IT201800005908A1 - GASTRORE-RESISTANT TABLET COATED WITH FILM FOR THE PROTRACT RELEASE OF BUTYRIC ACID - Google Patents
GASTRORE-RESISTANT TABLET COATED WITH FILM FOR THE PROTRACT RELEASE OF BUTYRIC ACID Download PDFInfo
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- IT201800005908A1 IT201800005908A1 IT102018000005908A IT201800005908A IT201800005908A1 IT 201800005908 A1 IT201800005908 A1 IT 201800005908A1 IT 102018000005908 A IT102018000005908 A IT 102018000005908A IT 201800005908 A IT201800005908 A IT 201800005908A IT 201800005908 A1 IT201800005908 A1 IT 201800005908A1
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- cellulose
- tablet
- butyric acid
- film
- tablet according
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- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 title claims description 116
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
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- 229940107702 grapefruit seed extract Drugs 0.000 claims description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 8
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 8
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- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 4
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- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
Descrizione dell’invenzione industriale dal titolo: Description of the industrial invention entitled:
COMPRESSA GASTRORESISTENTE RIVESTITA CON FILM PER IL RILASCIO PROTRATTO DI ACIDO BUTIRRICO. GASTRORE-RESISTANT TABLET COATED WITH FILM FOR THE PROTRACT RELEASE OF BUTYRIC ACID.
Campo dell’invenzione: Field of the invention:
La presente invenzione riguarda una compressa gastroresistente rivestita con film per il rilascio protratto di acido butirrico. The present invention relates to a film-coated gastro-resistant tablet for the prolonged release of butyric acid.
La invenzione origina nel settore della nutraceutica e dei prodotti a fini medici speciali. The invention originates in the field of nutraceuticals and products for special medical purposes.
Nello specifico l’invenzione concerne una compressa che contiene acido butirrico come principio attivo ed è provvista di uno specifico rivestimento polimerico che si dissolve progressivamente lungo l’intero colon rilasciando il principio attivo al suo interno, al raggiungimento di un valore di pH 6.5. Specifically, the invention concerns a tablet that contains butyric acid as an active ingredient and is provided with a specific polymeric coating that progressively dissolves along the entire colon releasing the active ingredient inside it, upon reaching a pH value of 6.5.
Stato dell’arte State of the art
Notoriamente gli acidi grassi a catena corta presentano una catena alifatica da uno a cinque atomi di carbonio e vengono identificati con l’acronimo SCFA. Short-chain fatty acids are known to have an aliphatic chain of one to five carbon atoms and are identified with the acronym SCFA.
Solo una minima percentuale di SCFA viene introdotta con l’alimentazione mentre la maggior parte è il risultato della fermentazione anaerobica delle fibre presenti negli alimenti ingeriti, in particolare pectina ed amido non digerito, ad opera dei batteri che colonizzano il colon. La fermentazione porta alla formazione di acetato, butirrato, propionato, idrogeno ed anidride carbonica e di altri SCFA in modeste quantità. Only a minimal percentage of SCFA is introduced with food while most of it is the result of the anaerobic fermentation of the fibers present in ingested foods, in particular pectin and undigested starch, by the bacteria that colonize the colon. Fermentation leads to the formation of acetate, butyrate, propionate, hydrogen and carbon dioxide and other SCFAs in modest quantities.
In particolare l’acido butirrico insieme all’acido propionico rappresentano circa il 90-95% in peso degli acidi grassi a catena corta presenti all’interno dell’intestino crasso. Inoltre, tra gli acidi grassi a catena corta il butirrato rappresenta insieme alla glutammina la principale fonte energetica delle cellule del colon, denominate colonociti. La carenza di butirrato nell’intestino crasso conseguentemente rappresenta una delle principali cause dell’atrofia della mucosa intestinale e di stati infiammatori della mucosa intestinale. In particular, butyric acid together with propionic acid represent about 90-95% by weight of the short-chain fatty acids present within the large intestine. Furthermore, among the short-chain fatty acids, butyrate represents, together with glutamine, the main energy source of the colon cells, called colonocytes. The lack of butyrate in the large intestine consequently represents one of the main causes of intestinal mucosal atrophy and inflammatory states of the intestinal mucosa.
Inoltre, è stato dimostrato che la carenza di SCFA, in particolare acido butirrico, incrementa il rischio di sviluppare tumori intestinali, in particolare a livello del colon. Furthermore, it has been shown that the deficiency of SCFA, in particular butyric acid, increases the risk of developing intestinal tumors, particularly in the colon.
Viceversa, è stato documentato che l’incremento dei valori di acido butirrico nell’area intestinale svolge un’azione preventiva e di trattamento su alcune patologie intestinali quali il cancro del colon-retto, la colite sia di tipo infettivo che non, la colite ulcerosa, la rettocolite ulcerosa, il morbo di Crohn e la sindrome da colon irritabile (ISB). Conversely, it has been documented that the increase in butyric acid values in the intestinal area carries out a preventive and treatment action on some intestinal pathologies such as colorectal cancer, both infectious and non-infectious colitis, ulcerative colitis , ulcerative colitis, Crohn's disease and irritable bowel syndrome (ISB).
