IT202000002146A1 - COMPOSITION FOR THE PREVENTION AND TREATMENT OF MUCOSITES - Google Patents
COMPOSITION FOR THE PREVENTION AND TREATMENT OF MUCOSITES Download PDFInfo
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- IT202000002146A1 IT202000002146A1 IT102020000002146A IT202000002146A IT202000002146A1 IT 202000002146 A1 IT202000002146 A1 IT 202000002146A1 IT 102020000002146 A IT102020000002146 A IT 102020000002146A IT 202000002146 A IT202000002146 A IT 202000002146A IT 202000002146 A1 IT202000002146 A1 IT 202000002146A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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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
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
TITOLO: TITLE:
COMPOSIZIONE PER LA PREVENZIONE ED IL TRATTAMENTO DI MUCOSITI COMPOSITION FOR THE PREVENTION AND TREATMENT OF MUCOSITES
Campo dell?invenzione Field of invention
La presente invenzione riguarda una composizione per la prevenzione ed il trattamento di mucosite. The present invention relates to a composition for the prevention and treatment of mucositis.
La presente invenzione ha origine nei settori nutrizionale e farmaceutico. The present invention originates in the nutritional and pharmaceutical sectors.
Nello specifico, la presente invenzione concerne formulazioni o integratori per l'applicazione topica o somministrazione orale che sono idonei per la prevenzione e trattamento di mucosite. Specifically, the present invention relates to formulations or supplements for topical application or oral administration which are suitable for the prevention and treatment of mucositis.
STATO DELLA TECNICA DELL?INVENZIONE STATE OF THE INVENTION TECHNIQUE
La mucosite ? una complicazione significativa di chemioterapia e/o radioterapia, che si verifica in 80?100% di pazienti sottoposti a regimi ?ad alto rischio? e in 40% di pazienti sottoposti a chemioterapia a dose standard. Mucositis? a significant complication of chemotherapy and / or radiotherapy, occurring in 80-100% of patients undergoing "high-risk" regimens and in 40% of patients undergoing standard-dose chemotherapy.
In genere, la mucosite ? localizzata nella bocca di un individuo e pu? anche estendersi ad altre aree del tratto gastrointestinale. Typically, mucositis? localized in the mouth of an individual and can? also extend to other areas of the gastrointestinal tract.
Inizialmente, la mucosite si manifesta, specialmente nella bocca, come lesioni eritematose 4-5 giorni dopo chemioterapia, progredisce in lesioni erosive e ulcerative entro 7-10 giorni e persiste per 2-4 settimane. Initially, mucositis manifests, especially in the mouth, as erythematous lesions 4-5 days after chemotherapy, progresses to erosive and ulcerative lesions within 7-10 days and persists for 2-4 weeks.
Le lesioni associate a mucosite causano dolore grave, difficolt? di eloquio e deglutizione e una diminuzione di qualit? di vita del paziente. Lesions associated with mucositis cause severe pain, difficulty. of speech and swallowing and a decrease in quality? of life of the patient.
Inoltre, una mucosite predispone il paziente a un rischio pi? elevato di infezione locale e sistemica e interferisce con la capacit? di erogare la dose prevista di terapia antitumorale, costituendo quindi una minaccia per la vita del paziente, nonch? causando un aumento della durata di un ricovero. Furthermore, a mucositis predisposes the patient to a higher risk. elevated of local and systemic infection and interferes with the capacity? to deliver the prescribed dose of anticancer therapy, thus constituting a threat to the patient's life, as well as? causing an increase in the length of a hospital stay.
Mucosite pu? colpire l'intero rivestimento mucoso del tratto gastrointestinale, con mucose orale e orofaringea essendo siti comuni di insorgenza patologica. Mucositis can affect the entire mucous lining of the gastrointestinal tract, with oral and oropharyngeal mucosa being common sites of pathological onset.
L'evoluzione di mucosite orale indotta da terapia antitumorale, ? stata classificata nel seguente modello a cinque fasi da Sonis ST: inizio, sovraregolazione/attivazione, amplificazione di segnale, ulcerazione e guarigione. The evolution of oral mucositis induced by anticancer therapy,? was classified in the following five-step model by Sonis ST: initiation, upregulation / activation, signal amplification, ulceration and healing.
Nella fase di inizio, radiazione o agenti chemioterapici causano la rottura diretta di DNA, generazione di ROS e di conseguenza morte cellulare in epitelio, endotelio e tessuti sottomucosi. Successivamente, avviene un rilascio di sostanze infiammatorie come IL-1 e IL-33. Questa fase non ha manifestazioni cliniche. In the initiation phase, radiation or chemotherapeutic agents cause direct breakdown of DNA, generation of ROS and consequently cell death in epithelium, endothelium and submucosal tissues. Subsequently, a release of inflammatory substances such as IL-1 and IL-33 occurs. This stage has no clinical manifestations.
La fase di sovraregolazione/attivazione ? caratterizzata da attivazione di recettori di sistema immunitario innato e delle fibre nervose nocicettive periferiche, aumento di citochine proinfiammatorie (come IL-6) e metalloproteinasi di matrice. Clinicamente, questa fase si presenta con eritema e prurito deboli transitori. Nella fase di amplificazione di segnale, sono stati documentati elevati livelli sierici di NF-kB, TNF-a, IL-1 e IL-6, che portano a edema ed eritema mucosi. Nella fase di ulcerazione, barriera della mucosa si disgrega seguita da colonizzazione batterica. In aggiunta, microrganismi penetrano nella mucosa danneggiata e stimolano un'infiltrazione di macrofagi per produrre citochine proinfiammatorie aggiuntive. In questa fase ulcerazione e infezione locali sono evidenti clinicamente. The over-regulation / activation phase? characterized by activation of receptors of the innate immune system and peripheral nociceptive nerve fibers, increase in proinflammatory cytokines (such as IL-6) and matrix metalloproteinases. Clinically, this phase presents with transient weak erythema and itching. In the signal amplification phase, elevated serum levels of NF-kB, TNF-a, IL-1 and IL-6 have been documented, leading to mucosal edema and erythema. In the ulceration stage, the mucosal barrier breaks down followed by bacterial colonization. In addition, microorganisms penetrate the damaged mucosa and stimulate an infiltration of macrophages to produce additional proinflammatory cytokines. Local ulceration and infection are clinically evident at this stage.
Al momento, una terapia disponibile per mucosite ? principalmente palliativa, inclusa un'applicazione di analgesici topici come lidocaina e/o somministrazione sistemica di narcotici e Currently, a therapy available for mucositis? mainly palliative, including application of topical analgesics such as lidocaine and / or systemic administration of narcotics e
antibiotici. antibiotics.
Attualmente, non ? disponibile alcun trattamento efficace per mucosite approvato dalle autorit? sanitarie. Currently, not? Is there any effective treatment for mucositis approved by the authorities? sanitary.
Sebbene siano stati impiegati numerosi nuovi approcci a mucosite orale, non ? stato ancora identificato alcun intervento efficace per profilassi o gestione di mucosite orale. Di conseguenza, al momento sono necessarie formulazioni e metodi per trattamento e prevenzione di mucosite. Although numerous new approaches to oral mucositis have been employed, haven't they? No effective intervention for prophylaxis or management of oral mucositis has yet been identified. Consequently, formulations and methods for the treatment and prevention of mucositis are currently needed.
