Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1997-12-18
2002-07-09
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S529000, C554S123000, C554S115000
Reexamination Certificate
active
06417231
ABSTRACT:
This invention pertains to a method and composition for delivering pyruvate to a mammal.
Pyruvate (2-oxo-propanoate), or its acid form pyruvic acid (2-oxo-propanoic acid), has many potential therapeutic uses.
Beneficial effects that have been reported for pyruvate or pyruvic acid include the following, among others: increasing athletic endurance up to 20%, reducing serum glucose in diabetics, reducing serum lipids and fat deposition, treating alcoholic “fatty” liver, reducing obesity while maintaining lean body tissue, acting as an anti-oxidant, preventing cataracts, improving cardiac function, protecting the heart or intestine from ischemia and reperfusion injury, reversing insulin resistance, inhibiting the growth of breast cancer cells, preventing neuropathy associated with some neurotoxins such as DDC (used in treating HIV infections), improving wound healing, preventing oxalate kidney stones, and treating hyperkeratotic skin lesions.
A major obstacle to many potential uses of pyruvate has been the lack of an effective, non-toxic vehicle to deliver pyruvate to the body at the levels needed for therapeutic effects. Therapeutic effects have typically been reported at levels of 7% to 20% of total dietary calories. Pyruvic acid itself is toxic at such levels, because it presents far too large an acid load to the digestive tract. Nor are soluble salts of pyruvic acid acceptable at such levels, because they produce electrolyte loads well above safe levels.
Prior approaches have included substituting dihydroxyacetone for some of the pyruvate, or administering the pyruvate as an amino acid conjugate such as pyruvyl-glycine. Dihydroxyacetone is inferior to pyruvate in producing beneficial metabolic changes. Pyruvyl-glycine is unacceptable because the required amount would include a nitrogen equivalent of more than half of normal daily protein intake.
U.S. Pat. No. 5,536,751 discloses several demonstrated and proposed, desirable metabolic roles of pyruvate, including the following: (1) raising cytoplasmic phosphorylation potential, increasing the free energy available to a cell; (2) immediate substrate of and autocatalytic agent for pyruvate dehydrogenase, leading to increased availability of NADH to mitochondria, improving a cell's ability to adapt promptly to changing energy demands; (3) immediate substrate of pyruvate carboxylase, which maintains the small concentration of mitochondrial oxaloacetate, which is important in the citric acid cycle and in maintaining ATP synthesis and cellular energy status; (4) by its effect on lactate dehydrogenase, pyruvate can help prevent accumulation of NADH
2
, which can be hazardous to heart mitochondria; (5) preventing the accumulation of free ferrous ion during ischemia-acidosis/reperfusion, which in turn can reduce the concentration of damaging free radicals produced by the catalytic effect of ferrous ions in the Fenton reaction; (6) several mechanisms for metabolic removal of intracellular hydrogen ions (as opposed to buffering or neutralization); (7) protection of labile but essential —SH groups on various important enzymes and other compounds from free-radical oxidative stress; (8) non-enzymatic neutralization of hydrogen peroxide; and (9) improving blood oxygen transport. Despite the recognition of these multiple physiological roles for pyruvate, the only compositions disclosed by the U.S. Pat. No. 5,536,751 patent for administering pyruvate are the acid and salt forms, generically described as R—C(O)(CO)OH, or a pharmaceutically acceptable salt. However, the only specific embodiments mentioned among that patent's many examples were salts of pyruvic acid such as sodium pyruvate.
U.S. Pat. No. 5,533,973 describes an apparatus and method for modifying a liquid enteral nutritional product during delivery. Included as part of a list of possible nutrients to be administered with the apparatus were “pyruvate precursors such as pyruvamide, or pyruvyl-amino acids, such as, pyruvyl-glycine, pyruvyl-alanine, pyruvyl-leucine, pyruvyl-valine, pyruvyl-sarcosamine and their amides, esters and salts.” See similarly U.S. Pat. Nos. 5,531,734; and 5,531,681.
