Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/42—Phosphorus; Compounds thereof

Definitions

• the present invention relates to a solution suitable for administration to patients who require parenteral nutrition.
• 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.
• 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.
• Intravenous amino acid solutions are administered clinically to patients requiring intravenous nutrition. They are usually administered along with glucose, fat, electrolytes, and vitamins. Co ⁇ mercial 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.
• 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.
• ethylenedi amine tetra acetic acid as its salts
• water soluble polyethylene glycols ethyl eneglycoldi acetic acid (as its salts)
• saccharate salts ethylenedi amine tetra acetic acid (as its salts)
• 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.
• 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
• CIRCULATION cerebral infarction
• 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.
• 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.
• 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.
• 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.
• 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.
• a polyalcohol energy source such as glycerol, xylitol or sorbitol, or combinations thereof
• 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.
• 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.
• 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.
• concentrations of the ingredients of the present solution may vary depending on the purpose for which the solution is administered.
• concentration of amino acids, electrolytes and polyhydric alcohol energy substrates are acceptable for the purposes of the present invention:
• 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
• the solution has the following composition:
• 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.
• amino acids used in practicing the present invention are preferably pure crystalline amino acids.
• the amino acids should be in their L-form, rather than the D-form or a mixture of D and L.
• amino acids are employed as free amino acids, but can be amino acid salts or derivatives.
• L-lysine acetate may be used, and derivatives of L-tyrosine which are converted to tyrosine in the body may also be used.
• 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.
• 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.
• the formulations may be advantageously prepared in the form of sterile aqueous solutions adapted for intravenous administration.
• 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.
• peripheral intravenous infusion techniques may be used.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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:
• 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
• 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:
• Glycerol or Sorbitol, or Xylitol, or combinations thereof, provided that the concentration of any one energy substrate does not exceed 100 g/l
• 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
• 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
• 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:
• 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
• 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.

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• 1982
  • 1982-04-12 WO PCT/US1982/000447 patent/WO1982003552A1/en not_active Application Discontinuation
  • 1982-04-12 EP EP19820901484 patent/EP0076841A4/de not_active Withdrawn
  • 1982-04-12 JP JP57501516A patent/JPS58500526A/ja active Pending
  • 1982-04-19 IT IT48250/82A patent/IT1147849B/it active

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