance, the problem is not necessarily simply solved by adding amino acids to the dialysis solution to cause the amino acids to migrate into the bloodstream.

Similarly, particularly in the case of the 25 per- cent of end stage renal patients who are diabetics, their maintenance with a peritoneal dialysis regime can be difficult, and can have significant side effects in view of the relatively high glucose concentration that has in the past been placed in peritoneal dialysis solu- tion, to increase the osmolarity for purposes of removing water from the patient. The glucose migrates into the bloodstream of the patient, causing the problems described above.

In accordance with this invention, the addition of insulin to the solution provides benefits relating to both the metabolizing of glucose, and also the assimila¬ tion of amino acids into the cells to form a protein. While these are known functions of insulin, it has not been previously used as a combined ingredient in a dialy- sis solution to simultaneously facilitate the metabolizing of amino acids and glucose or other sugar by the patient.

As the result of this, measured amounts of amino acids and glucose or other sugar may be used in the peritoneal dialysis solution, initially for the purpose of increasing the osmolarity of the solution so that ultrafiltration of water may take place from the patient during the dialysis procedure. Following this, the insulin serves to facilitate the metabolizing of glucose and amino acids which diffuse from the dialysis solution into the bloodstream of the patient. The amount of insulin required can be predetermined beforehand, depending upon the concentrations of amino acids and sugar present, so that a premeasured solution may be provided for a dialysis procedure, for the combined benefits of dialyzing uremic patients who are diabetic and protein starved, so that the patients receive the optimum amount of insulin to f cilitate their metabolism of the amino acids and sugar provided, without the need in the case of diabetic patients to recalculate their normal administra¬ tion schedule of insulin. Also, less sugar may be used, being partly or completely replaced by amino acids.

Disclosure of Invention

In accordance with this invention, a medical solution is provided for administration to patients, typically for use as a dialysis solution. It comprises a water solution having the presence of physiological salts in sufficient concentration to be osmotically compatible with blood. There is also included a mixture of physiological amino acids, and optionally a source of carbohydrate nutrition such as glucose is present. There is also added insulin in proportions sufficient to permit the substantial assimilation of both the source of carbohy¬ drate nutrition when present, and amino acids by a dia¬ betic or other type of patient. If desired, other sugars such as fructose may be used as an equivalent substitute for glucose. Also glucose polymers and the like, or a sugar alcohol such as glycerol may be used as the source of carbohydrate nutrition. The term "glucose" as used below is intended to include these equivalent materials as alternatives. The solution is particularly contemplated for use as a peritoneal dialysis solution where a relatively high osmolarity is desirable to stimulate ultrafiltration of water from a patient, but it may also be used as an intra- venous nutrient solution or a he odialysis solution.

Initially, the mixture of glucose and amino acids serves as an osmolarity-promoting agent to provide higher ultrafiltration. During the dialysis process, the amino acids, glucose, and insulin diffuse into the bloodstream of the patient. There, the glucose and amino acids pro¬ vide nutrition to the patient, with the assimilation of the glucose and amino acids being facilitated by the presence of insulin to help reverse the typically negative nitrogen balance found in persons in renal failure while treated under prior art procedures.

The solution also assists in the management of diabetic patients, since the premeasured amount of insulin present in the medical solution facilitates the assimila¬ tion of the glucose present without the diabetic patient having to change the normal regime of his prescribed dosage of insulin taken conventionally. Alternatively, the patient's entire insulin requirements can be taken care of by the insulin in the solution of this invention, if desired, to reduce the numbers of injections that the patient must subject himself to in the instance that the patient is engaging in a continuous and daily regime of CAPD, with several changes of dialysis solution being made every day.

The solutions of this invention may be premixed, typ- ically with a separate sterilization of different solution portions containing respectively the glucose and amino acids in a separate, interconnected container system, followed by mixing without breaching the sterile conditions of the system. This avoids the known incompatability problems encountered on sterilizing a mixture of sugar

^Q---FI and amino acids.

Alternatively, the glucose and amino acid solutions may be separately sterilized in separate containers, and then brought together by the use of a sterile connector system similar to that shown in U.S. Patent No. 4,157,723 or the like, providing a reliably sterile connection per¬ mitting the sterile mixing of the two solutions to form the medical solution of this invention.

As a further alternative, separate aliquots of glucose and amino acid solutions may be premixed shortly before infusion under conditions which are substantially aseptic although not necessarily completely sterile.

Preferably, from 0.5 to 4 grams per liter of glucose or an equivalent material may be present in the solution of this invention, in conjunction with from 1 to 4 grams per liter of a mixture of amino acids preferably containing at least 50 percent by weight of essential amino acids, optionally including other nonessential amino acids as may be desired. For example, the mixture of amino acids found in Travasol® amino acid solutions sold by Travenol Laboratories, Inc. of Deerfield, Illinois may be utilized to formulate the solutions of this invention, or any other available mixture of amino acids for parenteral administration may be used. Added to this may preferably be 1 to 10 units of insulin per liter of solution for the beneficial purposes described above.