Uno degli scopi della presente invenzione sta nel fornire un prodotto farmaceutico o nutrizionale che possa essere somministrato a un individuo affetto da mucosite che necessita di trattamento. One of the objects of the present invention is to provide a pharmaceutical or nutritional product that can be administered to an individual with mucositis in need of treatment.
Un altro obiettivo sta nel fornire una composizione per somministrazione orale che riduca le lesioni e ulcere causate da mucosite soprattutto in un individuo. Another goal is to provide an oral composition that reduces lesions and ulcers caused by mucositis especially in an individual.
Uno scopo aggiuntivo dell'invenzione consiste nel fornire una composizione per somministrazione o applicazione orale che riduca l'infiammazione e dolore associati a mucosite, specialmente nella bocca di un individuo sottoposto a trattamento antitumorale e/o radioterapia. An additional object of the invention is to provide a composition for oral administration or application that reduces the inflammation and pain associated with mucositis, especially in the mouth of an individual undergoing anticancer treatment and / or radiotherapy.
SOMMARIO DELL'INVENZIONE SUMMARY OF THE INVENTION
In conformit? ad alcuni aspetti della presente invenzione, gli inventori hanno trovato che la combinazione di andrografolidi selezionati con idrossiltirosolo esercita un'attivit? sinergica sul metabolismo di cellule mucose del corpo umano, che stimola il meccanismo fisiologico di riparazione di tessuto e/o mucosa. In accordance with to some aspects of the present invention, the inventors have found that the combination of selected andrographolides with hydroxytyrosol exerts an activity? synergistic on the metabolism of mucous cells in the human body, which stimulates the physiological repair mechanism of tissue and / or mucosa.
Alla luce di questo, gli inventori hanno formulato e testato una composizione contenente una combinazione di andrografolidi e idrossitirosolo su un gruppo di individui affetti da mucosite e hanno avuto evidenze che il trattamento fornisce un efficace effetto protettivo e riparativo su organi colpiti da mucosite. In light of this, the inventors formulated and tested a composition containing a combination of andrographolides and hydroxytyrosol on a group of individuals affected by mucositis and found that the treatment provides an effective protective and restorative effect on organs affected by mucositis.
In conformit? a un primo aspetto della presente invenzione, viene fornita una composizione sinergica per la prevenzione e/o trattamento di mucosite, detta composizione comprendendo una combinazione di andrografolidi con idrossitirosolo in una quantit? farmaceuticamente efficace e un veicolo o eccipiente fisiologicamente accettabile. In accordance with In a first aspect of the present invention, there is provided a synergistic composition for the prevention and / or treatment of mucositis, said composition comprising a combination of andrographolides with hydroxytyrosol in an amount? pharmaceutically effective and a physiologically acceptable carrier or excipient.
Gli inventori hanno anche trovato che una fonte idonea di andrografolidi per gli usi secondo l'invenzione ? rappresentata da una pianta di Andrographis paniculata. The inventors have also found that a suitable source of andrographolides for the uses according to the invention? represented by a plant of Andrographis paniculata.
Pertanto, secondo alcune forme di realizzazione dell'invenzione, gli andrografolidi sono ottenuti da un estratto vegetale di Andrographis paniculata. Therefore, according to some embodiments of the invention, andrographolides are obtained from a plant extract of Andrographis paniculata.
Ciascuno dei principi attivi contenuti nella composizione dell'invenzione, ? fornito in una quantit? farmaceuticamente e nutrizionalmente efficace. Each of the active ingredients contained in the composition of the invention,? supplied in a quantity? pharmaceutically and nutritionally effective.
Secondo alcune forme di realizzazione, la composizione dell'invenzione ? una composizione farmaceutica, un nutraceutico, un integratore alimentare che pu? essere introdotto nel regime alimentare di un individuo affetto da mucosite o che ? sottoposto a radioterapia o a un trattamento farmaceutico con un farmaco antitumorale. According to some embodiments, the composition of the invention? a pharmaceutical composition, a nutraceutical, a food supplement that can? be introduced into the diet of an individual with mucositis or what? undergoing radiation therapy or pharmaceutical treatment with an anticancer medicine.
In conformit? a un altro aspetto, l'invenzione riguarda una composizione comprendente una combinazione di un andrografolide e idrossitirosolo e un veicolo o eccipiente fisiologicamente accettabile per l'uso nella prevenzione e/o trattamento di mucosite. Tipicamente, gli andrografolidi della composizione sono selezionati da andrografolide, neo-andrografolide, deossiandrografolide e relative miscele. In accordance with To another aspect, the invention relates to a composition comprising a combination of an andrographolide and hydroxytyrosol and a physiologically acceptable vehicle or excipient for use in the prevention and / or treatment of mucositis. Typically, the andrographolides of the composition are selected from andrographolide, neo-andrographolide, deoxiandrographolide and their mixtures.
La presente invenzione ? descritta in dettaglio nel presente documento in seguito, facendo riferimento alle figure allegate. The present invention? described in detail hereinafter in this document, with reference to the attached figures.
BREVE DESCRIZIONE DEI DISEGNI BRIEF DESCRIPTION OF THE DRAWINGS
Alcune caratteristiche e vantaggi della presente invenzione risulteranno evidenti dai disegni allegati, in cui: Some features and advantages of the present invention will become evident from the attached drawings, in which:
Figura 1 mostra grafici a barre che illustrano i risultati di un saggio MTT per rilevare una vitalit? cellulare (test di sopravvivenza) dopo trattamento con andrografolide, idrossitirosolo da soli e in combinazione secondo l'invenzione contro citotossicit? indotta da 5-fluorouracile in cheratinociti orali (n = 5). Figure 1 shows bar graphs illustrating the results of an MTT assay to detect viability. cell (survival test) after treatment with andrographolide, hydroxytyrosol alone and in combination according to the invention against cytotoxicity? induced by 5-fluorouracil in oral keratinocytes (n = 5).
Figura 2 mostra grafici a barre che illustrano l'induzione del fattore Nrf2, inducendo geni protettivi, in tempi differenti (1, 3, 6, 12 ore), mediante trattamento con andrografolide (And), idrossitirosolo (Hyx) da soli e una miscela/combinazione di andrografolide e idrossitirosolo (And Hyx). L'effetto sinergico della combinazione ? evidenziato dai grafici a barre in nero. Le evidenze sperimentali sono descritte in esempio 3. Figure 2 shows bar graphs illustrating the induction of Nrf2 factor, inducing protective genes, at different times (1, 3, 6, 12 hours), by treatment with andrographolide (And), hydroxytyrosol (Hyx) alone and a mixture / combination of andrographolide and hydroxytyrosol (And Hyx). The synergistic effect of the combination? highlighted by the bar graphs in black. The experimental evidences are described in example 3.