Inoltre, si è riscontrato che la presenza di livelli fisiologici o superiori di butirrato nel colon ha un’influenza sulla risposta immunitaria dell’organismo ed è in grado di modulare la risposta immunitaria. In addition, it was found that the presence of physiological or higher levels of butyrate in the colon has an influence on the body's immune response and is able to modulate the immune response.
Inoltre, alcuni studi scientifici documentano il ruolo dell’acido butirrico nell’inibire la perdita di fluidi in mammiferi affetti da infezioni intestinali in particolare affetti da colera. In addition, some scientific studies document the role of butyric acid in inhibiting the loss of fluids in mammals suffering from intestinal infections, in particular with cholera.
L’acido butirrico, per la sua specifica azione antinfiammatoria e riparatrice della mucosa, trova inoltre applicazione nel trattamento della Sindrome del Colon Irritabile (IBS) o Colite Infiammatoria, patologia che si caratterizza per la presenza di una infiammazione della mucosa del Colon che si accompagna a manifestazioni diarroiche e meteorismo. Butyric acid, due to its specific anti-inflammatory and mucosal repairing action, also finds application in the treatment of Irritable Colon Syndrome (IBS) or Inflammatory Colitis, a pathology that is characterized by the presence of an inflammation of the colon mucosa that accompanies to diarrheal manifestations and meteorism.
Nei casi di una ridotta o insufficiente concentrazione endoluminale di acido butirrico, è quindi raccomandata la supplementazione della dieta con un quantitativo esogeno di acido butirrico. In cases of a reduced or insufficient endoluminal concentration of butyric acid, it is therefore recommended to supplement the diet with an exogenous quantity of butyric acid.
L’integrazione di acido butirrico nella dieta trova quindi applicazione nel trattamento delle patologie sopra menzionate. The integration of butyric acid in the diet therefore finds application in the treatment of the aforementioned diseases.
Generalmente l’acido butirrico esogeno viene somministrato in forma di sali di metalli alcalini solubili. Tuttavia si è riscontrato che la somministrazione di acido butirrico e dei suoi sali è affetta da due ordini di problemi. Generally, exogenous butyric acid is administered in the form of soluble alkali metal salts. However, it has been found that the administration of butyric acid and its salts is affected by two types of problems.
Il primo è rappresentato dall’odore penetrante di questa molecola che lo rende particolarmente sgradevole. Questo inconveniente può indurre il paziente ad interrompere il trattamento o la sua integrazione nel regime dietetico. The first is represented by the penetrating odor of this molecule which makes it particularly unpleasant. This drawback can cause the patient to interrupt the treatment or its integration in the dietary regimen.
Un secondo inconveniente è rappresentato dal fatto che l’acido butirrico viene assorbito principalmente nella porzione iniziale o media del tratto gastrointestinale. Le compresse tradizionali contenenti acido butirrico, venendo a contatto con i succhi gastrici, tendono a sciogliersi nello stomaco o nel duodeno e sono così assorbiti dalla mucosa gastrointestinale prima di pervenire nel parte terminale dell’intestino ove è richiesta la loro azione. Conseguentemente, il quantitativo di acido butirrico che raggiunge il colon è inadeguato a svolgere un’efficace attività terapeutica o preventiva delle patologie precedentemente menzionate. A second drawback is represented by the fact that butyric acid is mainly absorbed in the initial or middle portion of the gastrointestinal tract. Traditional tablets containing butyric acid, coming into contact with gastric juices, tend to dissolve in the stomach or duodenum and are thus absorbed by the gastrointestinal mucosa before reaching the terminal part of the intestine where their action is required. Consequently, the amount of butyric acid that reaches the colon is inadequate to carry out an effective therapeutic or preventive activity of the aforementioned diseases.
Attualmente esiste pertanto la necessità di disporre di formulazioni che non rilascino acido butirrico prima di giungere nella porzione dell’intestino dove è richiesta la sua attività terapeutica. Currently, there is therefore a need to have formulations that do not release butyric acid before reaching the portion of the intestine where its therapeutic activity is required.
Uno degli scopi della presente invenzione consiste quindi nel fornire una compressa a cessione protratta di acido butirro o suoi sali che liberi il principio attivo quando raggiunge la porzione terminale dell’intestino, dove il pH è pari o superiore a pH 6.5. One of the purposes of the present invention therefore consists in providing a tablet with prolonged release of butyric acid or its salts that releases the active ingredient when it reaches the terminal portion of the intestine, where the pH is equal to or higher than pH 6.5.
Un ulteriore scopo dell’invenzione risiede nel provvedere una compressa a cessione protratta di acido butirrico o suo sale la quale, dopo l’assunzione, non lasci un gusto cattivo in bocca e non rilasci un odore sgradevole. A further purpose of the invention lies in providing a prolonged release tablet of butyric acid or its salt which, after taking, does not leave a bad taste in the mouth and does not release an unpleasant odor.
Un ulteriore scopo dell’invenzione consiste nel fornire una compressa gastroresistente ad azione prolungata che rilasci un quantitativo farmaceuticamente attivo di acido butirrico o suoi sali selettivamente nel colon dell’individuo trattato. A further purpose of the invention is to provide a long-acting gastro-resistant tablet that releases a pharmaceutically active amount of butyric acid or its salts selectively into the colon of the individual being treated.
