WO1991016067A1 - Sources stables et solubles de tyrosine, de cysteine et de glutamine pour une alimentation parenterale totale - Google Patents

Sources stables et solubles de tyrosine, de cysteine et de glutamine pour une alimentation parenterale totale Download PDF

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Publication number
WO1991016067A1
WO1991016067A1 PCT/US1991/002777 US9102777W WO9116067A1 WO 1991016067 A1 WO1991016067 A1 WO 1991016067A1 US 9102777 W US9102777 W US 9102777W WO 9116067 A1 WO9116067 A1 WO 9116067A1
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Prior art keywords
tpn
tyrosine
patient
solution
cysteine
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PCT/US1991/002777
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English (en)
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Mary A. Hilton
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Research Corporation Technologies, Inc.
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Priority to EP91919013A priority Critical patent/EP0608217A1/fr
Priority to JP91508666A priority patent/JPH05507472A/ja
Publication of WO1991016067A1 publication Critical patent/WO1991016067A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0029—Parenteral nutrition; Parenteral nutrition compositions as drug carriers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the present invention provides soluble and/or stable sources of tyrosine, cysteine and glutamine for use in total parenteral nutrition (TPN) as well as a
  • sustained-release source of glutamic acid are gamma-L-glutamyl-L-tyrosine ( ⁇ -GluTyr) gamma-L-glutamyl-L-cysteine ( ⁇ -GluCys) gamma-L-glutamyl- L-glutamine ( ⁇ -GluGln) and their derivatives, water soluble peptides that, after parenteral administration, are
  • tissue enzymes hydrolysed by tissue enzymes to release free tyrosine and glutamic acid, free cysteine and glutamic acid, or free glutamine and glutamic acid, respectively.
  • tissue enzymes hydrolysed by tissue enzymes to release free tyrosine and glutamic acid, free cysteine and glutamic acid, or free glutamine and glutamic acid, respectively.
  • These peptides are formulated into amino acid solutions for administration in TPN, to produce normal plasma levels of tyrosine,
  • This invention provides TPN formulations, and methods of formulating and using TPN solutions containing ⁇ -GluTyr, ⁇ -GluCys, ⁇ -GluGln either singly or in combination.
  • TPN Total parenteral nutrition
  • the optimal composition is one that produces a normal pattern of plasma amino acids (i.e., a normal plasma aminogram).
  • the plasma amino acid levels are determined by the balance between the rate of administration of each amino acid and its rate of utilization.
  • a normal plasma aminogram corresponds to one produced after digestion of dietary protein and hepatic release of amino acids or one produced in normal breast-fed infants. Examples of normal plasma amino acid patterns in normal breast-fed infants is described by
  • TPN amino acid solutions The relative insolubility of tyrosine in aqueous solutions at physiological pH has long presented problems in formulating TPN amino acid solutions.
  • the ability to provide optimal tyrosine levels in TPN solutions is important in normalizing plasma levels of this amino acid.
  • infants, especially low-birth weight and premature infants the metabolic pathway for conversion of phenylalanine, an
  • tyrosine nutrition in early development may be crucial since it is a precursor of several hormones and neurotransmitters. Since the enzyme system which converts phenylalanine to tyrosine is primarily a liver enzyme, there may be particular disease conditions in adults, children and animals, especially liver diseases, in which the formation of tyrosine is impaired.
  • Typical amino acid solutions for TPN in pediatric patients contain tyrosine at about 44 mg/dl (e.g.,
  • N-acetyl-L-tyrosine N-acetyl-L-tyrosine
  • GlyTyr L-glycyl-L-tyrosine
  • L-alanyl-L-tyrosine (AlaTyr) or general dipeptides containing tyrosine where the two amino acids have a normal peptide linkage joining the ⁇ -carboxyl group of the first residue and the ⁇ -amino group of the second residue and have the general formula X-Tyr or Tyr-Y wherein X is alanine, arginine, histidine, lysine, serine, glycine or glutamate and Y is arginine, histidine, glycine or glutamate.
  • X is alanine, arginine, histidine, lysine, serine, glycine or glutamate
  • Y is arginine, histidine, glycine or glutamate.
  • Formation of diketopiperazines may be a concern as illustrated in the case of aspartame, an unstable methyl ester of a dipeptide of aspartic acid and phenylalanine which limits the shelf-life of soft drinks in which it is used as a sweetener, because of loss of sweetness with formation of a diketopiperazine. While not a concern m foods ingested orally, data establishing the safety of diketopiperazines administered intravenously, as in TPN into very small
  • Aminosyn-PF 10% contains high levels of
  • phenylalanine based on the assumption that phenylalanine can serve as a precursor for tyrosine. While this may be a fair assumption for some adults, newborn infants appear unable to convert phenylalanine into tyrosine. For example, breast-fed infants have a plasma ratio of phenylalanine to tyrosine
  • NAcTyr Another source of tyrosine examined because of its increased aqueous solubility, and which avoids the problem of diketopiperazine formation, is NAcTyr.
  • NAcTyr Another source of tyrosine examined because of its increased aqueous solubility, and which avoids the problem of diketopiperazine formation, is NAcTyr.
