Implantable drug-eluting devices (also referred to as implantable drug delivery systems) offer several advantages over conventional oral or parenteral drug delivery methods. For instance, they can provide localised, site specific drug delivery,[i] which is especially important in applications such as cardiology and oncology, where targeted delivery can improve the effectiveness of treatment and minimize side effects or damage to healthy tissue.[ii],[iii] The dosage requirements often are lower than alternatives, further reducing the potential for side effects.1 Also, drug-eluting devices can improve patient compliance, one of the greatest challenges in healthcare, as about 50% of conventional medications are not used as prescribed.[iv] The treatment regimen can be simpler because it requires fewer doctor’s visits and dosages than traditional therapies.1
Tenofovir
a. Intravaginal ring employing both hydrophobic and hydrophilic TPUs for the sustained co-delivery of the microbicide tenofovir and contraceptive levonorgestrel. Photo courtesy of The Kiser Lab.
Applications of implantable drug eluting devices include, among others, diabetes management, contraception, HIV/AIDS prevention, chronic pain management, cardiology, oncology, and central nervous system (CNS) health. Along with subcutaneous implantation, various body regions can serve as implantation sites (e.g. intravaginal, intravascular, intraocular, intrathecal, and peritoneal). In the below image, a) an intravaginal ring and a b) non-biodegradable drug-eluting device for chronic pain as examples.
In this article, developmental and commercial examples of non-biodegradable drug-eluting devices will be presented, along with the versatile properties of thermoplastic polyurethanes, specifically Lubrizol LifeScience’s Pathway TPU Excipients for the development of effective drug delivery systems.
Biodegradable vs non-biodegradable
There are two categories of drug-eluting devices: Biodegradable and non-biodegradable. Biodegradable drug-eluting devices (also referred to as bioerodible) use biocompatible materials such as polyesteramide (PEA) and poly lactic-co-glycolic acid (PLGA) to deliver drugs, and, once implanted, decompose over time.1,[i],[ii]
Axxia Pharmaceuticals
b. Axxia Pharmaceuticals’ subcutaneous drug delivery system was developed to deliver an opiate continuously for 30-90 days with zero-order kinetics. Photo courtesy of Axxia Pharmaceuticals, LLC.
In contrast to biodegradable, non-biodegradable drug-eluting devices (also referred to as biodurable) use biocompatible materials like silicone rubber (polydimethylsiloxane or PDMS), polyethylene-vinyl acetate (EVA), and thermoplastic polyurethane (TPU) to deliver drugs.[iii] Non-biodegradable drug-eluting devices can be designed as matrix, reservoir, or osmotic systems to deliver drugs via diffusion or osmosis and are generally less costly than biodegradable devices.1,15 Non-biodegradable drug-eluting devices can be refilled with medication (e.g. via injection) and the device’s effects are almost immediately reversible upon removal.1,11,[iv]
Non-biodegradable Pathway TPU excipients are designed to be versatile and customisable to a broad range of chemical and physical properties providing variety along a number of dimensions, including drug release kinetics (short or long term); active pharmaceutical ingredient selection (hydrophobic or hydrophilic APIs); processing methods (extrusion, injection molding or solvent casting), and mechanical performance.16,[v],[vi],[vii],[viii],[ix] These attributes provide developers with design flexibility.
Thermoplastic polyurethanes for non-biodegradable drug-eluting devices
Lubrizol LifeSciences partners with pharmaceutical companies from concept to commercialisation. The company’s non-biodegradable PathwayTPU excipients can be tailored to suit a range of drug delivery applications and can be processed into a variety of shapes (e.g. rods, tubes, films and a variety of matrix-type designs) via methods such as hot-melt extrusion, injection moulding, and solvent casting. Ethylene oxide, hydrogen peroxide, E-beam radiation and gamma radiation are acceptable methods of sterilisation.
