ITMI20081947A1 - NEW USE OF A RESVERATROL COMBINATION OR ITS ANALOGUE AND A METABOLITY OF CISTEIN - Google Patents
NEW USE OF A RESVERATROL COMBINATION OR ITS ANALOGUE AND A METABOLITY OF CISTEIN Download PDFInfo
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- ITMI20081947A1 ITMI20081947A1 IT001947A ITMI20081947A ITMI20081947A1 IT MI20081947 A1 ITMI20081947 A1 IT MI20081947A1 IT 001947 A IT001947 A IT 001947A IT MI20081947 A ITMI20081947 A IT MI20081947A IT MI20081947 A1 ITMI20081947 A1 IT MI20081947A1
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Classifications
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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
- A61K31/045—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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Birds (AREA)
- Peptides Or Proteins (AREA)
Description
DESCRIZIONE DESCRIPTION
Annessa a domanda di brevetto d’INVENZIONE INDUSTRIALE avente per titolo: Attached to an INDUSTRIAL INVENTION patent application entitled:
NUOVO USO DI UNA COMBINAZIONE DI RESVERATROLO O SUO ANALOGO ED UN METABOLITA DELLA CISTEINA NEW USE OF A COMBINATION OF RESVERATROL OR ITS ANALOG AND A CYSTEINE METABOLITE
CAMPO DELL’INVENZIONE FIELD OF THE INVENTION
La presente invenzione riferisce del nuovo uso di una composizione nutraceutica comprendente come ingredienti attivi, resveratrolo o suo analogo, ed un metabolita della cisteina. The present invention relates to the new use of a nutraceutical composition comprising as active ingredients, resveratrol or its analogue, and a metabolite of cysteine.
Più specificamente, l’invenzione si riferisce all’uso di detto nutraceutico per il trattamento e la prevenzione di un disordine ialuronidasi -dipendente quali la senescenza cutanea e Partitrite articolare, in particolare in mammiferi comprendenti l’uomo. More specifically, the invention refers to the use of said nutraceutical for the treatment and prevention of a hyaluronidase-dependent disorder such as skin senescence and joint partitritis, in particular in mammals including humans.
11 termine “nutraceutico” come ivi utilizzato denota un’utilità applicativa sia in campo nutrizionale che farmaceutico. Pertanto, le nuove composizioni nutraceutiche possono trovare uso come integratori in cibi e bevande, integratori dietetici e formulazioni farmaceutiche per applicazione enterale e parenterale in formulazioni solide come capsule e compresse, o in formulazioni liquide come sospensioni e sospensioni. E’ inoltre evidente da quanto citato poco sopra che il termine composizione nutraceutica comprende inoltre cibi e bevande contenenti gli ingredienti attivi sopra menzionati. The term "nutraceutical" as used therein denotes application utility in both the nutritional and pharmaceutical fields. Therefore, the new nutraceutical compositions can find use as supplements in foods and beverages, dietary supplements and pharmaceutical formulations for enteral and parenteral application in solid formulations such as capsules and tablets, or in liquid formulations such as suspensions and suspensions. It is also evident from the aforementioned that the term nutraceutical composition also includes foods and drinks containing the active ingredients mentioned above.
BACKGROUND OF THE INVENTION BACKGROUND OF THE INVENTION
Da notare che mentre l’attività di inibizione della ialuronidasi del resveratrolo è uno strumento potenzialmente importante per la protezione della cute e di altri tessuti connettivi (es. giunture) dalla degradazione dell’IA, la scarsa biodisponibilità sistemica nell’uomo del resveratrolo (Walle T, e coll. Drug Metab Dispos. 2004;32(1 2): 1377-82) richiede un qualche meccanismo che renda effettiva tale azione nelle condizioni in vivo reali. Note that while the hyaluronidase inhibitory activity of resveratrol is a potentially important tool for the protection of skin and other connective tissues (e.g. joints) from AI degradation, the poor systemic bioavailability of resveratrol in humans (Walle T, et al. Drug Metab Dispos. 2004; 32 (1 2): 1377-82) requires some mechanism that makes this action effective under real in vivo conditions.
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
La presente invenzione è basata sul fatto che la combinazione di resveratrolo o suo analogo ed un metabolita della cisteina è sorprendentemente efficace nelfinibizione del fattività della ialuronidasi. The present invention is based on the fact that the combination of resveratrol or its analog and a metabolite of cysteine is surprisingly effective in inhibiting the effectiveness of hyaluronidase.
Di conseguenza, la presente invenzione fornisce una composizione adeguata all’uso medicinale comprendente resveratrolo o suo analogo e almeno un metabolita della cisteina. La composizione può prendere forma ed esercitare l’azione di un integratore dietetico o di una vera e proprio farmaco, in funzione dal ruolo di supporto o di azione preventiva, o dall’attività strettamente terapeutica che si intende affidare alla composizione in relazione al trattamento e/o alla prevenzione dei disordini ial urani dase-d spendenti. Consequently, the present invention provides a composition suitable for medicinal use comprising resveratrol or its analogue and at least one metabolite of cysteine. The composition can take shape and exercise the action of a dietary supplement or a real drug, depending on the role of support or preventive action, or on the strictly therapeutic activity that is intended to be entrusted to the composition in relation to the treatment and / or to the prevention of uranium-dase-d-spending disorders.
In un aspetto, la composizione dell’invenzione può essere somministrata ad un soggetto il cui disordine ialuronidasi -dipendente è la senescenza cutanea. In one aspect, the composition of the invention can be administered to a subject whose hyaluronidase-dependent disorder is skin senescence.
In un altro aspetto, la composizione dell’invenzione può essere somministrata ad un soggetto il cui disordine ialuronidasi-d Spendente è l’artitrite articolare. In another aspect, the composition of the invention can be administered to a subject whose hyaluronidase-d Spending disorder is joint arthritis.
