doktorska disertacija
Anja Veronovski (Author), Zoran Novak (Mentor), Željko Knez (Co-mentor)

Abstract

Veliko število polimerov danes v farmaciji uporabljajo za sintezo nosilcev aktivnih substanc. Ti polimeri morajo biti kemijsko stabilni, zanesljivi, z veliko specifično površino, primerno kemijsko strukturo površine in poroznostjo, zagotovili pa naj bi tudi nizke stroške procesiranja. Obetavni kandidati za takšno uporabo so naravni polisaharidi kot alginat, guar, ksantan, agar in citozan. V naših raziskavah smo za pripravo biorazgradljivih organskih aerogelov uporabili alginate. Alginati so varni, stabilni, netoksični in iz pridobljenih obnovljivih virov. Podobni so izvencelični matrici z veliko kemijsko prilagodljivostjo, imajo dobro biološko delovanje, njihova razgradnja pa je vodena encimsko ali celično. V vodnih raztopinah in stiku z divalentnimi kationi kot so Sr2+, Ca2+ in Ba2+ so podvrženi reverzibilnemu geliranju in nastanku ionskih vezi. Namen naše raziskave je bil sintetizirati stabilne biorazgradljive aerogele ter jih uporabiti kot nosilce aktivnih substanc nikotinske kisline in teofilina z namenom kontroliranega sproščanja iz končne formulacije. Za sol-gel sintezo alginatnihhidrogelov smo uporabili dve temeljni metodi ionskega zamreženja: difuzijsko metodo in notranjo vgrajevalno metodo. V primeru prve metode pride do zamreženja z difuzijo ionov iz raztopine v alginatno raztopino in dobimo gel v obliki sferičnih zrn. Prav tako smo okoli sferičnega jedra sintetiziralialginatne membrane zaradi možnosti bolj kontroliranega sproščanja. Pri notranji vgrajevalni metodi se kationi s pomočjo spreminjanja pH sproščajo kontrolirano iz inertnega vira kationov znotraj alginatne raztopine. Po tej metodi dobimo monolitni gel. Po pripravi hidrogela smo z uporabo 100% etanola izmenjali vodo ter dobili alkogel. Etanol smo kasneje odstranili s superkritičnim sušenjem s CO2 (100 bar, 40°C) in dobili aerogel, ki smo ga uporabili kot nosilec aktivnih substanc, dodanih med samo sol-gel sintezo. Alginatne sferične in monolitne aerogele smo analizirali z uporabo DSC, SEM-a ter porozimetrije. Proučevali smo vpliv koncentracije in viskoznosti alginata v začetni raztopini in vpliv uporabljene sintezne metode na sproščanje nikotinske kisline ter teofilina kot modelnih substanc. Izkazalose je, da z višanjem začetne koncentracije in viskoznosti alginatne raztopine dobimo bolj zamrežene aerogele z večjo mehansko močjo. Prav tako je uporaba sinteze z notranjo vgrajevalno metodo med sproščanjem modelne substance le to uspešneje zadržala v aerogelu in s tem upočasnila sproščanje. Proučevali smo tudi vpliv sproščanja aktivnih substanc iz multi-membranskih sferičnih nosilcev v odvisnosti od koncentracije alginata v vodni raztopini ter koncentracije soli CaCl2 in BaCl2. Ker je alginat anionski polisaharid, smo glede na literaturo pričakovali, da ima končni alginatni aerogel afinitetodo vezave in počasnejšega sproščanja ionskih aktivnih substanc. Rezultati so pokazali, da v primeru ionske substance nikotinske kisline z zamreženjem alginata s Ca ioni in večanjem števila membran okoli sferičnega jedra dosežemo kontrolirano sproščanje, medtem ko uporaba Ca ionov za zamreženje alginata v primeru substance teofilina ni bila uspešna, zato smo uporabili Ba ione, ki pa so uspeli v alginatnem aerogelu zadržati substanco daljši čas. Višja kot je bila koncentracija Ba ionov v vodni raztopini za zamreženje alginata, počasnejše je bilo sproščanje teofilina iz multi-membranskega sferičnega aerogela.

