ITMI20102308A1 - TOPIC COMPOSITIONS FOR THE CURE OF INJURIES OF THE ORAL CABLE - Google Patents
TOPIC COMPOSITIONS FOR THE CURE OF INJURIES OF THE ORAL CABLE Download PDFInfo
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- ITMI20102308A1 ITMI20102308A1 IT002308A ITMI20102308A ITMI20102308A1 IT MI20102308 A1 ITMI20102308 A1 IT MI20102308A1 IT 002308 A IT002308 A IT 002308A IT MI20102308 A ITMI20102308 A IT MI20102308A IT MI20102308 A1 ITMI20102308 A1 IT MI20102308A1
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- Prior art keywords
- spermidine
- composition according
- oral
- gel
- treatment
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- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0063—Periodont
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/16—Cyclodextrin; Derivatives thereof
Description
D E S C R I Z I O N E DESCRIPTION
COMPOSIZIONI TOPICHE PER LA CURA DELLE LESIONI DEL CAVO ORALE TOPICAL COMPOSITIONS FOR THE TREATMENT OF INJURIES OF THE ORAL CABLE
CAMPO DELL’INVENZIONE FIELD OF INVENTION
Composizioni odontostomatologiche per la cura delle affezioni del cavo orale comprendenti spermidina tal quale o in forma complessata. Odontostomatological compositions for the treatment of diseases of the oral cavity comprising spermidine as it is or in complexed form.
STATO DELL’ARTE STATE OF THE ART
Le forme infiammatorie ed infettive del cavo orale con coinvolgimento di mucose e gengive sono ampiamente diffuse nella popolazione a diversi livelli sociali, di età e di genere. Inflammatory and infectious forms of the oral cavity with involvement of mucous membranes and gums are widespread in the population at different social, age and gender levels.
La mucosite e le ulcere aftose sono patologie multifattoriali con assottigliamento epiteliale associato a intenso eritema, ulcera, dolore, sanguinamento e aumento del rischio infettivo. La stomatite à ̈ un’infiammazione diffusa delle mucose orali con eziologie diverse: infezioni, malattie sistemiche, stessogene o da agenti fisici. Infezioni collegate sono sostenute da batteri (es. Streptococchi), da virus (es. Herpes) o da funghi e lieviti (es. Candida spp), favorite dall’iposalivazione. Ulteriori cause di stomatite di tipo fisico sono causate da denti con bordi incongrui, apparecchi ortodontici, protesi dentali imprecise, bruxismo, morsicatura, abuso di alcol, fumo, spezie e cibi caldi, o stressogene. La sensibilizzazione verso farmaci, coloranti, metalli, dentifrici e collutori causa la sindrome di Stevens-Johnson, che rientra nelle stomatiti. La definizione mucosità si sovrappone sovente a quella di stomatite, dove la prima definisce più specificamente un infiammazione non-infettiva a carico della mucosa del cavo orale. Mucositis and aphthous ulcers are multifactorial diseases with epithelial thinning associated with intense erythema, ulcer, pain, bleeding and increased infectious risk. Stomatitis is a diffuse inflammation of the oral mucous membranes with different etiologies: infections, systemic, stress or physical diseases. Related infections are caused by bacteria (eg Streptococci), viruses (eg Herpes) or fungi and yeasts (eg Candida spp), favored by hyposalivation. Additional causes of physical stomatitis are caused by teeth with incongruous edges, orthodontic appliances, inaccurate dental prostheses, bruxism, biting, alcohol abuse, smoking, spices and hot foods, or stressors. Sensitization to drugs, dyes, metals, toothpastes and mouthwashes causes Stevens-Johnson syndrome, which is part of stomatitis. The definition of mucosity often overlaps with that of stomatitis, where the first defines more specifically a non-infectious inflammation of the mucous membrane of the oral cavity.
Nelle manifestazioni cliniche delle mucositi ritroviamo inizialmente atrofia delle mucose, quindi intenso eritema che evolve in ulcerazioni; le sedi più colpite sono le mucose non cheratinizzate: pavimento orale, mucose gengivali, mucose labiali e lingua. La mucosite orale à ̈ inoltre un effetto collaterale della chemioterapia e della radioterapia, diffusa nel 30-40% dei pazienti sottoposti chemio-radio terapia e fino all’80% dei pazienti sottoposti a trapianto di cellule staminali ematopoietiche. Gli effetti citotossici dei farmaci chemioterapici e delle radiazioni nei confronti dei tessuti ad elevato turnover, come l’epitelio orale sono responsabili di questa manifestazione che compromette in maniera importante la qualità di vita e può interferire con la gestione della malattia primaria. In the clinical manifestations of mucositis we initially find atrophy of the mucous membranes, then intense erythema which evolves into ulcerations; the sites most affected are the non-keratinized mucous membranes: oral floor, gingival mucosa, labial mucosa and tongue. Oral mucositis is also a side effect of chemotherapy and radiotherapy, widespread in 30-40% of patients undergoing chemo-radio therapy and up to 80% of patients undergoing haematopoietic stem cell transplantation. The cytotoxic effects of chemotherapy drugs and radiation on high turnover tissues, such as the oral epithelium, are responsible for this manifestation which significantly compromises the quality of life and can interfere with the management of the primary disease.
La gengivite à ̈ la caratteristica infiammazione reversibile delle gengive, causata solitamente dalla placca batterica qualora trascurata. La stomatite ulcerativa à ̈ una forma acuta di gengivite con la formazione di ulcerazioni evidenti, molto dolorosa ed a volte curabile con terapia antibiotica e sciacqui con acqua ossigenata. Gingivitis is the characteristic reversible inflammation of the gums, usually caused by bacterial plaque if neglected. Ulcerative stomatitis is an acute form of gingivitis with the formation of evident ulcerations, very painful and sometimes treatable with antibiotic therapy and rinsing with hydrogen peroxide.
Nelle farmacie sono disponibili vari prodotti per il trattamento di stomatiti, afte e gengiviti, come illustrato da Pomponio G. in INFODENT, 2009 (4):37-9. La fonte cita in particolare: Aftamedâ„¢ (Bioplax Ltd) a base di sodio jaluronato; la linea Alovexâ„¢ (Ricordati) contenente aloe vera, jaluronato e acido glicirretinico; Collutorio Bier (Bier Farmaceutici) con clorexidina 0,20% e aloe vera 0,5%; OralMedicâ„¢ (Epien Medical) con l’ativo HybenXâ„¢; e Xentafidâ„¢ (Fidia Farmaceutici) con benzidamina jaluronato 0,13%. Various products are available in pharmacies for the treatment of stomatitis, canker sores and gingivitis, as illustrated by Pomponio G. in INFODENT, 2009 (4): 37-9. The source mentions in particular: Aftamedâ „¢ (Bioplax Ltd) based on sodium hyaluronate; the Alovexâ „¢ (Remember) line containing aloe vera, hyaluronate and glycyrrhetinic acid; Bier mouthwash (Bier Farmaceutici) with 0,20% chlorhexidine and 0,5% aloe vera; OralMedicâ „¢ (Epien Medical) with the active HybenXâ„ ¢; and Xentafidâ „¢ (Fidia Farmaceutici) with 0.13% benzydamine hyaluronate.
Se trascurata e non curata la gengiviteevolve in periodontite con distruzione del’osso fino a perdita del dente. La parodontite o periodontite à ̈ la conseguenza di gengiviti non curate che diffonde ai tessuti parodontali, legamenti e ossa che sostengono i denti con rischio di caduta. Il trattamento di elezione per le periodontiti sono i peptidi odontogenetici tipoEmdogainâ„¢. Tuttavia à ̈ ancora sentita la necessità di ottimizzare le proprietà terapeutiche di preparati attualmente utilizzati per le affezioni della mucosa orale. If neglected and untreated, gingivitis evolves into periodontitis with destruction of the bone and the loss of the tooth. Periodontitis or periodontitis is the consequence of untreated gingivitis that spreads to the periodontal tissues, ligaments and bones that support the teeth with the risk of falling. The treatment of choice for periodontitis is Emdogainâ „¢ type odontogenic peptides. However, the need is still felt to optimize the therapeutic properties of preparations currently used for affections of the oral mucosa.
Ad esempio studi recenti rilevano che le componenti infiammatorie ed infettive sono in grado di attivare le collagenasi nella mucosa. La loro azione degrada la matrice connettivale e favorisce l’ulterioredecorso erosivo-infiammatorio (Salvi GE e coll. J Clin Periodontol. For example, recent studies show that the inflammatory and infectious components are able to activate collagenases in the mucosa. Their action degrades the connective tissue matrix and favors the further erosive-inflammatory course (Salvi GE and coll. J Clin Periodontol.
2010;37(1):9-16) con aumento di MMP-3: L’aumentata espressione genica di MMP-2 e MMP-9 si correla con la cinetica di reclutamento di macrofago e neutrofili (Lorencini M e coll. Histol Histopathol. 2009;24(2):157-66). Nell’infezione orale sono stati identificati alcuni patogeni responsabili del ’ativazione di MMP-8 e MMP-9 quale risposta immunomediata a livello odontostomatologiche (Ramseier CA e coll. J Periodontol.2009;80(3):436-46). 2010; 37 (1): 9-16) with increased MMP-3: The increased gene expression of MMP-2 and MMP-9 correlates with the recruitment kinetics of macrophages and neutrophils (Lorencini M et al. Histol Histopathol. 2009; 24 (2): 157-66). In the oral infection some pathogens have been identified responsible for the activation of MMP-8 and MMP-9 as an immune-mediated response at the odontostomatological level (Ramseier CA and coll. J Periodontol. 2009; 80 (3): 436-46) .
