EP0076841A4

EP0076841A4 - Improved solution for parenteral nutrition.

Info

Publication number: EP0076841A4
Application number: EP19820901484
Authority: EP
Inventors: Robert C Tao; Norman N Yoshimura
Original assignee: American Hospital Supply Corp
Current assignee: American Hospital Supply Corp
Priority date: 1981-04-17
Filing date: 1982-04-12
Publication date: 1984-01-16
Also published as: IT8248250A0; EP0076841A1; IT1147849B; JPS58500526A; WO1982003552A1

Abstract

Parenteral solution comprising pharmacologically acceptable nutritionally effective amounts of amino acides and electrolytes including calcium and phosphate ions, along with a polyhydric alcohol which provides a source of energy and prevents precipitation of calcium phosphate.

Description

IMPROVED SOLUTION FOR PARENTERAL NUTRITION

Background of the Invention

The present invention relates to a solution suitable for administration to patients who require parenteral nutrition. In particular, the invention relates to a parenteral solution comprising pharmacologically acceptable amounts of amino acids and electrolytes, including calcium and phosphate, along with a polyhydric alcohol which provides a source of energy and prevents precipitation of calcium and phosphate. More particularly, the present invention relates to a solution containing pharmacologically acceptable nutritionally effective amounts of amino acids and electrolytes and sufficient polyhydric alcohols and their derivatives selected from the group consisting of glycerol, sorbitol and xylitol, and combinations thereof, to prevent precipitation of calcium phosphate.

Certain patients must receive all or most of their nutrition parenterally because of medical or surgical dysfunction of the gastrointestinal tract or in keeping with a physician's prescription. Such patients are temporarily incapable of ingesting protein, carbohydrates, fats, vitamins and other nutrients and must turn to endogenous sources and to nutrients provided parenterally for survival. One problem encountered with patients receiving parenteral nutrition is that the body begins to use endogenous sources of protein and fat, although the patients are on a parenteral diet which should be sufficient to prevent starvation.

Various solutions have been proposed for providing parenteral nutrition. Most solutions are extemporaneously mixed prior to administration due to incompatibilities of amino acids, reducing sugars, fat, and electrolytes. It is desirable to administer the essential elements, calcium and phosphorus (phosphate) to patients receiving parenteral nutrition. However, due to their tendency to form calcium phosphate and precipitate out of solution, it has been necessary to alternate solutions containing calcium with those containing phosphate to avoid precipitation. The tendency to form calcium phosphate is enhanced when the solution is sterilized with steam. Steam sterilization is preferred because of its ease and reliability. However, when parenteral solutions containing amino acids and reducing carbohydrates such as glucose are steam sterilized, an undesirable browning effect occurs. It has surprisingly been discovered that the use of a polyhydric alcohol, such as glycerol, xylitol or sorbitol, or combinations thereof, as the energy source in parenteral solutions containing amino acids, electrolytes, calcium and phosphate, provides a solution which can be steam sterilized without the precipitation of calcium phosphate and without the browning effect.

In Cuthbertson, D.B., "The Disturbances of Metabolism Produced by Bony and Nonbony Injury, with Notes on Certain Abnormal Conditions of Bone," BIOCHEM. J., 24: 1244 (1930), it was first reported that there was a marked loss of nitrogen, phosphorus and sulfur in young men suffering from long bone fractures who were on a diet presumed adequate to maintain balance. Since that time, loss of nitrogen following trauma, elective operation, sepsis and burns, in excess of that expected under normal conditions with an equivalent caloric balance, has been confirmed by others. It is believed that the increase in nitrogen excretion after injury reflects the mobilization of amino acids to meet increased demands for metabolic fuels. Moore, F. D., "Bodily Changes During Surgical Convalescence," ANN. SURG., 137:289 (1953), using serial measurements of body composition, concluded that the tissue loss during surgical convalescence is approximately half fat and half lean body mass by weight.

It is known that severe loss of nitrogen accompanying severe weight loss during trauma, sepsis, disease, injury or other illness is a major contributor to morbidity and mortality in patients [See Studley,

H. D., JAMA, 106:458, and Taylor μ Keyes, ANN. N.Y. ACAD. SCI., 73:465 (1958)]. Because of this problem various attempts have been made to avoid starvation in patients unable to take nutrients orally for extended periods of time. Such patients are usually treated by infusion of parenteral fluids, typically receiving from 200 to 600 Kcal/day in the form of glucose (carbohydrate), thereby avoiding complete starvation. It is recognized that glucose, in addition to providing some substrate for oxidation, reduces the urinary excretion of nitrogen and therefore the overall catabolism of labile protein by nearly 50 percent, and further reduces or prevents starvation ketosis (See Schwartz, ed., "Principles of Surgery," McGraw Hill, N.Y. 1969, pp.77-81). Thus investigators have sought to prevent starvation by the administration of parenteral fluids containing carbohydrate, typically glucose.

To further diminish nitrogen losses, which reflect decreases of the lean body mass, it is customary to parenterally administer amino acids in combination with other substrates to meet the energy requirements (carbohydrates).

