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Title: The degradation and drug release mechanisms of poly(ethylene glycol)-functionalised poly(L-lactide) polymers
Author: Azhari, Zein
ISNI:       0000 0004 7229 8918
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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Poly(L-lactide) (PLLA) is a well-recognised bioresorbable polymer known to degrade after 1.5 to 5 years by hydrolysis. For certain medical device or drug delivery applications, it would be desirable to reduce this degradation time as strategies for tailoring degradation and drug release rates remain limited. This work aimed to examine a consistent series of polymers based on a large block of PLLA and small quantities of hydrophilic poly(ethylene glycol) (PEG) initiator. The polymers had PLLA number average molecular weight (Mn) values ranging between about 60 kDa and 200 kDa and PEG Mns ranging between 550 Da and 5000 Da giving very low PEG wt% values ranging between 0.1 and 1.5 wt%. There are currently no studies which consider high molecular weight PLLA polymers with small quantities of PEG for potential use in structural implants. Furthermore, reports in the literature do not consider the individual effects of PEG addition and PEG and PLLA lengths. The focus of this project was on the impact of processing, hydrolytic degradation and drug release on the morphological aspects of the materials. The materials were thoroughly characterised in their as-synthesised and processed forms. The assynthesised polymers were semi-crystalline and retained the unit cell of PLLA. The glass transition temperature (Tg) was significantly reduced by PEG functionalisation. After injection moulding, nuclear magnetic resonance (NMR) indicated that the PEG component was still present. The Mn of the PEG functionalised samples decreased by approximately two-fold compared with the as-synthesised materials while the PLLA control polymers, processed beyond 200 °C, were more affected as the processing temperature was increased. The degradation properties of the materials were considered. The processed materials were submerged in phosphate buffered saline (PBS) (pH = 7.4) at 37 °C over an 8-month degradation study. During hydrolytic degradation, PEG functionalisation resulted in an increased water uptake. Mass loss began in all polymers when the Mn fell below a threshold of about 20 kDa. In the PEG functionalised samples, the degree of crystallinity increased with time, facilitated by plasticisation from PEG and the increased water content. The molecular degradation rate, k for the PEG-functionalised polymers was dependent on the presence of PEG functionalisation but was little affected by PEG length or PLLA length in the ranges studied. The time taken to reach the critical Mn, and hence the time for mass loss to begin, therefore depended on both the initial Mn and the presence or absence of PEG functionalisation. In the presence of PEG, k, was dramatically enhanced: k for PEG-functionalised polymers fell in the range of 6 x $10^{-4}$ $h^{-1}$ to 1 x $10^{-3}$ $h^{-1}$, as compared with that of the PLLA control of 2.9 x $10^{-5}$ $h^{-1}$. The mechanism of drug release from an analogous series of polymers was investigated. Propranolol. HCl was selected as a model drug for the drug release studies due to its thermal stability and solubility in PBS. Drug loading of propranolol.HCl was achieved by mixing the polymer and drug then injection moulding. A second method of drug incorporation using supercritical CO2 to load propranolol into as-synthesised polymer granules before injection moulding was examined for comparison. The materials processed through injection moulding showed that while drug crystals were present at the surface and in the polymer matrix, a level of drug solubility was also achieved in the PEG-functionalised polymers whereas the PLLA control showed no signs of polymer-drug interaction and only a distribution of drug crystals confined to the surface. The presence of drug crystals on the surface of the PLLA control resulted in the instant dissolution of propranolol.HCl and gave a burst release compared with an initial burst release in the PEG-functionalised polymers followed by a gradual release of the drug. This initial burst release was eliminated from the profile of the samples processed via supercritical CO2. The amorphous dispersion of the drug in the matrix gave a slow, sustained release throughout the duration of the drug release study. The results in this thesis have elucidated the intricate mechanisms of degradation and drug release from PEG-functionalised PLLA polymers. The overall outcome shows new ways of controlling the degradation and drug release rates of already medically established poly(-hydroxy acid) polymers extending their potential for use within temporary structural implants.
Supervisor: Cameron, Ruth E. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Polymers ; Biomaterials ; Degradation ; Drug Release