Sommario dell’Invenzione Summary of the Invention
La presente invenzione origina dall’avere trovato che rivestendo un nucleo di una compressa contenente acido butirrico o suoi sali o esteri dispersi in un eccipiente polimerico a base di cellulosa con un film a base di uno specifico copolimero anionico di metacrilato si rallenta l’erosione della compressa durante il transito gastrointestinale in maniera da rilasciare l’acido butirrico nel colon dove il valore di pH è superiore o uguale a 6.5, preferibilmente 6.8. The present invention stems from having found that coating a core of a tablet containing butyric acid or its salts or esters dispersed in a cellulose-based polymeric excipient with a film based on a specific anionic methacrylate copolymer slows down the erosion of the compressed during gastrointestinal transit in order to release butyric acid in the colon where the pH value is greater than or equal to 6.5, preferably 6.8.
In accordo ad un primo aspetto dell’invenzione viene fornita una compressa gastroresistente rivestita con film per il rilascio protratto di acido butirrico caratterizzata dal fatto di comprendere un nucleo comprendente acido butirrico o un suo sale farmaceuticamente accettabile e un polimero non ionico a base di cellulosa rivestito da un film a base di un copolimero anionico di metacrilato comprendente acido metacrilico, metil metacrilato e metil acrilato. According to a first aspect of the invention, a film-coated gastro-resistant tablet is provided for the protracted release of butyric acid characterized in that it comprises a core comprising butyric acid or a pharmaceutically acceptable salt thereof and a coated non-ionic cellulose-based polymer. from a film based on an anionic methacrylate copolymer comprising methacrylic acid, methyl methacrylate and methyl acrylate.
Il film che riveste il nucleo della compressa è resistente all’ambiente acido, non si dissolve nello stomaco e transita lungo l’intestino tenue sostanzialmente non degradandosi evitando o riducendo in maniera sostanziale il rilascio di acido butirrico nella prima parte del tratto gastrointestinale (stomaco e intestino tenue). La Richiedente ha osservato che quando la compressa transita attraverso l’ileo e raggiunge il colon si viene a trovare in un ambiente a pH 6.5, valore al quale il film della compressa inizia a disciogliersi gradualmente. In queste condizioni il film di rivestimento si discioglie e l’acido butirrico viene rilasciato gradualmente dal nucleo. In questo modo l’acido butirrico svolge un’attività terapeutica e/o preventiva selettiva, lungo tutto il tratto dell’intestino crasso in necessità di trattamento. Tipicamente, il rilascio dell’acido butirrico dalla compressa provvista di film è localizzato nell’intestino crasso, specificatamente nel colon. The film that covers the core of the tablet is resistant to the acidic environment, does not dissolve in the stomach and travels along the small intestine substantially not degrading, thus avoiding or substantially reducing the release of butyric acid in the first part of the gastrointestinal tract (stomach and small intestine). The Applicant has observed that when the tablet transits through the ileum and reaches the colon it finds itself in an environment with a pH of 6.5, a value at which the film of the tablet begins to gradually dissolve. Under these conditions, the coating film dissolves and the butyric acid is gradually released from the core. In this way, butyric acid carries out a selective therapeutic and / or preventive activity along the entire tract of the large intestine in need of treatment. Typically, the release of butyric acid from the film-supplied tablet is localized in the large intestine, specifically in the colon.
Tipicamente, la compressa dell’invenzione contiene un nucleo in cui è presente l’acido butirrico disperso in eccipienti a base di cellulosa che contribuiscono a prolungare il rilascio del principio attivo contenuto in essa. Typically, the tablet of the invention contains a core in which there is butyric acid dispersed in cellulose-based excipients which help to prolong the release of the active ingredient contained therein.
Ulteriori forme di realizzazione della compressa sono indicate nelle accluse rivendicazioni 2-8. Further embodiments of the tablet are indicated in the attached claims 2-8.
In accordo ad un altro aspetto l’invenzione concerne l’uso in ambito medico della compressa gastroresistente rivestite con film in accordo alla rivendicazione 9. In accordance with another aspect, the invention concerns the use in the medical field of the gastro-resistant film-coated tablet in accordance with claim 9.
La compressa gastroresistente rivestita con film trova così applicazione nel prevenire o trattare disturbi e malattie del colon in cui è presente una componente infiammatoria. The film-coated gastro-resistant tablet thus finds application in preventing or treating disorders and diseases of the colon in which an inflammatory component is present.
In accordo ad un altro aspetto la compressa gastroresistente rivestita con film contribuisce a ripristinare le condizioni fisiologiche dell’intestino crasso, in particolare del colon. According to another aspect, the film-coated gastro-resistant tablet helps to restore the physiological conditions of the large intestine, in particular the colon.
Secondo una forma di realizzazione la compressa gastroresistente con filmatura dell’invenzione contiene un estratto di semi di pompelmo o Grapefruit Seed Extract, identificato con l’acronimo G.S.E. come ulteriore componente attivo. According to one embodiment, the film-coated gastro-resistant tablet of the invention contains a grapefruit seed extract or Grapefruit Seed Extract, identified with the acronym G.S.E. as an additional active component.
