From 3-D printing, to non-oral delivery of biologics, to advances in nanotechnology, the future for drug delivery is ripe with innovation, but what is likely primed for market success? DCAT Value Chain Insights (VCI) examines recent developments.

Innovation is drug delivery is an important part in product lifecycle management as well as for product differentiation in new drug development. Facing greater challenges in bringing new molecular entities to market, the large pharma companies are seeking to capitalize on advances in drug delivery for a competitive advantage.

Market estimates
The market for drug delivery is diverse reflecting the different types of systems and routes of administration. Drug delivery refers to technologies, formulations/systems (based on drug vehicles/carriers) and approaches (route of administration) used to deliver drugs for various applications/therapeutic use. One segment of the drug-delivery market are advanced drug-delivery technologies, which refer to the technologies used for controlling the rate of drug release, such as modified drug-delivery technologies such as extended release (controlled and sustained release), controlled release, targeted release, delayed release, and pulsatile release. The advanced drug delivery market is expected to increase from about $178.8 billion in 2015 to nearly $227.3 billion in 2020, reflecting a five-year compound annual growth rate (CAGR) of 4.9%, according to a March 2016 analysis by BCC Research, a Wellesley, Massachusetts-based market research firm. North America leads the global advanced drug-delivery market, followed by Europe. Asia-Pacific is projected to grow the fastest during the forecast period with a five-year CAGR of 6.4%.

According to the BCC analysis, advanced drug delivery technologies have been a boon for the market as advanced formulations have proven to increase the efficiency and efficacy of drug-delivery systems, resulting in better outcome of treatments. Advanced drug-delivery systems have become what the firm deems “the Holy Grail in the treatment of several diseases and in unlocking the potential/value of the pharma industry’s existing compounds as well as in exploring the potential of several new compounds. BCC estimates that the market is growing at a moderately healthy rate that should continue for the next five years. The market is not expected to saturate any time soon. In fact, patent expiries, targeted drug-delivery systems, gene therapy, nanotechnology, and biologics, are expected to open up further opportunities for growth. The advantages that advanced drug-delivery systems offer over traditional drug-delivery systems is a key driver. These benefits include higher efficacy, localized treatment of diseases, duration of drug delivery, convenient routes of administration, better targeting and lower dosing frequency.

Charting developments
So what may be on the horizon for drug delivery? Drug delivery is filled with promising research; below are some recent developments. 

Nanotechnology and oral delivery of difficult-to-administer drugs. Researchers at Texas A&M University are developing nano-systems to orally deliver difficult-to-administer drugs. Ravikumar Majeti, PhD, a professor of pharmaceutical sciences at the Texas A&M Irma Lerma Rangel College of Pharmacy, and his team are developing nanosystems to deliver types of difficult-to-administer drugs orally, according to a university press release. Kumar’s team’s nanoparticles bind non-competitively, meaning the cells will still take up the particle even if they’re saturated with naturally occurring ligands. In order to achieve the non-competitive active transport, the Kumar team used gambogic acid, a natural product that is known for its ability to kill cancer cells (1)..

“Our strategy is non-competitive active transport,” Kumar said in commenting on the research. “These nanosystems have the ability to cross the intestinal barrier to reach other parts of the body and stay in circulation for a long time.” This ability to cross the intestinal barrier in sufficient quantities has been a major problem with oral medications—and part of why insulin, for example, is injected, not swallowed. In this case, the nanoparticle makes the body itself help the drug become absorbed.”The way we put these things together is completely novel,” Kumar said. “This approach enables the development of carrier systems that have no equivalent in the world of competitive ligands.”

The system can also penetrate the blood-brain barrier, which could have important implications for drugs that need to reach the brain.”We can fine-tune the nanosystems to match the disease in question,” said Ganugula Raghu, PhD, one of the researchers in Kumar’s lab and a co-author of a recent paper on the team’s research (1). “It is also relatively easy to adjust the timing of the drug release, either fast or slow, depending on the needs of the patient. For example, such systems can be designed to benefit diabetic patients by facilitating hepatic (liver) and peripheral insulin in a single dose.” Exact concentrations of the active pharmaceutical and the ligand density on the particle can also be ‘tuned’ by controlling the ratios of functional to non-functional polymers.

“We really think these small particles will open up new avenues in receptor-mediated oral delivery of poorly soluble and permeable compounds that constitute about 40% of the new chemical entities requiring specialized delivery systems,” said Meenakshi Arora, PhD, another member of Kumar’s lab and co-author of the paper.

In another recent development in nanotechnology-based drug delivery, Aphios Corporation, a Woburn, Massachusetts-based clinical-stage biotechnologyl company, was recently awarded a subcontract for the nanoformulation of a super hydrophobic anticancer drug administered through the Frederick National Laboratory for Cancer Research in Frederick, Maryland. Several promising natural products being developed as the active pharmaceutical ingredients (APIs) of investigational drug products have encountered roadblocks that nanotechnology may be able to address. One of these promising anticancer drugs is Brefeldin A (BFA), a cyclic macrolide with a lactone ring. BFA has demonstrated potent activities in controlling protein trafficking, signal transduction cycles and apoptosis. However, clinical development of this promising anticancer drug has been halted because of the inability to develop an intravenous formulation of this water-insoluble, highly hydrophobic API.

