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WO2008038119A2 - Composition contenant un complexe de coenzyme q10 et de cyclodextrines et son utilisation pour le traitement de pathologies du système nerveux central - Google Patents

Composition contenant un complexe de coenzyme q10 et de cyclodextrines et son utilisation pour le traitement de pathologies du système nerveux central Download PDF

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Publication number
WO2008038119A2
WO2008038119A2 PCT/IB2007/002820 IB2007002820W WO2008038119A2 WO 2008038119 A2 WO2008038119 A2 WO 2008038119A2 IB 2007002820 W IB2007002820 W IB 2007002820W WO 2008038119 A2 WO2008038119 A2 WO 2008038119A2
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WO
WIPO (PCT)
Prior art keywords
composition according
treatment
production
cyclodextrin
drug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2007/002820
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English (en)
Other versions
WO2008038119A3 (fr
Inventor
Rosario Ammirante
Felice Piero Molinari
Federico Mauro Del Monte
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Individual
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Individual
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Publication of WO2008038119A2 publication Critical patent/WO2008038119A2/fr
Publication of WO2008038119A3 publication Critical patent/WO2008038119A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/385—Concentrates of non-alcoholic beverages
    • A23L2/39—Dry compositions
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/30—Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
    • A23L29/35—Degradation products of starch, e.g. hydrolysates, dextrins; Enzymatically modified starches
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A23L33/155—Vitamins A or D
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A23L5/10—General methods of cooking foods, e.g. by roasting or frying
    • A23L5/15—General methods of cooking foods, e.g. by roasting or frying using wave energy, irradiation, electrical means or magnetic fields, e.g. oven cooking or roasting using radiant dry heat
    • 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
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a composition comprising a complex of coenzyme QlO and cyclodextrins and the use thereof for the treatment of various diseases, in particular of neurodegenerative pathologic states of the central nervous system, more particu- larly of Parkinson's disease.
  • Parkinson's disease is a neurodegenerative pathology wherein the component of protein degradation of Sommering' s substantia nigra causes a functional alteration thereof.
  • This proteolytic stress therefore, results in a serious deficit in the production of dopamine, a cate- cholamin neurotransmitter involved in the nervous circuit of the nuclei of the base of telencephalon.
  • proteins having a struc- ture that is unsuitable to their function are destroyed by the ⁇ biquitin Proteasome System (USP) complex.
  • USP ⁇ biquitin Proteasome System
  • the degradation process for these proteins starts with the bond of a chain of ubiquitin molecules (a protein with 76 amino acids and MW of 8,500 Da) as signal for identification and degradation by a protea- some .
  • Ubiquitin monomers are activated during an ATP- dependant thioesterification by enzyme El of UPS complex.
  • Activated ubiquitin is transferred to enzyme E2, a specific carrier, and then bound with covalent bonds by enzyme E3 (a ubiquitin protein ligase) to free amino groups of the lysines of the proteins to be de-
  • UPS complex results in an accumulation of abnormal proteins, among which ⁇ -synuclein is crucial: in physiological conditions, this protein is involved in mechanisms of synaptic plasticity, since it manages the transport and exchange of vesicles in synaptic terminals.
  • oxidative stress belongs to a sequence of events leading to neuronal death: it acts in synergy with other malfunctions, among which mitochondrial de- ficits and alterations of UPS system of degradation of cell proteins.
  • Dopamine metabolism is responsible for the high levels of oxidative stress in substantia nigra: as a matter of fact, the degradation of this neurotransmitter by the enzyme monoamine oxidase produces hydrogen perox- ide (H 2 O 2 ) . This leads first to an increase in the formation of oxidized glutathione (GSSG) , which means a serious damage to the most important antioxidant system of the cell.
  • GSSG oxidized glutathione
  • nitric oxide causes iron to separate from ferritin, thus increasing the concentration of free iron in the cell.
  • This process does not only involve dopaminergic neurons, but also occurs in glial cells, which indeed express enzymes belonging to the class of monoamine oxidases .
  • glial cells which indeed express enzymes belonging to the class of monoamine oxidases .
  • the task of the present invention is to prepare a composition having an inhibitory effect on the progress of neurodegenerative pathologic states of the central nervous system and in particular in Parkinson' s disease (PD) .
  • an aim of the invention is to prepare a composition based on CoEnQlO, as active substance, complexed with cyclodextrins .
  • Neuroprotective treatments can be useful during the onset of PD. This would mean beginning the treatment in the initial stage of the disease.
  • Coenzyme QlO also known as ubiquinone or ubidecarenone
  • Coenzyme QlO is a physiological molecule with antioxidant properties to be found in all cell membranes, among which inner mitochondrial membranes, where it is part of the complex I of the so- called respiratory chain, involved in the production of energy by mitochondria.
  • US patent 6,861,447 B2 describes a method for producing complexes of coenzyme QlO and ⁇ - cyclodextrin by thermal or ultrasonic treatment.
  • International patent application WO 2005/111224 A2 describes water-soluble complexes of coenzyme QlO and ⁇ - cyclodextrin as well as a process for producing them, in which the temperature of ⁇ -cyclodextrin dissolution in water and of the following addition of coenzyme QlO is suitably controlled.
  • US patent application US 2006/0078549 describes a method for the therapeutic treatment of neurodegenerative diseases, of Huntington' s disease for instance, by administering a complex of coenzyme QlO and cyclo- dextrins .
  • preparations containing CoEQlO as active substance for single-dose administrations are available at present on the mar- ket .
  • Such preparations are therefore unsuitable for the treatment of neurodegenerative diseases as described above, which require quite high doses (300 mg/die to 1,200 mg/die) .
