Therapeutic compositions

Abstract

Compositions comprising ketone bodies and/or their metabolic precursors are provided that are suitable for administration to humans and animals and which have the properties of, inter alia, (i) increasing cardiac efficiency, particularly efficiency in use of glucose, (ii) for providing energy source, particularly in diabetes and insulin resistant states and (iii) treating disorders caused by damage to brain cells, particularly by retarding or preventing brain damage in memory associated brain areas such as found in Alzheimer's and similar conditions. These compositions may be taken as nutritional aids, for example for athletes, or for the treatment of medical conditions, particularly those associated with poor cardiac efficiency, insulin resistance and neuronal damage. The invention further provides methods of treatment and novel esters and polymers for inclusion in the compositions of the invention.

1 . A method of treating a patient for a neuro-degenerative disorder comprising administering to that patient a therapeutically effective amount of one or more of D-β-hydroxybutyric acid, acetoacetate, or a metabolic precursor or physiologically acceptable salt of D-β-hydroxybutyric acid or acetoacetate, such as to elevate the patient's blood level of ketone bodies, defined as the sum total of D-β-hydroxybutyric acid and acetoacetate, to a therapeutic level effective to treat the disorder  
       wherein when a metabolic precursor is administered it is not hydroxybutyryl carnitine.  
     
     
         2 . A method of treating a patient in order to treat a neuro-degenerative disorder comprising administering to that patient a therapeutically effective amount of at least one of D-β-hydroxybutyric acid, acetoacetate, or a metabolic precursor or physiologically acceptable salt of D-β-hydroxybutyric acid or acetoacetate, such as to elevate the patient's blood level of ketone bodies, defined as the sum total of D-β-hydroxybutyric acid and acetoacetate, to a therapeutic level effective to treat the disorder  
       wherein the patient's blood level is elevated to from 0.3 mM to 20 mM.  
     
     
         3 . A method of treating a CNS cell, peripheral nerve cell, or otherwise insulin insensitive cell in need of therapy for one or more of neuro-degeneration, GABA preventable seizure, or insufficient ability to metabolise glucose, comprising administering to that cell one or more compounds selected from the group consisting of D-β-hydroxybutyric acid, acetoacetate, compounds which are oligomers of D-β-hydroxybutyric acid, acetoacetyl esters of D-β-hydroxybutyric acid and acetoacetyl esters of oligomers of D-β-hydroxybutyric acid, and physiologically acceptable salts thereof.  
     
     
         4 . A method of treating an patient for epilepsy, diabetes or an insulin resistant state comprising administering to that patient a therapeutically effective amount of one or more compounds selected from the group consisting of D-β-hydroxybutyric acid, acetoacetate and metabolic precursors of D-β-hydroxybutyric acid or acetoacetate which comprise moieties selected from the group consisting of R-1,3-butandiol, acetoacetyl and D-β-hydroxybutyryl moieties and physiologically acceptable salts and esters thereof.  
     
     
         5 . A method as claimed in any one of    claim 1   ,    claim 2   ,    claim 3    and    claim 4    wherein on administration of the compound to an unfasted patient in need of such therapy, the blood level of ketone bodies, defined as the sum total of D-β-hydroxybutyric acid and acetoacetate, is raised to between 0.3 and 20 mM.  
     
     
         6 . A method as claimed in    claim 1    or    claim 2    wherein the neurodegenerative disorder is selected from the group consisting of neurodegenerative disorders involving inability to metabolise glucose, memory loss in ageing, neurotoxic peptides or proteins, and genetic abnormality.  
     
     
         7 . A method as claimed in    claim 6    wherein the neurodegenerative disorder is selected from those involving neurotoxic protein plaques.  
     
     
         8 . A method as claimed in    claim 1    or    claim 2    wherein the metabolic precursor is selected from the group consisting of Free Fatty Acids and compounds comprising 1,3-butandiol, acetoacetyl or D-β-hydroxybutyryl moieties.  
     
     
         9 . A method as claimed in    claim 1   ,    claim 2   ,    claim 3    or    claim 4    wherein the metabolic precursor is a polymer or oligomer of D-β-hydroxybutyrate.  
     