Due to the recognition that excessive nitrogen loss is detrimental and possibly fatal, there has been a continuing search for a method of treatment that would minimize nitrogen loss further or even eliminate it in patients receiving parenteral nutrition.

Intravenous amino acid solutions are administered clinically to patients requiring intravenous nutrition. They are usually administered along with glucose, fat, electrolytes, and vitamins. Coπmercial intravenous amino acid solutions are formulated in accordance with the amino acid requirements of man as delineated by William C. Rose and associates. [See Rose, FED. PROC. 8, 546 (1949); Rose et al., J. BIOL. CHEM., 217, 987 (1955).]

U.S. Pat. No. 3,920,838 discloses a method of treatment of patients during periods of severe negative caloric balance due to dysfunction or disuse of the gastrointestinal tract. The method is based on the parenteral application of amino acids while substantially withholding the patient's intake of carbohydrates. The elimination of carbohydrates allows for the development of starvation ketosis in the patient, thus facilitating the utilization of fat stores and substantially reducing or even eliminating net nitrogen losses.

In addition to a carbohydrate source and amino acids, it is desirable that patients requiring parenteral nutrition receive certain vitamins and minerals necessary to maintain health. When protein conservation regimens are undertaken, it is of physiological importance to maintain normal extracellular and intracellular concentrations of the major electrolytes. Thus it is desirable to add adequate amounts of sodium, potassium, magnesium, calcium, and phosphate to the parenteral solution [See Ballinger, W. F., ed., "Manual of Surgical Nutrition," pp. 296-305, W. B. Saunders Co., Philadelphia, Pennsylvania (1975).]

When calcium salts are added to solutions containing phosphate, precipitation may occur either immediately or upon long-term storage. Immediate precipitation can sometimes be avoided by thorough mixing and by avoiding the consecutive addition of calcium and phosphate to the mixture. Ballinger discloses that, where sodium or potassium glycerophosphate and calcium gluconate or heptonate are available for clinical parenteral use, precipitation problems can be avoided. This is because the phosphate radical is covalently bound to the organic moiety in the solution until biochemical cleavage occurs in the liver or other tissues (Ballinger et al., p. 299).

Certain non-metabolizable chelating agents which prevent precipitation of calcium phosphate are ethylenedi amine tetra acetic acid (as its salts), water soluble polyethylene glycols, ethyl eneglycoldi acetic acid (as its salts) and saccharate salts. However, use of these compounds is undesirable since they cannot be metabolized and may have unwanted side effects if used in the quantities necessary to maintain sufficient amounts of calcium and phosphate in solution.

J. M. Culebras et al., in SURGICAL FORUM, 62nd Annual Clinical Congress, American College of Surgeons, p. 37 (1976), disclose that glycerol exhibits a nitrogen sparing effect when administered intravenously in combination with amino acids. U.S. Patent No. 3,793,450 discloses that glycerol and other polyalcohols such as sorbitol and xylitol may be used as an osmotic agent in intravenously administered aqueous fat emulsions containing amino acids. These compounds improve the stability of the fat emulsions containing amino acids.

Glycerol, a three-carbon polyalcohol, has been used intravenously in patients with cerebral infarction [J. S. Meyer et al., CIRCULATION,

51: 701:712 (1975)] and for reducing intracranial pressure during brain surgery [K. Hagnevik et al., LANCET, Jan 19, pp. 75-77 (1974)].

In recent years, the application of fat emulsions containing glycerol in parenterai nutrition has been advocated to be an effective and relatively safe means to provide part of the caloric needs of patients

(see Symposium, "The Use of Fat Emulsion in Parenteral Nutrition," sponsored by the American Society of Parenteral and Enteral Nutrition,

Chicago, Illinois, October 10, 1976). Glycerol has the following advantages when used in combination with the amino acids to promote protein sparing: It is (1) gluconeogenic and inhibits gluconeogenesis from amino acids, (2) insulinogenic to a small degree, (3) antiketotic, (4) chemically compatible with amino acids, and (5) higher in caloric density than dextrose. None of the above references discloses that calcium and phosphate may be administered together without precipitation problems when glycerol is used as the energy source in parenterai solutions.

Heretofore, it was necessary to alternate solutions of amino acids containing calcium with those containing phosphate in order to avoid precipitation. It is known that xylitol and sorbitol may be used as energy sources in parenteral solutions (Ballinger et al., p. 22); however, it has surprisingly been discovered that the use of polyhydric alcohols, such as glycerol, sorbitol and/or xylitol, as energy substrates permits calcium and phosphate to be incorporated in the same solution without the precipitation, which usually occurs, of calcium phosphate.

Another problem associated with parenteral solutions incorporating glucose as the carbohydrate source is the intense browning or Maillard reaction which occurs in concentrated carbohydrate/ amino acid or carbohydrate/protein hydrolysate mixtures when they are steam sterilized. By replacing glucose with glycerol or other polyhydric alcohols or their derivatives, the parenteral solution can be steam sterilized without the occurrence of a browning effect, and it has been shown to be stable with no precipitation of calcium phosphate for at least 18 months at room temperature and at 40°C. Storage of an identical formulation without the glycerol or polyhydric alcohol or their derivatives eventually precipitates calcium phosphate.