The company’s primary goal of this research program is to pair BFA with Aphios’ SuperFluids critical fluid nanosomes (SFS-CFN) technology for intravenous administration to achieve and maintain therapeutic plasma concentrations. “Our rationale for pairing BFA with SFS-CFN technology is that BFA is highly hydrophobic and insoluble in water,” said Dr. Trevor P. Castor, principal vnvestigator of the subcontract, in an Aphios press release. “As such, during the encapsulation process, BFA will be sequestered in the lipid bilayer of phospholipid nanosomes making an aqueous-based nanoformulation of this water-insoluble drug. This process is very similar to one that we have developed for camptothecin (CPT), a highly hydrophobic and water-insoluble lactone, derivatives of which are approved by the FDA for colorectal, cervical, pancreatic and other cancers. Aphios is also developing nanosomes of neat CPT, camposomes, to improve efficacy and reduce toxicity of this potent topoisomerase-1 inhibitor for pancreatic and other cancers.”

Oral delivery of peptides. In September 2015, Novo Nordisk formed a research collaboration with the Langer Laboratory at the Massachusetts Institute of Technology (MIT) for drug-delivery devices for the administration of peptides.The aim of the research collaboration, which will be conducted at both MIT in Boston and at Novo Nordisk’s research facilities in MÃ¥løv and Hillerød, Denmark, is to develop drug-delivery devices as an alternative to parenteral or injection-based delivery of peptides. MIT Professor Robert Langer’s laboratory is engaged in developing new approaches for delivering drugs such as peptides and proteins across complex barriers in the body such as the blood-brain barrier, the intestine, the lung and the skin. Together with Dr Giovanni Traverso, a gastroenterologist and biomedical engineer at Harvard Medical School, and research affiliate of MIT, they will lead a team in the development of a platform enabling the oral delivery of peptides.

There are many challenges of developing and producing a reliable peptide delivery vehicle, as outlined by Novo Nordisk in announcing the collaboration. They include avoiding premature degradation in the body, overcoming poor peptide transport over epithelial barriers, limiting variability of absorption (caused, for example, by interaction with food in the stomach), and producing both peptide and the delivery vehicle in sufficient scale and numbers cost-effectively. If these challenges can be overcome, as recent research suggests, drug-delivery devices hold therapeutic promise for diseases where patients need to take frequent injections. The collaboration will establish a number of research positions to be hosted by the Langer Laboratory and funded by Novo Nordisk. The initial term of the collaboration is three years with the option to extend for up to three additional years.

Microchips. In 2015, Teva Pharmaceutical Industries and Microchips Biotech formed a partnership under which the companies will explore ways to apply Microchips Biotech’s implantable drug delivery device to Teva’s portfolio of products with the goal of enhancing clinical outcomes for patients on chronic drug therapies. Microchips Biotech’s electronic device is made up of microchip arrays that can store therapeutic doses of drug for periods ranging from months to years. The device can be programmed to release drug on a pre-determined schedule and will have wireless control features.

Under the agreement Teva makes a $35 million upfront payment to Microchips Biotech in the form of an equity investment and technology access fee. The partnership has an initial focus on one selected disease area, but will provide Teva with the option to later expand the program into several additional therapeutic areas and sensing applications that are proprietary to Teva. As programs advance, Microchips Biotech will receive development and commercial milestone payments and royalties on future product sales. Microchips Biotech will also receive funding to develop products for any future additional indications Teva may develop, and Teva will be responsible for Phase II and Phase III clinical development and regulatory filings.

The microchip-based implant is a self-contained hermetically-sealed drug delivery device that can be implanted and removed in a physician’s office. The implant has been clinically validated in human studies delivering parathyroid hormone in osteoporosis patients, and the system is fully programmable via wireless communications to adjust dosing by physician and/or patient. The microchip-based technology was originally developed by researchers at the Massachusetts Institute of Technology, Robert Langer, PhD and Michael J. Cima, PhD.

Gene delivery. Earlier this year, Takeda Pharmaceutical Company Ltd. and enGene, Inc., a privately held biotechnology company, developing a proprietary non-viral vector platform for gene delivery to mucosal cells lining the gut, have formed a strategic alliance to discover, develop, and commercialize therapies for specialty gastrointestinal (GI) diseases using enGene’s “Gene Pill” gene delivery platform. The strategic alliance will leverage enGene’s expertise and intellectual property position in delivering therapeutic genes to cells of the gut lining by using its proprietary non-viral vector platform.

