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Controlled Drug Release from Biodegradable Hydrogels.
Oborná, Jana ; Chýlková, Jaromíra (referee) ; Kráčmar, Stanislav (referee) ; Kučerík, Jiří (referee) ; Vávrová, Milada (advisor)
This dissertation is focused on the controlled release of drugs from a biodegradable amphiphilic hydrogel based on hydrophobic poly(lactic acid), poly(glycolic acid) and hydrophilic poly(ethylene glycol) (PLGA-PEG-PLGA, ABA) and its modification with itaconic anhydride (ITA). The resulting ,-itaconyl(PLGA-PEG-PLGA) copolymer is referred to as ITA/PLGA-PEG-PLGA/ITA or ITA/ABA/ITA. Itaconic acid provides reactive double bonds and a functional carboxyl group at the ends of the PLGA-PEG-PLGA copolymer chain, thereby rendering the modified ITA/ABA/ITA copolymer less hydrophobic and offering the possibility of forming a carrier for hydrophilic drug substances. These functional copolymers are thermosensitive and change in the external environment (e.g. temperature) causes a sol-gel phase transition due to the formation of micellar structure. The bioactive substances can thus be mixed with a copolymer which is in a low viscous phase (sol phase) and subsequently the mixture can be injected into patient's body at the target site where it forms a gel at 37 °C. This hydrogel becomes a drug depot, which gradually releases the active substance. Prediction of the substance’s release profile from the hydrogel is an effective tool to determine the frequency of administration, potentially enhancing efficacy, and assessment of side effects associated with dosing. The analgesic paracetamol and the sulfonamide antibiotic sulfathiazole were used as model drugs, representing hydrophilic and hydrophobic substances, respectively. The active substances had a significant effect on the resulting hydrogel stiffness. Type of solvent, incubation medium and nanohydroxyapatite also influenced on the gel stiffness and subsequent stability of the hydrogel-drug system. Controlled release of drugs took place in simulated conditions of the human body. Verification of Korsmeyer-Peppas (KP) drug-release model is also discussed in this thesis. The KP model was found suitable for simulating the release of sulfathiazole from ABA and ITA/ABA/ITA hydrogels. On the contrary, the performance of KP model was not suitable for describing the release of paracetamol from the ABA hydrogels. Therefore, a new regression model suitable for both buffered simulated media and water has been proposed. The proposed model fitted better the release of both sulfathiazole and paracetamol from composite material prepared from ABA hydrogel and nanohydroxyapatite.
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Hyaluronic gels for control release of active substances
Hekrlová, Veronika ; Smilek, Jiří (referee) ; Klučáková, Martina (advisor)
This diploma thesis is focused on the development of materials based on oxidized hyaluronic acid derivative (HA-Ox) crosslinked using bifunctional alkoxyamine POA. Hydrogels have been studied as potential matrices for the controlled release of biological drugs. For this purpose, hydrogels containing bovine serum albumin (BSA) as model of the active substances were prepared. The properties of the hydrogels were affected by the concentration of the derivative (10 mg / ml, 20 mg / ml and 30 mg / ml). In the first part of the work, the viscoelastic properties, swelling and dry matter content of the prepared hydrogels were evaluated. The dry matter of the starting hyaluronan derivative and the weight of the polymer network in the hydrogels were determined gravimetrically and by TGA (in all cases about 80% w/w). The difference in weight of the polymer contained in the hydrogels before and after swelling showed that the non-crosslinked sol leaches out of the hydrogel during swelling (about 10-20% w/w). Due to this phenomenon, hydrogels with a concentration of 10 mg / ml are depleted of hydrogels, while their more concentrated analogues swell even after the sol has washed off. The sizes of elastic moduli needed to calculate the mesh of the polymer network were determined using rheological measurements (amplitude and frequency test). The mesh size of the polymer network itself is calculated using two commonly used theories: Equilibrium SwellingTheory (EST) and Rubber Elasticity Theory (RET). The mesh size of BSA-free gels with a derivative concentration of 10 to 30 mg/ml was determined according to EST to 347 ± 29 nm, 319 ± 15 nm, 295 ± 6 nm and according to RET345 ± 30 nm, 308 ± 14 nm, 268 ± 5 nm. For hydrogels with BSA, the mesh sizes of the polymer network were determined according to EST 373 ± 34 nm, 307 ± 11 nm, 281 ± 7 nm and according to RET 372 ± 32 nm, 297 ± 11 nm, 258 ± 6 nm. The mesh size of the polymer network decreases with higher derivative concentration. In the second part of the work, the release of the model active substance BSA was monitored spectrophotometrically using fluorescent labeling. Using the Korsmeyer-Peppas model, it was found that diffusion release is the primary mechanism.