Figura 3 mostra grafici che illustrano i risultati del test di esempio 4 e la sovraregolazione di enzimi di detossicazione HO-1 e di fase II in differenti cellule in tempi diversi (6 e 24 ore) usando solo andrografolide (And), solo idrossitirosolo (Hyx) e una miscela/combinazione di andrografolide e idrossitirosolo (And Hyx). Le barre mostrano un aumento significativo di mRNA HO-1 per la combinazione di AND e HXT. Le evidenze sperimentali sono descritte in esempio 4. Figure 3 shows graphs illustrating the results of Example 4 test and the upregulation of HO-1 and phase II detoxification enzymes in different cells at different times (6 and 24 hours) using only andrographolide (And), only hydroxytyrosol (Hyx ) and a mixture / combination of andrographolide and hydroxytyrosol (And Hyx). The bars show a significant increase in HO-1 mRNA for the combination of AND and HXT. The experimental evidences are described in example 4.
Figura 4 mostra una rappresentazione grafica degli effetti su citochine infiammatorie Il-1?, IL-6, secrezione di TNF-? in cheratinociti in coltura esposti al 5-FU. I grafici mostrano che la combinazione di andrografolide e idrossitirosolo (And Hyx/blocchi neri) esercita una riduzione sinergica di produzione di citochine che porta a infiammazione. Le evidenze sperimentali sono descritte in esempio 1. Figure 4 shows a graphical representation of the effects on inflammatory cytokines Il-1 ?, IL-6, secretion of TNF-? in cultured keratinocytes exposed to 5-FU. The graphs show that the combination of andrographolide and hydroxytyrosol (And Hyx / black blocks) exerts a synergistic reduction of cytokine production leading to inflammation. The experimental evidence is described in example 1.
Figura 5 mostra grafici a barre che illustrano i risultati dell'attivit? di legame di DNA di NF-kB p65. I risultati mostrano che la combinazione di AND HXT riduce fortemente un'attivit? di legame a DNA di p65 di NF-kB in cheratinociti in coltura, dimostrando un effetto sinergico della composizione di combinazione rivendicata. Le evidenze sperimentali sono descritte in esempio 2. Figure 5 shows bar graphs illustrating the results of the activity. of DNA binding of NF-kB p65. The results show that the combination of AND HXT strongly reduces an activity? DNA binding of NF-kB p65 in cultured keratinocytes, demonstrating a synergistic effect of the claimed combination composition. The experimental evidences are described in example 2.
DESCRIZIONE DETTAGLIATA DELL'INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
A partire dal meccanismo di mucosite orale indotta da 5-fluoruracile (FU), gli inventori hanno esplorato e verificato che l'attivazione e traslocazione di fattore di trascrizione, fattore nucleare-?B (NF-?B), dal citosol al nucleo, ? una degli elementi chiave nell'inizio di mucosite indotta da 5-FU. Questo meccanismo porta alla sovraregolazione di geni e alla successiva produzione di citochine pro-infiammatorie come il fattore di necrosi tumorale-? (TNF-?), interleuchina (IL)-1? e IL-6. Starting from the mechanism of 5-fluoruracil-induced oral mucositis (FU), the inventors explored and verified that the activation and translocation of transcription factor, nuclear factor-? B (NF-? B), from the cytosol to the nucleus, ? one of the key elements in the initiation of 5-FU-induced mucositis. This mechanism leads to the upregulation of genes and the subsequent production of pro-inflammatory cytokines such as tumor necrosis factor-? (TNF-?), Interleukin (IL) -1? and IL-6.
Interleuchina-1? (IL-1?) ? una potente citochina e regolatore della risposta immunitaria innata, rilasciata precocemente durante uno sviluppo di mucosite, stimolando la sua propria sintesi e attivazione di NF-?B attraverso circuiti di retroazione. NF-?B ? un modulo di segnalazione conservato evolutivo, inducibile dal percorso canonico (classico) o alternativo. Interleukin-1? (IL-1?)? a powerful cytokine and regulator of the innate immune response, released early during the development of mucositis, stimulating its own synthesis and activation of NF-? B through feedback loops. NF-? B? an evolutionary conserved signaling module, inducible from the canonical (classical) or alternative path.
A partire da questo stato della tecnica, gli inventori hanno inaspettatamente trovato che combinando andrografolidi e idrossitirosolo, si ottiene una riduzione sinergica di citotossicit? e infiammazione su cheratinociti orali trattati con un agente chemioterapico con benefici sulla sintomatologia di mucosite. Starting from this state of the art, the inventors have unexpectedly found that by combining andrographolides and hydroxytyrosol, a synergistic reduction of cytotoxicity is obtained. and inflammation on oral keratinocytes treated with a chemotherapeutic agent with benefits on the symptomatology of mucositis.
Questo risultato ? confermato usando un modello in vitro con cheratinociti orali. This result? confirmed using an in vitro model with oral keratinocytes.
Di conseguenza, un aspetto generale dell'invenzione riguarda una composizione di combinazione per la prevenzione e o trattamento di mucosite, in particolare di mucosite orale in un individuo umano. Accordingly, a general aspect of the invention relates to a combination composition for the prevention and or treatment of mucositis, in particular oral mucositis in a human individual.
In accordo con un primo aspetto, la presente invenzione fornisce una composizione per prevenire un trattamento di mucosite orale come rivendicato in rivendicazione 1 allegata. In accordance with a first aspect, the present invention provides a composition for preventing oral mucositis treatment as claimed in attached claim 1.
Forme di realizzazione della composizione dell'invenzione sono definite in rivendicazioni allegate 2-10. Embodiments of the composition of the invention are defined in attached claims 2-10.
La composizione dell'invenzione ? idonea a prevenire e/o trattare mucosite, specialmente quella che si sviluppa dopo o durante la somministrazione di un farmaco chemioterapico o radioterapia o una relativa combinazione. The composition of the invention? suitable for preventing and / or treating mucositis, especially that which develops after or during the administration of a chemotherapy or radiotherapy drug or a combination thereof.
Un principio o componente biologicamente attivo della composizione di combinazione dell'invenzione ? rappresentato da andrografolidi, selezionati specialmente tra andrografolide (a), neo-andrografolide (b), deossiandrografolide (c) avente le seguenti formule: A biologically active principle or component of the combination composition of the invention? represented by andrographolides, specially selected among andrographolide (a), neo-andrographolide (b), deoxiandrographolide (c) having the following formulas:
Andrografolide (a), un triidrossi lattone insaturo con formula molecolare C20H30O5 ? preferito, tuttavia, possono anche essere usate miscele dei suddetti ingredienti (a), (b) e (c). Andrographolide (a), an unsaturated trihydroxy lactone with molecular formula C20H30O5? Preferably, however, mixtures of the above ingredients (a), (b) and (c) can also be used.
Gli andrografolidi sopraccitati sono terpenoidi biologicamente attivi presenti in natura che possono essere ottenuti mediante estrazione da una pianta come Andrographis paniculata, una pianta erbacea della famiglia delle Acanthaceae. The aforementioned andrographolides are naturally occurring biologically active terpenoids that can be obtained by extraction from a plant such as Andrographis paniculata, a herbaceous plant of the Acanthaceae family.
