Composition for preventing and treating neurodegenerative diseases and cognitive disorders

Abstract

A composition for preventing and treating neurodegenerative diseases and cognitive disorders is provided, comprising a mixture of active ingredients and characterized in that said mixture of active ingredients includes diosmin, hesperidin, ginkgo flavonoids, triterpenes, red Rooibos tea extracts, coumarin, and proanthocyanidins.

Description

[0001] DESCRI PTION

[0002] COMPOSITION FOR PREVENTING AND TREATING NEURODEGENERATIVE

[0003] DISEASES AND COGNITIVE DISORDERS

[0004] The present invention relates to a composition for preventing and treating neurodegenerative diseases and cognitive disorders.

[0005] It originates in the field of pharmaceutical, nutraceuticals, products and dietary supplements and concerns a preparation for preferably, oral administration, suitable for preventing or treating cognitive disorders, cerebral involutional processes, and degenerative processes of nerve cells.

[0006] Cognitive disorders typically affect the adult population aged over 50-60 years. In particular, it has been observed that approximately 5% of the population over 65 years old and approximately 30% of the population over 85 years old suffer from a cognitive disorder.

[0007] The main cognitive disorders can be classified as three types of diseases: reversible, vascular, and degenerative diseases.

[0008] In the first type, the onset of the disease is traumatic or results from an external agent, such as an infection, and tends to regress once the triggering cause is corrected.

[0009] Conversely, the other two types, more representative of cognitive disorders, have a progressive degeneration matrix. In detail, as these are chronic diseases, it is not possible to restore the initial physiological condition, but it is possible only to slow down the disease progression and control its symptoms. Typical examples of degenerative vascular diseases include cerebrovascular insufficiency, stroke, transient ischemic attack, and cerebral haemorrhages.

[0010] Generally, when the first symptoms of a form of cerebral decline (such as, for example, loss of balance and movement difficulties and / or speaking difficulties) manifest, indications are given to initiate an appropriate therapeutic treatment aimed at slowing down the progression of the disease and preventing acute events.

[0011] The type of therapeutic treatment is selected based on the severity of the symptoms and the individual’s age.

[0012] The initial forms of cognitive decline are generally treated by supplementing the diet with specific nutritional products, herbal products with antioxidant or cerebrovascular action. The nutraceutical products currently used to prevent or treat mild forms of cognitive decline generally contain, for example, vitamins or selenium, resveratrol, omega-3, and omega-6 fatty acids.

[0013] Pharmacological therapy, on the other hand, is reserved for the treatment of moderate-to-severe forms in which the symptoms related to cognitive decline begin to impact the quality of life and daily activities of the individual. The drugs currently most used for treating moderate-to-severe cognitive decline forms, such as senile dementia and Alzheimer’s disease, include acetylcholinesterase inhibitors, such as donepezil, rivastigmine, and galantamine. Other drugs, such as memantine, are reserved for the treatment of more severe forms of neurodegenerative diseases and Alzheimer’s disease.

[0014] The known technique described includes some important drawbacks.

[0015] In particular, it has been found that the administration of these drugs is accompanied, in most cases, by the appearance of side effects that can become significant in the case of chronic pharmacological therapies.

[0016] Furthermore, the nutraceutical products currently on the market and suitable for treating mild or moderate forms of cognitive disorders provide an inadequate or entirely unsatisfactory therapeutic response. Currently, therefore, there is a gap in the market for products for treating involutional diseases and mild cognitive disorders, as there are hardly any products available that exert a nootropic action substantially free of side effects even in the case of prolonged intake for chronic treatments.

[0017] In this context, the technical task underlying the present invention is to devise a composition for preventing and treating neurodegenerative diseases and cognitive disorders capable of substantially overcoming at least part of the aforementioned drawbacks.

[0018] Within said technical task, an important object of the invention is to obtain a composition for improving the clinical condition and / or symptoms deriving from mild and severe neurodegenerative diseases and cognitive disorders.

