ITMI20080746A1 - COMPOSITIONS FOR THE TREATMENT AND PREVENTION OF ORAL CABLE INFECTIONS - Google Patents
COMPOSITIONS FOR THE TREATMENT AND PREVENTION OF ORAL CABLE INFECTIONS Download PDFInfo
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- ITMI20080746A1 ITMI20080746A1 ITMI20080746A ITMI20080746A1 IT MI20080746 A1 ITMI20080746 A1 IT MI20080746A1 IT MI20080746 A ITMI20080746 A IT MI20080746A IT MI20080746 A1 ITMI20080746 A1 IT MI20080746A1
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- oral
- benzophenanthridine alkaloids
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- Medicinal Preparation (AREA)
Description
Descrizione del brevetto per invenzione industriale avente per titolo: Description of the patent for industrial invention entitled:
“COMPOSIZIONI PER IL TRATTAMENTO E LA PREVENZIONE DELLE INFEZIONI DEL CAVO ORALE” "COMPOSITIONS FOR THE TREATMENT AND PREVENTION OF INFECTIONS OF THE ORAL CABLE"
RIASSUNTO SUMMARY
La presente invenzione riguarda composizioni a base di alcaloidi benzofenantridinici, composti benzofuranici e polifenoli catechici, utili nel trattamento e nella prevenzione delle infezioni del cavo orale. The present invention relates to compositions based on benzophenanthridine alkaloids, benzofuran compounds and catechetical polyphenols, useful in the treatment and prevention of infections of the oral cavity.
Le composizioni della presente invenzione sono dotate di attività antibatterica, antifungina ed antienzimatica, utili nell’igiene orale e nel trattamento e nella prevenzione di forme patologiche di varia origine legate all’apparato dentale, all’implantologia e alle complicanze nella chirurgia del cavo orale. The compositions of the present invention have antibacterial, antifungal and anti-enzymatic activity, useful in oral hygiene and in the treatment and prevention of pathological forms of various origins related to the dental apparatus, implantology and complications in oral surgery.
Tali composizioni possono essere somministrate in forma di compresse a lenta dissoluzione nel cavo orale, in forma di collutorio o come gomma da masticare. These compositions can be administered in the form of slowly dissolving tablets in the oral cavity, in the form of mouthwash or as chewing gum.
STATO DELLA TECNICA STATE OF THE TECHNIQUE
La formazione di film batterici o fungini a livello orale è molto frequentemente alla base di forme patologiche, carie, piorrea ed infezioni paradentali e gengivali. In particolare, la formazione di film batterici o fungini è estremamente comune nell’implantologia, nel mantenimento delle protesi e più in generale in odontoiatria nel soggetto anziano. The formation of bacterial or fungal films at the oral level is very frequently at the basis of pathological forms, caries, pyorrhea and periodontal and gingival infections. In particular, the formation of bacterial or fungal films is extremely common in implantology, in the maintenance of prostheses and more generally in dentistry in the elderly.
È noto dalla letteratura che gli alcaloidi benzofenantridinici sono dotati di attività antibatterica e antifungina, in particolare sui batteri Gram , e sono in grado di rompere il film batterico rendendo il patogeno sensibile ai composti batteriostatici o agli antibiotici. It is known from the literature that benzophenanthridine alkaloids are endowed with antibacterial and antifungal activity, in particular on Gram bacteria, and are able to break the bacterial film making the pathogen sensitive to bacteriostatic compounds or antibiotics.
È altresì nota l’attività di blocco della formazione di film batterici e fungini o di rottura del film già formato, evitandone la riformazione, da parte di composti benzofuranici a struttura neolignanica, presenti in estratti di Krameria triandra, Eupomatia laurina e Piper sp, in particolare Eupomatenoidi e 2-(2,4-diidrossifenil)-5-propenilbenzofurano. It is also known the activity of blocking the formation of bacterial and fungal films or breaking of the film already formed, avoiding its reformation, by benzofuran compounds with a neolignanic structure, present in extracts of Krameria triandra, Eupomatia laurina and Piper sp, in particular Eupomatenoids and 2- (2,4-dihydroxyphenyl) -5-propenylbenzofuran.
