The oral cavity represents the main entrance into our organism. It carries out essential activities for an individual's life. Furthermore, through the mouth numerous xenobiotics from drugs to contaminants present in food or in the air enter. It is therefore important to maintain the health of the mouth to ensure a good quality of life. Pathologies affecting the mouth are numerous and very common such as cavities and the development of plaque and other teeth diseases. Unfortunately, it is not easy to treat this area of the body due to the complexity of its environment. The presence of saliva, hydrolytic enzymes, and the continuous interaction with external sources such as food and beverages make it challenging to apply formulations that remain at the site of action for a sufficient time. Furthermore, the active ingredients can be rapidly degraded. In this study, liposomes were produced by the thin film method followed by extrusion and characterized as a possible drug delivery system in the presence of various active ingredients that can be used to treat different ailments of the mouth. The liposomal systems were initially prepared in the presence of different amounts of glycerol to develop a formulation that can be used to increase the hydration of the oral cavity due to its humectant properties for the treatment of diseases related to hyposalivation (e.g. xerostomia). Furthermore, to solve the problem of the short residence time on the oral mucosa, the liposomes were coated with polymers previous shown to be mucoadhesive i.e alginate, chitosan and hyaluronic acid. The formulations were characterized by studying the size, polydispersity index (PDI) and zeta potential after being prepared and over time to evaluate their stability and to understand which formulation was most appropriate. Uncoated liposomes were subsequently used to encapsulate lidocaine hydrochloride or chlorhexidine digluconate and characterized by measuring size, PDI, zeta potential by the help of light scattering, and encapsulation efficiency measured by an indirect UV-method. Liposomes were also prepared with different amounts of charged lipid to investigate any potential effect of the charge on lidocaine hydrochloride’s encapsulation efficiency. The results showed that the presence of glycerol in different amounts slightly influenced the characteristics of the liposomes and, therefore, their stability. The encapsulation of the investigated drugs proved effective for chlorhexidine digluconate with an encapsulation efficiency of around 90% for both positively and negatively charged liposomes. The encapsulation efficiency of lidocaine hydrochloride was instead lower and influenced by the charge of the liposomes. 20% of the drug was encapsulated into positively charged liposomes and 40% into negatively charged liposomes. Therefore, a correlation between the surface charge of liposomes and the ability to encapsulate the drug was hypothesized. However, increasing the amount of charged lipids did not increase the encapsulation efficiency. The study has shown that it is possible to obtain liposomes coated with mucoadhesive polymers such as chitosan and alginate stable in the presence of glycerol up to 20%. On the contrary, hyaluronic acid-coated liposomes with glycerol included did not show promising results in terms of shell life. Furthermore, the lipid vesicles were able to encapsulate other drugs such as lidocaine hydrochloride and chlorhexidine digluconate. Therefore, liposomes represent a promising drug delivery system for treating oral ailments but further studies are required to increase the stability and improve the encapsulation efficiency of the active ingredients.
La cavità orale rappresenta la principale via di ingresso nel nostro organismo svolgendo numerose funzioni essenziali per la vita dell’individuo. Mantenere la salute della bocca è fondamentale, dal momento che è direttamente correlata alla salute generale dell’organismo, e dunque per assicurare un’ottimale qualità della vita. Le patologie che possono interessare la cavità orale sono numerose e molto comuni. Sfortunatamente, non è semplice trattare quest’area del corpo a causa della complessità del suo ambiente. La presenza della saliva, degli enzimi idrolitici e della continua interazione con fonti esterne quali cibo e bevande rende difficoltosa l’applicazione di formulazioni farmaceutiche che rimangano nel sito d’azione per un tempo sufficiente ad esplicare la loro azione. Inoltre, il principio attivo potrebbe essere degradato rapidamente. In questo studio, sono stati preparati liposomi con il metodo dell’idratazione dello strato sottile (Thin-Film Hydration Method) seguito dall’estrusione e sono stati caratterizzati per una loro possibile applicazione come sistema di veicolazione di farmaci nella bocca. I sistemi liposomiali sono stati inizialmente preparati in presenza di diverse quantità di glicerolo per sviluppare formulazioni che potessero essere utilizzate per il trattamento di disturbi legati all’iposalivazione (come ad esempio la xerostomia) grazie alla sua azione umettante. Inoltre, per risolvere il problema del breve tempo di residenza sulla mucosa orale, i liposomi sono stati rivestiti con polimeri che hanno mostrato proprietà muco-adesive, ovvero alginato, chitosano e acido ialuronico. Le formulazioni sono state caratterizzate studiandone le dimensioni, l’indice di polidispersione (PDI) e il potenziale zeta dopo averle preparate e nel tempo per valutarne la stabilità e comprendere quale formulazione fosse la più appropriata. Successivamente, liposomi non rivestiti sono stati utilizzati per incapsulare la