[0019] Another object of the present invention is to provide a composition for preventing or treating neurodegenerative disorders and cognitive disorders, the administration of which, especially if chronic, is not accompanied by severe side effects and allows for long-term treatment of neurodegenerative disorders.

[0020] A further object of the present invention is a method for preventing or treating neurodegenerative disorders or cognitive disorders in a mammal, in particular a human being.

[0021] The technical task and specified objects are achieved by a composition for preventing and treating neurodegenerative diseases and cognitive disorders as claimed in the attached claim 1. Preferred embodiment examples are described in the dependent claims.

[0022] In this document, the measurements, values, shapes, and geometric references (such as perpendicularity and parallelism), when associated with words like “about” or similar terms such as “approximately” or “substantially”, are to be understood as allowing for measurement errors or inaccuracies due to production and / or manufacturing errors and, above all, to allow for a slight deviation from the value, measure, shape, or geometric reference with which it is associated. For example, such terms, if associated with a value, preferably indicate a deviation of no more than 10% of the value itself.

[0023] Furthermore, when terms such as “first”, “second”, “upper”, “lower”, “main”, and “secondary” are used, they do not necessarily identify an order, a priority relationship, or a relative position but may simply be used to distinguish different components from each other more clearly.

[0024] The measurements and data reported in this text are to be considered, unless otherwise indicated, as carried out under Standard International Atmosphere ICAO (ISO 2533:1975).

[0025] The present invention provides a composition for preventing and / or treating neurodegenerative and / or cognitive disorders in a mammal, preferably in a human patient. Therefore, the composition of the invention can be applied to the prevention or treatment of cognitive disorders, regardless of their origin and / or as an adjuvant against the symptoms associated with such disorders.

[0026] According to some embodiments, the composition is a pharmaceutical composition, a nutraceutical product, a dietary supplement that, for example, can be introduced into the diet of an individual affected by a neurodegenerative and / or cognitive disorder.

[0027] The composition comprises a mixture of active ingredients and, as appropriate, one or more excipients.

[0028] The mixture of active ingredients may comprise micronized diosmin, as appropriate. The diosmin content may be substantially between 40% and 70%, particularly between 50% and 60%, and more particularly between 50% and 55% of the total weight of the mixture. For example, the diosmin content may be substantially 53- 50% of the total weight of the active ingredients mixture.

[0029] The mixture of active ingredients may comprise hesperidin.

[0030] As appropriate, the hesperidin content is substantially lower than that of diosmin. It may be substantially lower than 20%, particularly lower than 10%, and more specifically it may be between 5% and 10% of the total weight of the mixture. For example, the hesperidin content may be approximately 7-6% of the total weight of the active ingredients mixture.

[0031] The mixture of active ingredients may include ginkgo flavonoids.

[0032] As appropriate, the ginkgo flavonoid content is substantially lower than that of diosmin. It may be substantially lower than 5%, particularly lower than 3%, and more specifically lower than 1 % of the total weight of the mixture. For example, the hesperidin content may be approximately 0.2-0.1 % of the total weight of the active ingredients mixture.

[0033] More specifically, the mixture of active ingredients may include Ginkgo extracts (also referred to as Ginkgo biloba) containing said ginkgo flavonoids. These extracts may be obtained from Ginkgo leaves.

[0034] The ginkgo flavonoid content in the Ginkgo extracts may be substantially lower than 10% and, in detail, approximately 3%.

[0035] As appropriate, the Ginkgo extract content is substantially lower than that of diosmin and preferably equivalent to that of hesperidin. The Ginkgo extract content may be substantially lower than 20%, particularly lower than 10%, and more specifically it may range between 5% and 10% of the total weight of the mixture. For example, it may be approximately 7-6% of the total weight of the active ingredients mixture. The mixture of active ingredients may comprise triterpenes.

[0036] As appropriate, the triterpenes content is substantially lower than that of diosmin. It may be substantially lower than 5%, particularly lower than 3%, and more specifically between 1 % and 2% of the total weight of the mixture. For example, the triterpene content may be approximately 1 % of the total weight of the active ingredients mixture.