La composizione dell'invenzione pu? contenere andrografolidi come tali o come estratto di pianta. Ad esempio, un estratto vegetale ricco di andrografolidi pu? essere ottenuto mediante estrazione da foglie di Andrographis paniculata. The composition of the invention can? contain andrographolides as such or as a plant extract. For example, a plant extract rich in andrographolides can? be obtained by extraction from leaves of Andrographis paniculata.
In alternativa, la composizione pu? contenere anche uno o pi? andrografolidi di origine sintetica. Alternatively, the composition can? also contain one or more? andrographolides of synthetic origin.
Gli andrografolidi presenti in natura possono essere ottenuti attraverso tecniche di estrazione convenzionali dei componenti bioattivi da una porzione di una pianta che li contiene, come ad esempio Andrographis paniculata. Naturally occurring andrographolides can be obtained through conventional techniques for extracting bioactive components from a portion of a plant that contains them, such as Andrographis paniculata.
Tecniche di estrazione convenzionali possono essere usate per ottenere i suddetti lattoni diterpenoidi bioattivi. Conventional extraction techniques can be used to obtain the aforementioned bioactive diterpenoid lactones.
Tipicamente, nella fase di estrazione possono essere usati solventi fisiologicamente accettabili idonei, ad esempio solventi organici polari come etanolo. Typically, suitable physiologically acceptable solvents, for example polar organic solvents such as ethanol, can be used in the extraction step.
A titolo di esempio, l'estrazione di Soxhlet ? una tecnica idonea a un'estrazione e separazione dei relativi andrografolidi da una fonte vegetale. As an example, the extraction of Soxhlet? a technique suitable for the extraction and separation of the related andrographolides from a plant source.
Ad esempio, una tecnica di estrazione idonea comprende le fasi di immersione di un campione di Andrographis paniculata in un bagno includente solvente organico polare, ad esempio, alcool etilico, aumentando opzionalmente la temperatura del bagno per raggiungere una temperatura da 30 a 70?C in modo tale che il calore applicato alla beuta di distillazione raggiunga la cavit? di estrazione. For example, a suitable extraction technique includes the steps of immersing a sample of Andrographis paniculata in a bath including polar organic solvent, e.g., ethyl alcohol, optionally increasing the temperature of the bath to reach a temperature of 30 to 70 ° C in so that the heat applied to the distillation flask reaches the cavity? extraction.
Un'idonea estrazione solido-liquido di andrografolide ? descritta da R. Wongkittipong et al. in Solid-liquid extraction of Andrographolide from Plants-Experimental Study, Kinetic Reaction and Model; Sepn. Purifn. Technol. 40: 147-154 il cui contenuto ? completamente incorporato nel presente documento per riferimento. A suitable solid-liquid extraction of andrographolide? described by R. Wongkittipong et al. in Solid-liquid extraction of Andrographolide from Plants-Experimental Study, Kinetic Reaction and Model; Sepn. Purifn. Technol. 40: 147-154 whose content? fully incorporated herein by reference.
In alcune forme di realizzazione, gli andrografolidi sono presenti nella composizione dell'invenzione in una quantit? da 0,01 a 30% in peso, da 0,1 a 20% in peso, da 0,5 a 10% in peso del peso totale (p/p). In some embodiments, the andrographolides are present in the composition of the invention in a quantity? 0.01 to 30% by weight, 0.1 to 20% by weight, 0.5 to 10% by weight of the total weight (w / w).
In alcune forme di realizzazione, andrografolidi sono presenti nella composizione dell'invenzione in una quantit? da 0,01 a 30% in peso, da 0,1 a 20% in peso, da 0,5 a 10% in peso del peso totale (p/p). In some embodiments, andrographolides are present in the composition of the invention in an amount? 0.01 to 30% by weight, 0.1 to 20% by weight, 0.5 to 10% by weight of the total weight (w / w).
Un altro componente biologicamente attivo della composizione di combinazione dell'invenzione ? rappresentato dall'idrossitirosolo, un composto feniletanoide, dotato di propriet? antiossidanti in vitro. Another biologically active component of the combination composition of the invention? represented by hydroxytyrosol, a phenylethanoid compound, with properties? in vitro antioxidants.
In natura, idrossitirosolo si trova in foglia d'olivo e olio d'oliva, specialmente nella forma della sua oleuropeina di estere di acido elenolico e, specialmente, dopo degradazione, nella sua forma normale In nature, hydroxytyrosol is found in olive leaf and olive oil, especially in the form of its elenolic acid ester oleuropein and, especially, after degradation, in its normal form
Idrossitirosolo ? estratto dall'albero di olivo e dalle sue foglie come un sottoprodotto ottenuto dalla fabbricazione di olio d'oliva. Hydroxytyrosol? extracted from the olive tree and its leaves as a by-product obtained from the manufacture of olive oil.
Secondo alcune forme di realizzazione, idrossitirosolo ? di origine naturale e pu? essere ottenuto attraverso processi di produzione convenzionali. According to some embodiments, hydroxytyrosol? of natural origin and pu? be obtained through conventional manufacturing processes.
Secondo alcune forme di realizzazione, la composizione dell'invenzione contiene idrossitirosolo in una quantit? da 0,1 a 100 mg, da 0,5 a 30 mg, da 1 a 10 mg. According to some embodiments, the composition of the invention contains hydroxytyrosol in an amount? 0.1 to 100 mg, 0.5 to 30 mg, 1 to 10 mg.
Secondo alcune forme di realizzazione, la composizione dell'invenzione contiene idrossitirosolo in una quantit? da 0,1 a 95% in peso, da 1 a 90% in peso, da 10 a 85%, da 30 a 80% in peso. According to some embodiments, the composition of the invention contains hydroxytyrosol in an amount? 0.1 to 95% by weight, 1 to 90% by weight, 10 to 85%, 30 to 80% by weight.
In alcune forme di realizzazione la composizione comprende un diluente, eccipiente o veicolo commestibile e/o fisiologicamente accettabile. Il diluente, eccipiente o veicolo fisiologicamente accettabile pu? essere scelto in base alla via di somministrazione prevista della composizione risultante. In some embodiments the composition comprises an edible and / or physiologically acceptable diluent, excipient or carrier. The physiologically acceptable diluent, excipient or vehicle can be selected based on the intended route of administration of the resulting composition.
Le sostanze biologicamente attive contenute nella composizione possono essere combinate o miscelate come principi attivi in miscela completa con un veicolo commestibile adatto e/o un eccipiente secondo l'industria farmaceutica e alimentare o tecniche nutrizionali tradizionali. The biologically active substances contained in the composition can be combined or mixed as active ingredients in complete mixture with a suitable edible carrier and / or an excipient according to the pharmaceutical and food industry or traditional nutritional techniques.
In certe forme di realizzazione, la composizione dell'invenzione comprende ulteriori sostanze biologicamente attive o ingredienti attivi. In certain embodiments, the composition of the invention comprises further biologically active substances or active ingredients.
Ad esempio, la composizione pu? includere una o pi? vitamine, ad esempio la vitamina del gruppo B come B1, B6, vitamina A, vitamina C, vitamina D. For example, the composition can? include one or more? vitamins, for example B vitamins such as B1, B6, Vitamin A, Vitamin C, Vitamin D.
