Thesis (Ph. D.)--University of Adelaide, 1986. / Includes bibliographical references.

Thesis (Ph.D.)--Murdoch University, 2002. / Thesis submitted to the Division of Veterinary and Biomedical Sciences. Bibliography: leaves 237-283.

Thesis (Ph.D.) -- University of Adelaide, Dept. of Chemistry, 2000. / Includes errata attached to first leaf. Includes bibliographical references.

Thesis (Ph. D.)--Textile and Fiber Engineering, Georgia Institute of Technology, 2006. / Srinivasarao, Mohan, Committee Chair ; Bunz, Uwe, Committee Co-Chair ; Griffin, Anselm, Committee Member ; Tolbert, Laren, Committee Member ; Park, Jung, Committee Member ; Beckham, Haskell, Committee Member. Includes bibliographical references.

Οι κυκλοδεξτρίνες είναι κυκλικοί ολιγοσακχαρίτες αποτελούμενοι από μόρια α-D-γλυκοπυρανόζης συνδεδεμένα με α-1→4 γλυκοζιτικούς δεσμούς. Λόγω στερεοχημικών περιορισμών οι κυκλοδεξτρίνες δεν έχουν απόλυτα κυλινδρικό σχήμα αλλά μοιάζουν περισσότερο με κόλουρο κώνο. Αποτέλεσμα της χαρακτηριστικής των δομής είναι η δημιουργία μιας υδρόφιλης εξωτερικής επιφάνειας και μιας υδρόφοβης εσωτερικής κοιλότητας. Στην εσωτερική κοιλότητα μπορούν να εισέλθουν, μερικά ή ολικά, υδρόφοβα μόρια τα οποία αλληλεπιδρώντας μέσω ασθενών διαμοριακών αλληλεπιδράσεων σχηματίζουν σύμπλοκα έγκλεισης. Ο σχηματισμός συμπλόκων έγκλεισης βιοδραστικών ενώσεων με κυκλοδεξτρίνες αυξάνει την διαλυτότητα δυσδιάλυτων στο νερό βιοδραστικών ενώσεων, βελτιώνει την βιοδιαθεσιμότητά τους, αυξάνει την σταθερότητά τους και μειώνει σημαντικά τυχόν παρενέργειές των. Μια ακόμη τεχνική που χρησιμοποιείται για την αύξηση της διαλυτότητας δυσδιάλυτων στο νερό βιοδραστικών ενώσεων είναι η διαλυτοποίησή τους στο εσωτερικό μικυλλίων επιφανειοδραστικών ενώσεων. Η τεχνική αυτή προσφέρει ανάλογα πλεονεκτήματα όπως και η συμπλοκοποίηση των βιοδραστικών ενώσεων με τις κυκλοδεξτρίνες και χρησιμοποιείται ήδη σε εμπορικά σκευάσματα. Στην παρούσα εργασία μελετήθηκε η επίδραση της φύσης και της συγκέντρωσης κυκλοδεξτρινών (β-CD, Μe-β-CD, HP-β-CD, HP-γ-CD) στην διαλυτότητα της βιοδραστικής ένωσης ρισπεριδόνη (risperidone). Επίσης, προσδιορίσθηκε η μέθοδος παρασκευής ενώσεων έγκλεισης της ρισπεριδόνης με τις παραπάνω κυκλοδεξτρίνες χρησιμοποιώντας κατάλληλες τεχνικές χαρακτηρισμού των σχηματιζόμενων στερεών. Ακόμη, μελετήθηκε η διαλυτοποίηση της ρισπεριδόνης σε μικύλλια τριών επιφανειοδραστικών ενώσεων (SDS, Brij35, Cremophor EL). Η ρισπεριδόνη είναι μια αντιψυχωσική βιοδραστική ένωση που ανήκει σε μια νέα κατηγορία ενώσεων τα παράγωγα της benzisoxazole. Η φαρμακολογική δράση της εστιάζεται στους υποδοχείς της D2 (dopamine) και 5-ΗΤ2 (serotonin) στον εγκέφαλο. Πρόκειται για μια δυσδιάλυτη στο νερό βιοδραστική ένωση με αποτέλεσμα να δημιουργούνται προβλήματα στις φαρμακοτεχνικές μορφές της. Είναι ασθενής βάση με δύο στάδια πρωτονίωσης με συνέπεια η διαλυτότητά της να μειώνεται με την αύξηση του pH. Παρασκευάσθηκαν στερεά μίγματα της ρισπεριδόνης με τις κυκλοδεξτρίνες (β-CD, Μe-β-CD, HP-β-CD, HP-γ-CD) χρησιμοποιώντας διαφορετικές τεχνικές(απλή ανάμιξη, λειοτρίβηση με τον σχηματισμό πάστας, συγκαταβύθιση και λυοφιλοποίηση) προκειμένου να προσδιορισθεί η τεχνική ή οι τεχνικές που οδηγούν στο σχηματισμό συμπλόκου έγκλεισης. Για την μελέτη των στερεών μιγμάτων και την πιστοποίηση του σχηματισμού συμπλόκων έγκλεισης μεταξύ της ρισπεριδόνης και των υπό μελέτη κυκλοδεξτρινών χρησιμοποιήθηκαν οι τεχνικές α) Περίθλαση Ακτίνων-Χ, β) Διαφορική Θερμιδομετρία Σάρωσης και γ) Ηλεκτρονική Μικροσκοπία Σάρωσης. Επίσης μελετήθηκε η στερεοχημεία των σχηματιζόμενων συμπλόκων