  • the Applicants have faced the problem of providing preparations based on coenzyme QlO at high concentrations, having a high water solubility and a high pho- tostability, so as to enable the administration of the required dose also in a single step, preferably in liquid form or as water-soluble granules.
  • the present invention therefore re- lates to a composition
  • a composition comprising:
  • the present invention relates to a composition as defined above for use as a medicament.
  • the present invention relates to the use of a composition as defined above in the preparation of a drug for the treatment of neurodegenerative diseases of the central nervous system, in particular of Parkinson's disease (PD).
  • PD Parkinson's disease
  • the present invention relates to the use of a composition as defined above as food supplement .
  • Cyclodextrins are cyclic oligosaccharides containing at least 6 units of D- (+) -glucopyranose bound to one another with a ⁇ , 1-4 glucoside bond.
  • the three natural cyclodextrins ⁇ , ⁇ , ⁇ differ in ring size and solubility, ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin contain 6, 7 or 8 units of D- (+) -glucopyranose, re- spectively.
  • Cyclodextrins have the appearance of fine white, basically odourless powders, with a slight sweet taste.
  • ⁇ -cyclodextrin, ⁇ - cyclodextrin or ⁇ -cyclodextrin, or mixtures thereof can be used, ⁇ -cyclodextrin is particularly preferred.
  • Cyclodextrins have a stiff molecular structure of frusto-conical shape, with a central cavity whose size varies depending on the number of glucopyranose units present . Due to the arrangement of hydroxyl groups, the inside of the cavity is hydrophobic, whereas the outside is hydrophilic. This configuration allows cyclodextrins to house the host molecule of coenzyme QlO inside the cavity so as to form an inclusion complex ("host- guest" complex) .
  • the amount of coenzyme QlO in the composition according to the present invention is as a rule above 20% by weight, preferably of from 1% to 10% by weight, referred to the total weight of the composition.
  • the composition according to the present invention comprises from 40% to 100% by weight, more preferably from 50% to 90% by weight, of at least one cyclodex- trin, the percentage being expressed referred to the weight of coenzyme QlO.
  • the composition according to the present invention further comprises at least one carotene.
  • Carotene is preferably selected from: ⁇ -carotene, ⁇ - carotene, lycopene, or mixtures thereof. More preferably, carotene is ⁇ -carotene.
  • the composition according to the present invention comprises from 0.01% to 0.5% by weight of at least one carotene, more preferably from 0.05% to 0.3% by weight, the percentage being expressed referred to the total weight of the composition.
  • carotene As is known, carotenes are commonly marketed with a content of active substance of about 1-2%, the rest being made up of suitable additives and of carotene degradation products. Obviously, the above percentages refer to carotene that is actually present in the com- position.
  • composition according to the present invention solves the problems of solubility and photostability of coenzyme QlO as disclosed above, and is advantageous both for therapeutic use and for its technologi- cal properties, particularly for the flowability properties of the product.
  • composition in granular form has a controlled fri- -li ⁇
  • composition according to the present invention can comprise further pharmacologically acceptable excipi-
  • composition according to the present invention can include at least one com- io pound selected from: lactose, maltodextrins and lipoic acid.
  • the product is obtained by dividing the manufacturing process into two separate steps:
  • composition according to the present invention is used as inhibitor of neurodegenerative progress, in particular in Parkinson's disease.
  • the active substance acts by blocking the propagation of radical reaction, preventing the propagation thereof and therefore the lipoper- oxidation of cell membranes and thus cell death.
  • Such action is enhanced by the presence of carotene which, beyond having such chemical and physical characteristics as to improve the bioavailability and pho- tostability of coenzyme QlO, performs an antioxidant action and promotes the inhibition of mechanisms producing free radicals.
  • the end product can be portioned in suitable sealed containers so as to avoid any contamination from outside .
  • the product thus obtained has a duration not below 24 months in suitable conditions of temperature, humidity and package integrity.
  • composition according to the present invention can be used in several other diseases, such as: (a) mitochondrial diseases in general, with doses of coenzyme QlO of 1 mg/die to 10,000 mg/die;
  • cardiovascular diseases in which the oxidation of low density lipoproteins (LDL) is deemed to be the essential element for the development of atherosclero- sis, with doses of coenzyme QlO of 1 mg/die to 4,000 mg/die (it is believed that coenzyme QlO, thanks to its key role in energy production, contributes to the safeguard of vascular endothelium), such as: heart diseases in general, congestive heart failure, fatigue syndrome, dyspnea, essential hypertension, angina pectoris, surgical ischemiae;
  • LDL low density lipoproteins
  • I 5 carotene (commercial product distributed by A. C. E. F. with a titer of 1% and fine granulometry: 95% gets through a 80 mesh sieve) in such an amount as to obtain 0.1% by weight of ⁇ -carotene referred to the total weight of the composition.
  • S ⁇ concentration of coenzyme QlO (free and bound) ;
  • S w intrinsic solubility;
  • K f complexation constant;
  • L ⁇ concentration of binder.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Nutrition Science (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Mycology (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Botany (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition contenant : (a) un complexe de coenzyme Q10 et au moins une cyclodextrine; et (b) au moins un carotène. L'invention concerne également l'utilisation de ladite composition pour le traitement de diverses maladies, en particulier de maladies neurodégénératives du système nerveux central, spécialement la maladie de Parkinson (PD).
PCT/IB2007/002820 2006-09-29 2007-09-26 Composition contenant un complexe de coenzyme q10 et de cyclodextrines et son utilisation pour le traitement de pathologies du système nerveux central Ceased WO2008038119A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2006A001874 2006-09-29
IT001874A ITMI20061874A1 (it) 2006-09-29 2006-09-29 Composizione per il trattamento degli stati patologici neurodegenerativi del sistema nervoso centrale ed in particolare nel morbo di parkinson

