IT202100017528A1 - IMPROVED COMPOSITION FOR THE TREATMENT OF CUTANEOUS, MUCOSAL AND CARTILAGE LESIONS IN GENERAL - Google Patents
IMPROVED COMPOSITION FOR THE TREATMENT OF CUTANEOUS, MUCOSAL AND CARTILAGE LESIONS IN GENERAL Download PDFInfo
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- IT202100017528A1 IT202100017528A1 IT102021000017528A IT202100017528A IT202100017528A1 IT 202100017528 A1 IT202100017528 A1 IT 202100017528A1 IT 102021000017528 A IT102021000017528 A IT 102021000017528A IT 202100017528 A IT202100017528 A IT 202100017528A IT 202100017528 A1 IT202100017528 A1 IT 202100017528A1
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- 229960001340 histamine Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
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- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
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- 230000010354 integration Effects 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- KXCLCNHUUKTANI-RBIYJLQWSA-N keratan Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@H](COS(O)(=O)=O)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@H](O[C@@H](O[C@H]3[C@H]([C@@H](COS(O)(=O)=O)O[C@@H](O)[C@@H]3O)O)[C@H](NC(C)=O)[C@H]2O)COS(O)(=O)=O)O[C@H](COS(O)(=O)=O)[C@@H]1O KXCLCNHUUKTANI-RBIYJLQWSA-N 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- -1 lipid hydroperoxides Chemical class 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
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- 230000004060 metabolic process Effects 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 230000009854 mucosal lesion Effects 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 102000006776 nephronectin Human genes 0.000 description 1
- 108010086803 nephronectin Proteins 0.000 description 1
- 108010008217 nidogen Proteins 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
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- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
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- 239000011049 pearl Substances 0.000 description 1
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- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 230000009719 regenerative response Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
-
- 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
-
- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
Description
Descrizione del Brevetto per Invenzione Industriale avente per titolo: "COMPOSIZIONE DI TIPO MIGLIORATO PER IL TRATTAMENTO DELLE LESIONI CUTANEE, MUCOSALI E CARTILAGINEE IN GENERE" Description of the Patent for Industrial Invention entitled: "IMPROVED COMPOSITION FOR THE TREATMENT OF CUTANEOUS, MUCOSAL AND CARTILAGE INJURIES IN GENERAL"
DESCRIZIONE DESCRIPTION
La presente invenzione concerne una composizione di tipo migliorato per il trattamento delle lesioni cutanee, mucosali e cartilaginee acute e croniche in genere. Pi? in particolare la composizione dell'invenzione risulta particolarmente efficace per il trattamento delle lesioni orodigestive e bronchiali, come le lesioni esofago gastriche da reflusso o da farmaci o da radioterapia e chemioterapia, nonch? delle lesioni anorettali e rettosigmoidee da flogosi aspecifiche, post attiniche. The present invention relates to an improved composition for the treatment of acute and chronic skin, mucosal and cartilaginous lesions in general. Pi? in particular, the composition of the invention is particularly effective for the treatment of orodigestive and bronchial lesions, such as gastric and oesophageal reflux lesions or from drugs or from radiotherapy and chemotherapy, as well as of anorectal and rectosigmoid lesions from non-specific, post-actinic inflammation.
Il crescente interesse del mondo scientifico verso le Scienze Rigeneranti ed i pazienti che presentano patologie disabilitanti che possono beneficiare dei trattamenti ultraspecialistici, nasce dalla consapevolezza che siamo di fronte ad una svolta culturale e clinica. The growing interest of the scientific world in Regenerating Sciences and in patients with disabling pathologies who can benefit from ultra-specialist treatments, stems from the awareness that we are facing a cultural and clinical turning point.