U.S. Pat. No. 5,256,697 describes a method for administering pyruvate to a mammal with a pyruvate precursor in the form of a pyruvamide or a pyruvyl-amino acid, such as pyruvyl-glycine, pyruvyl-alanine, pyruvyl-leucine, pyruvyl-valine, pyruvyl-isoleucine, pyruvyl-phenylalanine, pyruvyl-proline, pyruvyl-sarcosine, their amides, esters, and salts. See similarly U.S. Pat. No. 5,283,260.
U.S. Pat. No. 4,874,790 describes treating animals with diabetic tendencies by oral administration of pyruvate and dihydroxyacetone.
U.S. Pat. No. 5,134,162 describes a process for lowering the blood cholesterol of hyperlipidemic patients by oral ingestion of pyruvate and a confection (cereal bar, fruit bar, candy) containing pyruvate.
U.S. Pat. No. 5,294,641 describes a method for treating a patient prior to or during heart trauma by administering pyruvate orally or intravenously. The disclosure states that the pyruvate may be in the form of organic salts such as calcium or sodium pyruvate, or esters of pyruvic acid such as ethyl amino pyruvate.
U.S. Pat. Nos. 4,981,687; 5,089,477; 5,147,650; 5,236,712; and 5,238,684 disclose compositions and methods to reduce or prevent adverse physiological effects of physical exercise or environmental exposure, or to ameliorate adverse physiological effects of blood loss. The compositions may include glycerol or an ester of glycerol, or pyruvate, or both glycerol and pyruvate.
U.S. Pat. No. 5,100,677 describes processes and compositions for accomplishing fluid therapy with various anions, including pyruvate, or the acid forms, including pyruvic acid.
U.S. Pat. No. 4,401,827 describes acyl derivatives of &bgr;-hydroxy-&ggr;-butyrobetaine such as pyruvyl carnitine hydrochloride for use as therapeutic agents in the treatment of cardiac disorders, hyperlipidaemias, and hyperlipidproteinaemias.
J. W. Bailey et al., “Triacetin: A Potential Parenteral Nutrient,”
J. Parental and Enteral Nutrition
, vol. 15, pp. 32-36 (1991) discloses infusing dogs with triacetin, the triglyceride of acetate, to provide calories without any resulting overt acute toxicity. Administering triacetin was observed to reduce circulating pyruvate levels.
A novel method and composition have been discovered for administering pyruvate in high doses to mammals, including humans. The novel method and composition do not produce an excessive acid load, salt load, or nitrogen load. Bioavailability of pyruvate from the novel composition is high. The novel composition has been named “tripyruvin” (tripyruvyl glycerol, or glycerol tripyruvate), and has the following structure:
Tripyruvin is about 86% pyruvate by weight.
The novel method comprises administering tripyruvin to a mammal in therapeutic amounts, preferably by oral administration. Even with a consumption sufficient to produce therapeutically effective levels of pyruvate, tripyruvin does not produce a concomitant acid load, salt load, or nitrogen load in the recipient.
Synthesis of Tripyruvin
The synthesis of tripyruvin was a modification of the method of M. Saroja et al., “A Convenient Method of Esterification of Fatty Acids. Preparation of Alkyl Esters, Sterol Esters, Wax Esters and Triacylglycerols,”
Synthetic Communications
, vol. 16, pp. 1423-1430 (1986). Briefly, bromine was combined with pyruvic acid to form pyruvyl bromide. Pyruvyl bromide was condensed with glycerol to form tripyruvin, which was then purified through a series of extractions, and concentrated by lyophilization. Tripyruvin was then separated from residual free pyruvate by passage through a strongly basic anion exchange column.
Step 1. Fifty mL methylene chloride were placed in a 125 mL flask. Triphenylphosphine (7.86 g, 0.03 M) was added with stirring by a magnetic stir bar. Bromine was added dropwise until a faint yellow color persisted.
Step 2. Fifty mL methylene chloride were placed in a second 125 mL flask. Pyruvic acid (2.64 g, 0.03 M) was added to the flask, followed by 10 mg
Greenway Frank L.
Rood Jennifer C.
Jones Dwayne C.
Runnels John H.
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