BREVE DESCRIZIONE DELLE FIGURE BRIEF DESCRIPTION OF THE FIGURES
Le caratteristiche e vantaggi della presente invenzione risulteranno più evidenti dalle accluse figure in cui: The characteristics and advantages of the present invention will become more evident from the accompanying figures in which:
la Figura 1 mostra un grafico relativo a cromatogramma relativo al rilascio dopo 2 ore di dissoluzione in HCL 0.1 M (corrispondente a 2 ore dalla ingestione della compressa). Come si osserva, il cromatogramma non evidenzia nessun picco relativo al rilascio di acido butirrico. Figure 1 shows a chromatogram graph relating to the release after 2 hours of dissolution in 0.1 M HCL (corresponding to 2 hours from the ingestion of the tablet). As can be seen, the chromatogram does not show any peak relative to the release of butyric acid.
la Figura 2 mostra un grafico relativo a cromatogramma relativo al rilascio dopo 4 ore di dissoluzione in medium tampone fosfato pH 6.8, più due ore di dissoluzione in medium HCl 0,1M a pH 2, corrispondente a 6 ore dalla ingestione della compressa, Figure 2 shows a chromatogram graph relating to the release after 4 hours of dissolution in phosphate buffer medium pH 6.8, plus two hours of dissolution in 0.1M HCl medium at pH 2, corresponding to 6 hours from the ingestion of the tablet,
la Figura 3 mostra un grafico relativo a cromatogramma relativo al rilascio dopo 8 ore di dissoluzione in medium tampone fosfato pH 6.8, più due ore di dissoluzione in medium HCl 0,1M a pH 2, corrispondente a 10 ore dalla ingestione della compressa; Figure 3 shows a chromatogram graph relating to the release after 8 hours of dissolution in phosphate buffer medium pH 6.8, plus two hours of dissolution in 0.1M HCl medium at pH 2, corresponding to 10 hours from the ingestion of the tablet;
la Figura 4 illustra un grafico relativo a cromatogramma relativo al rilascio dopo 12 ore di dissoluzione in medium tampone fosfato pH 6.8, più due ore di dissoluzione in medium HCl 0,1M a pH 2, corrispondente a 14 ore dalla ingestione della compressa; Figure 4 illustrates a graph relating to a chromatogram relating to the release after 12 hours of dissolution in phosphate buffer medium pH 6.8, plus two hours of dissolution in 0.1M HCl medium at pH 2, corresponding to 14 hours from the ingestion of the tablet;
la Figura 5 illustra un grafico relativo a cromatogramma relativo al rilascio dopo 16 ore di dissoluzione, in medium tampone fosfato pH 6.8, più due ore di dissoluzione in medium HCl 0,1M a pH 2, corrispondente a 18 ore dalla ingestione della compressa; Figure 5 illustrates a graph relating to a chromatogram relating to the release after 16 hours of dissolution, in phosphate buffer medium pH 6.8, plus two hours of dissolution in 0.1M HCl medium at pH 2, corresponding to 18 hours from the ingestion of the tablet;
la Figura 6 illustra un grafico relativo a cromatogramma relativo al rilascio dopo 20 ore di dissoluzione, in medium tampone fosfato pH 6.8, più due ore di dissoluzione in medium HCl 0,1M a pH 2, corrispondente a 22 ore dalla ingestione della compressa; Figure 6 illustrates a graph relating to a chromatogram relating to the release after 20 hours of dissolution, in phosphate buffer medium pH 6.8, plus two hours of dissolution in 0.1M HCl medium at pH 2, corresponding to 22 hours from the ingestion of the tablet;
la Figura 7 illustra un grafico relativo a cromatogramma relativo al rilascio dopo 24 ore di dissoluzione, in medium tampone fosfato pH 6.8, più due ore di dissoluzione in medium HCl 0,1M a pH 2, corrispondente a 26 ore dalla ingestione della compressa; Figure 7 illustrates a graph relating to a chromatogram relating to the release after 24 hours of dissolution, in phosphate buffer medium pH 6.8, plus two hours of dissolution in 0.1M HCl medium at pH 2, corresponding to 26 hours from the ingestion of the tablet;
la Figura 8 mostra grafici a barre relativi alla percentuale di acido butirrico rilasciato dalle compresse alle diverse ore; Figure 8 shows bar graphs relating to the percentage of butyric acid released from the tablets at different hours;
la Figura 9 mostra un grafico che raffigura la percentuale di acido butirrico rilasciato dalle compresse alle diverse ore. Figure 9 shows a graph showing the percentage of butyric acid released from the tablets at different hours.
Descrizione dettagliata dell’Invenzione Detailed description of the Invention
La presente invenzione origina dall’avere osservato che rivestendo un nucleo di una compressa contenente acido butirrico o suo sale o estere disperso in un polimero non ionico a base di cellulosa con un film in uno specifico copolimero anionico di metacrilato, si ottiene a) il rilascio localizzato del principio attivo nel colon dove la mucosa e la parete intestinale sono maggiormente soggetti a processi infiammatori e alla formazione di lesioni precancerose e b) il prolungamento del rilascio di un quantitativo terapeuticamente efficace di acido butirrico o suo sale nella porzione di intestino di interesse clinico. Il rilascio prolungato di acido butirrico o suo sale consente di mantenere la concentrazione attiva di attivo nel lume dell’intestino crasso, in particolare nel colon, per un elevato periodo di tempo migliorando così il risultato profilattico o terapeutico. The present invention originates from having observed that by coating a core of a tablet containing butyric acid or its salt or ester dispersed in a non-ionic cellulose-based polymer with a film in a specific anionic methacrylate copolymer, a) the release localization of the active ingredient in the colon where the mucosa and intestinal wall are more subject to inflammatory processes and the formation of precancerous lesions and b) the prolongation of the release of a therapeutically effective quantity of butyric acid or its salt in the portion of the intestine of clinical interest. The prolonged release of butyric acid or its salt allows to maintain the active concentration of active in the lumen of the large intestine, particularly in the colon, for a long period of time, thus improving the prophylactic or therapeutic result.