DESCRIZIONE DEL DISEGNO DESCRIPTION OF THE DRAWING
La figura 1 illustra la cascata dei metaboliti della cisteina, dove: Figure 1 illustrates the cascade of cysteine metabolites, where:
Cys 1-Cisteina N3⁄4-CH(COOH)-Cff2-SH Cys 1-Cysteine N3⁄4-CH (COOH) -Cff2-SH
(a) Cisteina sulfmìc acid NH2-CH(C00H)-CH2-S03H (a) Cysteine sulfmìc acid NH2-CH (C00H) -CH2-S03H
(b) Cisteamina NH2-CH2-CH2-SH (b) Cysteamine NH2-CH2-CH2-SH
(c) Ci stami ne NH2-CH2-CH2-S-S-CH2-CH2-NH2(c) Ci stamens in NH2-CH2-CH2-S-S-CH2-CH2-NH2
(d) = Fosfocisteamina NH2-CH2-CH2-S-P03H2(d) = Phosphocysteamine NH2-CH2-CH2-S-P03H2
(e) = Ipo taurina NH2-CH2-CH2-S02H (e) = Hypo taurine NH2-CH2-CH2-S02H
(f) ~ Taurina NH2-CH2-CH2-SO3H (f) ~ Taurine NH2-CH2-CH2-SO3H
(g) = Acido cisteico NH2-CH(C00H)-CH2-S03H (g) = Cysteic acid NH2-CH (C00H) -CH2-S03H
(h) = Acido 3-mercaptopiruvico HOOC-CO-CH2-SH (h) = 3-mercaptopyruvic acid HOOC-CO-CH2-SH
CDO= Ciste ina diossgenasi CDO = Dioxgenase cyst
CSD = Cisteina sulfinato decarbossilasi CSD = Cysteine sulfinate decarboxylase
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Si è sorprendentemente trovato che una composizione contenente una combinazione con le seguenti componenti caratteristiche: resveratrolo o suo analogo, ed un metabolita della cisteina, o un loro sale farmacologicamente accettabile, è estremamente efficace della prevenzione e/o nel trattamento terapeutico dei disordini causati dalla iperattività della ialuronidasi, quale risultato del potente effetto sinergico esercitato dai suoi componenti. It has surprisingly been found that a composition containing a combination with the following characteristic components: resveratrol or its analogue, and a metabolite of cysteine, or a pharmacologically acceptable salt thereof, is extremely effective in the prevention and / or therapeutic treatment of disorders caused by hyperactivity of hyaluronidase, as a result of the powerful synergistic effect exerted by its components.
Pertanto, la presente invenzione rivela l’uso del resveratrolo o suo analogo, ed un metabolita della cisteina, o un loro sale farmacologicamente accettabile, per preparare un prodotto farmaceutico nel quale i due componenti sono mescolati insieme o confezionati separatamente per la prevenzione e il trattamento di forme collegate a disordi da ialuronidasi. Therefore, the present invention discloses the use of resveratrol or its analogue, and a metabolite of cysteine, or a pharmacologically acceptable salt thereof, to prepare a pharmaceutical product in which the two components are mixed together or packaged separately for prevention and treatment. of forms connected with hyaluronidase disorders.
I due ingredienti possono essere mescolati insieme o confezionati separatamente per “l’uso coordinato” di detti ingredienti. The two ingredients can be mixed together or packaged separately for "coordinated use" of said ingredients.
II termine "resveratrolo, o suo analogo” come utilizzato in questo contesto comprende composti descritti dalla formula (I): The term "resveratrol, or its analogue" as used herein includes compounds described by formula (I):
A denota un legame carbonio-carbonio singolo o doppio che quindi può essere trans o cis, e R<1>, R<2>, R<3>, R<4>, R<5>e R<6>, indipendentemente ciascun dall’altro denotano idrogeno, o gruppi idrossi, idrossi eterificati, o idrossi esterificati. A denotes a single or double carbon-carbon bond which therefore can be trans or cis, and R <1>, R <2>, R <3>, R <4>, R <5> and R <6>, independently each on the other denote hydrogen, or hydroxy, etherified hydroxy, or esterified hydroxy groups.
I gruppi idrossi eterificati o esterificati possono derivare da catene alchiliche non-sostituite o sostituite, lineari o ramificate di da 1 a 26 atomi di carbonio; o da acidi carbossilici alifatici, arilalifatici o aromatici non-sostituiti o sostituiti, lineari o ramificati aventi da 1 a 26 atomi di carbonio. I gruppi idrossi eterificati possono inoltre essere un gruppo glicoside e i gruppi esterificati possono inoltre essere un gruppo glucuronide o sulfato. The etherified or esterified hydroxy groups can derive from non-substituted or substituted, linear or branched alkyl chains of from 1 to 26 carbon atoms; or from aliphatic, arylaliphatic or aromatic non-substituted or substituted linear or branched carboxylic acids having from 1 to 26 carbon atoms. The etherified hydroxy groups can also be a glycoside group and the esterified groups can also be a glucuronide or sulfate group.
Esempi di composti di formula 1 dove A è -CH=CH- sono il resveratrolo (R<1>= R<3>= R<5>= H; R<2>= R<4>= R<6>= OH); il piceatannolo (R<3>= R<s>= H; R<1>= R<2>- R<4>= R<6>- OH), e la rapontigenina (R<5>= H; R<1>= R<3>= R<4>= R<6>= OH; R<2>= OMe). Examples of compounds of formula 1 where A is -CH = CH- are resveratrol (R <1> = R <3> = R <5> = H; R <2> = R <4> = R <6> = OH); piceatannol (R <3> = R <s> = H; R <1> = R <2> - R <4> = R <6> - OH), and rapontigenin (R <5> = H; R <1> = R <3> = R <4> = R <6> = OH; R <2> = OMe).
Esempi di composti di formula 1 dove A è -CH2-CH2- sono il di idro resveratrolo (R<l>= R<3>= R<5>= H; R<2>= R<4>= R<6>= OH), di idropi ceatanno lo (R<3>= R<5>= H; R<1>= R<2>= R<4>= R<6>= OH) e la tristian (R<3>= R<3>= H; R<2>= R<4>= R<6>= OH; R<1>= OMe). Examples of compounds of formula 1 where A is -CH2-CH2- are the of hydro resveratrol (R <l> = R <3> = R <5> = H; R <2> = R <4> = R <6 > = OH), of hydropic creatures the (R <3> = R <5> = H; R <1> = R <2> = R <4> = R <6> = OH) and the tristian (R < 3> = R <3> = H; R <2> = R <4> = R <6> = OH; R <1> = OMe).