[0037] More specifically, the mixture of active ingredients may include Centella extracts (also known as Centella asiatica) containing said triterpenes. These extracts may be derived from Centella leaves.

[0038] The triterpene content in Centella extracts may be substantially between 10% and 30%, and, in detail, approximately 20%.

[0039] As appropriate, the Centella extract content is substantially lower than that of diosmin and preferably equivalent to that of hesperidin. The Centella extract content may be substantially lower than 25%, particularly lower than 15%, and more specifically it may range between 5% and 10% of the total weight of the mixture. For example, it may be approximately 7-6% of the total weight of the active ingredients mixture.

[0040] The mixture of active ingredients may comprise coumarin.

[0041] As appropriate, the coumarin content is substantially lower than that of diosmin. It may be substantially lower than 5%, particularly lower than 3%, and more specifically between 1 % and 2% of the total weight of the mixture. For example, the coumarin content may be approximately 1 % of the total weight of the mixture.

[0042] More specifically, the mixture of active ingredients may include Melilotus extracts (also known as Melilotus officinalis) containing said coumarin. These extracts may be obtained from the aerial parts of Melilotus. The coumarin content in Melilotus extracts may be substantially between 10% and 30% and, in detail, approximately 20%.

[0043] As appropriate, the Melilotus extract content is substantially lower than that of diosmin and preferably equivalent to that of hesperidin. The Melilotus extract content may be substantially lower than 20%, particularly lower than 10%, and more specifically it may range between 5% and 10% of the total weight of the mixture. For example, it may be approximately 7-6% of the total weight of the active ingredients mixture.

[0044] The mixture of active ingredients may comprise proanthocyanidins.

[0045] As appropriate, the proanthocyanidin content is substantially lower than that of diosmin. It may be substantially lower than 20%, particularly lower than 10%, and more specifically it may range between 5% and 10% of the total weight of the mixture. For example, the proanthocyanidin content may be approximately 6% of the total weight of the mixture.

[0046] More specifically, the mixture of active ingredients may include red vine extracts (also known as Vitis vinifera) containing said proanthocyanidins. These extracts may be obtained from the seeds of red vine.

[0047] The proanthocyanidin content in red vine extracts may be at least 90% and, in detail, approximately 95%.

[0048] As appropriate, the red vine extract content is substantially lower than that of diosmin and preferably equivalent to that of hesperidin. The red vine extract content may be substantially lower than 20%, particularly lower than 10%, and more specifically it may range between 5% and 10% of the total weight of the mixture. For example, it may be approximately 7-6% of the total weight of the active ingredients mixture. The mixture of active ingredients may comprise red Rooibos tea extracts (also known as Aspalathus linearis (Burm.f.).

[0049] As appropriate, the red Rooibos tea extract content is substantially lower than that of diosmin and preferably substantially higher than that of hesperidin. The red Rooibos tea extract content may be substantially lower than 25%, particularly lower than 15%, and more specifically it may range between 10% and 15% of the total weight of the mixture. For example, it may be approximately 12-13% of the total weight of the active ingredients mixture.

[0050] In a first, non-limiting embodiment of the composition, the mixture may weigh 1500 mg and comprise diosmin, appropriately micronized, in an amount of 800 mg; hesperidin in an amount of 100 mg; Ginkgo in an amount of 100 mg of which 3% is ginkgo flavonoids; Centella in an amount of 100 mg of which 20% is triterpenes; red Rooibos tea in an amount of 200 mg; Melilotus in an amount of 100 mg of which 20% is coumarin; and red vine in an amount of 100 mg of which 95% is proanthocyanidins.

[0051] The above-described extracts can preferably be obtained by Soxhlet-type reflux extraction and, in particular, by ultrasound or supercritical gas methods, with the addition of sulphur dioxide as a solvent. Preferably, these extracts are obtained using the Soxhlet reflux method with methanol. This method involves fermentation and hydrolysis of the plant part (for example, fruit, flower, or leaf) from which the extracts are to be obtained, with the addition of yeast, preferably Saccharomycetaceae (such as Saccharomyces cerevisiae), and preferably operating at pH 7 for approximately 4 days; evaporation and centrifugation to remove the solvent from the solution obtained above Soxhlet extraction; removal by heating at the boiling point of methanol and its subsequent extraction by evaporation. It is noted that other methods may be employed to achieve these extracts, preferably in a dry form and, in detail, as a powder.