Il permanere di un quantitativo terapeuticamente efficace di acido butirrico nel lume intestinale in particolare del colon, crea condizioni idonee a ripristinare una flora batterica fisiologica che previene la formazioni di lesioni precancerose e riduce i processi infiammatori all’origine di numerose patologie del colon-retto. In accordo ad un primo aspetto viene fornita una compressa gastroresistente rivestita con film come definito nella rivendicazione 1. The persistence of a therapeutically effective amount of butyric acid in the intestinal lumen, in particular in the colon, creates suitable conditions for restoring a physiological bacterial flora that prevents the formation of precancerous lesions and reduces inflammatory processes at the origin of numerous colorectal diseases. According to a first aspect, a film-coated gastro-resistant tablet is provided as defined in claim 1.
Ulteriori forme di realizzazione della compressa dell’invenzione sono definite nelle rivendicazioni dipendenti 2-8. Further embodiments of the tablet of the invention are defined in dependent claims 2-8.
La compressa gastroresistente rivestita con il film comprende acido butirrico o un suo sale farmaceuticamente accettabile come principio attivo. The film-coated gastro-resistant tablet comprises butyric acid or a pharmaceutically acceptable salt thereof as an active ingredient.
Con il termine di sali farmaceuticamente accettabili di acido butirrico si intendono, sia sali organici che inorganici. Idonei sali inorganici sono i sali di calcio, sodio e magnesio dell’acido butirrico. Preferibilmente la compressa contiene calcio butirrato. The term pharmaceutically acceptable salts of butyric acid are understood to mean both organic and inorganic salts. Suitable inorganic salts are the calcium, sodium and magnesium salts of butyric acid. Preferably the tablet contains calcium butyrate.
Tipicamente la compressa gastroresistente rivestita con film contiene un nucleo centrale comprendente l’acido butirrico o suoi sale ed almeno un eccipiente a base di un polimero non ionico cellulosico (G.S.E) che rilascia progressivamente il principio attivo. Typically, the film-coated gastro-resistant tablet contains a central core comprising butyric acid or its salt and at least one excipient based on a non-ionic cellulosic polymer (G.S.E) which progressively releases the active ingredient.
Idonei polimeri non ionici a base di cellulosa sono cellulosa e cellulose eterificate o esterificate. Suitable cellulose-based non-ionic polymers are cellulose and etherified or esterified cellulose.
Idonei esteri della cellulosa includono esteri organici tra cui cellulosa acetato, cellulosa triacetato, cellulosa proprionato, cellulosa acetato propionato (CAP), cellulosa acetato butirrato (CAB) oppure esteri inorganici tra cui nitrocellulosa, cellulosa solfato e miscele di esteri organici e/o inorganici. Suitable cellulose esters include organic esters including cellulose acetate, cellulose triacetate, cellulose propionate, cellulose acetate propionate (CAP), cellulose acetate butyrate (CAB) or inorganic esters including nitrocellulose, cellulose sulfate and mixtures of organic and / or inorganic esters.
Idonei eteri della cellulosa includono i) eteri alchilici tra cui metilcellulosa, etilcellulosa, etilmetilcellulosa; ii) idrossialchil eteri tra cui idrossietilcellulosa, idrossipropilcellulosa (HPC), idrossietilmetilcellulosa, idrossipropilmetilcellulosa (HPMC), etilidrossietilcellulosa o iii) carbossialchil eteri di cellulosa tra cui carbossimetilcellulosa (CMC). Suitable cellulose ethers include i) alkyl ethers including methylcellulose, ethylcellulose, ethylmethylcellulose; ii) hydroxyalkyl ethers including hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxyethylmethylcellulose, hydroxypropylmethylcellulose (HPMC), ethylhydroxyethylcellulose or iii) carboxyalkyl cellulose ethers including carboxymethylcellulose (CMC).
Tra i polimeri non ionici a base di cellulosa rientra anche l’emicellulosa e la cellulosa microcristallina. The non-ionic cellulose-based polymers also include hemicellulose and microcrystalline cellulose.
Preferibilmente il nucleo della compressa gastroresistente contiene idrossipropilmetilcellulosa (HPMC) e cellulosa microcristallina come eccipienti. La compressa gastroresistente rivestita con film può comprendere anche altri ingredienti attivi nella prevenzione o trattamento di patologie dell’intestino, in particolare del colon come ad esempio: G.S.E., Aloe, Lapacho, Curcumina, MSM (metilsulfonilmetano). Preferably the core of the gastro-resistant tablet contains hydroxypropylmethylcellulose (HPMC) and microcrystalline cellulose as excipients. The film-coated gastro-resistant tablet may also include other active ingredients in the prevention or treatment of intestinal diseases, in particular of the colon such as: G.S.E., Aloe, Lapacho, Curcumin, MSM (methylsulfonylmethane).