La comprensione dei meccanismi eziopatogenetici delle lesioni cutanee, mucosali e cartilaginee croniche, nonch? l?approccio scientifico ai meccanismi che regolano il processo di riparazione e di rigenerazione tissutale, pongono oggi le basi per una nuova cultura che diffonde ed effonde la necessit? di un diverso metodo di inquadramento e di cura del paziente e del mondo che lo circonda, valido per ogni forma di disabilit?. Understanding the etiopathogenetic mechanisms of chronic skin, mucosal and cartilage lesions, as well as the scientific approach to the mechanisms that regulate the process of tissue repair and regeneration, today lay the foundations for a new culture that spreads and spreads the need? of a different method of classification and care of the patient and the world around him, valid for all forms of disability.
La Medicina Rigenerativa per definizione ? la branca della medicina che si occupa di riprodurre i processi fisiologici della rigenerazione tissutale, utilizzando terapie cellulari, tessuti ingegnerizzati e sostanze biologiche, capaci di mimare gli stessi processi rigenerativi sia per applicazione topica, sia per via sistemica. Regenerative Medicine by definition? the branch of medicine that deals with reproducing the physiological processes of tissue regeneration, using cell therapies, engineered tissues and biological substances, capable of mimicking the same regenerative processes both for topical and systemic application.
Il processo di rigenerazione tissutale si evolve in tre fasi ben definite, che coincidono anche con i campi di azione di una terapia cellulare, di un dispositivo medico e di un tessuto ingegnerizzato destinato ad innescare o determinare una risposta rigenerativa. La capacit? diretta o indiretta di modulare, in senso pro-infiammatorio prima e antinfiammatorio dopo, il processo che coinvolge sostanze umorali (fattori di crescita, ormoni, citochine, neuropeptidi e simili) e cellulari (macrofagi, fibroblasti, cheratinociti), ? la prima fase del processo infiammatorio, che si realizza contemporaneamente alla modulazione della proliferazione cellulare e alla modulazione del rimodellamento strutturale della ECM (Extra Cellular Matrix). The tissue regeneration process evolves in three well-defined phases, which also coincide with the fields of action of a cell therapy, a medical device and an engineered tissue intended to trigger or determine a regenerative response. The capacity? directly or indirectly to modulate, firstly pro-inflammatory and then anti-inflammatory, the process involving humoral substances (growth factors, hormones, cytokines, neuropeptides and the like) and cellular substances (macrophages, fibroblasts, keratinocytes), ? the first phase of the inflammatory process, which occurs simultaneously with the modulation of cell proliferation and the modulation of the structural remodeling of the ECM (Extra Cellular Matrix).
Le reviews pongono l?accento sulla causa, sempre pi? identificata e conosciuta delle lesioni cutaneo e mucose croniche, rappresentata dall?infiammazione patologica non risolta e cronica, alimentata e che alimenta i processi umorali e cellulari, diversi da quelli fisiologici e che, per vari motivi biochimici, non tendono alla normale evoluzione fisiologica di spegnimento e di riparazione della lesione. The reviews put the emphasis on the cause, more and more? identified and known chronic cutaneous and mucous membrane lesions, represented by the unresolved and chronic pathological inflammation, fed and which feeds the humoral and cellular processes, different from the physiological ones and which, for various biochemical reasons, do not tend towards the normal physiological evolution of extinction and wound repair.
Al di l? delle cause eziologiche delle lesioni cutanee e delle lesioni mucose, la flogosi cronica unitamente alle relative concause (ipossia tissutale, aging cellulare, infezioni, alterazioni del pH, ecc.), condiziona la mancata guarigione. beyond of the etiological causes of skin lesions and mucous lesions, chronic inflammation together with the related causes (tissue hypoxia, cellular aging, infections, pH alterations, etc.), conditions the lack of healing.
