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Tyrosol Derived Poly(ester-arylate)s for Sustained Drug Delivery from Microparticles

New biodegradable polymers are needed for use in drug delivery systems to overcome the high burst release, lack of sustained drug release, and acidic degradation products frequently observed in current formulations. Commercially available poly(lactide-co-glycolide) (PLGA) is often used for particle drug release formulations; however, it is often limited by its large burst release and acidic degradation products. Therefore, a biocompatible and biodegradable tyrosol-derived poly(ester-arylate) library has been used to prepare a microparticle drug delivery system which shows sustained delivery of hydrophobic drugs. Studies were performed using polymers with varying hydrophilicity and thermal properties and compared to PLGA. Various drug solubilizing cosolvents were used to load model drugs curcumin, dexamethasone, nicotinamide, and acyclovir. Hydrophobic drugs curcumin and dexamethasone were successfully loaded up to 50 weight percent (wt %), and a linear correlation between drug wt % loaded and the particle glass transition temperature (Tg) was observed. Both curcumin and dexamethasone were visible on the particle surface at 20 wt % loading and higher. By adjusting the polymer concentration during particle formation, release rates were able to be controlled. Release studies of dexamethasone loaded particles with a lower polymer concentration showed a biphasic release profile and complete release after 47 days. Particles prepared using a higher polymer concentration showed sustained release for up to 77 days. Comparably, PLGA showed a traditional triphasic release profile and complete release after 63 days. This novel tyrosol-derived poly(ester-arylate) library can be used to develop injectable, long-term release formulations capable of providing sustained drug delivery.


The development of novel biodegradable polymers has advanced the field of sustained drug delivery allowing for the formulation of more accurate dosing delivery systems. Amide, anhydride, ester, and carbonate polymers are among the most commonly explored polymer libraries due to their biocompatibility and biodegradability and their potential to provide sustained drug release while protecting the drug from degradation.

In particular, poly(lactide-co-glycolide) (PLGA) has been at the forefront of drug delivery applications for the past several decades. Its ease of use in forming carrier systems, high encapsulation of active pharmaceutical ingredients (APIs), low toxicity, and history of approval by the Food and Drug Administration (FDA) for human clinical use has resulted in numerous applications using PLGA. Despite this, injectable, long-term release PLGA formulations are limited by their inherent burst release and by an incomplete understanding of the molecular and mechanistic properties of prepared formulations. PLGA microparticles tend to aggregate upon drying, exhibit a triphasic release profile (high initial burst release, sustained release lasting days to weeks, rapid release as particle integrity is lost), and often do not stabilize the encapsulated biomolecule.Additionally, degradation of the polymer can lead to the accumulation of acidic monomers (lactic and glycolic acid) which causes a localized acidic environment. This is especially true at the core of microparticles where the length of the diffusion pathway is the longest. Excipients can be added to formulations to reduce these negative effects but are not always successful. Despite these shortcomings, injectable PLGA microparticles have been used in clinical practice since 1989. However, between 2013−2018, only four new PLGA microparticle products were approved by the FDA, adding to the 15 already approved formulations on the market; a small number compared to the thousands of oral sustained-release formulations approved by the FDA.

Over the past few decades, new synthetic polymers have offered alternatives to PLGA. For drug delivery applications, significant progress has been made in the design of biodegradable carriers capable of providing sustained drug delivery while improving drug bioavailability.Incorporating amphiphilic poly(l-amino acids) into the polymer backbone has resulted in polymers useful for drug delivery applications due to their ability to self-assemble into nanostructures, high drug encapsulation, and nontoxic degradation products. In particular, tyrosine containing poly(ester)s, poly(urethane)s, poly(amide)s, and poly(carbonate)s have paved the way for new nontoxic, biodegradable, and mechanically robust polymer libraries and have previously been used for drug delivery applications. For example, tyrosine-derived poly(ester-amide)s have been used in self-assembling nanospheres for the delivery of hydrophobic cancer drugs.Polyesters are favorable polymers for biomaterial applications as they contain a labile bond susceptible to hydrolytic and enzymatic degradation under in vitro conditions.

Recently, a novel polymer library was developed replacing tyrosine with tyrosol in order to remove the slow degrading amide bond, thereby improving the degradation and resorption of the polymer system while still maintaining its biocompatibility.

This research investigates the formulation of select tyrosol-derived poly(ester-arylate)s using a continuous flow particle preparation method and shows how polymer properties affect drug loading and release compared to PLGA microparticles. Four model drugs, curcumin, dexamethasone, nicotinamide, and acyclovir, were selected due to their varying physical and chemical properties. All model drugs selected have previously been incorporated into PLGA microparticles for drug delivery applications. This work exemplifies the potential for a new poly(ester-arylate) system to be used in drug delivery applications, providing polymer microparticle formulations that exhibit a reduced burst release and sustained release for several weeks to months1.

Experimental design schematic.

(A) Polymer and drug selection offering a series of poly(ester-arylate)s and PLGA control with variable physical and thermal properties. Selected drugs range from very hydrophobic (curcumin) to very hydrophilic (acyclovir). (B) Formation of microparticles using a continuous flow method to evaluate drug loading using various drug cosolvents and polymer concentrations.

Drug LC of (A) curcumin, (B) dexamethasone, (C) nicotinamide, and (D) acyclovir in pHTy3, pHTy10, and PLGA particles prepared with both a drug cosolvent and as a solid suspension. All particles were prepared at a polymer concentration of 9% w/v in DCM and with 20 wt % attempted drug loading.

Maximum drug loading of curcumin, dexamethasone, nicotinamide, and acyclovir in pHTy6 microparticles prepared with the drug loaded as a solid suspension. All particle formulations were prepared at a polymer concentration of 9% w/v in DCM. Samples were extracted in triplicate for drug loading wt %, and error bars represent the SD between the extractions.

Representative SEM images of pHTy6 and PLGA microparticles loaded with 20 wt % drug at different polymer concentrations. (A) 6% pHTy6 + curcumin; (B) 9% pHTy6 + curcumin; (C) 12% pHTy6 + curcumin; (D) 9% PLGA + curcumin; (E) 6% pHTy6 + dexamethasone; (F) 9% pHTy6 + dexamethasone; (G) 12% pHTy6 + dexamethasone; (H) 9% PLGA + dexamethasone. Particles were prepared by loading the drug as a solid suspension. Images taken at 1000×, and the scale bar represents 80 μm.

Release profiles of (A) the entire 126-day study and (B) the initial 14 days of 10–50 wt % dexamethasone loaded pHTy6 and PLGA microparticles. Release profiles of (C) the entire 126-day study and (D) the initial 14 days of dexamethasone loaded pHTy6 and PLGA microparticles prepared at 6–12% concentration. All particles prepared by loading the drug as a solid suspension. Samples were run in triplicate, and error bars represent the SD between the three samples removed at every time point.

  1. Miles, C. E., Gwin, C., Zubris, K. A. V., Gormley, A. J. & Kohn, J. (2021). Tyrosol Derived Poly(ester-arylate)s for Sustained Drug Delivery from Microparticles. ACS biomaterials science & engineering. doi:10.1021/acsbiomaterials.1c00448

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