Connecting the Dots in Drug Delivery

Welcome to the first part of a four-article series that will explore the unprecedented challenges facing pharmaceutical scientists – in particular, the ability to offer good bioavailability and patient-friendly drug delivery for increasingly complex new medicines. Over the coming months, we will review the current and emerging technologies that are likely to play a role, discuss the need for a more collaborative approach, and speculate on the future of drug delivery in an attempt to connect all the dots.

The high fruit

“There has been a significant trend over the last 10-15 years for more and more lipophilic drug candidates. Up to 70 percent of new drug candidates now belong to what’s called BCS class II, meaning low solubility compounds with high permeability,” explains Ralph Lipp, a pharma consultant and founding advisory board member of Catalent’s Applied Drug Delivery Institute (see “Running the Institute” on page 3). “These compounds are often difficult to deliver orally as they do not dissolve fast enough during gastrointestinal passage. In general, a drug that is not dissolved cannot be absorbed into the body.”

But a reduction in bioavailability isn’t the only problem. Poor solubility is also often associated with unacceptable variability in blood levels of the drug, both within and between patients – and it increases the risk of food effects.

Despite the challenges, oral dosage forms (read: convenient and non-invasive) remain the preferred route of administration for traditional small molecule drugs, making up around 40 percent of all prescription drugs (1). In essence, to deliver the convenient dosage forms that patients want, we must find ways to enhance the bioavailability of poorly soluble drugs. To do that, we need to connect more than a few dots...

Simple solubility?

Improving solubility is simple in theory: we (just!) need to break down the crystal lattice structure before the patient ingests the medicine. In practice though, with the demands of stability and patient acceptability to contend with, it’s a much trickier proposition. Typically, the lattice can be broken down by applying heat, shear stress or solvents to the API and adding suitable excipients. Hot-melt extrusion or spray drying to create solid dispersions, self-emulsifying drug delivery systems and nanocrystal formation are just some of the techniques available to aid formulation scientists in rendering the insoluble soluble. And new advances are being made every day (2). However, there is no one-size-fits-all solution. What is needed is a toolbox approach – and the more tools at our disposal, the better.

In the midst of all the technological options open to us, it’s important that we don’t lose sight of our end users. Indeed, we must bear them in mind at the earliest stages of development. It’s not just about finding a drug delivery strategy that works, but one that works for patients.

“The first step in patient-centered design is to understand that patients are not a homogenous group but made up of many different groups, often with vastly different needs,” says Lipp. “For example, we have an opportunity as an industry to do more to meet the needs of geriatric patients, who make up an increasing proportion of the population.” Those needs could include anything from developing easily distinguishable tablets (to avoid negative drug interactions in this highly medicated population) to improving packaging to make life easier for those with rheumatoid arthritis.

Age is just one factor to consider – social, cultural and convenience factors play important roles too, and there are subtle differences between territories. For example, a tablet mass of over 300mg is considered acceptable by most patients in Europe, but is too large in Japan. Even biologic drugs, which have traditionally been delivered by injection, are moving towards more patient-friendly options, with inhalable, topical and oral dosage forms being explored by researchers (3, 4, 5).

Team delivery

The diverse challenges involved in creating the best formulations for patients will not be overcome by single organizations, operating in a vacuum. To fill the gaps in our knowledge – and to get the best results for patients – will require input from industry, academia, and equipment and chemical suppliers.

Kurt Nielsen Ph.D., Senior Vice President of R&D at Catalent, believes that knowledge sharing between and within organizations is vital. “Drug development scientists are no different from anyone else – they tend to stick with the tools they know well. Sometimes, that means that progress isn’t as fast as it could be if they were using a broader range of drug delivery tools.”

Life sciences companies are becoming increasingly aware that precompetitive collaboration is good for business – and for patients. PhRMA Executive Vice President William Chin describes it as a “tide that raises all boats.” Companies are already coming together to explore disease mechanisms and identify potential drug targets. To encourage a similar knowledge-sharing approach to speed innovation in drug delivery, Catalent set up the Applied Drug Delivery Institute in 2012. Lipp says his role within the Institute taps into an absolute passion for improving drug delivery for patients. “The Institute’s mission is to bring together scientists from both industry and academia, with a goal of moving the needle for drug delivery as a whole – that very much matches my ambitions.”

