COBALAMIN COMPOSITIONS AND USE THEREOF FOR IMPROVING COGNITIVE FUNCTION

Abstract

The invention provides cobalamin (vitamin B.sub.12) nutraceutical compositions and methods for use thereof for improving cognitive function in subjects having disorders of cognitive function such as neurodegenerative disorders, neurodevelopmental disorders, and neuropsychiatric disorders. This improvement in cognitive function is achieved through the ability of the cobalamin (vitamin B.sub.12) nutraceutical compositions to increase methylation capacity and vitamin B.sub.12 activity in the brains of the subjects.

Claims

1-42. (canceled)

43. A nutraceutical composition comprising methylcobalamin, hydroxycobalamin, and methylfolate.

44. The nutraceutical composition according to claim 43, wherein the methylcobalamin and hydroxycobalamin are combined as vitamin B.sub.12.

45. The nutraceutical composition according to claim 44, further comprising lithium.

46. The nutraceutical composition according to claim 45, wherein the lithium is lithium orotate.

47. A pharmaceutical composition for increasing methylation capacity in a brain of a subject, the pharmaceutical composition comprising a therapeutically-effective amount of the nutraceutical composition according to claim 43 and at least one pharmaceutically-effective carrier or non-medicinal ingredient.

48. The pharmaceutical composition according to claim 47, wherein the methylcobalamin and hydroxycobalamin are combined as vitamin B.sub.12.

49. The pharmaceutical composition according to claim 48, further comprising lithium.

50. The pharmaceutical composition according to claim 49, wherein the pharmaceutical composition is formulated for sublingual administration.

51. A pharmaceutical composition for increasing methylation capacity in a brain of a subject, the pharmaceutical composition comprising therapeutically-effective amounts of methylcobalamin, hydroxycobalamin, methylfolate, and lithium and at least one pharmaceutically-acceptable carrier or non-medicinal ingredient (NMI).

52. The pharmaceutical composition according to claim 51, wherein the pharmaceutical composition is formulated for sublingual administration.

53. The pharmaceutical composition according to claim 52, wherein the methylcobalamin and hydroxycobalamin are combined as vitamin B.sub.12.

54. The pharmaceutical composition according to claim 53, wherein the lithium is lithium orotate.

55. The pharmaceutical composition according to claim 54, wherein the therapeutically-effective amount of methylcobalamin and hydroxycobalamin combined as vitamin B.sub.12 is about 2 mg, the therapeutically-effective amount of methylfolate is about 400 mcg, and the therapeutically-effective amount of lithium orotate is 130 mg.

56. The pharmaceutical composition according to claim 55, further comprising a therapeutically-effective amount of astaxanthin.

57. A method for increasing methylation capacity in a brain of a subject in need thereof, the method comprising: providing a pharmaceutical composition formulated for sublingual administration comprising therapeutically-effective amounts of methylcobalamin, hydroxycobalamin, methylfolate, and lithium and at least one pharmaceutically-acceptable carrier or non-medicinal ingredient (NMI); and administering the pharmaceutical composition to the subject, thereby increasing methylation capacity in the brain of the subject.

58. A method for elevating levels of methylcobalamin in a brain of a subject in need thereof, the method comprising: providing a composition formulated for sublingual administration comprising the pharmaceutical composition according to claim 51; and administering the composition to the subject, thereby elevating levels of methylcobalamin in the brain of the subject.

59. A method for increasing plasma cobalamin and antioxidant levels in a subject, the method comprising: providing a composition formulated for sublingual administration comprising the pharmaceutical composition according to claim 51; and administering the composition to the subject, thereby increasing plasma cobalamin and antioxidant levels in the subject.

60. The method according to claim 59, wherein increasing antioxidant levels includes increasing glutathione (GSH) levels in the subject.

61. A method for increasing cellular cobalamin and antioxidant levels in a subject, the method comprising: providing a composition formulated for sublingual administration comprising the pharmaceutical composition according to claim 51; and administering the composition to the subject, thereby increasing cellular cobalamin and antioxidant levels in the subject.

62. The method according to claim 61, wherein increasing antioxidant levels includes increasing glutathione (GSH) levels in the subject.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0010] For the purpose of promoting an understanding of the principles of the invention, reference will now be made to embodiments illustrated herein and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended. Any alterations and further modification in the described compositions, pharmaceutical/nutraceutical formulations, methods, therapeutic treatments, and any further application of the principles of the invention as described herein, are contemplated as would normally occur to one skilled in the art to which the invention relates.