In accordance with the present invention, solutions are disclosed herein which contain pharmacologically acceptable nutritionally effective amounts of amino acids and electrolytes, which include calcium and phosphate ions, and sufficient polyhydric alcohol selected from the group consisting of glycerol, sorbitol and xylitol, to prevent precipitation of calcium phosphate, wherein the improvement comprises retaining in solution calcium and phosphate ions in pharmacologically acceptable nutritionally effective amounts.

Detailed Description of the Invention The present invention relates to a novel solution suitable for administration to patients who require parenteral nutrition. Additionally, this invention relates to a solution containing a complete amino acid and electrolyte pattern including calcium and phosphate along with a polyalcohol energy source, such as glycerol, xylitol or sorbitol, or combinations thereof, which is suitable for administration to patients who require intravenous nutrition. More particularly, the present invention relates to a solution containing pharmacologically acceptable nutritionally effective amounts of amino acids and electrolytes which include calcium and phosphate ions, and sufficient polyhydric alcohol selected from the group consisting of glycerol, sorbitol and xylitol, and combinations thereof, to prevent precipitation of calcium phosphate, wherein the improvement comprises retaining in solution calcium and phosphate ions in pharmacologically acceptable nutritionally effective amounts. In a preferred embodiment of the invention, the solution contains pharmacologically acceptable nutritionally effective amounts of essential and non-essential amino acids, glycerol, and electrolytes, including calcium and phosphate. Pharmacologically acceptable amounts refers to amounts which are not toxic. Nutritionally effective amounts refers to amounts which will promote health and well-being. These amounts may vary depending on the purpose for which the solution is administered.

The solution preferably contains 2.5 to 13 percent weight/volume of L-amino acids and/or their organic and inorganic salt equivalents, the major intra- and extracellular electrolytes in concentrations sufficient for maintenance of normal values, and 2 to 10 percent glycerol, a metabolizable antiketotic energy substrate chemically compatible with amino acids, which acts as a stabilizing agent for the chemically incompatible calcium and phosphate ions. In addition to stabilizing amino acid solutions, glycerol is unique in that it is antiketotic; that is, it prevents patients from becoming ketotic when metabolizing amino acids alone or amino acids and fat. Antiketotic compounds other than glycerol which stabilize calcium and phosphate and prevent metabolic ketoacidosis are the polyhydric alcohols sorbitol and xylitol, which may be used in place of or in combination with glycerol.

The concentrations of the ingredients of the present solution may vary depending on the purpose for which the solution is administered. The following concentration of amino acids, electrolytes and polyhydric alcohol energy substrates are acceptable for the purposes of the present invention:

Compound g/l

L-Methionine 1.07 8.32 L-Isoleucine 1.40 10.92 L-Leucine 1.80 14.04 L-Phenylalanine 1.13 8.84 L-Valine 1.33 10.40 L-Threonine 0.80 6.24 L-Lysine 1.47 11.44 L-Alanine 1.41 - 11.02

L-Arginine 1.93 - 15.08

L-Histidine 0.57 - 4.42

L-Proline 2.27 - 17.68

L-Serine 1.20 - 9.36

Amino Acetic Acid 2.80 - 21.84

L-Tryptophan 0.31 - 2.39

L-Cysteine HCl H₂O 0.03 - 2.50

Sodium Acetate 3 H₂O 1.94 - 2.14

Magnesium Acetate 4 H₂O 0.50 - 0.58

Calcium Acetate 0.244 - 0.284

Sodium Chloride 1.11 - 1.23

Potassium Chloride 1.42 - 1.56

Potassium Metabisulfite 0.55

Energy Substrates 20 - 300

Glycerol, or Sorbitol, or Xylitol, or combinations thereof, provided that the concentration of any one energy substrate does not exceed 100 g/l Phosphoric Acid 85% 0.212 0.264 ml

Glacial Acetic Acid pH Adjustment

Water for Injection q.s.

In a preferred embodiment of the present invention, the solution has the following composition:

Compound g/l

L-Methionine 1.28 _ 1.92

L-Isoleucine 1.68 - 2.52

L-Leucine 2.16 - 3.24

L-Phenylalanine 1.36 - 2.04

L-Valine 1.60 - 2.40

L-Threonine 0.96 - 1.44

L-Lysine 1.87 _ 2.53 L-Alanine 1.70 - 2.54

L-Arginine 2.32 - 3.48

L-Histidine 0.68 - 1.02

L-Proline 2.72 - 4.08

L-Serine 1.44 - 2.16

Amino Acetic Acid 3.00 - 5.04

L-Tryptophan 0.37 - 0.55

L-Cysteine HCl H₂O 0.03 - 0.30

Sodium Acetate 3H₂O 1.94 - 2.14

Magnesium Acetate 4H₂O 0.50 - 0.58

Calcium Acetate 0.244 - 0.284

Sodium Chloride 1.11 - 1.23

Potassium Chloride 1.42 - 1.56

Potassium Metabisulfite 0.55

Glycerol 20 - 100

Phosphoric Acid 85% 0.216 - 0.264 ml

Glacial Acetic Acid pH Adjustment

Water for Injection q.s.