Nel cavo orale sono presenti degli enzimi, come α-amilasi, glucosidasi e tacadiastasi, che promuovono la degradazione dei carboidrati con conseguente formazione di glucosio, che tuttavia è notoriamente dannoso per l’igiene orale in quanto contribuisce alla formazione del film batterico a livello orale. Gli inibitori di questi enzimi, pertanto, contribuiscono a prevenire la formazione del film batterico. In the oral cavity there are enzymes, such as α-amylase, glucosidase and tacadiastase, which promote the degradation of carbohydrates with consequent formation of glucose, which however is notoriously harmful for oral hygiene as it contributes to the formation of the bacterial film at the oral level. . Therefore, inhibitors of these enzymes help prevent bacterial film formation.
Le procianidine, in particolare gli oligomeri catechici esterificati con l’acido gallico, sono degli inibitori delle glucosidasi e della tacadiastasi. Procyanidins, in particular catechetical oligomers esterified with gallic acid, are glucosidase and tacadiastase inhibitors.
I polifenoli estratti da Vitis vinifera sono potenti inibitori sia dell’αamilasi sia della glucosidasi. The polyphenols extracted from Vitis vinifera are powerful inhibitors of both α amylase and glucosidase.
DESCRIZIONE DELL’INVENZIONE DESCRIPTION OF THE INVENTION
La presente invenzione ha per oggetto composizioni a base di: The present invention relates to compositions based on:
a) alcaloidi benzofenantridinici, a) benzophenanthridine alkaloids,
b) composti benzofuranici e b) benzofuran compounds e
c) polifenoli catechici, c) catechetical polyphenols,
dotate di attività antibatterica, antifungina ed antienzimatica, che consentono di ridurre la formazione a livello orale del film batterico e fungino, riducendo l’alitosi e la formazione di placche a livello dentale. with antibacterial, antifungal and anti-enzymatic activity, which allow to reduce the formation of the bacterial and fungal film at the oral level, reducing bad breath and the formation of plaques at the dental level.
Alcaloidi benzofenantridinici preferiti sono cheleritrina o sanguinarina, mentre composti benzofuranici preferiti sono composti a struttura neolignanica, presenti in estratti di Krameria triandra, Eupomatia laurina e Piper sp, in particolare Eupomatenoidi e 2-(2,4-diidrossifenil)-5-propenilbenzofurano. Preferred benzophenanthridine alkaloids are cheleritrine or sanguinarine, while preferred benzofuran compounds are compounds with a neolignanic structure, present in extracts of Krameria triandra, Eupomatia laurina and Piper sp, in particular Eupomatenoids and 2- (2,4-dihydroxyphenyl) -5-propenylbenzofuran.
Secondo la presente invenzione, i composti benzofuranici hanno la seguente formula According to the present invention, the benzofuran compounds have the following formula
dove R può essere idrogeno oppure una catena alchilica lineare o ramificata da 2 a 6 atomi di carboni, o una catena alchilica sostituita da gruppi amminici, nitro. R è preferibilmente idrogeno o alchile C1-C3. where R can be hydrogen or a linear or branched alkyl chain from 2 to 6 carbon atoms, or an alkyl chain substituted by amino groups, nitro. R is preferably hydrogen or C1-C3 alkyl.
Tali composti benzofuranici sono noti e sono preparabili con metodi convenzionali, ad esempio per reazione di un fenolo opportunamente sostituito con 2-fenossi-2’,4’-dimetossiacetofenone nelle condizioni riportate in Chimie Therapeutique 1973, 8, 398, seguita da ciclizzazione in presenza di acido polifosforico in xilene e idrolisi dei gruppi metossi ad idrossi. Such benzofuran compounds are known and can be prepared with conventional methods, for example by reaction of a phenol suitably substituted with 2-phenoxy-2 ', 4'-dimethoxyacetophenone under the conditions reported in Chimie Therapeutique 1973, 8, 398, followed by cyclization in the presence of polyphosphoric acid in xylene and hydrolysis of methoxy to hydroxy groups.
