A Composition for Managing Cadasil

Abstract

The present invention provides use of a composition for the manufacture of a medicament for mitigating debilitating effects of Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), wherein the composition comprises vitamin E tocotrienols in a mixture of squalenes, phytosterols and pharmaceutically acceptable excipients.

Claims

1.-16. (canceled)

17. A composition for the manufacture of a medicament for mitigating debilitating effects of Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), comprising: vitamin E tocotrienols in a mixture of squalenes, phytosterols and pharmaceutically acceptable excipients.

18. The composition according to claim 17, wherein the composition further comprises vitamin E tocopherols.

19. The composition according to claim 17, wherein the debilitating effects is any one or any combination of abnormal brain lesions, cognitive impairment, dementia, memory deterioration, occurrence of ischemic events, occurrence of disability, migraine headaches, multiple strokes, seizures, vision problems, depression, apathy and mood disturbances.

20. The composition according to claim 17, wherein the vitamin E tocotrienol is any one or any combination of alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, and delta-tocotrienol.

21. The composition according to claims 17, wherein the vitamin E tocotrienols are present at a concentration ranging from 10 to 40% by weight of the composition.

22. The composition according to claim 20, wherein the alpha-tocotrienol is present at a concentration ranging from 3 to 20% by weight of the composition.

23. The composition according to claim 20, wherein the beta-tocotrienol is present at a concentration ranging from 0.7 to 3.0% by weight of the composition.

24. The composition according to claim 20, wherein the gamma-tocotrienol is present at a concentration ranging from 6 to 30% by weight of the composition.

25. The composition according to claim 20, wherein the delta-tocotrienol is present at a concentration ranging from 1.5 to 12% by weight of the composition.

26. The composition according to claim 20, wherein the alpha-tocopherol is present at a concentration ranging from 3 to 15% by weight of the composition.

27. The composition according to claim 17, wherein the squalene is present at a concentration ranging from 2.5 to 10% by weight of the composition.

28. The composition according to claim 17, wherein the pharmaceutically acceptable excipient is present at a concentration ranging from 0.1 to 50% by weight of the composition.

29. The composition according to claim 18, wherein the vitamin E tocotrienols and vitamin E tocopherols are derived from plants selected from the group consisting of palm oil, rice bran oil, barley, oat, rye, wheat germ and annatto.

30. The composition according to claim 17, wherein the squalene is derived from plants.

31. The composition according to claim 17, wherein the pharmaceutically acceptable excipient is any one or any combination of plant-based oil, water-based emulsifiers, oil-based emulsifiers, co-emulsifiers, antioxidants, and suspending agents.

32. The composition according to claim 17, wherein the medicament is formulated into dosage form selected from the group consisting of capsule, tablet, emulsion and suspension.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0015] One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The embodiment described herein is not intended as limitations on the scope of the invention.

[0016] The present invention discloses use of a composition for the manufacture of a medicament for mitigating or managing effects of Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) and related disorders, wherein the composition comprises vitamin E tocotrienols in a mixture of squalenes and pharmaceutically acceptable excipients. Particularly, the composition can be used in the manufacture of a medicament capable of managing or mitigating manifestations of CADASIL including cognitive impairment, memory deterioration, dementia, occurrence of ischemic events, occurrence of disability, migraine headaches, multiple strokes, seizures, vision problems and/or psychiatric problems such as depression, apathy and mood disturbances.

[0017] Vitamin E tocotrienols may constitute 10 to 40% of the composition, or more particularly 15 to 35% of the composition. In accordance with the preferred embodiment of the invention, the vitamin E tocotrienols can be any one or any combination of alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, and delta-tocotrienol. Preferably, the composition further comprises alpha-tocopherol. In another embodiment of the invention, the composition may further comprise vitamin E tocopherols including, but not limited to, beta-tocopherol, gamma-tocopherol, and delta-tocopherol. Preferably, the vitamin E tocotrienols and tocopherols are derived from natural sources. More preferably, the vitamin E tocotrienols and tocopherols are derived from sources selected from the group consisting of palm oil, rice bran oil, annatto, and cereal grains such as barley, oat, rye and wheat germ.

[0018] Preferably, the composition disclosed herein is adapted for oral consumption. Vitamin E tocotrienols, and tocopherols, in the orally administered composition can reach the cerebrospinal fluid and brain. Vitamin E tocotrienols and tocopherols in the brain provide protection to the members of the nervous system against damage. In more particular, vitamin E tocotrienols and tocopherols target and inhibit the cSrc-regulated 12-lipoxygenase pathway which is known to be implicated in neurodegeneration associated with ischemic stroke. In the 12-lipoxygenase pathway, free arachidonic acid (AA) is cleaved and released from the membrane phospholipids by phospholipase, specifically phospholipase A2 during an ischemic event and hypoperfusion in the cerebrovascular network in the brain. Arachidonic acid is subsequently converted by 12-lipoxygenase to hydroperoxyeicosatetraenoic acid which is the key mediator of neurotoxicity, leading to neurodegeneration. Inhibition of the cSrc-regulated 12-lipoxygenase pathway by vitamin E tocotrienols and tocopherols protect against cerebrovascular hypoperfusion-induced injuries such as neurotoxicity and brain cell death, thus suggesting the ability of vitamin E tocotrienols and tocopherols to prevent or delay cognitive decline and dementia related to the death of brain neuron cells

[0019] In addition, arachidonic acid is highly susceptible to oxidative metabolism under pathologic conditions. AA that is cleaved from the phospholipid bilayer by phospholipase A.sub.2 (PLA.sub.2) can undergo uncontrolled oxidative metabolism, which is also known as AA cascade. Metabolism of AA amplifies the overall production of free radicals in the brain and subsequently causes oxidative damage to the brain tissues. vitamin E tocotrienols and tocopherols, however, are able to attenuate the AA cascade. In more particular, vitamin E tocotrienols and tocopherols inhibit the oxidative damage caused by free radicals generated during a pathologic condition.