Secondo alcune forme di realizzazione, la composizione dell'invenzione comprende inoltre uno o pi? micronutrienti e/o minerali come sali di Zn, Mg, K, Na, Fe, Cr, Se, Mn, Ca e relative miscele. According to some embodiments, the composition of the invention further comprises one or more? micronutrients and / or minerals such as salts of Zn, Mg, K, Na, Fe, Cr, Se, Mn, Ca and related mixtures.
In alcune forme di realizzazione la composizione contiene anche amminoacidi come valina, lisina, istidina, arginina, leucina e relative miscele. In some embodiments the composition also contains amino acids such as valine, lysine, histidine, arginine, leucine and their mixtures.
Come usato nel presente documento, il termine "commestibile" significa sostanze commestibili il cui uso nella formulazione di una composizione nutrizionale o alimentare ? approvato dalle autorit? sanitarie. As used herein, the term "edible" means edible substances whose use in the formulation of a nutritional or food composition? approved by the authorities? sanitary.
Il termine "fisiologicamente accettabile" si riferisce a sostanze comunemente usate nella formulazione di prodotti nutrizionali, alimentari o farmaceutici. Un veicolo "fisiologicamente accettabile" pu? essere un veicolo farmaceuticamente accettabile. Il termine "veicolo" come usato nel presente documento indica un mezzo, eccipiente, diluente con cui ? somministrata la combinazione di principi terapeutici o attivi. The term "physiologically acceptable" refers to substances commonly used in the formulation of nutritional, food or pharmaceutical products. A "physiologically acceptable" vehicle can? be a pharmaceutically acceptable vehicle. The term "vehicle" as used herein means a medium, excipient, diluent with which? administered the combination of therapeutic or active ingredients.
Qualsiasi veicolo e/o eccipiente idoneo alla forma desiderata di preparazione per una somministrazione agli esseri umani ? contemplato per uso con i composti descritti nella presente invenzione. Any vehicle and / or excipient suitable for the desired form of preparation for administration to humans? contemplated for use with the compounds disclosed in the present invention.
Come usato nel presente documento, il termine combinazione significa che uno o pi? dei principi attivi sono aggiunti o miscelati con uno o altri ingredienti. As used herein, the term combination means that one or more? active ingredients are added or mixed with one or other ingredients.
Il termine combinazione non intende significare che i principi attivi sono associati tra loro con la formazione di legami chimici o di altro tipo. The term combination does not mean that the active ingredients are associated with each other with the formation of chemical or other bonds.
Le composizioni dell'invenzione sono idonee a un uso alimentare, nutrizionale, dietetico o farmaceutico in mammiferi, in particolare in esseri umani. The compositions of the invention are suitable for food, nutritional, dietary or pharmaceutical use in mammals, in particular in humans.
La composizione dell'invenzione pu? assumere un'ampia variet? di forme di preparazione, secondo la via di somministrazione desiderata. The composition of the invention can? take on a wide variety? of forms of preparation, according to the desired route of administration.
La composizione dell'invenzione pu? essere in forma solida. The composition of the invention can? be in solid form.
Quando la composizione dell'invenzione ? presentata in forma solida, pu? essere sotto forma di una compressa, capsula, polvere, granuli, dentifricio, crema o gel orale, caramella, pillola o striscia solubile, gomma da masticare, pastiglia da sciogliere in bocca e polvere che possa essere spruzzata direttamente nella cavit? orale. When the composition of the invention? presented in solid form, can? be in the form of a tablet, capsule, powder, granules, toothpaste, oral cream or gel, candy, soluble pill or strip, chewing gum, melt-in-the-mouth tablet and powder that can be sprayed directly into the cavity. oral.
Le preparazioni in forma solida possono comprendere uno o pi? eccipienti/come ad esempio amidi, zuccheri, cellulosa microcristallina e opzionalmente diluenti, agenti di granulazione, lubrificanti, ligandi, agenti di disintegrazione. The solid form preparations can comprise one or more? excipients / such as for example starches, sugars, microcrystalline cellulose and optionally diluents, granulating agents, lubricants, ligands, disintegrating agents.
Tipicamente la composizione in forma solida pu? contenere un ligando come gomma adragante, gomma, amido di mais o gelatina; eccipienti come fosfato bicalcico; un agente di disintegrazione come amido di mais, fecola di patate, acido alginico; un lubrificante come magnesio stearato; un agente dolcificante come saccarosio, lattosio o saccarina. Se lo si desidera, le compresse possono essere rivestite usando tecniche tradizionali. Typically the composition in solid form can be contain a ligand such as tragacanth, gum, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin. If desired, the tablets can be coated using traditional techniques.
Quando la forma unitaria ? una capsula, pu? contenere, in aggiunta ai materiali di cui sopra, un veicolo liquido come un olio grasso. When the unitary form? a capsule, can? contain, in addition to the above materials, a liquid carrier such as a fatty oil.
Secondo alcune forme di realizzazione, la composizione dell'invenzione contiene un eccipiente a base di cellulosa che comprende i) esteri organici di cellulosa, ad esempio selezionati da acetato di cellulosa, propionato di cellulosa, triacetato di cellulosa, propionato di acetato di cellulosa, butirrato di acetato di cellulosa, ii) esteri inorganici di cellulosa, ad esempio selezionati da nitrocellulosa, solfato di cellulosa, iii) eteri di cellulosa selezionati da a) alchil eteri di cellulosa, ad esempio selezionati da metil cellulosa, etil cellulosa, etil metil cellulosa; b) idrossialchil eteri di cellulosa, ad esempio selezionati da idrossietil cellulosa, idrossipropil cellulosa, idrossietil cellulosa, idrossipropil metil cellulosa, etil idrossietil cellulosa; c) carbossialchil cellulosa, ad esempio carbossi metil cellulosa, relativi sali e relative miscele. In alcune forme di realizzazione, gli eccipienti a base di cellulosa sono reticolati con agenti reticolanti fisiologicamente accettabili. According to some embodiments, the composition of the invention contains a cellulose-based excipient which comprises i) organic cellulose esters, for example selected from cellulose acetate, cellulose propionate, cellulose triacetate, cellulose acetate propionate, butyrate cellulose acetate, ii) inorganic cellulose esters, for example selected from nitrocellulose, cellulose sulfate, iii) cellulose ethers selected from a) cellulose alkyl ethers, for example selected from methyl cellulose, ethyl cellulose, ethyl methyl cellulose; b) hydroxyalkyl ethers of cellulose, for example selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, ethyl hydroxyethyl cellulose; c) carboxyalkyl cellulose, for example carboxy methyl cellulose, relative salts and relative mixtures. In some embodiments, the cellulose-based excipients are crosslinked with physiologically acceptable crosslinking agents.
In alcune forme di realizzazione, la composizione dell'invenzione comprende inoltre uno o pi? componenti aggiuntivi come additivi, cariche, stabilizzanti, emulsionanti, texturizzanti, agenti filmogeni, plastificanti, agenti umettanti e addensanti. In some embodiments, the composition of the invention further comprises one or more? additional components such as additives, fillers, stabilizers, emulsifiers, texturizers, film-forming agents, plasticizers, wetting agents and thickeners.