[0011] Methylation reactions regulate almost every aspect of metabolism, including epigenetic regulation of gene expression. Methylation is controlled by the vitamin B.sub.12 and folate-dependent enzyme methionine synthase (MS), through its dual influence over the methyl donor S-adenosylmethionine (SAM) and the methylation inhibitor S-adenosylhomocysteine (SAH). It has been shown, in a postmortem human brain study, that MS mRNA levels in frontal cortex decrease dramatically across the lifespan (400-fold), accompanied by increased alternative splicing (Muratore CR et al. Age-dependent decrease and alternative splicing of methionine synthase mRNA in human cerebral cortex and an accelerated decrease in autism. PloS One. 2013; 8: e56927), indicating that methylation is dynamically regulated in the brain. Recently, it has been reported that brain levels of vitamin B.sub.12 levels decrease with age, with the level of methyl B.sub.12 being >10-fold lower in 60-80 yr old control subjects as compared to 0-20 yr old subjects (Zhang et al. Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PLoS One. 2016; 1-19). This highly significant decrease is not mirrored in plasma levels, indicating that deficits in brain B.sub.12 are not detected by routine B.sub.12 testing. Additionally, 3-fold lower brain B.sub.12 levels in autistic and schizophrenia subjects has been found, suggesting that low B.sub.12 may be a feature of brain disorders.

[0012] A large number of studies implicate impaired methylation status in Alzheimer's disease (AD), including elevated plasma and brain levels of homocysteine, the substrate of MS, and decreased levels of SAM. Hyperhomocysteinemia and DNA hypomethylation are associated with elevated presenillinl expression and Abeta (amyloid beta) production. Impaired SAM-dependent methylation of Tau protein and the Tau phosphatase PP2A can contribute to neurofibrillary tangle formation. The VITACOG study, conducted in the UK, showed significant clinical benefit of treatment with vitamin B.sub.12, folic acid and vitamin B.sub.6 in mild cognitive impairment (MCI), including diminished gray matter loss. Importantly, follow-up analyses showed that a therapeutic response was restricted to individuals in the two higher percentiles of plasma omega-3 fatty acids (primarily DHA), suggesting a crucial role for methylation of DHA-containing membrane phospholipids. The instant inventors were the first to describe the unique ability of the D4 dopamine receptor to carry out MS-dependent phospholipid methylation in human neuronal cells in response to dopamine and proposed its role in attention (Sharma A, Kramer M L, Wick P F, Liu D, Chari S, Shim S. et al. D4 dopamine receptor-mediated phospholipid methylation and its implications for mental illnesses such as schizophrenia. Mol Psychiatry. 1999; 4:235-246). Subsequent research confirmed D4 receptor involvement in gamma synchrony during attention (Kocsis, B, Lee, P, Deth, R. Brain Struct Funct 2014 219(6) 2173-2180). The specific phospholipid that is primarily methylated by the D4 receptor contains DHA. Recent and as yet unpublished results in cultured cells show that D4 receptor activation by dopamine is associated with increased antioxidant (glutathione or GSH) levels, a 3-fold increase in SAM/SAH and a 2-fold increase of global DNA methylation.

[0013] Oxidative stress is a well-recognized risk factor for AD and other neurodegenerative diseases. It has been shown that insulin-like growth factor 1 (IGF1) stimulates cysteine uptake in neuronal cells, leading to increased GSH levels and improved methylation status (Hodgson N, Trivedi M, Muratore C, Li S, Deth R. Soluble oligomers of amyloid- cause changes in redox state, DNA methylation, and gene transcription by inhibiting EAAT3 mediated cysteine uptake. J Alzheimers Dis. 2013; 36:197-209.). Moreover, Amyloid Beta had the opposite effect, causing a decrease in cysteine uptake and GSH, while antagonizing the effect of IGF1.

[0014] Furthermore, it has been shown that treatment of patients with Alzheimer's disease, who had elevated homocysteine level, with a B.sub.12-based nutraceutical, CerefolinNAC (commercial name), caused a highly significant decrease in brain atrophy. CerefolinNAC contains L-methylfolate, methylcobalamin, and N-acetyl-cysteine. (Shankle, W R et al. CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atropy in Alzheimer's Disease and Cerebrovascular Disease, Journal of Alzheimer's Disease, 2016 54:1073-1084). N-acetyl-cysteine promotes formation of the antioxidant glutathione, but a combination of methylcobalamin and hydroxocobalamin leads to increased glutathione in the absence of N-acetyl-cysteine. The above-described experimental results provide a strong rationale for pursuing formulations designed to optimize vitamin B.sub.12 activity in the brain and/or formulations for augmenting methylation capacity in the brain.

