In Vitro Evaluation of Self-Nano-Emulsifying Drug Delivery Systems (SNEDDS) Containing Room Temperature Ionic Liquids (RTILs) for the Oral Delivery of Amphotericin B

Amphotericin B (AmpB), one of the most commonly used agents in the treatment of severe fungal infections and life-threatening parasitic diseases such as visceral Leishmaniasis, has a negligible oral bioavailability, primarily due to a low solubility and permeability. To develop an oral formulation, medium chain triglycerides and nonionic surfactants in a self-nano-emulsifying drug delivery system (SNEDDS) containing AmpB were combined with room temperature ionic liquids (RTILs) of imidazolium. The presence of ionic liquids significantly enhanced the solubility of AmpB, exhibited a low toxicity and increased the transport of AmpB across Caco-2 cell monolayers. The combination of RTILs with a lipid formulation might be a promising strategy to improve the oral bioavailability of AmpB

In Vitro and Ex Vivo Evaluation of Tablets Containing Piroxicam-Cyclodextrin Complexes for Buccal Delivery

In the current study, the development of mucoadhesive tablets for buccal delivery of a non-steroidal anti-inflammatory drug was investigated. Binary complexes with piroxicam and cyclodextrins (beta-cyclodextrin (b-CD), methylated-beta-cyclodextrin (Me-b-CD), and hydroxypropyl-beta-cyclodextrin (HP-b-CD)) were prepared by the co-evaporation method. All formulations were characterized by means of diferential scanning calorimetry, infrared spectroscopy and powder X-ray diffractometry. Mucoadhesive tablets of binary systems were formulated by direct compression using chitosan as mucoadhesive polymer. The in vitro release profiles of tablets were conducted in simulated saliva and, the drug permeation studies, across porcine buccal mucosa. The results suggest that the rank order effect of cyclodextrins for the drug release was Me-b-CD >HP-b-CD > b-CD, whereas the ex vivo studies showed that the tablets containing chitosan significantly increased the transport of the drug compared to their free complexes. Finally, histological assessment revealed loss of the superficial cell layers, which might be attributed to the presence of cyclodextrins

Fibrous polymeric buccal film formulation, engineering and bio-interface assessment

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Polymer based dosages form the mainstay of drug delivery systems either as simple matrix carrier materials or active release behavior modulating agents. In addition, several techniques have been developed further to deliver novel polymeric structures. One such method is electrospinning (ES); a maturing process which is operational at the ambient environment and enables drug loading (in molecularly dispersed form) directly into a fibrous polymer matrix system. Since there is an impending need to address healthcare challenges arising from an increase in the aging population (requiring enhanced treatments), the ES method was used to develop fibrous polymer composite-indomethacin (INDO) films for potential use in the buccal region. Films were assessed for their inter-facial behavior at bio-interfaces (in-vitro and ex-vivo). Polymeric excipients possessing an established profile for commercial dosage form development were selected. Fibrous films (all fibre components <400 nm) were characterised using DSC, TGA, FTIR, Raman and XRD. DSC and XRD demonstrated INDO change from crystalline to amorphous state. FTIR and Raman data suggest INDO, PVP and co-polymers (Methocel™ E5, Methocel™ E15 and Tween® 80) were integrated in stable fashion into filamentous structures via ES. Variable INDO release behavior from several matrices was observed suggesting a potential route to tailor drug release based on polymeric excipient use and ratio. Furthermore, permeation studies using a porcine buccal model demonstrated sustained permeation once dosages are attached to the buccal mucosa. The insoluble nature of cellulose excipients were used to promote sustained release while the use of Tween® 80 surfactant was used to enhance permeation of INDO through polymer interaction with excised tissue. Finally, histology studies indicate polymer excipient selection impacts the bio-interface. In summary, a facile approach to formulate, encapsulate and engineer fibrous polymeric buccal films (on demand) is shown. The method enables drug dispersion directly within the composite polymeric system, which has a clear impact on drug release, in-vitro and ex-vivo bio-interaction

Development of self nano emulsifying drug delivery systems (SNEDDS) for the treatment of Leishmaniasis