  • TPN for pre-term neonates has been reported (Helms, R.A. et al. (1987) J. Pediatr. 110: 466-470).
  • NAcTyr were lost through renal excretion. These results suggest that NAcTyr is not efficiently converted to tyrosine, that substantial amounts are excreted and that, despite its increased solubility, NAcTyr is not satisfactory to replace or supplement tyrosine in TPN solutions. NAcTyr suffers the further disadvantage of not being a normal product of
  • AlaTyr has also been investigated as an alternative source of tyrosine in ammo acid solutions for TPN (Stegink, supra). Like NAcTyr, AlaTyr is suffiently soluble under aqueous, physiological conditions to deliver potentially adequate nutritional levels of free tyrosine. However, administration of AlaTyr to rats at a rate of 0.5 mmol/kg/day or 2 mmol/kg/day indicated that after 24 h of administration, the plasma tyrosine levels were unchanged at the lower rate and merely increased two-fold at the higher rate. Renal excretion of AlaTyr also occurred but at a slightly lower rate than NAcTyr loss. AlaTyr as well as the soluble
  • dipeptides discussed above suffer a major disadvantage in that they are unstable in aqueous solution, especially upon the prolonged storage periods to which TPN amino acid
  • ⁇ -carboxyl-linked peptides cannot be added to TPN amino acid solutions subjected to long storage periods and are, thus, best added just prior to administration of the TPN solution, a practice that leaves room for error and
  • GlyTyr dipeptide also suffers the disadvantage of being unstable during storage in aqueous solution.
  • the present invention provides a soluble source of tyrosine which does not exhibit the
  • TPN TPN.
  • the subject tyrosine source, ⁇ -GluTyr readily supplies adequate and optimal amounts of tyrosine to the patient, is stable upon prolonged storage periods in aqueous solutions used for TPN since it does not contain an ⁇ -carboxyl linkage, and is a naturally occurring dipeptide, being generated during the ⁇ -glutamyl cycle as described by Meister (1973)
  • ⁇ -GluTyr is readily metabolized to release free tyrosine at least in part via degradation by ⁇ -glutamyl transpeptidase. Since ⁇ -GluTyr is a normal product of metabolism, it provides a safe source of tyrosine in vivo, with little potential for producing toxicity in high-risk infants and other patients, including humans and animals.
  • cysteine has been difficult to supply in adequate amounts via TPN.
  • cysteine in an aqueous solution at neutral pH in the presence of oxygen, cysteine is spontaneously converted to cystine with release of hydrogen peroxide as shown below:
  • cyst(e)ine refers either to the oxidized or reduced form of cysteine. Cystine is quite insoluble in water (1 mg/dl) especially at the neutral pH required for TPN. Thus, despite the solubility of cysteine, its
  • cyst(e)ine is not considered a dietary "essential” amino acid for children or adults, it may be essential for neonates. This amino acid is formed via a metabolic pathway called “trans-sulfuration.” In this process the "essential” amino acid, methionine, donates its sulfur atom to serine, forming cysteine. The metabolic pathway to cysteine , which involves five different
  • Cystathionase the enzyme which catalyzes the final step in the biosynthesis of cysteine, is primarily a liver enzyme and is fully operative only after birth. Thus, the neonate, and particularly the pre-term neonate, cannot meet the need for cysteine via the normal biosynthetic route. The intermediate cystathionme accumulates and is excreted in the urine, thus causing cysteine to become a nutritionally "essential" amino acid for these infants.
  • Cysteine has a number of important intracellular functions in addition to its role in protein synthesis: (a)
  • Cysteine is required for the conversion of the vitamin, pantothenic acid, to coenzyme A, its metabolically active form, (b) Cysteine is a metabolic precursor of the amino sulfonic acid, taurine. Taurine is currently included in TPN solutions, reducing some of the dietary need for cysteine.
  • Glutathione gamma-glutamyl-cysteinylglycine
  • Glutathione GSH is also important in the detoxification of xenobiotics and in the maintenance of functional thiol groups in proteins.
  • Water-soluble GSH, and fat-soluble vitamin E are important antioxidants and may be of special significance in protecting infants exposed to hyperbaric oxygen.
  • a cysteine deficiency can lead to export of GSH from the liver to replenish plasma cyst(e)ine through degradation of plasma GSH Meister, A. (1988) J. Biol. Chem. 263: 17205-17208].
  • liver GSH may lead to numerous matabolic aberrations.
  • cyst(e)ine One major concern in the delivery of cyst(e)ine via
  • TPN is that this amino acid has been shown to be lethal when fed to weanling rats at a level of 15.7 g N/kg basal diet, and neurotoxic when administered in a single subcutaneous dose (1.2 mg/kg body weight) to 4-day-old rats, and in a single intraperitoneal dose (10 mmol/kg body weight) to mice
  • Cysteine-hydrochloride (cysteine-HCl) has been administered as a separate solution, not combined in the mixture of the other amino acids used in TPN. This soluble form of cysteine is stable at low pH. The amount of HCl which high-risk infants can tolerate is limited and this, in turn, limits the amount of cysteine-HCl which may be used in
  • NAcCys N-acetylcysteine
  • NAcCys was not found to be a satisfactory replacement source for cysteine (Magnussen et al.).