     
         10 . A method as claimed in    claim 9    wherein the metabolic precursor is an acetoacetyl ester.  
     
     
         11 . A method as claimed in    claim 9    wherein metabolic precursor is selected from the group consisting of compounds of general formulae  
       
         
           
           
               
               
           
         
         or physiologicial acceptable salts or esters thereof  
         wherein in each case n is selected such that the polymer or oligomer is readily metabolised on administration to a human or animal body to provide elevated ketone body levels in blood.  
       
     
     
         12 . A method as claimed in    claim 11    wherein n is an integer of 0 to 1,000.  
     
     
         13 . A method as claimed in    claim 11    wherein n is an integer of from 1 to 5.  
     
     
         14 . A method as claimed in    claim 1   ,    claim 2   ,    claim 3    or    claim 4    wherein the level of ketone bodies produced in the blood is in the ratio 1:1 to 20:1 of D-β-hydroxybutyrate to acetoacetate.  
     
     
         15 . A method as claimed in    claim 9    wherein the oligomer is a cyclic oligomer of formula  
       
         
           
           
               
               
           
         
       
       where n is an integer of 1 or more  
       or a complex thereof with one or more cations or a salt thereof.  
     
     
         16 . A method as claimed in    claim 15    wherein the one or more cations are selected from the group consisting of sodium, potassium, magnesium and calcium.  
     
     
         17 . A method as claimed in    claim 15    wherein n is an integer from 1 to to 20.  
     
     
         18 . A method as claimed in    claim 1    wherein it is (R, R, R)-4, 8, 12-trimethyl-1, 5, 9-trioxadodeca-2, 6, 10-trione.  
     
     
         19 . A compound of formula  
       
         
           
           
               
               
           
         
         or physiologicial acceptable salts or esters thereof.  
         wherein n is an integer from 0 to 1000.  
       
     
     
         20 . A compound as defined in    claim 19    wherein the ester is selected from the group consisting of monohydric, dihydric or trihydric alcohol esters.  
     
     
         21 . A compound as claimed in    claim 19    wherein the ester is of (R)-1,3-butandiol.  
     
     
         22 . A compound as claimed in    claim 19    wherein n is selected from the group of integers 0, 1, 2,3 and 4.  
     
     
         23 . A foodstuff comprising poly D-β-hydroxybutyrate characterised in that it is derived from a foodstuff generating organism that has had a gene capable of producing D-β-hydroxybutyrate inserted therein.  
     
     
         24 . A foodstuff charactersied in that it comprises at least 5% ketone bodies by weight.  
     
     
         25 . A method for the synthesis of D-β-hydroxybutyryl-acetoacetate or poly or oligo-D-β-hydroxybutyryl-acetoacetate esters comprising the reaction of acetoacetic acid halide with D-β-hydroxybutyrate or poly- or oligo-D-β-hydroxybutyrate.  
     
     
         26 . A method for synthesis of D-β-hydroxybutyryl-acetoacetate or oligo-D-β-hydroxybutyryl-acetoacetate comprising reacting D-β-hydroxybutyryic acid with diketene.  
     
     
         27 . A method of synthesising an oligomer of D-β-hydroxybutyric acid comprising heating a solution of D-β-hydroxybutyric acid in a solvent until an oligomer of a desired number of repeats is produced.  
     
     
         28 . Use of D-β-hydroxybutyric acid, acetoacetate, or a metabolic precursor or physiologically acceptable salt of D-β-hydroxybutyric acid or acetoacetate for the manufacture of a medicament for the treatment of a disorder by a method as set out in any one of claims 1 to 14 provided that when the use is of a metabolic precursor that is not racemic hydroxybutyryl carnitine.  
     
     
         29 . A foodstuff as claimed in    claim 23    or    claim 24    for use in therapy.  
     
     
         30 . Poly-D-β-hydroxybutyrate for use in therapy.  
     
     
         31 . A composition comprising a compound selected from those claimed in any one of    claims 15    to    18    and poly D-β-hydroxybutyrate together with a physiologically acceptable carrier, in sterile and pyrogen free form.