In a particularly preferred embodiment of the invention, the concentration of glycerol in the above solution is 30-90 g/l.

The formulations of this invention may include both essential and non-essential amino acids, but the inclusion of some non-essential amino acids, including but not limited to aspartic acid, glutamic acid, ornithine, asparagine, glutamine, tyrosine and taurine, is desirable.

The amino acids used in practicing the present invention are preferably pure crystalline amino acids. In general, the amino acids should be in their L-form, rather than the D-form or a mixture of D and L. Also, in general, the amino acids are employed as free amino acids, but can be amino acid salts or derivatives. For example, L-lysine acetate may be used, and derivatives of L-tyrosine which are converted to tyrosine in the body may also be used.

Optionally, part of the L-methionine in the present invention may be replaced by D-methionine, a mixture of EL-methionine being used on an equivalent basis to L-methionine. D-Methionine has approximately 75% of the nutritional value of L-methionine, and this percentage can be used to determine the desirable equivalent range for a mixture of DL-methionine. However, it is preferred to employ only L-methionine. In addition, it is convenient to incorporate the cysteine in the form of its hydrochloride salt (L-cysteine HCl H₂O).

It will be understood that, in addition to the nutrient ingredients, the formulation may include preservatives or stabilizers, as required, such as sodium bisulfite, ascorbic acid (vitamin C), or other compatible preservative agents. Nitrogen gas may also be used to preserve the solution.

The formulations are preferably free of ammonia. When prepared from crystalline amino acids, the resultant formulation will be low in free ammonia. In general, the formulations preferably contain less than 0.02% free ammonia.

The formulations of the present invention are designed to provide maintenance quantities of the major intracellular and extracellular ions. Salts of metabolizable organic weak acids and inorganic salts are utilized in combination to provide a solution which is steam sterilizable and which remains stable and acceptable for intravenous administration. Potassium metabisulfite is used as a source of potassium, as part of the antioxidant system, and as a means to adjust the pH. The pH range of the solution claimed in this disclosure is that which is used in good clinical practices.

It is recognized that a wide concentration of electrolytes can be used to maintain intracellular and extracellular electrolyte concentrations. The range cited herein serves as a guide only and is not limited to the specific ranges.

The formulations may be advantageously prepared in the form of sterile aqueous solutions adapted for intravenous administration. In accordance with known practice for such solutions, the solutions will be sterile, pyrogen-free, and at a suitable pH for intravenous administration. The most desirable pH for the solution may vary, but, in general, the pH of the solution can range from 5.0 to 7.8. Where the patient is being fed a protein-restricted diet and the intravenous solution is to be used as a supplement to such diet, in some cases, peripheral intravenous infusion techniques may be used. In other cases, where no nutrients are taken orally, the solutions described herein can be administered into a central vein, a procedure known clinically as hyperalimentation. In this technique, either a subclavian or internal jugular indwelling catheter may be used.

Infusion solutions prepared for intravenous administration use can contain from 2 to 14 weight percent of total amino acids based on the solution. In preferred embodiments, which can be used for total parenteral nutrition, it is believed that the optimum concentration of total emino acids will be from 2.5 to 4.5 weight percent based on the solution as prepared for protein conservation of mildly stressed surgical patients, 4.0 to 9.0 weight percent based on the solution for patients who require hyperalimentation, and 8.0 to 13.0 weight percent based on the solution for hyperalimentation of hypercatabolic patients.

With intravenous solutions prepared as described above, it is expected that full protein nutrition can be provided by administration from about 1 to 3 liters of solution per patient during each 24 hours. The maximum amount which may be administered will depend on the amino acid tolerance of the particular patient. The desirable clinical procedure will be to begin the infusion at a daily level below full protein nutrition, and to gradually increase the amount administered. For example, the administration can be started at levels equivalent to about 20 to 25 grams of protein per day (24 hrs.), and then increased to at least 40 to 50 equivalent grams of protein per day, providing the patient tolerates the infusion. It is expected that the average patient will be able to tolerate at least the equivalent of 50 grams of protein per 24 hrs., and in some cases, much higher administration levels, up to as high as 100 to 140 grams of protein equivalents, may be feasible. For the purpose of the present invention, and as known to biochemists, the equivalency of amino acids to protein can be calculated by determining the total grams of amino acid nitrogen, and then multiplying this amount by 6.25 to obtain the grams of equivalent protein.

Specific formulations for practicing the present invention are set out in the following examples which are intended to be purely illustrative of the use of the invention. Other embodiments of the invention will be apparent to those skilled in the art from a consideration of this specification or practice of the invention disclosed herein.

In the following examples it is preferable to use USP grade sodium acetate 3H₂O, sodium chloride, potassium chloride, and water and to use reagent grade magnesium acetate 4Hp0, phosphoric acid 85%, glacial acetic acid and potassium metabisulfite.

