A Novel Controlled Release Material-Poly (Lactide-co-p-Dioxanone) And Its Microparticle Preparation

Polylactic acid (PLA) is an extensively researched biomaterial in the filed of drug delivery system due to its good biocompatibility and biodegradability. However, its strong hydrophobicity and acidic degrading products tend to result in clotting or denaturalizing peptides and acid-sensitive drugs. Furthermore, its acidity-induced auto-accelerated degradation may lead to drug burst release or lag release as well. In order to overcome these shortcomings, a new biomedical material, hydroxyl-ended poly(lactide-co-p-dioxanone) (HO-P(LA-co-PDO)-OH) was designed and prepared from D,L-lactide (D,L-LA) and 1,4-dioxan-2-one (p-dioxanone, PDO) via melt ring-opening copolymerization using a novel co-initiating system, i.e. Sn(Oct)2 as initiator and small diol such as ethylene glycol (EG) or diethanolamine (DEA) as coinitiator. Fourier transform infrared spectrometry (FTIR), nuclear magnetic resonance spectrometry (NMR), differential scanning calorimeter (DSC), multi-angle laser light scattering (MALLS-GPC), contact angle meter and classical chemical analysis were employed to characterize the structures and properties of the obtained polymers, and the biocompatibility of HO-P(LA-co-PDO)-OH with MC3T3-E1 ostoblasts was further investigated. Thereafter, the preparation of microparticles was explored by using HO-P(LA-co-PDO)-OH as a drug carrier and progestogen norethindrone as a model drug. The main works and conclusions are summarized as follows:(1) HO-P(LA-co-PDO)-OH was synthesized via melt ring-opening polymerization of D,L-LA and PDO using Sn(Oct)2 as initiator and EG or DEA as coinitiator. Then, an extensive investigation effort was made in order to know the effects of feed ratio PDO/LA and co-initiator dosage on the molecular weight and glass transition temperature (Tg).①FTIR and 1H NMR analysis showed that HO-P(LA-co-PDO)-OH was successfully prepared by using above-mentioned co-initiating system. The obtained HO-P(LA-co-PDO)-OH was a random copolymer of PDO and D,L-LA, with one ended hydroxyl from PDO or D,L-LA and the other mainly from EG or DEA.②DSC detection indicated that there was a single Tg for HO-P(LA-co-PDO)-OH, and Tg decreased with the increasing amount of PDO, proving the successful copolymerization of PDO and D,L-LA, and the efficient purification method to produce pure HO-P(LA-co-PDO)-OH. ③The results of MALLS-GPC and hydroxyl group analysis exhibited that the molar ratio of PDO to D,L-LA (PDO/LA) and the amount of coinitiator were the main factors affecting the number-average molecular weight ( M n) and Tg of HO-P(LA-co-PDO)-OH. In detail, when PDO/LA was constant, M n and Tg of HO-P(LA-co-PDO)-OH decreased with increasing EG or DEA; when the amount of EG or DEA was constant, M n and Tg decreased with increasing PDO/LA.④Surface wettability was evaluated based on static water contact angle. The results indicated that the static water contact angles decreased with the increasing PDO/LA, suggesting the incorporation of PDO may improve the hydrophilicity of PLA.(2) A series of microparticles were prepared from HO-P(LA-co-PDO)-OH by means of emulsification-solvent evaporation technique with progestogen norethindrone as a model drug. The effects of emulsifier Tween-80 on the particle size and stability of microparticles were examined and discussed. In this study, the utilization of norethindrone as a model drug aimed at developing a drug delivery system to treat postmenopausal osteoporosis (PMOP) or PMOP-induced bone fracture or bone defect, promoting bone repair and regeneration.①When the proportion of oil phase to water phase, stirring rate and temperature were constant, it was found that obtained particle size and size distribution decreased with increasing emulsifier concentration, then tended to unchanged.②When the proportion of oil phase to water phase, stirring rate and temperature were constant, the zeta potentials of obtained microparticles kept a high absolute value when emulsifier concentrations were within a certain range, suggesting stable norethindrone-loaded microparticles could be produced from HO-P(LA-co-PDO)-OH according to the said technique in this study.③Size Distributions Analyzer detections and SEM images showed that microparticles with a particle size of about 100nm could be prepared from HO-P(LA-co-PDO)-OH according to the said technique in this study.(3) The biocompatibility of HO-P(LA-co-PDO)-OH with rats osteoblast-like cell line MC3T3-E1 was preliminarily evaluated by means of cell proliferation (MTT assay), differentiation (ALP activity) and total protein secretion (Bicinchoninic acid). The results revealed:①Compared with controls, all obtained results showed that both series of HO-P(LA-co-PDO)-OH, i.e. that with EG as coinitiator and that with DEA as coinitiator, had sound biocompatibility with MC3T3-E1. ②Compared to HO-P(LA-co-PDO)-OH with DEA as coinitiator, HO-P(LA-co-PDO)-OH with EG as coinitiator exhibited better biocompatibility with MC3T3-E1 in terms of proliferation, differentiation and protein secretion.(4) A novel shape memory polymer (SMP) based on HO-P(LA-co-PDO)-OH was designed and prepared, with HO-P(LA-co-PDO)-OH as soft segments and hexamethylene diisocyanate (HDI) and butanediamine (BDA) as hard segments. FTIR, 1H NMR were used to characterize the structure of the obtained polyurethane, indicating the successful synthesis of HO-P(LA-co-PDO)-OH-based polyurethane. The DSC detection showed that the Tg, i.e. the shape memory temperature of the obtained polyurethane was close to 37°C, which suggests that HO-P(LA-co-PDO)-OH-based polyurethane might be a promising shape memory polymer employed as a biomedical material in human body.