Advances in Biodegradable Polymer Technologies Facilitate Sustained Release of Parenteral Drugs

Biodegradable polymers make it possible for parenteral drugs to be delivered over an extended period of time. New processing methods may make extended-release parenteral drugs easier and safer to use, especially for therapies based on targeted nanoparticle conjugates. Kevin W. Burton, global head of injectable services with Evonik Industries, spoke with Cynthia Challener, editor of the Pharmaceutical Sciences, Manufacturing & Marketplace Report, about current biodegradable polymer technology, recent advances, and where the field is headed.

Well-characterized, safe, and predictable

Pharmaceutical Sciences, Manufacturing and Marketplace Report: What are the key attributes of successfully designed biodegradable polymers intended for sustained-release of parenteral drugs?

Burton (Evonik): Biodegradable polymers used for the controlled release of parenteral drugs must be well characterized, have an excellent safety profile, a well-defined metabolic pathway, and exhibit very predictable degradation behavior. It is also necessary to be able to tailor the degradation rate in order to customize the release performance for a specific drug. Ideally, this customization is achieved by making simple changes to the polymer composition, terminal group, and molecular weight to effect changes in the physical/mechanical properties of the delivery system.

Pharmaceutical Sciences, Manufacturing and Marketplace Report:What types of polymers (in terms of chemistry) have proven most effective and why?

Burton (Evonik): Polyester-based systems derived from hydroxy acids, particularly poly(lactic-co-glycolic acid) (PLGA), have become the most widely used systems. These systems were first introduced as suture materials several decades ago and are well characterized, have an established safety profile, and their metabolic pathway is well known. In addition, the physical and mechanical properties can be varied by changing the molecular weight, the lactic acid/glycolic acid composition, and/or the terminal end groups. The degradation kinetics are highly predictable and produce predictable controlled-release products because the polymers degrade primarily by hydrolysis.

Pharmaceutical Sciences, Manufacturing and Marketplace Report: How do the polymers function? By what mechanism(s) do they degrade?

Burton (Evonik): This class of polymers contains hydrolytically degradable ester bonds along the polymer backbone; on exposure to aqueous environments such as biological fluids, they swell as they take up water and then begin to degrade by random hydrolysis of the ester linkages. This random chain-scission process continues over time and results in lowering of the molecular weight of the polymer. Eventually, the molecular weight drops significantly, causing the polymer formulation to lose its mechanical integrity and begin breaking apart.

The polymer degradation, in turn, impacts the release rate of the drug, which is typically dictated through an erosion-mediated diffusion mechanism. A drug that is at or near the surface dissolves soon after the matrix hydrates and swells, opening a channel through which the drug can diffuse. As the polymer begins to erode, pores within the matrix are formed, and the drug migrates through these water-filled pores. As time goes on, additional pores are formed, releasing more material until the remaining drug is depleted. Hydrolysis of the polymer continues until only the individual monomeric constituents remain (glycolic acid and/or lactic acid). Thus, tese polymers are biodegradable and biocompatible because these final breakdown products of the polymers are naturally occurring, endogenous entities.

Evaluating alternatives

Pharmaceutical Sciences, Manufacturing and Marketplace Report: What other technologies do biodegradable polymers compete with and what advantages do the polymers offer? When are polymers the optimal choice and why?

Burton (Evonik): There are other methods for the sustained-release of parenteral drugs. Nonbiodegradable polymers, such as ethyl vinyl acetate (EVA) copolymers, acting as diffusional barriers are used as drug-delivery implants. These systems, however, are best suited when a long release time can be achieved (a year or more) because they do not biodegrade and are generally explanted. Stents coated with nondegradable polymers designed to release drugs from their surfaces have also been used, but interest has waned in the last couple of years due to a variety of long-term safety concerns. Other biodegradable polymers such as polyanhydrides have seen some level of success, but their shelf life is typically limited due to their high moisture sensitivity.

Combining controlled- and targeted-release

Pharmaceutical Sciences, Manufacturing and Marketplace Report:What recent advances have been made in biodegradable polymer technology for sustained release of parenteral drugs?

Burton (Evonik): The real advances with sustained-release polymers have to do more with the delivery platforms rather than the PLGA chemistry. We are seeing a lot of convergence with medical devices, from biodegradable stents where these polymers are used to deliver steroids, antibiotics, or anti-inflammatory agents, to localized sustained-release delivery as an add-on to medical devices such as nanoparticles delivered through angioplasty balloons at the site of the insult.

There is also a lot of interest in targeted drug-delivery devices, where the sustained-release system helps enable the targeted administration of the drug to a specific site. Active targeting systems that have an antibody or antigen bound to the surface of the nanoparticle can be administered systemically and then localized to the site of action, wherein the drug can be released directly to the diseased area, minimizing systemic toxicity. In the last couple of years, there has also been growing interest in IV administration, particularly for passively targeting solid tumors. For these applications, the PLG particles must be below 1 micrometer and ideally 100-200 nm.

While participating actively in all of these areas, Evonik has also developed a platform technology that produces particles allowing delivery through much smaller gauge needles (27G or 29G) while also providing a much higher concentration of solids without compromising the particle size or release characteristics of the formulations. Compared to conventional microparticle technologies currently on the market, which are typically administered through 19-23G needles, our technology offers significant advantages. More drugs can be delivered, which enables a longer release period and higher doses, and in a needle size that makes self-administration possible for drugs that previously required delivery in a doctor’s office or the hospital.

Loading limits

Pharmaceutical Sciences, Manufacturing and Marketplace Report: What limitations remain and what is being done to address them?

Burton (Evonik): The potency of the drug dictates the amount that can be administered. In a typical sustained-release parenteral product, the drug accounts for no more than 30% of the load, with the remainder being the polymer carrier. That means 100 mg of formulation may only contain 30 mg of the active agent. While the number of higher-potency drugs is increasing, additional advances in platform technologies that enable higher drug loading and higher solids content are still needed.

Block copolymers and nanoparticles lead the way

Pharmaceutical Sciences, Manufacturing and Marketplace Report: What specifically is Evonik working on with respect to biodegradable polymers for sustained release of parenteral drugs?

Burton (Evonik): We believe the future is very bright for drug-delivery technologies and are actively developing a variety of approaches from exploring novel biomaterials to discovering alternate drug delivery platforms in order to help our clients realize safer and more effective pharmaceutical products and medical devices. Most recently, we have been interested in antibody-drug conjugates and polymer-drug conjugates.

Based on our significant expertise in drug manufacturing and drug delivery, these systems fit well within our core competency. We are also engaged in improving drug delivery through the use of block copolymers. Derived from well-known polymeric components such as PLGA, poly(caprolactone), and/or polyethylene glycol, these polymers have interesting properties that make them viable alternatives for sustained-release delivery systems and medical devices.