EXAMPLE 1 A sterile, non-pyrogenic, stable solution suitable for intravenous infusion into patients requiring parenteral nutrition is prepared from the following amino acids, energy substrates, electrolytes and water in the following concentrations:

Compound g/l

L-Methionine 1.28 - 1.92

L-Isoleucine 1.68 - 2.52

L-Leucine 2.15 - 3.29

L-Phenylalanine 1.36 - 2.04

L-Valine 1.60 - 2.40

L-Threonine 0.96 - 1.44

L-Lysine 1.76 - 2.64

L-Alanine 1.70 - 2.54

L-Arginine 2.32 - 3.48

L-Histidine 0.68 - 1.02

L-Proline 2.72 - 4.08

L-Serine 1.44 - 2.16

Amino Acetic Acid 3.00 - 5.04

L-Tryptophan 0.37 - 0.55

L-Cysteine HCl H₂O 0.03 - 0.30 Sodium Acetate 3H₂O 1.94 - 2.14 Magnesium Acetate 4H₂O 0.50 - 0.58 Calcium Acetate 0.244 - 0.284 Sodium Chloride 1.11 - 1.23 Potassium Chloride 1.42 - 1.56

Potassium Metabisulfite 0.55 Energy Substrates 20 - 300

Glycerol, or Sorbitol, or Xylitol, or combinations thereof, provided that the concentration of any one energy substrate does not exceed 100 g/l Phosphoric Acid 85% 0.212 - 0.264 ml

Glacial Acetic Acid pH Adjustment

Water for Injection q.s.

In the manufacture of the solution described herein, the order of mixing of the potentially incompatible ingredients is crucial for the preparation of stable units. The critical and acceptable order of mixing is:

a. All amino acids except L-tryptophan and L-cysteine HCl H₂O b. Sodium acetate 3H₂O c. Magnesium acetate 4H₂O d. Calcium acetate H₂O e. Sodium chloride f. Potassium chloride g. Phosphoric acid 85% h. Energy Substrates (glycerol, sorbitol or xylitol, or combinations thereof) i. Glacial acetic acid j. L-Tryptophan k. L-Cysteine-HCI H₂O l. Potassium metabisulfite m. Water for Injection Solutions made by using this order of addition and composition can be packaged in standard intravenous containers and steam sterilized. Standard sterilization cycles and equipment can be used.

EXAMPLE 2 A sterile, non-pyro genie, stable solution suitable for intravenous infusion into patients requiring parenteral nutrition is prepared from the following amino acids, energy substrates, electrolytes and water in the following concentrations:

Compound g/l

L-Methionine 2.56 - 3.84

I-Isoleucine 3.36 - 5.04

L-Leucine 4.32 - 6.48

L-Phenylalanine 2.72 - 4.08

L-Valine 3.20 - 4.80

L-Threonine 1.92 - 2.88

L-Lysine 3.52 - 5.28

L-Alanine 3.40 - 5.08

L-Arginine 4.64 - 6.96

L-Histidine 1.36 - 2.04

L-Proline 5.44 - 8.16

L-Serine 2.88 - 4.32

Amino Acetic Acid 6.72 - 10.08

L-Tryptophan 0.74 - 1.10

L-Cysteine HCl H₂O 0.03 - 0.30

Sodium Acetate 3H₂O 1.94 - 2.14

Magnesium Acetate 4H2O 0.50 - 0.58

Calcium Acetate 0.244 - 0.284

Sodium Chloride 1.11 - 1.23

Potassium Chloride 1.42 - 1.56

Potassium Metabisulfite 0.55

Energy Substrates 20 - 300

Glycerol, or Sorbitol, or Xylitol, or combinations thereof, provided that the concentration of any one energy substrate does not exceed 100 g/l

Phosphoric Acid 85% 0.212 - 0.264 ml Glacial Acetic Acid pH Adjustment

Water for Injection q.s.

a. All amino acids except L-tryptophan and L-cysteine HCl H₂O b. Sodiun acetate 3 H₂O c. Magnesium acetate 4 H₂O d. Calcium acetate H₂O e. Sodium chloride f. Potassium chloride g. Phosphoric acid 85% h. Energy substrates (glycerol, sorbitol or xylitol, or combinations thereof) i. Glacial acetic acid j. L-Tryptophan k. L-Cysteine HCl H₂O l. Potass iun metabisulfite m. Water for Injection

Solutions made by using this order of addition and composition can be packaged in standard intravenous containers and steam sterilized. Standard sterilization cycles and equipment can be used.