The aim of this Doctoral Thesis is the methodology of investigating various types and proportions of oils, surfactants and co-solvents in the development of self-emulsifying drug delivery systems (SNEDDS), which are intended for the oral administration of active pharmaceutical ingredients. In addition, the possibility of incorporating multifunctional polymers and ionic liquids into these systems as alternative excipients which provide several advantages was investigated and their therapeutic efficacy in vitro, ex vivo and in vivo was evaluated. In particular, the first study aimed to investigate various combinations of the concentration of the excipients for the manufacture of preconcentrates of self-emulsifying drug delivery systems and their evaluation at various dilution ratios in different aqueous media. The most suitable formulation was chosen to carry out the incorporation of different concentrations of permeation enhancer and the Amphotericin B. Trimethyl-chitosan was used for this purpose, due to its improved absorption through paracellular transport through the tight synapses of cells in the small intestine. In addition, cellular studies were carried out in order to investigate the penetration of the active pharmaceutical ingredient and the cell viability after the application of the produced formulations. The second study focused on investigating the interaction of ionic liquids for the preparation of preconcentrates of self-emulsifying delivery systems of Amphotericin B, in order to enhance the aqueous solubility and permeability of the drug. Three different types of imidazole ionic liquids, namely 1-butyl-3-methylimidazole hexafluorophosphate (BMIMPF6), 1-butyl-3-methylimidazole tetrafluoroborate (BMIMBF4), and 1-hexyl-3-methylimidazole chloride (HMIMCl), which are found in liquid form at ambient temperature, were integrated into the already evaluated system of the previous study and evaluated in vitro in Caco-2 cells in terms of cell permeability and viability. The next stage of the study was a combination of the two previous studies and evaluated trimethyl-chitosan (TMC) and 1-hexyl-3-methylimidazolium chloride (HMIMCl) as enhancers of the absorption of Amphotericin B by the developed self-emulsifying systems. The static digestion model (in vitro) and the non-inverted intestinal gut sac model (ex vivo) were used to simulate the physiological process of drug absorption to predict the in vivo behavior. The in vivo evaluation of the therapeutic efficacy of the self-emulsifying systems was performed after oral administration to rats, in conjunction with the intravenous administration of a commercial formulation of Amphotericin B.Σκοπός της παρούσας Διδακτορικής Διατριβής είναι η μεθοδολογία διερεύνησης διαφόρων ειδών και αναλογιών ελαίων, επιφανειδραστικών ουσιών και συν-διαλυτών στην ανάπτυξη αυτογαλακτωματοποιούμενων συστημάτων χορήγησης φαρμάκων (SNEDDS), τα οποία προορίζονται για την από του στόματος χορήγηση δραστικών ουσιών. Επιπλέον, διερευνήθηκε η δυνατότητα ενσωμάτωσης πολυλειτουργικών πολυμερών και ιοντικών υγρών σε αυτά τα συστήματα ως εναλλακτικά έκδοχα τα οποία παρέχουν αρκετά πλεονεκτήματα και αξιολογήθηκε η θεραπευτική αποτελεσματικότητάς τους in vitro, ex vivo και in vivo. Συγκεκριμένα, η πρώτη μελέτη είχε ως σκοπό την διερεύνηση διαφόρων συνδιασμών της συγκέντρωσης των εκδόχων για την κατασκευή προσυμπυκνωμάτων αυτογαλακτωματοποιούμενων συστημάτων χορήγησης φαρμάκων και την αξιολόγηση τους σε διάφορες αναλογίες αραίωσης ως προς διαφορετικά υδατικά μέσα. Η καταλληλότερη σύνθεση επιλέχτηκε για να πραγματοποιηθεί η ενσωμάτωση διαφορετικών συγκεντρώσεων ενισχυτικού διαπέρασης και της δραστικής ουσίας Αμφοτερικίνης Β. Η τριμεθυλ-χιτοζάνη χρησιμοποιήθηκε για το σκοπό αυτό, λόγω της βελτιωμένης απορρόφησή της μέσω παρακυτταρικής μεταφοράς μέσω των στενών συνάψεων των κυττάρων στο λεπτό έντερο. Επιπλέον, πραγματοποιήθηκαν κυτταρικές μελέτες, προκειμένου να διερευνηθεί η διαπέραση της δραστικής ουσίας και η κυτταρική βιωσιμότητα έπειτα από την εφαρμογή των παραχθέντων σκευασμάτων. Η δεύτερη μελέτη εστίασε στην διερεύνηση της αλληλεπίδρασης των ιοντικών υγρών για την παρασκευή προσυμπυκνωμάτων αυτογαλακτωματοποιούμενων συστημάτων χορήγησης Αμφοτερικίνης Β, προκειμένου να ενισχυθεί η υδατική διαλυτότητα και η διαπερατότητα της δραστικής ουσίας. Τρείς διαφορετικοί τύποι ιοντικών υγρών ιμιδαζολίου και συγκεκριμένα το εξαφθοροφωσφορικό 1-βουτυλ-3-μεθυλιμιδαζόλιο (BMIMPF6), το τετραφθοροβορικό 1-βουτυλ-3-μεθυλιμιδαζόλιο (BMIMBF4) και το χλωριούχο 1-εξυλ-3-μεθυλιμιδαζόλιο (HMIMCl), τα οποία βρίσκονται σε υγρή μορφή σε θερμοκρασία περιβάλλοντος, ενσωματώθηκαν στο ήδη αξιολογημένο σύστημα της προηγούμενης μελέτης και αξιολογήθηκαν in vitro σε κύτταρα Caco-2 ως προς την κυτταρική διαπερατότητα αλλά και βιωσιμότητα. Το επόμενο στάδιο της μελέτης αποτέλεσε συνδιασμό των δύο προηγούμενων μελετών και αξιολογήθηκε η τριμεθυλ-χιτοζάνη (TMC) και το χλωριούχο 1-εξυλ-3-μεθυλιμιδαζόλιο (HMIMCl) ως ενισχυτές της απορρόφησης της Αμφοτερικίνης Β από τα ανεπτυγμένα αυτογαλακτωματοποιούμενα συστήματα. Το μοντέλο στατικής πέψης (in vitro) και το μοντέλο μη ανεστραμμένου εντερικού σάκου (ex vivo), χρησιμοποιήθηκαν για την προσομοίωση της φυσιολογικής διαδικασίας απορρόφησης του φαρμάκου, ώστε να προβλεφθεί η in vivo συμπεριφορά. Η in vivo αξιολόγηση της θεραπευτικής αποτελεσματικότητας των αυτογαλακτωματοποιούμενων συστημάτων πραγματοποιήθηκε έπειτα από του στόματος χορήγηση σε επίμυες, σε σύγκιση με την ενδοφλέβια χορήγηση εμπορικού σκευάσματος Αμφοτερικίνης Β