Lubrizol’s 2013 implementation of the International Pharmaceutical Excipients Council's Good Manufacturing Practice quality system for excipients and database generation of Drug Master Files facilitate non-biodegradable drug-eluting device development. As a result of its 2014 acquisition of Vesta and 2015 acquisition of Particle Sciences, Lubrizol provides complete drug product development including pharmaceutical-grade polymer supply, contract research/analytical and contract manufacturing capabilities through to commercialisation.
Thermoplastic polyurethanes have exceptional safety records with over 30 years of use in medical devices, such as catheters and pacemakers.[i] The unique ability to customize TPU properties allows for the development of advanced drug delivery systems.
References
[i]Polyurethanes and Medical Applications. American Chemistry Council. Available at: http://polyurethane.americanchemistry.com/Introduction-to-Polyurethanes/Applications/Polyurethanes-and-Medical-Applications. Accessed 2015.
[i] Drug Delivery. Products & Technologies. DSM Biomedical. Available at: http://www.dsm.com/markets/medical/en_US/products-page/products-resorbable-materials.html. Accessed 2015.
[ii] Shuwisitkul, Duangratana. Biodegradable Implant With Different Drug Release Profiles. Freie Universitat, 2011. Available at: http://www.diss.fu-berlin.de/diss/servlets/MCRFileNodeServlet/FUDISS_derivate_000000009580/Duangrat_thesis_online.pdf. Accessed 2015.
[iii] Marchant, Nancy. Drug Release and Non Degradable Polymers: Thermoplastic Polyurethanes offer greater control.
[iv] Mccall AA, Swan EE, Borenstein JT, Sewell WF, Kujawa SG, Mckenna MJ. Drug delivery for treatment of inner ear disease: current state of knowledge. Ear Hear. 2010;31(2):156-65.
[v] Clark, Johnson et al. 2012. A hot-melt extruded intravaginal ring for the sustained delivery of the antiretroviral microbicide UC781. J Pharm Sci 101(2): 576-587.
[vi] Clark, Justin T., Meredith R. Clark, Namdev B. Shelke, Todd J. Johnson, Eric M. Smith, Andrew K. Andreasen, Joel S. Nebeker, Judit Fabian, David R. Friend, and Patrick F. Kiser. Engineering a Segmented Dual-Reservoir Polyurethane Intravaginal Ring for Simultaneous Prevention of HIV Transmission and Unwanted Pregnancy. PLoS ONE. Burnet Institute, Australia, 2014.
[vii] Clark, Meredith R., Justin T. Clark, Todd J. Johnson, Namdev B. Shelke, Joel S. Nebeker, Gustavo F. Doncel, David R. Friend, and Patrick F. Kiser. Development and Pharmacokinetics of a 90-Day Intravaginal Ring for the Sustained Co-Delivery of the Microbicide Tenofovir and Contraceptive Levonorgestrel. USAID.
[viii] J.Y Cherng, T.Y. Houa, M.F.Shihb, H. Talsma, and W.E. Hennink. Polyurethane-based drug delivery systems. Int J Pharm 2013
[ix] Khandwekar, A.P., Patil, D. P. Hardikar, A. A. Shouche, Y.S. and Doble, M. In vivo modulation of foreign body response on polyurethane by surface entraptment technique. J. Biomed Mater. Res. 2010
[i] Zaki AJ, M, Patil, SK, Baviskar, DT, Jain, DK. Implantable Drug Delivery System: A Review. International Journal of PharmTech Research. 2012;4(1):280–292. Available at: http://sphinxsai.com/2012/pharm/pharm/pt=40(280-292)jm12.pdf. Accessed 2015.
[ii] Drug-eluting stent. Wikipedia. Wikimedia Foundation. Available at: https://en.wikipedia.org/wiki/Drug-eluting_stent. Accessed 2015.
[iii] Brachytherapy. Johns Hopkins Medicine. Available at: http://www.hopkinsmedicine.org/radiation_oncology/treatments/brachytherapy.html. Accessed 2015.
[iv] Medication Adherence. CDC. 2013. Available at: http://www.cdc.gov/primarycare/materials/medication/docs/medication-adherence-01ccd.pdf. Accessed 2015.