[0052] The mixture of active ingredients described above, and therefore the composition of the invention, can take various forms of preparation depending on the desired type of administration.

[0053] The composition of the invention may be in solid form and, for example, be in the form of a tablet, capsule, powder, or granules. In this case, the preparations may include one or more vehicles such as starches, sugars, microcrystalline cellulose, and, if necessary, diluents, granulating agents, lubricants, binders, disintegrants. Typically, tablets, pills, capsules, granules may also contain a binder such as acacia, tragacanth gum, corn starch, or gelatine; excipients such as calcium phosphate; a disintegrant such as com starch, potato starch, alginic acid; a lubricant such as magnesium stearate; a sweetener such as sucrose, fructose, lactose, or saccharin. If in liquid form, it may be in the form of a suspension, emulsion, or solution. In these cases, the vehicle is liquid and may be chosen, for example, from water, glycol, oils, alcohols, and their mixtures.

[0054] The compositions for pharmaceutical or nutritional use can be appropriately presented in a single pharmaceutical form and prepared using any of the methods well known in pharmaceutical or food technology.

[0055] According to another aspect, the present invention relates to a method for preventing or treating neurodegenerative and / or cognitive diseases, comprising the administration to an individual of the mixture of active ingredients described above and, therefore, of the composition.

[0056] The composition for preventing and / or treating neurodegenerative and / or cognitive disorders according to the invention achieves significant advantages. In fact, the specific mixture, as demonstrated by studies conducted by the inventor on 60-65 years old healthy subjects, has confirmed the positive impact on global cognitive health, as well as the effect on specific domains, including memory and verbal and executive functions, with a marked improvement in motor aspects and quality of life.

[0057] Indeed, the particular combination of the active ingredient mixture has proven effective in reducing oxidative stress, especially in the brain, through interaction with various pathways of the inflammatory process, such as Nrf2 activation.

[0058] Furthermore, these active ingredients have demonstrated blocking or at least limiting capabilities on neurodegenerative and / or cognitive decline, especially in human patients. Studies have shown that they inhibit the activation of JNK, c-Jun, and caspase-3; modulate PKC activity leading to activation of the anti-apoptotic (PI3K) / Akt-dependent pathway; inhibit the activity of glycogen synthase kinase-3 (GSK-3); activate Akt, which is responsible for inhibiting pro-apoptotic proteins in cortical neurons, such as kinase 1 (ASK1 ), Bad, caspase-9, and caspase-3; interact with secretase enzymes that cleave the amyloid precursor, shifting the balance toward the non-amyloidogenic pathway coordinated by alpha-secretase enzymes; and inhibit lipoxygenase, cyclooxygenase, monooxygenase, xanthine oxidase, NADH oxidase, phospholipase A2, certain protein kinases, and various transcriptional factors such as NF-kB. Furthermore, these active ingredients have shown a high capacity to attenuate the neurodegenerative process, contribute to a partial restoration of physiological functions, decrease the formation of misfolded protein aggregates (tangles), decrease their formation, and increase the expression of neurotrophic factors.

[0059] In summary, the composition is capable of preventing and / or treating neurodegenerative disorders, neuroinflammation, neuromodulation, and / or cognitive disorders by acting on the nervous system, including a beneficial effect on the vascular system. Consequently, patients taking the composition subject to this invention have shown a marked improvement in cognitive abilities as well as movement and posture, without severe side effects, allowing long-term treatment. Therefore, patients exhibited a significant cognitive improvement (observed in activities such as executive functions, attention, memory, information processing speed, verbal fluency) and motor improvements, both conventionally and technologically (such as balance, fall risk, and muscle strength), resulting in enhanced quality of life and mood.

