Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
2000-08-15
2003-10-07
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S464000, C424S484000, C424S489000, C514S724000, C514S866000
Reexamination Certificate
active
06630157
ABSTRACT:
FIELD
The invention relates to therapeutic and dietary compositions.
FATTY ACIDS
Gamma-linolenic acid (GLA), its immediate metabolite dihomogamma-linolenic acid, (DGLA) and, in certain circumstances, the DGLA metabolite arachidonic acid (AA), have wide ranges of desirable biological effects as essential nutrients and as nutrients or therapeutic agents specific preventative or therapeutic effects in various diseases including those of the skin (such as eczema and psoriasis), those of metabolism (in particular diabetes and its complications such as retinopathy, neuropathy, nephropathy and cardiovascular problems), those of inflammation and autoimmunity (such as rheumatoid arthritis, osieoarthritis, Sjogren's syndrome, systemic lupus, Crohn's disease, ulcerative colitis), those of the respiratory system (including asthma, pulmonary hypertension and pulmonary fibroses), those of the psyche and central nervous system (such as schizophrenia, dementia of Alzheimer and vascular or other types, depression and multiple sclerosis), those of the cardiovascular system (such as hypertension and coronary and peripheral arterial disease), those of the kidney (such as glomerulonephritis and other inflammatory and autiommuune conditions), those of the gastrointestinal system (such as oesophagitis, gastritis, peptic ulcer, Crohn's disease and ulcerative colitis) and those of the endocrine system and its target organs (such as benign breast disease and benign prostatic disease). Cancer and pre-cancerous conditions may also respond to treatment with GLA and DGLA. GLA and DGLA have also been found to be beneficial in animal diseases and also in the care of diseased and of normal skin where they improve skin blood flow and skin smoothness.
Other essential fatty acids, of the n-3 series, notably stearidonic acid (SA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) also have many desirable nutritional and therapeutic effects, and many of the prior patents filed by the present applicants, relate to use of either or both series of essential fatty acids in various condition EPA 0 218 460, concerning the complications of diabetes being one example.
Both series of essential fatty acids are well known in themselves and their terminology and relations are set out below
TABLE 1
n-6 EFA's
n-3 EFA's
18:2n-6
18:n-3
(Linoleic acid, LA)
(&agr;-Linolenic acid, ALA)
↓
delta-6-desaturase
↓
18:3n-6
18:4n-3
(&ggr;-Linolenic acid
(Stearidonic acid)
GLA)
↓
elongation
↓
20:3n-6
20:4n-3
(Dihomo-&ggr;-linolenic
↓
acid, DGLA)
↓
delta-5-desaturase
20:4n-6
20:5n-3
(Arachidonic acid,
(Eicosapentaenoic acid, EPA)
AA)
↓
elongation
↓
22:4n-6
22:5n-3
(Adrenic acid, AdrA)
↓
delta-4-desaturase
↓
22:5n-6
22:6n-3
(Docosahexaenoic acid, DHA)
The acids, which in nature are of the all—cis configuration, arc systematically named as derivatives of the corresponding octadecanoic, cicosanoic or docosanoic acids, e.g. z,z-octadeca-9,12 -dienoic acid or z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoic acid, but numerical designations based on the number of carbon atoms, the number of centres of unsaturation and the number of carbon atoms from the end of the chain to where the unsaturation begins, such as, correspondingly, 18:2 n-6 or 22.6 n-3, are convenient. Initials, e.g. EPA, and shortened forms of the name e.g. eicosapentaenoic acid, are used as trivial names in some instances. Further the acids beyond the 6desaturation step are informally known as the “6-desaturated” acids.
