Secant Group is developing Hydralese (PGSU) (poly(glycerol sebacate) urethane) for use in drug-delivery devices. The company created Hydralese (PGSU) from crosslinking poly(glycerol sebacate) (PGS) using urethane chemistry and is marketing it under the Hydralese platform. PGSU is a biodegradable, flexible elastomer that is known to have regenerative and anti-inflammatory properties, according to Secant. MD+DI asked Dr. Stephanie Reed, Director of Advanced Biomaterials Development, a few questions on the history of its use and prospects for the future. Reed will also be speaking in the upcoming BIOMEDevice Digital Express on August 6 in a Digital Tech Talk at 10:00 AM EDT.

Can Hydralese (PGSU) be used as just a drug-delivering implant coating or as the entire implant itself? Are there benefits/challenges to either approach? Would just the coating itself bioabsorb, or does the entire implant bioabsorb, too?

Reed: Hydralese (PGSU) may be used in a variety of implant and parenteral injection forms, including those where it comprises the entire device, such as a rod-shaped implant, microspheres, microneedles, fibers, sheets, and scaffolds of various geometries. Hydralese (PGSU) may also be used in concert with another device, for example, as a coating applied onto a stent, suture, or orthopedic implant. In either scenario, Hydralese (PGSU) will bioabsorb slowly over the course of many weeks to many months, and in some cases can last longer than a year, based on tuning the formulation. Hydralese (PGSU) biodegrades by contact with water into its starting components, glyercol and sebacic acid, which are metabolized by cells and leave no residue in the body. Hydralese (PGSU) degrades through surface erosion, so if it comprises the entire implant, the implant will gradually get smaller over time, while still retaining mechanical integrity and remaining intact. If Hydralese (PGSU) is a coating on a non-degradable implant, the coating will gradually get thinner over time, leaving behind the bare non-degradable implant material. Because Hydralese (PGSU) can be cured at room temperature, applying a Hydralese (PGSU) coating onto an existing implant will not damage that implant device. Because Hydralese (PGSU) is cured using a two-part process, it can be molded into a variety of stand-alone implants and devices, much like silicone and polyurethane manufacturing today.

PGSU is presented as an alternative to bulk-degrading polymers such as poly(lactic-co-glycolic acid) (PLGA), polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL), and non-degradable polymers such as poly(ethylene-co-vinyl acetate) (EVA), polyurethane (PU), and silicone. Can you summarize why it should be considered?

Reed: The limitation of bulk-degrading polymers and non-degradable polymers is that they rely on diffusion to release the drug from the polymer matrix. In bulk-degrading polymers, there is typically first a swelling phase when fluids infiltrate the matrix, followed by a polymer chain scission phase when the implant loses mechanical structure. During this bulk degradation process, the drug is diffusing out, but this release is usually inconsistent and erratic due to the uncontrolled degradation. In non-degradable polymers, the drug is permeating through the matrix, and in some cases the drug forms a percolating network of interconnected channels by which it exits the matrix. During this release process from non-degradable polymers, the drug is diffusing out, and matrix permeability and percolation can sustain release.

The downside of both diffusion-driven approaches is that diffusion is sensitive to drug loading and corresponding concentration gradients. As you increase drug loading within the polymer, the concentration gradient between the inside of the matrix and the outside environment becomes steeper, and this drives release to occur faster. This becomes problematic when you want to achieve a long-lasting drug-delivering implant. You need large amounts of drug in order to cover a year’s worth of dose, but release then occurs too quickly and cannot last long enough to cover a year. This ultimately limits drug loading in the final drug product, which limits the duration of therapy and type of drug that can be delivered. Another disadvantage of diffusion-driven polymers is that they can be prone to high burst release at the start of treatment, have difficulty maintaining a steady dosing over many months, and often display dose tapering at the end of treatment. Lastly, diffusion-driven polymers often struggle to sustain release of very hydrophilic drugs and simultaneously fail to deliver very hydrophobic drugs.

Surface-eroding Hydralese (PGSU) eliminates the issues of diffusion, swelling, permeation, and percolation, since only the exterior of the hydrophobic polymer matrix is exposed to fluids, so only the outermost layer of polymer degrades away, releasing the drug contained within. This surface erosion process happens repeatedly, layer by layer, achieving a steady release of both hydrophilic and hydrophobic drugs. Secant Group has demonstrated the competitive advantage of Hydralese PGSU over diffusion-driven polymers like EVA, PLA, PLGA, and PCL in direct comparison pharmacokinetic studies. Through surface erosion, Hydralese (PGSU) offers unprecedented controlled drug delivery at very high drug loadings over many months, expanding the possibilities for pharmaceutical formulators and medical device engineers.

