IT201700116383A1 - Characterization of a combination for the treatment of oral mucositis induced by oncological treatments (radiation, chemotherapy or monoclonal antibodies) - Google Patents
Characterization of a combination for the treatment of oral mucositis induced by oncological treatments (radiation, chemotherapy or monoclonal antibodies)Info
- Publication number
- IT201700116383A1 IT201700116383A1 IT201700116383A IT201700116383A IT201700116383A1 IT 201700116383 A1 IT201700116383 A1 IT 201700116383A1 IT 201700116383 A IT201700116383 A IT 201700116383A IT 201700116383 A IT201700116383 A IT 201700116383A IT 201700116383 A1 IT201700116383 A1 IT 201700116383A1
- Authority
- IT
- Italy
- Prior art keywords
- agents
- derivative
- hyaluronic acid
- hyaluronate
- hemp
- Prior art date
Links
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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
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
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Description
Descrizione della domanda di brevetto dal titolo: Description of the patent application entitled:
Caratterizzazione di una combinazione per il trattamento delle mucositi orali indotte da trattamenti oncologici (radiazioni, chemioterapici o anticorpi monoclonali) Characterization of a combination for the treatment of oral mucositis induced by oncological treatments (radiation, chemotherapy or monoclonal antibodies)
La presente invenzione ha per oggetto la caratterizzazione di una combinazione di composizione comprendente olio vergine alimentare di canapa sativa (Cannabis Sativa) o suo derivato, acido ialuronico, suo sale o suo derivato, ed eccipienti nutrizionalmente e farmaceuticamente accettabili, destinata al trattamento di mucositi indotte da radiazioni, chemioterapici o anticorpi monoclonali. STATO DELLA TECNICA The present invention relates to the characterization of a composition combination comprising hemp sativa virgin edible oil (Cannabis Sativa) or its derivative, hyaluronic acid, its salt or its derivative, and nutritionally and pharmaceutically acceptable excipients, intended for the treatment of induced mucositis from radiation, chemotherapy or monoclonal antibodies. STATE OF THE TECHNIQUE
La mucosite orale (MO) è uno degli effetti collaterali più frequenti e potenzialmente gravi della terapia oncologica non chirurgica. Oral mucositis (MO) is one of the most frequent and potentially serious side effects of non-surgical cancer therapy.
Clinicamente è un'infiammazione acuta caratterizzata da eritema, formazione di ulcere con o senza pseudo-membrane, sanguinamenti, formazione di essudati e/o infezioni localizzate a livello superiore<i>; può evolvere in una forma debilitante che compromette la qualità di vita del paziente, fino ad impedire la deglutizione della semplice acqua. Clinically it is an acute inflammation characterized by erythema, ulcer formation with or without pseudo-membranes, bleeding, exudate formation and / or infections located at an upper level; it can evolve into a debilitating form that compromises the patient's quality of life, to the point of preventing the swallowing of simple water.
Il danno alle mucose può estendersi dal cavo orale fino alla faringe: pertanto, nella presente invenzione, con “mucosite orale” si intende anche la mucosite a livello faringeo. Damage to the mucous membranes can extend from the oral cavity to the pharynx: therefore, in the present invention, with "oral mucositis" we also mean mucositis at the pharyngeal level.
La percezione da parte del paziente dei disturbi legati alla MO va dalla sensazione di dolore in bocca sino alla grave alterazione di diverse funzioni orali<ii>. La MO è nella maggioranza dei casi associata a sintomi dolorosi quali disgeusia, disfagia, difficoltà nel parlare, masticare e deglutire, con conseguente compromissione della capacità di alimentarsi, perdita di peso e necessità di alimentazione mediante sondini naso-gastrici. The patient's perception of OM-related disorders ranges from the sensation of pain in the mouth to the severe alteration of various oral functions <ii>. OM is in most cases associated with painful symptoms such as dysgeusia, dysphagia, difficulty in speaking, chewing and swallowing, resulting in impaired ability to feed, weight loss and the need for nasogastric tube feeding.
Classicamente, nella patogenesi della MO, sono distinti cinque stadi: Classically, in the pathogenesis of OM, five stages are distinguished:
1. Iniziazione: chemioterapici, radiazioni ionizzanti o anticorpi monoclonali generano specie reattive dell'ossigeno (ROS) che danneggiano il tessuto connettivo, il DNA e le membrane cellulari, stimolano i macrofagi e innescano una cascata di altri eventi biologici a valle. Il DNA e ad altri componenti cellulari sono danneggiati sia con meccanismo diretto che attraverso la formazione di radicali liberi (ROS). I ROS possono causare immediatamente morte cellulare nell’epitelio basale e nelle cellule sottomucose, ma il danno non è di entità tale da provocare la manifestazione clinica della MO. 1. Initiation: Chemotherapy, ionizing radiation or monoclonal antibodies generate reactive oxygen species (ROS) that damage connective tissue, DNA and cell membranes, stimulate macrophages and trigger a cascade of other downstream biological events. DNA and other cellular components are damaged both by direct mechanism and through the formation of free radicals (ROS). ROS can immediately cause cell death in the basal epithelium and submucosal cells, but the damage is not of such a magnitude as to cause the clinical manifestation of OM.