Secondo una particolare realizzazione dell'invenzione la compressa contiene Grapefruit Seed Extract (G.S.E.) composto naturale, tipicamente in forma di polvere, provvisto di attività contro i batteri, sia Gram-positivi che Gram-negativi, oltre ad avere i attività anti-micotiche e anti-infiammatorie. According to a particular embodiment of the invention, the tablet contains Grapefruit Seed Extract (G.S.E.) a natural compound, typically in the form of a powder, with activity against bacteria, both Gram-positive and Gram-negative, as well as having anti-fungal and anti-fungal activities. anti-inflammatory.
La presenza, nella compressa a rilascio protratto, del G.S.E. permette di combinare l’azione antinfiammatoria e riparatrice dell’acido butirrico con una attività antibatterica e/o antimicotica sostanzialmente priva di effetti collaterali. In accordo ad alcune forme di realizzazione la compressa dell’invenzione comprende ulteriormente uno o più componenti addizionali, come additivi, riempitivi, cariche, stabilizzanti, emulsionanti, plasticizzanti, agenti filmanti, agenti umidificanti, addensanti o strutturanti. The presence, in the prolonged-release tablet, of G.S.E. allows you to combine the anti-inflammatory and restorative action of butyric acid with an antibacterial and / or antifungal activity substantially free of side effects. According to some embodiments, the tablet of the invention further comprises one or more additional components, such as additives, fillers, fillers, stabilizers, emulsifiers, plasticizers, filming agents, humectants, thickeners or structuring agents.
Ad esempio, le compresse gastroresistenti possono anche contenere un agente legante come gomma adragante, acacia, amido di mais, o gelatina; ulteriori eccipienti come glicerolo, un agente disgregante come amido di patata, amido di mais; un agente lubrificante come magnesio stearato; un agente dolcificante come saccarosio, lattosio o saccarina. For example, the gastro-resistant tablets may also contain a binding agent such as tragacanth, acacia, corn starch, or gelatin; additional excipients such as glycerol, a disintegrating agent such as potato starch, corn starch; a lubricating agent such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin.
In accordo ad alcune forme di realizzazione la compressa gastroresistente è un prodotto nutraceutico, un prodotto dietetico, un prodotto nutrizionale, un medicinale o un medical device. According to some embodiments, the gastro-resistant tablet is a nutraceutical product, a dietary product, a nutritional product, a medicine or a medical device.
In accordo ad un altro aspetto la presente invenzione riguarda l’uso in ambito medico della compressa precedentemente descritta, in particolare nella prevenzione o trattamento di un disturbo e malattia localizzate nell’intestino crasso, in particolare colon, in cui è presente una componente infiammatoria. According to another aspect, the present invention relates to the use in the medical field of the previously described tablet, in particular in the prevention or treatment of a disorder and disease localized in the large intestine, in particular colon, in which an inflammatory component is present.
La Richiedente ha riscontrato che il trattamento con la compressa dell’invenzione consente di ridurre significativamente l’infiammazione delle mucose e delle pareti dell’intestino crasso riducendo i tempi di recupero dell’attività fisiologica con un allungamento delle recidive. The Applicant has found that treatment with the tablet of the invention significantly reduces the inflammation of the mucous membranes and walls of the large intestine by reducing the recovery time of physiological activity with a lengthening of relapses.
Tipicamente, la compressa a rilascio protratto trova utilizzo nel trattamento di malattie dell’intestino crasso e specificatamente del colon con una componente infiammatoria quali, ad esempio Rettocolite Ulcerosa sindrome dell’intestino irritabile, Morbo di Crohn, colite, colite ulcerosa, diverticolosi, malattia diverticolare, e poliposi. In particolare, la diverticolite è una patologia con una componente lesiva ed infiammatoria dell’intestino crasso e del colon che può portare alla formazione di anse che frequentemente si trasformano in diverticoli. Typically, the prolonged-release tablet is used in the treatment of diseases of the large intestine and specifically of the colon with an inflammatory component such as, for example, Ulcerative colitis irritable bowel syndrome, Crohn's disease, colitis, ulcerative colitis, diverticulosis, diverticular disease , and polyposis. In particular, diverticulitis is a disease with a damaging and inflammatory component of the large intestine and colon that can lead to the formation of loops that frequently turn into diverticula.
In alcuni casi, come nel trattamento della sindrome da intestino irritabile, trova particolare applicazione la combinazione di acido butirrico e G.S.E. poiché previene o tratta malattie infettive. In some cases, such as in the treatment of irritable bowel syndrome, the combination of butyric acid and G.S.E. as it prevents or treats infectious diseases.
La compressa a rilascio protratto può contenere altri eccipienti come magnesio stearato, glicerolo, talco, oppure amido modificato, biossido di titanio, trietil citrato. In alcune forme di realizzazione l’acido Butirrico è presente in un quantitativo compreso da 50 mg a 1500 mg, da 100 a 1000 mg, preferibilmente da 200 a 600 mg. The sustained release tablet may contain other excipients such as magnesium stearate, glycerol, talc, or modified starch, titanium dioxide, triethyl citrate. In some embodiments, butyric acid is present in an amount ranging from 50 mg to 1500 mg, from 100 to 1000 mg, preferably from 200 to 600 mg.