Under the terms of the agreement, enGene will develop up to two undisclosed targets selected by Takeda through pre-clinical proof of concept and investigational new drug-enabling studies. At that point, Takeda will have an option to exclusively license the global rights for the product candidates. Following option exercise, Takeda will be responsible for all clinical development and commercialization of those products. enGene will receive an upfront payment and reimbursement of all R&D costs incurred during the development of the selected targets. In addition, enGene is eligible to earn milestone payments for the product candidates based on accomplishment of specific research, clinical, regulatory and commercial milestones. enGene also will receive tiered royalties on future net sales of the collaboration products. Further details of the agreement were not disclosed. Takeda will also collaborate with enGene in developing Gene Pill into a platform for oral delivery of antibodies. Takeda has the exclusive option to obtain a right of first negotiation for up to three antibody targets.

3-D printing. Aprecia Pharmaceuticals, a pharmaceutical company based in Blue Ash, Ohio, reported launched earlier this year Spritam (levetiracetam) tablets, for oral suspension, is as an adjunctive therapy in the treatment of partial onset seizures, myoclonic seizures, and primary generalized tonic-clonic seizures, making it the first prescription drug product approved by the US Food and Drug Administration (FDA) that is manufactured using 3-D printing technology. The drug disintegrates in the mouth with a sip of liquid and is designed as a new option for patients, including those who may struggle to take their medicine. Spritam is formulated with Aprecia’s proprietary ZipDose Technology, which combines 3-D printing and formulation science to produce rapidly disintegrating formulations of medications. Manufactured in a regulated commercial-scale facility, the drug is available in four unit-dose strengths, including 250 mg, 500 mg, 750 mg and 1,000 mg.

Aprecia developed its ZipDose Technology platform using the 3-D printing technology that originated at the Massachusetts Institute of Technology (MIT). Using 3-D printing as a catalyst, Aprecia created a novel manufacturing system to produce fast-melt formulations of medicines that exceed the disintegration speed and dose-load capacity of products made by other fast-melt technologies, such as orally disintegrating tablets and oral thin films. The company says that the ZipDose products are also more portable than liquid formulations and have greater dosing accuracy than liquids, which may be more susceptible to measurement errors. The company manufactures them on Aprecia’s proprietary equipment. Aprecia holds an exclusive, worldwide license for pharmaceutical applications of this 3-D printing technology. The company says it has the rights to more than 50 patents related to pharmaceutical applications of 3-D printing technology and has filed patent applications to protect its proprietary manufacturing system through 2033.Aprecia is privately owned, with Prasco Laboratories and its parent company, Scion Companies, holding a controlling interest.

The FDA approved Spritam in August 2015, and the drug became commercially available in March 2016. Earlier this year, Aprecia also announced that it is investing $25 million in a 190,000-square-foot manufacturing facility in Blue Ash, Ohio, which will add 150 new jobs. Spritam is the first in a line of products in the central nervous system therapeutic area that Aprecia plans to introduce over the next several years.

Aprecia was founded in 2003. Powder-liquid 3-D printing, a technology that forms objects layer by layer, was originally developed by researchers at MIT in the late 1980s as a rapid-prototyping technique. This technology uses an aqueous fluid to stitch together multiple layers of powder. From 1993 to 2003, this work was expanded into the distinct areas of tissue engineering and pharmaceuticals. While 3-D printing technology rights are currently licensed for a diverse range of industrial fields, pharmaceutical rights to MIT’s 3-D printing process are exclusively licensed to Aprecia. In 2007, after refining the 3-D printing process, the company began developing its orodispersible platform, known as ZipDose technology. In 2008, Aprecia began working with a proprietary forming system that enhances manufacturing efficiency and output in the 3-D printing process, which enabled the company to achieve its initial goal of reaching commercial production rates for its 3-D printing formulations. This initiative continued through 2011, when the company further refined this process to prepare for commercialization and ultimately comply with FDA regulatory standards. In 2011, Aprecia also began operations at its registration and launch facility in East Windsor, New Jersey. After refining and commissioning its first full production line, this operations site became prepared for registration of the initial ZipDose Technology product set. The company submitted its first new drug application for Spritam in October 2014, received FDA approval in August 2015, and launched the product earlier this month.

Using its proprietary, computer-aided, 3-D printing manufacturing process, Aprecia developed the ZipDose Technology platform, which is designed to enable delivery of high-dose medications in a rapidly disintegrating form. ZipDose technology product candidates are assembled layer-by-layer without using compression forces or traditional molding techniques. Thin layers of powdered medication are repeatedly spread on top of one another as patterns of liquid droplets (an aqueous fluid) are deposited or printed onto selected regions of each powder layer. Interactions between the powder and liquid bond these materials together at a microscopic level. The company says that the platform yields highly porous structures even at high loading and doses of drug and can support dose loading up to 1,000 mg.

Reference
1. P. Saini, R. Ganugula, M. Arora, M. N. V. Ravi Kumar, “The Next Generation Non-competitive Active Polyester Nanosystems for Transferrin Receptor-mediated Peroral Transport Utilizing Gambogic Acid as a Ligand,” Scientific Reports, 6, p. 29501 (2016).