II resveratrolo può essere preparato sinteticamente, o può essere estratto da prodotti naturali contenenti resveratrolo, come Vitis vinifera, Vitis rotundifolia, Vitis lambrusca e altre Vitis spp. O dalle radici del genus Polygonum genus, ad es. P. cuspidatum e P. multiflorum. Resveratrol can be prepared synthetically, or it can be extracted from natural products containing resveratrol, such as Vitis vinifera, Vitis rotundifolia, Vitis lambrusca and other Vitis spp. Or from the roots of the genus Polygonum genus, eg. P. cuspidatum and P. multiflorum.
Il termine "metabolite della cisteina” come utilizzato in questo contesto comprende composti descritti dalla formula (II): The term "cysteine metabolite" as used herein includes compounds described by formula (II):
(NH2)m-CYX-CH2-S(0)nZ (II) (NH2) m-CYX-CH2-S (0) nZ (II)
dove: where is it:
m denota 0, o 1 ; n denota 0, 1, 2, o 3; m denotes 0, or 1; n denotes 0, 1, 2, or 3;
X denota H, o COOH; e Y denota H; 0 X e Y denotano O; X denotes H, or COOH; and Y denotes H; 0 X and Y denote O;
Z denota H, -P03H2, o -S-CH2-CH2-NH2; Z denotes H, -P03H2, or -S-CH2-CH2-NH2;
con esclusione della 1-cisteina. with the exception of 1-cysteine.
In generale l’espressione “metaboliti della cisteina” comprende la cascata di metabolìti della cisteina da (a) a (h) descritti in figura 1, quindi comprende acido ci stein sul fi ni co, cìsteamina, cistamina, fosfoci steam ina, ipotaurina, taurina, acido cisteico e acido 3-mercaptopiruvico, nonché loro sali fisiologicamente accettabili. In general, the expression "metabolites of cysteine" includes the cascade of cysteine metabolites from (a) to (h) described in figure 1, therefore it includes cystein acid sulfine, cysteamine, cystamine, phosphocy steam ina, hypotaurine, taurine, cysteic acid and 3-mercaptopyruvic acid, as well as their physiologically acceptable salts.
Per gli scopi della presente invenzione, il termine sali fisiologicamente accettabili si riferisce a sali medicalmente accettabili che non riducono fattività inibitoria sulla ialuronidasi. Esempi appropriati comprendono sali di addizione con acidi organici o inorganici come acido acetico, acido tartarico, acido trifìuoroacetico, acido lattico, acido maleico, acido fumarico, acido citrico, acido metanesulfonico, acido solforico, acido fosforico, acido nitrico, o acido cloridrico. In aggiunta, per la fosfoci steam ina o altri cisteinmetabolici con gruppo anionico, imo o entrambi gli idrogeni acidi possono essere rimpiazzati da appropriati cationi, ad es. Na<+>, K<+>, Mg<2+>, Ca<2+>, NFÌ4<+>, o NR4<+>(where R è un CM alchile). E’ inoltre inteso che i metaboliti della cisteina per i nostri scopi possono essere nella forma zwitterionica, quando compatibile, ed in tutte le forme idrate così come nelle forme anidre. La composizione nutraceutìca della presente invenzione contiene resveratrolo o suo analogo in quantità sufficiente a fornire ad un uomo adulto (di peso circa 70 kg) un dosaggio da circa 0.5 mg/giomo a circa 3000 mg/giomo, preferibilmente da circa 25 mg/giomo a circa 500 mg/giomo. Pertanto, se la composizione nutraceutìca è un cibo o bevanda la quantità di resveratrolo è opportunamente dosata nell’ intervallo da circa 1 mg a circa 500 mg per porzione. Se la composizione nutraceutìca è una formulazione medicinale tale formulazione potrà contenere da circa 0.5 mg a circa 1500 mg per unità dosata solida, ad es. per capsule o compresse, o da circa 0.5 mg per dose giornaliera a circa 3000 mg per dose giornaliera di una formulazione liquida. For the purposes of the present invention, the term physiologically acceptable salts refers to medically acceptable salts which do not reduce inhibitory effectiveness on hyaluronidase. Suitable examples include organic or inorganic acid addition salts such as acetic acid, tartaric acid, trifluoroacetic acid, lactic acid, maleic acid, fumaric acid, citric acid, metanesulfonic acid, sulfuric acid, phosphoric acid, nitric acid, or hydrochloric acid. In addition, for steam phosphocy or other anionic metabolic cysteins, imo or both acidic hydrogens can be replaced by appropriate cations, e.g. Na <+>, K <+>, Mg <2+>, Ca <2+>, NFÌ4 <+>, or NR4 <+> (where R is a CM alkyl). It is also understood that the metabolites of cysteine for our purposes can be in the zwitterionic form, when compatible, and in all the hydrated forms as well as in the anhydrous forms. The nutraceutical composition of the present invention contains resveratrol or its analog in an amount sufficient to provide an adult man (weighing about 70 kg) with a dosage from about 0.5 mg / day to about 3000 mg / day, preferably from about 25 mg / day to about 500 mg / day. Therefore, if the nutraceutical composition is a food or drink, the amount of resveratrol is suitably dosed in the range from about 1 mg to about 500 mg per serving. If the nutraceutical composition is a medicinal formulation, this formulation may contain from about 0.5 mg to about 1500 mg per solid dosed unit, e.g. for capsules or tablets, or from about 0.5 mg per daily dose to about 3000 mg per daily dose of a liquid formulation.
il rapporto peso-su-peso tra resveratrolo e metabolita della cisteina varia da 100: 1 a 1 :1000. the weight-to-weight ratio of resveratrol to the cysteine metabolite ranges from 100: 1 to 1: 1000.