  • the plasma levels of cyteine four hours after administration of 5 g cysteine in a 200 mg/ml solution decreased relative to the basal cysteine level (134 vs 207 ⁇ mol/1).
  • the basal cysteine level 134 vs 207 ⁇ mol/1
  • NAcCys levels increased dramatically in the same time frame (from 2 to 488 ⁇ mol/l), 11% of the administered NAcCys was excreted in the urine within 4 h.
  • Stegink et al. also reported large urinary losses of N,N'-bis-acetylcystine when administered for TPN and concluded that this compound was not a suitable alternative source for cysteine in TPN.
  • GSH has also been used as a source of cysteine during long-term TPN in the growing rat [Neuhauser-Berthold,
  • ⁇ -GluCys and its derivatives may provide a more efficient means to increase the GSH content in tissues as well as to provide a stable source of cysteine.
  • the present invention provides a soluble source of cysteine which does not exhibit the
  • cysteine source ⁇ -GlyCys and derivatives described below, readily supplies adequate and optimal amounts of cysteine to the patient, is stable upon prolonged storage periods in aqueous solutions used for TPN since it lacks an ⁇ -carboxyl linkage.
  • ⁇ -GluCys is a naturally occurring dipeptide, which can be generated by the tissue enzymes, ⁇ -glutamyl transpeptidease or by ⁇ -glutamylcysteine synthetase.
  • ⁇ -GluCys provides a safe source of cysteine in vivo, with little potential for producing toxicity in high risk infants and other patients, including humans and
  • Glutamine is yet another amino acid which has been difficult to supply in adequate amounts via TPN.
  • glutamine is present in plasma at the highest concentration of any amino acid, glutamine is not included in TPN because of its instability in aqueous solutions. In particular, glutamine breaks down in aqueous solution to form pyro
  • TPN solution containing glutamine which are stored even for short lengths of time can accumulate toxic ammonia. While a fresh glutamine solution can be added to the TPN solution, this greatly increases the risk of contamination and error in formulation. Thus, TPN solutions in present use do not contain glutamine.
  • the present invention provides a stable source of glutamine which does not exhibit the
  • ⁇ -carboxyl linkage is a naturally occurring dipeptide, being generated during the ⁇ -glutamyl cycle as described by Meister, supra.
  • ⁇ -GluGln is readily metabolized to release free glutamine, at least in part via degradation by ⁇
  • ⁇ -GluGln is a normal product of metabolism, it provides a safe source of glutamine in vivo, with little potential for producting toxicity in high-risk infants and other patients, including humans and animals.
  • the present invention provides a means to reduce free glutamic acid in TPN
  • the present invention provides an improved method for obtaining normal plasma levels of free tyrosine in a patient during total parenteral nutrition (TPN) by
  • ⁇ -GluTyr X-glutamyltyrosine
  • TPN solution X-glutamyltyrosine
  • ⁇ -GluTyr is ⁇ -L-glutamyl-L-tyrosine.
  • the patient may be a human or an animal.
  • this method of obtaining tyrosine is especially useful in low birth weight infants with an immature metabolic system and in any age patient with a disease condition that prevents adequate biosynthesis of tyrosine, e.g., by
  • the present invention further provides an improved method for obtaining normal plasma levels of cysteine in a patient during TPN by administering ⁇ -glutamylcysteine
  • ⁇ -GluCys is provided as ⁇ -L-glutamyl- L-cystine or
  • N,N'-bis-( ⁇ -L-glutamyl)-L-cysteine Specifically the patient can be a human or an animal.
  • Still another aspect of the invention provides an improved method for obtaining normal plasma levels of
  • ⁇ -glutamylglutamine in a TPN solution in an amount effective to obtain adequate or optimal plasma levels of glutamine in the treated patient.
  • ⁇ -GluGln is ⁇ -L-glutamyl-L-glutamine.
  • ⁇ -GluGln can be provided at a level to obtain normal plasma Gin:Glu ratios.
  • the patient can be a human or an animal
  • a method for obtaining optimal nutrition via TPN solutions which embodies all the or part of the aspects of the invention as summarized above, i.e., administration of ⁇ -GluTyr, ⁇ -GluCys, ⁇ -GluGln, or any combination of these three compounds can be provided
  • TPN solutions including amino acid solutions for use in TPN, wherein tyrosine, cysteine or glutamine is supplemented or replaced by ⁇ -GluTyr, ⁇ -GluCys or ⁇ -GluGln,
  • TPN solutions with ⁇ -GluTyr, ⁇ -GluCys, ⁇ -GluGln or any combination of these three are also contemplated. In any of these solutions phenylalanine, methionine, and glutamic acid can be reduced by an appropriate amount.
  • the present invention provides an improved method for obtaining normal plasma levels of tyrosine, cysteine or glutamine in a patient during total parenteral nutrition (TPN) by supplementing or replacing the tyrosine, cysteine or glutamine in a TPN solution to be administered with an amount of ⁇ -glutamyltyrosine ( ⁇ -GluTyr), ⁇ -glutamylcysteine
  • TPN This method of TPN is provided for animals and humans, and especially to those animals or humans in a condition with a reduced ability to produce or metabolize tyrosine, cysteine, or glutamine biosynthetically.