Keywords

naravni polisaharidi;organski biorazgradljivi geli;sol-gel sinteza;aerogeli;nosilci aktivnih substanc;kontrolirano dostavljanje aktivnih substanc;

Data

Language: Slovenian
Year of publishing:
Source: Maribor
Typology: 2.08 - Doctoral Dissertation
Organization: UM FKKT - Faculty of Chemistry and Chemical Engineering
Publisher: [A. Veronovski]
UDC: 547.458:544.774.2(043.3)
COBISS: 16904726 Link will open in a new window
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Other data

Secondary language: English
Secondary title: SYNTHESIS AND USE OF ORGANIC BIODEGRADABLE AEROGELS IN CONTROLLED DRUG RELEASE
Secondary abstract: A number of polymers has been nowadays used in the production of carriers for drug delivery applications. These polymers have to be safe, non-toxic, they should possess high surface area, appropriate surface chemistry and porosity, chemical stability and low costs of processing. One of these promising candidates are natural polysaccharides such as alginic acid sodium salt, guar gum, xanthan gum, agar and chitosan. Alginates were used in the present research with the aim of organic biodegradable aerogels preparation. They have been proved to be safe, stable, non-toxic and renewable and have low costs because of their abundance in nature and ease of processing. They are similar to extracellular matrix having high chemical versatility, good biological performance and cell or enzyme-controlled degradability. Alginates are able to undergo reversible gelation in aqueous solution through interaction with divalent cations such as Sr2+, Ca2+ and Ba2+, which create ionic inter-chain bridges. The aim of the present research was to synthesize stable biodegradable aerogels used for controlled drug release of nicotinic acid and theophylline from the formulation. Two fundamental methods of ionic cross-linking were used to prepare alginate hydrogels: the diffusion method and the internal setting method. In the case of the first method cross-linkingis allowed by ion diffusion from a large outer reservoir into an alginate solution. Here single gel beads can be obtained. Also definite number of membranes was synthesized around spherical core to achieve even more controlled drug release. By internal setting method cationic ions are released in a controlled fashion from an inert cationic source within the alginate solution. Controlled release of ions is achieved by changing pH. Heremonolithic gel is obtained. After forming organic hydrogel by sol-gel method, the alcogels are formed by solvent exchange using 100% ethanol. Ethanol is later replaced by liquid CO2 with supercritical drying (100 bar, 40°C) and aerogel, used as a carrier of drugs, is obtained. Alginate aerogels were characterized by DSC, SEM and porosimetry. Drugs were added into alginate solution during sol-gel synthesis. The effects of the alginate concentration, viscosity and synthesis methods on model drug nicotinic acid and theophylline release were investigated. The results showed that by increasing alginate concentration and viscosity of alginate solution more cross-linked aerogels with higher mechanical strength were obtained. Moreover,after using the internal setting method synthesized carriers were more successful to retain drug inside the formulation, what resulted in inhibited drug release. The influence of dug release from multi-membrane spherical aerogels was also studied dependent on alginate solution concentration and CaCl2 and BaCl2 concentration. Since alginate is ionic polysaccharide, the resultant alginate aerogel is expected to bind ionic drugs and release them slower. The effect of the number of membranes on model drugs nicotinic acid and theophylline loading and release was also investigated. Results show that by adding more membranes around the core and using Ca2+ for ionic cross-linking nicotinic acid release was prolonged. Retarded theophylline release was obtained only by using Ba2+ ions for alginate cross-linking. By increasing membrane number and BaCl2 concentration theophylline release was successfully extended, namely in all cases drug release became linear versus time. In the case of nicotinic acid loading increased by adding more membranes around the core, however for theophylline the opposite results were obtained, namely due to the nature of model drugs.
Secondary keywords: natural polysaccharides;organic biodegradable aerogels;sol-gel synthesis;aerogels;drug carriers;controlled drug release;Aerogeli;Disertacije;Polisaharidi;
URN: URN:SI:UM:
Type (COBISS): Dissertation
Thesis comment: Univ. Maribor, Fak. za kemijo in kemijsko tehnologijo
Pages: XVII f., 117 str.
Keywords (UDC): mathematics;natural sciences;naravoslovne vede;matematika;chemistry;crystallography;mineralogy;kemija;organic chemistry;organska kemija;mathematics;natural sciences;naravoslovne vede;matematika;chemistry;crystallography;mineralogy;kemija;physical chemistry;fizikalna kemija;chemistry of surface phenomena and colloids;kemija površinskih pojavov in koloidov;
ID: 82286