È stato sorprendentemente trovato che le composizioni dell’invenzione esercitano un’attività antibatterica, antifungina ed antienzimatica estremamente potente, superiore a quella ottenuta dalla somma dei diversi componenti somministrati separatamente. È ipotizzabile che tale effetto sia dovuto a un meccanismo d’azione sinergico che si instaura tra i diversi componenti dell’associazione in oggetto. It was surprisingly found that the compositions of the invention exert an extremely powerful antibacterial, antifungal and anti-enzymatic activity, higher than that obtained from the sum of the different components administered separately. It is conceivable that this effect is due to a synergistic mechanism of action that is established between the various components of the association in question.
Pertanto, le composizioni dell’invenzione risultano utili nell’igiene orale e nel trattamento e nella prevenzione di forme patologiche di varia origine legate all’apparato dentale, all’implantologia e alle complicanze nella chirurgia del cavo orale. Therefore, the compositions of the invention are useful in oral hygiene and in the treatment and prevention of pathological forms of various origins related to the dental apparatus, implantology and complications in oral surgery.
Più particolarmente, la presente invenzione ha per oggetto composizioni a base di: More particularly, the present invention relates to compositions based on:
a) alcaloidi benzofenantridinici scelti tra sanguinarina e/o cheleritrina e/o loro derivati; a) benzophenanthridine alkaloids selected from sanguinarine and / or cheleritrina and / or their derivatives;
b) composti benzofuranici come sopra definiti; b) benzofuran compounds as defined above;
c) polifenoli catechici monomerici o oligomerici. c) monomeric or oligomeric catechetical polyphenols.
Secondo la presente invenzione, le composizioni conterranno i vari componenti entro i seguenti intervalli (in peso per dosaggio unitario): According to the present invention, the compositions will contain the various components within the following ranges (by weight per unit dosage):
a) alcaloidi benzofenantridinici: da 0,5 mg a 10 mg; a) benzophenanthridine alkaloids: from 0.5 mg to 10 mg;
b) benzofuranici: da 5 a 25 mg; b) benzofurans: from 5 to 25 mg;
c) composti polifenolici: da 10 a 100 mg. c) polyphenolic compounds: from 10 to 100 mg.
Secondo un aspetto particolarmente preferito, le composizioni in oggetto conterranno i vari componenti entro i seguenti intervalli (in peso per dosaggio unitario): According to a particularly preferred aspect, the compositions in question will contain the various components within the following ranges (by weight per unit dosage):
a) alcaloidi benzofenantridinici: da 2,5 a 5 mg; a) benzophenanthridine alkaloids: from 2.5 to 5 mg;
b) composti benzofuranici: da 3 a 10 mg; b) benzofuran compounds: from 3 to 10 mg;
c) composti polifenolici: da 40 a 50 mg. c) polyphenolic compounds: from 40 to 50 mg.
Gli alcaloidi benzofenantridinici sanguinarina e cheleritrina potranno essere presenti in forma libera o salificata, come tali in forma sostanzialmente pura o sotto forma di estratti di Sanguinaria canadensis, di Macleaya cordata o Macleaya macrocarpa. Secondo un aspetto preferito, gli alcaloidi benzofenantridinici saranno presenti in forma salificata con l’acido luteico. Questi sali, che vengono preparati per reazione dei solfati o dei cloruri degli alcaloidi con il sale di sodio o di potassio dell’acido luteico e per successiva cristallizzazione, si sono infatti dimostrati particolarmente efficaci ai fini della presente invenzione. The benzophenanthridine alkaloids sanguinarine and cheleritrina may be present in free or salified form, as such in substantially pure form or in the form of extracts of Sanguinaria canadensis, Macleaya cordata or Macleaya macrocarpa. According to a preferred aspect, the benzophenanthridine alkaloids will be present in salified form with luteic acid. These salts, which are prepared by reaction of the sulphates or chlorides of the alkaloids with the sodium or potassium salt of luteic acid and by subsequent crystallization, have in fact proved particularly effective for the purposes of the present invention.