In questo senso abbiamo considerato le attività biologiche della spermidina, metabolita ubiquitario, per un efficace ed innovativo trattamento delle affezioni odontostomatologiche. L’analisi dela leteratura,tuttavia, non forniva alcuna indicazioni utile, cioà ̈ univocamente utilizzabile in tal senso. In this sense we have considered the biological activities of spermidine, a ubiquitous metabolite, for an effective and innovative treatment of odontostomatological diseases. The analysis of the literature, however, did not provide any useful information, that is, univocally usable in this sense.
Per esempio l’atività dela spermidina nei confronti delle collagenasi à ̈ assai controversa. Un primo lavoro evidenziava l’attivazione delle MMP in un classico modello angiogenico (Takigawa M e coll. Biochem Biophys Res Commun. 1990; 28; 171(3):1264-71). Al contrario altri studi correlano deplezione di poliammine con l’incremento del ’espressione di MMP-1 e -2, ad es. in fibroblasti gengivali (Stabellini G e coll. J Periodontol. 2005; 76(3):443-9) o in cellule renali canine (Prunotto M e coll. Lab Invest.2010; 90(6):929-39). Gli studi citati disorientano sia per risultati che per il metodo, in quanto non sono misurate l’azione direta ma gli efeti di sostanze interferenti con il metabolismo della spermidina. Ugualmente controverse sono la capacità della spermidina di favorire la crescita cellulare, che risulterebbero utili nella riparazione di mucose e tessuti orali affetti da lesioni. Difatti parte della letteratura indica un ruolo positivo pro-mitotico e rigenerativo della spermidina; mentre un’altrettanto se non superiore mole di ricerche segnala viceversa un comportamento pro-apoptotico e persino citotossico. A questo scopo si citano i riferimenti dal numero 13 al 29 citati in bibliografa da Kaneko S e coll. in Invest Ophthalmol Vis Sci.2007; 48(1):455-63. A fine di sviluppare una composizione efficace e mirata al trattamento delle affezioni del cavo orale, per le quali sussiste un bisogno terapeutico fortemente sentito, risultano decisivi gli studi ed i modelli dose-attività citati nella presente applicazione. For example, the activity of spermidine against collagenases is highly controversial. A first work highlighted the activation of MMPs in a classic angiogenic model (Takigawa M et al. Biochem Biophys Res Commun. 1990; 28; 171 (3): 1264-71). On the contrary, other studies correlate polyamine depletion with the increase in the expression of MMP-1 and -2, eg. in gingival fibroblasts (Stabellini G et al. J Periodontol. 2005; 76 (3): 443-9) or in canine kidney cells (Prunotto M et al. Lab Invest. 2010; 90 (6): 929-39). The studies cited are confusing both for results and for the method, as the direct action is not measured but the effects of substances interfering with the metabolism of spermidine. Equally controversial are the ability of spermidine to promote cell growth, which would be useful in the repair of oral mucous membranes and tissues affected by lesions. In fact, part of the literature indicates a positive pro-mitotic and regenerative role of spermidine; while an equally if not greater amount of research indicates, on the contrary, a pro-apoptotic and even cytotoxic behavior. For this purpose, references from numbers 13 to 29 cited in the bibliographic by Kaneko S and coll. in Invest Ophthalmol Vis Sci. 2007; 48 (1): 455-63. In order to develop an effective and targeted composition for the treatment of diseases of the oral cavity, for which there is a strongly felt therapeutic need, the studies and dose-activity models mentioned in this application are decisive.
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
Si à ̈ sorprendentemente trovato che la spermidina à ̈ utile nel trattamento di lesioni del cavo orale. It has been surprisingly found that spermidine is useful in the treatment of oral lesions.
L’invenzione si riferisce a composizioni odontostomatologiche per la cura di affezioni della mucosa orale quali stomatiti, mucositi ed afte comprendenti spermidina quale inibitore delle collagenasi e promotore di riproliferazione dello strato mucoso-epiteliale nel cavo orale. The invention relates to odontostomatological compositions for the treatment of diseases of the oral mucosa such as stomatitis, mucositis and aphthae including spermidine as an inhibitor of collagenases and promoter of re-proliferation of the mucosal-epithelial layer in the oral cavity.
L’invenzione si riferisce inoltre a composizioni odontostomatologiche per la cura di affezioni dei tessuti molli e duri della mucosa orale quali gengiviti e periodontiti comprendenti spermidina quale attivatore della riparazione di odontoblasti e fibroblasti. The invention also relates to odontostomatological compositions for the treatment of diseases of the soft and hard tissues of the oral mucosa such as gingivitis and periodontitis including spermidine as an activator of the repair of odontoblasts and fibroblasts.
In un ambito inventivo la spermidina à ̈ utilizzata nele composizioni secondo l’invenzione a concentrazioni micro o sub-micromolari in forma salificata o di complesso supramolacolare con spermidina per il rilascio controllato a concentrazioni nanomolari della stessa. In an inventive context, spermidine is used in compositions according to the invention at micro or sub-micromolar concentrations in salified form or as a supramolacular complex with spermidine for controlled release at nanomolar concentrations of the same.
In un ulteriore ambito le composizioni per il trattamento di stomatiti, mucositi ed afte comprende inoltre altri attivi utili per la cura delle affezioni citati quali cortisonici, anestetici, biocidi, inibitori di adesione batterica e/o distruttori del biofilm. In a further context, the compositions for the treatment of stomatitis, mucositis and canker sores also comprise other active ingredients useful for the treatment of the aforementioned diseases such as cortisone drugs, anesthetics, biocides, bacterial adhesion inhibitors and / or biofilm destroyers.
In un ulteriore ambito le composizioni per il trattamento di gengiviti e periodontiti comprende inoltre uno o più peptidi odontogenetici. In a further context, the compositions for the treatment of gingivitis and periodontitis also comprise one or more odontogenic peptides.
In un ulteriore ambito le composizioni inventive comprendono inoltre un polimero mucoadesivo e/o altri composti complementari al trattamento di affezioni del cavo orale. In a further context, the inventive compositions further comprise a mucoadhesive polymer and / or other compounds complementary to the treatment of diseases of the oral cavity.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Le composizioni odontostomatologiche, cosmetiche o medicali comprendenti spermidina secondo l’invenzione risultano eficaci nel tratamento dele affezioni del cavo orale quali stomatiti, mucositi, afte, gengiviti e periodontiti. The odontostomatological, cosmetic or medical compositions comprising spermidine according to the invention are effective in treating affections of the oral cavity such as stomatitis, mucositis, canker sores, gingivitis and periodontitis.
I modelli di inibizione diretta della collagenasi e di azione stimolante-proliferativa dei fibroblasti mucosali, gengivali e/o su odontoblasti nonché un utilizzo preliminare in vivo riportati indicano per la prima volta chiaramente ed in maniera univoca l’utilità inventiva di dette composizioni. The models of direct collagenase inhibition and stimulating-proliferative action of mucosal, gingival and / or odontoblast fibroblasts as well as a preliminary in vivo use reported clearly and unambiguously indicate for the first time the inventive usefulness of said compositions.
La spermidina utilizzabile nelle composizioni inventive à ̈ la sostanza di struttura: NH2(CH2)3NH(CH2)4NH2, formula C7H19N3; alias N-(3-aminopropil)-1,4-butanediammina. La spermidina risulta essere un principio attivo facilmente incorporabile nelle formulazioni tipiche per il trattamento delle affezioni della mucosa del cavo orale e relativamente stabile, con l’accortezza di non aggiungere sostanze ossidanti quali H2O2o NaClO. Per un corretto utilizzo inventivo di questo principio attivo à ̈ importante il dosaggio locale. The spermidine usable in the inventive compositions is the structural substance: NH2 (CH2) 3NH (CH2) 4NH2, formula C7H19N3; aka N- (3-aminopropyl) -1,4-butanediamine. Spermidine is an active ingredient that can be easily incorporated into the typical formulations for the treatment of diseases of the mucous membrane of the oral cavity and is relatively stable, taking care not to add oxidizing substances such as H2O2 or NaClO. For a correct inventive use of this active ingredient, the local dosage is important.
Una composizione inventiva conterrà spermidina in forma salificata in concentrazione tra circa 200 Î1⁄4M a 2 nM (da 30 ppm a 0,3 ppb su base libera), ancora più preferibilmente compresa tra circa 20Î1⁄4M a 200 nM (da 3 ppm a 30 ppb) della composizione. An inventive composition will contain spermidine in salified form in a concentration between about 200 Î1⁄4M to 2 nM (from 30 ppm to 0.3 ppb on a free basis), even more preferably between about 20Î1⁄4M to 200 nM (from 3 ppm to 30 ppb) of the composition.
In un’ulteriore realizzazione le composizioni conteranno un complesso supramolacolare di spermidina (meglio definito di seguito) in grado di rilasciare una quantità di spermidina compresa tra 4x10<-7>e 4x10<-9>moli/ora/g di prodotto applicato. In a further embodiment, the compositions will contain a supramolacular complex of spermidine (better defined below) capable of releasing a quantity of spermidine between 4x10 <-7> and 4x10 <-9> moles / hour / g of applied product.