Rispeto all’attività sinergica sull’inibizione della ialuronidasi, i metaboliti della cisteina si distinguono in metaboliti ad alta potenza come la cisteamina, e a potenza medio-bassa.Compared to the synergistic activity on the inhibition of hyaluronidase, the metabolites of cysteine are divided into high-powered metabolites such as cysteamine, and medium-low-potency ones.
Pertanto la composizione preferibilmente comprenderà resveratrolo o suoi analoghi a cisteamina, o un metabolica della cisteina parimenti potente, in rapporto ponderale da 10:1 a 1:10, preferibilmente da 1 : 1 a l :5. La composizione preferibilmente comprenderà resveratrolo o suoi analoghi e taurina in rapporto ponderale da 1 :1 al: 1,000, preferibilmente da 1:100 a 1:200. Therefore, the composition will preferably comprise resveratrol or its analogues to cysteamine, or an equally potent metabolic of cysteine, in a weight ratio from 10: 1 to 1:10, preferably from 1: 1 to 1: 5. The composition will preferably comprise resveratrol or its analogs and taurine in a weight ratio from 1: 1 to: 1,000, preferably from 1: 100 to 1: 200.
La composizione può essere somministrata con una frequenza di varie volte al giorno fino a una volta ogni due giorni, preferibilmente quotidianamente. I) trattamento dovrebbe essere continuativo. In generale per la somministrazione ad adulti, un dosaggio giornaliero appropriato è nell’intervallo da circa 5 mg a circa 500 mg, sebbene il limite superiore possa essere oltrepassato se/quando necessario. Il dosaggio giornaliero può essere somministrato in una singola dose o in dosi suddivise. The composition can be administered with a frequency of several times a day up to once every two days, preferably daily. I) processing should be continuous. In general, for administration to adults, an appropriate daily dosage is in the range from about 5 mg to about 500 mg, although the upper limit can be exceeded if / when necessary. The daily dosage can be administered in a single dose or in divided doses.
La presente composizione può essere somministrata in qualsiasi forma convenzionale, preferibilmente per via orale, per esempio come compressa, compressa rivestita, dragea, pastiglia, losanga, sospensione acquosa o oleosa, soluzione liquida, polvere o granuli disperdibìli, emulsioni, capsule molli o dure, o sciroppi o elisir. Le composizioni concepite per l’uso orale posso essere preparate secondo ogni metodo noto nella fabbricazione dì composizioni medicinali e tali composizioni possono contenere uno o più agenti scelti nel gruppo comprendente edulcoranti, aromatizzanti, coloranti e conservanti in modo da ottenere preparazioni medicinalmente eleganti e palatabili. The present composition can be administered in any conventional form, preferably orally, for example as a tablet, coated tablet, dredge, lozenge, aqueous or oily suspension, liquid solution, dispersible powder or granules, emulsions, soft or hard capsules, or syrups or elixirs. The compositions designed for oral use can be prepared according to any known method in the manufacture of medicinal compositions and these compositions can contain one or more agents selected from the group comprising sweeteners, flavorings, dyes and preservatives in order to obtain medicinally elegant and palatable preparations.
Le compresse contengono i principi attivi in miscela con eccipienti atossici e medicinalmente accettabili appropriati per la fabbricazione di compresse. Questi eccipienti sono ad esempio diluenti inerti, tipo calcio carbonato, sodio carbonato, lattosio, destrosio, saccarosio, cellulosa, amido di mais, fecola di patate, calcio o sodio fosfato; agenti di granulazione e disintegranti, ad esempio, amido di maisena, acido alginico, alginati o amido glicolato sodico; agenti leganti, ad esempio amido, gelatina o acacia; agenti lubricanti, ad esempio silice, magnesio o calcio stearato, acido stearico o talco; miscele effervescenti; coloranti, edulcoranti, bagnanti come la lecitina, polisorbati o lauril solfato. Le compresse possono essere non ricoperte o ricoperte con tecniche note per ritardare la disintegrazione e l’assorbimento nel tratto gastrointestinale in modo da fornire un’azione prolungata in un lungo periodo. Per esempio, possono essere impiegati materiali a ritardo quali gliceril monostearato o gliceril distearato. Tali preparazioni possono essere fabbricate con metodi noti, per esempio mediante miscelazione, granulazione, compressazione, ricopertura a zucchero o processi di film coating. The tablets contain the active ingredients in admixture with non-toxic and medicinally acceptable excipients appropriate for the manufacture of tablets. These excipients are for example inert diluents, such as calcium carbonate, sodium carbonate, lactose, dextrose, sucrose, cellulose, corn starch, potato starch, calcium or sodium phosphate; granulating and disintegrating agents, for example, maize starch, alginic acid, alginates or sodium starch glycolate; binding agents, for example starch, gelatin or acacia; lubricating agents, for example silica, magnesium or calcium stearate, stearic acid or talc; effervescent mixtures; dyes, sweeteners, wetting agents such as lecithin, polysorbates or lauryl sulfate. The tablets can be uncoated or coated with known techniques to delay disintegration and absorption in the gastrointestinal tract in order to provide a prolonged action over a long period. For example, delayed materials such as glyceryl monostearate or glyceryl distearate can be employed. Such preparations can be manufactured with known methods, for example by mixing, granulating, compressing, sugar coating or film coating processes.