2. Produzione di segnali di messaggio: la chemioterapia, le radiazioni e gli anticorpi monoclonali, i ROS (direttamente) e le cellule e il loro DNA danneggiato (indirettamente) attivano la sintesi e il rilascio di mediatori tra cui un fattore nucleare, NF-κB, che induce la produzione di citochine pro infiammatorie e molecole di adesione cellulare. Attraverso circuiti a feed-back si ha la liberazione di ulteriori mediatori (TNF-α, IL 1β, COX 2, tirosin-chinasi, MAPK) che amplificano il danno tissutale. Altri enzimi attivati dalle radiazioni, chemioterapia e ROS includono ceramide sintasi e sfingomielinasi, che possono aumentare il tasso di apoptosi. Insieme, questi fattori di trascrizione servono a innescare una serie di processi distruttivi che possono essere letali per le cellule epiteliali e i fibroblasti circostanti e distruggere l'integrità del collegamento tra l'epitelio e sottomucosa alla membrana basale. 2. Production of message signals: chemotherapy, radiation and monoclonal antibodies, ROS (directly) and cells and their damaged DNA (indirectly) activate the synthesis and release of mediators including a nuclear factor, NF- κB, which induces the production of pro-inflammatory cytokines and cell adhesion molecules. Through feed-back circuits, further mediators are released (TNF-α, IL 1β, COX 2, tyrosine kinase, MAPK) which amplify tissue damage. Other enzymes activated by radiation, chemotherapy, and ROS include ceramide synthase and sphingomyelinase, which can increase the rate of apoptosis. Together, these transcription factors serve to trigger a series of destructive processes that can be lethal to surrounding epithelial cells and fibroblasts and destroy the integrity of the link between the epithelium and submucosa at the basement membrane.
3. Amplificazione del segnale: consiste in meccanismi di feedback che aumentano ulteriormente il numero e il livello di attivazione dei segnali. Questa fase precede la MO clinica. 3. Signal amplification: consists of feedback mechanisms that further increase the number and level of activation of signals. This phase precedes the clinical OM.
4. Ulcerazione: perdita della integrità mucosa con comparsa di lesioni clinicamente dolenti. Clinicamente, la fase ulcerativa è la più significativa. Le ulcerazioni della MO sono generalmente profonde, larghe, e dolorose. Di solito sono coperte da pseudomembrane composte da cellule morte e fibrina, un ambiente ottimo per la colonizzazione batterica secondaria. I batteri Gram-positivi e gram-negativi prosperano all'interno delle pseudomembrane e possono penetrare e invadere i vasi della sottomucosa e produrre batteriemia. Inoltre, i prodotti della parete cellulare batterica che riescono ad arrivare nella sottomucosa stimolano i macrofagi e portano alla produzione di tossine, citochine infiammatorie e fattori angiogenici. Questa fase ulcerativa è responsabile dei principali sintomi clinici della MO (dolore, infiammazione e la perdita di funzione). 4. Ulceration: loss of mucosal integrity with the appearance of clinically painful lesions. Clinically, the ulcerative phase is the most significant. OM ulcerations are usually deep, wide, and painful. They are usually covered in pseudomembranes made up of dead cells and fibrin, an excellent environment for secondary bacterial colonization. Gram-positive and gram-negative bacteria thrive within pseudomembranes and can penetrate and invade submucosal vessels and produce bacteremia. Furthermore, the products of the bacterial cell wall that manage to reach the submucosa stimulate macrophages and lead to the production of toxins, inflammatory cytokines and angiogenic factors. This ulcerative phase is responsible for the main clinical symptoms of OM (pain, inflammation and loss of function).
5. Guarigione: la cicatrizzazione inizia quando l’insulto è superato e quando si risolve la neutropenia. Nella maggior parte dei casi, le ulcere della MO si risolvono spontaneamente entro due o tre settimane dopo l’interruzione del trattamento. Di tutte le fasi della MO, la guarigione è probabilmente la meno chiara. La cicloossigenasi-2 (COX-2), espressa nei fibroblasti e nell’endotelio vascolare, può svolgere un ruolo importante nella ricostruzione della sottomucosa, dal momento che la COX-2 potenzia l'angiogenesi, un segno distintivo della fine della fase ulcerativa. Le cellule epiteliali, sotto il controllo dei segnali della matrice extracellulare, migrano, crescono e si differenziano. Questi segnali vengono poi ridotti per evitare iperplasia. Con il processo di guarigione in corso, i sintomi cominciano a diminuire. 5. Healing: healing begins when the insult is overcome and when the neutropenia resolves. In most cases, OM ulcers resolve spontaneously within two or three weeks after stopping treatment. Of all the stages of OM, healing is probably the least clear. Cyclooxygenase-2 (COX-2), expressed in fibroblasts and vascular endothelium, can play an important role in the reconstruction of the submucosa, since COX-2 enhances angiogenesis, a hallmark of the end of the ulcerative phase. Epithelial cells, under the control of extracellular matrix signals, migrate, grow and differentiate. These signals are then reduced to avoid hyperplasia. As the healing process progresses, the symptoms begin to subside.
Recentemente, è stato evidenziato che le cellule epiteliali ai margini delle aree interessate dalla MO presentano spesso aspetti senescenti, cellule vecchie con ridotta capacità proliferativa. E’ logico assumere che la presenza di cellule senescenti sulla superficie ed i bordi di un’ulcera cutanea risulta in una compromissione della guarigione. Ci sono diverse implicazioni cliniche derivanti dal fatto che la senescenza cellulare potrebbe essere un fattore importante nel fallimento della guarigione delle ulcere. Recently, it has been shown that the epithelial cells at the margins of the areas affected by OM often have senescent aspects, old cells with reduced proliferative capacity. It is logical to assume that the presence of senescent cells on the surface and edges of a skin ulcer results in impaired healing. There are several clinical implications that cellular senescence could be a major factor in ulcer healing failure.
Il sintomo più debilitante della MO è rappresentato dal dolore e dalla perdita di funzionalità. The most debilitating symptom of OM is pain and loss of function.
