京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18133号 / 医博第3853号 / 新制||医||1001(附属図書館) / 30991 / 京都大学大学院医学研究科医学専攻 / (主査)教授 坂田 隆造, 教授 瀬原 淳子, 教授 開 祐司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19010号 / 工博第4052号 / 新制||工||1623(附属図書館) / 31961 / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 田畑 泰彦, 教授 岩田 博夫, 教授 木村 俊作 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19189号 / 工博第4066号 / 新制||工||1627(附属図書館) / 32181 / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 北川 進, 教授 濵地 格, 教授 森 泰生 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

Etoposide has been shown to be effective in the treatment of testicular and small-cell lung cancers, lymphoma, leukemia and Kaposi's sarcoma. Several clinical investigations have suggested that the prolonged maintenance of greater than 1 $\mu$g/ml concentration in plasma would provide better therapeutic response in patients. Thus use of a sustained/controlled release formulation of etoposide was indicated. This investigation focused on the potential for the development of a sustained/controlled release dosage form of etoposide for a 7-15 day delivery using selected polylactic and polylactic-co-glycolic acid polymers. During the course of studies involving the enhancement of aqueous solubility of etoposide in our laboratory evidence of a potential thermally induced polymorphic transition was detected. Therefore, further characterization of this phenomenon was also included in this investigation. Thermal behavior of etoposide was characterized by differential scanning calorimetry, thermal gravimetric analysis, X-ray diffractometry, mass spectroscopy, IR spectra and HPLC analyses. A method for the preparation of micromatrices of etoposide was developed utilizing a suspension and solvent evaporation technique. DSC, IR and NMR investigations did not indicate any potential etoposide-polymer interaction. Etoposide I, a monohydrate, underwent a dehydration reaction between 85-115$\sp\circ$C to yield Etoposide Ia, which upon further heating melted at 198$\sp\circ$C and crystallized to a new polymorph, Etoposide IIa at 206$\sp\circ$C. Etoposide IIa was found to melt at 269$\sp\circ$C and converted to its hydrated form, Etoposide II when exposed to atmosphere at room temperature. The polymorphic transition was found to be irreversible and monotropic. Etoposide I, the currently marketed drug was used in all delivery systems examined. Formulation studies with polylactic acid polymers indicated that the molecular weight of the polymer was a key parameter in influencing the percent of drug entrapped in the micromatrices, particles size distribution and the drug release profiles. Glycolide-containing polymers demonstrated control of etoposide release only at low drug loadings: larger micromatrices showing better control. Polylactic acid 50,000 at 1:5 and 1:15 drug to polymer ratios exhibited maximum rate of drug release of 1.57 mg/hr. At this release rate, a delivery system containing 350 mg of etoposide could be expected to maintain a plasma concentration of 1.08 $\mu$g/ml over a period of 7 days. Additionally, drug release profile of polylactide-co-glycolide (85:15, 75-180 $\mu$m) microsphere formulation with 1:10 drug to polymer ratio, was found to be more appropriate for a 15-day release system based upon 700 mg of etoposide.

The capability of precisely controlling the kinetics of therapeutic delivery at the optimal location and rate for a given patient would have great potential to improve health and well-being in a range of current drug therapies (insulin, chemotherapeutics, vaccines, etc.). Indeed, if successfully developed, locally administered injectable drug delivery vehicles capable of remotely-triggered release would be the gold standard for many treatments. Multiple injectable nanocomposites have been investigated for this purpose that are generally comprised of a thermosensitive polymeric material and superparamagnetic iron oxide nanoparticles (SPIONs). SPIONs generate heat when exposed remote alternating magnetic fields (AMFs), and the transfer of this heat to thermosensitive polymers can be used to control the release of therapeutics. Ideally, these systems would be capable of returning to their original state and basal release rate when the external AMF trigger is removed. Several novel injectable nanocomposite materials that explore interactions between SPIONs and thermosensitive polymers to mediate drug release, from the macroscale to the nanoscale, were developed and demonstrated to be capable of remotely-triggered, AMF-mediated enhanced release. The macroscale magnetic nanocomposites have thermosensitive hydrogel and/or microgel components that regulate release based on the heat produced from SPIONs in response to an external AMF. On the millimeter-scale, a microinjection system capable of producing thermosensitive hydrogel beads that could potentially incorporate SPIONs is described. On the nanoscale, nanoparticles with a glass transition temperature and thermosensitive microgels are combined with SPIONs and investigated for their remote, AMF-mediated release characteristics. The engineered macroscale and nanoscale systems are capable of up to ~4:1 and ~7:1 enhancements in release due to an AMF application, respectively, compared to the basal release rate. Collectively, these nanocomposites represent a promising stride towards improved remote-actuation of drug release and a stepping stone for future attempts at precisely controlling the site and kinetics of drug release. / Thesis / Doctor of Philosophy (PhD) / This thesis focuses on the development of nanocomposite materials that can be injected into a specific location in the body and deliver therapeutic drugs by a remote-controlled process. These nanocomposites are composed of magnetic particles and polymers that respond to changes in temperature. The combination of these materials results in nanocomposites that can change their properties in response to specific magnetic fields to switch from releasing drug slowly (or not at all) to releasing drug quickly on demand. The changes are fully reversible and solely depend on whether the external magnetic field is switched on or off. These novel systems offer an alternative to therapies that require frequent injections, such as insulin for diabetes, or therapies that need the drug to be released in very precise locations, such as cancer treatments, and could improve the safety, reduce the risk of side effects, and lower the cost of many medical treatments.

The feasibility of hot melt extrusion (HME) was explored for development of amorphous solid dispersion systems. Controlled release formulations were developed using a cellulose based derivative, AffinisolTMHPMC 100cP and 4M grades. BCS class II drugs ibuprofen and posaconazole were selected due to their difference in glass transition temperature and lipophilicity. This study focused on investigation of the impact the material attributes and process parameters on the critical quality attributes in preparation of amorphous solid dispersions using hot melt extrusion. The critical quality attributes were sub divided into three main attributes of material, process and product. Rheology of ibuprofen-Affinisol 100cP from melt phase to extrudate phase was tracked. A partial factorial design was carried out to investigate the critical parameters affecting HME. For optimisation of 40%IBU-Affinisol 100cP blends, a feed rate of 0.6kg/hr, screw speed of 500rpm and screw configuration with two mixing elements were found to be optimum for single phase extrudates. ATR-FTIR spectroscopy was found to be an indirect technique of choice in predicting the maximum ibuprofen drug load within extrudates. Prediction was based on the prepared extrudates without charging them to stability conditions. An alternative strategy of incorporation of di-carboxylic acids to increase the dissolution of posaconazole-Affinisol 4M blends was investigated. Succinic acid and L- malic acid incorporation was found to increase the dissolution of posaconazole. Although, the extrudates crystallised out quicker than the naïve posaconazole-Affinisol 4M, but free posaconazole formed eutectic and co-crystal with succinic and L-malic acid within extrudates. This lead to an increase in dissolution of the extrudates compared to day 0.

No description available.

No description available.

No description available.

No description available.