In questo ambito una composizione inventiva potrà contenere spermidina complessata in concentrazione 10x, cioà ̈ tra 2 mM e 20 nM (da 300 ppm a 3 ppb di base libera), preferibilmente tra circa 200Î1⁄4M a 2Î1⁄4M (da 30 ppm a 300 ppb) della composizione. In this context, an inventive composition may contain complexed spermidine in 10x concentration, i.e. between 2 mM and 20 nM (from 300 ppm to 3 ppb of free base), preferably between about 200Î1⁄4M to 2Î1⁄4M (from 30 ppm to 300 ppb) of the composition.
Nel caso di complessi supramolecolari con polimeri polianionici sono preferiti quelli con rapporti eq.anionici/eq.cationicicompresi tra 10:1 e 10<5>:1. In the case of supramolecular complexes with polyanionic polymers, those with anionic / cationic equation ratios comprised between 10: 1 and 10 <5>: 1 are preferred.
Come citato la spermidina à ̈ utilizzabile in forma salificata o di complessi supramolacolari. Esempio di forme salificate sono quelli formati da spermidina con acidi inorganici quali HCl, H2SO4, H3BO3, H3PO4, ecc., o con acidi organici quali acido acetico, metilensolfonico, ascorbico, laurico, oleico, glicolico, lattico, piruvico, mandelico, succinico, aspartico, glutamico, maleico, fumarico, malico, tartarico, ecc. In caso di utilizzo di spermidina base, i sali sono formati in situ con le sostanze a carattere acido presenti nella composizione As mentioned, spermidine can be used in salified form or in supramolacular complexes. Example of salified forms are those formed by spermidine with inorganic acids such as HCl, H2SO4, H3BO3, H3PO4, etc., or with organic acids such as acetic, methylene sulphonic, ascorbic, lauric, oleic, glycolic, lactic, pyruvic, mandelic, succinic acids, aspartic, glutamic, maleic, fumaric, malic, tartaric, etc. When using spermidine base, the salts are formed in situ with the acidic substances present in the composition
In una realizzazione i complessi supramolacolari di spermidina sono formati con polimeri polianionici, cioà ̈ polimeri anionici come carbossilati, solfati/solfonati, fosfati/fosfonati. In one embodiment the spermidine supramolacular complexes are formed with polyanionic polymers, i.e. anionic polymers such as carboxylates, sulfates / sulfonates, phosphates / phosphonates.
Detti polimeri polianionici comprendono “polimeri polianionicamente derivatizzati†, cioà ̈ privi di leganti polianionici e successivamente modificati con opportuno reattivo. Said polyanionic polymers include â € œpolymers polyanionically derivatizedâ €, ie free of polyanionic binders and subsequently modified with a suitable reagent.
Esempi di polimeri polianionico comprendono: fito/fico-polisaccaridi carbossilati come alginato, pectina e gomma xantana; endopolisaccaridi come acido ialuronico ed oligomeri (OHA); polisaccaridi semi-sintetici come carbossimetil cellulosa, crosscaramellose, carbossimetil amido, carbossimetil dextrano e carbossimetil chitosano; i carbossilati sintetici come acrilati e metacrilati in forma di omopolimeri lineari e reticolati e di copolimeri, Carbopol, polycarbophil, ecc.; ed i copolimeri metilviniletere/maleico tipo Gantrez. Examples of polyanionic polymers include: carboxylated phyto / phyco-polysaccharides such as alginate, pectin and xanthan gum; endopolysaccharides such as hyaluronic acid and oligomers (OHA); semi-synthetic polysaccharides such as carboxymethyl cellulose, crosscaramellose, carboxymethyl starch, carboxymethyl dextran and carboxymethyl chitosan; synthetic carboxylates such as acrylates and methacrylates in the form of linear and cross-linked homopolymers and copolymers, Carbopol, polycarbophil, etc .; and methylvinylether / maleic copolymers such as Gantrez.
Altri esempi sono i polimeri polianionici con gruppo solfato tra i quali i glicosoaminoglicani e fito-/fico-polisaccaridi quali carragenani, xilomannan solfato, fucoidano e fucogalactano. I complessi supramolecolari formati da polimeri polianionici con spermidina sono caratterizzati da un rapporto tra equivalenti anionici del polimero polianionico e quelli cationici della spermidina (eq.anionici/eq.cationici) compreso tra 10:1 e 10<6>:1 eq/eq. Ancor più preferibilmente detti complessi supramolecolari sono caratterizzati da un rapporto eq.anionici/eq.cationicicompreso tra 10:1 e 10<3>:1 eq/eq.. Other examples are polyanionic polymers with sulfate group including glycosaminoglycans and phyto- / phyco-polysaccharides such as carrageenans, xylomannan sulfate, fucoidan and fucogalactane. The supramolecular complexes formed by polyanionic polymers with spermidine are characterized by a ratio between the anionic equivalents of the polyanionic polymer and the cationic equivalents of the spermidine (anionic eq / eq.cationic) between 10: 1 and 10 <6>: 1 eq / eq. Even more preferably, said supramolecular complexes are characterized by an anion / eq.cation ratio comprised between 10: 1 and 10 <3>: 1 eq / eq ..
In un’altra realizzazioneinventiva i complessi supramolacolari di spermidina sono formati con ciclodestrine. In another inventive embodiment the supramolacular complexes of spermidine are formed with cyclodextrins.
Sono utilizzabili vari tipi e gradi di ciclodestrine, ad es: α-ciclodestrine, β-ciclodestrine, e γciclodestrine; derivati di β-ciclodestrina quali idrossipropil-β-ciclodestrina, β-ciclodestrina metilata random, maltosil-β-ciclodestrina, sulfobutil eter β-ciclodestrina, dimetil-βciclodestrina e simili; derivati di α-ciclodestrina quali α-ciclodestrina metilata, idrossietil-αciclodestrina, idrossipropil-α-ciclodestrina e maltosil-α-ciclodestrina; e derivati di γciclodestrina quali γ-ciclodestrina metilata, ecc. Various types and grades of cyclodextrins can be used, for example: Î ± -cyclodextrins, β-cyclodextrins, and γcyclodextrins; β-cyclodextrin derivatives such as hydroxypropyl-β-cyclodextrin, random methylated β-cyclodextrin, maltosyl-β-cyclodextrin, sulfobutyl ether β-cyclodextrin, dimethyl-βcyclodextrin and the like; Î ± -cyclodextrin derivatives such as methylated Î ± -cyclodextrin, hydroxyethyl-Î ± cyclodextrin, hydroxypropyl-Î ± -cyclodextrin and maltosyl-Î ± -cyclodextrin; and γcyclodextrin derivatives such as methylated γ-cyclodextrin, etc.
Ulteriori dettagli dei complessi supramolecolari sono contenuti nel precedente co-deposito MI2010A 001491 del 04/08/2010, qui citato nella sua interezza. Further details of the supramolecular complexes are contained in the previous co-filing MI2010A 001491 of 04/08/2010, cited here in its entirety.
Preferibilmente la composizione della presente invenzione assumerà la forma di gel, film, gel su film, granuli, pasta e polvere dentale, creme e altri prodotti spalmabili e/o applicabili sulla mucosa orale direttamente o con supporto esterno tipo film o cerotto. Preferably, the composition of the present invention will take the form of gel, film, gel on film, granules, dental paste and powder, creams and other spreadable products and / or applicable on the oral mucosa directly or with an external support such as film or patch.
Altre forme di composizioni comprendono colluttori, dentifrici e prodotti masticabili. Other forms of compositions include mouthwashes, toothpastes and chewable products.
Il termine “colutorio†include composizioni orali non-ingeribili liquide come soluzioni colluttorie idroalcoliche, spray ed altri prodotti da risciacquo. Il termine “dentifricio†comprende composizioni concepite per l’igienedentale come dentifrici mono- e multi-fase, liquidi o in polvere, tavolette, creme e gel dentali.Il termine “prodotti masticabili†comprende tavolette masticabili, losanghe, chewing gum, pastiglie ed altre modalità palatabili. The term â € œcolutorioâ € includes liquid non-ingestible oral compositions such as hydroalcoholic mouthwash solutions, sprays and other rinse products. The term â € œtoothpasteâ € includes compositions designed for dental hygiene such as single- and multi-phase toothpastes, liquid or powder, tablets, creams and dental gels.The term â € œchewable productsâ € includes chewable tablets, lozenges, chewing gum , tablets and other palatable modalities.
Le composizioni secondo l’invenzione potranno contenere svariati ingredienti utilizzati nei preparati odontodentali ad es. agenti anti-carie, desensibilizzanti, viscosizzanti, diluenti, tensioattivi ed emulsionanti, modulatori di schiuma, modificatori di pH, abrasivi, umettanti, modificatori di gusto, dolcificanti, aromi, coloranti, conservanti, ecc. The compositions according to the invention may contain various ingredients used in dental preparations, for example. anti-caries agents, desensitizers, thickeners, thinners, surfactants and emulsifiers, foam modulators, pH modifiers, abrasives, humectants, taste modifiers, sweeteners, flavors, dyes, preservatives, etc.
In una modalità applicativa, le composizioni secondo l’invenzione saranno utilizzate da 1 a 3 volte al giorno in soggetti, o almeno una volta al giorno, oppure una o due volte la settimana. Il trattamento potrà variare da qualche giorno ad una/due settimana o oltre, ovvero per il periodo di tempo suficiente ala scomparsa del’afezione. In one application mode, the compositions according to the invention will be used from 1 to 3 times a day in subjects, or at least once a day, or once or twice a week. The treatment may vary from a few days to one / two weeks or more, or for the period of time sufficient for the infection to disappear.