  • the present method of TPN is not limited to such individuals, since it readily provides all the amino acids necessary to sustain proper nutrition and is thus useful for any individual requiring intravenous administration of nutrients, supplementation of amino acids and other nutrients, or administration of TPN solutions and the like.
  • the present method may be modified to simultaneously provide free tyrosine, free cysteine, free glutamine, or any combination of these three compounds to satisfy nutrition requirements in a patient as described above. Further, in supplementing or replacing tyrosine, cysteine and/or glutamine as provided herein, free glutamic acid in TPN solutions can be proportionally reduced.
  • TPN solutions can be reduced if necessary or desirable.
  • total parenteral nutrition refers to a regimen of obtaining nutrition by a parenteral route when enteral (oral or gastrointestinal) nutrition is impossible or impaired. Such conditions may occur in certain disease states, in new born infants, or comatose patients.
  • TPN is generally administered to the patient via an intravenous route, either in a central or peripheral vein. Any other known route of administering TPN is also contemplated by this invention, e.g.,
  • TPN solutions are usually administered continuously by intravenous infusion.
  • nutrients administered during TPN is determined by the total body weight and status of the patient.
  • the dosage is then typically expressed as the dosage of nutrients/kg body weight/24 h period.
  • One skilled in the art can readily determine the proper dosage and rate of administration to achieve the desired nutritional state.
  • the optimal mixture of amino acids is one which will produce a normal pattern of amino acids in the plasma.
  • TPN solutions having first been developed in the 1950s.
  • TPN solutions are prepared as separate groups of components, i.e., as an amino acid solution or a dextrose solution, and then mixed together before administration at a ratio to give final nutrient concentrations to meet the optimal nutritional requirements for the patient.
  • the present practice of TPN provides a solution of amino acids which can be mixed with a solution of dextrose (i.e., carbohydrate) and other necessary supplements. While the improved method of administering TPN in the instant invention is described for TPN amino acid solutions, it should be understood that all the considerations for formulating these solutions apply equally to any TPN formulation, especially solutions or compositions including multiple groups of components, e.g. a TPN solution containing premixed
  • tyrosine, cysteine or glutamine can be supplemented, replaced or augmented by
  • TPN solutions are well known and many commercial preparations are available.
  • TPN amino acid solutions are usually provided as about 5-10% solutions of amino acids.
  • the conventional TPN formulations can be used in the present invention by adding ⁇ -GluTyr, ⁇ -GluCys or ⁇ -GluGln to these solutions.
  • ⁇ -GluTyr, ⁇ -GluCys, ⁇ -GluGln or any combination of these can be added during formulation of TPN solutions in accordance with this invention.
  • the 20 common amino acids can be included in such solutions although some TPN products are limited to the essential and semi-essential amino acids as deemed appropriate for the exigency of the situation.
  • the amino acid solutions can also include ornithine, citrulline and taurine if desired. For example, in pediatric
  • compositions for TPN which contain ⁇ -GluTyr, ⁇ -GluCys or ⁇ -GluGln in accordance with the present invention are also contemplated.
  • ⁇ -glutamyltyrosine or “ ⁇ -GluTyr” refers to a dipeptide formed by covalent bonding of the ⁇ -carb ⁇ xyl group of glutamic acid with the ⁇ -amino group of tyrosine. While it is metabolically preferable that the L forms of these amino acids be used, the invention is not so limited if the need arises, i.e., one or the other amino acids could be in the D form. Thus, the preferred species of ⁇ -GluTyr is ⁇ -L-glutamyl-L-tyrosine. This dipeptide is known to occur naturally, being synthesized during the
  • ⁇ -GluTyr is commercially available or may be synthesized by standard peptide chemical routes. Such synthetic methods are well known in the art and include, for example, the Merrifield method of solid phase peptide
  • ⁇ -Glutamylcysteine refers to peptides having at least one peptide unit formed by covalent bonding of the ⁇ -carboxyl group of glutamic acid with the ⁇ -amino group of cysteine.
  • the ⁇ -GluCys is stably and preferably provided as ⁇ -glutamylcystine, i.e., ⁇ -Glu(Cys) 2 , or N,N'-bis( ⁇ -glutamyl)cystine, i.e.,
  • the preferred peptide species of ⁇ -GluCys are ⁇ -L-glutamyl-L-cysteine and N,N'-bis( ⁇ -L-glutamyl)-L-cystine]. Both peptides are already oxidized (in the disulfide form) and thus will not oxidize further to produce H 2 O 2 in solution or in vivo. Both peptides are freely soluble in water due to the presence of the polar glutamyl group(s). Moreover, these peptides are also stable in aqueous solution since they lack the
  • ⁇ -GluCys and the herein defined derivatives may be synthesized by standard peptide chemical routes. Such synthetic methods are well known in the art and include, for example, the Merrifield method of solid phase peptide
  • ⁇ -GluGln refers to a dipeptide formed by covalent bonding of the ⁇ -carboxyl group of glutamic acid with the ⁇ -amino group of glutamine. While it is metabolically preferable that the L forms of these amino acids be used, the invention is not so limited if the need arises, i.e., one or the other amino acids could be in the D form.