της ρισπεριδόνης με τις υπό μελέτη κυκλοδεξτρίνες με την τεχνική του Πυρηνικού Μαγνητικού Συντονισμού (NMR). Για την παρασκευή των διαλυμάτων χρησιμοποιήθηκε ο δευτεριωμένος διαλύτης d6-DMSO. Πραγματοποιήθηκαν μελέτες διαλυτότητας της ρισπεριδόνης σε υδατικά διαλύματα παρουσία διαφορετικών συγκεντρώσεων των β-CD, Μe-β-CD, HP-β-CD, HP-γ-CD σε θερμοκρασίες 25, 30 και 35°C σε διαλύματα PBS με pH=10. Η μελέτη της επίδρασης των επιφανειοδραστικών ενώσεων έγινε στους 25°C και σε pH=10. Οι τεχνικές της διαφορικής θερμιδομετρίας σάρωσης και περίθλασης ακτίνων-Χ είναι οι καταλληλότερες για την μελέτη και τον χαρακτηρισμό των στερεών συμπλόκων της ρισπεριδόνης με τις κυκλοδεξτρίνες. Συγκεκριμένα, η απουσία της ισχυρής ενδόθερμης κορυφής που αντιστοιχεί στο σημείο τήξεως της ρισπεριδόνης στα θερμογραφήματα των στερεών μιγμάτων που παρασκευάσθηκαν με την μέθοδο της συγκαταβύθισης αποτελεί σαφή ένδειξη για τον σχηματισμό συμπλόκων έγκλεισης της ρισπεριδόνης με τις κυκλοδεξτρίνες. Ανάλογα, στα φάσματα περίθλασης ακτίνων-X η απουσία των χαρακτηριστικών κορυφών της ρισπεριδόνης στα μίγματα που παρασκευάσθηκαν με την μέθοδο της συγκαταβύθισης αποτελεί μια επιπλέον ένδειξη για τον σχηματισμό συμπλόκων ενώσεων μεταξύ της ρισπεριδόνης και των υπό μελέτη κυκλοδεξτρινών. Αντίθετα, η τεχνική της ηλεκτρονικής μικροσκοπίας σάρωσης δεν αποτελεί από μόνη της ασφαλή τεχνική για την ταυτοποίηση των συμπλόκων έγκλεισης μεταξύ τη ρισπεριδόνης και των κυκλοδεξτρινών. Από την μελέτη των φασμάτων NMR των διαλυμάτων που περιείχαν σε διάφορες αναλογίες ρισπεριδόνη και τις υπό μελέτη κυκλοδεξτρίνες προσδιορίσθηκε η στερεοχημεία των σχηματιζόμενων συμπλόκων. Από την μελέτη των ισοθέρμων διαλυτότητας διαπιστώθηκε ότι: α) η διαλυτότητα της ρισπεριδόνης αυξάνει με την συγκέντρωση της κυκλοδεξτρίνης σε όλες τις θερμοκρασίες για όλες τις κυκλοδεξτρίνες που μελετήθηκαν και β) οι ισόθερμοι διαλυτότητας είναι της μορφής AL στην οποία όλα τα σχηματιζόμενα σύμπλοκα είναι ευδιάλυτα και έχουν στοιχειομετρία 1:1. Στους 25°C, την μεγαλύτερη συμπλεκτική ικανότητα παρουσίασε η β- CD. Οι Me-β-CD και HP-β-CD παρουσίασαν μικρότερη συμπλεκτική ικανότητα ενώ η συμπλεκτική ικανότητα για την HP-γ-CD ήταν σημαντικά μειωμένη. Με βάση την συμπλεκτική ικανότητά τους, οι υπό μελέτη κυκλοδεξτρίνες μπορούν να ταξινομηθούν με την ακόλουθη σειρά: β-CD > Me-β-CD > HP-β-CD >> HP-γ-CD Η αύξηση της θερμοκρασίας δεν επηρέασε την μορφή των ισοθέρμων διαλυτότητας, επηρέασε την διαφορά της συμπλεκτικής ικανότητας των β-CD και Me-β-CD. Στους 30°C, η συμπλεκτική ικανότητα της Me-β-CD ήταν ελάχιστα μικρότερη από αυτή της β-CD ενώ στους 35°C έγινε λίγο μεγαλύτερη σε σύγκριση με την β-CD. Για τις άλλες δύο κυκλοδεξτρίνες HP-β-CD και HP-γ-CD διατηρήθηκε η ίδια κατάσταση και στις δύο θερμοκρασίες. Από την κλίση των ισοθέρμων διαλυτότητας προσδιορίσθηκαν οι σταθερές σχηματισμού των συμπλόκων έγκλεισης της ρισπεριδόνης με τις υπό μελέτη κυκλοδεξτρίνες. Η διαφοροποίηση της συμπλεκτικής ικανότητας των β-CD, Me-β-CD, HP-β-CD και HP-γ-CD μπορεί να αποδοθεί α) στο διαφορετικό μέγεθος της υδρόφοβης κοιλότητας και β) στην διαφορετική υδροφοβικότητα των υποκατεστημένων κυκλοδεξτρινών. Από την μεταβολή των σταθερών σχηματισμού των συμπλόκων με την αύξηση της θερμοκρασίας υπολογίσθηκε η μεταβολή της ενθαλπίας (ΔΗ) και η μεταβολή της εντροπίας (ΔS) για τον σχηματισμό των συμπλόκων. Σε όλες τις κυκλοδεξτρίνες υπολογίσθηκε αρνητική μεταβολή της ενθαλπίας και θετική αλλά μικρή μεταβολή της εντροπίας. Οι μεταβολές αυτές συνδέονται άμεσα με την απελευθέρωση των μορίων νερού ‘υψηλής ενθαλπίας’ που βρίσκονται στην υδρόφοβη κοιλότητα της κυκλοδεξτρίνης και με υδρόφοβες αλληλεπιδράσεις ανάμεσα στην ρισπεριδόνη και στην κυκλοδεξτρίνη. Οι δύο αυτές αλληλεπιδράσεις ευνοούν τον σχηματισμό και την σταθερότητα των σχηματιζόμενων συμπλόκων. Τέλος, από τα πειράματα διαλυτότητας της ρισπεριδόνης παρουσία των επιφανειοδραστικών (SDS, Brij35 και Cremophor EL) διαπιστώθηκε ότι α) την μεγαλύτερη αύξηση διαλυτότητας προκάλεσε το SDS και β) η διαλυτοποιητική ικανότητα του Brij35 ήταν λίγο μικρότερη από αυτή του Cremophor EL. / Cyclodextrins are cyclic oligosaccharides composed of a-D-glucopyranose units connected with a-1→4 glucosidic bonds. Because of stereochemical restrictions, cyclodextrins do not have absolutely a cylindrical shape but they resemble a truncated cone. As a result of their characteristic structure is the formation of a hydrophilic external surface and a hydrophobic internal cavity. In the internal cavity can enter partly or wholly hydrophobic molecules which by interacting through weak intermolecular interactions form inclusion complexes. The inclusion complex formation of bioactive compounds, improves their bioavailability, enhances their stability and reduces considerably the side effects after administration. Another technique which is used for increasing the solubility of water sparingly soluble bioactive compounds is their solubilization in the micelles of surfactants. This technique offers analogous advantages such as the complexation of bioactive compounds with cyclodextrins and is used already in commercial drugs. In this study, the influence of the nature and concentration of cyclodextrins (β-CD, Μe-β-CD, HP-β-CD, HP-γ-CD) was studied on the solubility of the bioactive compound risperidone. It was also determined the inclusion compounds preparation method of risperidone with the above cyclodextrins by using appropriate characterization techniques of the formed solids. In addition, the solubilization of risperidone in micelles of three surfactant compounds (SDS, Brij35, Cremophor EL) was studied. Risperidone is an antipsychotic bioactive compound which belongs to a new chemical class, the benzisoxazole derivatives. Its pharmacological action focuses on the D2 (dopamine) and 5-HT2 (serotonin) receptors in the brain. It is about a water sparingly soluble bioactive compound resulting in problems on its pharmaceutical formulations. It is a weak base, with two protonization stages, and as such its solubility decreases with pH increase. Risperidone solid mixtures with the cyclodextrins (β-CD, Μe-β-CD, HP-β-CD, HP-γ-CD) were prepared by using different techniques (physical mixture, kneading, coprecipitation, lyophilisation) in order to determine the technique or the techniques that lead to the formation of inclusion complex. For the study of solid mixtures and the assessment of inclusion complex formation between the risperidone and the cyclodextrins under investigation the following techniques were used: a) X-Ray Diffraction (XRD) b) Differential Scanning Calorimetry (DSC) and c) Scanning Electron Microscopy (SEM). Furthermore, the stereochemistry of the formed inclusion complexes of risperidone with the specific cyclodextrins was also assessed with the technique of Nuclear Magnetic Resonance (NMR). As a solvent for the preparation of the solutions it was used the deuterated solvent d6-DMSO. Solubility studies in aqueous solutions of risperidone with the cyclodextrins were performed in 25, 30 and 35°C in PBS (phosphate buffered saline) at pH=10. The study of the influence