Le composizioni inventive potranno inoltre comprendere un inibitore di adesione batterica e/o un agente di disruzione del biofilm baterico ad incrementare ulteriormente l†̃eficacia della spermidina nel trattamento delle lesioni del cavo orale. The inventive compositions may furthermore comprise a bacterial adhesion inhibitor and / or a bacterial biofilm disrupting agent to further increase the efficacy of spermidine in the treatment of oral cavity lesions.
Esempi di inibitori di adesione batterica includono d-mannosio, N-acetil-D-galattosamina (GalNAc), proantocianidine oligomere, claritromicina, eritromicina e decapinolo. Examples of bacterial adhesion inhibitors include d-mannose, N-acetyl-D-galactosamine (GalNAc), oligomeric proanthocyanidins, clarithromycin, erythromycin and decapinol.
Esempi di agenti di disruzione del biofilm batterico comprendono in particolare un aminoacido tiolato come la N-acetil-l-cisteina (NAC) o altre molecole tiolate, es cisteamina. Esempi preferiti nella due categorie citate sono il d-mannosio ed il NAC in concentrazione opportune, ad esempio segnalate negli esempi. Examples of bacterial biofilm disrupting agents include in particular a thiolated amino acid such as N-acetyl-1-cysteine (NAC) or other thiolated molecules, eg cysteamine. Preferred examples in the two cited categories are d-mannose and NAC in suitable concentrations, for example reported in the examples.
In un ulteriore realizzazione preferita, le composizioni comprendono uno o più polimeri mucoadesivi per aumentare i tempi di permanenza e la cessione di spermidina in loco. In a further preferred embodiment, the compositions comprise one or more mucoadhesive polymers to increase residence times and the release of spermidine in situ.
Esempi di polimeri mucoadesivi comprendono carbopol e polycarbophil; derivati della cellulosa come etil cellulosa (EC), idrossipropil cellulosa (HPC), sodio carbossimetil cellulosa (CMC), idrossipropilmetil cellulosa (HPMC), idrossietil cellulosa (HEC); polivinilpirrolidone (PVP); polivinilalcol (PVA); poliisobutilene (PIB) e poliisoprene; acidi poliacrilici a poliacrilamidi; gomme naturali come xantana, gomma di tamarindo; chitosano e pectina, macrogol ecc. Da notare che alcuni i polimeri polianionici citati in precedenza, es. jaluronato e alginato, hanno un comportamento di elevata mucoadesività . Examples of mucoadhesive polymers include carbopol and polycarbophil; cellulose derivatives such as ethyl cellulose (EC), hydroxyethyl cellulose (HPC), sodium carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC); polyvinylpyrrolidone (PVP); polyvinyl alcohol (PVA); polyisobutylene (PIB) and polyisoprene; polyacrylic acids to polyacrylamides; natural gums such as xanthan, tamarind gum; chitosan and pectin, macrogol etc. It should be noted that some of the polyanionic polymers mentioned above, eg. hyaluronate and alginate have a highly mucoadhesive behavior.
Esempi preferiti di polimeri mucoadesivi sono i polimeri idrocolloidali modificati con gruppi tiolici, denominati “tiomeri†, esemplificato daBernkop-SchnÃ1⁄4rch in Nanomedicine 2007, 2(1):41-50“Thiomers: forms, functions and applications to nanomedicine“. Preferred examples of mucoadhesive polymers are hydrocolloidal polymers modified with thiol groups, called â € œthiomersâ €, exemplified by Bernkop-SchnÃ1⁄4rch in Nanomedicine 2007, 2 (1): 41-50â € œThiomers: forms, functions and applications to nanomedicineâ € œ .
Le composizioni odontostomatologiche secondo l’invenzione rivolte al trattamento di afte, mucositi e stomatiti possono beneficiare della presenza di ulteriori principi attivi noti ed utilmente impiegati in tali affezioni. The odontostomatological compositions according to the invention aimed at the treatment of canker sores, mucositis and stomatitis can benefit from the presence of further active ingredients known and usefully used in such affections.
Esempi non limitativi di detti attivi comprendono in particolare: corticosteroidi, come idrocortisone, prednisolone, ecc.; anestetici rapidi come procaina e clorprocaina; anestetici a durata intermedia come lidocaina e prilocaina; anestetici a lunga durata quali bupivacaina, ropivacaina, levobupivacaina ed anestetici aspecifici quali benzil alcol. Non-limiting examples of said active ingredients include in particular: corticosteroids, such as hydrocortisone, prednisolone, etc .; rapid anesthetics such as procaine and chlorprocaine; intermediate-duration anesthetics such as lidocaine and prilocaine; long-lasting anesthetics such as bupivacaine, ropivacaine, levobupivacaine and non-specific anesthetics such as benzyl alcohol.
Ulteriori esempi di detti attivi comprendono: antibiotici, ad es. minociclina, doxiociclina e tetracicline antimicotici, ad es. econazolo, miconazolo, rilopirox, ciclopirox e sodio piritione; antivirali, ad es. aciclovir; biocidi, ad es. benzalconio cloruro, clorexidina, triclosan ecc.; gel d’aloe; complessi o sali di Zn e F; amlexanox; ï §-globuline; dapsone; MAO-inibibitori; allantoina; vasocostrittori, ad es. epinefrina, pseudoepinefrina, metilfenidato, ossimetazolina; antistaminici, ad es. azelastina, olopatadina, difenidramina, teofillina e altre metilxantine; cicatrizzanti, ad es. sali di Al e Zn o sucralfato; coagulanti, ad es. tranilst, vitamina K, acido 6-amino-caproico; inibitori del fattore Xa, ad es. fondaparina e idraparina, inibitori della degradazione dei mastociti, ad es. picetannolo, benzamidine, tenidap, tiacrilast, disodio cromoglicato, lodoxamide, staurosporina, amiloride; FANS, ad es. flurbiprofene, ibuprofene, sulindac, diclofenac, salicilati e aspirina; e inibitori COX-2 specifici. Further examples of said actives include: antibiotics, e.g. minocycline, doxiocycline and tetracyclines antifungals, eg. econazole, miconazole, rilopirox, ciclopirox and sodium pyrithione; antivirals, eg. acyclovir; biocides, eg. benzalkonium chloride, chlorhexidine, triclosan etc .; aloe gel; complexes or salts of Zn and F; amlexanox; ï §-globulins; dapsone; MAO-inhibitors; allantoin; vasoconstrictors, eg. epinephrine, pseudoepinephrine, methylphenidate, oxymetazoline; antihistamines, eg. azelastine, olopatadine, diphenhydramine, theophylline and other methylxanthines; cicatrisants, eg. salts of Al and Zn or sucralfate; coagulants, eg. tranilst, vitamin K, 6-amino-caproic acid; factor Xa inhibitors, eg. fondaparin and hydraparin, inhibitors of mast cell degradation, eg. picetannol, benzamidines, tenidap, thiacrilast, cromolyn disodium, lodoxamide, staurosporine, amiloride; NSAIDs, eg. flurbiprofen, ibuprofen, sulindac, diclofenac, salicylates and aspirin; and specific COX-2 inhibitors.
Le composizioni odontostomatologiche secondo l’invenzione rivolte al tratamento di gengiviti e periodontiti possono beneficiare della presenza di peptidi odontogenetici. The odontostomatological compositions according to the invention aimed at the treatment of gingivitis and periodontitis can benefit from the presence of odontogenic peptides.
Esempi di peptidi odontogenetici sono denominati“enamel matrix proteins†(Ten Cate: Oral Histology, 1994; Robinson: Eur. J. Oral Science, 1998, 106 Suppl. 1:282-91) comprendenti amelogenine, proteine non-amelogenine ricche in prolina, ameline (ameloblastina, sheathlina) e tuftelina, loro miscele e derivati. Un esempio commerciale di detti peptidi odontogenetici à ̈ l’Emdogainâ„¢ (Institut Straumann AG, Basilea, Svizzera). Examples of odontogenic peptides are called â € œenamel matrix proteinsâ € (Ten Cate: Oral Histology, 1994; Robinson: Eur. J. Oral Science, 1998, 106 Suppl. 1: 282-91) including amelogenins, proline-rich non-amelogenin proteins , ameline (ameloblastina, sheathlina) and tuftelina, their mixtures and derivatives. A commercial example of said odontogenic peptides is Emdogainâ „¢ (Institut Straumann AG, Basel, Switzerland).
Ulteriori esempi di peptidi odontogenetiche utili sono le proteine ricche in prolina come quelle del Colostro, la poliprolina di sintesi utilizzata come conservante alimentare (in USA e Giappone) nonché il collagene e collagene idrolizzato, ricchi in prolina e idrossiprolina. Further examples of useful odontogenic peptides are proteins rich in proline such as those of Colostrum, synthetic polyproline used as a food preservative (in the USA and Japan) as well as hydrolyzed collagen and collagen, rich in proline and hydroxyproline.
Gli ativi sopra citati possono essere aggiunti ale composizioni secondo l’invenzione oppure utilmente utilizzati in terapia combinata ad ottimizzare il trattamento delle affezioni. Gli esempi seguenti illustrano l’invenzione, non essendo intesi a limitarne gli scopi. The above mentioned actives can be added to the compositions according to the invention or usefully used in combined therapy to optimize the treatment of the affections. The following examples illustrate the invention, not being intended to limit its scope.