Vari altri materiali possono essere presenti come rivestimenti o per modificare la forma fisica dell'unit? farmaceutica. Ad esempio, le compresse possono essere rivestite con gomma lacca, zucchero o entrambi. Per prevenire la rottura durante il transito attraverso la parte superiore del tratto gastrointestinale, la composizione pu? essere una formulazione con un rivestimento gastroresistente o enterico. Various other materials may be present as coatings or to change the physical form of the unit? pharmaceutical. For example, the tablets can be coated with shellac, sugar, or both. To prevent rupture during transit through the upper gastrointestinal tract, the composition can be a formulation with a gastro-resistant or enteric coating.
Nella composizione possono anche esserci agenti aromatizzanti, conservanti, agenti coloranti e simili. There may also be flavoring agents, preservatives, coloring agents and the like in the composition.
In alcune forme di realizzazione la composizione dell'invenzione ? in forma di compressa solida. In some embodiments the composition of the invention? in the form of a solid tablet.
Secondo alcune forme di realizzazione, la composizione ? in una forma per il rilascio modulato o controllato di ingredienti attivi. A titolo di esempio, la composizione pu? essere una formulazione a rilascio ritardato, a rilascio rapido o a rilascio lento-veloce. Tipicamente, formulazioni a rilascio modulato o controllato contengono uno o pi? eccipienti a base di cellulosa, in particolare del tipo precedentemente descritto. According to some embodiments, the composition? in a form for the modulated or controlled release of active ingredients. As an example, the composition can? be a delayed-release, fast-release or slow-fast release formulation. Typically, modulated or controlled release formulations contain one or more? cellulose-based excipients, in particular of the type described above.
In alcune forme di realizzazione, la composizione dell'invenzione comprende come un eccipiente, un acido grasso idrogenato, preferibilmente avente una catena con da 3 a 20 atomi di carbonio, da 14 a 18 atomi di carbonio. Un tipico esempio di un acido grasso idrogenato ? olio di palma idrogenato. In some embodiments, the composition of the invention comprises as an excipient, a hydrogenated fatty acid, preferably having a chain with from 3 to 20 carbon atoms, from 14 to 18 carbon atoms. A typical example of a hydrogenated fatty acid? hydrogenated palm oil.
La composizione dell'invenzione pu? essere in forma liquida. The composition of the invention can? be in liquid form.
Quando la composizione ? in forma liquida, pu? essere sotto forma di sospensione, emulsione, soluzione, spray orale, collutorio. In questi casi il veicolo ? liquido e pu? essere selezionato ad esempio da acqua, glicoli, oli, alcool e relative miscele. When the composition? in liquid form, can? be in the form of suspension, emulsion, solution, oral spray, mouthwash. In these cases the vehicle? liquid and can? be selected for example from water, glycols, oils, alcohols and related mixtures.
In alcune forme di realizzazione in cui la formulazione ? in forma liquida, ad esempio in caso di una soluzione, sciroppo o elisir pu? contenere, in aggiunta all'associazione di principi attivi, un agente dolcificante come saccarosio e/o metil e propil-parabeni come conservanti, un agente colorante e un aroma come ciliegia o arancia aromatizzanti. In some embodiments where the formulation? in liquid form, for example in the case of a solution, syrup or elixir can? contain, in addition to the combination of active ingredients, a sweetening agent such as sucrose and / or methyl and propyl-parabens as preservatives, a coloring agent and a flavoring such as cherry or orange flavoring.
Le composizioni possono essere idoneamente presentate in un'unica forma farmaceutica e preparate usando uno qualsiasi dei metodi ben noti nello stato dell?arte farmaceutico o dietetico. The compositions may suitably be presented in a single pharmaceutical form and prepared using any of the methods well known in the pharmaceutical or dietary state of the art.
In alcune forme di realizzazione, nelle composizioni della presente invenzione, gli ingredienti attivi sono normalmente formulati in un'unit? di dosaggio. L'unit? di dosaggio pu? contenere da 0,1 a 1.000 mg di ciascun ingrediente attivo per unit? di dosaggio per una somministrazione giornaliera. In some embodiments, in the compositions of the present invention, the active ingredients are normally formulated in one unit. dosage. The unit of dosage can? contain from 0.1 to 1,000 mg of each active ingredient per unit? of dosage for a daily administration.
In alcune forme di realizzazione la dose ? nell'intervallo da 0,001% in peso a circa 60% in peso della formulazione. In some embodiments the dose? in the range of 0.001% by weight to about 60% by weight of the formulation.
Secondo alcune forme di realizzazione, la composizione dell'invenzione ? un prodotto medicinale. According to some embodiments, the composition of the invention? a medicinal product.
Secondo alcune forme di realizzazione, la composizione dell'invenzione ? un integratore nutraceutico, alimentare, un prodotto nutrizionale o un prodotto dietetico In conformit? ad alcuni aspetti, nel presente documento ? altres? divulgato un metodo per il trattamento o prevenzione di mucosite, in particolare mucosite a seguito della somministrazione di farmaci chemioterapici o una combinazione di detti farmaci con radioterapia, in cui il metodo che comprende la somministrazione simultanea, separata o sequenziale dei componenti biologicamente attivi ? descritto nel presente documento. According to some embodiments, the composition of the invention? a nutraceutical, food supplement, a nutritional product or a dietary product. to some aspects, in this document? also? disclosed a method for the treatment or prevention of mucositis, in particular mucositis following the administration of chemotherapeutic drugs or a combination of said drugs with radiotherapy, wherein the method comprising the simultaneous, separate or sequential administration of the biologically active components? described in this document.
In conformit? ad alcuni aspetti, una composizione come definita nel presente documento, prima deve essere usata nel trattamento di infiammazione della mucosa dell?organismo umano, come mucose vaginali od orali. Secondo questo aspetto, la composizione pu? essere usata per trattare un affezione buccale, ad esempio in odontologia od odontoiatria, in particolare per trattamento di gengivite. In accordance with in some respects, a composition as defined herein must first be used in the treatment of inflammation of the mucous membrane of the human organism, such as vaginal or oral mucosa. According to this aspect, the composition can? be used to treat a buccal affection, for example in odontology or dentistry, in particular for the treatment of gingivitis.
La composizione secondo la presente invenzione pu? essere somministrata localmente o sistemicamente. Resta inteso che una somministrazione sistemica si riferisce a qualsiasi modalit? o via di somministrazione che risulti in quantit? efficaci di estratto che appare nel sangue o in un sito remoto dal sito di somministrazione. The composition according to the present invention can? be administered locally or systemically. It is understood that a systemic administration refers to any modality? or route of administration that results in quantity? effective of extract appearing in the blood or at a remote site from the site of administration.
L'importo effettivo somministrato, nonch? la velocit? e il decorso di somministrazione, dipenderanno dalla natura e gravit? della condizione da trattare. Prescrizione di trattamento, ad esempio, decisioni relative al dosaggio, ecc., ? in definitiva di responsabilit? e a discrezione di medici di medicina generale e di altri medici e tipicamente tiene conto della condizione da trattare, della condizione del soggetto individuale, del sito di erogazione, del metodo di somministrazione e di altri fattori noti ai professionisti. La dose precisa dipender? da una serie di fattori, inclusa la forma della composizione da somministrare. The actual amount administered as well as? the speed? and the course of administration, will depend on the nature and severity? of the condition to be treated. Prescription of treatment, e.g. dosing decisions, etc.,? ultimately of responsibility? and at the discretion of general practitioners and other physicians and typically takes into account the condition being treated, the condition of the individual subject, the delivery site, the method of administration, and other factors known to practitioners. The precise dose will depend? by a number of factors, including the form of the composition to be administered.