I composti a struttura benzofuranica come sopra definiti potranno essere presenti come tali o sotto forma di estratti che li contengono, per esempio estratti di Krameria triandra, Eupomatia laurina e Piper sp. I composti isolati da Krameria triandra risultati particolarmente attivi sono l’Eupomatenoide 6 e il neolignano 2-(2,4-diidrossifenil)-5-(E)-propenilbenzofurano, che hanno dimostrato un’attività antibatterica ed antifungina su numerosi ceppi sia di batteri Gram+, su funghi e batteri anaerobi. The compounds with a benzofuranic structure as defined above may be present as such or in the form of extracts containing them, for example extracts of Krameria triandra, Eupomatia laurina and Piper sp. The compounds isolated from Krameria triandra found to be particularly active are Eupomatenoid 6 and neolignano 2- (2,4-dihydroxyphenyl) -5- (E) -propenylbenzofuran, which have shown antibacterial and antifungal activity on numerous strains of both bacteria Gram +, on anaerobic fungi and bacteria.
I composti polifenolici potranno essere presenti sotto forma di unità monomeriche quali catechina, epicatechina, e gallocatechina e suoi esteri gallici all’ossidrile in C3, o di unità oligomeriche, preferibilmente fino a cinque unità. Secondo un aspetto particolarmente preferito, le unità oligomeriche saranno esterificate con acido gallico in C3. I composti polifenolici potranno anche essere presenti sotto forma di estratti da semi o parti aeree di Vitis vinifera, Aesculus hippocastanum, Camellia sinensis, Theobroma cacao e simili. Tali composti risultano particolarmente indicati nell’igiene orale, nell’alitosi e nelle infezioni gengivali. The polyphenolic compounds may be present in the form of monomeric units such as catechin, epicatechin, and gallocatechin and its gallic esters with hydroxyl in C3, or oligomeric units, preferably up to five units. According to a particularly preferred aspect, the oligomeric units will be esterified with gallic acid in C3. The polyphenolic compounds may also be present in the form of extracts from seeds or aerial parts of Vitis vinifera, Aesculus hippocastanum, Camellia sinensis, Theobroma cacao and the like. These compounds are particularly suitable for oral hygiene, bad breath and gum infections.
Le composizioni dell’invenzione saranno convenientemente formulate in compresse orodispersibili, in collutori, in gel da disperdere nella cavità orale, in gomme masticabili o simili. Tali formulazioni potranno essere preparate secondo metodi convenzionali ben noti, come quelli descritti in “Remington’s Pharmaceutical Handbook”, Mack Publishing Co., N.Y., USA, insieme a opportuni eccipienti. The compositions of the invention will be conveniently formulated in orodispersible tablets, in mouthwashes, in gels to be dispersed in the oral cavity, in chewable gums or the like. These formulations can be prepared according to well-known conventional methods, such as those described in "Remington's Pharmaceutical Handbook", Mack Publishing Co., N.Y., USA, together with suitable excipients.
Le formulazioni dell’invenzione saranno somministrate ai pazienti fino a 5 volte nelle 24 ore e per più giorni a seconda della patologia da trattare. Per la sola igiene orale il numero delle somministrazioni potrà essere ridotto a 2, in concomitanza con i pasti principali. The formulations of the invention will be administered to patients up to 5 times in 24 hours and for several days depending on the pathology to be treated. For oral hygiene alone, the number of administrations can be reduced to 2, concurrently with the main meals.