ESEMPI EXAMPLES
Esempio 1–Inibizione della collagenasi Example 1â € “Inhibition of collagenase
Il metodo di Mandl e coll. (J Clin Invest.1953, 32, 1323) modificato à ̈ la base di questo test. Campioni con collagenasi sono incubati per 2, 4 e 24 ore con collagene nativo. Il grado di degradazione à ̈ determinato per colorimetria con ninidrina come descritto da Moore & Stein (Biol Chem.. 1948, 176, 367). Gli amminoacidi liberati sono espressi come Î1⁄4moli di leucina per mg collagenase. Un unità equivale aÎ1⁄4mole di L-leucina eq. di collagene a 37°C e pH 7,5. Per ciascun campione si prepara una provetta con 5 mg di collagene nativo e 1 ml di TES 0,05M pH 7.5, si scalda a 37°C, si aggiungono 0,1 ml di campione e si pone a 37°C per 5 ore. Dopo incubazione 0,2 ml della miscela di reazione (escludendo il collagene intero) à ̈ trasferito in 1 ml di ninidrina, soluz. 2% e posto in bagno maria a bollore per 20 minuti. La miscela raffreddata à ̈ diluita in 50% n-propanolo, lasciato a riposo per 15 minuti e letto a 570 nm. L’atività colagenasica à ̈ calcolata per interpolazione del dato ottenuto su curva standard ottenuta con quantità scalari di unità collagenasi. I risultati sono illustrati in Tabella I. The method of Mandl et al. (J Clin Invest. 1953, 32, 1323) modified is the basis of this test. Collagenase samples are incubated for 2, 4 and 24 hours with native collagen. The degree of degradation is determined by colorimetry with ninhydrin as described by Moore & Stein (Biol Chem .. 1948, 176, 367). The released amino acids are expressed as Î1⁄4moles of leucine per mg collagenase. One unit is equivalent to Î1⁄4mole of L-leucine eq. of collagen at 37 ° C and pH 7.5. For each sample, prepare a test tube with 5 mg of native collagen and 1 ml of TES 0.05M pH 7.5, heat to 37 ° C, add 0.1 ml of sample and place at 37 ° C for 5 hours. After incubation 0.2 ml of the reaction mixture (excluding whole collagen) is transferred into 1 ml of ninhydrin, solut. 2% and place in a bain-marie to boil for 20 minutes. The cooled mixture is diluted in 50% n-propanol, left to rest for 15 minutes and read at 570 nm. The cholagenase activity is calculated by interpolation of the data obtained on a standard curve obtained with scalar quantities of collagenase units. The results are shown in Table I.
TABELLA I TABLE I
Concentrazione Unità di % di inibizione Concentration Unit of% inhibition
di spermidina Collagenase della collagenase of collagenase spermidine Collagenase
2 h 4 h 24 h 2 h 4 h 24 h
10Î1⁄4M 0.58 0.60 0.58 -42.33% 10Î1⁄4M 0.58 0.60 0.58 -42.33%
100 nM 0.83 0.83 0.81 -26.08% 100 nM 0.83 0.83 0.81 -26.08%
Si evidenzia un comportamento concentrazione-dipendente rispetto al ’atività di inibizione delle collagenasi attivate dai processi infiammatori ed infettivi nel cavo orale. Pur essendo significativi, i dati necessitano di ulteriore verifica su collagenasi tipizzate nello spettro di concentrazioni utili inoltre in presenza di complessi supramolecolari. There is a concentration-dependent behavior with respect to the inhibition activity of collagenases activated by inflammatory and infectious processes in the oral cavity. Although significant, the data require further verification on typed collagenases in the spectrum of useful concentrations also in the presence of supramolecular complexes.
Esempio 2–Capacità di riproliferazione della spermidina Example 2â € “Repoliferation capacity of spermidine
Il modello per la valutazione della performance riparatrice à ̈ un test di proliferazione di fibroblasti primari. I terreni di coltura con le sostanze test sono aggiunti ai pozzetti contenenti fibroblasti in fase G0, esposti a 24 e 48 ore, con sostituzione del terreno di coltura a 24 h. Al termine si esegue il test MTT per valutare vitalità ed incremento della popolazione cellulare. Il sale di tetrazolio MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide) si prepara in situ aggiungendo 15 mg di MMT a 30 mL di terreno di coltura à ̈ ridotto a sale di formazano dalla succinato deidrogenasi mitocondriale e dalle deidrogenasi citoplasmatiche. Dopo esposizione, le cellule sono sciacquate con 200 µL di PBS. Successivamente la soluzione di lavaggio à ̈ rimossa e sono aggiunti a ogni pozzetto 200 µL di medium con MTT; le cellule sono incubate per 4 ore a 37°C e 5% di CO2. Quindi il medium con MTT à ̈ rimosso e si aggiungono 200 µl di una soluzione solvente l’MTTcostituita da 10% Triton X-100 e 0,1 N di HCl in isopropanolo. La piastra à ̈ posta su agitatore rotante per 20-30’ a formare una soluzione omogenea, con lettura a 570 nm (background a 690 nm). The model for the assessment of restorative performance is a primary fibroblast proliferation test. The culture media with the test substances are added to the wells containing fibroblasts in the G0 phase, exposed at 24 and 48 hours, with replacement of the culture medium at 24 hours. At the end, the MTT test is performed to evaluate viability and increase of the cell population. MTT tetrazolium salt (3- (4,5-Dimethylthiazol-2-yl) -2,5diphenyltetrazolium bromide) is prepared in situ by adding 15 mg of MMT to 30 mL of culture medium is reduced to formazan salt from succinate mitochondrial dehydrogenases and cytoplasmic dehydrogenases. After exposure, the cells are rinsed with 200 µL of PBS. Subsequently the washing solution is removed and 200 µL of medium with MTT are added to each well; cells are incubated for 4 hours at 37 ° C and 5% CO2. Then the medium with MTT is removed and 200 µl of a solvent solution the MTT consisting of 10% Triton X-100 and 0.1 N of HCl in isopropanol are added. The plate is placed on a rotating shaker for 20-30 'to form a homogeneous solution, with reading at 570 nm (background at 690 nm).
I risultati espressi come % di vitalità cellulare su fibroblasti primari rispetto al controllo non trattato espressi come valore medio di prova in quintuplicato sono riportati nella tabella II. TABELLA II The results expressed as% of cell viability on primary fibroblasts compared to the untreated control expressed as mean test value in five times are reported in Table II. TABLE II
Concentrazione Incremento della popolazione di fibroblasti (vs controllo) di spermidina 24 h 48 h Concentration Increase in the population of spermidine fibroblasts (vs control) 24 h 48 h
1 mM -0,16% -3,22% 1 mM -0.16% -3.22%
100Î1⁄4M 1,31% 4,09% 100Î1⁄4M 1.31% 4.09%
10Î1⁄4M 2,30% 8,48% 10Î1⁄4M 2.30% 8.48%
1Î1⁄4M 7,55% 13,01% 1Î1⁄4M 7.55% 13.01%
100 nM 26,27% 29,39% 100 nM 26.27% 29.39%
10 nM 31,86% 35,96% 10 nM 31.86% 35.96%
I risultati evidenziano un comportamento bimodale in funzione della concentrazione di spermidina, favorevole a partire da concentrazioni del’ordine micromolari ed aumento fino alle concentrazioni nanomolari. The results show a bimodal behavior as a function of the spermidine concentration, favorable starting from micromolar concentrations and increasing up to nanomolar concentrations.
Tenendo in conto l’efeto di diluizione nel’applicazione in vivo, tali dati sono comunque indicativi per la determinazione del dosaggio utile. Si à ̈ in pratica dimostrato univocamente che a tali dosaggi la spermidina risulta efficace e compatibile sia con l’azione di blocco della degenerazione tissutale causata dal’ativazione infiammatoria sia con il concomitante effetto di ripopolazione dello strato epiteliale depauperato della mucosa orale. Taking into account the dilution effect in the in vivo application, these data are however indicative for the determination of the useful dosage. In practice, it has been unequivocally demonstrated that at these dosages spermidine is effective and compatible both with the blocking action of tissue degeneration caused by inflammatory activation and with the concomitant effect of repopulating the depleted epithelial layer of the oral mucosa.
Esempio 3–Capacità di riproliferazione della spermidina in forma complessata Example 3â € “Repoliferation capacity of spermidine in complexed form
Il modello di proliferazione come da esempio 3 à ̈ applicato a complessi di spermidina con jaluronato, alginato e copolimero vinilmetiletere-maleato (PMVE/MA) per tempi di 24 e 48 ore. I risultati esposti nella Tabella III riportano direttamente il rapporto di attività dei complessi espressi come % incremento popolazione cellulare del complesso diviso per la % incremento popolazione cellulare della spermidina cloridrato a parità di concentrazione. The proliferation model as in example 3 is applied to complexes of spermidine with hyaluronate, alginate and vinylmethylether-maleate copolymer (PMVE / MA) for times of 24 and 48 hours. The results shown in Table III directly report the activity ratio of the complexes expressed as the% increase in the cell population of the complex divided by the% increase in the cell population of spermidine hydrochloride at the same concentration.
