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Jennifer Markarian is manufacturing editor of Pharmaceutical Technology.
Innovative technologies, such as drug-loaded devices and 3D printing, enable advances in implantable devices and other novel dosage forms.
The pharma industry is increasingly focusing on patients as it considers drug development. Both innovative dosage forms, such as implantable drug–device combination products, and novel manufacturing methods, such as three-dimensional printing, are creating opportunities for solving drug-delivery challenges.
Interest from both pharmaceutical companies and medical device companies in developing drug-device combination products, such as drug-loaded implants for local delivery, is growing. Device makers in this arena typically seek to add a drug functionality to a device, such as a steroid-eluting pacemaker lead or an antimicrobial-eluting catheter, notes Jim Arps, director of Pharma Services at ProMed Pharma, a contract manufacturer of polymer-based, drug-releasing dosage forms and combination device components. Pharma manufacturers, on the other hand, are typically looking for a drug-delivery format, particularly for controlled release. “The beauty of these systems is their capability for long-term, consistent release,” says Arps.
Drug-loaded implants can improve patient compliance by reducing dosing and side effects. “Side effects are minimized because the drug is delivered at the site of action and does not have to travel through the many natural barriers in place in the human body (e.g., stomach and other organs), and dosing can be reduced because the implants deliver the dose over a long period of time (e.g., weeks or months) as opposed to hours for oral dosage forms,” says Tony Listro, vice-president of Technical Business Development at Foster Delivery Science.
One of the commercial uses for drug-loaded implants is ocular drug delivery; ocular indications are difficult to treat with oral dosage forms, and the eye itself has many barriers to protect it from topical treatment, notes Listro.
Approved uses are expanding into other areas. Titan Pharmaceuticals, for example, produces the Probuphine (buprenorphine) Implant, a six-month subdermal implant for long-term maintenance treatment of opioid addiction that was approved by FDA in 2016. The product is being commercialized by Titan in the United States and, upon approval by the European Medicines Agency, will be commercialized in Europe and certain other territories by Molteni Farmaceutici of Italy. The company says that the proprietary ProNeura implant technology has the potential to be used in developing treatments for many chronic conditions such as Parkinson's disease, Type 2 diabetes, hypothyroidism, and others for which consistent, around-the-clock dosing is important.
Some of the earliest commercial drug-loaded implants were contraception products that are matchstick-sized rod-shaped implants injected subcutaneously into the arm, where they release the drug for multiple years and then are surgically removed. For years, researchers have hoped to develop biodegradable implants that would eliminate the need for surgical removal.
Most recently, Hera Health Solutions, a start-up out of the Georgia Institute of Technology, is developing proprietary, biodegradable implants for extended-release drug delivery using existing generic drugs in combination with FDA-approved structural materials, notes company cofounder and CEO, Idicula Mathew. All of the company’s potential products use bioresorbable excipients and are intended to eliminate the need for an implant removal procedure, and the company’s biodegradable contraceptive arm implant, Eucontra, is currently concluding in-vitro testing. The company’s proprietary manufacturing process creates a layered drug-excipient matrix that erodes over a long period of time and retains its shape, strength, and flexibility, notes Mathew.
Drug-loaded devices deliver controlled release of a drug either by diffusion or by an erodible matrix. “In diffusion-controlled drug delivery, the polymer matrix remains intact while the drug is gradually deployed to the therapeutic site, either by encapsulating the drug in a polymer shell or coating, or by distributing the drug throughout a non-degradable (i.e., biodurable) polymer matrix,” explains Listro. “Erodible matrix implants are produced through the encapsulation or distribution of the drug in an erodible polymer, such as a water-soluble or bioresorbable polymer. As the polymer erodes in the body, the drug is released.”
Biodurable polymers that can be used as matrices for drug-loaded devices include low density polyethylene (LDPE); ethylene co-vinyl acetate (EVA), at various levels of vinyl acetate; polyurethanes; and silicone. Polymer excipients used for hot-melt extrusion of oral dosage forms (e.g., polyvinylpyrrolidones, cellulosics, and acrylics) can also be used. Bioresorbable polymers include polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), polydiaxanone (PDO), and others. PLA and PGA are commonly used, but they degrade by hydrolysis into acidic byproducts; other polymers that have enzymatic degradation pathways may work better with certain APIs, notes Arps.
Drug-loaded implants are typically manufactured by mixing the API into the excipients before forming the final shape, using extrusion to make simple shapes (e.g., fibers, monofilaments, rods, tubes, sheets, or other profiles) or injection molding to make either simple or complex, three-dimensional shapes. An alternative method sometimes used with silicones is to form the implant and then infuse it with the drug.
High-precision injection molding creates tight dimensional tolerances (controlled within a few microns) and good surface finishes, says Arps. “In addition to complex shapes, such as stents, injection molding can be beneficial for simple shapes, such as rods, especially if the material is brittle and difficult to cut. A drawback for rods is that molding may be a little slower in overall throughput and produce more waste material than extrusion,” Arps adds.
Coextrusion can be used to make multi-layer shapes, such as a drug core with a rate-controlling membrane. “The drug-loaded layer can also be the outer layer with a [unloaded] polymer used on the inside as a strength member for explantation,” adds Listro. The type of extrusion equipment used can be selected depending on the formulation (i.e., the processing conditions it can handle) and the tolerance needed in the final part, with a variation of less than 10 microns possible.