Gli eventuali altri principi attivi come ad esempio il G.S.E., possono essere contenuti da 20 mg a 900 mg, più preferibilmente da 40 mg a 200 mg. Any other active ingredients such as for example G.S.E., can be contained from 20 mg to 900 mg, more preferably from 40 mg to 200 mg.
Le compresse possono essere ottenute mediante tecniche farmaceutiche convenzionali, ad esempio miscelando in un miscelatore acido butirrico con uno o più eccipienti a base di cellulosa ad esempio HPMC. La miscela ottenuta viene poi compressa utilizzando una comprimitrice le compresse così ottenute vengono poi rivestite con il film copolimerico gastroresistente in una bassina fino ad ottenere lo spessore desiderato. Successivamente le compresse vengono blisterate. The tablets can be obtained by conventional pharmaceutical techniques, for example by mixing butyric acid in a blender with one or more cellulose-based excipients, for example HPMC. The mixture obtained is then compressed using a tablet press, the tablets thus obtained are then coated with the gastro-resistant copolymer film in a pan until the desired thickness is obtained. The tablets are then blistered.
Nel seguito vengono riportati alcuni esempi di realizzazione dell'invenzione. Some examples of embodiment of the invention are reported below.
ESEMPIO 1 EXAMPLE 1
Composizione di una compressa gastroresistente contenente calcio butirrato e GSE come principi attivi nel nucleo Composition of a gastro-resistant tablet containing calcium butyrate and GSE as active ingredients in the core
ESEMPIO 2 EXAMPLE 2
Metodo per la preparazione delle compresse rivestite con filmatura. Method for preparing film-coated tablets.
Le materie prime vengono pesate nei quantitativi indicati nella tabella sottostante e nel seguente ordine: Raw materials are weighed in the quantities indicated in the table below and in the following order:
1) Calcio butirrato 1) Calcium butyrate
2) Estratto semi di pompelmo (GSE) 2) Grapefruit Seed Extract (GSE)
3) Idrossipropilmetilcellulosa 3) Hydroxypropylmethylcellulose
4) Cellulosa microcristallina 4) Microcrystalline cellulose
5) Glicerolo dibeenato (Compritol e ato) 5) Glycerol dibeenate (Compritol and ato)
6) Magnesio stearato 6) Magnesium stearate
La pesata di tutte le materie prime viene ricontrollata, prima della setacciatura, seguita poi dalla miscelazione dei componenti per 20 minuti. The weighing of all raw materials is double-checked, before sieving, followed by mixing the components for 20 minutes.
Al termine della miscelazione si aggiunge il magnesio stearato setacciato e si lascia in funzione il miscelatore per ulteriori 10 minuti. At the end of the mixing, the sieved magnesium stearate is added and the mixer is left running for a further 10 minutes.
Le miscelazioni occorrenti a comporre il lotto sono 3 e prevedono tutte gli stessi step. The mixes needed to make up the lot are 3 and all involve the same steps.
La miscelazione è seguita da una fase di comprimitura diretta e dalla fase di filmatura; in questa fase viene spruzzata una soluzione acquosa di copolimero poli(metilacrilato-co-metilmetacrilato-co-acido metacrilico), mantenendo il nucleo ad una temperatura compresa tra 25 e 30 gradi e fino ad un peso finale di 1050 mg per compressa. The mixing is followed by a direct compressing phase and by the filming phase; in this phase an aqueous solution of poly copolymer (methylacrylate-co-methylmethacrylate-co-methacrylic acid) is sprayed, keeping the core at a temperature between 25 and 30 degrees and up to a final weight of 1050 mg per tablet.
ESEMPIO 3 EXAMPLE 3
E' stata effettuata una prova di gastro-resistenza delle compresse dell’invenzione mediante test di disaggregazione effettuato secondo Ph. Eur. ed. corrente. A gastro-resistance test of the tablets of the invention was carried out by means of a disaggregation test carried out according to Ph. Eur. Ed. current.
Prima fase: First stage:
Test di disaggregazione in acido cloridrico 0, 1M: azionare l'apparecchio per 2 h, senza i dischi e controllare lo stato delle compresse. Le compresse devono rimanere integre per almeno 2 ore ossia, nessuna compressa mostra segni sia di disaggregazione (a parte frammenti di rivestimento) che di rotture che permetterebbero la fuoriuscita dei contenuti. Disaggregation test in 0, 1M hydrochloric acid: operate the device for 2 h, without the discs and check the condition of the tablets. The tablets must remain intact for at least 2 hours, that is, no tablet shows signs of either disaggregation (apart from fragments of the coating) or breakage that would allow the contents to escape.
Questa prima fase ha confermato, per le compresse di Colon Life, che il film di rivestimento del nucleo risulta impenetrabile dai succhi gastrici e dagli acidi biliari, permettendo così al nucleo, contenente l'acido butirrico, di attraversare indenne l'intestino tenue. This first phase confirmed, for the Colon Life tablets, that the film covering the core is impenetrable by gastric juices and bile acids, thus allowing the core, containing the butyric acid, to pass through the small intestine unharmed.
