WO2020008359A1 - Formulation utilisée pour la prévention et en tant que traitement co-adjuvant de maladies neurodégénératives - Google Patents

Formulation utilisée pour la prévention et en tant que traitement co-adjuvant de maladies neurodégénératives Download PDF

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Publication number
WO2020008359A1
WO2020008359A1 PCT/IB2019/055632 IB2019055632W WO2020008359A1 WO 2020008359 A1 WO2020008359 A1 WO 2020008359A1 IB 2019055632 W IB2019055632 W IB 2019055632W WO 2020008359 A1 WO2020008359 A1 WO 2020008359A1
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WIPO (PCT)
Prior art keywords
association
use according
formulation
coenzyme
resveratrol
Prior art date
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PCT/IB2019/055632
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English (en)
Inventor
Giuseppe SAMARITANI
Simone CASTELLI
Original Assignee
Inpha Duemila S.R.L.
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Application filed by Inpha Duemila S.R.L. filed Critical Inpha Duemila S.R.L.
Publication of WO2020008359A1 publication Critical patent/WO2020008359A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • 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.
  • 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 processes 8 .
  • 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 .
  • 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 .
  • 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.
  • acutester intended as an ester of sucrose with fatty acids
  • 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,
  • 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.
  • ALS amyotrophic lateral sclerosis
  • Alzheimer's disease and Parkinson's disease and more preferably ALS.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • polysorbate 80 and ii)ester are each contained in a range variable between 10 and 20% by weight on the total weight of the sum of the active principles.
  • 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.
  • 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.
  • 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:
  • 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).
  • 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 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.
  • 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.
  • 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.
  • a further object of the present invention is the process that allows obtaining the aforesaid type of formulations and comprises the following steps:
  • step 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;
  • step d adding to the mixture of step c. the powder obtained from the dry mixing of
  • a suitable mixer until obtaining a wet powder
  • step d 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.
  • Curcuma E.S. Tit. 95% Curcuminoids equal to 100 mg of Curcuminoids Coenzyme Q10 75 mg
  • Piper Nigrum e.s. 95% piperine equal to 5 mg of piperine
  • Caprylic triglyceride as a novel therapeutic approach to effectively improve the performance and attenuate the symptoms due to the motor neuron loss in ALS disease.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Emergency Medicine (AREA)
  • Zoology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une association de curcumine, de trans-resvératrol, de coenzyme Q10 et d'acide caprylique pour une utilisation dans la prévention ou dans le traitement adjuvant de maladies neurodégénératives, telles que la sclérose latérale amyotrophique, la sclérose en plaques, la maladie d'Alzheimer et la maladie de Parkinson. Le déposant a également découvert que cette association est encore plus efficace si elle est administrée sous la forme de formulations orales contenant des promoteurs d'absorption entérique.
PCT/IB2019/055632 2018-07-03 2019-07-02 Formulation utilisée pour la prévention et en tant que traitement co-adjuvant de maladies neurodégénératives WO2020008359A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT102018000006893 2018-07-03
IT201800006893 2018-07-03

Publications (1)

Publication Number Publication Date
WO2020008359A1 true WO2020008359A1 (fr) 2020-01-09

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8021701B1 (en) * 2005-04-13 2011-09-20 Perry Stephen C Composition to retard the onset of symptoms of alzheimer's disease
US8349376B1 (en) * 2011-03-08 2013-01-08 Bezzek Mark S Anti-dementia regimen
US8846061B1 (en) * 2011-03-08 2014-09-30 Mark S. Bezzek Multivitamin-mineral regimens for longevity and wellness
WO2017004436A2 (fr) * 2015-07-01 2017-01-05 The Regents Of The University Of California Système thérapeutique comprenant des produits pharmaceutiques combinés à une amélioration métabolique pour traiter la neurodégénérescence

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8021701B1 (en) * 2005-04-13 2011-09-20 Perry Stephen C Composition to retard the onset of symptoms of alzheimer's disease
US8349376B1 (en) * 2011-03-08 2013-01-08 Bezzek Mark S Anti-dementia regimen
US8846061B1 (en) * 2011-03-08 2014-09-30 Mark S. Bezzek Multivitamin-mineral regimens for longevity and wellness
WO2017004436A2 (fr) * 2015-07-01 2017-01-05 The Regents Of The University Of California Système thérapeutique comprenant des produits pharmaceutiques combinés à une amélioration métabolique pour traiter la neurodégénérescence

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AMY NORTON: "Report Claims Success Treating Alzheimer's Memory Loss", 6 October 2014 (2014-10-06), pages 1 - 6, XP002789255, Retrieved from the Internet <URL:https://consumer.healthday.com/senior-citizen-information-31/misc-aging-news-10/report-claims-success-treating-alzheimer-s-memory-loss-692387.html> [retrieved on 20190226] *
ARUN SWAMINATHAN ET AL: "Nutrition and prevention of Alzheimer's dementia", FRONTIERS IN AGING NEUROSCIENCE, vol. 6, 20 October 2014 (2014-10-20), XP055561902, DOI: 10.3389/fnagi.2014.00282 *
LUCIA CHICO ET AL: "Curcumin as an ROS Scavenger in Amyotrophic Lateral Sclerosis", REACTIVE OXYGEN SPECIES, vol. 2, no. 5, 1 January 2016 (2016-01-01), pages 339 - 354, XP055562376, DOI: 10.20455/ros.2016.861 *
WEI ZHAO ET AL: "Caprylic Triglyceride as a Novel Therapeutic Approach to Effectively Improve the Performance and Attenuate the Symptoms Due to the Motor Neuron Loss in ALS Disease", PLOS ONE, vol. 7, no. 11, E49191, 7 November 2012 (2012-11-07), pages 1 - 8, XP055374823, DOI: 10.1371/journal.pone.0049191 *

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