Nella personale esperienza del Centro di Medicina Rigenerativa presso Humanitas Castellanza (Varese), con inizio dell?attivit? clinica nella met? del 2015 si ? riscontrata la seguente incidenza delle patologie a carico dei tessuti vascolari, connettivi e della cute: In the personal experience of the Regenerative Medicine Center at Humanitas Castellanza (Varese), with the beginning of the activity? clinic in the middle from 2015, yes? the following incidence of pathologies affecting the vascular, connective and skin tissues was found:
Costituisce lo scopo principale della presente invenzione quello di risolvere il problema della lesione cutaneo?mucosa nel modo pi? completo possibile e che, pur nel rispetto delle linee guida internazionali per la gestione della detersione profonda della lesione, del pH dell?ambiente lesionale e delle infezioni, permetta di modulare il processo antiinfiammatorio (approccio locoregionale, topico e sistemico) e rigenerativo, con una soluzione capace di sfruttare dei processi complementari e sinergici per il trattamento delle lesioni cutanee, mucosali e cartilaginee croniche, migliorativi rispetto ai risultati offerti dalle sostanze che fanno parte della composizione dell?invenzione, quando prese isolatamente. The main purpose of the present invention is to solve the problem of skin?mucosal lesion in the most efficient way? complete as possible and which, while complying with the international guidelines for the management of deep wound cleansing, the pH of the wound environment and infections, allows to modulate the anti-inflammatory process (locoregional, topical and systemic approach) and regenerative, with a solution capable of exploiting complementary and synergistic processes for the treatment of chronic skin, mucosal and cartilaginous lesions, improving on the results offered by the substances which form part of the composition of the invention, when taken in isolation.
Questo ed altri scopi sono raggiunti con la composizione della rivendicazione 1. Dei preferiti modi per realizzare l?invenzione risultano dalle restanti rivendicazioni. This and other objects are achieved with the composition of claim 1. Preferred ways of carrying out the invention result from the remaining claims.
Una delle molecole impiegate nella composizione dell?invenzione ? costituita dai derivati dell?acido ialuronico, come per esempio lo ialuronato di sodio o gli ialuronati composti con sulfamidici o aminoacidi, o glicosamminoglicano, glicoproteina, cheratina, collagene, e loro miscele. One of the molecules used in the composition of the invention ? made up of hyaluronic acid derivatives, such as for example sodium hyaluronate or hyaluronates composed with sulfonamides or amino acids, or glycosaminoglycan, glycoprotein, keratin, collagen, and mixtures thereof.
Con ?glicosamminoglicano? si intendono condroitin solfato, dermatan solfato, cheratan solfato, eparina, eparan solfato, o loro miscele. With ?glycosaminoglycan? means chondroitin sulfate, dermatan sulfate, keratan sulfate, heparin, heparan sulfate, or mixtures thereof.
Con ?glicoproteina? si intendono mucoproteina, integrina, fibronectina, laminina, vitronectina, trombospondina, tenascina, entactina, nefronectina, fibrinogeno, undulina, o loro miscele. With ?glycoprotein? mean mucoprotein, integrin, fibronectin, laminin, vitronectin, thrombospondin, tenascin, entactin, nephronectin, fibrinogen, undulin, or mixtures thereof.
Come si pu? apprezzare, la molecola naturale nella composizione della presente invenzione ? tale in quanto costituita da componenti che si trovano naturalmente nella matrice extracellulare, offrendo quindi completa biocompatibilit? nonch? un ruolo attivo nella idratazione dei tessuti danneggiati e nella loro rigenerazione. How can you? appreciate, the natural molecule in the composition of the present invention ? such as it is made up of components that are found naturally in the extracellular matrix, thus offering complete biocompatibility? as well as an active role in the hydration of damaged tissues and in their regeneration.
L?acido ialuronico ? un disaccaride naturale formato da due monosaccaridi, l?acido D-glucuronico e l?N-acetil-D-glicosammina. In media il corpo umano contiene circa 15 grammi di acido ialuronico, dei quali la met? (7-8 grammi) si trovano nella pelle. L?acido ialuronico ? altamente tollerato, perch? non presenta specificit? di organo o di specie e rappresenta un candidato ideale per creare volume nei tessuti molli e nella pelle o nelle mucose. Tuttavia, specialmente nella pelle, la sua emivita ? piuttosto limitata e dura meno di 24 ore. Hyaluronic acid? a natural disaccharide formed by two monosaccharides, D-glucuronic acid and N-acetyl-D-glycosamine. On average, the human body contains about 15 grams of hyaluronic acid, half of which is (7-8 grams) are found in the skin. Hyaluronic acid? highly tolerated, why? has no specificity? organ or species and is an ideal candidate for creating volume in soft tissue and skin or mucous membranes. However, especially in the skin, its half-life is quite limited and lasts less than 24 hours.