  • the preferred species of ⁇ -GluGln is ⁇ -L-glutamyl-L-glutamine. This dipeptide is known to occur naturally, being synthesized during the ⁇ -glutamyl cycle (Meister supra). Importantly, there exists a metabolic pathway for degradation of this dipeptide into its substituent amino acid residues to provide for release of free glutamine and glutamate. This
  • ⁇ -GluGln is commercially available or may be synthesized by standard peptide chemical routes. Such synthetic methods are well known in the art and include, for example, the Merrifield method of solid phase peptide synthesis.
  • the present invention provides a method of normalizing plasma levels of free tyrosine during TPN which comprises administering a TPN solution containing ⁇ -GluTyr to a patient undergoing TPN treatment, wherein the free tyrosine of the TPN solution has been supplemented or replaced by ⁇ -Gl ⁇ Tyr at a level sufficient to satisfy the nutritional requirements of the patient.
  • a reduction in the phenylalanine and glutamic acid content of the TPN solution is possible.
  • the patient can be a human or an animal, and is generally in a condition in which enteral feeding is ineffective to obtain proper nutrition.
  • the free tyrosine in such a solution is supplemented or replaced by an amount of ⁇ -GluTyr effective to provide a sufficient nutritional level of free tyrosine, i.e., to normalize plasma tyrosine levels and plasma Phe/Tyr ratios.
  • ⁇ -GluTyr is formulated into a TPN amino acid solution at a concentration ranging from about 150 to about 600 mg/dl. Any other amino acids in the solution are provided in the typical amounts for TPN solutions with the exception that the glutamic acid content may be reduced by the amount of glutamic acid calculated to be released during hydrolysis of ⁇ -GluTyr or by any other appropriate amount compatible with maintaining an adequate, but not neurotoxic, amount of glutamic acid in the patient.
  • Table 1 compares four formulas containing ⁇ -GluTyr and a commercial TPN amino acid solution, showing the levels of ⁇ -GluTyr, Tyr, Glu, Phe as well as other parameters
  • the amount of phenylalanine in TPN solutions may also be adjusted to normalize plasma Phe/Tyr
  • Another aspect of the present invention provides a method of normalizing plasma leyels of free cysteine during
  • TPN which comprises administering a TPN solution containing ⁇ -GluCys to a patient undergoing TPN treatment, wherein the free cysteine of the TPN solution has been supplemented or replaced by ⁇ -GluCys at a level sufficient to satisfy the nutritional requirements of the patient.
  • the patient can be a human or an animal, and is generally in a condition in which enteral feeding is ineffective to obtain proper nutrition.
  • cysteine or cystine if present, in such a solution is supplemented or replaced by an amount of ⁇ -GluCys effective to provide a sufficient nutritional level of free cysteine, i.e., to normalize plasma cysteine levels and plasma Cys/Met ratios.
  • ⁇ -GluCys or the herein defined derivatives are formulated into a TPN amino acid solution at a concentration ranging from about 150 to about 600 mg/dl. Any other amino acids in the solution are
  • glutamic acid content may be reduced by the amount of glutamic acid calculated to be released during hydrolysis of ⁇ -GluCys or by any other appropriate amount compatible with maintaining an adequate, but not neurotoxic, amount of glutamic acid in the patient.
  • Table 2 compares
  • TPN solutions Since ⁇ -GluCys and derivatives readily dissolve in aqueous media at physiological pH, it is easily incorporated into TPN solutions without the need for special procedures. As is well known, all TPN solutions must be sterilized by a
  • the present invention provides a method of normalizing plasma levels of free glutamine during TPN which comprises administering a TPN solution containing ⁇ -GluGln to a patient undergoing TPN treatment, wherein the glutamine, of the TPN solution is provided by ⁇ -GluGln at a level sufficient to satisfy the nutritional requirements of the patient.
  • a reduction in the glutamic acid content of the TPN solution is possible.
  • the patient can be a human or an animal, and is generally in a condition in which enteral feeding is ineffective to obtain proper
  • ⁇ -GluGln an effective amount of ⁇ -GluGln is added to the TPN solution to provide a sufficient nutritional level of free glutamine, i.e., to normalize plasma glutamine levels and plasma Gln/Glu ratios. Additionally or alternatively, the amount of
  • ⁇ -GluGln can be adjusted to maintain normal gut physiology, or to prevent gastrointestinal distress in infants, adults or animals during a transfer from TPN to normal and feeding.
  • free glutamine is normally omitted from TPN solutions, if present, the free glutamine can be supplemented or replaced by ⁇ -GluGln in accordance with the present invention.
  • ⁇ -GluGln is formulated into a TPN amino acid solution at a concentration ranging from about 150 to about 1000 mg/dl. Any other amino acids in the solution are provided in the typical amounts for TPN solutions with the exception that the glutamic acid content may be reduced by the amount of glutamic acid calculated to be released during hydrolysis of ⁇ -GluGln or by any other appropriate amount compatible with maintaining an adequate, but not neurotoxic, amount of glutamic acid in the patient. Since ⁇ -GluGln readily dissolves in acqueous media at physiological pH, it is easily incorporated into TPN
  • the present invention provides a method of simultaneously normalizing plasma levels of free tyrosine, free cysteine, free glutamine or any combination of these three compounds during TPN in accordance with the methods described above, wherein free tyrosine, free cysteine and/or free glutamine are supplemented or replaced by ⁇ -GluTyr, ⁇ -GluCys and/or ⁇ -GluGln in accordance with the separate provisions of this invention for each of these as a single amino acid.