TABELLA III TABLE III
Eq. Rapporto di attività proliferativa del Eq. Proliferative activity report of the
anionici/Eq. Complesso vs Spermidina anionic / Eq. Complex vs Spermidin
Concentrazione cationici del Jaluronato- Alginato- PMVE/MAtodi Spermidina complesso spermidina spermidina sperimdina Cationic concentration of Hyaluronate- Alginate- PMVE / MAtodi Spermidina complex spermidina spermidina sperimdina
24 h 24 h 24 h 24 h 24 h 24 h
100 Î1⁄4M ~ 10:1 10,53 11,31 7,97 100 Î1⁄4M ~ 10: 1 10.53 11.31 7.97
10 Î1⁄4M ~ 10E2:1 17,06 12,30 21,52 10 Î1⁄4M ~ 10E2: 1 17.06 12.30 21.52
1 Î1⁄4M ~ 10E3:1 7,29 6,93 11,06 1 Î1⁄4M ~ 10E3: 1 7.29 6.93 11.06
100 nM ~ 10E4:1 2,82 2,46 3,41 100 nM ~ 10E4: 1 2.82 2.46 3.41
10 nM ~ 10E5:1 2,14 1,61 2,52 10 nM ~ 10E5: 1 2.14 1.61 2.52
48 h 48 h 48 h 48 h 48 h 48 h
100 Î1⁄4M ~ 10:1 4,56 2,48 2,08 100 Î1⁄4M ~ 10: 1 4.56 2.48 2.08
10 Î1⁄4M ~ 10E2:1 4,70 2,49 2,74 10 Î1⁄4M ~ 10E2: 1 4.70 2.49 2.74
1 Î1⁄4M ~ 10E3:1 4,38 3,50 3,23 1 Î1⁄4M ~ 10E3: 1 4.38 3.50 3.23
100 nM ~ 10E4:1 2,55 1,61 1,96 100 nM ~ 10E4: 1 2.55 1.61 1.96
10 nM ~ 10E5:1 2,18 1,10 1,11 10 nM ~ 10E5: 1 2.18 1.10 1.11
I risultati evidenziano un effetto di potenziamento da 2 fino a 20 volte nelle 24 h e circa 4 x The results show an enhancement effect of 2 to 20 times in 24 h and approximately 4 x
nelle 48 h, con un effetto massimizzato (da 7 a 20 x) per i complessi da 10:1 a 10<3>:1 eq/eq, in 48 h, with a maximized effect (from 7 to 20 x) for complexes from 10: 1 to 10 <3>: 1 eq / eq,
con i quali à ̈ possibile utilizzare spermidina a concentrazioni almeno di un log superiore with which it is possible to use spermidine at concentrations at least one log higher
rispetto a quelle utilmente impiegabili di spermidina in forma salificata (non complessata). than those usefully usable of spermidine in salified form (not complexed).
Una serie di composizioni secondo l’invenzione à ̈ ilustrata diseguito, con gli ingredienti A series of compositions according to the invention is illustrated below, with the ingredients
riportati in nomenclatura internazionale. Se non diversamente specificato, la spermidina (Spd) reported in international nomenclature. Unless otherwise specified, spermidine (Spd)
à ̈ introdotta come soluzione al 0,025% p/v in acqua sterile (sol.1 mM) deareata. It is introduced as a 0.025% w / v solution in deaerated sterile water (sol. 1 mM).
Esempio 5–Gel buccale con ialuronato-spermidina Example 5â € “Buccal gel with hyaluronate-spermidine
Ingrediente Quantità (in 100 g) Ingredient Quantity (in 100 g)
Sodium hyaluronate 1,00 g Sodium hyaluronate 1.00 g
Spermidine 3HCl, sol. 0,025% 10,0 mg Spermidine 3HCl, sol. 0.025% 10.0 mg
Xylitol 7,50 g Xylitol 7.50 g
Dichlorobenzyl alcohol 0,50 g Dichlorobenzyl alcohol 0.50 g
Cu chlorophyll 0,12 mg Cu chlorophyll 0.12 mg
Aroma 0,30 g Aroma 0.30 g
Acqua q.b. a 100 g Water q.s. to 100 g
Il sodio jaluronato ad alto peso molecolare à ̈ sciolto in acqua con formazione di gel viscoso. Si aggiunge sotto agitazione la soluzione di spermidina a formare il complesso Jaluronato-Spd 10<4>:1 eq/eq e, di seguito, gli altri componenti nelle proporzioni indicate. The high molecular weight sodium hyaluronate is dissolved in water with the formation of a viscous gel. The spermidine solution is added under stirring to form the Hyaluronate-Spd 10 <4> complex: 1 eq / eq and, subsequently, the other components in the proportions indicated.
Esempio 6–Gel buccale pluricolloidale con spermidina Example 6â € “Multicolloid buccal gel with spermidine
Ingrediente Quantità (in 100 g) Ingredient Quantity (in 100 g)
Sodium hyaluronate 0,20 g Sodium hyaluronate 0.20 g
Sodium carboxymethylcellulose 4,50 g Sodium carboxymethylcellulose 4.50 g
Polycarbophil 0,30 g Polycarbophil 0.30 g
Spermidine 3HCl, sol. 0,025% 0,50 g Spermidine 3HCl, sol. 0.025% 0.50 g
PEG-40 hydrogenated castor oil 1,00 g PEG-40 hydrogenated castor oil 1.00 g
Disodium EDTA 0,05 g Disodium EDTA 0.05 g
Xylitol 7,50 g Xylitol 7.50 g
Dichlorobenzyl alcohol 0,50 g Dichlorobenzyl alcohol 0.50 g
Cu chlorophyll 0,12 mg Cu chlorophyll 0.12 mg
Aroma 0,30 g Aroma 0.30 g
NaOH q.b. a pH 6,5 NaOH q.s. at pH 6.5
Acqua q.b. a 100 g Water q.s. to 100 g
La serie di idrocolloidi costituita da sodio ialuronato, carbossimetilcellulosa e polycarbophil à ̈ mescolata in acqua fino ad ottenere un gel viscoso. Si aggiunge sotto agitazione la soluzione di spermidina e, a seguire, gli altri componenti nelle proporzioni indicate. The hydrocolloid series consisting of sodium hyaluronate, carboxymethylcellulose and polycarbophil is mixed in water to obtain a viscous gel. The spermidine solution is added under stirring and, subsequently, the other components in the proportions indicated.
Esempio 7–Gel buccale composito modificato Example 7â € “Modified composite buccal gel
Una serie di 10 tubetti da 10 ml ciascuno di Cikaflogoâ„¢ contenente i seguenti ingredienti: Aqua, Aloe barbadensis, Macadamia ternifolia, Tocopheryl Acetate, Triethanolamine, Carbomer, Propylene Glycol, Imidazolidinyl urea, Sodium Dehydroacetate, Allantoin, Thymus vulgaris, Cupressus sempervirens, Phenoxyethanol, Trigonella foenum graecum, Centella asiatica, Melaleuca alternifolia, Sodium Hyaluronate, Parabens, Ubiquinone, Phytonadione sono miscelati con 200Î1⁄4l di Spermidine 3HCl, sol.0,025%. A series of 10 tubes of 10 ml each of Cikaflogoâ „¢ containing the following ingredients: Aqua, Aloe barbadensis, Macadamia ternifolia, Tocopheryl Acetate, Triethanolamine, Carbomer, Propylene Glycol, Imidazolidinyl urea, Sodium Dehydroacetate, Allantoin, Thymus vulgaris, Cupressus semper Phenoxyethanol, Trigonella foenum graecum, Centella asiatica, Melaleuca alternifolia, Sodium Hyaluronate, Parabens, Ubiquinone, Phytonadione are mixed with 200Î1⁄4l of Spermidine 3HCl, sol.0.025%.
Esempio 8–Gel buccale con tiomero idrocolloide-spermidina Example 8â € “Buccal gel with hydrocolloid-spermidine thiomer
Ingrediente Quantità (in 100 g) Ingredient Quantity (in 100 g)
Polyacrylate-Cys MC (°) 0,40 g Polyacrylate-Cys MC (°) 0.40 g
Spermidine 3HCl, sol. 0,025% 0,05 g Spermidine 3HCl, sol. 0.025% 0.05 g
Xylitol 7,50 g Xylitol 7.50 g
Cethylpyridinium chloride 0,20 g Cethylpyridinium chloride 0.20 g
Cu chlorophyll 0,12 mg Cu chlorophyll 0.12 mg
Aroma 0,30 g Aroma 0.30 g
NaOH q.b. a pH 6,5 NaOH q.s. at pH 6.5
Acqua q.b. a 100 g Water q.s. to 100 g
Il poliacrilato-cisteina a media coniugazione (°) fornito da Green River Polymers GmbH (Insbruck, Austria) à ̈ sospeso nella soluzione contenente acqua e xilitolo, si aggiunge soda (pH 6,5). Si aggiunge la soluzione di spermidina e quindi gli altri componenti, infine si corregge il pH con soda. Si ottiene un gel buccale caratterizzato da elevata mucoadesività . The medium conjugation polyacrylate-cysteine (°) supplied by Green River Polymers GmbH (Insbruck, Austria) is suspended in the solution containing water and xylitol, soda is added (pH 6.5). The spermidine solution is added and then the other components, finally the pH is corrected with soda. A buccal gel characterized by high mucoadhesiveness is obtained.