of the surfactant compounds (SDS, Brij35, Cremophor EL) was realised at 25°C and pH=10. The techniques of DSC and XRD are the most appropriate for the investigation and characterization of solid complexes of risperidone with cyclodextrins. Particularly, the absence of the strong endothermic peak which corresponds to the melting point of risperidone in the DSC thermograms of the solid mixtures which were prepared by the coprecipitation method constitutes a clear indication of the inclusion complex formation of risperidone with the cyclodextrins. Accordingly, in the XRD spectra the absence of the characteristic peaks of risperidone in the mixtures prepared by the coprecipitation method comprises an additional indication for the formation of inclusion complexes between risperidone and the cyclodextrins under investigation. On the contrary, the SEM does not constitute per se a safe method for the identification of the inclusion complexes between risperidone and the cyclodextrins. The stereochemistry of the formed inclusion compounds was assessed through the spectra received by the application of NMR on solutions which contained risperidone and the specific cyclodextrins in different proportions. In particular, it was determined which part of risperidone molecule enters the hydrophobic cavity of cyclodetxrin. The study of solubility isotherms showed that: a) solubility of risperidone increases with the concentration of cyclodextrins at all temperatures studied, for all the cyclodextrins studied and b) solubility isotherms have a graphical representation of the AL type, which shows that all formed complexes are water soluble with 1:1 stoichiometry. At 25°C, β-CD presented the greatest complexive ability, Me-β-CD and HP-γ-CD presented a smaller complexive ability whereas that of HP-γ-CD was significantly decreased. Based on the complexive ability, the cyclodextrins under discussion can be classified in the following order: β-CD>Me-β-CD>HP-β-CD>> HP-γ-CD The temperature increase did not affect the solubility isotherms but affected the difference of complexation ability of β-CD and Me-β-CD. At 30°C, the complexation ability of Me-β-CD was slightly smaller than β-CD’s, whereas at 35°C became slightly greater compared to that of β-CD. For the other two cyclodextrins; namely HP-β-CD and HP-γ-CD the same behavior was maintained at both temperatures. From the gradient of the solubility isotherms the inclusion complex formation constants were determined. The differentiation of the complexation ability of cyclodextrins can be attributed a) to the different size of the hydrophobic cavity and b) to the different hydrophobicity of the substituted cyclodextrins. The enthalpy change (ΔH) and the entropy change (ΔS) during complex formation were calculated from the change of the complexation constants with the increase of the temperature. In all of the cyclodextrins it was found negative enthalpy change and positive but small entropy change. These alterations are directly connected to the release of ‘high enthalpy’ water molecules which are located in the cyclodextrin’s hydrophobic cavity and to hydrophobic interactions among risperidone and cyclodextrin. These two interactions favor the complex formation and stability. Finally, from the solubility experiments of risperidone in the presence of surfactant compounds SDS, Brij35 and Cremophor EL, it was established that a) the greatest solubility increase was caused by the SDS and b) the solubilization ability of Brij35 was a little smaller than Cremophor’s one.