I pazienti sottoposti a chemio, radioterapia e trattamento con anticorpi monoclonali riportano un’ampia varietà di disagi orali correlati: bocca dolente, gengive e labbra dolenti, ulcere orali, labbra secche, lingua dolente, bocca secca, cambiamento del gusto, incapacità a nutrirsi normalmente e ricorso a nutrizione per via enterale o parenterale, impossibilità ad attuare le normali pratiche di igiene orale. Patients undergoing chemo, radiotherapy, and monoclonal antibody treatment report a wide variety of related oral discomforts: sore mouth, sore gums and lips, oral ulcers, dry lips, sore tongue, dry mouth, change in taste, inability to feed normally and recourse to enteral or parenteral nutrition, inability to implement normal oral hygiene practices.
Le conseguenze della MO possono essere lievi e richiedere piccoli interventi o severe (ipovolemia, anomalie elettrolitiche e malnutrizione) e possono portare a complicanze fatali. I sintomi, infatti, possono andare da un lieve bruciore del cavo orale ad un dolore severo, urente, che impedisce qualsiasi introduzione di cibo e bevande, ed anche la capacità di parlare. Le forme severe, pseudomembranose, sono a rischio d’infezioni secondarie anche gravi. Nei casi più severi i pazienti necessitano di Nutrizione Parenterale Totale (NPT) e di terapia analgesica con oppiacei. La MO può essere ulteriormente complicata da nausea e vomito che spesso si associano al trattamento; inoltre i pazienti con una mucosa orale danneggiata e una ridotta risposta immunitaria sono più esposti a infezioni opportunistiche del cavo orale. The consequences of OM can be mild and require minor or severe interventions (hypovolemia, electrolyte abnormalities, and malnutrition) and can lead to fatal complications. The symptoms, in fact, can range from a slight burning of the oral cavity to a severe, burning pain, which prevents any introduction of food and drink, and even the ability to speak. Severe, pseudomembranous forms are at risk of even serious secondary infections. In severe cases, patients require Total Parenteral Nutrition (NPT) and opioid analgesic therapy. OM can be further complicated by nausea and vomiting often associated with treatment; moreover, patients with damaged oral mucosa and a reduced immune response are more exposed to opportunistic infections of the oral cavity.
L'approccio terapeutico classico della MO si è concentrato sulla palliazione. Il controllo del dolore è una componente essenziale nella gestione della MO, perché questo è spesso il primo sintomo del paziente. Questa terapia inizia con analgesici e prosegue con farmaci sistemici sempre più potenti. Nei pazienti sottoposti a radio, chemioterapia o trattamento con anticorpi monoclonali, la MO è caratterizzata da un danno indotto da ROS alla mucosa. The classical therapeutic approach of OM has focused on palliation. Pain control is an essential component in managing OM because this is often the patient's first symptom. This therapy begins with analgesics and continues with increasingly potent systemic drugs. In patients undergoing radiotherapy, chemotherapy, or monoclonal antibody treatment, OM is characterized by ROS-induced damage to the mucosa.
Tutto ciò non solo ha un impatto negativo sulla qualità di vita del paziente, ma può anche portare alla sospensione della terapia o alla riduzione delle relative dosi di farmaco antitumorale, con conseguente diminuzione dell’aspettativa di vita del paziente<iii>. Anche dal punto di vista economico, i frequenti ricoveri ospedalieri dei pazienti affetti da MO e la loro assistenza a domicilio da parte di personale specializzato per la somministrazione di farmaci o per l’alimentazione parenterale comportano un notevole aggravio per la sanità pubblica. All this not only has a negative impact on the patient's quality of life, but can also lead to the suspension of therapy or the reduction of the relative doses of anticancer drug, with a consequent decrease in the patient's life expectancy <iii>. Also from an economic point of view, the frequent hospitalizations of patients with OM and their home care by specialized personnel for the administration of drugs or parenteral nutrition entail a significant burden for public health.
Nonostante la gravità e la frequenza di casi di MO ed i molti studi condotti al riguardo, ad oggi non esiste una strategia standard ed universalmente accettata per la prevenzione ed il trattamento di questa complicanza potenzialmente molto grave. Nonostante alcuni studi abbiano dimostrato che sia possibile evitare o ridurre l’insorgenza della MO, essi sono stati condotti su un numero insufficiente di partecipanti e non soddisfano standard adeguati che consentano la redazione di linee guida per la pratica clinica<iv>. Despite the severity and frequency of OM cases and the many studies conducted on it, to date there is no standard and universally accepted strategy for the prevention and treatment of this potentially very serious complication. Although some studies have shown that it is possible to avoid or reduce the onset of OM, they have been conducted on an insufficient number of participants and do not meet adequate standards that allow the drafting of guidelines for clinical practice <iv>.
Ad oggi, il trattamento della MO e del dolore da essa indotto comprende: anestetici topici di base, analgesici sistemici, antiinfiammatori, agenti di rivestimento delle mucose, risciacqui orali, igiene orale in generale, antimicrobici<v>. To date, the treatment of OM and the pain induced by it includes: basic topical anesthetics, systemic analgesics, anti-inflammatories, mucosal coating agents, oral rinses, oral hygiene in general, antimicrobials <v>.
Recentemente è stato dimostrato che un gel a base di acido ialuronico allo 0,2% per uso topico non solo dà sollievo in caso di dolore/bruciore associato a stomatiti aftose ricorrenti e lichen planus orale atrofico/erosivo, e in casi limitati può concorrere anche alla risoluzione clinica di aree che presentano ulcere, erosioni o atrofia<vi>. Recently it has been shown that a gel based on 0.2% hyaluronic acid for topical use not only gives relief in case of pain / burning associated with recurrent aphthous stomatitis and atrophic / erosive oral lichen planus, and in limited cases it can also contribute clinical resolution of areas presenting ulcers, erosions or atrophy <vi>.
