Glycerol- and diglycerol-based polyesters: Evaluation of backbone alterations upon nano-formulation performance.

Despite the success of polyethylene glycol-based (PEGylated) polyesters in the drug delivery and biomedical fields, concerns have arisen regarding PEG's immunogenicity and limited biodegradability. In addition, inherent limitations, including limited chemical handles as well as highly hydrophobic nature, can restrict their effectiveness in physiological conditions of the polyester counterpart. To address these matters, an increasing amount of research has been focused towards identifying alternatives to PEG. One promising strategy involves the use of bio-derived polyols, such as glycerol. In particular, glycerol is a hydrophilic, non-toxic, untapped waste resource and as other polyols, can be incorporated into polyesters via enzymatic catalysis routes. In the present study, a systematic screening is conducted focusing on the incorporation of 1,6-hexanediol (Hex) (hydrophobic diol) into both poly(glycerol adipate) (PGA) and poly(diglycerol adipate) (PDGA) at different (di)glycerol:hex ratios (30:70; 50:50 and 70:30 mol/mol) and its effect on purification upon NPs formation. By varying the amphiphilicity of the backbone, we demonstrated that minor adjustments influence the NPs formation, NPs stability, drug encapsulation, and degradation of these polymers, despite the high chemical similarity. Moreover, the best performing materials have shown good biocompatibility in both in vitro and in vivo (whole organism) tests. As preliminary result, the sample containing diglycerol and Hex in a 70:30 ratio, named as PDGA-Hex 30%, has shown to be the most promising candidate in this small library analysed. It demonstrated comparable stability to the glycerol-based samples in various media but exhibited superior encapsulation efficiency of a model hydrophobic dye. This in-depth investigation provides new insights into the design and modification of biodegradable (di)glycerol-based polyesters, potentially paving the way for more effective and sustainable PEG-free drug delivery nano-systems in the pharmaceutical and biomedical fields.

Screening and Matching Polymers with Drugs to Improve Drug Incorporation and Retention in Nanoparticles.

Key challenges hindering the clinical translation of the use of nanoparticles (NP) for delivery of drugs to tumors are inadequate drug loading and premature drug release. This study focused on understanding the conditions required to produce nanoparticles that can reach their target site with sufficient drug loading and drug retention for effective pharmacological action. Etoposide, etoposide phosphate, and teniposide were screened against modified poly(glycerol) adipate (PGA) based polymers by monitoring drug release from 40% drug in polymer films and using Fourier transform infrared spectroscopy (FTIR) and contact angle measurements to help understand the release results. Polymers were matched with the specific drugs based on the interactions observed. NP were then prepared by an interfacial deposition method. NPs were characterized and resulted in drug loadings ranging from 3.5% and 5%, respectively, for etoposide phosphate and etoposide with PGA modified with stearate (PGA85%C18) up to 13.4% for teniposide with PGA modified with tryptophan (PGA50%Try) and drug release of just 22-35% over 24 h. Assessment of cytotoxicity showed that etoposide nanoparticles with PGA85%C18 were more potent than an equivalent amount of free drug. This screening method to match polymers to drugs to monitor based drug and polymer interactions thus resulted in the formulation of nanoparticles with higher drug loading and slower release and potential for further development for clinical applications.

Poly (Glycerol Adipate): From a Functionalized Nanocarrier to a Polymeric-Prodrug Matrix to Create Amorphous Solid Dispersions.

Amorphous solid dispersions are a promising strategy to overcome poor solubility and stability limitations, reducing the crystallinity of the drug through incorporation within a polymer matrix. However, to achieve an effective amorphous solid dispersion, the polymer and drug must be compatible, otherwise the drug can undergo recrystallization. In this work, we investigated the potential of the enzymatically synthesized poly(glycerol-adipate), as a pharmaceutical tool for producing a nanoamorphous formulation. A polymeric prodrug of poly(glycerol-adipate) was synthesized by coupling mefenamic acid as drug. The amorphicity of the polymeric prodrug was assessed combining differential scanning calorimetry and polarized optical microscopy. The prodrug was then formulated into nanoparticles and studied for stability and drug release in the presence of lipase. To realize the goal of combination drug therapies for overcoming drug resistance and improving treatment outcomes, the prodrug was screened as a solubility enhancer for a series of fenamic drugs and compared with commercially available polymers commonly used in solid dispersions. Screening was carried out by developing a high-throughput miniaturized screening assay using a 2D printer to dispense the polymer and drug combinations. Finally, the collected data showed that drug conjugation could improve drug-polymer compatibility, in addition to facilitating the release of drugs by 2 different mechanisms.

Poly (glycerol adipate) (PGA), an Enzymatically Synthesized Functionalizable Polyester and Versatile Drug Delivery Carrier: A Literature Update.

The enzymatically synthesized poly (glycerol adipate) (PGA) has demonstrated all the desirable key properties required from a performing biomaterial to be considered a versatile "polymeric-tool" in the broad field of drug delivery. The step-growth polymerization pathway catalyzed by lipase generates a highly functionalizable platform while avoiding tedious steps of protection and deprotection. Synthesis requires only minor purification steps and uses cheap and readily available reagents. The final polymeric material is biodegradable, biocompatible and intrinsically amphiphilic, with a good propensity to self-assemble into nanoparticles (NPs). The free hydroxyl group lends itself to a variety of chemical derivatizations via simple reaction pathways which alter its physico-chemical properties with a possibility to generate an endless number of possible active macromolecules. The present work aims to summarize the available literature about PGA synthesis, architecture alterations, chemical modifications and its application in drug and gene delivery as a versatile carrier. Following on from this, the evolution of the concept of enzymatically-degradable PGA-drug conjugation has been explored, reporting recent examples in the literature.

Exploring the enzymatic degradation of poly(glycerol adipate).

Poly(glycerol adipate) (PGA) is a biodegradable, biocompatible, polymer with a great deal of potential in the field of drug delivery. Active drug molecules can be conjugated to the polymer backbone or encapsulated in self-assembled nanoparticles for targeted and systemic delivery. Here, a range of techniques have been used to characterise the enzymatic degradation of PGA extensively for the first time and to provide an indication of the way the polymer will behave and release drug payloads in vivo. Dynamic Light Scattering was used to monitor change in nanoparticle size, indicative of degradation. The release of a fluorescent dye, coupled to PGA, upon incubation with enzymes was measured over a 96 h period as a model of drug release from polymer drug conjugates. The changes to the chemical structure and molecular weight of PGA following enzyme exposure were characterised using FTIR, NMR and GPC. These techniques provided evidence of the biodegradability of PGA, its susceptibility to degradation by a range of enzymes commonly found in the human body and the polymer's potential as a drug delivery platform.

A big data approach to pharmaceutical flow properties.

Flowability is a key consideration during the formulation and process development of oral solid dosage forms as it can have a critical impact on product quality. With a limited number of examples available in the literature, there is a need to better understand and share the typical flow properties of pharmaceutical materials. Here, historical data (3909 experiments) from a shear cell apparatus were extracted and analysed. These data were composed of different material types, including APIs, excipients, blends and granules from nearly a decade of development projects. APIs were found to have poor flow properties (ffc <2), while other materials (excipients, blends and granules) generally had good flow properties. This analysis provided an enhanced understanding of the typical flow properties of pharmaceutical materials. By combining these data with information on the process and achieved drug load, it was possible to characterise our current operating space as a process flow map which could be used to focus future development.