Novel techniques for the incorporation of proteins in biodegradable polymeric drug delivery devices for their controlled release
This thesis describes two novel technologies for the encapsulation of proteins in biodegradable polymers. Protein loaded nanofiber nonwovens and microparticles were manufactured and characterized regarding their suitability as drug delivery devices. Chapter 1 gave a detailed overview on the current...
Pharmazeutische Technologie und Biopharmazie
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|Zusammenfassung:||This thesis describes two novel technologies for the encapsulation of proteins in biodegradable polymers. Protein loaded nanofiber nonwovens and microparticles were manufactured and characterized regarding their suitability as drug delivery devices. Chapter 1 gave a detailed overview on the current status of electrospinning as a technique for the generation of nanofibrous scaffolds. Several biodegradable polymers (Poly(L-lactide) (PLLA) Resomer L210, poly(lactide-co-glycolide) (PLGA) Resomer RG858 and Poly(ethylene carbonate) (PEC)) were investigated in Chapter 2 for their application in electrospinning of emulsions. Suitable process parameters were determined for all polymers to generate protein loaded nanofiber nonwovens (NNs). The resulting NNs were examined regarding their morphology and regarding their protein release profile. PLLA NNs released the protein very slowly and in a controlled manner. PLLA NNs exhibited the most promising characteristics and hence were chosen for further studies. In Chapter 3 protein loaded PLLA NNs were electrospun from differently concentrated solutions. The NNs featured a superhydrophobic surface and it was demonstrated, that the wettability of these scaffolds was the major factor influencing the protein release. Although TEM images showed that the major part of the protein was most likely located between the fibers and not encapsulated inside the fibers, the protein was released very slowly from the PLLA NNs. Only 20 – 30% of the protein was released within one month. The addition of hydrophilic polymers like poly(ethylene imine) (PEI) or poly(L-lysine) (PLL) to the aqueous phase of the electrospinning emulsion yielded NNs composed of polymer blends of PLLA and the respective hydrophilic polymer. It was demonstrated that the amount of added hydrophilic polymer had a significant effect on the release profile. A higher amount of hydrophilic polymer led to a faster release of the protein and gave us the opportunity to tailor the release profile of these NNs. Compositions of 5 or 10% PLL or PEI and 95 or 90% PLLA respectively, showed the most promising release profiles. Further screening of compositions ranging from 1 to 10% of hydrophilic polymers should be investigated to find the most appropriate release pattern. Whether NNs electrospun from emulsions are suitable scaffolds for their application in tissue engineering was determined in Chapter 4. The prepared NNs met all requirements for a tissue engineering scaffold: Mean fiber diameters of the scaffolds were very similar to fibrous protein structures of the extracellular matrix (ECM), meaning these scaffolds could physically resemble the ECM. Cell adhesion, cell proliferation and cell spreading on all NNs were at least as good as on a glass surface. For a composition of 5% PLL and 95% PLLA these values were even significantly higher. NNs took up water and swelled in the cell medium. The extent of swelling depended on the amount of hydrophilic polymer with a higher fraction leading to increased swelling. Cells still adhered to the fibers and were able to proliferate in all three dimensions. There were no significant differences in cell viability for cells grown on NNs compared to the cell viability on a glass surface. These results strongly suggest a huge potential of these nanofiber nonwovens for their application in tissue engineering. Chapter 5 gave an overview on microencapsulation focusing on phase separation and coacervation techniques. The development of these techniques and its application in the pharmaceutical industry were elucidated. The development of a new microencapsulation technique which utilizes an ionic liquid as one common solvent for a biodegradable polymer and a hydrophilic macromolecule was presented in Chapter 6. Some of the tested ionic liquids were good solvents for biodegradable polymers, but none of them was able to dissolve hydrophilic macromolecules. Even though there was no suitable ionic liquid among the tested compounds, the probability of finding a suitable ionic liquid is very high, since there are almost countless possibilities for the synthesis of different ionic liquids. Nevertheless the feasibility of encapsulating BSA via an emulsion based phase separation technique was demonstrated. Generally, it can be stated that the presented novel techniques for the encapsulation of proteins in biodegradable polymers demonstrated their huge potential for the preparation of drug delivery devices. Protein loaded nanofiber nonwovens exhibited very promising properties for their use as tissue engineering scaffolds and will definitely find application in this field. Screening the huge library of ionic liquids to find a compound with suitable solvent properties will be a difficult task, but the discovery of an appropriate ionic liquid will be a powerful tool for the encapsulation of proteins in microparticles|