EXAMPLE 3 A sterile, non-pyrogenic, stable solution suitable for intravenous infusion into patients requiring parenteral nutrition is prepared from the following amino acids, energy substrates, electrolytes and water in the following concentrations: Compound g/l

L-Methionine 3.84 - 5.76

L-Isoleucine 5.04 - 7.56

L-Leucine 6.48 - 9.72

L-Phenylalanine 4.08 - 6.12

L-Valine 4.80 - 7.20

L-Threonine 2.88 - 4.32

L-Lysine 5.28 - 7.92

L-Alanine 5.40 - 7.62

L-Arginine 6.96 - 10.44

L-Histidine 2.04 - 3.12

L-Proline 8.16 - 12.24

L-Serine 4.32 - 6.48

Amino Acetic Acid 10.08 - 15.12

L-Tryptophan 1,10 - 1.65

L-Cysteine HCl H₂O 0.03 - 0.30

Sodium Acetate 3H₂O 1.94 - 2.14

Magnesium Acetate 4H₂O 0.50 - 0.58 Calcium Acetate 0.244 - 0.284 Sodium Chloride 1.11 - 1.23 Potassium Chloride 1.42 - 1.56 Potassium Metabisulfite 0.55 Energy Substrates 20 - 300

Glycerol, or Sorbitol, or Xylitol, or combinations thereof, provided that the concentration of any one energy substrate does not exceed 100 g/1 Phosphoric Acid 85% 0.212 - 0.264 ml

Glacial Acetic Acid pH Adjustment

Water for Injection q.s.

a. All amino acids except L-tryptophan and L-cysteine HCl H₂O b. Sodium acetate 3H₂O c. Magnesium acetate 4H₂O d. Calcium acetate H₂O e. Sodium chloride f. Potassium chloride g. Phosphoric acid 85% h. Energy substrates (glycerol, sorbitol or xylitol, or combinations thereof) i. Glacial acetic acid j. L-Tryptophan k. L-Cysteine HCl H₂0 l. Potassium metabisulfite m. Water for Injection

Solutions made by using this order of addition and composition can be packaged in standard intravenous containers and steam sterilized. Standard sterilizations cycles and equipment can be used.

EXAMPLE 4 A sterile, non-pyrogenic, stable solution suitable for intravenous infusion into patients requiring parenteral nutrition is prepared from the following amino acids, energy substrates, electrolytes and water in the following concentration:

Compound g/l

L-Methionine 5.12 - 7.68

L-Isoleucine 6.72 - 10.08

L-Leucine 8.64 - 12.96

L-Phenylalanine 5.44 - 8.16

L-Valine 6.40 - 9.60

L-Threonine 3.84 - 5.76

L-Lysine 7.04 - 10.56

L-Alanine 6.80 - 11.16 L-Arginine 9.28 - 13.92

L-Histidine 2.72 - 4.08

L-Proline 10.88 - 16.32

L-Serine 5.76 - 8.64

Amino Acetic Acid 13.44 - 20.16

L-Tryptophan 1.48 - 2.20

L-Cysteine HCl H₂O 0.03 - 0.30

Sodium Acetate 3H₂O 1.94 - 2.14

Magnesium Acetate 4H₂O 0.50 - 0.58

Calcium Acetate 0.244 - 0.284

Sodium Chloride 1.11 - 1.23

Potassium Chloride 1.42 - 1.56

Potassium Metabisulfite 0.55

Energy Substrates 20 - 300

Glacial Acetic Acid pH Adjustment

Water for Injection q.s.

a. All amino acids except L-tryptophan and L-cysteine HCl H₂O b. Sodium acetate 3H₂O c. Magnesium acetate 4H₂O d. Calcium acetate H₂O e. Sodium chloride f. Potassium chloride g. Phosphoric acid 85% h. Energy substrates (glycerol, sorbitol or xylitol, or combinations thereof) i. Glacial acetic acid j. L-Tryptophan k. L-Cysteine HCl H₂O l. Potassium metabisulfite m. Water for Injection

Claims

1. A solution containing pharmacologically acceptable nutritionally effective amounts of amino acids and electrolytes, which include calcium and phosphate ions, and sufficient polyhydric alcohol, selected from the group consisting of glycerol, sorbitol or xylitol, and combinations thereof, to prevent precipitation of calcium phosphate, wherein the improvement comprises retaining in solution calcium and phosphate ions in pharmacologically acceptable nutritionally effective amounts.

2. A solution according to claim 1 in which the polyhydric alcohol is glycerol.

3. A solution according to claim 1 in which the polyhydric alcohol is sorbitol.

4. A solution according to claim 1 in which the polyhydric alcohol is xylitol.

5. A solution according to claim 1 in which the polyhydric alcohols are glycerol and sorbitol.

6. A solution according to claim 1 in which the polyhydric alcohols are glycerol and xylitol.

7. A solution according to claim 1 in which the polyhydric alcohols are sorbitol and xylitol.

8. A solution according to claim 1 in which the polyhydric alcohols are glycerol, sorbitol and xylitol.

9. A solution according to claim 1 in which the amino acids are L-methionine, L-isoleucine, L-leucine, L-phenylalanine, L-valine, L-threonine, L-lysine, L-alanine, L-arginine, L-histidine, L-proline, L-serine, amino acetic acid, L-tryptophan, and L-cysteine HCl H₂O.

10. A solution according to claim 1 in which the electrolytes are sodium acetate, magnesium acetate, calcium acetate, sodium chloride, potassium chloride, potassium metabisulfite, and phosphoric acid.