The term "amino acids" is intended to include suitable short-chain polypeptides as equivalent substitute materials for the free amino acids. Typically, the concentration of glucose can be re¬ duced in this manner from a typical high glucose concen¬ tration of up to 4.25 percent as found in prior art solutions, while the osmolarity of the solution can remain elevated because of the presence of the amino acid. Thus a dialysis solution, having the desired high osmolarity coupled with a better nutrient mix for the patient, may be provided in which the nutrients are better assimilated or metabolized by the patient because of the presence of the insulin.

Preferably, the medical solution of this invention may comprise a water solution at a pH of 5.0 to 7.4, con¬ taining from 130 to 140 mEq/liter of sodium, 100 to 140 mEq/liter of chloride, 0 to 6 mEq/liter of calcium, 0 to 4 mEq/liter of magnesium, and, if desired, other ions, for example, 30 to 40 mEq/liter of bicarbonate precursors such as one or more of lactate, acetate, malate, and/or succinate ions.

The above ions may be provided by the addition of conventional physiological salts such as sodium chloride, calcium chloride, sodium lactate, sodium acetate, and traces of other salts such as potassium chloride, magne¬ sium chloride, and the like, added in accordance with the known requirements for proper ion balance in a dialysis solution.

It is generally preferable for the osmolarity of the solutions of this invention to be from 272 to 700 milliosmols per liter, preferably 279 to 480 milliosmols per liter. The bicarbonate precursor acid ions mentioned above, as well as other acid ions of the Krebs cycle, may be added to also offer advantages in pH control of the peri¬ toneal dialysis solution of this invention. The sodium or potassium salts of such ions, for exmaple, may be used for this purpose, or the free acids.

Sulfhydryl-type antioxidants, for example N-acyl cysteine, may be also added to stabilize the amino acids in the peritoneal dialysis solution of this invention. Description of Preferred Embodiment

Preferably, a peritoneal dialysis solution in ac¬ cordance with this invention may be provided by adding, per liter of water, 5.55 grams of sodium chloride, 3.92 grams of sodium lactate, 0.257 gram of calcium chloride dihydrate, 0.152 gram of magnesium chloride hexahydrate, 1 gram of glucose, 3.25 grams of a mixture of essential and other amino acids, and 3 units per liter of insulin. ^■

As stated above, the various components of the solu- tions may be broken down into two solutions with the glu¬ cose being in one portion and the amino acids in the other, for separate sterilization. Each of the solutions may be in a conventional flexible, collapsible container con¬ nected by tubing and sealed with any desired internal tubing seal, so that the solution may be separately ster¬ ilized. Thereafter, the internal tubing seal may be broken and the solutions may be joined together into the single solution of this invention without disruption of the ster¬ ile seal of the solution. The solution container ultimately used to store the mixed, sterile solution of this invention may be stored in a container of the design illustrated, for example, in U.S. Patent No. 4,232,721, being made out of a substantially polypropylene plastic. The connection tube to the other container may be heat-sealed shut and severed after mix¬ ing of the containers in conventional manner.

The above has been offered for illustrative purposes only, and is not intended to limit the scope of this present invention, which is as defined in the claims below.

Claims

THAT WHICH IS CLAIMED IS;

1. A medical solution for administration to pa¬ tients which comprises a water solution having physio¬ logical salts in sufficient concentration to be osmo- tically compatible with blood, a mixture of physiological amino acids, and insulin in proportions sufficient to permit the substantial assimilation of said amino acids by a patient.

2. The medical solution of Claim 1 which also in- eludes a source of carbohydrate nutrition.

3. The solution of Claim 2 which is a peritoneal dialysis solution.

4. The solution of Claim 3 in which said source of carbohydrate nutrition is glucose.

5. The solution of Claim 3 in which said source of carbohydrate nutrition is glycerol.

6. The solution of Claim 3 which contains from 0.5 to 4 grams per liter of said source of carbohydrate nutrition, from 1 to 4 grams per liter of a mixture of physiological amino acids, and from 1 to 10 units of insulin.

7. The solution of Claim 3 which contains from

130 to 140 mEq/liter of sodium, from 100 to 140 mEq/liter of chloride, from 0 to 6 mEq/liter of calcium, and from 0 to 4 mEq/liter of magnesium.

8. The solution of Claim 3 which contains from 30 to 40 mEq/liter of at least one type of bicarbonate precursor ion selected from the group consisting of lactate, acetate, alate, and succinate.

9. The solution of Claim 3 which has an osmolarity of 272 to 700 milliosmols.

10. The solution of Claim 3 which has a pH of 5.0 to 7.2.

11. The solution of Claim 3 which contains an amount of a sulfhydryl-type antioxidant such as N-acyl cysteine sufficient to improve the stability of the amino acids present.