Gli esempi qui di seguito riportati illustreranno l’invenzione senza tuttavia limitarne la portata. The examples below will illustrate the invention without however limiting its scope.
Esempio 1 - Preparazione dei composti benzofuranici Example 1 - Preparation of benzofuran compounds
Stadio A. Preparazione del 2-fenossi-2’,4’-dimetossiacetofenone (a) Una soluzione di 2-bromo-2’,4’-dimetossiacetofenone (5 g, 19,1 mmoli) in 25 mL di 2-butanone fu aggiunta a una sospensione di fenolo (1,8 g, 19,1 mmoli), K2CO3(2,6 g, 19,1 mmoli) e KI (41,5 mg, 0,25 mmoli) in 20,0 mL dello stesso solvente. La soluzione fu quindi posta a ricadere per 20 ore. La miscela fu filtrata e il solvente fu eliminato sotto vuoto. Il residuo ottenuto fu sciolto in EtOAc e lavato con una soluzione acquosa di NaOH al 10% e poi con acqua. L’estratto organico fu seccato su Na2SO4, filtrato ed evaporato sotto vuoto. Infine il residuo grezzo fu lavato con Et2O e seccato sotto pressione ridotta a fornire 4,4 g (resa: 84%) di composto del titolo. Stage A. Preparation of 2-phenoxy-2 ', 4'-dimethoxyacetophenone (a) A solution of 2-bromo-2', 4'-dimethoxyacetophenone (5 g, 19.1 mmol) in 25 mL of 2-butanone was added to a suspension of phenol (1.8 g, 19.1 mmol), K2CO3 (2.6 g, 19.1 mmol) and KI (41.5 mg, 0.25 mmol) in 20.0 mL thereof solvent. The solution was then allowed to reflux for 20 hours. The mixture was filtered and the solvent was removed in vacuo. The residue obtained was dissolved in EtOAc and washed with a 10% aqueous solution of NaOH and then with water. The organic extract was dried on Na2SO4, filtered and evaporated under vacuum. Finally the crude residue was washed with Et2O and dried under reduced pressure to yield 4.4 g (yield: 84%) of the title compound.
Stadio B. Preparazione del 2-(2’,4’-dimetossifenil)benzofurano (b) 12 g di acido polifosforico furono aggiunti a una soluzione di composto dello stadio A (4,4 g, 16,2 mmoli) in 130,0 mL di xilene. La miscela fu posta a ricadere per 2 ore, poi lasciata raffreddare a temperatura ambiente. La soluzione fu quindi decantata ed evaporata sotto pressione ridotta. Il residuo risultante (3,7 g, resa: 90%) fu usato nello stadio successivo senza ulteriore purificazione. Stage B. Preparation of 2- (2 ', 4'-dimethoxyphenyl) benzofuran (b) 12 g of polyphosphoric acid was added to a solution of compound of stage A (4.4 g, 16.2 mmol) in 130.0 mL of xylene. The mixture was refluxed for 2 hours, then allowed to cool to room temperature. The solution was then decanted and evaporated under reduced pressure. The resulting residue (3.7 g, yield: 90%) was used in the next step without further purification.
Stadio C. Preparazione del-(2’,4’-diidrossifenil)benzofurano (1) Una miscela di composto dello stadio B (3,7 g, 14,5 mmoli) e piridinio cloridrato (11,1 g, 96,4 mmoli) fu scaldata a 225°C per 45 minuti. Il prodotto rosso formatosi fu versato in HCl al 10%. La miscela fu lavata ripetutamente con EtOAc; gli strati organici combinati furono seccati su Na2SO4ed evaporati. Il residuo fu purificato mediante cromatografia su colonna (esano/EtOAc= 7:3) a fornire. Il composto finale fu ottenuto con resa del 41% (1,36 g) dopo cristallizzazione da benzene. Stage C. Preparation of - (2 ', 4'-dihydroxyphenyl) benzofuran (1) A mixture of stage B compound (3.7 g, 14.5 mmol) and pyridinium hydrochloride (11.1 g, 96.4 mmol ) was heated to 225 ° C for 45 minutes. The red product formed was poured into 10% HCl. The mixture was washed repeatedly with EtOAc; the combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by column chromatography (hexane / EtOAc = 7: 3) to yield. The final compound was obtained in a yield of 41% (1.36 g) after crystallization from benzene.