Made available in DSpace on 2014-06-11T19:32:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-08-18Bitstream added on 2014-06-13T18:43:05Z : No. of bitstreams: 1 franzini_cm_dr_arafcf.pdf: 2677878 bytes, checksum: 26759573900040571415a3fa5cbf34b2 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Universidade Estadual Paulista (UNESP) / O tratamento das infecções fúngicas sistêmicas impõe grandes dificuldades devido ao fato da terapia endovenosa requerer administração do fármaco solubilizado ou disperso em partículas de diminutas dimensões, além da necessidade de hospitalização. A anfotericina B (AmB) continua sendo um dos antibióticos mais efetivos para tais tratamentos, apesar de sua baixa solubilidade e graves efeitos colaterais. Considerando que microemulsões permitem contornar esses problemas e proporcionar administração oral do fármaco, essas formulações lipídicas contendo AmB estão sendo cada vez mais estudadas. Adicionalmente, a formação de complexos de inclusão com ciclodextrinas (CDs) também tem sido promissora no desenvolvimento de novas formas farmacêuticas. Neste trabalho os parâmetros de formação de microemulsões (MEs) contendo fosfatidilcolina de soja (FS), Tween-20 (Tw) e oleato de sódio (OS) como tensoativos e colesterol (CHO) como fase oleosa e a formação de complexos de inclusão com diferentes derivados de CD e sua incorporação nas MEs foi estudado. Um diagrama de fases pseudoternário foi elaborado objetivando caracterizar MEs. O comportamento reológico e a estruturação interna foram empregadas para avaliação e ainda caracterização por espalhamento dinâmico de luz. Foi avaliado o efeito da proporção de tensoativo e óleo na determinação do diâmetro da fase interna nos sistemas com ou sem AmB, além da avaliação da contribuição da fase oleosa e do tensoativo na incorporação do fármaco nas MEs. Um diagrama de solubilidade de AmB em CDs foi desenvolvido e suas constantes de estabilidade determinadas. O preparo de ME contendo CDs em sua fase aquosa, parâmetros de incorporação de AmB e estudos de liberação foram realizados seguidos de análise termogravimétrica, difração de raios x (DRX) e ressonância magnética nuclear (RMN)... / The fungal infections treatment imposes many difficulties mainly because the intravenous therapy requires administration of solubilized or dispersed drug in particles of smaller dimension beyond the need for hospitalization. Despite its low solubility and serious adverse effects the amphotericin B (AmB) remains one of the most effective antibiotics to the treatment. Microemulsions allow circumvent these problems and provide oral administration. Therefore these lipid formulations containing AmB have been increasingly studied. Additionally, the formation of inclusion complexes with cyclodextrins (CDs) has also been promising in developing new dosage forms. In this work the formation parameters of microemulsions (MEs) containing soybean phosphatidylcholine (FS), Tween-20 (Tw) and sodium oleate (SO) as surfactant and cholesterol (CHO) as oil phase and the formation of inclusion complexes with different CDs derivatives and their incorporation into MEs were studied. The pseudo ternary phase diagram was built in order to characterize MEs. The rheological behavior and internal structure were evaluated and characterized by dynamic light scattering. The effect of the proportion of surfactant and oil phase in the diameter of the internal phase in systems with or without AmB was evaluated. Therefore the contribution of the oil phase and surfactant in the drug loading eficience was studied. The Solubility diagram of AmB in CDs was developed and its stability constants determined. The preparation of ME containing CDs in its aqueous phase, the incorporation AmB parameters and the release studies were performed followed by thermal analysis, x-ray (XRD) diffraction and nuclear magnetic resonance (NMR). The results reveal the MEs formation in regions containing up to 30% surfactant and about 11% of the oil phase. Under polarized light, the interest systems showed a dark background and lamellar structure... (Complete abstract click electronic access below)