In alcune forme di realizzazione la composizione ? somministrata o applicata quotidianamente a un soggetto. In some embodiments the composition? administered or applied daily to a subject.
Se non altrimenti definito, tutti i termini tecnici e scientifici usati nel presente documento hanno il significato comunemente compreso da un tecnico del ramo della presente invenzione. Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one skilled in the art of the present invention.
ESEMPIO 1 EXAMPLE 1
Evidenza sperimentale dell'attivit? della composizione di combinazione sinergica di invenzione. Experimental evidence of the activity? of the invention synergistic combination composition.
Materiali Materials
Cheratinociti orali sono stati ottenuti da ScienCell Research Laboratories Oral keratinocytes were obtained from ScienCell Research Laboratories
Cellule sono state mantenute in un mezzo di cheratinociti orale completo integrato con supplemento di crescita di cheratinociti e soluzione di penicillina/streptomicina. Cellule sono state mantenute a 37?C in atmosfera umidificata contenente 5% di CO2 e 95% di aria. Tutte le cellule sono state messe in coltura in terreno Opti-MEM-I privo di siero per almeno 15 ore prima di un trattamento per eliminare il possibile effetto collaterale di fattori di crescita. Cells were maintained in a complete oral keratinocyte medium supplemented with keratinocyte growth supplement and penicillin / streptomycin solution. Cells were kept at 37 ° C in a humidified atmosphere containing 5% CO2 and 95% air. All cells were cultured in serum-free Opti-MEM-I medium for at least 15 hours prior to treatment to eliminate the possible side effect of growth factors.
Razionale Rational
Effetti di una composizione contenente una combinazione di andrografolide (chiamato qui di seguito come AND) e idrossiltirosolo (chiamato qui di seguito HXT) su secrezione di citochine infiammatorie in cheratinociti in coltura, esposti a 5-FU (figura 4). Effects of a composition containing a combination of andrographolide (hereafter referred to as AND) and hydroxyltyrosol (hereafter referred to as HXT) on inflammatory cytokine secretion in cultured keratinocytes exposed to 5-FU (Figure 4).
Metodo Method
Sono state pretrattate o meno cellule per 1 ora con 15 ?m di AND, 15 ?m di HXT o 15 ?m di AND HXT e quindi esposte a 10 ?g/ml di 5-FU per altre 24 ore. Cells were pretreated or not for 1 hour with 15µm of AND, 15µm of HXT or 15µm of AND HXT and then exposed to 10µg / ml of 5-FU for a further 24 hours.
IL-1b, IL-6 e TNF-a sono stati rilevati mediante kit ELISA acquistati da Abcam, Cambridge, (MA) USA. Sono espressi dati come media ? SEM, n = 4; *p <0,001 vs. 5-FU, **p <0,001 vs. AND o HXT da soli. IL-1b, IL-6 and TNF-a were detected by ELISA kits purchased from Abcam, Cambridge, (MA) USA. Are data expressed as averages? SEM, n = 4; * p <0.001 vs. 5-FU, ** p <0.001 vs. AND or HXT alone.
In primo luogo, un'esposizione di 24 ore di cellule a 10 ?g/ml di 5-FU ha indotto la secrezione massima di IL-1?, IL-6 e TNF-?, che sono tutti rilasciati in piccole quantit? in condizioni basali, come mostrato in figura 4 First, 24-hour exposure of cells to 10? G / ml of 5-FU induced maximal secretion of IL-1 ?, IL-6 and TNF-?, All of which are released in small amounts? in basal conditions, as shown in figure 4
5-FU ha aumentato notevolmente una secrezione di citochine. La preincubazione (1 ora) con 15 ?m di AND o 15 ?m di HXT ha ridotto significativamente una secrezione di citochine stimolate da 5-FU. 5-FU markedly increased cytokine secretion. Preincubation (1 hour) with 15µm of AND or 15µm of HXT significantly reduced 5-FU-stimulated cytokine secretion.
Sorprendentemente, dopo un'incubazione di 1 ora con una composizione con la combinazione (miscela) di AND HXT (barre nere in figura 4) ? stata fortemente ridotta la secrezione di IL-1?, IL-6 e TNF-?, dimostrando un effetto sinergico dei due composti nell'inibizione di produzione di citochine. Surprisingly, after a 1 hour incubation with a composition with the combination (blend) of AND HXT (black bars in figure 4)? the secretion of IL-1 ?, IL-6 and TNF-? was strongly reduced, demonstrating a synergistic effect of the two compounds in the inhibition of cytokine production.
ESEMPIO 2 EXAMPLE 2
Evidenze sperimentali Experimental evidence
La combinazione di AND e HXT riduce l'attivit? di legame a DNA di NF-kB p65 nei cheratinociti in coltura. The combination of AND and HXT reduces activity? DNA binding of NF-kB p65 in cultured keratinocytes.
? noto che la via di NF-kB svolge un ruolo chiave nell'eziogenesi di malattie infiammatorie croniche. La famiglia di fattori trascrizionali NF-kB svolge un ruolo critico in regolazione dell'espressione di un'ampia variet? di geni, in particolare nel processo infiammatorio, incluse citochine come IL-1?, IL-6 e TNF-?. ? It is known that the NF-kB pathway plays a key role in the etiology of chronic inflammatory diseases. The NF-kB family of transcription factors plays a critical role in regulating the expression of a wide variety of transcriptional factors. of genes, particularly in the inflammatory process, including cytokines such as IL-1 ?, IL-6 and TNF- ?.
Per valutare la capacit? della composizione sinergica dell'invenzione di inibire attivit? di nf-kb in macrofagi di ratti, abbiamo usato il saggio di attivit? di legame a DNA di p65 di NF-kB mediante kit ELISA per fattore di trascrizione p65 di TransAM (Active Motif, Carlsbad, CA). Le cellule sono state stimolate con 10 ?g/ml di 5-FU in presenza e assenza di 15 ?m di AND, 15 ?m di HXT o una combinazione da 15 ?m di AND HXT, per 12 ore, secondo l'invenzione. Quindi, ? stata determinata l'attivit? di legame a DNA di p65 di NF-kB. To assess the ability? of the synergistic composition of the invention to inhibit activity? of nf-kb in rat macrophages, we used the activity assay? DNA binding of NF-kB p65 by TransAM (Active Motif, Carlsbad, CA) p65 transcription factor ELISA kit. The cells were stimulated with 10 μg / ml of 5-FU in the presence and absence of 15 μm of AND, 15 μm of HXT or a combination of 15 μm of AND HXT, for 12 hours, according to the invention . Therefore, ? the activity was determined? of binding to DNA of p65 of NF-kB.
