Polymers for Pharmaceutical Packaging and Delivery Systems

Charlotte Juel Fristrup

Research output: Book/ReportPh.D. thesisResearch

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Selection of polymer materials which will be exposed to protein drugs in either containers or medical devices is often very challenging due to the demands on the polymers. Suitable polymer materials should comply with requirements like compatibility with proteins, sterilisability, good barrier properties towards preservatives, and no toxic leachables. The basis of the thesis was hydrophilization of commercially available hydrophobic polymer materials in order to inhibit non-specific fouling. Hydrophilic polymeric grafts were prepared by Surface-Initiated Atom Transfer Radical Polymerization (SI-ATRP) from commercially available polymers. Initially, poly(ether ether ketone) (PEEK) films were applied as a model system to demonstrate that hydrophilization of a substrate could be obtained by SI-ATRP. PEEK has ketone groups which can be reduced to hydroxyl groups and used for anchoring of 2-bromoisobutyrate initiating sites. Each modification step of PEEK as well as grafting of poly(ethylene glycol) methacrylate (PEGMA) was followed and confirmed by Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy, water contact angle (WCA) measurements, and Thermal Gravimetric Analysis. X-ray Photoelectron Spectroscopy also confirmed the presence of the poly(PEGMA) grafts on the PEEK surface by comparing the C/O ratio and the chemical composition after each modification step. The surface topography was evaluated by Atomic Force Microscopy.

Polypropylene (PP) is one of the polymeric materials of interest for pharmaceutical packaging and delivery systems. Confocal fluorescence microscopy studies and stability studies with insulin aspart (AspB28 insulin) were conducted to evaluate the impact of modified PP compared to unmodified PP. In contrast to PEEK, PP did not contain any functional groups which could easily be used for attachment of initiating sites for SI-ATRP. An UV initiator, benzophenonyl 2-bromoisobutyrate was synthesized from 4-hydroxybenzophenone and 2-bromoisobutyryl bromide. Irradiation (λ=365 nm) of the UV initiator applied to PP plates resulted in formation of covalent C-C bonds between the photoactive benzophenone and the aliphatic C-H groups on the PP surface. The experimental work was carried out in two rounds. Grafts of poly(PEGMA) and N,N-dimethylacrylamide (DMAAm), respectively were prepared by conventional SI-ATRP from PP and used in the first experimental round. In order to decrease the amount of catalyst residual in the modified materials, activator regenerated by electron transfer (ARGET) SI-ATRP was applied in the second experimental round. Two poly(ethylene glycol)methyl ether methacrylate (MPEGMA) monomers with 4 and 23 ethylene oxide units in the side chain were grafted from PP by ARGET SIATRP. The hydrophilic grafts engineered by either conventional or ARGET SI-ATRP were characterized by ATR-FTIR and WCA measurements. Insulin adsorption studies with confocal fluorescence microscopy showed that only the poly(PEGMA) coating was able to repel labelled AspB28 insulin at the present conditions. The first stability study revealed an inverse correlation between AspB28 insulin related impurities and higher molecular weight
proteins and the same trend seemed to be present in the second study. PP coated with poly(DMAAm) resulted in a poor chemical stability and a significantly improved physical stability of AspB28 insulin compared with unmodified PP. Increased physical stability was determined as a lower tendency to form fibrils. Additionally, observations like higher content of AspB28 insulin related impurities, lower phenol concentration, and presence of copper were made for the poly(DMAAm) coating. Scanning Electron Microscope analysis was applied to visualize inhibition of AspB28 insulin fibrillation or differences in the fibrillar structures which caused lower fluorescence intensities in the Thioflavin T test. The second stability study has until know been going on for 4 months and the poly(MPEGMA) coatings have not shown a significant change in the AspB28 insulin stability compared with unmodified PP. The results from the poly(PEGMA) coating in the first stability study after 8 months of testing looked very promising with respect to the stability of AspB28 insulin in comparison with the data from unmodified PP.
Original languageEnglish
Place of PublicationKgs. Lyngby
PublisherTechnical University of Denmark
Number of pages82
Publication statusPublished - 2010

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