Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1995-04-06
2001-10-23
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S023000, C536S115000, C536S119000
Reexamination Certificate
active
06306828
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention generally relates to the field of enteral and parenteral nutritional formulations. More particularly, it relates to new and improved enantiomerically-enriched energy substrates for use in nutritional formulations providing high caloric density and low osmolarity which may also be used to beneficially direct intermediate metabolism in metabolically impaired patients.
Nutritional formulations are known which are used to supply the total nutritional needs of a patient. Other nutritional formulations are intended as supplements to provide certain special nutritional needs associated with various patient conditions and/or disease states. Most formulations include a protein component, a carbohydrate component and a lipid component.
The energetic and protein needs of patients having high metabolic activity are difficult to satisfy. Fats or lipids represent the richest nutrients from the point of view of energy. However, excessive consumption of fats presents a large number of health risks, especially cardiovascular health risks. Certain metabolic disorders involving lipids such as hyperlipidemia, obesity and diabetes also require restricted intake of fats generally, and saturated fats and cholesterol, in particular. The use of various substrates in nutritional formulations in above-normal quantities may induce metabolic perturbations and imbalances in the homeostasis of the patient.
It has been determined that not only the quantity but also the component makeup of the lipid fraction of a nutritional formulation may be very important for patients suffering from certain disease states or recovering from surgery, chemotherapy or traumatic injury. For example, hypernutrition for patients with respiratory failure may be a problem. Long chain triglycerides (LCTS) should be avoided during sepsis. Patients with insulin resistance should have their glucose requirements carefully regulated. The formulations, depending on their chemical composition, may also cause intestinal transit problems leading to diarrhea.
U.S. Pat. No. 5,283,260 to Miller, et al., describes the use of pyruvyl amino acid compounds, as alternative energy sources for the treatment of obesity and diabetes.
U.S. Pat. No. 5,283,260 to Galeb, et al., describe the use of low glucose-containing nutritional formulations for head trauma patients based on n-6 and n-3 fatty acids as alternative energy sources.
Hermanson, et al. in
Acta Physiol. Scand
., 1972, Vol. 86, pages 191-201, disclosed their findings that blood lactate appears to be metabolized by skeletal muscle in significant quantities rather than exclusively by the liver as was previously thought.
Jensen, et al., in
Laboratory Investigation
, Vol. 54, No. 5, page 574, 1986, describe a study which indicated that high lactate concentration encouraged macrophage cultures to secrete angiogenesis factors. Jensen, et al. concluded that high lactate concentrations may stimulate angiogenesis in wound healing. The authors also found that pyruvate did not cause the same response.
Stephanie Amiel, in
Proceedings of the Nutrition Society
, (1994), Vol. 54, pages 401-405, states that lactate studies suggest that lactate is able to support cerebral glucose metabolism and maintain cognitive functions during hypoglycemia. The author states that the development of therapeutic regimens to provide non-glucose fuels for cerebral metabolism during hypoglycemia needs to be more fully explored.
Maran, et al. in
The Lancet
, Vol. 343, Jan. 1, 1994, describe lactate as protective of brain function during hypoglycemia and recommend its therapeutic use in treating insulin dependent diabetes mellitus patients.
Some lipid components may be metabolized to form substrates whose concentration positively or negatively may affect the equilibria of other substrates. Moreover, many substrates may only be metabolized if present in a specific isomer form, such as (S)-(−) lactate, D-glucosides and the like. The presence of unhelpful and unusable substrates in nutritional formulations may lead to various problems including incomplete metabolism, toxic metabolites, side effects, and insufficient water solubility, to name but a few. It has been suggested that providing lactate may shift the equilibrium of the LDH enzyme catalyzed reaction:
Pyruvate+NADH+H
+
→lactate+NAD
+
to the left, preventing or reducing the likelihood for developing lactic acidosis. Nutritional formulations having lipid fractions which comprise substantially only the useful enantiomeric forms of certain substrates and metabolites are generally not known.
SUMMARY OF THE INVENTION
The present invention provides new and improved enantiomerically-enhanced energy substrates for use in nutritional formulations.
In an embodiment, new energy substrates comprise monoisomeric forms of glyceryl tri(chiral alkanoates). An example of an energy substrate of this type includes a synthetic triester of glycerol with (S)-(−)-lactic acid, providing three enantiomerically appropriate, so-called “L-form” lactate moieties per glycerol molecule.
In an embodiment, a method for making substantially monoisomeric chiral alkanoic acid esters is provided in which a protected chiral intermediate is formed before esterification and, after esterification is complete, the chiral protecting group is removed to yield the chiral ester product. Asymmetry of all asymmetric carbons is maintained through the reaction process without forming undesirable isomeric or other byproducts or intermediates.
In accordance with still another embodiment, enantiomerically enhanced nutritional substrates comprising anomeric glucoside and galactoside-containing alkanoic acid esters are provided. An example of these substrates includes an anomeric mixture of &agr;,&bgr;-D-glucopyranosyl C
2
-C
20
alkanoate, wherein the ratio of &agr;:&bgr; anomers is greater than about 2:1, respectively. A synthetic method for directly making these substrate compositions employing protected chiral intermediates is also provided by this invention.
In a further embodiment, novel enantiomerically enhanced nutritional substrates comprising chiral &agr;- or &bgr;-hydroxyalkanoyl C
2
-C
2
alkanoic acid esters and methods for making them are provided.
In another embodiment of the invention, new and improved nutritional formulations are provided comprising an enantiomerically enriched lipid fraction designed to provide high caloric density and low osmolarity. The new lipid fraction comprises at least one enantiomerically enriched energy substrate selected from chiral &agr;- and/or &bgr;-hydroxyalkanoyl alkanoates, glyceryl tri(chiral alkanoates), anomeric &agr;,&bgr;-D-glycopyranosyl alkanoates and mixtures of any of these substrates.
In accordance with a further embodiment of the invention, a method for treating a patient previously diagnosed as having a metabolic disorder or suffering from trauma or nutritional deficit is provided comprising administering to the patient an improved nutritional formulation including an enantiomerically-enhanced lipid fraction.
An advantage of the present invention is that new substrates and formulations are provided for enteral and parenteral nutrition which are present in biologically available forms.
Another advantage provided by the present invention is that new and improved substrates, lipid fractions and nutritional formulations are provided which are adapted to be used in enteral and parenteral nutritional formulations. The formulations are intended for therapeutic use in treating various metabolic disorders, post-operative, traumatic and/or disease conditions of a patient.
In accordance with the present invention, new energy substrates are provided having good caloric density. For example, in an embodiment, a preferred substrate comprises glucose octanoate. The molecular weight of glucose octanoate is 306 g/mole. ATP yield per mole of glucose=30 moles of ATP per mole of glucose oxidized to CO
2
and H
2
O. ATP yield per mole of octanoic acid=48 moles of ATP per mole of o
Jonas Patrick Francis
Leverve Xavier
Pereira David Eugene
Rose Francis
Rowe Bruce
Baxter International Inc.
Buonaiuto Mark J.
Kowalik Francis C.
Nichols Jeffrey C.
Peselev Elli
LandOfFree
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