Formulazioni per uso orale possono essere presentate come capsule di gelatine dura dove l’ingrediente attivo è mescolato con un diluente solido, ad es. calcio carbonato, calcio fosfato o caolino, o come capsule di gelatina molle dove il principio attivo è presente tal quale, o mescolato con acqua o con mezzo oleoso, ad es. olio di arachidi, di oliva o paraffina lìquida. Le sospensioni acquose contengono i materiali attivi in miscela con eccipienti appropriati per la fabbricazione di sospensioni acquose. Tali eccipienti sono agenti sospendenti, ad es. sodio carbossimetil cellulosa, metilcellulosa, idrossipropilmetil-cellulosa, sodio alginato, polivinylpirrolidone, gomma tragacanta e gomma acacia; disperdenti o agenti bagnanti possono essere i fosfatidi naturali, ad es. lecitina, o i prodotti di condensazione di un alchilene ossido con un acido grasso, ad es. poliossietìlene stearato, o i prodotti di condensazione di un etilene ossido con un alcol alifatico, ad es. eptadecaetileneossìcetanol, o i prodotti di condensazione di etilene ossido con un estere parziale derivato da acidi grassi e exitolo come il poliossietìlene sorbitol monooleato. Formulations for oral use can be presented as hard gelatine capsules where the active ingredient is mixed with a solid diluent, eg. calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is present as it is, or mixed with water or an oily medium, eg. peanut, olive or liquid paraffin oil. The aqueous suspensions contain the active materials in admixture with excipients appropriate for the manufacture of aqueous suspensions. Such excipients are suspending agents, e.g. sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; dispersants or wetting agents can be natural phosphatides, eg. lecithin, or the condensation products of an alkylene oxide with a fatty acid, e.g. polyoxyethylene stearate, or the condensation products of an ethylene oxide with an aliphatic alcohol, e.g. heptadecaethylene oxycetanol, or the condensation products of ethylene oxide with a partial ester derived from fatty acids and exitol such as polyoxyethylene sorbitol monooleate.
Dete sospensioni acquose possono contenere uno o più conservanti, ad es.etil o n-propil pidrossibenzoato, uno o più coloranti, e/o uno o più agenti edulcoranti quali saccarosio, saccarina, glucosio, sorbitolo e mannìtolo. Said aqueous suspensions may contain one or more preservatives, e.g. ethyl or n-propyl hydroxybenzoate, one or more dyes, and / or one or more sweetening agents such as sucrose, saccharin, glucose, sorbitol and mannitol.
Le sospensioni oleose possono essere formulate sospendendo gli ingredienti ativi in olio vegetale, ad es. olio di arachidi, di oliva, di sesamo, di cocco, o in un olio minerale come la paraffina liquida. Le sospensioni oleose possono contenere agenti viscosizzanti, ad es. cera d’api, paraffina solida, o alcohol cetilico. Oily suspensions can be formulated by suspending the active ingredients in vegetable oil, e.g. peanut, olive, sesame, coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain viscosifying agents, e.g. beeswax, solid paraffin, or cetyl alcohol.
Agenti edulcoranti, quali quelli illustrate sopra e agenti aromatizzanti possono fornire una preparazione orale palatabile. Queste composizioni possono essere conservate mediante aggiunta di un antiossidante quale l’acido ascorbico. Polveri e granulati disperdibili appropriati per la preparazione di una sospensione acquosa mediante addizione di acqua forniscono gli ingredienti ativi in miscela con un agente disperdente o bagnate, un agente sospendente e uno o più conservanti. Adeguati agenti disperdenti e bagnanti o agenti sospendenti sono esemplificati da quelli citati in precedenza. Sweetening agents such as those illustrated above and flavoring agents can provide a palatable oral preparation. These compositions can be preserved by adding an antioxidant such as ascorbic acid. Suitable dispersible powders and granulates for the preparation of an aqueous suspension by addition of water provide the active ingredients in admixture with a dispersing agent or wets, a suspending agent and one or more preservatives. Suitable dispersing and wetting agents or suspending agents are exemplified by those mentioned above.
Altri eccipienti come agenti edulcoranti, aromatici e coloranti possono essere presenti. Other excipients such as sweetening, flavoring and coloring agents may be present.
Le composizioni medicinali dell’invenzione possono essere anche in forma di emulsioni O/A. La fase oleosa può essere un olio vegetale, ad es. olio di olive o di arachidi, o un olio minerale, ad es. paraffina liquida, o miscele tra questi. The medicinal compositions of the invention can also be in the form of O / A emulsions. The oily phase can be a vegetable oil, e.g. olive or peanut oil, or a mineral oil, eg. liquid paraffin, or mixtures of these.
Adeguati agenti emulsionanti possono essere le gomme naturali, ad es. gomma acacia o gomma tragacanta, fosfolipidi naturali, ad es. lecitina di soia e esteri o esteri parziali derivati da acidi grassi e sorbitolo, ad es. sorbitan mono-oleato e prodotti di condensazione con ossido di etilene, ad es. poliossietilene sorbitan monooleato. Suitable emulsifying agents can be natural rubbers, eg. acacia gum or tragacanth gum, natural phospholipids, eg. soy lecithin and esters or partial esters derived from fatty acids and sorbitol, e.g. sorbitan mono-oleate and condensation products with ethylene oxide, e.g. polyoxyethylene sorbitan monooleate.
L’emulsione può inoltre contenere un agente edulcorante o aromatizzante. Sciroppi e elisir possono essere formulati con agenti edulcoranti, ad es. glicerina, sorbitolo o saccarosio. In particolare uno sciroppo per diabetici potrà contenere solo prodotti come ad es. sorbitolo, che non metabolizza a glucosio o solo in limitatissime quantità. The emulsion may also contain a sweetening or flavoring agent. Syrups and elixirs can be formulated with sweetening agents, eg. glycerin, sorbitol or sucrose. In particular, a syrup for diabetics may contain only products such as eg. sorbitol, which does not metabolise to glucose or only in very limited quantities.
La sospensione può essere formulate secondo tecniche note utilizzando appropriati agenti bagnanti o disperdenti come già citato in precedenza. The suspension can be formulated according to known techniques using appropriate wetting or dispersing agents as already mentioned above.
In un ambito realizzativo preferito, la composizione secondo la presente invenzione comprende anche un fitosterolo e/o un fitoestrogeno estratti/purificati da fonti naturali mediante tecniche note. In a preferred embodiment, the composition according to the present invention also comprises a phytosterol and / or a phytoestrogen extracted / purified from natural sources by known techniques.
In alternativa sono inoltre utili alla presente composizione versioni sintetiche o semisintetiche o derivati di fitosteroli e fìtoestrogeni, dato che i metodi di sintesi o derivatizzazione sono conosciuti. Alternatively, synthetic or semi-synthetic versions or derivatives of phytosterols and phytoestrogens are also useful for the present composition, since the synthesis or derivatization methods are known.