Tuttavia, il solo impiego di acido ialuronico non è risolutivo delle problematiche, più sopra descritte, alle quali va incontro il paziente in trattamento con radio, chemioterapia o anticorpi monoclonali, soprattutto il ragione di un significativo controllo dei primi stadi di manifestazione della MO e di una sua rapida remissione. However, the use of hyaluronic acid alone does not resolve the problems, described above, which the patient undergoing treatment with radio, chemotherapy or monoclonal antibodies faces, above all the reason for a significant control of the first stages of manifestation of OM and its rapid remission.
Di conseguenza, la ricerca è oggi focalizzata su nuove strategie di trattamento della MO e relative formulazioni. Consequently, research is now focused on novel OM treatment strategies and related formulations.
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
Scopo della presente invenzione è quello di superare gli inconvenienti precedentemente evidenziati e presenti nelle soluzioni utilizzate dallo stato dell'arte, assicurando, in caso di MO, un corretto processo di guarigione e un corretto reintegro di quegli acidi grassi essenziali che possano assicurare: The purpose of the present invention is to overcome the drawbacks previously highlighted and present in the solutions used by the state of the art, ensuring, in the case of OM, a correct healing process and a correct reintegration of those essential fatty acids that can ensure:
- la riduzione dell’infiammazione - the reduction of inflammation
- il controllo della produzione di ROS - control of ROS production
- la pronta remissione di ulcere - prompt remission of ulcers
- il controllo del dolore - pain control
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
La presente invenzione riguarda la caratterizzazione di una composizione di elementi, comprendente olio di canapa sativa (Cannabis Sativa), e acido ialuronico, suo sale o suo derivato. Sotto un altro aspetto, la presente invenzione concerne l’uso della composizione sopra descritta come medicamento, essendosi mostrata particolarmente adatta all’uso nel trattamento delle ulcere che caratterizzano una fase avanzata di MO. In particolare, dette ulcere sono ferite aperte, per le quali il processo di cicatrizzazione deve essere adiuvato e promosso. The present invention relates to the characterization of a composition of elements, comprising hemp sativa oil (Cannabis Sativa), and hyaluronic acid, its salt or its derivative. From another aspect, the present invention concerns the use of the composition described above as a medicament, having proved to be particularly suitable for use in the treatment of ulcers that characterize an advanced stage of OM. In particular, these ulcers are open wounds, for which the healing process must be assisted and promoted.
L’olio canapa sativa (Cannabis sativa), preferibilmente estratto con procedimento meccanico di spremitura a freddo dai semi decorticati di canapa sativa, possiede alcune peculiari caratteristiche che lo rendono particolarmente adatto al trattamento di affezioni cutanee. Hemp sativa oil (Cannabis sativa), preferably extracted with a mechanical cold pressing process from the hulled seeds of hemp sativa, has some peculiar characteristics that make it particularly suitable for the treatment of skin conditions.
Con l’espressione “derivato di olio vergine di canapa sativa” si intende, per gli scopi della presente invenzione, estere alchilico C1-C4 di acido grasso polinsaturo presente nell’olio di canapa sativa. Preferibilmente, detto derivato è una miscela di esteri alchilici C1-C4 di acidi grassi polinsaturi presenti nell’olio di canapa sativa. Più preferibilmente, detto derivato è una miscela di esteri etilici di acidi grassi polinsaturi presenti nell’olio di canapa sativa. The expression "derivative of virgin hemp sativa oil" means, for the purposes of the present invention, C1-C4 alkyl ester of polyunsaturated fatty acid present in hemp sativa oil. Preferably, said derivative is a mixture of C1-C4 alkyl esters of polyunsaturated fatty acids present in hemp sativa oil. More preferably, said derivative is a mixture of ethyl esters of polyunsaturated fatty acids present in hemp sativa oil.
In particolare, nell’olio vergine di canapa sativa (Cannabis sativa) si riscontra: In particular, in the virgin oil of hemp sativa (Cannabis sativa) we find:
- una elevata biodisponibilità di acidi grassi essenziali a lunga catena (acido linoleico, acido α-linolenico, acido γ-linolenico, acido stearidonico) - a high bioavailability of long-chain essential fatty acids (linoleic acid, α-linolenic acid, γ-linolenic acid, stearidonic acid)
- una elevata biodisponibilità di vitamina E come α-tocoferolo e γ-tocoferolo. - a high bioavailability of vitamin E such as α-tocopherol and γ-tocopherol.
Gli acidi grassi essenziali svolgono una funzione di normalizzazione degli strati lipidici intercellulari, permettendo la corretta ossidazione e degradazione del materiale organico necrotico tossico che ostacola il naturale processo di cicatrizzazione. The essential fatty acids perform a normalizing function of the intercellular lipid layers, allowing the correct oxidation and degradation of the toxic necrotic organic material that hinders the natural healing process.
Gli acidi grassi essenziali rivestono poi una funzione di barriera a livello della mucosa: essi infatti integrano i lipidi intercellulari presenti nello strato granuloso e zone inferiori, evitando la dispersione di acqua e di altre molecole intercellulari dagli strati superiori della mucosa. The essential fatty acids then play a barrier function at the level of the mucosa: in fact they integrate the intercellular lipids present in the granular layer and lower areas, avoiding the dispersion of water and other intercellular molecules from the upper layers of the mucosa.