[0060] The invention is open to variations within the scope of the inventive concept defined by the claims.

[0061] The triterpene content may vary from that described above and, for example, be substantially lower than that of diosmin. It may be substantially lower than 5%, particularly lower than 3%, and more specifically between 2% and 3% of the total weight of the mixture. For example, the coumarin content may be approximately 2.5% of the total weight of the active ingredients mixture. Consequently, the Centella extract content may be substantially lower than 25%, particularly lower than 15%, and more specifically between 10% and 15% of the total weight of the mixture. For example, it may be approximately 12-13% of the total weight of the active ingredients mixture.

[0062] In accordance with this example, in a second non-limiting embodiment of the composition, the mixture may have a weight of 1600 mg and include diosmin, appropriately micronized, in an amount of 800 mg; hesperidin in an amount of 100 mg; Ginkgo in an amount of 100 mg of which 3% is ginkgo flavonoids; Centella in an amount of 200 mg of which 20% is triterpenes; red Rooibos tea in an amount of 200 mg; Melilotus in an amount of 100 mg of which 20% is coumarin; and red vine in an amount of 100 mg of which 95% is proanthocyanidins.

[0063] Within this scope, all details may be replaced by equivalent elements, and materials, shapes, and dimensions may be any.

Claims

C LAI M S1. A composition for preventing and treating neurodegenerative diseases and cognitive disorders, comprising a mixture of active ingredients, characterized in that said mixture of active ingredients includes- diosmin,- hesperidin,- ginkgo flavonoids,- triterpenes,- red Rooibos tea extracts,- coumarin, and- proanthocyanidins.

2. A composition according to claim 1 , wherein the content of said diosmin can be approximately 53-50% of the total weight of said mixture of active ingredients.

3. A composition according to at least one preceding claim, wherein the content of said hesperidin can be approximately 7-6% of the total weight of said mixture of active ingredients.

4. A composition according to at least one preceding claim, wherein said mixture of active ingredients includes Ginkgo extracts containing said ginkgo flavonoids; and wherein the content of said Ginkgo extracts is approximately 7-6% of the total weight of said mixture of active ingredients.

5. A composition according to at least one preceding claim, wherein said mixture of active ingredients includes Centella extracts containing said triterpenes; and wherein the content of said Centella extracts is approximately 7-6% or 12-13% of the total weight of said mixture of active ingredients.

6. A composition according to at least one preceding claim, wherein said mixture of active ingredients includes Melilotus extracts containing said coumarin; and wherein the content of said Melilotus extracts is approximately 7-6% of the total weight of said mixture.

7. A composition according to at least one preceding claim, wherein said mixture of active ingredients includes red vine extracts containing said proanthocyanidins; and wherein the content of said red vine extracts is approximately 7-6% of the total weight of said mixture.

8. A composition according to at least one preceding claim, wherein the content of said red Rooibos tea extracts is approximately 12-13% of the total weight of said mixture of active ingredients.

9. A composition according to at least one preceding claim, wherein said mixture of active ingredients has a weight of 1500 mg; wherein said diosmin content is 800 mg; wherein said hesperidin content is 100 mg; wherein said Ginkgo content is 100 mg of which 3% is said ginkgo flavonoids; wherein said Centella content is 100 mg of which 20% is said triterpenes; wherein said red Rooibos tea content is 200 mg; wherein said Melilotus content is 100 mg of which 20% is said coumarin; and wherein said red vine content is 100 mg of which 95% is said proanthocyanidins.

10. A composition according to at least one claim 1 -8, wherein said mixture of active ingredients has a weight of 1600 mg; wherein said diosmin content is 800 mg; wherein said hesperidin content is 100 mg; wherein said Ginkgo content is 100 mg of which 3% is said ginkgo flavonoids; wherein said Centella content is 200 mg of which 20% is said triterpenes; wherein said red Rooibos tea content is 200 mg; wherein said Melilotus content is 100 mg of which 20% is said coumarin; and wherein said red vine content is 100 mg of which 95% is said proanthocyanidins.