Can you offer more details about surface erosion benefits? How would these benefits be different from surface erosion benefits from other materials?

Reed: Besides the ability to provide zero-order release kinetics for a more controlled drug delivery, a surface-eroding biomaterial that is hydrophobic and minimally swelling like PGSU can protect and shield drugs on the polymer interior from bodily fluids and harsh environments, which may otherwise degrade, denature, or deteriorate the drug. This is especially important for large-molecule drugs such as peptides, proteins, and antibodies, which are known to be unstable to heat, pH, hydration, shear forces, and enzymatic activity. Currently no commercially available polymers for medical or pharmaceutical use degrade via surface erosion.

What benefits would PGSU offer in terms of biocompatibility or drug compatibility, or other patient benefits? How would these benefits compare with those of bulk-degrading polymers?

Reed: Hydralese (PGSU) demonstrates excellent biocompatibility, with zero inflammatory response following tests for implantation, irritation, acute systemic toxicity, and cytotoxicity. Even after 6 months of subcutaneous implantation, no fibrous encapsulation is observed. Fibrosis can occur in response to other polymers and can hinder drug release and alter pharmacokinetics. Additionally, Hydralese (PGSU) hydrolytically degrades into less acidic byproducts, avoiding a pH-drop at the tissue site that is well-known to PLGA and can autocatalyze degradation and cause inflammation. Moreover, Hydralese (PGSU)’s degradation byproducts can be metabolized by, provide nutrients to, and quell the inflammatory response of cells.

Hydralese (PGSU) is a highly flexible elastomer, allowing it to be more compliant with native tissue than other degradable polymers. Implant flexibility provides enhanced safety and comfort for the patient, improving compliance. Existing commercial polymers are not simultaneously flexible and bioresorbable. Silicone and polyurethane are non-degradable elastomers, while PLGA, PLA, PGA, and PCL are prone to brittle fracture, especially when loaded with drugs. The surface erosion of Hydralese (PGSU) conveys an additional benefit for patient safety, allowing the implant to remain retrievable and intact for many months, in the event of an adverse reaction to the drug where the implant requires removal. Commercially available degradable polymers, like PLGA, are known to become soft and diffuse soon after implantation and cannot be easily retrieved.

The Hydralese (PGSU) polymer matrix is a highly branched, polydisperse, and complex three-dimensional structure, with mostly hydrophobic but also interspersed hydrophilic regions. Drugs with a variety of physiochemical properties are compatible with the PGSU matrix, including both hydrophilic and hydrophobic drugs exhibiting a range of partition coefficients, acid dissociation constants, solubilities, and particle morphologies. The intricate and accommodating nature of Hydralese (PGSU) broadens the selection of drugs that may be considered for long-acting delivery.

What questions would design and mechanical engineers developing such drug-delivering implants have when considering PGSU? How can PGSU meet their design, engineering, processing, sterilization, and manufacturing needs?

Reed: Hydralese (PGSU) can be manufactured under cGMP conditions at a commercial scale, using traditional processes for polyurethanes and liquid silicone rubbers like meter-mix-dispense equipment, reactive extrusion, and reaction injection molding. Hydralese (PGSU) can be sterilized using gamma irradiation between 20-30 kGy without any detrimental effects on performance or physiochemical properties. In head-to-head comparisons with thermoplastic polymers like PLGA and PCL, Hydralese (PGSU) demonstrates significantly less polymer chain scission following sterilization, avoiding deterioration of molecular weight and crosslinking. Hydralese (PGSU) has a very stable shelf life and can be stored at ambient temperature and ambient humidity for at least three years, unlike biodegradable polyesters PLGA and PCL, which require cold storage. Lastly, sustained release from Hydralese (PGSU) has been demonstrated in multiple small animal studies, with one such study providing more than 7 months of release of a hydrophilic drug loaded at 40% w/w in the elastomer. A large animal study commenced in May 2020 with the goal of delivering a hydrophobic drug. 

Secant Group has established robust intellectual property around the use and synthesis of  PGS resin, with another patent pending covering the formulation and manufacture of Hydralese (PGSU) for drug delivery. From a regulatory standpoint, Secant Group has a Device Master File (MAF) on file with the FDA for PGS resin. Secant Group is presently working to submit a Drug Master File (DMF) Type IV for Hydralese (PGSU) as a new pharmaceutical excipient within the next year.

From：MDDI