KEY SUPPORTIVE DATA POINTS

[0015] Alzheimer's disease (AD) and other neurodegenerative disorders are associated with oxidative stress.

[0016] Oxidative stress inhibits folate and vitamin B.sub.12-dependent methionine synthase (MS), resulting in inhibition of 1,000 methylation reactions, including DNA and histone methylation.

[0017] Impaired MS activity and impaired methylation are features of AD.

[0018] The recent VITCOG clinical trial clearly demonstrated benefit of a B.sub.6, B.sub.12 and folate supplement in mild cognitive impairment (MCI), including decreased gray matter loss and cognitive improvement.

[0019] Analysis of responders vs. in the VITACOG trial showed that only individuals in the upper two percentiles of DHA (omega-3 fatty acid) benefitted from the treatment.

[0020] Recent postmortem brain study showed an age-dependent decline in brain levels of vitamin B.sub.12, particularly the methylB.sub.12 form, which was 10-fold lower in 60-80 yr old subjects vs. 0-20 yr old subjects.

[0021] The incidence of neurodegenerative disorders is low in bipolar subjects because of their treatment with lithium.

[0022] Lithium affects the transport process that bring vitamin B.sub.12 into the brain.

[0023] The instant inventors have developed a sublingually-deliverable nutraceutical composition designed for improving cognitive functions. The composition contains at least methylcobalamin and hydroxycobalamin, separately or as combined vitamin B12. In addition to methylcobalamin and hydroxycobalamin, the composition can also contain methylfolate or methylfolate and lithium. The inclusion of lithium includes low dose forms.

[0024] In one aspect, the invention provides a pharmaceutical or nutraceutical composition including therapeutically-effective amounts of methylcobalamin, hydroxycobalamin, methylfolate, and lithium and at least one pharmaceutically-acceptable carrier or non-medicinal ingredient (NMI).

[0025] In another aspect, the invention provides a pharmaceutical or nutraceutical composition including therapeutically-effective amounts of methylcobalamin, hydroxycobalamin, methylfolate, and at least one pharmaceutically-acceptable carrier or non-medicinal ingredient (NMI).

[0026] In yet another aspect, the invention provides a pharmaceutical or nutraceutical composition including therapeutically-effective amounts of methylcobalamin, hydroxycobalamin, and at least one pharmaceutically-acceptable carrier or non-medicinal ingredient (NMI).

[0027] As used herein, the phrase improving cognitive functions refers to bringing mental processes into a more desired or better functioning condition.

[0028] As used herein, a nutraceutical refers to a pharmaceutical grade nutrient or food ingredient.

[0029] The composition is formulated for sublingual delivery to a subject. Sublingual delivery differs from conventional oral delivery in that the tablet disintegrates in the mouth of the subject.

[0030] The term subject includes any human being or animal who would benefit from improved cognitive function; i.e. having methylation capacity of the brain increased and/or vitamin B.sub.12 activity in the brain optimized. The terms patient and human patient are also used herein to refer to the subject.

[0031] The phrase optimize vitamin B.sub.12 activity refers to one or both of an increase in amount of activity and an increase in effectiveness of the activity. The vitamin B.sub.12 activity is preferentially increased within the brain, but is not limited to an increase therein.

[0032] In one embodiment, the carotenoid antioxidant, Astaxanthin, can be included within the formulation. Ingredients, in the suggested ranges, for this formulation include: Methylcobalaminfrom about 1 to about 10 mg; Hydroxocobalaminfrom 0 to about 5 mg; Astaxanthin-from about 1 to about 10 mg; and Lithium-from about 0.1 to about 1 mg. One particular embodiment of the formulation of the composition includes: about 2 mg of combined vitamin B12 (as methylcobalamin about 1600 mg; hydroxycobalamin about 400 mg); about 400 mcg methylfolate; and about 5 mg of lithium (equivalent to about 130 mg lithium orotate).

[0033] Another embodiment of the formulation of the composition includes: about 2 mg of combined vitamin B12 (as methylcobalamin about 1600 mg; hydroxycobalamin about 400 mg) and about 400 mcg methylfolate.

[0034] Another embodiment of the formulation of the composition includes: about 2 mg of combined vitamin B12 (as methylcobalamin about 1600 mg; hydroxycobalamin about 400 mg).

