New Drug-Delivery Methods: From Concept to Patient

Increasing complexity is a trend in the bio/pharmaceutical industry. Both small- and large-molecule drug substances are becoming more complex and presenting both manufacturing and formulation challenges. Market pressures are also more complicated today than ever before. Expectations for lower-cost drugs that are easy to administer and offer significantly improved outcomes over existing treatments are growing.

There are many strategies being adopted by pharmaceutical companies to address these issues, such as the adoption of continuous processing and single-use technologies. Novel drug-delivery technologies that can improve drug efficacy and safety by controlling the time, rate, and place of drug release in the body; improve patient compliance; extend patent protection; and provide competitive differentiation for pharmaceuticals are also frequently sought, according to Dean Shirazi, chief scientific officer of Alcami.

According to Shirazi, some of the areas where notable advances or significant R&D investments are already being made include the following:

• Targeted release of drugs to specific sites in the body 
• Controlled-release technologies, including pulsatile release systems where the drug is released in pulses in defined time intervals
• Orally disintegrating tablets
• Mini-tablets
• Injectable delivery methods 
• Depot injectable delivery
• Improved drug-delivery methods for protein and peptide therapeutics
• Dry powder inhalers (DPIs)
• Pressurized metered dose inhalers (pmDIs)
• Nanotechnology
• Combination approaches.

Increasing challenges

There are two main drivers of new drug-delivery technologies according to Elliott Berger, vice-president of global marketing and strategy at Catalent Pharma Solutions: increasingly challenging molecules and increasingly challenging markets. “On the molecule side, the pipeline is full of molecules with bioavailability, stability, targeted delivery, controlled release, and manufacturability challenges. Drug-delivery technologies are well placed to help solve these challenges,” he says.

New technologies to overcome bioavailability issues have been the hottest areas, according to Berger. “Amorphous dispersion and particle-size engineering are two prime examples. There have also been advances in targeted and controlled-release drug delivery, including the first use of a vegetable-based softgel capsule with an extended-release profile in an FDA-approved product,” Berger observes. He also notes that technologies that drive non-invasive delivery of biologics are beginning to develop through to actionable stages, including oral, inhaled, and micro-needle routes.

From a market perspective, Berger notes that increasing demands from doctors, patients, and especially payers for real-world demonstrated efficacy require initial early-stage drug design to focus on real-world patient acceptance that is required to deliver optimal clinical outcomes. “Drug-delivery technologies are vital for achieving this goal by providing important tools and enhancements, including reduced pill burdens, improved palatability, elimination of the food effect, and patient preferred dose forms.”

Need for targeted delivery

Another key driver for the development of new drug delivery technologies is the need to have improved site-specific delivery, according to David Lyon, senior vice-president of research with Bend Research, a division of Capsugel. “Primary examples include targeted cancer treatments, where delivery predominantly to the tumor is key to improving the therapeutic safety index; improved lung delivery for lung-specific diseases; and gut-specific delivery where delivery of a compound to the duodenum may be critical to achieving improved oral absorption or where delivery of a compound to the colon is crucial for treatment of diseases such as irritable bowel syndrome,” he explains.

Differentiation for patient groups

Patient adherence is an important issue facing the pharmaceutical industry and one that has been receiving increasing attention given the significant, negative consequences of poor patient compliance with medication regimens. In the United States alone, greater than 50% of prescribed medications are taken incorrectly or not at all, and incorrect use of medications has been linked to up to 125,000 deaths annually (1). The IMS Institute for Healthcare Informatics reported in 2013 that more than $200 billion (approximately 8% of the US healthcare expenditures at the time) could potentially be saved each year by increasing patient adherence (2).

Drug manufacturers are trying to address this issue by developing differentiated products for specific patient groups that address the particular needs of each group. “Even relatively sophisticated technologies such as orally disintegrating tablets (ODTs) are evolving further so that, in addition to avoiding the intended function of the body’s digestive system to break down any substance that is swallowed, they can be adapted to deliver an ever wider range of drugs, such as vaccines and macromolecules, through the oral mucosae,” comments Berger.

Delivery of larger doses is appealing too, but requires effective taste-masking. Berger uses a pain medication as an example. “Such a drug can be delivered with all of the benefits of rapid onset of action and the convenience of an ODT, and when combined with taste-masking can be pleasant to take without water.”

Oral drug delivery is still preferred

It is important to recognize that oral technologies remain the ‘gold standard’ for most medicines, at least when self-administered and when intended to have a systemic effect. They are easiest for patients to use and thus have higher adherence levels and often times can be the least expensive dosage form to manufacture.

In oral drug delivery, a key trend during the past two decades has been the need for discovery organizations to work in chemical spaces where the deliverability and developability of the molecules is challenging, according to Lyon. Some of this chemical space, particularly in therapeutic areas such as oncology and anti-virals, leads to poorly water-soluble and, hence, poorly bioavailable compounds. “Technologies such as amorphous dispersions and lipid solutions of compounds have become more mainstream over recent years. In addition, the vast majority of commercialized products that utilize an enabling technology for improved bioavailability have immediate-release delivery profiles. However, an increasing number of development projects utilize bioavailability-enhancing technologies in conjunction with extended release or targeted delivery approaches,” he observes.

In addition to overcoming the challenge posed by poorly soluble molecules, formulation technologies are evolving to overcome many of the challenges presented by molecules that will not travel easily into the blood from the gastrointestinal tract. These technologies can include basic micronization, where the control of particle size is important, to salt-form optimization, lipid-based formulation, amorphous dispersion, and spray drying, according to Berger.

