Synthesis and characterization of a new biodegradable semi-solid poly(ortho ester) for drug delivery systems

Abstract

Since the late 1970s, three families of poly(ortho esters) (POE) were synthesized to provide bioerodible carriers for drug delivery devices. The most recent POE is a semi-solid polymer with a viscous behavior at room temperature. Polymer synthesis by a transesterification reaction between a triol and a trialkyl ortho ester is described. The structure of the polymer was confirmed by conventional methods such as 1H-NMR, 13C-NMR and FT-IR. Information concerning average molecular weight and intrinsic viscosity was obtained respectively by GPC and viscosimetry. Residual solvents in the polymer were determined using gas chromatography. The chromatographic conditions were optimized to enable the quantification of the solvents in concentrations of a few percent. The mechanical behavior of the semi-solid POE was determined by rheometric measurements. Hydrolysis of the polymer leads to the formation of the original triol and the carboxylic acid derived from the trialkyl ortho ester used in the transesterification step. No toxicological problems associated with these compounds are anticipated.

Polymeric Delivery Systems for Biopharmaceuticals

“…The third generation of POEs, POE III, is a viscous polymer that was developed at the University of Geneva in the 1990s (Merkli et al, 1993). This generation is characterized by an ointment-like consistency, providing significant and unique advantages, such as the ability to incorporate therapeutic agents or additives by simple mixing, without the need to use solvents or elevated temperatures, which allows fragile and thermolabile drugs peptides, proteins, or oligonucleotides to be formulated (Einmahl et al, 2001).…”

A viscous bioerodible poly(ortho ester) as a new biomaterial for intraocular application

“…As previously described, 17 POE was synthesized by a transesterification reaction between 1,2,6-hexanetriol and trimethyl orthoacetate (Aldrich Chemie, Steinheim, Germany) under anhydrous conditions. POE was further purified by a precipitation procedure to remove impurities such as residual monomers and oligomers.…”

“…The structure of the polymer was confirmed by 1 H and 13 C nuclear magnetic resonance, as well as by infrared spectroscopy. 17 The average molecular weight of the batches used in this study was approximately 4 (low molecular weight, POE LMW ) and 14 kD (high molecular weight, POE HMW ), as determined by size exclusion chromatography (SEC) using a Waters 150 CV instrument with four Ultrastyragel columns of 500, 10 3 , 10 4 , and 10 5 Å pore size in series (Waters, Volketswil, Switzerland) and stabilized tetrahydrofuran as eluent. Monodisperse polystyrene standards were used for calibration.…”

“…[14][15][16] The chemical reaction of POE degradation occurs in two steps: the first is a rapid hydrolysis of the labile ortho ester bonds, and the second is a slower hydrolysis which produces acetic acid and hexanetriol. 17 Kinetics of drug release from POE, as well as polymer degradation rate, can be controlled by many factors such as polymer molecular weight and physicochemical properties of the excipients and drugs incorporated, 1 notably their water solubility, hydrophilic/hydrophobic balance, and acidobasicity. 18,19 The use of acids leads to a fast polymer degradation and drug release because ortho ester bonds are sensitive to acid catalysis.…”

Subconjunctival biocompatibility of a viscous bioerodable poly(ortho ester)

“…By using different ratios of trimethyl orthoacetate and 1,2,6-hexanetriol, and by varying the heating time, a family of POEs having different molecular weights can be produced. 14,15 After heating for an additional 8-24 h, the solution is cooled to room temperature and a few drops of triethylamine (TEA) (Fluka) are added to neutralize the acid catalyst and stabilize the polymer. Excess solvent is poured off and the polymer is dried under vacuum.…”