[0020] Moreover, vitamin E tocotrienols and tocopherols are capable of preventing loss of white matter fiber tract connectivity after a stroke event by improving the cerebrovascular collateral circulation to the area of hypoperfusion in the brain by inducing arteriogenic tissue inhibitor of metalloprotease 1 expression to promote cerebrovascular arteriogenesis. This helps to improve blood circulation to the hypoperfusion sites in the brain. In addition, the composition is effective in mitigating injury present during cerebrovascular ischemic event in patients suffering from CADASIL and related disorder, in which the composition reduces stroke lesion volume, promotes vascular angiogenesis, and improves cerebrovascular collateral circulation.

[0021] In one embodiment of the invention, the composition comprises alpha-tocotrienol in a concentration range of 3 to 20% by weight. In a more preferred embodiment of the invention, alpha-tocotrienol presents in the composition at a concentration ranging from 5 to 16% by weight of the composition. Beta-tocotrienol constitute 0.7 to 3% by weight of the composition, or more preferably 0.8 to 2% by weight of the composition. Gamma-tocotrienol is present at a concentration ranging from 6 to 30% by weight of the composition in one embodiment of the invention, or 8 to 25% by weight of the composition in a more preferred embodiment. Alternatively, delta-tocotrienol constitute 1.5 to 12% by weight of the composition, or more preferably 2 to 10% by weight of the composition. In one embodiment of the invention, 3 to 15% by weight of the composition is made up of alpha-tocopherol. In a more preferred embodiment, 5 to 12% by weight of the composition is made up of alpha-tocopherol.

[0022] As set forth in preceding description, vitamin E tocotrienols and tocopherols are present in the composition in conjunction with squalenes and pharmaceutically acceptable excipients. Preferably, squalene in the composition is plant-based squalene. Sources for squalene used in the composition include, but not limited to, olive, oil palm fruits, amaranth seed, and rice bran. Squalene in the composition is beneficial in preventing memory deterioration due to its anti-oxidant activity. Preferably, the composition disclosed herein comprises 2.5 to 10% of squalene by weight of the composition. More preferably, squalene constitutes 3 to 8.5% by weight of the composition.

[0023] Pharmaceutically acceptable excipients are compounds that are inert to the other ingredients and generally have no pharmacological effects. They are included in the composition disclosed herein for the purpose of long-term stabilization and/or enhancement of bioavailability of vitamin E tocotrienols, vitamin E tocopherols and squalene. The composition of the invention may comprise one or more pharmaceutically acceptable excipients selected from the group consisting of plant-based oil, water-based emulsifiers, oil-based emulsifiers, co-emulsifiers, antioxidants, and suspending agents. Preferably, pharmaceutically acceptable excipients is present at a concentration ranging from 0.1 to 50% by weight of the composition. More preferably, pharmaceutically acceptable excipients is present at a concentration ranging from 0.15 to 40% by weight of the composition.

[0024] The medicament manufactured from the composition described in the preceding description is preferably formulated into dosage forms including, but not limited to, capsules, tablets, emulsions, and suspensions. More preferably, the medicament is present in the dosage form of soft capsules for enhanced bioavailability. Administration of the medicament over a period of time ranging from 1 to 5 years can effectively result in slowing of the progressive neurodegenerative disease.

EXAMPLE

[0025] The following non-limiting example has been carried out to illustrate the preferred embodiments of the invention.

Example 1

[0026] Case study of CADASIL patient progression under 24 months administering of the composition.

[0027] The composition of the present invention is capable of mitigating progression of abnormal brain lesions and reducing migraine headaches, without further occurrence of ischemic evens, disability, dementia, multiple strokes, seizures, vision problems or psychiatric problems, for at least 4 years from administering the composition.

TABLE-US-00001 TABLE 1 Progression of white matter lesion volume in CADASIL patient over 2 years supplementation of the composition. 6- 12- 24- Assessment Baseline month month month White Matter 24,144 22,105 19,756 19,073 Lesion (WML) (100%) (92%) (82%) (79%) volume (mm.sup.3) Total Brain volume 1,240,930 1,237,441 1,200,312 1,203,070 (mm.sup.3) WML to Brain volume 1.94% 1.79% 1.65% 1.59% ratio

TABLE-US-00002 TABLE 2 Assessment of headache impact and cognitive function in CADASIL patient over 2 years supplementation of the composition. 6- 12- 18- 24- Assessment Baseline month month month month Headache Impact 57 — 36 36 36 Test (HIT-6) (substantial (no (Migraine ≥50) impact) impact) Montreal Cognitive 29 30 26 27 28 Assessment (Normal ≥26)

REFERENCES

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