Esempio 9 –Gel buccale con complesso polimaleato-spermidina ed inibitori di adesione e disruttori di biofilm batterico Example 9 - Buccal gel with polymaleate-spermidine complex and adhesion inhibitors and bacterial biofilm breakers
Ingrediente Quantità (in 100 g) Ingredient Quantity (in 100 g)
Gantrez S97BF 0,15 g Gantrez S97BF 0.15 g
Spermidine 3HCl, sol. 0,025% 0,50 g Spermidine 3HCl, sol. 0.025% 0.50 g
Polaxamer 427 20,0 g Polaxamer 427 20.0 g
PEG-40 hydrogenated castor oil 1,00 g PEG-40 hydrogenated castor oil 1.00 g
Povidone 5,00 g Povidone 5.00 g
Sodium saccharinate 0,30 g Sodium saccharinate 0.30 g
Benzalkonium chloride 0,10 g Benzalkonium chloride 0.10 g
N-acetyl-cysteine (NAC) 0,30 g N-acetyl-cysteine (NAC) 0.30 g
d-Mannose 4,00 g d-Mannose 4.00 g
NaOH q.b. a pH 6 NaOH q.s. at pH 6
Acqua q.b. a 100 g Water q.s. to 100 g
Il polimaleato (Gantrez S97BF, ISP, Wayne, NJ, USA) Ã ̈ sospeso in acqua e titolato con NaOH fino a pH 6. Si aggiunge sotto agitazione la soluzione di spermidina ottenendo il complesso PMVE-MAto-Spd 3x10<3>:1 eq/eq. Si aggiungono gli altri componenti a formare un gel di media consistenza. The polymaleate (Gantrez S97BF, ISP, Wayne, NJ, USA) is suspended in water and titrated with NaOH up to pH 6. The spermidine solution is added under stirring to obtain the PMVE-MAto-Spd 3x10 <3>: 1 complex eq / eq. The other components are added to form a gel of medium consistency.
Esempio 10–Collutorio con complesso α-ciclodestrina-spermidina Example 10â € “Mouthwash with Î ± -cyclodextrin-spermidine complex
Si prepara α-CD-Spermidina 2:1 M/M sciogliendo 2 g di α-CD Cawamaxâ„¢ (ISP; Wayne, NJ, USA) in 7,5 ml d’acquacon 1 ml di Spd 3HCl, sol.0,025% e 0,2 ml di NaOH 1N. Î ± -CD-Spermidine 2: 1 M / M is prepared by dissolving 2 g of Î ± -CD Cawamaxâ „¢ (ISP; Wayne, NJ, USA) in 7.5 ml of water with 1 ml of Spd 3HCl, sol .0.025% and 0.2 ml of 1N NaOH.
Ingrediente Quantità (in 100 g) Ingredient Quantity (in 100 g)
α-CD-Spermidina 2:1 0,01 g Î ± -CD-Spermidine 2: 1 0.01 g
Potassium sorbate 0,30 g Potassium sorbate 0.30 g
Benzoate sodium 0,30 g Benzoate sodium 0.30 g
Hydroxyethyl cellulose 0,30 g Hydroxyethyl cellulose 0.30 g
Benzalkonium chloride 0,10 g Benzalkonium chloride 0.10 g
PEG-40 Hydrogenated Castor Oil 0,10 g PEG-40 Hydrogenated Castor Oil 0,10 g
Sodium saccharinate 0,05 g Sodium saccharinate 0.05 g
Cu chlorophyll 0,12 mg Cu chlorophyll 0.12 mg
Aroma 0,30 g Aroma 0.30 g
Acqua q.b. a 100 g Water q.s. to 100 g
Dalla soluzione del complesso α-CD-Spermidina 2:1 M/M si prelevano 10 ml e si procede quindi con la formulazione aggiungendo gli altri componenti nelle proporzioni indicate. From the solution of the Î ± -CD-Spermidine 2: 1 M / M complex, 10 ml are taken and the formulation is then proceeded by adding the other components in the proportions indicated.
Esempio 11–Collutorio con spermidina Example 11â € “Mouthwash with spermidine
Ingrediente Quantità (in 100 g) Ingredient Quantity (in 100 g)
Spermidine 3HCl, sol. 0,025% 0,02 g Spermidine 3HCl, sol. 0.025% 0.02 g
Glycerol 5,00 g Glycerol 5.00 g
Xanthan gum 0,12 g Xanthan gum 0.12 g
Sodium saccharinate 0,10 g Sodium saccharinate 0,10 g
Aroma 0,15 g Aroma 0.15 g
PEG-40 Hydrogenated Castor Oil 0,10 g PEG-40 Hydrogenated Castor Oil 0.10 g
Acqua q.b. a 100 g Water q.s. to 100 g
Esempio 12–Gel-dentifricio con spermidina Example 12â € “Gel-toothpaste with spermidine
Ingrediente Quantità (in 100 g) Ingredient Quantity (in 100 g)
Spermidine 3HCl, sol. 0,025% 0,05 g Spermidine 3HCl, sol. 0.025% 0.05 g
Sorbitol 70% 43,0 g Sorbitol 70% 43.0 g
Glycerin 5,00 g Glycerin 5.00 g
Propylen glycol 2,50 g Propylen glycol 2.50 g
Sodium lauryl sulfate 1,70 g Sodium lauryl sulfate 1.70 g
Macrogol 1600 1,00 g Macrogol 1600 1.00 g
Xylitol 1,00 g Xylitol 1.00 g
Aroma 0,90 g Aroma 0.90 g
Sodium carboxymethyl cellulose 0,80 g Sodium carboxymethyl cellulose 0.80 g
Sodium saccharinate 0,20 g Sodium saccharinate 0.20 g
Sodium phosphate 0,20 g Sodium phosphate 0.20 g
Parabens 0,20 g Parabens 0.20 g
Acqua q.b. a 100 g Water q.s. to 100 g
Esempio 13–Dentifricio in pasta con spermidina Example 13â € “Toothpaste with spermidine
Ingrediente Quantità (in 100 g) Ingredient Quantity (in 100 g)
Spermidine 3HCl, sol. 0,025% 0,05 g Spermidine 3HCl, sol. 0.025% 0.05 g
Sorbitol 50,0 g Sorbitol 50.0 g
Hydrated silica 8,00 g Hydrated silica 8.00 g
Sarcosine sodium lauroyl 3,50 g Sarcosine sodium lauroyl 3.50 g
Carboxymethyl cellulose 1,50 g Carboxymethyl cellulose 1.50 g
Potassium sorbate 0,30 g Potassium sorbate 0.30 g
Benzoate sodium 0,30 g Benzoate sodium 0.30 g
PEG-40 Hydrogenated Castor oil 0,16 g PEG-40 Hydrogenated Castor oil 0.16 g
Sodium saccharinate 0,10 g Sodium saccharinate 0,10 g
Aroma 0,50 g Aroma 0.50 g
Acqua q.b. a 100 g Water q.s. to 100 g
La preparazione delle formulazioni degli esempi 11, 12 e 13 avviene mediante comune tecnica di incorporazione degli ingredienti nelle proporzioni indicate con riscaldamento blando e agitazione fino a formare masse omogenee, successivamente dearate in vuoto a circa 45-55°C. In fase finale viene incorporata la spermidina, introdotta come soluzione diluita di spermidina cloridrato allo 0,025%. The preparation of the formulations of Examples 11, 12 and 13 takes place by means of a common technique of incorporating the ingredients in the proportions indicated with gentle heating and stirring until homogeneous masses are formed, subsequently dearated in vacuum at about 45-55 ° C. In the final phase, spermidine is incorporated, introduced as a dilute solution of 0.025% spermidine hydrochloride.
Esempio 14–Chewing gum con complesso HPβ-ciclodestrina-spermidina Example 14â € “Chewing gum with HPβ-cyclodextrin-spermidine complex
Si prepara una soluzione di 1,135 g di HPβ-cyclodextrin (Kleptoseâ„¢ HPB; Roquette) e 254 mg di spermidina 3HCl in 50 ml di acqua distillata e 0,2 ml di NaOH 1N. Si agita per 20 minuti a 20° C e quindi si essica in rotavapor a 50° C, i granuli sono setacciati a 50 mesh a dare un complesso di β-cyclodextrin-spermidina HCl 2:1 M:M. A solution of 1.135 g of HPβ-cyclodextrin (Kleptoseâ „¢ HPB; Roquette) and 254 mg of spermidine 3HCl in 50 ml of distilled water and 0.2 ml of 1N NaOH is prepared. The mixture is stirred for 20 minutes at 20 ° C and then dried in a rotavapor at 50 ° C, the granules are sieved at 50 mesh to give a 2: 1 M: M β-cyclodextrin-spermidine HCl complex.
Ingrediente Quantità (in 100 g) Ingredient Quantity (in 100 g)
HPβ-Cyclodestrin-Spermidina 2:1 0,40 g HPβ-Cyclodextrin-Spermidine 2: 1 0.40 g
Gomma base 42,95 g Base gum 42.95 g
Guar gum 0,40 g Guar gum 0.40 g
Glycerin 0,05 g Glycerin 0.05 g
Mannitol 22,0 g Mannitol 22.0 g
Glycine 18,5 g Glycine 18.5 g
Silica gel (Sident 22) 2,80 g Silica gel (Sident 22) 2.80 g
Behenic acid 1,90 g Behenic acid 1.90 g
Aspartame 4,50 g Aspartame 4.50 g
Aroma menta 5,00 g Mint aroma 5.00 g
Magnesium stearate 1,50 g Magnesium stearate 1.50 g
Il complessoHPBβ-CD-spermidina à ̈ prelevato in quantità indicata e mescolato con gomma base (Gum Base Co SpA, Lainate, Italia) raffreddata a -10° C in mulino meccanico, nel quale si addiziona guar gum (0,9% p/p) e glicerina (0,1% p/p). Il tutto à ̈ mescolato in mixer e passato in setaccio a 50 mesh. I granuli ottenuti sono mescolati con i polioli, la glicina e la silica nelle proporzioni indicate per 20 min. in a temperatura di circa 20° C. Successivamente si aggiungono glu ltimi 3 ingredienti, si miscela per 5 min., si setaccia e infine si lavora in estrusione-compressione ad ottenere dei chewing gum di circa 1,4 g in peso ciascuno. The HPBβ-CD-spermidine complex is taken in the indicated quantity and mixed with base gum (Gum Base Co SpA, Lainate, Italy) cooled to -10 ° C in a mechanical mill, in which guar gum is added (0.9% w / p) and glycerin (0.1% w / w). The whole is mixed in a mixer and passed through a 50 mesh sieve. The obtained granules are mixed with the polyols, glycine and silica in the indicated proportions for 20 min. in at a temperature of about 20 ° C. Subsequently, the last 3 ingredients are added, mixed for 5 min., sieved and finally worked in extrusion-compression to obtain chewing gum of about 1.4 g in weight each.