[0035] In describing the formulations, the term about refers to near or close to the disclosed quantities and encompasses quantities in which the composition can be formulated with and still reasonably achieve the described and/or desired function of the formulation. Additionally, when referring to amounts of the pharmaceutical composition, the term about refers to dosages at or near the stated amounts at which the desired function can be achieved.

[0036] The phrase pharmaceutically-acceptable carrier refers to an inactive and non-toxic substance used in association with an active substance, i.e. in this formulation the active substances are preferably, but not limited to, methylcobalamin, hydroxocobalamin, methylfolate, and lithium, especially for aiding in the application/delivery of the active substance. Non-limiting examples of pharmaceutically-acceptable carriers are diluents, binders, disintegrants, superdisintegrants, flavorings, fillers, and lubricants. Pharmaceutically-acceptable carriers can have more than one function within a formulation, a non-limiting e.g. a filler can also be a disintegrant. Additionally, pharmaceutically-acceptable carriers may also be referred to as non-medicinal ingredients (NMIs) or pharmaceutically-acceptable excipients.

[0037] The phrase effective amount and refers to the amount of a composition/formulation necessary to achieve the intended function of the composition/formulation. An effective amount can also be referred to as a therapeutically-effective amount.

[0038] The described pharmaceutical/nutraceutical compositions have various applications/functions. Non-limiting examples include increasing methylation capacity in the brain, elevating levels of methylcobalamin in the brain, increasing plasma cobalamin and antioxidant levels, increasing cellular cobalamin and antioxidant levels, optimizing vitamin B12 activity in the brain, increasing energy and alertness, and improving cognitive functions. Glutathione (GSH) is a non-limiting example of an antioxidant of which levels may be increased.

[0039] In one aspect, the invention provides a method for increasing methylation capacity in a brain of a subject in need thereof or who could benefit therefrom. The method includes steps for providing a cobalamin composition described herein and administering the cobalamin to the subject to achieve increased methylation capacity in the brain of the subject.

[0040] In another aspect, the invention provides a method for elevating levels of methylcobalamin in a brain of a subject in need thereof or who could benefit therefrom. The method includes steps for providing a cobalamin composition described herein and administering the cobalamin to the subject to achieve elevated levels of methylcobalamin in the brain of the subject.

[0041] In yet another aspect, the invention provides a method for increasing cobalamin (plasma and/or cellular) and antioxidant levels (such as, but not limited to, glutathione) in a subject in need thereof or who could benefit therefrom. The method includes steps for providing a cobalamin composition described herein and administering the cobalamin to the subject to achieve increased cobalamin (plasma and/or cellular) and antioxidant levels in the subject.

[0042] Any of the pharmaceutical/nutraceutical cobalamin compositions described herein, which have been formulated for sublingual administration, are contemplated for use with the methods descried herein.

[0043] In another aspect, any of the above-described epinephrine fine particles (including epinephrine nanoparticles or nanocrystals and epinephrine microparticles or microcrystals) can be used in the manufacture of any of the above-described compositions and pharmaceutical compositions.

[0044] In another aspect, any of the above-described ingredients, methylcobalamin, hydroxycobalamin, methylfolate, and lithium, can be used in the manufacture of any of the above-described pharmaceutical/nutraceutical compositions.

[0045] The novel cobalamin compositions described herein are contemplated for therapeutic use in conditions which can benefit from improved cognitive function and/or optimized vitamin B.sub.12 activity (in the brain); such as, but not limited to, neurodegenerative disorders, neurodevelopmental disorders, and neuropsychiatric disorders. Specific, but non-limiting examples of such disorders are Alzheimer's disease (AD), mild cognitive impairment (MCI), chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), aging, autism, schizophrenia, and attention deficit hyperactivity disorder (ADHD).

[0046] All patents and publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. It is to be understood that while a certain form of the invention is illustrated, it is not intended to be limited to the specific form or arrangement herein described and shown. It will be apparent to those skilled in the art that various changes may be made without departing from the scope of the invention and the invention is not to be considered limited to what is shown and described in the specification. One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objectives and obtain the ends and advantages mentioned, as well as those inherent therein. The compositions, nutraceutical formulations, pharmaceutical/therapeutic compositions and methods, procedures, and techniques described herein are presently representative of the preferred embodiments, are intended to be exemplary and are not intended as limitations on the scope. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention. Although the invention has been described in connection with specific, preferred embodiments, it should be understood that the invention as ultimately claimed should not be unduly limited to such specific embodiments. Indeed various modifications of the described modes for carrying out the invention which are obvious to those skilled in the art are intended to be within the scope of the invention.