Orientadores: Francisco Carlos Groppo, Maria Cristina Volpato / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-20T01:18:43Z (GMT). No. of bitstreams: 1 Serpe_Luciano_M.pdf: 1055627 bytes, checksum: 5bd220cdbda1df9bd75a85c3d1bb9159 (MD5) Previous issue date: 2012 / Resumo: Este estudo teve como objetivo avaliar a eficácia anestésica da formulação de bupivacaína complexada com 2-hidroxipropil-ß-ciclodextrina, comparando-a com soluções comerciais de bupivacaína com e sem vasoconstritor, em dois modelos experimentais: bloqueio do nervo alveolar inferior (BNAI) e infiltração subcutânea em ferida cirúrgica (ISFC). Para o BNAI 30 ratos receberam, próximo ao forame mandibular, 0,2ml de uma das seguintes formulações: bupivacaína 0,5% (Bupi), bupivacaína 0,5% com epinefrina 1:200.000 (Bupi-Epi) e formulação de bupivacaína 0,5% complexada com 2-hidroxipropil-ß-ciclodextrina (Bupi-HP?CD). Os lados contralaterais (controle) receberam solução de NaCl 0,9% ou solução de 2-hidroxipropil-ß-ciclodextrina (HPßCD) sem anestésico local. Foram avaliadas latência, sucesso e duração da anestesia pulpar por meio da aplicação de estímulo elétrico ("pulp tester"). Para a ISFC, 30 animais receberam 0,1mL de cada uma das formulações anestésicas ou o respectivo controle na pata traseira direita, 24h após indução de hipernocicepção (ferida cirúrgica - incisão e sutura). A pata traseira esquerda também recebeu injeção, constituindo o controle sem hipernocicepção. A anestesia foi avaliada pela aplicação de força ao lado da ferida (analgesímetro de von Frey). Os resultados foram submetidos à ANOVA e aos testes de Tukey, Student-Newman-Keuls, Kruskal-Wallis, Log Rank e Qui-Quadrado (alfa = 5%). No BNAI não foram observada s diferenças na latência entre as formulações (p>0,05); Bupi apresentou menor duração de anestesia (p<0,05) que Bupi-Epi e Bupi-HPßCD, sem diferença entre estas (p>0,05). Bupi-Epi apresentou maior sucesso de anestesia que Bupi-HPßCD e esta, maior sucesso que Bupi (p<0,05). Para ISFC, nas patas sem hipernocicepção Bupi-Epi induziu maior duração de anestesia do que Bupi (p<0,05); Bupi-HPßCD não diferiu das demais (p>0,05); quanto ao sucesso, Bupi-Epi induziu maior sucesso que as demais soluções e Bupi-HPßCD, maior sucesso que Bupi (p<0,05). Nas patas com hipernocicepção Bupi-Epi induziu maior sucesso de anestesia do que as demais formulações (p<0,05), sem diferença entre estas (p>0,05). Não houve diferença entre as formulações quanto à duração da anestesia nas patas com hipernocicepção (p>0,05). Concluí-se que a complexação da bupivacaína em HP?CD aumentou a taxa de sucesso, mas não a duração da anestesia no BNAI e na ISFC na ausência de hipernocicepção, em relação à bupivacaína sem aditivos, não sendo eficaz em aumentar a eficácia da bupivacaína em tecido com hipernocicepção. A epinefrina aumentou a eficácia anestésica da bupivacaína, à exceção do modelo de ISFC com hipernocicepção, o qual diminuiu a eficácia de todas as soluções de bupivacaína estudadas / Abstract: The aim of the present study was to evaluate the anesthetic efficacy of 2-hydroxypropyl ß-cyclodextrin bupivacaine formulation, compared with commercial bupivacaine solutions, in two experimental models: inferior alveolar nerve block (IANB) and subcutaneous infiltration in surgical wound (SISW). For IANB, 30 rats received an injection of 0.2mL of one of the following formulations, near to the mandibular foramen: 0.5% bupivacaine (Bupi), 0.5% bupivacaine with 1:200.000 epinephrine (Bupi-Epi), and 0.5% bupivacaine in 2-hydroxypropyl-ß-cyclodextrin inclusion complex (Bupi-HPßCD). The contralateral sides (control) received 0.9% NaCl or anesthetic free 2-hydroxypropyl-ß-cyclodextrin (HPß CD) solution. The onset, success and duration of pulpal anesthesia were assessed by electrical stimulation ("pulp tester"). For SISW, 30 animals received 0.1 mL of each anesthetic formulation (both hind paws) or their respective control, 24 hours after hypernociception induction (surgical wound - incision and suture) in the right hind paw. The left hind paw also received the injection and was the control without hypernociception. Analgesia was evaluated by applying force lateral to the incision (von Frey aesthesiometer). Results were submitted to ANOVA and Tukey, Student-Newman-Keuls, Kruskal-Wallis, Log Rank and Chi-square tests (alfa = 5%). No differences were observed among the formulations concerning IANB onset (p>0.05); Bupi presented lower anesthesia