Utili fitosteroli comprendono campesterolo, sitosterolo, fucosterolo, stigmasterolo, stigmastanolo, o stigmastadienone. Un composto fìtosterolico preferito è il β-sitosterolo, ma anche a-o γ-sitosterolo sono utili. Altri fitosteroli preferiti comprendono i loro derivati o coniugati, ad es. P-sitosterol-3-0-P-D-glucopiranoside. Nella presente composizione può anche essere impiegata una miscela dì fitosteroli. Useful phytosterols include campesterol, sitosterol, fucosterol, stigmasterol, stigmastanol, or stigmastadienone. A preferred phytosterol compound is β-sitosterol, but a- or γ-sitosterol are also useful. Other preferred phytosterols include their derivatives or conjugates, e.g. P-sitosterol-3-0-P-D-glucopyranoside. A mixture of phytosterols can also be used in the present composition.
Utili fìtoestrogeni comprendono lignani, isoflavoni, flavoni, o cumestani e loro derivati o coniugati. I fìtoestrogeni comprendono sia le forme libere (non-coniugate) che le coniugate, per esempio, coniugati solfati o solfonati. o coniugati glucosidi, glucuronici, or sulfoglucuronici. Può inoltre essere utilizzata una miscela di Fìtoestrogeni. Useful phytoestrogens include lignans, isoflavones, flavones, or cumestanes and their derivatives or conjugates. Phytoestrogens include both free (non-conjugated) and conjugated forms, for example, sulfated or sulphonated conjugates. or glucoside, glucuronic, or sulfoglucuronic conjugates. A mixture of Phytoestrogens can also be used.
Appropriati lignani comprendono sesamina, justiciresinolo, lariciresinolo, isolariciresinolo. secoìsolariciresinolo, O-demetilsecoisolariciresinolo, didemetilseco isolariciresinolo, demetossisecoìsolaricìresinolo, matairesinolo, siringaresi nolo, episiringaresinolo, diasiringaresinolo, massoniresinolo, lirioresinolo, entrodiolo, enterolattone, gomisin A, gomisin C, gomisin D, acido nordiidroguaiaretico, acido 3’-0-metil nordiidroguaiaretico, arctigenina, o 3’-0-demetilarctigenina e loro derivati o coniugati. Tipici lignani coniugati comprendono siringaresìnol-3-D~glucoside, massoniresinolo 4’-0-D-glucopiranoside, seco isolarìciresi nolo diglicoside, butirrolactone lignan-disaccaride. Suitable lignans include sesamine, justiciresinol, lariciresinol, isolariciresinol. secoìsolariciresinol, O-demethylsecoisolaricresinol, didemethylsecum isolaricresinol, demethoxysecoissolaricyresinol, matairesinol, syringaresi nolo, episyringaresinol, diasyringaresinol, masoniresinol, lyrioresinol, nordiomiaresinetic acid, Arogidylactogenetic acid, Dygenylactone-gyrogen-synthetic acid, nordiomiarisinua-gyrogynthia , or 3'-0-demethylarctigenin and their derivatives or conjugates. Typical conjugated lignans include syringaresinol-3-D ~ glucoside, masoniresinol 4'-0-D-glucopyranoside, seco isolarìcyresi nolo diglycoside, butyrolactone lignan-disaccharide.
Appropriati isoflavoni comprendono genisteina, daidzeina, biocanin A, gliciteina, zearalenone, β-zearalenolo, formononetina, labumetina, isoprunetina, O-desmetìlangolensina, ipriflavone, floretina, baicaleina, alpinumisoflavone, idrossialpinumisoflavone e loro derivati o coniugati. Un tipico derivato di fitoestrogeni è l’equolo, un metabolita della daidzeina. Altri utili derivati comprendono diidrodaidzeina, tetraidrodaidzeina, di idrogeni steina, 2-deidro-O-demetilangolensina. Suitable isoflavones include genistein, daidzein, biocanin A, glycitein, zearalenone, β-zearalenol, formononetin, labumetin, isoprunetin, O-desmethylangolensin, ipriflavone, phloretin, baicalein, alpinumisoflavone, hydroxyalpinumisoflavone and their derivatives. A typical derivative of phytoestrogens is equol, a metabolite of daidzein. Other useful derivatives include dihydrodaidzein, tetrahydrodaidzein, dihydrogen stein, 2-dehydro-O-demethylangolensin.
Appropriati flavoni comprendono apigenina, galangina, fisetina, morina, crisma, tectocrisìna, miricetina, Iuteolina, 2,5-diidrossi-6,7-dÌmetossifIavonone e loro derivati o coniugati. Suitable flavones include apigenin, galangin, fisetin, morina, chrysma, tectocrisina, myricetin, juteolin, 2,5-dihydroxy-6,7-di-methoxy-avonone and their derivatives or conjugates.
Sono inoltre preferiti xantumolo, isoxantumolo, desmetossixantumolo, naringenina, 6- e 8-prenilnaringenine, 6-geranilnaringenìna, ottenuti dal luppolo e dalla birra. Utili flavoni coniugati comprendono i flavon glucosidì, ad es. 7-metossi-flavone-5-0-glucoside. Also preferred are xanthumol, isoxanthumol, desmethoxyxanthumol, naringenin, 6- and 8-prenylnaringenine, 6-geranylnaringenine, obtained from hops and beer. Useful conjugated flavones include the flavon glucosides, e.g. 7-methoxy-flavone-5-0-glucoside.
In un altra forma realizzatìva, il fitoestrogeno è un cumestano. Esempi comprendono cumestrolo, wedelolattone, 4’-metossicoumestrolo e plicadina, o loro derivati o coniugati. Esempi utili di derivati di cumestani comprendono LQB16, LQB34 (PCALC36), LQB93 e LQB96 (Kaushik-Basu N. e coll., Nucleic Acids Research, 2008, 36(5): 1482- 1496, Identification e characterization of coumestans as novel HCV NS5B polymerase inhibitors). Gli esempi a seguire illustrano ulteriormente la presente invenzione. In another embodiment, the phytoestrogen is a coumestane. Examples include cumestrol, wedelolactone, 4'-methoxycoumestrol and plicadine, or their derivatives or conjugates. Useful examples of cumestane derivatives include LQB16, LQB34 (PCALC36), LQB93 and LQB96 (Kaushik-Basu N. et al., Nucleic Acids Research, 2008, 36 (5): 1482- 1496, Identification and characterization of coumestans as novel HCV NS5B polymerase inhibitors). The following examples further illustrate the present invention.