Esempio di Formulazione 1 - Compresse orodispersibili Alcaloide benzofenantridinico 2,5 mg Composto benzofuranico 10,0 mg Estratto di Vitis vinifera 50,0 mg Xilitolo 500,0 mg Mannitolo 400,0 mg Aroma liquirizia 50,0 mg Magnesio stearato 10,0 mg Acesulfame K 5,0 mg Esempio di Formulazione 2 - Gel orale Formulation Example 1 - Orodispersible tablets Benzophenanthridine alkaloid 2.5 mg Benzofuran compound 10.0 mg Vitis vinifera extract 50.0 mg Xylitol 500.0 mg Mannitol 400.0 mg Licorice flavor 50.0 mg Magnesium stearate 10.0 mg Acesulfame K 5.0 mg Example of Formulation 2 - Oral gel
Alcaloide benzofenantridinico 3,0 mg Composto benzofuranico 10,0 mg Estratto di Camellia sinensis 50,0 mg Glicerina 400,0 mg Sorbitolo liquido 200,0 mg Idrossietilcellulosa 30,0 mg Aroma menta 20,0 mg Metile para-idrossi benzoato 10,0 mg Acesulfame K 5,0 mg Acqua depurata q.b. a 2,0 g Benzophenanthridine alkaloid 3.0 mg Benzofuran compound 10.0 mg Camellia sinensis extract 50.0 mg Glycerin 400.0 mg Liquid sorbitol 200.0 mg Hydroxyethylcellulose 30.0 mg Mint flavor 20.0 mg Methyl para-hydroxy benzoate 10.0 mg Acesulfame K 5.0 mg Purified water q.s. to 2.0 g
Claims (13)
Priority Applications (11)
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ITMI20080746 ITMI20080746A1 (en) | 2008-04-24 | 2008-04-24 | COMPOSITIONS FOR THE TREATMENT AND PREVENTION OF ORAL CABLE INFECTIONS |
EP09735454A EP2268276A1 (en) | 2008-04-24 | 2009-04-06 | Compositions for the treatment and prevention of infections of the oral cavity |
JP2011505396A JP5752593B2 (en) | 2008-04-24 | 2009-04-06 | Oral infection treatment and prevention composition |
CN2009801140232A CN102014892A (en) | 2008-04-24 | 2009-04-06 | Compositions for the treatment and prevention of infections of the oral cavity |
CA2722209A CA2722209C (en) | 2008-04-24 | 2009-04-06 | Compositions for the treatment and prevention of infections of the oral cavity |
PCT/EP2009/002515 WO2009129926A1 (en) | 2008-04-24 | 2009-04-06 | Compositions for the treatment and prevention of infections of the oral cavity |
AU2009240294A AU2009240294B2 (en) | 2008-04-24 | 2009-04-06 | Compositions for the treatment and prevention of infections of the oral cavity |
KR1020107023536A KR20100134685A (en) | 2008-04-24 | 2009-04-06 | Compositions for the treatment and prevention of infections of the oral cavity |
RU2010143220/15A RU2504378C2 (en) | 2008-04-24 | 2009-04-06 | Compositions for treating and preventing oral infections |
US12/988,870 US8496975B2 (en) | 2008-04-24 | 2009-04-06 | Compositions for the treatment and prevention of infections of the oral cavity |
IL208848A IL208848A (en) | 2008-04-24 | 2010-10-21 | Compositions for the treatment and prevention of infections of the oral cavity |
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