lidocaina cloridrato o la clorexidina digluconato. Le formulazioni sono state caratterizzate misurandone le dimensioni, PDI, e potenziale zeta, utilizzando la tecnica del light scattering, e l’efficienza di incapsulamento, misurata con un metodo UV indiretto. I liposomi sono stati poi preparati con differenti quantità di lipide carico per investigarne l’effetto sull’efficienza di incapsulamento della lidocaina cloridrato. Lo studio ha mostrato che è possibile ottenere liposomi rivestiti con polimeri muco-adesivi come chitosano e alginato stabili in presenza di glicerolo fino al 20%. Al contrario, i liposomi rivestiti con acido ialuronico non hanno mostrato risultati promettenti in termini di shell life. L’incapsulamento dei farmaci investigati si è rivelato efficace soprattutto per la clorexidina digluconato con un'efficienza di incapsulamento di circa il 90% per liposomi sia con carica positiva che negativa. Diversamente, l’efficienza di incapsulamento della lidocaina cloridrato è risultata inferiore e influenzata dalla carica. È stata raggiunta un’efficienza di incapsulamento del 20% per il liposomi carichi positivamente e del 40% per quelli carichi negativamente. Dunque è stata ipotizzata esserci una correlazione tra la carica superficiale dei liposomi e l’abilità di incapsulare il farmaco. Tuttavia, l’aumento della quantità di lipidi caricati non ha portato ad un incrementato dell’efficienza di incapsulamento. I liposomi rappresentano un promettente sistema di veicolazione di farmaci per il trattamento di disturbi della cavità orale ma ulteriori studi sarebbero necessari per incrementare la loro stabilità e migliorare l’efficienza di incapsulamento dei principi attivi.
Sviluppo e produzione di sistemi di somministrazione di farmaci biocompatibili a base di liposomi per migliorare il trattamento locale della cavità orale
MARTINELLI, GAIA
2021/2022
Abstract
The oral cavity represents the main entrance into our organism. It carries out essential activities for an individual's life. Furthermore, through the mouth numerous xenobiotics from drugs to contaminants present in food or in the air enter. It is therefore important to maintain the health of the mouth to ensure a good quality of life. Pathologies affecting the mouth are numerous and very common such as cavities and the development of plaque and other teeth diseases. Unfortunately, it is not easy to treat this area of the body due to the complexity of its environment. The presence of saliva, hydrolytic enzymes, and the continuous interaction with external sources such as food and beverages make it challenging to apply formulations that remain at the site of action for a sufficient time. Furthermore, the active ingredients can be rapidly degraded. In this study, liposomes were produced by the thin film method followed by extrusion and characterized as a possible drug delivery system in the presence of various active ingredients that can be used to treat different ailments of the mouth. The liposomal systems were initially prepared in the presence of different amounts of glycerol to develop a formulation that can be used to increase the hydration of the oral cavity due to its humectant properties for the treatment of diseases related to hyposalivation (e.g. xerostomia). Furthermore, to solve the problem of the short residence time on the oral mucosa, the liposomes were coated with polymers previous shown to be mucoadhesive i.e alginate, chitosan and hyaluronic acid. The formulations were characterized by studying the size, polydispersity index (PDI) and zeta potential after being prepared and over time to evaluate their stability and to understand which formulation was most appropriate. Uncoated liposomes were subsequently used to encapsulate lidocaine hydrochloride or chlorhexidine digluconate and characterized by measuring size, PDI, zeta potential by the help of light scattering, and encapsulation efficiency measured by an indirect UV-method. Liposomes were also prepared with different amounts of charged lipid to investigate any potential effect of the charge on lidocaine hydrochloride’s encapsulation efficiency. The results showed that the presence of glycerol in different amounts slightly influenced the characteristics of the liposomes and, therefore, their stability. The encapsulation of the investigated drugs proved effective for chlorhexidine digluconate with an encapsulation efficiency of around 90% for both positively and negatively charged liposomes. The encapsulation efficiency of lidocaine hydrochloride was instead lower and influenced by the charge of the liposomes. 20% of the drug was encapsulated into positively charged liposomes and 40% into negatively charged liposomes. Therefore, a correlation between the surface charge of liposomes and the ability to encapsulate the drug was hypothesized. However, increasing the amount of charged lipids did not increase the encapsulation efficiency. The study has shown that it is possible to obtain liposomes coated with mucoadhesive polymers such as chitosan and alginate stable in the presence of glycerol up to 20%. On the contrary, hyaluronic acid-coated liposomes with glycerol included did not show promising results in terms of shell life. Furthermore, the lipid vesicles were able to encapsulate other drugs such as lidocaine hydrochloride and chlorhexidine digluconate. Therefore, liposomes represent a promising drug delivery system for treating oral ailments but further studies are required to increase the stability and improve the encapsulation efficiency of the active ingredients.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/14351