ESEMPI EXAMPLES
Esempi 1. 2 Examples 1. 2
resveratrolo mg 25 mg 25 resveratrol 25 mg 25 mg
taurina mg 250 taurine 250 mg
cisteamina HCi - mg 12.5 cysteamine HCi - 12.5 mg
acido citrico - mg 30 citric acid - 30 mg
tocoferil acetato mg 20 mg 20 tocopheryl acetate 20 mg 20 mg
isoflavoni di soia mg 60 mg 60 soy isoflavones 60 mg 60 mg
lignani da semi di lino mg 30 mg 30 acido a-lipoico _ mg 10 _ mg 10 linseed lignans mg 30 mg 30 a-lipoic acid _ mg 10 _ mg 10
Esempi 3. 4 Examples 3. 4
resveratrolo mg 30 mg 30 acido cisteico H20 mg 25 resveratrol mg 30 mg 30 cysteic acid H20 mg 25
taurina - mg 150 isofiavoni di soia mg 60 mg 60 β-sitosterolo mg 25 taurine - 150 mg soy isofiavones 60 mg 60 mg β-sitosterol 25 mg
cumestani mg 30 mg 30 ascorbil palmitato mg 100 mg 100 cumestans mg 30 mg 30 ascorbyl palmitate mg 100 mg 100
Esempi 5. 6 Examples 5. 6
resveratrolo mg 25 mg 25 sodio 3-mercaptopiruvato mg 10 resveratrol mg 25 mg 25 sodium 3-mercaptopyruvate mg 10
cisteamina bitartrato - mg 10 taurina - mg 150 fosfatidilcolina mg 50 mg 50 fosfatidii scrina mg 50 mg 50 gl icero-fos fori lco lina mg 50 mg 50 Vit.E mg 10 cysteamine bitartrate - 10 mg taurine - 150 mg phosphatidylcholine 50 mg 50 phosphatidylcholine mg 50 mg 50 glycero-phosphorine mg 50 mg 50 Vit.E mg 10
selenio pg 10 selenium pg 10
magnesium cloruro mg 50 magnesium chloride 50 mg
zinco oro tato _ mg 30 zinc gold tato _ mg 30
Esempio 7 Example 7
Resveratrolo mg 20 Resveratrol 20 mg
cistamina 2HC1 mg 5 cystamine 2HC1 mg 5
riamine HC1 (Vit. Bl ) mg 1 riamine HC1 (Vit. Bl) mg 1
riboflavina (Vit. B2) mg 1 riboflavin (Vit. B2) mg 1
piridossal fosfato (Vit. B6) mg 2 pyridoxal phosphate (Vit. B6) mg 2
pantetina mg 5 pantethine 5 mg
serina mg 10 serine 10 mg
colina mg 10 choline mg 10
1-arginina HC1 mg 15 1-arginine HCl 15 mg
lisina mg 10 lysine 10 mg
Esempio 8 _ _ Example 8 _ _
resveratrolo g 2 resveratrol g 2
taurina g 2 taurine g 2
isoflavoni di soia mg 60 60 mg soy isoflavones
lignani da semi di lino mg 60 lignans from flaxseed 60 mg
eccipienti per granulazione q.b. a 4 g Esempio in vitro - Test di inibizione di ialuronidasì excipients for granulation to taste a 4 g In vitro example - Hyaluronidase inhibition test yes
L’effetto inibitore del resveratrolo e dei metaboliti della cisteina sulla ialuronidase da testicolo bovino può essere misurata con un metodo turbìdìmetrico (Di Ferrante N.; J. Biol. Chem., 1956, 220, 303-306). The inhibitory effect of resveratrol and cysteine metabolites on hyaluronidase from bovine testis can be measured with a turbidimetric method (Di Ferrante N .; J. Biol. Chem., 1956, 220, 303-306).
L’attività enzimatica è quantificata mediante determinazione della turbidità causata dalla precipitazione del residuo substrato ad alto peso molecolare (PM > 6-8 kDa) con cetiltrìmetillammonio algonuro. Tale sistema si utilizza anche per il throughput screening degli inibitori di ialuronidase (Tung JS, Mark GE, Hollis GF; AnaL Bioehem. 1994, 223, 149-152). L’enzima (800 U/ml) e IA (0.40 mg/ml) sono incubati a 37°C per 1 h. L’attività enzimatica è misurata come percentuale dell’IA indigesto con precipìtatom di cetilpiridinio cloruro con assorbenza a 415 nm (A<415>nm) dopo la reazione enzimatica. Le seguenti formule sono state utilizzate per i calcoli: The enzymatic activity is quantified by determining the turbidity caused by the precipitation of the residual substrate with a high molecular weight (MW> 6-8 kDa) with cetyltrimethylammonium algonide. This system is also used for the throughput screening of hyaluronidase inhibitors (Tung JS, Mark GE, Hollis GF; AnaL Bioehem. 1994, 223, 149-152). The enzyme (800 U / ml) and IA (0.40 mg / ml) are incubated at 37 ° C for 1 h. Enzymatic activity is measured as a percentage of indigestible AI with cetylpyridinium chloride precipitate with absorbency at 415 nm (A <415> nm) after the enzymatic reaction. The following formulas were used for the calculations:
(i) A<415>nm valore del IA intatto indigesto, preso come riferimento 100%. (i) At <415> nm intact indigestible IA value, taken as 100% reference.
