Pharmaceutically active carotenoids

Details Pharmaceutically active carotenoids Pharmaceutically active carotenoids

1996-12-23

2001-04-17

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

C-o-group doai

C514S912000

Reexamination Certificate

active

06218436

ABSTRACT:

The invention related to the use of lutein and zeaxanthin which increase the deposition of macular pigment in the human eye. The invention is particularly but not exclusively concerned with lutein and/or zeaxanthin for use in the treatment by therapy or prophylaxis of disease of the macula and in particular age-related macular degeneration (AMD).
The macula is the anatomical region of the retina which in man is responsible for central vision. Centered on the fovea, where the visual axis meets the retina, it extends radially outwards to a distance of about 2.75 mm (Davson, 1990). The macula is divided into the inner macula and the outer macula. The inner macula extends radially out to a distance of 1.5 mm while the outer macula is defined by the surrounding annular ring. The central part of the macula is easily recognisable because of its yellow coloration which results from the presence of macular pigment.
Despite its small size the macula is endowed with the highest degree of visual acuity. It is therefore not surprising that considerable effort is devoted to understanding and, when possible, treating diseases which disrupt the normal functioning of the macula. One such disease is age-related macular degeneration (AMD) which occurs in about 20% of the population above the age of 65 and is the leading cause of visual impairment in the USA and UK. AMD has up to the present been an irreversible condition.
Pooled extracts of the macular pigment were found by Wald ((1945) to have a carotenoid-like absorption spectrum which appeared to match that of luetin. Further work in the 1980's demonstrated that it consisted of lutein and zeaxanthin (Bone et al 1985).
More recent work (Bone et al 1993) has shown that the zeaxanthin component found in the human retina is itself composed of all three of the possible stereoisomers.
FIG. 1
shows the stereochemical structures of the macular pigment components. The 3′ hydroxy groups on lutein and meso-zeaxanthin have the same absolute configuration making interconversion possible by a movement of the 4′-5′ double bond (lutein) to the 5′-6′ position (meso-zeaxanthin). Of the three stereoisomers, SSZ is present only as a relatively small component, RRZ is of dietary origin whereas RSZ (for meso-zeaxanthin) is not common in the diet and has yet to be detected in human serum. It has been suggested that the presence of RSZ may be the result of isomerization of lutein to RSZ by an enzyme.
The function of he macular pigment has not been unequivocally determined. It has been proposed that one function may be to reduce the adverse effect of chromatic aberration in the ocular media thereby increasing acuity (Walls 1967: Reading and Weale 1974). Currently, a more generally held view is that the pigment probably acts in a protective capacity against the damaging effects of blue light (Dicthburn 1973, Kirshfeld 1982, Bone et al 1984) which can induce the formation of reactive free radicals within the retina and the formation of such species may be greatly reduced in individuals having a high level of macular pigmentation. The macular pigment may also serve passively as a filter and shield sensitive tissues from harmful excessive blue light.
AMD is a disease which develops gradually over a period of many years with loss of sight being the ultimate result. The damaged tissue has an unusually high lipid content which it is has been suggested oxidises to form lipofuscin, a fluorescent product of lipid oxidation. It has been postulated that exposure of the retina to excessive blue light may increase the rate of lipofuscin formation. (Feeney-Burns et al 1990, Gottsch et al 1990).
To date, little is known about the factors which influence the uptake of carotenoids into the macula and there is no effective cure or prevention of AMD.
The studies of plasma carotenoids in case control studies of AMD have been equivocal. In the Beaver Dam eye study (Mares-Periman et al 1995), no differences were observed in 167 cases and 167 control in serum including lutein or zeaxanthin. In the Eye Disease Case Control Study Group (1993) results of 421 cases and 615 controls were reported. People with serum carotenoid levels in the medium to high group had one half to one third risk of AMD. All the carotenoids measured including lutein, zeaxanthin, beta carotene, alpha carotene and cryptoxanthin were implicated. In a further publication (Seddon et al, 1994), there authors found that the consumption of lutein and zeaxanthin (which are primarily obtained from dark green leafy vegetables) were most strongly associated with a reduced risk for AMD. However, some people with a high consumption of green vegetables still suffered from AMD.
In an abstract published in the March 1995 issue of Investigative Opthamology and Visual Science (36, suppl, 892), the carotenoid analysis of 8 normal eyes and 8 eyes from patients with AMD was reported. The results suggested a positive correlation existed between lowered macular pigment and the prevalence of AMD, but recommended that caution should be exercised in this interpretation because the reduced macular pigment could be a result, rather than a cause, of the disease. When the subject-matter of the above mentioned abstract was submitted for publication to a peer-reviewed journal, the referees recommended rejection because the number of samples analysed was too small. Further results were therefore necessary before any conclusion could be made on the possible preventative role of lutein/zeaxanthin in AMD.
It is the object of the present invention to increase macular pigment and to prevent or cure AMD by the administration of lutein and/or zeaxanthin.
It is a further object of the invention to provide a method of treatment of AMD by the use of lutein and/or zeaxanthin and further to provide a novel composition comprising these two hydroxy carotenoids in combination.
Within the above context we have now found surprisingly that by selecting a particular type of carotenoid namely lutein/zeaxanthin or an ester thereof it is possible to increase the macular pigment in the human macula which could lead to the prevention and/or treatment of AMD in those people at risk or with the disease.
Moreover the effective does is rather surprisingly greater than that which is normally achieved by the intake of lutein/zeaxanthin in rich green vegetables. While it could be suspected that since the macula contains lutein/zeaxanthin, the administration of lutein/zeaxanthin in quantities similar to that occurring in green vegetables would raise the concentration of macular pigment, it has been found rather surprisingly that when the caroteinoids are given orally in a concentrated form the amount required to be effective in the short term is considerably greater than expected.
Furthermore, it has ben found that in a sufficiently large enough sample to warrant conclusions, the lutein/zeaxanthin content of the retinas of eyes from people with AMD was 30% less than people with normal eyes.
Accordingly, the present invention in one aspect provides lutein/zeaxanthin or a mixture thereof for the use as a pharmaceutical or food supplement, particularly in the elevation of macular pigment and the prevention or management of age-related macular degeneration. For this purpose, the mixture can contain 10 to 90% of each carotenoid mixed with the other. Generally speaking, the active agent or agents (ie lutein and/or zeaxanthin) may be used in the total dosage regime of up to 100 mg per day typically 10-50 mg per day with an optimum dosage of 30 mg per day.
The dose depends on the time of administration. When the macula is depleted of macular pigment, a high dose (circa 30 mg/day) is normally used. Treatment methods according to the invention are principally directed to high dosage of the patient (ie amounts of 10 mg/day or higher) and are especially concerned in preferred embodiments to achieve serum levels of the carotenoid(s) of at least 0.7 or 0.8 mm/ml.
During the initial period of administration, it is preferred to use a large dose of circa 30 mg/d

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