  • ⁇ -GluTyr ⁇ -GluCys and/or ⁇ -GluGln
  • ⁇ -GluCys, ⁇ -GluGln, phenylalanine, methionine, and glutamic acid levels can be effected to produce a TPN solution that satisfies the nutritional requirements of the patient.
  • Another embodiment of the present invention provides TPN solutions and compositions wherein tyrosine is supplemented or replaced by ⁇ -GluTyr in an amount effective to provide a patient with a sufficient nutritional level of free tyrosine.
  • the amount of ⁇ -GluTyr can provide a normal Phe/Tyr ratio, optionally by also reducing the amount of phenylalanine in the TPN solution.
  • the glutamic acid content of the TPN solutions can be reduced.
  • the amount of ⁇ -GluTyr needed for adequate nutrition is about 150 to about 600 mg/dL, although higher levels may be required to normalize the plasma aminogram.
  • tyrosine is also present, although in much lower amounts since its aqueous solubility at physiological pH limits its concentration to about 40-60 mg/dL. It is important to avoid saturation with tyrosine to prevent formation of crystals.
  • TPN compositions include sterilized powders for formulation into sterile TPN
  • the present invention also provides TPN solutions and compositions wherein cysteine is supplemented or replaced by X-GluCys in an amount effective to provide a patient with a sufficient nutritional level of free cysteine.
  • the amount of ⁇ -GluCys can provide a normal Cys/Met ratio, optionally, by also reducing the amount of methionine. Further the glutamic acid content of the TPN solutions can be reduced. In a preferred embodiment,
  • ⁇ -GluCys is ⁇ -Glu(Cys) 2 or ( ⁇ -GluCys) 2 and provided in an amount needed for adequate nutrition, which is about 150 to about 600 mg/dL.
  • cysteine is not also present in TPN solutions because it oxidizes to form insoluble cystine.
  • TPN compositions include sterilized powders for formulation into sterile TPN solutions. Another embodiment of the present invention
  • the amount of ⁇ -GluGln can provide a normal Gln/Glu ratio, optionally by also reducing the amount of glutamic acid (glutamate) in the TPN solution.
  • the amount of ⁇ -GluGln needed for adequate nutrition is about 150 to about 1000 mg/dL, although higher levels may be required to normalize the plasma
  • TPN compositions include sterilized powders for formulation into sterile TPN
  • the present invention provides TPN solutions and compositions wherein tyrosine, cysteine and glutamine or any combination of these compounds, are simultaneously supplemented, replaced or included as provided above for each individual compound.
  • the pharmaceutical forms suitable for intravenous use include sterile aqueous solutions and sterile powders for the extemporaneous preparation of sterile solutions. In all cases the form must be sterile and the solution must be fluid to provide for easy flow. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or
  • dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof and vegetable oils or other compounds compatible in intravenous administration.
  • the solvent for amino acid mixtures is generally water with the pH adjusted to 5-6.5. The proper fluidity shall be maintained.
  • Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • the solution is sterilized by
  • the osmotic pressure of the solution should be compatible with maintenance of healthy blood cells and tissues.
  • Sterile solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by sterilization by
  • phenylalanine and tyrosine can be detected in as little as 30 ⁇ l of plasma by this method.
  • ⁇ -GluTyr from plasma was 2.2-2.6 ⁇ M/min.
  • mice were injected with saline as a control or 2.8 ⁇ mol ⁇ -GluTyr to compare plasma concentrations of tyrosine.
  • the levels of tyrosine and phenylalanine were measured at 10 min post-injection (Table 4) and indicate that a significant increase in plasma
  • ⁇ -GluTyr is consistent with release of tyrosine from the peptide and not to a generalized increase in plasma amino acids. a10 min post-injection of ⁇ -GluTyr.
  • mice remained anesthetized.
  • the urinary bladders were tied off, removed and blood was collected from the heart for analysis.
  • a maximum of 0.13% of the injected ⁇ -GluTyr was excreted in the urine whereas the plasma contained 12-25 ⁇ M ⁇ -GluTyr. If these mice are assumed to have a total plasma volume of 4 ml, then only about 4% of the injected ⁇ -GluTyr remained in the plasma at 60 min post-injection. Since a negligible amount of the total ⁇ -GluTyr was lost in the urine, then 96% of the peptide had apparently been hydrolyzed and was available for use as free tyrosine and glutamic acid.
  • ⁇ -GluTyr The most likely route for metabolic degradation of ⁇ -GluTyr involves the enzyme, ⁇ -glutamyl transpeptidase ( ⁇ -GTase), a widely distributed enzyme in mammalian tissues.
  • ⁇ -GTase ⁇ -glutamyl transpeptidase
  • ⁇ -GluTyr was added to Aminosyn-PF 10% and the solution treated with bovine kidney ⁇ -GTase (Sigma Type II) at pH 7.4.