11. A solution according to claim 1 which has the following composition:

Compound g/l

L-Methionine 1.07 - 8.32

L-Isoleucine 1.40 - 10.92

L-Leucine 1.80 - 14.04

L-Phenylalanine 1.13 - 8.84

L-Valine 1.33 - 10.40

L-Threonine 0.80 - 6.24

L-Lysine 1.47 - 11.44

L-Alanine 1.41 - 11.02

L-Arginine 1.93 - 15.08

L-Histidine 0.57 - 4.42 L-Proline 2.27 - 17.68 L-Serine 1.20 - 9.36

Amino Acetic Acid 2.80 - 21.84 L-Tryptophan 0.31 - 2.39 L-Cysteine HCl H₂O 0.03 - 2.50 Sodium Acetate 3H₂O 1.94 - 2.14 Magnesium Acetate 4H₂O 0.50 - 0.58 Calcium Acetate 0.244 - 0.284 Sodium Chloride 1.11 - 1.23 Potassium Chloride 1.42 - 1.56 Potassium Metabisulfite 0.55 Energy Substrates 20 - 300 Glycerol, Sorbitol, or Xylitol, or combinations thereof, provided that the concentration of any one energy substrate does not exceed 100 g/1 Phosphoric Acid 85% 0.212 - 0.264 ml

Glacial Acetic Acid pH Adjustment Water for Injection q.s.

12. A solution according to claim 11 in which the energy substrate is glycerol.

13. A solution according to claim 12 in which the glycerol concentration is 30 to 90 g/l.

14. A solution according to claim 11 in which the energy substrate is sorbitol.

15. A solution according to claim 11 in which the energy substrate is xylitol.

16. A solution according to claim 11 in which the energy substrates are glycerol and sorbitol.

17. A solution according to claim 11 in which the energy substrates are sorbitol and xylitol.

18. A solution according to claim 11 in which the energy substrates are glycerol and xylitol.

19. A method of preparing a solution according to claim 11 or

12 or 13 or 14 or 15 or 16 or 17 or 18 which comprises mixing the ingredients in the following order:

a. All amino acids except L-tryptophan and L-cysteine HCl H₂O b. Sodium acetate 3H₂O c. Magnesium acetate 4H₂O d. Calcium acetate H₂O e. Sodium chloride f. Potassium chloride g. Phosphoric acid 85% h. Energy substrates (glycerol, sorbitol or xylitol or combinations thereof) ι. Glacial acetic acid j. L-Tryptophan k. L-Cysteine HCl H₂O l. Potassium metabisulfite m. Water for Injection

20. A solution according to claim 1 which has the following composition:

Compound g/l

L-Methionine 1.28 - 1.92 L-Isoleucine 1.68 - 2.52 L-Leucine 2.16 - 3.29 L-Phenylalanine 1.36 - 2.04 L-Valine 1.60 - 2.40 L-Threonine 0.96 - 1.44 L-Lysine 1.76 - 2.64 L-Alanine 1.70 - 2.54 L-Arginine 2.32 - 3.48 L-Histidine 0.68 - 1.02 L-Proline 2.72 - 4.08 L-Serine 1.44 - 2.16

Amino Acetic Acid 3.00 - 5.04 L-Tryptophan 0.37 - 0.55 L-Cysteine HCl H₂O 0.03 - 0.30 Sodium Acetate 3H₂O 1.94 - 2.14 Magnesium Acetate 4H₂O 0.50 - 0.58 Calcium Acetate 0.244 - 0.284 Sodium Chloride 1.11 - 1.23 Potassium Chloride 1.42 - 1.56 Potassium Metabisulfite 0.55 Energy Substrates 20 - 300 Glycerol, or Sorbitol, or Xylitol, or combinations thereof, provided that the concentration of any one energy substrate does not exceed 100 g/l Phosphoric Acid 85% 0.212 - 0.264 ml

Glacial Acetic Acid pH Adjustment

Water for Injection q.s.

21. A solution according to claim 20 in which the energy substrate is glycerol.

22. A method of preparing a solution according to claim 20 or 21 which comprises mixing the ingredients in the following order:

23. A solution according to claim 1 which has the following composition: Compound g/l

L-Methionine 2.56 - 3.84

I-Isoleucine 3.36 5.04 -

L-Leucine 4.32 - 6.48

L-Phenylalanine 2.72 - 4.08

L-Valine 3.20 - 4.80

L-Threonine 1.92 - 2.88

L-Lysine 3.52 - 5.28

L-Alanine 3.40 - 5.08

L-Arginine 4.64 - 6.96

L-Histidine 1.36 - 2.04

L-Proline 5.44 - 8.16

L-Serine 2.88 - 4.32

Amino Acetic Acid 6.72 - 10.08

L-Tryptophan 0.74 - 1.10

L-Cysteine HCl H₂O 0.03 - 0.30

Sodium Acetate 3H₂O 1.94 - 2.14

Glycerol, or Sorbitol, or Xylitol, or combinations thereof, provided that the concentration of any one energy substrate does not exceed 100 g/l Phosphoric Acid 85% 0.212 - 0.264 ml Glacial Acetic Acid pH Adjustment Water for Injection q.s.