duration (p<0.05) than Bupi-Epi and Bupi-HPßCD, with no difference between these two solutions (p>0.05). Bupi-Epi presented higher anesthesia success than Bupi-HP?CD, which showed higher success than Bupi (p<0.05). For SISW, Bupi-Epi showed higher anesthesia success than Bupi (p<0.05) in the non hypernociceptive paws; Bupi-HPßCD did not differ from the others (p>0.05). In this condition Bupi-Epi provided higher anesthesia success than the other formulations and Bupi-HPßCD presented higher anesthesia success than Bupi (p<0.05). In the hypernociceptive paws, Bupi-Epi promoted higher anesthesia success than the other formulations (p<0.05), with no difference between Bupi-HPß CD and Bupi (p<0.05). No difference among formulations were observed in relation to anesthesia duration in the hypernociceptive paws (p>0.05). In conclusion, the complexation of bupivacaine in HPßCD increased anesthesia success, but not duration in IANB and SISW without hypernociception in relation to bupivacaine; in the presence of hypernociception it did not improved bupivacaine efficacy. Epinephrine increased bupivacaine efficacy, except in SISW model with hypernociception, which decreased efficacy of all bupivacaine solutions studied / Mestrado / Farmacologia, Anestesiologia e Terapeutica / Mestre em Odontologia

M.Sc. / Water is often contaminated with organic and inorganic compounds by natural means and through human activities. Once contaminated, water of this nature has little or no use. However, water that is free from toxic chemicals is essential to both human health and the environment. Current water treatment techniques such as separation by membranes (reverse osmosis), adsorption (activated carbon) and ion exchange are not always very efficient at removing contaminants which may be present in parts per billion (ppb) levels. Techniques need to be developed that are reasonably inexpensive and easy to use, and yet effective at removing both organic and inorganic pollutants to acceptable levels. Adsorption is a technique that has the potential to meet these criteria. In our laboratories, insoluble beta cyclodextrin (β-CD) polymers have been used to remove pollutants from water at concentrations as low as ppb levels. However, they exhibited some disadvantages, such as poor structural integrity and difficulty in recovery. This project sought to deal with these limitations by incorporating functionalized multi-walled nanotubes (f-MWNTs) into the polymer, and then embedding polymer particles in an alginate matrix as small beads for ease of use. The polymer composites, 1% f-MWNTs with β-CD polyurethane, were synthesised and embedded in alginates to form alginate composite beads. Composite beads were tested against a model organic and heavy metal pollutants, namely p-nitrophenol and Pb2+, respectively. The composites were characterized using Fourier Transform Infra Red spectroscopy (FT-IR), Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM) and Energy Dispersive X-ray Spectroscopy (EDXS), among other techniques. The absorption capacity of f-MWNTs, β-CD, and alginates combined proved to be effective and stable adsorbents. They showed an adsorption efficiency of at least 95% for p-nitrophenol at a concentration of 10 mg/L and 98% for Pb2+ at a concentration of 50 mg/L. vii The novel adsorbents show a good thermal stability and maintain their structural integrity after repeated (thirty times) use in recycling experiments. The recycled beads maintained a high average adsorption efficiency of 96%, indicating the potential cost benefit of these materials. As a comparison, the plain calcium alginate (CaAG) beads and plain β-CD polyurethane beads showed an average adsorption of 55% and 74%, respectively, but their structural integrity was significantly compromised during similar recycling. Brunauer Emmett Teller (BET) surface area analysis showed that incorporation of f-MWNTs (1% loading) increased the surface area of the composite beads, and adsorption isotherms showed a good fit with both Langmuir and Freundlich models. This project has demonstrated the use of f-MWNTs as copolymer which improves the structural stability of the polymers, and that the combination of these polymers and alginates provide a potentially useful material for water treatment applications.