Publications (2)

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WO2008038119A2 true WO2008038119A2 (fr) 2008-04-03
WO2008038119A3 WO2008038119A3 (fr) 2008-11-06

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PCT/IB2007/002820 Ceased WO2008038119A2 (fr) 2006-09-29 2007-09-26 Composition contenant un complexe de coenzyme q10 et de cyclodextrines et son utilisation pour le traitement de pathologies du système nerveux central

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IT (1) ITMI20061874A1 (fr)
WO (1) WO2008038119A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LU100797B1 (en) * 2018-05-15 2019-11-15 Univ Luxembourg 2-hydroxypropyl-beta-cyclodextrin for use in a method of treatment of a parkinsonian condition
FR3117339A1 (fr) 2020-12-16 2022-06-17 Naos Institute Of Life Science Utilisation des bactériorubérines et leurs dérivés glycosylés pour prévenir et traiter les maladies impliquant une dérégulation de l’agrégation des protéines, comme les maladies neurodégénératives

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1708480B (zh) * 2002-07-29 2010-12-15 卡达克斯药物公司 用于抑制和改善疾病的类胡萝卜素结构类似物
US7030102B1 (en) * 2003-05-06 2006-04-18 Bioactives, Llc Highly bioavailable coenzyme Q-10 cyclodextrin complex
KR20060100402A (ko) * 2003-10-31 2006-09-20 가부시키가이샤 가네카 환원형 보효소 ｑ 함유 조성물
CN1319534C (zh) * 2004-10-28 2007-06-06 昆明翔昊科技有限公司 含番茄红素和辅酶q10的制剂及其制备方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LU100797B1 (en) * 2018-05-15 2019-11-15 Univ Luxembourg 2-hydroxypropyl-beta-cyclodextrin for use in a method of treatment of a parkinsonian condition
WO2019219741A1 (fr) * 2018-05-15 2019-11-21 Université Du Luxembourg 2-hydroxypropyl-bêta-cyclodextrine destinée à être utilisée dans une méthode de traitement d'un état parkinsonien
FR3117339A1 (fr) 2020-12-16 2022-06-17 Naos Institute Of Life Science Utilisation des bactériorubérines et leurs dérivés glycosylés pour prévenir et traiter les maladies impliquant une dérégulation de l’agrégation des protéines, comme les maladies neurodégénératives
WO2022129407A1 (fr) 2020-12-16 2022-06-23 Naos Institute Of Life Science Utilisation des bactériorubérines et leurs dérivés glycosylés pour prévenir et traiter les maladies impliquant une dérégulation de l'agrégation des protéines, comme les maladies neurodégénératives

Also Published As

Publication number Publication date
WO2008038119A3 (fr) 2008-11-06
ITMI20061874A1 (it) 2006-12-29

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