WO2020008359A1

WO2020008359A1 - A formulation for the prevention and as a coadjuvant treatment of neurodegenerative diseases

Info

Publication number: WO2020008359A1
Application number: PCT/IB2019/055632
Authority: WO
Inventors: Giuseppe SAMARITANI; Simone CASTELLI
Original assignee: Inpha Duemila Srl
Current assignee: Inpha Duemila Srl
Priority date: 2018-07-03
Filing date: 2019-07-02
Publication date: 2020-01-09
Anticipated expiration: 2021-01-03

Abstract

It is described an association of curcumin, trans-resveratrol, coenzyme Q10 and caprylic acid for use in the prevention or in the adjuvant treatment of neurodegenerative diseases, such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease and Parkinson's disease. The Applicant has also found that this association is even more effective if it is administered in the form of oral formulations containing enteric absorption promoters.

Description

“A formulation for the prevention and as a coadjuvant treatment of neurodegenerative diseases”

DESCRIPTION

FIELD OF THE INVENTION

The present invention relates to a combination of curcumin, trans-resveratrol, coenzyme Q10 and caprylic acid for use in the prevention and in the adjuvant treatment of neurodegenerative diseases.

STATE OF THE ART

There is growing scientific evidence about the action of some antioxidant substances on the pathogenesis of important neuro-degenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease and other forms of cognitive decline, Parkinson's disease. The common pathogenetic basis of these pathologies seems to involve the impairment of the intra-mitochondrial redox systems, which leads to an imbalance of the oxygenated and nitrogenous radical species that alter the iron- peptide homeostasis, favour the oxidation of proteins, membrane fatty acids and mitochondrial DNA (mtDNA)^{1 2}. This sequence of events produces the opening of the mitochondrial pore and the consequent cell death by apoptosis. The neuro- degenerative pathologies mentioned above seem to have a strong pathogenetic component deriving from the oxidative-mitochondrial phenomena. In consideration of this presently well ascertained pathogenetic moment, some polyphenolic substances having a mitochondria-tropic activity such as curcumin (Cur), t- resveratrol (Res), coenzyme Q10 (CoQlO) seem to show the greatest therapeutic and preventive potential^{3, 4} on the neurodegenerative pathologies indicated above. Recent work published in Neurotherapeutics on 54 patients double-blind treated with 85 mg curcumin vs placebo confirms the ability of Cur to increase, after one year, the survival of patients affected by ALS⁵ compared to patients in the placebo group. CoQlO, a molecule with specific mitochondrial tropism, exerts a protective action against redox/ox imbalance and seems able to prevent the mitochondrial degeneration underlying neurodegenerative disorders^{6, 7} and to support cellular energy production processes⁸. Res, a stilbenic molecule extracted from the skin and seeds of red grapes and from the root of Poligonum cuspidatum , has also been extensively studied for its biochemical activities of interaction with sirtuins and prevention of B-amyloid deposition and tau filaments in cerebral nuclei^{9, 10, u}.

As for the oral absorption of curcumin, coenzyme Q10 and of the same trans- resveratrol, they show a poor profile of oral bioavailability that can be traced back to poor solubility in enteric liquids^{12, 13} and reduced enteric trans-mural passage for the first two and to a high hepatic first-pass metabolism for transresveratrol^{14, 15, 16}. It is therefore necessary a technological strategy designed to increase the bioavailability of these substances in order to formulate an effective nutraceutical as an "add-on therapy" of the neurodegenerative-based pathologies mentioned above.

A further interesting nutraceutical approach to complement the above is the use of caprylic acid in the form of triglyceride. This substance seems to interfere with the energy metabolism of glucose in the neuron and improve and slow down the course of neuro-muscular degeneration in ALS and cognitive decline in Alzheimer's disease^{17, 18}.

SUMMARY OF THE INVENTION

In fact, the Applicant has now found that the combination of curcumin, trans- resveratrol, coenzyme Q10 and caprylic acid is effective in the adjuvant treatment and in the prevention of neurodegenerative diseases.

The Applicant has also found that if the aforementioned association is administered in the form of an oral formulation containing promoters of enteric absorption, it is even more effective.

The Applicant has indeed found that the association of the following enteric absorption promoters:

i) polysorbate 80,

ii) a sucrester, intended as an ester of sucrose with fatty acids,

iii) piperine from black pepper

gives a formulation that, depending on the additional excipients therein, can be:

• water-dispersible, in other words, if dissolved in a glass of water it can be drunk and, if in the presence of sweeteners and/or flavourings, has a pleasant taste and can be drunk,

• a orosoluble formulation, or

• a swallowable formulation able to release the active substances in the intestine. DESCRIPTION OF FIGURE 1

Figure 1 shows the mechanism of action at the enteric level of the oral formulations of the invention containing the absorption promoters i)-iii) in the intestine.