Capsugel has invested heavily in partnering with clients to offer pre-clinical-to-commercial capabilities in both spray-drying for amorphous dispersions and lipid-based formulations using liquid-fill hard capsules, soft gels, and lipid multiparticulate formats. A range of technologies are also available to enable targeted or controlled delivery including zero-order, first-order, pulsatile/dual-release, and capsule approaches that target the duodenum or colon.

Oral delivery of biologics

As with small molecules, oral delivery of macromolecules (peptides, proteins, etc.) is seen as the most preferable route of administration, with its associated ease and patient compliance. The industry faces many challenges, however, when delivering biologics in non-injection methods, and there are many options currently being evaluated, according to Berger. “Non-invasive technological advances, including lipid-based formulations within softgels and next-generation ODT formulations, could potentially be options for drug developers looking to pursue oral delivery, but others such as inhaled, transdermal, and ocular routes are also being explored,” he observes.

Working groups in each of these four areas have been set up as part of Catalent’s Applied Drug Delivery Institute, with members from industry and academia collaborating to evaluate whether the challenges faced, both in terms of efficacy and regulations, can be overcome. Catalent has also recently launched OptiForm Solution Suite Bio, which includes screening of two such technologies to identify potential oral drug-delivery options for macromolecules: Zydis Bio for buccal absorption and OptiGel Bio for duodenal delivery.

Capsugel, meanwhile, recently developed and introduced new capsule technologies that incorporate enteric protection into the capsule shell, thereby providing enteric protection and intestinal delivery without the use of functional coatings. “These ‘intrinsically enteric’ encapsulation technologies enable the oral delivery of certain acid-sensitive molecules such as microbiota, proteins, and peptides to the intestinal tract that would otherwise would be degraded in the gastric juice and under the high temperatures associated with coating processes for tablets and multiparticulates,” explains Lyon.

Particle engineering based on new spray-drying technologies is also allowing the oral delivery of biologics to the lung. Additional technology being developed at Capsugel enables the thermal stabilization of vaccines, proteins, peptides, and live cells, according to Lyon. “This development has the potential advantage of decreasing the reliance of the industry on cold-chain storage of thermally sensitive molecules. Decreasing reliance on the cold chain has significant implications in developing nations, storage of vaccines for epidemic breakouts, and in related industries such as animal health,” he notes.

Parenteral Drug delivery advances

For parenteral delivery, auto injectors and other novel forms of syringes, such as manual injector pens and needle-free devices, are at the forefront of new delivery developments, according to Shirazi. Many of these solutions combine patient safety and convenience features. This trend has provided opportunities to contract development and manufacturing organizations (CDMOs), according to Berger. “With no fixed standard in the design of devices, the ability of a CDMO to transfer technology from one organization to another may well be key to the program’s success,” he notes.

Companies are also looking to optimize filling of more preservative-free formulations and to mitigate against the risk of contamination using quality by design (QbD) to design out components and processes that require pre- and post-sterilization, according to Berger. In particular, he points to blow-fill-seal (BFS) technology as an increasingly preferred advanced filling technique due to the ability to avoid the use of glass and human handling of vials before and during filling.

There is, in fact, a general migration to glass-free delivery of parenteral solutions, according to Berger. “Technology is beginning to deliver on the long-promised benefits of glass-free delivery, which go beyond the obvious safety, weight, and cost considerations. Advanced sterile BFS technology (Catalent’s ADVASEPT technology is one example), for instance, reduces foreign particulates and decreases protein-surface interactions, as well as offering preservative-free single-use delivery, needle-free application, and a cold-chain-free supply chain,” he states.

Inhaled treatments for more than lung diseases

Historically, inhaled treatments focused on lung diseases. Currently, however, there is an emergence of strong pipelines for inhaled delivery for the treatment of systemic diseases, including both biologic and small-molecule drugs. “This trend is very promising for consumers, as new, non-invasive options could become available for life-threatening diseases,” Berger asserts. “It is a tough development task that will require strong integration and collaboration between molecule development, device design, and analytical experts, plus flexible manufacturing solutions that few in our industry have yet mastered. There is also an industry-wide need for clinically relevant in-vitro/ex-vivo models in this area,” he adds.

Engineered particles that have specific particle size ranges (e.g., 1-5 microns) greatly improve the delivery of compounds to the lung, according to Lyon. “The ability to engineer particles of these sizes has implications in the delivery of a number of indications (e.g., antibiotics to the lung for treatment of pneumonia),” he observes. Capsugel, for instance, has developed a particle-engineering technology based on its expertise in spray drying that produces more than 90% of the particles in the desired ‘lung-targeted’ range that has been deployed in several lung-targeted vaccine and protein clinical programs. The company has also developed improved particle engineering technology based on spray drying that allows highly efficient delivery of both small-molecule and large-molecule APIs to specific portions of the airways ranging from the nasal cavity to the deep lung.

More to come

In addition to the significant advances that have been achieved to date, there are many longer-term drug delivery solutions under investigation. “These technologies are at the very early stage of development and thus are still some way away from broad clinical application,” Berger notes. Some examples, according to Shirazi from Alcami, include drug/gene delivery, imaging and diagnostics, nanoliposomes, nanogels, and solid-lipid nanoparticles.

For Berger, robotics and continuous manufacturing processes are additional innovations that will have an impact in the future. “These new technologies provide potentially exciting new horizons in drug delivery and a bright future in this field in terms of helping more molecules to reach patients as better treatments, with real-world positive outcomes,” Berger states.

References

1. L. Osterberg and T. Blaschke, N Engl J Med. 353 (5), 487-489 (2005).
2. IMS Institute for Healthcare Informatics, IMS Health Study Identifies $200+ Billion Annual Opportunity from Using Medicines More Responsibly, Press Release, June 19, 2013.

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