M.Sc. / The prevalence of toxic contaminants in water remains a huge challenge for water supplying companies and municipalities. Both organic and inorganic contaminants (especially heavy metals) pollutants are often present in water distribution networks. Organic and inorganic pollutants often co-occur in drinking water networks. However, at present there is no water treatment intervention that simultaneously removes organic and inorganic pollutants from water. Additionally, current water treatment technologies fail to remove these contaminants to parts per billion (ppb or µg.L-1) levels. Methods that can simultaneously remove organic and inorganic pollutants to desired levels need to be developed. In our laboratories, both functionalised and unfunctionalised cyclodextrin (CD) polymers have demonstrated the ability to effectively remove organic species from water at low (ppb) concentrations. Cyclodextrins (CDs), which are cyclic oligomers consisting of glucopyranosyl units linked together through α-1,4-glycosidic linkages, behave like molecular hosts. They are capable of interacting with a range of guest molecules within their cylindrical hydrophobic cavities thereby forming the so-called inclusion complexes. Their solubility in water, however, precludes their application in the removal of organic pollutants from water. This limitation is easily dealt with by polymerizing the CDs into water insoluble polymers with suitable bifunctional linkers. On the other hand, ionic liquids (ILs) have been reported to “absorb” heavy metal ions from aqueous media. ILs are low melting point molten salts that are composed of organic cations (e.g. imidazolium and pyridinium ions) and mostly inorganic anions like Cl–, Br–, [PF6]– and [BF4]–. In this study, the two systems were combined by an initial attachment of the imidazolium or pyridinium rings to the cyclodextrin moiety. Polymerisation of the resulting cyclodextrin-ionic liquid (CD-IL) complexes with a suitable linker produced the corresponding water insoluble CD-IL polymers. This dual system has shown excellent capabilities for the removal of model pollutants such as p-nitrophenol (PNP) and 2,4,6-trichlorophenol (TCP) and chromium (Cr6+) from aqueous media. However, the CD-IL polymers showed very little affinity for the absorption of cadmium from water. TGA and DSC studies showed that these polymers are stable over a wide range of temperatures (100-400 C).

M.Sc. / Water that is free from toxic organic pollutants is essential to human health and the environment at large. Organic contaminants may affect the endocrine system of animals and humans, even when present in very low concentrations (i.e. levels ppb). Current technologies fail to remove these organic compounds efficiently from water at ppb levels. So, the development of new technologies that are capable of removing and degrading organic pollutants from water is crucial. Hence, recently in our laboratories cyclodextrin (CD) polymers have demonstrated that they are capable of removing organic pollutants from water at ppb levels. The research has also demonstrated that both functionalized and unfunctionalized CD polymers can remove organic species to as low as parts per billion (ppb) from water. In this project, Si and Ti based compounds which have been reported to degrade organic compounds through photocatalysis in an aqueous media were incorporated. Firstly, attempts were made to attach the silicon (Si) and titanium (Ti) pendent chains onto the CD moiety to form silicon-based cyclodextrin (Si-CD) and titanium based cyclodextrin (Ti-CD) precursors. The Si-CD precursor was synthesized by attaching the 3-(triethoxysilyl)propyl isocyanate onto the native b-CD moiety. The synthesis of the Si-CD precursor was successful and high yields (80%) of the product were obtained. A hydrolysis of this Si-CD precursor in an inert atmosphere led to the formation of silanol. This was followed by curing the silanol in air, after adding TiO2 nanoparticles, and the Ti-CD precursor was formed. The polymerization of Si-CD with suitable bifunctional linkers was a success and water-insoluble polymers were produced. An attempt to polymerize the Ti-CD precursor failed, because the precursor was decomposed. The Si-CD polymers were tested for their capabilities to encapsulate and destroy organic pollutants from water. 1H NMR, FT-IR and EDX spectroscopic techniques were used to prove the formation of the Si-CD and Ti-CD precursors and their corresponding polymers. The Si-CD polymers showed capabilities of being able to remove organic pollutants (33-55%) from water. Unfortunately, the removal is slightly less efficient than the corresponding native CD polymers. However, their efficiency in removing organic pollutants improved when exposed to light. Moreover, the polymers formed display good thermal stabilities, since they decompose at about 300- 400°C. This is observed from the thermograms obtain ed from DSC and TGA. Their morphological studies showed that most of the Si-CD polymers formed were crystalline. This was observed from the SEM images obtained. Based on the information provided by the FT-IR spectroscopy, the synthesis of the Ti-CD precursor was success. However, the challenge was the fact that it decomposed after a while. Hence, it was difficult polymerize it into a water insoluble polymer. The explanation of this phenomenon is not yet established.