DETAILED DESCRIPTION OF THE INVENTION

The use according to the present invention of the aforementioned association is intended for the adjuvant treatment or the prevention of degenerative diseases such as amyotrophic lateral sclerosis, (ALS) multiple sclerosis, Alzheimer's disease and Parkinson's disease, and more preferably ALS.

According to a preferred solution, the caprylic/capric acid is in the form of a triglyceride, which therefore has a specific therapeutic activity, but which in this way acts both as an active ingredient and as a liposoluble excipient.

This active ingredient for use according to the present invention can be either in the form of an oil or of a microencapsulated powder.

Preferably, this triglyceride for use according to the present invention is administered at dosages ranging from 35 to 500 mg, more preferably from 50 to 250 mg per unit dose.

For the use according to the present invention, curcumin is extracted from Curcuma longa with a titre of not less than 95% and is present in dosages ranging between 50 and 200 mg, more preferably between 75 and 125 mg.

For the use according to the present invention, resveratrol is preferably extracted from Poligonum cuspidatum with a titre not lower than 90% and is present in a dosage preferably ranging between 10 and 100 mg, more preferably between 30 and 75 mg per unit dose.

For the use according to the present invention, the coenzyme Q10 is preferably in the form of ubiquinone or ubiquinol and is administered at a dosage preferably ranging between 50 and 200 mg and more preferably between 75 and 150 mg per unit dose. The oral formulations are prepared with a process that involves the dispersion of T- Res and CoQlO in a matrix consisting of polysorbate 80, sucroesters and caprylic/capric triglyceride and subsequently the adsorption of the Cur so as to obtain a powder/tablet capable of forming a uniform aqueous dispersion of the aforementioned substances and capable of increasing its enteric permeability with a mechanism reported in Figure 1.

Preferably, in oral formulations for use according to the present invention, i) polysorbate 80 and ii) sucrester are each contained in a range variable between 10 and 20% by weight on the total weight of the sum of the active principles.

The presence of piperine, an alkaloid capable of effectively inhibiting UDP- glucuronyl transferase, the enzyme that catalyses the formation of glucuronides in the intestine and liver, is expected to improve the enteric bioavailability and bioaccessibility of t-Res and Cur.

Preferably, the oral formulations for use according to the present invention contain the pipeline extracted from Piper nigrum iii) with a titre not lower than 90% in an amount ranging between 5 and 10 mg per unit dose.

As pointed out in the summary, this allows obtaining a formulation which, depending on the excipients it contains, can be orosoluble or water-dispersible, a swallowable formulation capable of releasing the active substances in the intestine.

This type of formulations are therefore preferably selected from:

A) swallowable tablets;

B) water-dispersible tablets;

C) orosoluble tablets;

C) water-dispersible granulates;

D) swallowable granules;

E) animal or vegetable gelatine capsules;

F) soft gel.

In particular, the swallowable formulations are among those particularly preferred, especially for subjects suffering from ALS, such as tablets A), animal or vegetable gelatine capsules E) and soft gels F).

In fact, they promote swallowing in cases of dysphagia or of the partial impairment of the voluntary musculature involved in ALS.

Thanks to the presence of the enteric absorption promoters, this type of swallowable formulations produce a hydro-dispersion of trans-resveratrol, curcumin and coenzyme Q10 within 30 minutes from the disaggregation of the pharmaceutical form in the first enteric tract. The oral formulations for use according to the present invention, as previously remarked, may contain excipients whose presence or absence determines the types A)-E) indicated above, such as for example conventional excipients such as glidants, fillers, flow agents, flavourings and sweeteners.

The formulations for use according to the present invention are in the form of a food supplement or nutraceutical, more preferably they are in the form of a nutraceutical. For the purposes of the present invention, food supplements mean food products intended to supplement the common diet and constituting a concentrated source of nutrients, such as vitamins and minerals, or of other substances having a nutritional or physiological effect, in particular but not exclusively amino acids, essential fatty acids, fibres and extracts of vegetable origin, both mono-compounds and multi- compounds, in pre-dosed forms.

For the purposes of the present invention, nutraceutical formulations mean foods, or part of them, having a beneficial function on human health, including the prevention and treatment of a disease. These foods are also called functional foods or pharma foods. They are 'drug-foods', namely healthy foods that combine nutritional components, selected for characteristics such as high digestibility and hypoallergenicity, with the healing properties of natural active ingredients of proven and recognized effectiveness. Nutraceutical substances are normally derived from plants, foods and microbial sources.