L?apporto di acido ialuronico non altera, ma stimola la funzionalit? dei fibroblasti, la sintesi del collagene e delle fibrille di elastina, cos? come le altre componenti della matrice extracellulare. Il meccanismo d?azione ? associato all?elevata idrofilia. L?acido ialuronico attrae infatti molta acqua e gi? piccole quantit? possono occupare un grande volume quando l?acqua ? spinta nella matrice di acido ialuronico. The intake of hyaluronic acid does not alter, but stimulates the functionality of fibroblasts, the synthesis of collagen and elastin fibrils, so? like the other components of the extracellular matrix. The mechanism of action? associated with high hydrophilicity. In fact, hyaluronic acid attracts a lot of water and already? small quantities? can occupy a large volume when the water? thrust into the hyaluronic acid matrix.
L?osservazione sulle caratteristiche dell?acido ialuronico utilizzato pone le basi sul peso molecolare e sul raggio di girazione delle molecole di acido ialuronico, testimoni di una attivit? di apporto e rilascio di acqua biologica ai tessuti trattati e all?organismo intero e alle possibili integrazioni molecolari con molecole che ne potenziano non solo l?effetto idrodinamico, ma anche anti radicali liberi dell?ossigeno (effetto scavenger). The observation on the characteristics of the hyaluronic acid used lays the foundations on the molecular weight and on the gyration radius of the hyaluronic acid molecules, witnesses of an activity? of supply and release of biological water to the treated tissues and to the whole organism and to the possible molecular integrations with molecules which enhance not only the hydrodynamic effect, but also anti-oxygen free radicals (scavenger effect).
L?altra molecola impiegata in combinazione con l?acido ialuronico nella composizione dell?invenzione ? costituita dalla carcinina di formula: The other molecule used in combination with hyaluronic acid in the composition of the invention is? made up of the carcinine of the formula:
La Carcinina non ? solo un prodotto di carnosina sintetico e modificato, ma ? anche una sostanza naturale. Nel 1975 Arnould e Frantz isolarono la ?-alanil-istamina dal cuore di Carcinus maenas (granchio verde, granchio rabbioso) e gli diedero quindi il nome di ?Carcinina?. La quantit? trovata era di circa 3 mmol (Arnould & Tank). Arnould ha dimostrato che la carcinina ? stata sintetizzata da Carcinus dall'istidina, che viene prima decarbossilata in istamina e poi accoppiata alla beta-alanina per formare la carcinina. Carcinina isn't it? just a synthetic and modified carnosine product, but ? also a natural substance. In 1975 Arnould and Frantz isolated ?-alanyl-histamine from the heart of Carcinus maenas (green crab, rabid crab) and then gave it the name ?Carcinina?. The quantity? found was about 3 mmol (Arnould & Tank). Arnould demonstrated that carcinine ? was synthesized by Carcinus from histidine, which is first decarboxylated to histamine and then coupled to beta-alanine to form carcinine.