In secondo luogo, poiché ogni membrana cellulare, citoplasmatica, nucleare, mito-condriale contiene acidi grassi essenziali (incorporati come fosfolipidi), è fondamentale, in caso di lesioni provocate da radio, chemioterapia o anticorpi monoclonali, provvedere ad un significativo reintegro di essi, così da assicurare l’azione di fluidificante di membrana, e da permettere la modulazione dell'attività delle molecole proteiche legate ad esse. Secondly, since every cellular, cytoplasmic, nuclear, mito-chondrial membrane contains essential fatty acids (incorporated as phospholipids), it is essential, in case of lesions caused by radium, chemotherapy or monoclonal antibodies, to provide for a significant replenishment of them, so as to ensure the membrane fluidifying action, and to allow the modulation of the activity of the protein molecules bound to them.
I complessi vitaminici E, invece, applicati sulla cute svolgono un’azione meccanica di filtraggio dei raggi UVB, attraverso la struttura molecolare a doppi anello aromatico che li compone. Quando la cute è irradiata, gli ultravioletti provocano la formazione di specie reattive dell’ossigeno (ROS), stress ossidativo e formazione di radicali liberi. Ne risulta un’alterazione delle proteine e delle attività enzimatiche, per ossidazione dei lipidi e danni alle membrane cellulari. I complessi vitaminici E esplicano un’attività di scavenger di radicali liberi e stabilizzano le membrane cellulari. Con l’espressione “sale o derivato di acido ialuronico” si intende, per gli scopi della presente invenzione, ialuronato sodico, estere ialuronato, etere ialuronato, estere ialuronato-NHS, o loro miscela. Vitamin E complexes, on the other hand, applied to the skin perform a mechanical action of filtering UVB rays, through the molecular structure with double aromatic ring that composes them. When the skin is irradiated, ultraviolet rays cause the formation of reactive oxygen species (ROS), oxidative stress and the formation of free radicals. The result is an alteration of proteins and enzymatic activities, due to lipid oxidation and damage to cell membranes. Vitamin E complexes perform a free radical scavenger activity and stabilize cell membranes. The expression "salt or derivative of hyaluronic acid" means, for the purposes of the present invention, sodium hyaluronate, hyaluronate ester, hyaluronate ether, hyaluronate-NHS ester, or their mixture.
Di fondamentale importanza per le applicazioni qui descritte è la possibilità di ottenere composizioni farmaceutiche dotate di proprietà reologiche molto diverse tra loro: ciò dipende dalle caratteristiche intrinseche di HA, la cui molecola, prima di venire coniugata con il principio attivo farmaceutico, può essere profondamente modificata attraverso varie reazioni chimiche. Of fundamental importance for the applications described here is the possibility of obtaining pharmaceutical compositions with very different rheological properties: this depends on the intrinsic characteristics of HA, whose molecule, before being conjugated with the active pharmaceutical ingredient, can be profoundly modified. through various chemical reactions.
I derivati ottenuti attraverso tali reazioni conservano le caratteristiche biologiche del polisaccaride di partenza, ma sono dotati di migliori proprietà meccaniche; essi sono inoltre facilmente formulabili in forma di idrogel, film, cerotti, ecc., e permettono quindi di realizzare un'ampia gamma di forme topiche. The derivatives obtained through these reactions retain the biological characteristics of the starting polysaccharide, but are endowed with better mechanical properties; they are also easily formulated in the form of hydrogels, films, patches, etc., and therefore allow a wide range of topical forms to be made.
Preferibilmente, l’acido ialuronico, suo sale o suo derivato, nella presente invenzione ha un peso molecolare compreso tra 400 e 3.000.000 Da, più preferibilmente tra 50.000 e 1.000.000 Da. Preferably, the hyaluronic acid, its salt or its derivative, in the present invention has a molecular weight between 400 and 3,000,000 Da, more preferably between 50,000 and 1,000,000 Da.
Preferibilmente, la composizione dell’invenzione comprende 1-40% in peso di olio vergine di canapa sativa o suo derivato, e 0.05-20% in peso di acido ialuronico, suo sale o suo derivato, sul peso totale della composizione. Preferably, the composition of the invention comprises 1-40% by weight of virgin hemp sativa oil or its derivative, and 0.05-20% by weight of hyaluronic acid, its salt or its derivative, on the total weight of the composition.
Più preferibilmente, la composizione dell’invenzione comprende 3-25% in peso di olio vergine di canapa sativa o suo derivato, e 0.2-10% in peso di acido ialuronico, suo sale o suo derivato, sul peso totale della composizione. More preferably, the composition of the invention comprises 3-25% by weight of virgin hemp sativa oil or its derivative, and 0.2-10% by weight of hyaluronic acid, its salt or its derivative, on the total weight of the composition.
La composizione dell’invenzione può comprendere anche eccipienti cosmeticamente o farmaceuticamente accettabili. The composition of the invention may also include cosmetically or pharmaceutically acceptable excipients.
Sotto una prima forma di realizzazione preferita, la composizione dell’invenzione consiste in olio vergine di canapa sativa o suo derivato, acido ialuronico, suo sale o suo derivato, ed eccipienti farmaceuticamente accettabili. Under a first preferred embodiment, the composition of the invention consists of virgin hemp oil or its derivative, hyaluronic acid, its salt or its derivative, and pharmaceutically acceptable excipients.
Sotto una seconda forma di realizzazione preferita, la composizione dell’invenzione consiste in olio vergine di canapa sativa o suo derivato, acido ialuronico, suo sale o suo derivato, ed eccipienti cosmeticamente accettabili. Under a second preferred embodiment, the composition of the invention consists of virgin hemp oil or its derivative, hyaluronic acid, its salt or its derivative, and cosmetically acceptable excipients.
