In Vitro and In Vivo Hydrolytic Degradation Behaviors of a Drug-Delivery System Based on the Blend of PEG and PLA Copolymers.

This paper presents the in vitro and in vivo degradation of BEPO, a marketed in situ forming depot technology used for the formulation of long-acting injectables. BEPO is composed of a solution of a blend of poly(ethylene glycol)-block-poly(lactic acid) (PEG-PLA) triblock and diblock in an organic solvent, where a therapeutic agent may be dissolved or suspended. Upon contact with an aqueous environment, the solvent diffuses and the polymers precipitate, entrapping the drug and forming a reservoir. Two representative BEPO compositions were subjected to a 3-month degradation study in vitro by immersion in phosphate-buffered saline at 37 °C and in vivo after subcutaneous injection in minipig. The material erosion rate, as a surrogate of the bioresorption, determined via the depot weight loss, changed substantially, depending on the composition and content of polymers within the test item. The swelling properties and internal morphology of depots were shown to be highly dependent on the solvent exchange rate during the precipitation step. Thermal analyses displayed an increase of the depot glass transition temperature over the degradation process, with no crystallinity observed at any stage. The chemical composition of degraded depots was determined by 1H NMR and gel permeation chromatography and demonstrated an enrichment in homopolymers, i.e., free PLA and (m)PEG, to the detriment of (m)PEG-PLA copolymers in both formulations. It was observed that the relative ratio of the degradants within the depot is driven by the initial polymer composition. Interestingly, in vitro and in vivo results showed very good qualitative consistency. Taken together, the outcomes from this study demonstrate that the different hydrolytic degradation behaviors of the BEPO compositions can be tuned by adjusting the polymer composition of the formulation.

Regio- and stereoselective biocatalytic hydration of fatty acids from waste cooking oils en route to hydroxy fatty acids and bio-based polyesters.

The development of biorefinery approaches is of great relevance for the sustainable production of valuable compounds. In accordance with circular economy principles, waste cooking oils (WCOs) are renewable resources and biorefinery feedstocks, which contribute to a reduced impact on the environment. Frequently, this waste is wrongly disposed of into municipal sewage systems, thereby creating problems for the environment and increasing treatment costs in wastewater treatment plants. In this study, regenerated WCOs, which were intended for the production of biofuels, were transformed through a chemo-enzymatic approach to produce hydroxy fatty acids, which were further used in polycondensation reaction for polyester production. Escherichia coli whole cell biocatalyst containing the recombinantly produced Elizabethkingia meningoseptica Oleate hydratase (Em_OhyA) was used for the biocatalytic hydration of crude WCOs-derived unsaturated free fatty acids for the production of hydroxy fatty acids. Further hydrogenation reaction and methylation of the crude mixture allowed the production of (R)- 10-hydroxystearic acid methyl ester that was further purified with a high purity (> 90%), at gram scale. The purified (R)- 10-hydroxystearic acid methyl ester was polymerized through a polycondensation reaction to produce the corresponding polyester. This work highlights the potential of waste products to obtain bio-based hydroxy fatty acids and polyesters through a biorefinery approach.

Poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) Amphiphilic Copolymers for Long-Acting Injectables: Synthesis, Non-Acylating Performance and In Vivo Degradation.

This article presents the evaluation of diblock and triblock poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) amphiphilic copolymers (PEG-PTMCs) as excipients for the formulation of long-acting injectables (LAIs). Copolymers were successfully synthesised through bulk ring-opening polymerisation. The concomitant formation of PTMC homopolymer could not be avoided irrespective of the catalyst amount, but the by-product could easily be removed by gel chromatography. Pure PEG-PTMCs undergo faster erosion in vivo than their corresponding homopolymer. Furthermore, these copolymers show outstanding stability compared to their polyester analogues when formulated with amine-containing reactive drugs, which makes them particularly suitable as LAIs for the sustained release of drugs susceptible to acylation.

Poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) Copolymers for the Formulation of In Situ Forming Depot Long-Acting Injectables.

This article describes the utilization of (methoxy)poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) ((m)PEG-PTMC) diblock and triblock copolymers for the formulation of in situ forming depot long-acting injectables by solvent exchange. The results shown in this manuscript demonstrate that it is possible to achieve long-term drug deliveries from suspension formulations prepared with these copolymers, with release durations up to several months in vitro. The utilization of copolymers with different PEG and PTMC molecular weights affords to modulate the release profile and duration. A pharmacokinetic study in rats with meloxicam confirmed the feasibility of achieving at least 28 days of sustained delivery by using this technology while showing good local tolerability in the subcutaneous environment. The characterization of the depots at the end of the in vivo study suggests that the rapid phase exchange upon administration and the surface erosion of the resulting depots are driving the delivery kinetics from suspension formulations. Due to the widely accepted utilization of meloxicam as an analgesic drug for animal care, the results shown in this article are of special interest for the development of veterinary products aiming at a very long-term sustained delivery of this therapeutic molecule.

Towards Sustainable High-Performance Thermoplastics: Synthesis, Characterization, and Enzymatic Hydrolysis of Bisguaiacol-Based Polyesters.

The utilization of wood-derived building blocks (xylochemicals) to replace fossil-based precursors is an attractive research subject of modern polymer science. Here, we demonstrate that bisguaiacol (BG), a lignin-derived bisphenol analogue, can be used to prepare biobased polyesters with remarkable thermal properties. BG was treated with different activated diacids to investigate the effect of co-monomer structures on the physical properties of the products. Namely, derivatives of adipic acid, succinic acid, and 2,5-furandicarboxylic acid were used. Moreover, a terephthalic acid derivative was used for comparison purposes. The products were characterized by 1 H NMR spectroscopy, attenuated total reflectance FTIR spectroscopy, gel-permeation chromatography, thermogravimetric analysis, and differential scanning calorimetry to assess their structural and thermal properties in detail. The polymers showed glass-transition temperatures ranging up to 160 °C and thermal stabilities in excess of 300 °C. Furthermore, the susceptibility of the polyester to enzymatic hydrolysis was investigated to assess the potential for further surface functionalization and/or recycling and biodegradation. Indeed, hydrolysis with two different enzymes from the bacteria Thermobifida cellulosilytica led to the release of monomers, as quantified by HPLC. The results of this study indicate that our new polyesters represent promising renewable and biodegradable alternatives to petroleum-based polyesters currently employed in the plastics industry, specifically for applications in which high-temperature stability is essential to ensure overall system integrity.