La carcinina agisce su molti dei meccanismi dell'invecchiamento cutaneo: possiede infatti spiccate propriet? antiossidanti. Pu? ridurre gli idroperossidi degli acidi grassi (effetto simile alla perossidasi lipidica), eliminare i radicali liberi idrofili (effetto scavenger) e legare alcune aldeidi che sono tossiche per le cellule. Nel processo della riduzione degli idroperossidi degli acidi grassi la carcinina agisce a livello della membrana cellulare, dove lo stress ossidativo pu? indurre la perossidazione dei fosfolipidi. Gli analoghi della carnosina come N-acetilcarnosina o carcinina hanno un effetto simile alla perossidasi lipidica che ? stato dimostrato nel 1994 dal team di Babizhayev (Babizhayev et al, 1994). Questi composti riducono gli idroperossidi lipidici (LOOH) ai corrispondenti alcoli non tossici (LOH). Come effetto Scavenger di radicali liberi idrofili (effetto scavenger) la carcinina ha un meccanismo di azione elettivo come l?A.I. Un effetto scavenging riflette la capacit? di un composto di legare i radicali che sono pi? reattivi di s? stesso, e quindi pi? instabili, diventando di per s? un radicale stabile e meno reattivo. The carcinina acts on many of the mechanisms of skin aging: in fact, it has marked properties antioxidants. Can? reduce hydroperoxides of fatty acids (effect similar to lipid peroxidase), eliminate hydrophilic free radicals (scavenger effect) and bind some aldehydes which are toxic to cells. In the process of the reduction of hydroperoxides of fatty acids, carcinine acts at the level of the cell membrane, where oxidative stress can induce peroxidation of phospholipids. Carnosine analogues such as N-acetylcarnosine or carcinine have a similar effect to lipid peroxidase which is was demonstrated in 1994 by Babizhayev's team (Babizhayev et al, 1994). These compounds reduce lipid hydroperoxides (LOOH) to the corresponding non-toxic alcohols (LOH). As a scavenger effect of hydrophilic free radicals (scavenger effect), carcinine has an elective mechanism of action like A.I. A scavenging effect reflects the ability? of a compound to bind the radicals that are pi? reactive of s? same, and therefore more? unstable, becoming by itself? a stable and less reactive radical.
Gli pseudodipeptidi, in particolare la carcinina, sono composti contenenti un nucleo di imidazolo che ha attivit? antiossidante intrappolando il radicale idrossile. Pseudodipeptides, especially carcinine, are compounds containing an imidazole nucleus which has antioxidant by trapping the hydroxyl radical.
Nella sostanza, quindi, l'invecchiamento cutaneo ? un processo che ha una forte relazione con la degradazione della matrice extracellulare, che finisce per modificare le propriet? fisiche e fisiologiche della pelle ( 2011). Agenti esterni ed interni possono accelerare l'invecchiamento, come l'accumulo di prodotti tossici del metabolismo stesso. La glicazione prodotta per via endogena o i prodotti finali della glicazione avanzata (AGE) alterano la funzione di innumerevoli tessuti e il loro accumulo ? stato associato all'invecchiamento della pelle ( , 2015). L'HbA1C ? formato da una reazione di glicazione tra l'emoglobina (proteina) e uno zucchero riducente, solitamente il glucosio ( 2009). Alcuni studi hanno correlato l'aumento di HbA1c con l'invecchiamento ( In essence, therefore, skin aging? a process that has a strong relationship with the degradation of the extracellular matrix, which ends up modifying the properties? physical and physiological characteristics of the skin ( 2011). External and internal agents can accelerate aging, such as the accumulation of toxic products of the metabolism itself. Does endogenously produced glycation or advanced glycation end products (AGEs) alter countless tissue function and accumulation? been associated with skin aging ( , 2015). HbA1C? formed by a glycation reaction between hemoglobin (protein) and a reducing sugar, usually glucose ( 2009). Some studies have correlated the increase in HbA1c with aging (
2014) e l'accumulo di AGE nella pelle ( 2008). 2014) and the accumulation of AGEs in the skin ( 2008).
Pertanto, sostanze in grado di prevenire o inibire la formazione di AGE hanno generato un notevole interesse come agente antiaging. Sotto questo profilo la carcinina ? un metabolita della carnosina, in particolare un dipeptide con potenziale attivit? antiglicantionica ( , 2012). Therefore, substances capable of preventing or inhibiting the formation of AGEs have generated considerable interest as an antiaging agent. From this point of view, the carcinina ? a metabolite of carnosine, in particular a dipeptide with potential activity? antiglycanthionic ( , 2012).