  • mice were injected with a potent inhibitor of ⁇ -GTase , acivicin, prior to administration of ⁇ -GluTyr and the levels of the peptide, tyrosine and phenylalanine in plasma were monitored.
  • Control mice received saline rather than acivicin prior to intravenous injection of 2.8 ⁇ mol of ⁇ -GluTyr.
  • an intraperitoneal injection of acivicin was made 20 min prior to the injection of 2.8 ⁇ mol ⁇ -GluTyr.
  • Plasma was sampled after 10 min and 60 min, and urine was collected after 60 min. The results are shown in Table 5. The finding that the ⁇ -GluTyr concentration was significantly higher and the tyrosine concentration
  • the kidney is generally unable to prevent the loss of intact peptides in the urine. Instead, peptides are hydrolyzed to free amino acids, which can then be salvaged by absorption into the bloodstream.
  • ⁇ -GTase which is very active in the kidney, can hydrolyze the peptide to release free glutamic acid and tyrosine, which the kidney can then return to the blood.
  • ⁇ -GTase is inhibited by acivicin, unhydrolyzed peptide should be lost in the urine.
  • Table 5 are consistent with a role for ⁇ -GTase in the hydrolysis of ⁇ -GluTyr to prevent its excretion in the urine.
  • this enzyme is inhibited by acivicin, the amount of unhydrolyzed peptide which appears in the urine in 60 min increases almost 100-fold over peptide found in the urine of control mice.
  • a preliminary experiment is conducted to determine the stability of ⁇ -Gl ⁇ ( Cys ) 2 in aqueous solution.
  • An equal volume of either cysteine compound at a concentration of 200 mg/dl is mixed with an equal volume of Aminosyn-PF 10%, the pH is adjusted to 5.5, and the solution is sterilized by ultrafiltration.
  • an aliquot of the sample which has been stored at room temperature is taken for analysis by HPLC as indicated above.
  • a rat was implanted with a catheter into the inferior vena cava via the femoral vein on day 0. After recovery from surgery the rat was allowed free access to rat chow and water while physiological saline was delivered via the catheter. All solutions were delivered at 2 ml/h. On day 3, a blood sample was drawn and the catheter infusion was switched to a standard TPN formulation (standard TPN). Blood samples were withdrawn at 48 and 96 h after TPN
  • the standard TPN formulation contained:
  • Vitamins, electrolytes, trace elements and choline were also included.
  • the standard TPN solution was delivered at a rate of 252 cal/kg body wt/day and thus provided:
  • Non-protein calories per g N 150
  • the GluTyr TPN formulation was identical to the standard TPN formulation except that a special formulation of Aminosyn-PF 10% was used which contained ⁇ -GluTyr with reduced amounts of phenylalnine and glutamic acid.
  • the exact compositions are indicated in Table 6.
  • the standard TPN formulation is that of Aminosyn-PF 10%.
  • the GluTyr TPN formulation is identical to the Aminosyn-PF 10% except as indicated.
  • Lysine was added as the acetate salt.
  • Tau Taurine.
  • Measurement of ⁇ -GluGln, glutamine and glutamic acid in plasma is accomplished by modification of HPLC methods for amino acid analysis coupled with sensitive fluorescence detection [Larsen et al. (1980) J. Chromatogr. Sci. 18 :233-236] or accomplished by standard amino acid analysis techniques.
  • mice were injected with 29 ⁇ moles of ⁇ -GluGln via the external jugular vein. Control animals were injected with an equal volume of saline. Blood was sampled at 10 min. and at 60 min after injection. Plasma amino acids were determined by amino acid analysis. ⁇ -GluGln was detected in the plasma of only three of six mice at 10 min, suggesting that the peptide was efficiently degraded. Additionally, ⁇ -GluGln did not appear in the urine unless the mice were pretreated with acivicin, an inhibitor of ⁇ -GTase.
  • the plasma glutamine levels were measured and the results are provided in Table 8.
  • the plasma concentration of glutamine in animals injected with ⁇ -GluGln was
  • mice which received ⁇ -GluGln exhibited significantly higher glutamine levels at 10 min post injection relative to the control group (saline

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Abstract

Sources stables et/ou solubles de tyrosine, de cystéine et de glutamine pour une alimentation parentérale totale (APT), ainsi que source de diffusion graduelle d'acide glutamique. Ces sources sont notamment la gamma-glutamyltyrosine (η-GluTyr), des dérivés de gamma-glutamylcystéine (η-GluCys) et la gamma-glutamylglutamine (η-GluGln). On décrit aussi des formulations d'APT, des procédés de formulation et l'utilisation de telles solutions contenant de la η-GluTyr, des dérivés de η-GluCys et/ou de la η-GluGln pour assurer des niveaux nutritionnels appropriés de tyrosine, de cystéine ou de glutamine durant l'APT.