Seconda fase: Second phase:
Sostituire l'acido con tampone fosfato soluzione a pH 6,8 e aggiungere un disco in ciascun tubo. Azionare l'apparecchio ed esaminare lo stato delle compresse. Replace the acid with phosphate buffered solution at pH 6.8 and add a disc into each tube. Operate the device and check the status of the tablets.
Le compresse devono cominciare a disgregare, permettendo così il rilascio programmato dell'acido butirrico a livello del colon. The tablets must begin to break down, thus allowing the programmed release of butyric acid in the colon.
In tampone a pH 6,8 si osserva, per le compresse di Colon Life, che la filmatura si scioglie permettendo il rilascio dell'acido butirrico. In a buffer at pH 6.8 it is observed, for the Colon Life tablets, that the film melts allowing the release of the butyric acid.
2.0 VERIFICA DEL RILASCIO PROGRAMMATO 2.0 VERIFICATION OF THE SCHEDULED RELEASE
Mediante l'utilizzo dell'apparato per dissolution test, lo studio del profilo di rilascio viene effettuato determinando l'acido butirrico per via gas cromatografica. Using the dissolution test apparatus, the study of the release profile is carried out by determining the butyric acid by gas chromatography.
3.0 METODICA ANALITICA 3.0 ANALYTICAL METHOD
Condizioni del test di dissoluzione Conditions of the dissolution test
Apparato: 1 basket - 6 portacompresse Medium: Tampone a pH 6,8, 1000 ml Temperatura: 37±2 ° C Apparatus: 1 basket - 6 tablet holders Medium: Buffer pH 6.8, 1000 ml Temperature: 37 ± 2 ° C
Fasi operative e tempi: Porre 1 compressa in ciascun portacompresse; immergere il cestello in tampone ed attivare il sistema per la verifica del rilascio. Operating phases and times: Place 1 tablet in each tablet holder; immerse the basket in buffer and activate the system to check the release.
Sono state Effettuate le analisi del medium ai seguenti intervalli di tempo: Analyzes of the medium were carried out at the following time intervals:
Dopo 4h (corrispondente a 6 ore dalla ingestione della compressa): analisi del medium e verifica del suo volume; After 4 hours (corresponding to 6 hours from the ingestion of the tablet): analysis of the medium and verification of its volume;
Dopo 8h (corrispondente a 10 ore dalla ingestione della compressa): analisi del medium e verifica del suo volume; After 8 hours (corresponding to 10 hours from the ingestion of the tablet): analysis of the medium and verification of its volume;
Dopo 12h (corrispondente a 14 ore dalla ingestione della compressa): analisi del medium e verifica del suo volume; After 12 hours (corresponding to 14 hours from the ingestion of the tablet): analysis of the medium and verification of its volume;
Dopo 16h (corrispondente a 18 ore dalla ingestione della compressa): analisi del medium e verifica del suo volume; After 16h (corresponding to 18 hours from the ingestion of the tablet): analysis of the medium and verification of its volume;
Dopo 20h (corrispondente a 22 ore dalla ingestione della compressa): analisi del medium e verifica del suo volume; After 20h (corresponding to 22 hours from the ingestion of the tablet): analysis of the medium and verification of its volume;
Dopo 24h (corrispondente a 26 ore dalla ingestione della compressa): analisi del medium e verifica del suo volume; After 24 hours (corresponding to 26 hours from the ingestion of the tablet): analysis of the medium and verification of its volume;
Al termine di ogni intervallo, prelevare un'aliquota da 25ml di medium ed acidificare portando a pH 2 con acido formico; analizzare la soluzione risultante senza ulteriori trattamenti. At the end of each interval, take a 25ml aliquot of medium and acidify bringing it to pH 2 with formic acid; analyze the resulting solution without further treatment.
Condizioni cromatografiche: Chromatographic conditions:
Preparazione della Soluzione di riferimento: Preparation of the Reference Solution:
Pesare circa 88 mg, esattamente pesati, di acido butirrico di riferimento, in un matraccio tarato da 100 ml con soluzione tampone pH 6.8; Portare a pH 2 con acido formico. Weigh approximately 88 mg, exactly weighed, of reference butyric acid, into a 100 ml volumetric flask with buffer solution pH 6.8; Bring to pH 2 with formic acid.
E’ stato quindi verificato l’andamento del rilascio di acido butirrico dalla compressa dell’Esempio 1 in relazione al tempo di dissoluzione. I risultati del test sono riassunti nelle accluse Figure 1-9, precedentemente descritte. The trend of the release of butyric acid from the tablet of Example 1 was then verified in relation to the dissolution time. The test results are summarized in the accompanying Figures 1-9, previously described.
L’andamento del rilascio di acido butirrico in relazione al tempo di dissoluzione è raffigurato nelle accluse Figure 1-9 The trend of the release of butyric acid in relation to the dissolution time is shown in the attached Figures 1-9
Conclusioni Conclusions
Dai risultati delle analisi è emersa una graduale disgregazione delle compresse testate e parallelamente un incremento progressivo nel tempo di acido butirrico rilevato nel mezzo di dissoluzione. The results of the analyzes showed a gradual disintegration of the tablets tested and at the same time a progressive increase over time of butyric acid detected in the dissolution medium.
Claims (10)
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