Gli inventori hanno ora sorprendentemente scoperto che, combinando la carcinina con acido ialuronico oppure uno o pi? derivati dell?acido ialuronico, si ottiene una composizione per somministrazione orale o topica, particolarmente efficace nel trattamento delle lesioni cutanee, mucosali e cartilaginee croniche. The inventors have now surprisingly discovered that by combining carcinine with hyaluronic acid or one or more derivatives of hyaluronic acid, a composition is obtained for oral or topical administration, particularly effective in the treatment of chronic skin, mucosal and cartilaginous lesions.
Adatti per l'invenzione sono in particolare i sali di sodio, potassio e calcio di acido ialuronico, nonch? gli ialuronati composti con sulfamidici o aminoacidi, in combinazione con carcinina, eventualmente anche in presenza di una molecola naturale scelta tra glicosamminoglicano, glicoproteina, cheratina, collagene e loro miscele pi?, eventualmente, anche almeno un agente viscosizzante, in cui il rapporto in peso tra carcinina e acido ialuronico e/o derivati dell?acido ialuronico ? compreso tra 1/20 e 4/1. Suitable for the invention are in particular the sodium, potassium and calcium salts of hyaluronic acid, as well as hyaluronates composed of sulfonamides or amino acids, in combination with carcinine, possibly also in the presence of a natural molecule selected from glycosaminoglycan, glycoprotein, keratin, collagen and mixtures thereof plus, possibly, also at least one viscosifying agent, in which the ratio by weight between carcinine and hyaluronic acid and/or hyaluronic acid derivatives ? between 1/20 and 4/1.
In particolare per la somministrazione orale, la composizione dell?invenzione si contraddistingue per il fatto di presentare un rapporto in peso tra carcinina e acido ialuronico e/o derivati dell?acido ialuronico compreso tra 1/20 e 1/5, di preferenza tra 1/10 e 1/5. In particular for oral administration, the composition of the invention is characterized by the fact that it has a weight ratio between carcinine and hyaluronic acid and/or hyaluronic acid derivatives between 1/20 and 1/5, preferably between 1 /10 and 1/5.
Di preferenza la composizione dell'invenzione per somministrazione orale ? in forma di polvere confezionata in perle, capsule, pastiglie e simili, che comprende una miscela di gomma. Preferably the composition of the invention for oral administration? in powder form packaged in pearls, capsules, lozenges and the like, comprising a rubber blend.
Infatti si ? osservato che tale miscela offre una ottimale combinazione di aspetti vantaggiosi, tra i quali un adeguato tempo di transito esofageo, di fatto paragonabile a quello di un semplice bolo alimentare, una adeguata formazione di film sulle mucose ed al contempo una facile deglutibilit? da parte del paziente. Indeed yes ? observed that this mixture offers an optimal combination of advantageous aspects, including an adequate esophageal transit time, in fact comparable to that of a simple food bolus, an adequate film formation on the mucous membranes and at the same time easy swallowability. by the patient.
Per la somministrazione topica sono adatti dei rapporti in peso tra carcinina e acido ialuronico e/o derivati dell?acido ialuronico compresi tra 1/4 e 4/1, di preferenza tra 1/3 e 3/1. Per l?uso topico, gli ingredienti sono entrambi portati nella forma di gel o di creme o cerotti a rilascio prolungato. For topical administration, weight ratios between carcinine and hyaluronic acid and/or hyaluronic acid derivatives of between 1/4 and 4/1, preferably between 1/3 and 3/1, are suitable. For topical use, the ingredients are either brought in the form of gels or extended-release creams or patches.