Esempio 15–Mini-tavoletta buccale Example 15â € “Mini buccal tablet
Ingrediente Quantità (in 100 g) Ingredient Quantity (in 100 g)
Spermidina 3HCl 50,0Î1⁄4g Spermidine 3HCl 50.0Î1⁄4g
Mannitol 54,64 g Mannitol 54.64 g
Microcristalline cellulose 23,5 g Microcrystalline cellulose 23.5 g
Glycine 4,50 g Glycine 4.50 g
Fumaric acid 6,50 g Fumaric acid 6.50 g
Color 0,01 g Color 0.01 g
Aspartame 1,50 g Aspartame 1.50 g
Aroma menta 3,00 g Mint aroma 3.00 g
Polyethylene oxide 5,50 g Polyethylene oxide 5.50 g
Magnesium stearate 0,80 g Magnesium stearate 0.80 g
La preparazione dele tavolete segue il procedimento indicato nel’esempio 1 del breveto WO/2008/013710 con la sostituzione della spermidina in luogo della fenilefrina. The preparation of the table follows the procedure indicated in example 1 of the patent WO / 2008/013710 with the substitution of spermidine in place of phenylephrine.
Esempio 16–Cerotto Example 16â € “Patch
Ingrediente Quantità (in 100 g) Ingredient Quantity (in 100 g)
Spermidine 3HCl 5,00 mg Spermidine 3HCl 5.00 mg
Alginato sodico 27,4 g Sodium alginate 27.4 g
Propylen glycol 4,70 g Propylen glycol 4.70 g
PEG 1000 9,50 g PEG 1000 9.50 g
PEG 1500 10,4 g PEG 1500 10.4 g
PEG 4000 38,2 g PEG 4000 38.2 g
PEG 8000 3,80 g PEG 8000 3.80 g
Eucalyptol 0,50 g Eucalyptol 0.50 g
L’alginato (Satialgine 1100), il glicole e il PEG 1000 sono miscelati lentamente fino a produrre una massa omogenea. Gli altri componenti sono aggiunti alla massa e fusi a temperatura < 80°C. Sotto agitazione si lascia raffreddare fino a 30-40°C e quindi si aggiunge la spermidina, incorporando sotto miscelazione continua. Alginate (Satialgine 1100), glycol and PEG 1000 are slowly mixed to produce a homogeneous mass. The other components are added to the mass and melted at a temperature <80 ° C. Under stirring it is allowed to cool down to 30-40 ° C and then the spermidine is added, incorporating under continuous mixing.
Una quantità di massa ottenuta intorno a 150 mg à ̈ utilizzata per applicazione su un cerotto buccale di dimensioni 7-10 mm x 7-10 mm x 1 mm, quindi confezionato in blister pack a protezione da luce e aria. A quantity of mass obtained around 150 mg is used for application on a buccal patch of dimensions 7-10 mm x 7-10 mm x 1 mm, then packaged in blister packs to protect from light and air.
Esempio 17–Valutazione in vivo su afte (case study) Example 17⠀ "In vivo evaluation of canker sores (case study)
Ad un soggetto femminile di 46 anni con afte periodiche e ricorrenti viene dato un gel prodotto con sodio jaluronato alto peso molecolare (1150 kd, Bioiberica, Barcellona, Spagna) 0,5 g, spermidina HCl 2,5 mg e alcol benzilico 0,5 g sciolti in 50 ml di acqua da applicare 2-3 volte al giorno. Il soggetto testimonia una risoluzione delle ulcere aftose con decorso di circa una settimana contro le 3-4 generalmente necessarie per la regressione degli episodi aftosi. Il prodoto à ̈ ben tolerato a parte il retrogusto amarognolo dovuto al’alcol benzilico. A 46-year-old female subject with periodic and recurrent canker sores is given a gel produced with high molecular weight sodium hyaluronate (1150 kd, Bioiberica, Barcelona, Spain) 0.5 g, spermidine HCl 2.5 mg and benzyl alcohol 0.5 g dissolved in 50 ml of water to be applied 2-3 times a day. The subject testifies to a resolution of the aphthous ulcers with a course of about a week against the 3-4 generally necessary for the regression of the aphthosis episodes. The product is well tolerated apart from the bitter aftertaste due to benzyl alcohol.
Esempio 18–Valutazione in vivo su periodontite (case study) Example 18⠀ "In vivo evaluation of periodontitis (case study)
Un soggetto femminle di 40 anni con diagnosi di periodontite à ̈ trattato con Emdogainâ„¢ Plus (Institut Straumann AG, Basilea, CH) modificato con 1Î1⁄4mole di spermidina (150Î1⁄4g). Dapprima si scosta il lembo mucoperiosteo di accesso per l’esecuzione del debridement a lembo aperto (OFD) a rimuovere completamente placca, tartaro e tessuto di granulazione, quindi di applica lo Straumann PrefGelâ„¢ per rimuovere il fango dentinale. Infine si applica di Straumann Emdogainâ„¢, con veicolo 1 ml di veicolo a base di propylene glycol alginate modificato come sopra descritto, sulla superficie radicolare pulita e condizionata partendo dal livello osseoapicale per coprire l’intera superficie radicolare. A 40-year-old female subject diagnosed with periodontitis is treated with Emdogainâ „¢ Plus (Institut Straumann AG, Basel, CH) modified with 1Î1⁄4mole of spermidine (150Î1⁄4g). First, the mucoperiosteal access flap is moved away for open flap debridement (OFD) to completely remove plaque, tartar and granulation tissue, then Straumann PrefGelâ „¢ is applied to remove the smear layer. Finally, Straumann Emdogainâ „¢ is applied, with vehicle 1 ml of modified propylene glycol alginate-based vehicle as described above, on the cleaned and conditioned root surface starting from the apical bone level to cover the entire root surface.
Claims (10)
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
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ITMI2010A002308A IT1403262B1 (en) | 2010-12-16 | 2010-12-16 | TOPIC COMPOSITIONS FOR THE CURE OF INJURIES OF THE ORAL CABLE |
ES15153105T ES2704694T3 (en) | 2010-08-04 | 2011-08-01 | Compositions comprising supramolecular complexes of polyanionic polymers and spermidine for use in the treatment of periodontium and damaged oral tissue |
PCT/IB2011/001771 WO2012017288A2 (en) | 2010-08-04 | 2011-08-01 | Supramolecular complexes of polyanionic polymers and spermidine in tissue maintenance and repair |
PCT/IB2011/001789 WO2012017290A1 (en) | 2010-08-04 | 2011-08-01 | Inclusion complexes of cyclodextrins with spermidine, and proliferative/reparative compositions comprising thereof |
EP11814166.2A EP2608781A4 (en) | 2010-08-04 | 2011-08-01 | Inclusion complexes of cyclodextrins with spermidine, and proliferative/reparative compositions comprising thereof |
RS20181578A RS58287B1 (en) | 2010-08-04 | 2011-08-01 | Compositions comprising supramolecular complexes of polyanionic polymers and spermidine for use in the treatment of periodontum and damaged oral tissue |
PL15153105T PL2898881T3 (en) | 2010-08-04 | 2011-08-01 | Compositions comprising supramolecular complexes of polyanionic polymers and spermidine for use in the treatment of periodontum and damaged oral tissue |
EP20110814164 EP2600858A4 (en) | 2010-08-04 | 2011-08-01 | Supramolecular complexes of polyanionic polymers and spermidine in tissue maintenance and repair |
DK15153105.0T DK2898881T3 (en) | 2010-08-04 | 2011-08-01 | COMPOSITIONS COMPREHENSIVE SUPRAMOLECULAR COMPLEXES OF POLYANIONIC POLYMERS AND SPERMIDINE FOR USE IN TREATMENT OF THE PERIODONTY AND DAMAGED ORAL TISSUE. |
CN201180047745.8A CN103153293B (en) | 2010-08-04 | 2011-08-01 | For organizational protection and the multi-anion copolymer of reparation and the supramolecular complex of spermidine |
CN201610149456.3A CN105797159B (en) | 2010-08-04 | 2011-08-01 | Use of a composition comprising supramolecular complexes of polyanionic polymers and spermidine for periodontal and damaged oral tissue |
EP15153102.7A EP2902019B1 (en) | 2010-08-04 | 2011-08-01 | Compositions comprising inclusion complexes of cyclodextrins with spermidine for use in oral care |
CA2807266A CA2807266C (en) | 2010-08-04 | 2011-08-01 | Supramolecular complexes of polyanionic polymers and spermidine in tissue maintenance and repair |
EP15153105.0A EP2898881B1 (en) | 2010-08-04 | 2011-08-01 | Compositions comprising supramolecular complexes of polyanionic polymers and spermidine for use in the treatment of periodontum and damaged oral tissue |
US13/813,939 US20130310462A1 (en) | 2010-08-04 | 2011-08-01 | Supramolecular complexes of polyanionic polymers and spermidine in tissue maintenance and repair |
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