24. A solution according to claim 23 in which the energy substrate is glycerol.

25. A method of preparing a solution according to claim 23 or

24 which comprises mixing the ingredients in the following order:

a. All amino acids except L-tryptophan and L-cysteine HCl H₂O b. Sodium acetate 3H₂O c. Magnesium acetate 4H₂O d. Calcium acetate H₂O e. Sodium chloride f. Potassium chloride g. Phosphoric acid 85% h. Energy substrates (glycerol, sorbitol or xylitol, or combinations thereof) ι. Glacial acetic acid j. L-Tryptophan k. L-Cysteine HCl H₂O l. Potassiun metabisulfite m. Water for Injection

26. A solution according to claim 1 which has the following composition:

Compound g/l

L-Methionine 3.84 - 5.76

L-Isoleucine 5.04 - 7.56

L-Leucine 6.48 - 9.72

L-Phenylalanine 4.08 - 6.12

L-Valine 4.80 - 7.20

L-Threonine 2.88 - 4.32

L-Lysine 5.28 - 7.92

L-Alanine 5.40 - 7.62

L-Arginine 6.96 - 10.44

L-Histidine 2.04 - 3.12

L-Proline 8.16 - 12.24

L-Serine 4.32 - 6.48

Amino Acetic Acid 10.03 - 15.12

L-Tryptophan 1.10 - 1.65

L-Cysteine HCl H₂O 0.03 - 0.30 Sodium Acetate 3H₂O 1.94 - 2.14

Magnesium Acetate 4H₂O 0.50 - 0.58

Calcium Acetate 0.244 - 0.284

Sodium Chloride 1.11 - 1.23 Potassium Chloride 1.42 - 1.56

Potassium Metabisulfite 0.55

Energy Substrates 20 - 300

Glacial Acetic Acid pH Adjustment

Water for Injection q.s.

27. A solution according to claim 26 in which the energy substrate is glycerol.

28. A method of preparing a solution according to claim 26 or 27 which comprises mixing the ingredients in the following order:

a. All amino acids except L-tryptophan and L-cysteine HCl H₂O b. Sodium acetate 3H₂O c. Magnesium acetate 4H₂O d. Calcium chloride e. Sodium chloride f. Potassium chloride g. Phosphoric acid 85% h. Energy substrates (glycerol, sorbitol or xylitol, or combinations thereof) i. Glacial acetic acid j. L-Tryptophan k. L-Cysteine HCl H₂O l. Potassium metabisulfite m. Water for Injection

29. A solution according to claim 1 which has the following composition:

Compound g/1

L-Methionine 5.12 - 7.68

L-Isoleucine 6.72 - 10.08

L-Leucine 8.64 - 12.96

L-Phenylalanine 5.44 - 8.16

L-Valine 6.40 - 9.60

L-Threonine 3.84 - 5.76

L-Lysine 7.04 - 10.56

L-Alanine 6.80 - 11.16

L-Arginine 9.28 - 13.92

L-Histidine 2.72 - 4.08

L-Proline 10.88 - 16.32

L-Serine 5.76 - 8.64

Amino Acetic Acid 13.44 - 20.16

L-Tryptophan 1.48 - 2.20

L-Cysteine HCl H₂O 0.03 - 0.30

Sodium Acetate 31-LO 1.94 - 2.14

Magnesium Acetate 4.i,0 0.50 - 0.58

Calcium Acetate 0.244 - 0.284

Sodium Chloride 1.11 - 1.23

Potassium Chloride 1.42 - 1.56

Potassium Metabisulfite 0.55

Energy Substrates 20 - 300

30. A solution according to claim 29 in which the energy substrate is glycerol.

31. A method of preparing a solution according to claim 29 or 30 which comprises mixing the ingredients in the following order:

32. A solution according to claim 20 or 23 or 26 or 29 in which the energy substrate is sorbitol.

33. A solution according to claim 20 or 23 or 26 or 29 in which the energy substrate is xylitol.

34. A solution according to claim 20 or 23 or 26 or 29 in which the energy substrates are glycerol and sorbitol.

35. A solution according to claim 20 or 23 or 26 or 29 in which the energy substrates are glycerol and xylitol.

36. A solution according to claim 20 or 23 or 26 or 29 in which the energy substrates are xylitol and sorbitol.

37. A solution according to claim 20 or 23 or 26 or 29 in which the energy substrates are glycerol, xylitol, and sorbitol.

38. A solution according to claim 21 or 24 or 27 or 30 in which the glycerol concentration is 30 to 90 g/l.

39. A method of treatment of patients during periods of negative caloric balance due to disuse of the gastrointestinal tract which comprises parenterally administering to said patients the solution defined by claim 1.

40. A method of treatment of patients during periods of negative caloric balance due to disuse of the gastrointestinal tract which comprises parenterally administering to said patients the solution defined by claim 20 or 23 or 26 or 29.

41. A method of treatment of patients during periods of negative caloric balance due to disease of the gastrointestinal tract which comprises parenterally administering to said patients the solution defined by claim 12 or 21 or 24 or 27 or 30.