Preferibilmente detto acido ialuronico o suo sale ? in concentrazione fino a 0,5% in peso, sul peso della composizione, pi? preferibilmente fino a 0,3% in peso. Particolarmente preferite sono le composizioni in cui detto acido ialuronico o suo sale ? in concentrazione di 0,05-0,2% in peso, sul peso della composizione. Preferably called hyaluronic acid or its salt? in concentration up to 0.5% by weight, on the weight of the composition, more? preferably up to 0.3% by weight. Particularly preferred are the compositions in which said hyaluronic acid or its salt ? in a concentration of 0.05-0.2% by weight, based on the weight of the composition.
Preferibilmente la molecola naturale costituita da carcinina ? in concentrazione fino a 0,5% in peso, sul peso della composizione, pi? preferibilmente fino a 0,3% in peso. Particolarmente preferite sono le composizioni in cui detta molecola naturale ? in concentrazione di 0,05-0,2% in peso, sul peso della composizione. Preferably the natural molecule constituted by carcinine ? in concentration up to 0.5% by weight, on the weight of the composition, more? preferably up to 0.3% by weight. Particularly preferred are the compositions in which said natural molecule ? in a concentration of 0.05-0.2% by weight, based on the weight of the composition.
Alla composizione di carcinina e acido ialuronico e/o suoi derivati ? possibile aggiungere degli additivi, come per esempio almeno un agente viscosizzante come la gomma xantana, gomma guar, gomma di tara, gomma di semi di carruba, gomma di fieno greco, gomma arabica, acido alginico, sodio alginato, glicole propilenico alginato, calcio carbossimetilcellulosa, sodio carbossimetilcellulosa, etilcellulosa, gelatina, etilcellulosa, idrossietilcellulosa, idrossipropilcellulosa, polidestrosio, carragenina, metilcellulosa, saccarosio, sorbitolo, xilitolo, destrosio, fruttosio, maltitolo, alginato di sodio, gomma adragante, pectina, agar-agar, carbossipolimetilene, idrossipropilmetilcellulosa, o loro miscele. To the composition of carcinine and hyaluronic acid and/or its derivatives? It is possible to add additives, such as at least one viscosifying agent such as xanthan gum, guar gum, tara gum, locust bean gum, fenugreek gum, gum arabic, alginic acid, sodium alginate, propylene glycol alginate, calcium carboxymethyl cellulose , sodium carboxymethylcellulose, ethylcellulose, gelatin, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polydextrose, carrageenan, methylcellulose, sucrose, sorbitol, xylitol, dextrose, fructose, maltitol, sodium alginate, gum tragacanth, pectin, agar-agar, carboxypolymethylene, hydroxypropylmethylcellulose, or their blends.
Pi? preferibilmente, detto almeno un agente viscosizzante ? gomma xantana, gomma guar, gomma di tara, gomma di semi di carruba, gomma di fieno greco, gomma arabica, gomma adragante, carragenina, o loro miscele. Si tratta infatti di gomme naturali, che per le loro caratteristiche chimiche presentano una elevata affinit? con le proteine della mucosa orale, esofago/gastrica, rettale e non solo. Pi? preferably, called at least one viscosifying agent ? xanthan gum, guar gum, tara gum, locust bean gum, fenugreek gum, gum arabic, gum tragacanth, carrageenan, or mixtures thereof. In fact, they are natural rubbers, which due to their chemical characteristics have a high affinity with the proteins of the oral mucosa, esophagus / gastric, rectal and beyond.
Nel seguito si forniscono alcuni esempi della composizione dell?invenzione in dose unitaria. Some examples of the composition of the invention in unit dose are given below.
Esempio 1 Example 1
- fino a 50 mg di acido ialuronico o suo sale, - up to 50 mg of hyaluronic acid or its salt,
- fino a 20 mg di carcinina, - up to 20 mg of carcinine,
- fino a 50 mg di molecola naturale, - up to 50 mg of natural molecule,
- fino a 500 mg di almeno un agente viscosizzante, ed - up to 500 mg of at least one viscosifying agent, ed
- acqua. - waterfall.