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Hyaluronic gels for control release of active substances
Hekrlová, Veronika ; Smilek, Jiří (referee) ; Klučáková, Martina (advisor)
This diploma thesis is focused on the development of materials based on oxidized hyaluronic acid derivative (HA-Ox) crosslinked using bifunctional alkoxyamine POA. Hydrogels have been studied as potential matrices for the controlled release of biological drugs. For this purpose, hydrogels containing bovine serum albumin (BSA) as model of the active substances were prepared. The properties of the hydrogels were affected by the concentration of the derivative (10 mg / ml, 20 mg / ml and 30 mg / ml). In the first part of the work, the viscoelastic properties, swelling and dry matter content of the prepared hydrogels were evaluated. The dry matter of the starting hyaluronan derivative and the weight of the polymer network in the hydrogels were determined gravimetrically and by TGA (in all cases about 80% w/w). The difference in weight of the polymer contained in the hydrogels before and after swelling showed that the non-crosslinked sol leaches out of the hydrogel during swelling (about 10-20% w/w). Due to this phenomenon, hydrogels with a concentration of 10 mg / ml are depleted of hydrogels, while their more concentrated analogues swell even after the sol has washed off. The sizes of elastic moduli needed to calculate the mesh of the polymer network were determined using rheological measurements (amplitude and frequency test). The mesh size of the polymer network itself is calculated using two commonly used theories: Equilibrium SwellingTheory (EST) and Rubber Elasticity Theory (RET). The mesh size of BSA-free gels with a derivative concentration of 10 to 30 mg/ml was determined according to EST to 347 ± 29 nm, 319 ± 15 nm, 295 ± 6 nm and according to RET345 ± 30 nm, 308 ± 14 nm, 268 ± 5 nm. For hydrogels with BSA, the mesh sizes of the polymer network were determined according to EST 373 ± 34 nm, 307 ± 11 nm, 281 ± 7 nm and according to RET 372 ± 32 nm, 297 ± 11 nm, 258 ± 6 nm. The mesh size of the polymer network decreases with higher derivative concentration. In the second part of the work, the release of the model active substance BSA was monitored spectrophotometrically using fluorescent labeling. Using the Korsmeyer-Peppas model, it was found that diffusion release is the primary mechanism.
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Controlled Drug Release from Biodegradable Hydrogels.
Oborná, Jana ; Chýlková, Jaromíra (referee) ; Kráčmar, Stanislav (referee) ; Kučerík, Jiří (referee) ; Vávrová, Milada (advisor)
This dissertation is focused on the controlled release of drugs from a biodegradable amphiphilic hydrogel based on hydrophobic poly(lactic acid), poly(glycolic acid) and hydrophilic poly(ethylene glycol) (PLGA-PEG-PLGA, ABA) and its modification with itaconic anhydride (ITA). The resulting ,-itaconyl(PLGA-PEG-PLGA) copolymer is referred to as ITA/PLGA-PEG-PLGA/ITA or ITA/ABA/ITA. Itaconic acid provides reactive double bonds and a functional carboxyl group at the ends of the PLGA-PEG-PLGA copolymer chain, thereby rendering the modified ITA/ABA/ITA copolymer less hydrophobic and offering the possibility of forming a carrier for hydrophilic drug substances. These functional copolymers are thermosensitive and change in the external environment (e.g. temperature) causes a sol-gel phase transition due to the formation of micellar structure. The bioactive substances can thus be mixed with a copolymer which is in a low viscous phase (sol phase) and subsequently the mixture can be injected into patient's body at the target site where it forms a gel at 37 °C. This hydrogel becomes a drug depot, which gradually releases the active substance. Prediction of the substance’s release profile from the hydrogel is an effective tool to determine the frequency of administration, potentially enhancing efficacy, and assessment of side effects associated with dosing. The analgesic paracetamol and the sulfonamide antibiotic sulfathiazole were used as model drugs, representing hydrophilic and hydrophobic substances, respectively. The active substances had a significant effect on the resulting hydrogel stiffness. Type of solvent, incubation medium and nanohydroxyapatite also influenced on the gel stiffness and subsequent stability of the hydrogel-drug system. Controlled release of drugs took place in simulated conditions of the human body. Verification of Korsmeyer-Peppas (KP) drug-release model is also discussed in this thesis. The KP model was found suitable for simulating the release of sulfathiazole from ABA and ITA/ABA/ITA hydrogels. On the contrary, the performance of KP model was not suitable for describing the release of paracetamol from the ABA hydrogels. Therefore, a new regression model suitable for both buffered simulated media and water has been proposed. The proposed model fitted better the release of both sulfathiazole and paracetamol from composite material prepared from ABA hydrogel and nanohydroxyapatite.
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