PCT/US1991/002777 1990-04-23 1991-04-23 Sources stables et solubles de tyrosine, de cysteine et de glutamine pour une alimentation parenterale totale WO1991016067A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP91919013A EP0608217A1 (fr) 1990-04-23 1991-04-23 Sources stables et solubles de tyrosine, de cysteine et de glutamine pour une alimentation parenterale totale
JP91508666A JPH05507472A (ja) 1990-04-23 1991-04-23 経静脈栄養法のためのチロシン、システイン、グルタミンの可溶性で安定な供給源

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US51269890A 1990-04-23 1990-04-23
US512,698 1990-04-23

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WO1991016067A1 true WO1991016067A1 (fr) 1991-10-31

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992009277A1 (fr) * 1990-12-03 1992-06-11 Kabi Pharmacia Ab Source nutritive
EP0820285A1 (fr) * 1995-01-25 1998-01-28 University Of Southern California Procedes et compositions de lipidisation de molecules hydrophiles
US6093692A (en) * 1997-09-25 2000-07-25 The University Of Southern California Method and compositions for lipidization of hydrophilic molecules
DE102006018293A1 (de) * 2006-04-20 2007-10-25 Fresenius Kabi Deutschland Gmbh Pädiatrische Aminosäurelösung zur parenteralen Ernäherung
US20110262965A1 (en) * 2010-04-23 2011-10-27 Life Technologies Corporation Cell culture medium comprising small peptides

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011057702A (ja) * 2010-12-09 2011-03-24 Meiji Milk Prod Co Ltd 体温上昇飲食品用の剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4927808A (en) * 1986-07-07 1990-05-22 Teijin Limited γ-L-glutamyl-L-cysteine ethyl ester and pharmaceutical compositions containing the same as an effective ingredient

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4927808A (en) * 1986-07-07 1990-05-22 Teijin Limited γ-L-glutamyl-L-cysteine ethyl ester and pharmaceutical compositions containing the same as an effective ingredient

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Institute for Biological Chemistry and Nutritions, Volume 4, issued 1985, STEHLE et al., "The potential use of short chain peptides in parenteral nutrition", pages 116-123. *
Journal of Nutrition, Volume 118, issued 1988, STEHLE et al., "Protein and amino acids: in vivo utilization of cystine containing synthetic short-chain peptides after intravenous bolus injection in the rat", pages 1470-1474. *
Proceedings of the National Academy of Science, USA, Volume 80, issued February 1983, ANDERSON et al., "Transport and direct utilization of gamma-glutamylcyst(e)ine for glutathione synthesis", pages 707-711. *
See also references of EP0608217A4 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992009277A1 (fr) * 1990-12-03 1992-06-11 Kabi Pharmacia Ab Source nutritive
EP0820285A1 (fr) * 1995-01-25 1998-01-28 University Of Southern California Procedes et compositions de lipidisation de molecules hydrophiles
EP0820285A4 (fr) * 1995-01-25 1998-04-22 Univ Southern California Procedes et compositions de lipidisation de molecules hydrophiles
US5907030A (en) * 1995-01-25 1999-05-25 University Of Southern California Method and compositions for lipidization of hydrophilic molecules
US5936092A (en) * 1995-01-25 1999-08-10 The University Of Southern California Methods and compositions for lipidization of hydrophilic molecules
US6225445B1 (en) 1995-01-25 2001-05-01 The University Of Southern California Methods and compositions for lipidization of hydrophilic molecules
US7052704B2 (en) 1995-01-25 2006-05-30 University Of Southern California Methods and compositions for lipidization of hydrophilic molecules
US6093692A (en) * 1997-09-25 2000-07-25 The University Of Southern California Method and compositions for lipidization of hydrophilic molecules
DE102006018293A1 (de) * 2006-04-20 2007-10-25 Fresenius Kabi Deutschland Gmbh Pädiatrische Aminosäurelösung zur parenteralen Ernäherung
WO2007121807A1 (fr) * 2006-04-20 2007-11-01 Fresenius Kabi Deutschland Gmbh Solution d'acides aminés pour la nutrition parentérale pédiatrique
EA015709B1 (ru) * 2006-04-20 2011-10-31 Фрезениус Каби Дойчланд Гмбх Педиатрический аминокислотный раствор для парентерального питания и его применение
AU2007241469B2 (en) * 2006-04-20 2012-09-20 Fresenius Kabi Deutschland Gmbh Paediatric amino acid solution for parenteral nutrition
US8377876B2 (en) 2006-04-20 2013-02-19 Fresenius Kabi Deutschland Gmbh Pediatric amino acid solution for parenteral nutrition
CN104524542A (zh) * 2006-04-20 2015-04-22 费森尤斯卡比德国有限公司 用于胃肠外营养的儿科氨基酸溶液
US20110262965A1 (en) * 2010-04-23 2011-10-27 Life Technologies Corporation Cell culture medium comprising small peptides
US10793827B2 (en) 2010-04-23 2020-10-06 Life Technologies Corporation Cell culture medium comprising small peptides
AU2018202612B2 (en) * 2010-04-23 2020-10-29 Life Technologies Corporation Cell culture medium comprising small peptides
US11365389B2 (en) 2010-04-23 2022-06-21 Life Technologies Corporation Cell culture medium comprising small peptides

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EP0608217A4 (fr) 1993-12-06
CA2081023A1 (fr) 1991-10-24
AU7775591A (en) 1991-11-11
JPH05507472A (ja) 1993-10-28
EP0608217A1 (fr) 1994-08-03
IE911351A1 (en) 1991-10-23

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