DISULPHIDES
Quite different types of chemical entity are &agr;-lipoic acid, also known as thioctic acid (TA), and related compounds. In the body TA is converted to dihydrolipoic acid (DHL) during the formation of acetyl-CoA from pyruvic acid or the formation of succinyl-CoA from &agr;-oxoglutaric acid, and during other oxido-reduction reactions. DHL can be converted back to TA by lipoic acid dehydrogenase, which requires the co-factor AND. TA and DHL have been seen as equivalent since they are rapidly interconverted in the body. The structures are:
with R, S and racemic forms and
also with R, S and racemic forms. In the context of this application thioctic acid means isomerically pure D- or S- alpha-lipoic acid, racemic alpha-lipoic acid or any mixture of the R- and S- isomers, and correspondingly for compounds related to thioctic acid including the reduced forms.
TA and the related free disulphide compounds, which are strongly lipophilic, are antioxidant agents capable of forming a redox couple in the body and they have for example been found to be of therapeutic value in the management of complications of diabetes, especially diabetic neuropathy Such complications are believed to be associated with excessive rates of oxidation of lipids and proteins and the TA/DHL redox couple has been seen as significant in neutralising many species of free radicals. Furthermore it can “recycle” other important antioxidants such as &agr;-tocopherol and ascorbate and bring about an increase of intracellular glutathione. In addition to diabetic complications, there is evidence that TA can enhance sensitivity to insulins so being of value in the pre-diabetic syndrome X and in obesity.
Metabolites of TA with similar function to TA are tetranorlipoic acid (TALA), bisnorlipoic acid (BALA) and 8-hydroxy-bisnorlipoic acid (8BALA) with R and S isomers as a with lipoic acid.
The antioxidant properties and consequent previously proposed clinical applications of &agr;-lipoic acid and its reduced form in diabetes and other conditions are discussed in the Handbook of Antioxidants (eds. E Cadanas and L Packer, Marcel Dekkar, New York 1996) see Chapter 18 pages 545-591, by Packer Witt and Tritschler Further, the applicants' prior patent application PCT GB 96/01053 (WO 96/34846) discloses fatty acid/antioxidant derivatives of 1,3-propane diol and their use in conditions which antioxidants are beneficial including cardiovascular diseases, cancer and inflammatory disorders. Particular diesters disclosed are of GLA or DHA and lipoic acid. Related compounds, formally derivatives of dihydroxy methane, are disclosed in the applicants' further specification PCT GB 96/01052 (WO 96/34855). In those applications it is however emphasised that compounds containing moieties of the fatty acid and lipoic acid are used: there is no reference to the co-administration of fatty acids and lipoic acid as separate molecules nor for particular purposes. In Hoechst U.S. Pat. No. 5,043,328 lipoic acid is mentioned as an antioxidant though in a prostaglandin-metabolism context, on gastro-intestinal problems and skin and subdermal tissue malfunctions.
NEW WORK DONE INVENTION
Available therapies in treatment and prevention of most of the conditions mentioned so far, including diabetes, insulin resistance, syndrome X, and diabetic complications such as neuropathy and retinopathy, are far from satisfactory It seemed to us that the use of the above two different approaches simultaneously might be worth testing in relation to diabetic complications. GLA is believed to work mainly on the micro-circulation whereas TA/DHL is believed to work mainly on oxidation mechanisms, but it seemed reasonable to see whether the co-application of these agents might have at least additive effects.
In fact in measurements of nerve conduction velocity and nerve blood flow a dramatic and unexpected synergism was observed, with the effect of the two agents applied together being far greater than the sum of the effects of the two agents when applied alone. The results are shown in
FIGS. 1 and 2
. In diabetic animals both nerve conduction and nerve blood is flow are considerably affected. Both can be completely normalised by the co-administration of amounts of GLA and TA that have little effect alone.
The results with EFA's and their synergistic effects with TA were completely unexpected and we decided to investigate them further. Vitamin E, like TA, is a lipophilic antioxidant and is one which is generally regarded as being
Horrobin David F.
Tritschler Hans-Jurgen
Evans Charesse
Nixon & Vanderhye P.C.
Page Thurman K.
Viatris GmbH & Co. KG.
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