(ii) % Attività enzimatica = (100%) - (A<4 li>nm di IA enzima/ A<415>nm di IA x 100} (ii)% Enzyme activity = (100%) - (A <4 li> nm of IA enzyme / A <415> nm of IA x 100}
La miscela di incubazione contenente 20 μΐ di tampone citrato- fosfato (soluzione A: 0.1 M Na2HP04, 0.1 M NaCl, soluzione B: 0.1 M acido citrico, 0.1 M NaCl; soluzione A e B vengono mescolate in proporzioni appropriate a raggiungere pH 5,0), 30 μΐ di soluzione di BSA (0.2 mg/ml in acqua), 30 μΐ di soluzione di IA substrato (2 mg/ml in acqua), 50 μΐ di H20, 10 μΐ di Me2SO, e 30 μΐ di soluzione di enzima (54 ng di IA da testicolo bovino in 30 μΐ di soluzione BSA). Per determinare le attività inibenti dei vari composti, invece di 10 μΐ di Me2SO, sono state utilizzati 10 μΐ con varie concentrazioni. La concentrazione finale di Me2SO era 3,8% (v/v). Dopo incubazione della miscela del test per 30 min a 37 °C, 720 μΐ odi una soluzione al 2.5% (p/v) di cetiltrimetìllammonio cloruro (2.5 g in 100 mi di NaOH 1⁄2M, pH 12.5) sono state aggiunte per precipitare il substrato residuo ad alto peso molecoare e fermare la reazione enzimatica. La miscela è stata incubata a 25 °C per 20 min, e la turbidità di ciascun campione determinata a 415 nm con spettrofotometro Uvìkon 930 UV. Gli The incubation mix containing 20 μΐ of citrate-phosphate buffer (solution A: 0.1 M Na2HP04, 0.1 M NaCl, solution B: 0.1 M citric acid, 0.1 M NaCl; solution A and B are mixed in appropriate proportions to reach pH 5, 0), 30 μΐ of BSA solution (0.2 mg / mL in water), 30 μΐ of substrate IA solution (2 mg / mL in water), 50 μΐ of H20, 10 μΐ of Me2SO, and 30 μΐ of enzyme (54 ng of IA from bovine testis in 30 μΐ of BSA solution). To determine the inhibitory activities of the various compounds, instead of 10 μΐ of Me2SO, 10 μΐ with various concentrations were used. The final concentration of Me2SO was 3.8% (v / v). After incubation of the test mixture for 30 min at 37 ° C, 720 μΐ or a 2.5% (w / v) solution of cetyltrimethylammonium chloride (2.5 g in 100 ml of 1⁄2M NaOH, pH 12.5) was added to precipitate the residual substrate with high molecular weight and stop the enzymatic reaction. The mixture was incubated at 25 ° C for 20 min, and the turbidity of each sample determined at 415 nm with UVikon 930 UV spectrophotometer. The
sperimenti sono stati condotti (30 μΐ di soluzione of BSA usati invece di) sono stati presi experiments were conducted (30 μΐ of solution of BSA used instead of) were taken
come riferimento di attività enzimatica 0%. as a reference of 0% enzymatic activity.
Le sostanze delle prova inibiscono l’attività della ialuronidasi in modo dose-dipendente, The test substances inhibit the activity of hyaluronidase in a dose-dependent manner,
come illustrato nella Tabella I. as shown in Table I.
TABELLA I - Inibizione of ialuronidasi mediante sostanze pure TABLE I - Inhibition of hyaluronidase by pure substances
Sostanza Concentrazione Inib. Enzima (%) Substance Concentration Inhib. Enzyme (%)
pg/mg μΜ pg / mg μΜ
Resveratrolo 10 43 26 Resveratrolo 20 88 45 Resveratrolo 30 131 87 Resveratrolo 40 175 93 Resveratrol 10 43 26 Resveratrol 20 88 45 Resveratrol 30 131 87 Resveratrol 40 175 93
Cisteamina HC1 200 1760 30 Cysteamine HC1 200 1760 30
Cisteamina HC1 400 3521 51 Cysteamine HC1 400 3521 51
Cisteamina HC1 600 5281 94 Cysteamine HC1 600 5281 94
Cisteamina HC1 800 7042 100 Cysteamine HC1 800 7042 100
Taurina 800 6393 48 Taurine 800 6393 48
Taurina 1600 12786 88 Taurine 1600 12 786 88
Taurina 2400 19179 91 Taurine 2400 19179 91
Taurina 3200 25571 90 Taurine 3200 25571 90
Acido cisteico H20 400 2137 24 Cysteic acid H20 400 2137 24
Acido cisteico H20 800 4274 76 Cysteic acid H20 800 4274 76
Acido cisteico H20 1200 6411 89 Cysteic acid H20 1200 6411 89
Acido cisteico H20 1600 8548 100 Cysteic acid H20 1600 8548 100
Lo stesso metodo è stato applicato alla combinazioni di sostanze per verificare l’effetto The same method was applied to the combinations of substances to verify the effect
sinergistico, come illustrato nella Tabella IL synergistic, as shown in Table IL
TABELLA II - Inibizione della ialuronidasi mediante combinazione di sostanze TABLE II - Inhibition of hyaluronidase by combination of substances
Sostanza 1 Sostanza 2 Concentrazione 1 2 Inib, Enzima (%) Resveratrolo Cisteamina HC1 10 pg/ml 200 μg/ml 82 Substance 1 Substance 2 Concentration 1 2 Inib, Enzyme (%) Resveratrol Cysteamine HC1 10 pg / ml 200 μg / ml 82
Resveratrolo Cisteamina HC1 10 pg/ml 400 pg/ml 100 Resveratrolo Taurina 10 pg/ml 8 mg/ml 84 Resveratrol Cysteamine HC1 10 pg / ml 400 pg / ml 100 Resveratrol Taurine 10 pg / ml 8 mg / ml 84
Resveratrolo Taurina 20 μg/ml 8 mg/ml 93 Resveratrol Taurine 20 μg / ml 8 mg / ml 93
Resveratrolo Acido cisteico H20 20 pg/ml 1.2 mg/ml 72 Resveratrol Cysteic acid H20 20 pg / ml 1.2 mg / ml 72
Resveratrolo Acido cisteico 3⁄40 30 gg/mi 1.6 mg/mì 100 Resveratrol Cysteic acid 3⁄40 30 gg / ml 1.6 mg / ml 100
Claims (20)
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