Finally, a further object of the present invention is the process that allows obtaining the aforesaid type of formulations and comprises the following steps:

a. mixing caprylic/capric triglyceride and polysorbate 80 together;

b. finely dissolving or dispersing the coenzyme Q10 and the resveratrol in the oily solution of step a.; c. adsorbing the turmeric in the mixture of step b. until obtaining a dense and uniform paste;

d. adding to the mixture of step c. the powder obtained from the dry mixing of sucrester and piperine, mixing with a suitable mixer until obtaining a wet powder; e. adding to the mixture of step d. the excipients necessary for the compression, for filling a capsule and for obtaining a swallowable or water-dispersible granulate.

An example of a water-dispersible formulation is reported below for illustrative purposes.

Example of composition

Formulation:

Curcuma E.S. Tit. 95% Curcuminoids equal to 100 mg of Curcuminoids Coenzyme Q10 75 mg

Poligonum Cuspidatum root extract

(Tit. 98% t-resveratrol) equal to 30 mg of t-Res

Piper Nigrum e.s. 95% piperine equal to 5 mg of piperine

Caprylic/capric triglyceride 75 mg

(in the form of oil or microencapsulated powder, Delios or Labrafac)

Polysorbate 80 30 mg

Sucrester 30 mg

Bibliography

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Claims

1. Association of curcumin, trans-resveratrol, coenzyme Q10 and caprylic acid for use in the prevention or as an adjuvant treatment of neurodegenerative diseases.

2. Association for use according to claim 1, wherein the degenerative diseases are amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease and Parkinson's disease.

3. Association for use according to any one of claims 1 or 2, wherein the degenerative disease is amyotrophic lateral sclerosis.

4. Association for use according to any one of claims 1-3, wherein the caprylic acid is in the form of triglyceride of caprylic/capric acid.

5. Association for use according to claim 4, wherein said triglyceride is administered at dosages ranging from 35 to 500 mg, preferably from 50 to 250 mg per unit dose.

6. Association for use according to any one of claims 1-5 wherein curcumin is extracted from Curcuma longa with a titre not lower than 95% and is present in a dosage ranging from 50 to 200 mg, more preferably from 75 to 125 mg.

7. Association for use according to any one of claims 1-6, wherein the trans- resveratrol is extracted from Poligonum cuspidatum with a titre not lower than 90% and is present in a dosage ranging from 10 to 100 mg, more preferably from 30 to 75 mg per unit dose.

8. Association for use according to any one of claims 1-7, wherein the coenzyme

Q10 is present in the form of ubiquinone or ubiquinol and is administered at a dosage ranging from 50 to 200 mg and preferably from 75 to 150 mg per unit dose.

9. Association for use according to any one of claims 1-8, wherein said association is administered in the form of an oral formulation containing the following enteric absorption promoters: i) polysorbate 80,

ii) a sucrester, intended as a sucrose ester with fatty acids,

iii) piperine from black pepper.

10. Association for use according to claim 9, wherein the absorption promoters i) polysorbate 80 and ii) sucrester are each contained in a range ranging from 10 to

20% by weight on the total weight of the sum of the active ingredients.

11. Association for use according to claim 9 or 10, wherein the formulation contains the piperine iii) extracted from Piper nigrum with a titre not lower than 90% in an amount ranging from 5 to 10 mg per unit dose.

12. Association for use according to any one of claims 9-11, wherein said formulation is selected among:

A) swallowable tablets;

B) orosoluble tablets;

C) water-dispersible granulates;

D) swallowable granulates;

E) animal or vegetable gelatine capsules;

F) soft gel.

13. Association for use according to any one of claims 9-12, wherein said formulation is obtained with a process comprising the following steps:

a. mixing together caprylic/capric triglyceride and polysorbate 80;

b. finely dissolving or dispersing coenzyme Q10 and resveratrol in the oily solution of step a.;

c. adsorbing the turmeric in the mixture of step b. until obtaining a dense and uniform paste;

d. adding to the mixture of step c. the powder obtained from the dry mixing of sucrester and pipeline by mixing with a suitable mixer until obtaining a wet powder; e. adding to the mixture of step d. the excipients necessary for the compression, for filling a capsule and for obtaining a swallowable or water-dispersible granulate.

14. Association for use according to any one of claims 9-13, wherein said formulation is in the form of a nutraceutical or of a dietetic supplement, preferably of a nutraceutical.