Esempio 2 Example 2
- fino a 30 mg di acido ialuronico o suo sale, - up to 30 mg of hyaluronic acid or its salt,
- fino a 10 mg di carcinina, - up to 10 mg of carcinine,
- fino a 30 mg di molecola naturale, - up to 30 mg of natural molecule,
- fino a 250 mg di almeno un agente viscosizzante, ed - up to 250 mg of at least one viscosifying agent, ed
- acqua. - waterfall.
Esempio 3 Example 3
- 10-20 mg di acido ialuronico o suo sale, - 10-20 mg of hyaluronic acid or its salt,
- 05-10 mg di Carcinina, - 05-10 mg of Carcinine,
- 10-20 mg di molecola naturale, - 10-20 mg of natural molecule,
- 100-200 mg di almeno un agente viscosizzante, ed - 100-200 mg of at least one viscosifying agent, ed
- acqua. - waterfall.
Esempio 4 Example 4
- 10-20 mg di acido ialuronico o suo sale, - 10-20 mg of hyaluronic acid or its salt,
- 05-10 mg di Carcinina - 05-10 mg of Carcinine
- 10-20 mg di molecola naturale, - 10-20 mg of natural molecule,
- 100-200 mg di una miscela di componenti viscosizzanti o ristrutturanti, ed - 100-200 mg of a mixture of viscosifying or restructuring components, ed
- acqua. - waterfall.
Esempio 5 Example 5
- 10-20 mg di acido ialuronico o suo sale, - 10-20 mg of hyaluronic acid or its salt,
- 05-10 mg di Carcinina, - 05-10 mg of Carcinine,
- 10-20 mg di molecola naturale, - 10-20 mg of natural molecule,
- 80-100 mg di altro eccipiente viscosizzante o rigenerante - 80-100 mg of other viscosifying or regenerating excipient
- acqua. - waterfall.
La composizione della presente invenzione pu? essere preparata mediante metodi noti nella tecnica. The composition of the present invention can be prepared by methods known in the art.
Nella tabella che segue gli effetti della composizione dell?invenzione dell?Esempio 5 sono stati sperimentati, in un periodo di osservazione di 8 settimane, su 20 pazienti di sesso a prevalenza femminile con et? media di 68 anni, affetti da dermopatie multiformi con associate lesioni vascolari, da connettivopatie e da decubito, messi a confronto con quelli raggiungibili attraverso l?impiego dei singoli componenti carcinina e acido ialuronico che la compongono. Il criterio di valutazione ? definito in termini di riduzione del diametro delle lesioni dal 20 al 50% entro 8 settimane In the table that follows, the effects of the composition of the invention of Example 5 were tested, in an observation period of 8 weeks, on 20 patients of predominantly female sex with an age of 10 years. average of 68 years, suffering from multiform skin diseases with associated vascular lesions, connective tissue diseases and decubitus, compared with those achievable through the use of the single components carcinine and hyaluronic acid that compose it. The evaluation criterion? defined in terms of lesion diameter reduction of 20 to 50% within 8 weeks
Da questa tabella si pu? apprezzare che l?utilizzo della composizione dell'invenzione permette una stimolazione positiva del tessuto di riparazione, con risultati variabili sullo stato delle lesioni per l?intervento di multifattorialit?. From this table you can appreciate that the use of the composition of the invention allows a positive stimulation of the repair tissue, with variable results on the state of the lesions for the multifactorial intervention.
L?associazione di un derivato di acido ialuronico con Carcinina consente di raggiungere un miglioramento di oltre il 20% del processo di guarigione, da cui si dimostra che l'unione delle due molecole secondo l'invenzione, affini per struttura e azione, realizza un agglomerato molecolare dotato di una attivit? potenziata rispetto alla semplice azione singola. The association of a derivative of hyaluronic acid with Carcinina allows to achieve an improvement of over 20% of the healing process, from which it is demonstrated that the union of the two molecules according to the invention, similar in structure and action, achieves a molecular agglomeration endowed with an activity? enhanced compared to the simple single action.
Claims (11)
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