In particolare, adatti eccipienti sono additivi reologici, agenti tamponanti, agenti antimicrobici, agenti antiossidanti, agenti antistatici, agenti assorbenti, agenti astringenti, agenti chelanti, agenti coloranti, agenti conservanti, agenti coprenti, agenti denaturanti, agenti depigmentanti, agenti emollienti, agenti emulsionanti, agenti filmogeni, agenti gelificanti, agenti idratanti, agenti idrotropi, agenti leganti, agenti lenitivi, agenti leviganti, agenti opacizzanti, agenti protettivi, agenti riducenti, agenti rinfrescanti, agenti seborestitutivi, solventi, agenti stabilizzanti, agenti stabilizzanti delle emulsioni, agenti tonificanti, agenti umettanti, o loro miscele. In particular, suitable excipients are rheological additives, buffering agents, antimicrobial agents, antioxidant agents, antistatic agents, absorbent agents, astringent agents, chelating agents, coloring agents, preservative agents, covering agents, denaturing agents, depigmenting agents, emollient agents, emulsifying agents , film-forming agents, gelling agents, moisturizing agents, hydrotropic agents, binding agents, soothing agents, smoothing agents, matting agents, protective agents, reducing agents, cooling agents, sebum-restoring agents, solvents, stabilizing agents, stabilizing agents of emulsions, toning agents, wetting agents, or mixtures thereof.
Secondo una forma di realizzazione preferita, detti eccipienti sono tocoferil acetato, gliceril stearato, sali di potassio di idrolizzati di proteina di frumento palmitoil derivati, polialchilacrilati, pullulano, trealosio, inositolo, glucosidi, amido idrogenato, proteine del latte, fenossietanolo, glicerina, pantenolo, retinil palmitato, ceramide, acetil tripeptide-30, pentapeptide-18, glicoproteine, acido citrico, ascorbil palmitato, butilstearato, candelilla, ceresina, glicerolo, isopropil isostearato, isopropil stearato, lanolato di isopropile, propilenglicole, squalano, squalene, butil paraossibenzoato, bisabololo, acido poliacrilico, carragenina, deidro acetato sodico, diclorofene, metilparaossibenzoato, propil paraossibenzoato, silice pirogenica, sorbitolo, trietanolamina, o loro miscele. According to a preferred embodiment, said excipients are tocopheryl acetate, glyceryl stearate, potassium salts of hydrolysates of wheat protein, palmitoyl derivatives, polyalkylacrylates, pullulan, trehalose, inositol, glucosides, hydrogenated starch, milk proteins, phenoxyethanol, glycerin, panthenol , retinyl palmitate, ceramide, acetyl tripeptide-30, pentapeptide-18, glycoproteins, citric acid, ascorbyl palmitate, butylstearate, candelilla, ceresin, glycerol, isopropyl isostearate, isopropyl stearate, isopropyl lanolate, propylene glycol, squalane, squalane, butylbenzoate bisabolol, polyacrylic acid, carrageenan, sodium dehydroacetate, dichlorophene, methyl paraoxybenzoate, propyl paraoxybenzoate, fumed silica, sorbitol, triethanolamine, or mixtures thereof.
Sotto un altro aspetto, la presente invenzione concerne l’uso della composizione sopra descritta come medicamento. From another aspect, the present invention concerns the use of the composition described above as a medicament.
Coniugando l’olio vergine di canapa sativa (cannabis sativa) con l’acido ialuronico (HA) è stato sorprendentemente trovato che è possibile portare tali principi attivi in profondità nella mucosa. Come si potrà vedere dagli Esempi e dai Risultati dello studio clinico che seguono, la composizione si è mostrata particolarmente adatta all’uso nel trattamento delle MO. Le composizioni dell’invenzione sono risultate particolarmente efficaci sotto il profilo della gestione del dolore nei pazienti. Infatti, le composizioni della presente invenzione mostrano un notevole effetto di accelerazione della cicatrizzazione delle ulcere proprie della MO, ma soprattutto un sorprendente effetto sulla gestione del dolore, in termini di riduzione del dolore e di sollievo immediato (già 1 ora dopo la prima somministrazione). By combining virgin hemp sativa oil (cannabis sativa) with hyaluronic acid (HA) it was surprisingly found that it is possible to carry these active ingredients deep into the mucous membrane. As can be seen from the Examples and the Results of the clinical study that follow, the composition proved to be particularly suitable for use in the treatment of OM. The compositions of the invention were found to be particularly effective in terms of pain management in patients. In fact, the compositions of the present invention show a remarkable effect of accelerating the healing of ulcers typical of OM, but above all a surprising effect on pain management, in terms of pain reduction and immediate relief (already 1 hour after the first administration). .
La composizione dell’invenzione è da somministrarsi sulla mucosa orofaringea, come precedentemente definito. The composition of the invention is to be administered on the oropharyngeal mucosa, as previously defined.
Preferibilmente, detta composizione è in forma di gel, emulsione, latte, unguento, cerotto, pomata, lozione, schiuma o spray e saranno preparate secondo metodi convenzionali ben noti in tecnica farmaceutica, come quelli descritti in “Remington’s Pharmaceutical Handbook”, Mack Publishing Co., N.Y., USA, utilizzando eccipienti, solubilizzanti, emollienti, stabilizzanti, emulsionanti, regolatori di pH, conservanti accettabili per il loro uso finale. Preferably, said composition is in the form of a gel, emulsion, milk, ointment, patch, ointment, lotion, foam or spray and will be prepared according to conventional methods well known in the pharmaceutical art, such as those described in "Remington's Pharmaceutical Handbook", Mack Publishing Co. ., N.Y., USA, using excipients, solubilizers, emollients, stabilizers, emulsifiers, pH regulators, preservatives acceptable for their final use.