Understanding the physicochemical characteristics of the API (e.g., melting point, degradation temperature, flow characteristics) and any API-excipient interactions is important in developing the formulation and optimizing the manufacturing process. Twin-screw extruders used for mixing the API and excipient can be optimized for a formula, so getting a formulation to work can be more of an engineering exercise, notes Listro. Choosing an appropriate feeder, feeding point, screw design, and temperature profile, for example, are important variables.
Sensitivity of the ingredients to processing temperatures, shear energy, and moisture are other considerations. “Some silicones can be mixed and cured at room temperature. Thermoplastic polymers are processed in the range of 100–150 °C, and the API will need to be able to handle those temperatures for a short time period,” says Arps. He adds that some degradable materials may have moisture sensitivity and require processing under low humidity conditions to avoid degrading the polymer, which would affect the drug release.
While extrusion and injection molding are traditional methods of forming polymer devices, three-dimensional printing (3DP) is an emerging manufacturing technology being used to produce medical devices and, since the 2015 approval of Aprecia Pharmaceuticals’s Spritam (levetiracetam), solid-dosage drug forms as well. 3DP, also called additive manufacturing, is a category of manufacturing methods that are used to form a product by building it layer-by-layer using digital control. 3DP lends itself to customization of complex products, and it has been described as a way to allow personalized and even on-demand medicine, once requirements such as quality control and safety testing can be achieved.
3DP is also being investigated as a manufacturing method for microneedles used in transdermal patches, in which the ability to quickly change geometries could be useful for prototyping, and for making complex, delayed-release capsule shells that could be used in clinical trials (1).
Aprecia, which manufactures what is currently the only FDA-approved 3D-printed drug, is employing 3DP for cGMP manufacturing of solid-dosage drugs marketed through the conventional, FDA-approved regulatory path. Tim Tracy, CEO of Aprecia, comments that the greatest advantage of the process is “the ability to produce novel dosage forms that are not possible by traditional tablet and capsule processes. 3DP allows us to produce unique shapes, varying degrees of dispersion and disintegration, customization of dosage, and the potential for flexibility and combining multiple drugs.” The company uses its ZipDose technology to produce a tablet that combines the benefit of rapid disintegration in the mouth with taste-masking ability and high drug load; Spritam tablets, for oral suspension for treatment of seizures in adults and children with certain types of epilepsy, provide an easy-to-swallow alternative to existing, large pills. The technology could also be used to make extended-release forms. In December 2017, Aprecia announced a partnership with Cycle Pharmaceuticals to develop and commercialize orphan drugs using ZipDose technology, and an initial product is in the development and formulation stage.
To read an interview with researchers from the University College London and FabRx on their work in 3DP, go to www.PharmTech.com/considering-3d-printing-solid-dosage-forms.
FabRx, established in 2014 by researchers from the University College London, is focused on optimizing 3DP technology for manufacturing solid-dosage drugs and identifying drugs that would be most suitable for using 3DP for personalized medicine. “3DP offers many opportunities to researchers by creating customized formulations that will be useful in clinical trials for testing new drugs, in the treatment of rare diseases (where the number of patients is low and costs are high), or in treatments where doses change frequently depending on therapeutic needs (e.g., narrow therapeutic index medicines),” says Alvaro Goyanes, director of Development at FabRx. Ensuring that this novel manufacturing process can accurately produce quality drugs is crucial, notes Goyanes, who adds: “We are working to integrate a quality control system in the printer to enable both the production and real-time release of medicines at the dispensing point. In the near future, we envision that hospitals and pharmacies will have 3D printers on-site, enabling healthcare professionals to print out tailor-made medicines on-demand.”
Producing Monofilaments for 3DP
One method of three-dimensional printing (3DP), called fused filament fabrication or fused deposition modeling (FDM), uses a continuous filament of thermoplastic polymer, which is heated to its melting point and then layered to form the final shape. Foster Delivery Science produces monofilaments of custom formulations for use in 3DP for pharma applications. The API and excipient are mixed in a twin-screw extruder, and then drawn into a monofilament, which is wound on a spool. Implementing methods to control tension are key to producing a tight tolerance product, and feedback control systems can be used to control dimensions by automatically adjust process parameters, explains Tony Listro, vice-president of Technical Business Development at Foster Delivery Science.
Leistritz, which manufactures twin-screw extrusion systems for pharmaceutical and polymer applications, installed a filament production system in its process laboratory that can be used to develop new filaments and formulations. According to the company, formulations can be modified "on the fly" for rapid sampling of filaments with different formulation percentages, and a sample can be produced every 10 minutes (1).
1. Leistritz, “Leistritz Extrusion Expands NJ laboratory: Installs ZSE-3D Filament System Installed for Pharmaceutical, Nutraceutical, and Medical Device Development,” Press Release, Aug. 27, 2018.
3DP could be a disruptive technology in pharmaceutical manufacturing. Once technical and regulatory issues are addressed, it could enable the development of more personalized therapies. How soon this technology advances and to what extent it might replace traditional manufacturing remain to be seen. Considering how 3DP has found a niche in other manufacturing industries, however, pharmaceutical manufacturers should monitor 3DP developments closely.
1. A. Procopio, “3D Printing for Dosage Form Design and Delivery,” presentation at IFPAC (North Bethesda, MD, 2018).
Vol. 42, No. 10
When referring to this article, please cite it as J. Markarian, "New Dose Forms Focus on the Patient," Pharmaceutical Technology 42 (10) 2018.
Jennifer Markarian is manufacturing editor for Pharmaceutical Technology.