Ciascuna barra rappresenta la media ? DS (n = 4). *p <0,001 vs. 5-FU, **p <0,001 vs. AND o HXT da solo. 12 ore dopo, una stimolazione con 5-FU ha promosso in modo marcato un'attivit? di legame a DNA di p65 di NF-kB. Tuttavia, ? stata osservata un'attivit? di legame a DNA inferiore in cellule con stimolazione di 5-FU in presenza di AND e HXT, come mostrato in figura 5 (barra nera). Sorprendentemente, la combinazione di AND HXT ha fortemente ridotto un'attivit? di legame a DNA di p65 di NF-kB, dimostrando un effetto sinergico ottenuto dalla combinazione dei due composti. Does each bar represent the mean? DS (n = 4). * p <0.001 vs. 5-FU, ** p <0.001 vs. AND or HXT alone. 12 hours later, a stimulation with 5-FU markedly promoted an activity? of binding to DNA of p65 of NF-kB. However, ? was an activity observed? lower DNA binding in cells with 5-FU stimulation in the presence of AND and HXT, as shown in Figure 5 (black bar). Surprisingly, the combination of AND HXT greatly reduced an activity. DNA binding of p65 of NF-kB, demonstrating a synergistic effect obtained from the combination of the two compounds.
ESEMPIO 3 EXAMPLE 3
Attivazione di cheratinociti di espressione di Nrf2. Activation of Nrf2 expression keratinocytes.
Cellule sono state esposte ad AND, HXT o a una combinazione dei due composti alla concentrazione finale di 15 ?M, per valutare nel tempo l'espressione di proteina Nrf2. Come mostrato in figura 4, il trattamento con sulforafano ha causato un significativo aumento dipendente dal tempo di espressione di proteina Nrf2 negli estratti nucleari. Una quantificazione di tre western blot indipendenti ha mostrato che dopo 1 ora di esposizione a 15 ?M di AND, ? aumentata in modo significativo un'espressione di Nrf2 ed ? rimasta sovraregolata fino a 12 ore, mentre i livelli del fattore di trascrizione costitutivo Sp1 erano stabili. HXT ha indotto un incremento inferiore di Nrf2 nucleare. La combinazione dei due composti ha indotto in modo massiccio un'espressione di Nrf2. Cells were exposed to AND, HXT, or a combination of the two compounds at the final concentration of 15µM, to evaluate Nrf2 protein expression over time. As shown in Figure 4, sulforaphane treatment caused a significant time-dependent increase of Nrf2 protein expression in the nuclear extracts. A quantification of three independent western blots showed that after 1 hour of exposure to 15? M of AND,? significantly increased an expression of Nrf2 and d? remained upregulated for up to 12 hours, while the levels of constitutive transcription factor Sp1 were stable. HXT induced a lower increase in nuclear Nrf2. The combination of the two compounds massively induced an expression of Nrf2.
ESEMPIO 4 EXAMPLE 4
Sovraregolazione di enzimi di detossicazione HO-1 e di fase II in differenti cellule. Upregulation of HO-1 and phase II detoxification enzymes in different cells.
L'esposizione di cellule in coltura, per 6 ore a diverse concentrazioni di AND, HXT o a una combinazione dei due composti (5, 15, 25 e 50 ?M) ? risultata in un aumento significativo (p <0,05) di mRNA di HO-1, misurato mediante PCR quantitativa in tempo reale, con un valore massimo tra 15-25 ?M. AND provoca un aumento dose-dipendente di mRNA di HO-1, misurato rispetto al gene paralog HO-2 non inducibile, che raggiunge il massimo (circa 6 volte) a 15 ?M e diminuisce successivamente a 50 ?M. HXT ? invece molto meno attivo nell'indurre un'espressione di gene HO-1 alle stesse concentrazioni e raggiunge nuovamente il massimo a 15 ?M. Exposure of cultured cells for 6 hours to different concentrations of AND, HXT or a combination of the two compounds (5, 15, 25 and 50? M)? resulted in a significant (p <0.05) increase in HO-1 mRNA, measured by quantitative real-time PCR, with a maximum value between 15-25? M. AND causes a dose-dependent increase in HO-1 mRNA, measured against the non-inducible paralog HO-2 gene, which peaks (approximately 6-fold) at 15? M and subsequently decreases at 50? M. HXT? instead, it is much less active in inducing HO-1 gene expression at the same concentrations and again peaks at 15? M.
Per confermare che l'espressione del gene HO-1 misurata a livello di mRNA corrispondeva a un aumento equivalente di attivit? dell'eme ossigenasi, ? stata misurata questa attivit? alle stesse dosi di AND e HXT dopo 6 e 24 ore dalla somministrazione. To confirm that the HO-1 gene expression measured at the mRNA level corresponded to an equivalent increase in activity? heme oxygenase,? was this activity measured? at the same doses of AND and HXT 6 and 24 hours after administration.
Il modello di aumento dell'attivit? era paragonabile ai risultati ottenuti osservando gli mRNA cellulari, confermando il significato funzionale dei dati ottenuti dalle determinazioni di PCR in tempo reale. The model of increased activity? it was comparable to the results obtained by observing cellular mRNAs, confirming the functional significance of the data obtained from real-time PCR determinations.
ESEMPIO 5 EXAMPLE 5
Una composizione per somministrazione orale comprendente A composition for oral administration comprising
Andrografolidi 100 mg Andrographolides 100 mg
Idrossitirosolo 50 mg Hydroxytyrosol 50 mg
Eccipienti 3000 mg Excipients 3000 mg
ESEMPIO 6 EXAMPLE 6
Una composizione per applicazione topica comprendente A composition for topical application comprising
Andrografolidi 25 mg Andrographolides 25 mg
Idrossitirosolo 10 mg Hydroxytyrosol 10 mg
Eccipienti idonei per applicazione topica 3000 mg Excipients suitable for topical application 3000 mg
ESEMPIO 7 EXAMPLE 7
Formulazione liquida in una confezione per il trattamento di mucosite orale Liquid formulation in a package for the treatment of oral mucositis
Acqua 92,5% (p/v) Polivinilpirrolidone (PVP) 5,0% (p/v) Acido ialuronico 1,0 (p/v) Estratto secco di oliva titolato in idrossil tirosolo 20% 0,2 (p/v) andrograhis paniculata titolata a 30% in andrografolidi 0,1 (p/v) Gomma xantana 0,8 (p/v) Sale sodico di metil paraidrossibenzoato 0,1 (p/v) Sale sodico di propil paraidrossibenzoato 0,1 (p/v) Sucralosio 0,1 (p/v) Aromi 0,1 (p/v) Water 92.5% (w / v) Polyvinylpyrrolidone (PVP) 5.0% (w / v) Hyaluronic acid 1.0 (w / v) Dry extract of olive titrated in hydroxyl tyrosol 20% 0.2 (w / v ) andrograhis paniculata titrated to 30% in andrographolides 0.1 (w / v) Xanthan gum 0.8 (w / v) Sodium salt of methyl parahydroxybenzoate 0.1 (w / v) Sodium salt of propyl parahydroxybenzoate 0.1 (p / v) Sucralose 0.1 (w / v) Flavors 0.1 (w / v)
Claims (10)
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