Si riportano di seguito Esempi di realizzazione della presente invenzione forniti a titolo illustrativo e i Risultati di uno studio clinico effettuato con il prodotto oggetto della presente invenzione. Examples of embodiments of the present invention provided for illustrative purposes and the Results of a clinical study carried out with the product object of the present invention are reported below.
ESEMPIO - PREPARAZIONE DI COMPOSIZIONI DELL’INVENZIONE EXAMPLE - PREPARATION OF COMPOSITIONS OF THE INVENTION
- composizione A - composition A
Componenti % olio vergine di canapa sativa 25,00 Tocoferil Acetato 1,50 Gliceril stearato, Components% virgin oil of hemp sativa 25,00 Tocopheryl Acetate 1,50 Glyceryl stearate,
7,00 sali di potassio di idrolizzati di proteina di frumento palmitoil derivato propylene glicol 1,75 Acqua 58,35 Acrilati/ C10-30 polialchilacrilato reticolato 0,50 acido ialuronico, 0,25 glicosaminoglicani idrolizzati 0,20 Aroma 0,15 Sodium saccarhin 0,20 Sodium benzoate 0,10 disodium EDTA 0,10 Acqua, urea, amminoacidi di lievito, trealosio, inositolo 2,00 Acqua, glicoproteine 3,00 7.00 potassium salts of wheat protein hydrolysates palmitoyl derivative propylene glycol 1.75 Water 58.35 Acrylates / C10-30 cross-linked polyalkylacrylate 0.50 hyaluronic acid, 0.25 hydrolyzed glycosaminoglycans 0.20 Aroma 0.15 Sodium saccarhin 0.20 Sodium benzoate 0.10 disodium EDTA 0.10 Water, urea, yeast amino acids, trehalose, inositol 2.00 Water, glycoproteins 3.00
- composizione B - composition B
Componenti % olio vergine di canapa sativa 28,00 Tocoferim acetato 2,50 propylene glicol 7,00 Acqua 53,15 Acrilati/ C10-30 polialchilacrilato reticolato 0,50 acido ialuronico, 0,25 glicosaminoglicani idrolizzati 0,05 Acqua, acetil tripeptide-30, pentapeptide-18, 3,00 Sodium saccarhin 0,25 Sodium benzoate 0,15 disodium EDTA 0,15 Aroma 2,00 Acqua, glicoproteine 3,00 Components% virgin hemp oil 28.00 Tocoferim acetate 2.50 propylene glycol 7.00 Water 53.15 Acrylates / C10-30 cross-linked polyalkylacrylate 0.50 hyaluronic acid, 0.25 hydrolyzed glycosaminoglycans 0.05 Water, acetyl tripeptide- 30, pentapeptide-18, 3.00 Sodium saccarhin 0.25 Sodium benzoate 0.15 disodium EDTA 0.15 Aroma 2.00 Water, glycoproteins 3.00
- composizione C - composition C
Componenti % olio vergine di canapa sativa 18,00 propylene glicol 7,00 Acqua 65,45 Acrilati/ C10-30 polialchilacrilato reticolato 0,50 acido ialuronico, 3,10 Glicosaminoglicani idrolizzati 0,25 Aroma 3,00 sodium saccarhin 0,15 sodium benzoate 0,20 disodium EDTA 0,15 acqua, urea, amminoacidi di lievito, trealosio, inositolo 2,20 Components% virgin hemp oil sativa 18.00 propylene glycol 7.00 Water 65.45 Acrylates / C10-30 cross-linked polyalkylacrylate 0.50 hyaluronic acid, 3.10 Hydrolyzed glycosaminoglycans 0.25 Aroma 3.00 sodium saccarhin 0.15 sodium benzoate 0.20 disodium EDTA 0.15 water, urea, yeast amino acids, trehalose, inositol 2.20
RISULTATI – STUDIO CLINICO RESULTS - CLINICAL STUDY
La sperimentazione è stata condotta su 34 pazienti con MO, sottoposti entro due settimane a dosi giornaliere di radio, chemioterapia o anticorpi monoclonali, che manifestavano una MO almeno di grado 1 come valutata in base alla scala dell’Organizzazione Mondiale di Sanità (WHO) per la mucosite e nei quali il dolore non era alleviato dal trattamento con paracetamolo/codamol/acido acetilsalicilico. The trial was conducted on 34 patients with OM, who received daily doses of radium, chemotherapy or monoclonal antibodies within two weeks, who had at least Grade 1 OM as assessed on the World Health Organization (WHO) scale for mucositis and in which pain was not relieved by treatment with paracetamol / codamol / acetylsalicylic acid.
Ogni paziente era trattato per 3-4 volte al giorno per 14 giorni con la composizione dell’invenzione sotto forma di gel, che doveva essere mantenuto in situ per almeno 2 minuti, evitando di bere, mangiare e sciacquare la bocca per almeno 30 minuti. Each patient was treated 3-4 times a day for 14 days with the composition of the invention in the form of a gel, which had to be kept in place for at least 2 minutes, avoiding drinking, eating and rinsing the mouth for at least 30 minutes.
I risultati della sperimentazione sono illustrati nelle Tabelle I-II seguenti. The results of the experimentation are illustrated in Tables I-II below.
In Tabella I è riportato lo score del dolore ai diversi stadi di valutazione. Al tempo T0 (baseline – prima dell’inizio del trattamento) sono stati valutati i seguenti parametri: dolore (mediante scala analogica lineare visiva da 1 a 100) e gravità della MO (mediante scala WHO per la mucosite). L’efficacia del trattamento è stata valutata in base allo score del dolore, all’indice di risoluzione clinica e alla compliance dei pazienti ai tempi T1 (dopo 2 ore), T2 (dopo 24 ore), T3 (dopo 72 ore), T4 (dopo 7 giorni) e T5 (dopo 14 giorni). Table I shows the pain score at the various stages of assessment. At time T0 (baseline - before the start of treatment) the following parameters were assessed: pain (using the linear visual analog scale from 1 to 100) and severity of OM (using the WHO scale for mucositis). Treatment efficacy was assessed on the basis of pain score, clinical resolution index and patient compliance at T1 (after 2 hours), T2 (after 24 hours), T3 (after 72 hours), T4 times. (after 7 days) and T5 (after 14 days).
