Kargar, Negeen (2021) The use of polymers to enhance the delivery of antidiabetic drugs. (PhD thesis), Kingston University, .
Abstract
Background: Diabetes is one of the oldest and deadliest healthcare conditions to be reported in history. The currently available insulin delivery systems fail to maintain a basal insulin level in the blood. Closed-loop insulin delivery systems that intelligently release insulin according to the body’s needs will enable better control of glucose levels. Over the last decade, biodegradable and biocompatible polymers have been widely investigated as micro and nanoparticle diabetic drug delivery systems. Self-regulated release of drugs by stimuli-responsive polymers has been a research area in recent years. In the event of diabetes, a self-regulated insulin-releasing system responding to variations in glucose concentration would be a major therapeutic breakthrough. Aim: This project aims to synthesise a number of novel polymers to improve the delivery of antidiabetic drugs including a cosolvent approach and a smart glucose-sensitive delivery system that can release insulin only in response to high blood glucose levels. Method: Polyglycerols were end-functionalised using phenylboronic acid. Initially, polyglycerol was synthesised by ring-opening copolymerisation of glycerol and glycidol under acidic conditions. A novel end functionalised polymer was developed using an in situ deprotection method. Liquid formulations of hydrochlorothiazide (HCTZ) were prepared using glycerol, polyethylene glycol (PEG-400), commercial polyglycerine and synthetic polyglycerol and were tested for their solubility and stability using HPLC. Subsequently, RAFT polymerisation of sugar sensitive polymers was carried out, and optimised conditionsfor further block polymer synthesis were established. Results: A new efficient method was developed to synthesise end-functionalised polyglycerol using DL-1,2-isopropylideneglycerol,4-carboxyphenylboronic acid pinacol ester, with glycidol and glycerol polymerisation. Liquid formulations of the hydrophobic drug (HCTZ) which were stable at 25 °C, relative humidity (RH-65 %) and 40 °C (RH-75 %) were developed. The dielectric constant of each polymer was calculated, and the solubility of HCTZ in those polymers was determined. PEG-400 had a solubilisation power (σ) of 1.83, while polyglycerine and glycerol had σ of 1.77 and 1.56 respectively. The corresponding dielectric constant (Ɛ) for PEG-400 was 12.4 and for polyglycerine and glycerol, 30.5 and 42.5, respectively. RAFT polymerisation of 3 and (4-(Acrylamido)phenylboronic acid pinacol ester (4-APBAPE) was carried out at varying degrees of polymerisation (DP), (DP ≈ 150, 100, 50, 25 and 13) giving high to very high monomer conversions and a low fraction of dead chains as indicated by the GPC and NMR analysis. With shorter block copolymer chains, a living polymer was obtained, and a higher degree of conversion was observed. For the RAFT polymerisation of 4-APBAPE (DP = 150), the polymer chain growth began within 30 min and ceased after 90 min. Nevertheless, polymerisation with 150 blocks leads to broadening of the molecular weight distribution and (PDI = 1.64) reflecting the lack of living polymer. A polymer with DP= 150 at 30 min, Mn =1450 gmol-1 with 98 % livingness and 92 % AIBN remained, compared with (polymer 293), DP= 13, Mn = 2350 gmol-1 and a PDI = 1.08 gives 99.7 % livingness with AIBN (85 %) remained after the first hour. After 24 hours only 2.3% AIBN remained, demonstrating complete consumption of the initiator, giving a narrow polydispersity (PDI = 1.21) and a high monomer conversion. Conclusions: In conclusion, in situ polymerisation of end functionalised polyglycerol was successfully developed using cationic ring-opening polymerisation of glycerol and glycidol. Liquid formulations of HCTZ were developed using five different biodegradable polymers and tested for stability. RAFT polymerisation of block end functionalised sugar sensitive copolymers was optimised. This was the first time 4-APBAPE has been polymerised by RAFT, and a kinetic study was additionally conducted.
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