Tabella I. Score del dolore valutato con VAS ai diversi stadi di valutazione. Table I. Pain score assessed with VAS at different stages of assessment.
I risultati hanno mostrato una riduzione estremamente marcata dei sintomi dolorosi già dopo 2 ore dalla somministrazione del gel, in confronto alle misurazioni di baseline (p < 0,0001. Tale riduzione del dolore progrediva in maniera radicale nel corso delle due settimane di sperimentazione (p < 0,0001). The results showed an extremely marked reduction in painful symptoms as early as 2 hours after gel administration, compared to baseline measurements (p <0.0001. This pain reduction progressed dramatically over the two-week trial (p <0.0001).
In Tabella II è riportato l’effetto del trattamento sull’indice di risoluzione clinica. I pazienti trattati mostravano un significativo miglioramento clinico delle lesioni già a partire da 24 ore dal trattamento (p = 0,0001). Nel corso delle due settimane di osservazione, tutti i pazienti mostravano un significativo miglioramento rispetto alla baseline (p < 0,0001) e la loro capacità di inghiottire solidi e liquidi migliorava rapidamente e progressivamente. Table II shows the effect of the treatment on the clinical resolution index. Treated patients showed significant clinical improvement in lesions as early as 24 hours after treatment (p = 0.0001). Over the two weeks of observation, all patients showed significant improvement from baseline (p <0.0001) and their ability to swallow solids and liquids improved rapidly and progressively.
Tabella II. Effetto sull’indice di risoluzione clinica durante il trattamento. Table II. Effect on the clinical resolution index during treatment.
Tutti i pazienti mostravano una eccellente compliance e alla fine dello studio nessuno lamentava effetti collaterali. All patients showed excellent compliance and none complained of side effects at the end of the study.
Nessuno dei pazienti era inoltre costretto a interrompere il trattamento radio, chemioterapico o con anticorpi monoclonali. Furthermore, none of the patients was forced to stop radiotherapy, chemotherapy or monoclonal antibody treatment.
Dalla descrizione dettagliata e dagli Esempi sopra riportati, risultano evidenti i vantaggi conseguiti mediante la composizione dell’invenzione, la quale essendo in grado di ridurre lo stato infiammatorio della mucosa, a ridurre drasticamente il dolore e ad accelerare il processo di risoluzione delle ulcere orali, si dimostra una valida terapia di supporto per il paziente in trattamento radio, chemioterapico e con anticorpi monoclonali. From the detailed description and the Examples reported above, the advantages achieved by the composition of the invention are evident, which being able to reduce the inflammatory state of the mucosa, drastically reduce pain and accelerate the process of resolution of oral ulcers, proves to be a valid supportive therapy for the patient under radio, chemotherapy and monoclonal antibody treatment.
Bibliografia Bibliography
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<iv >Rubenstein EB, Peterson DE, Schubert M, Keefe D, McGuire D, Epstein J, Elting LS, Fox PC, Cooksley C, Sonis ST. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 2004; 100:2026-2046; Worthington HV, Clarkson JE, Eden OB. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2007:CD000978; Clarkson JE, Worthington HV, Eden OB. Interventions for treating oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2007:CD001973; Potting C, Mistiaen P, Poot E, Blijlevens N, Donnelly P, van Achterberg T. A review of quality assessment of the methodology used in guidelines and systematic reviews on oral mucositis. J Clin Nurs 2009; 18:3-12. <iv> Rubenstein EB, Peterson DE, Schubert M, Keefe D, McGuire D, Epstein J, Elting LS, Fox PC, Cooksley C, Sonis ST. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 2004; 100: 2026-2046; Worthington HV, Clarkson JE, Eden OB. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2007: CD000978; Clarkson JE, Worthington HV, Eden OB. Interventions for treating oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2007: CD001973; Potting C, Mistiaen P, Poot E, Blijlevens N, Donnelly P, van Achterberg T. A review of quality assessment of the methodology used in guidelines and systematic reviews on oral mucositis. J Clin Nurs 2009; 18: 3-12.
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Non-Patent Citations (3)
| Title |
|---|
| L. F. CUBA ET AL: "Cannabidiol: an alternative therapeutic agent for oral mucositis?", JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS., vol. 42, no. 3, 1 June 2017 (2017-06-01), GB, pages 245 - 250, XP055511648, ISSN: 0269-4727, DOI: 10.1111/jcpt.12504 * |
| NICOLA CIRILLO ET AL: "A hyaluronic acid-based compound inhibits fibroblast senescence induced by oxidative stress in vitro and prevents oral mucositis in vivo", JOURNAL OF CELLULAR PHYSIOLOGY, 1 December 2014 (2014-12-01), pages n/a - n/a, XP055163236, ISSN: 0021-9541, DOI: 10.1002/jcp.24908 * |
| PATRICIA C BUCHSEL ET AL: "Polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair): a bioadherent oral gel for the treatment of oral mucositis and other painful oral lesions", EXPERT OPINION ON DRUG METABOLISM & TOXICO, ASHLEY PUBLICATIONS, LONDON, GB, vol. 4, no. 11, 1 November 2008 (2008-11-01), pages 1449 - 1454, XP009165522, ISSN: 1742-5255, DOI: 10.1517/17425255.4.11.1449 * |
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