In the remaining three articles in the series, we’ll be exploring some of the most important strategies in the drug delivery toolbox, including the latest advances in existing techniques such as hot melt extrusion lipid-based systems, emerging technologies such as nanotechnology, and cutting-edge research on alternatives to injection for macromolecule drugs.

Delivering Events

The Journey to Optimizing Outcomes: Advances in Drug Delivery & Design

March 12, 2015
Pfizer Cambridge Campus, MA, USA

Innovative technology companies will present on the following topics:

• Dr. Dave Miller from Dispersol on solubility issues
• Stephen Tindal from Catalent on lipid based drug delivery applications
• Dr. Ben Maynor from Liquidia Technologies on nanotechnology
• Dr. Shahar Keinan from Cloud Pharmaceuticals on data driven drug design

Addressing the Challenges of Drug Delivery: Patient Centric Design, Non-invasive Delivery of Macromolecules, Bioavailability & Solubility

April 30, 2015
3M Customer Innovation Center, Bracknell, UK

Presenters and topics include:

• Dr. Ralph Lipp from Lipp Life Sciences on using patient insights to design drugs and medical systems
• Dr. Mark Tomai from 3M on the use of novel toll-like receptor agonists and delivery systems to increase the effectiveness of vaccines
• Professor Claus-Michael Lehr from the Helmholtz Institute on innovative drug delivery methods

Tech Incubator

The Applied Drug Delivery Institute acts as a technology incubator, offering help to both academic researchers and small companies.

Helping researchers: The Institute acts as a matchmaker, connecting university researchers and their promising technology with companies and experts who can help move their invention toward commercialization, by providing access to facilities, plus strategic and commercial expertise.

Helping emerging companies: The Institute helps start-ups develop their technology by giving them access to the resources and expertise that are typically only available in larger companies, and by helping to identify potential strategic partnerships and funding sources.

Running the Institute

Kurt Nielsen Ph.D., Chairman of the Catalent Applied Drug Delivery Institute and Senior Vice President of R&D at Catalent, shares founding philosophies, objectives achieved and future ambitions.

What’s the background to the Institute?

We have a fundamental belief that the pharmaceutical industry should compete on the application of knowledge, not the existence of knowledge itself. By becoming an educator and disseminator of information, we believe we can help expand the industry’s toolkit and allow more drug delivery problems to be solved.

We also felt that there was a connection missing between the drug development process and the patient. When a product is being developed, the focus tends to be firmly on clinical efficacy and safety. Making a drug product that is as easy as possible for the patient to take is not usually on the radar at such an early stage. We want to start the conversation about the needs of patients earlier, when the clinical protocols are being developed. In short, we don’t want drug delivery to be an afterthought in the development cycle.

Finally, we want to be a connection point, bringing together industry, academia and the healthcare authorities to share information about new technologies and help move them into the toolkit as quickly as possible.

It’s a grand ambition – what are you doing to achieve it?

We hold complimentary one-day symposia, organized around a specific drug delivery topic, such as bioavailability or controlled release, with invited speakers from academia and industry to start discussions. Past sessions have all attracted over 100 attendees, including everyone from vice presidents to principal scientists to graduate students. It’s an opportunity for scientists to learn, to network and to be exposed to new technologies.

We have also formed working groups and consortia that bring companies and academics together to address key issues. In terms of patient advocacy, we just kicked off a project with the Lung Cancer Alliance to gather information from patients on their feelings about the current treatment regimens. We hope to discover ways of improving their experience.

Which initiatives are you most proud of?

Our symposia have been a real success; fantastic collaborators, such as the Royal Society of Chemistry, and speakers made sure of that. There have been five so far, but more are planned (see “Delivering Events”). Participants have reported that the content was meaningful and provided a solid opportunity for learning.  We have also used their feedback on their most significant delivery challenges as a guide to shape the content of future symposia, which will cover solubility issues, drug release profiles, stability of API and targeted delivery. Ninety five percent of participants believe that drug delivery technology solutions should be determined during pre-clinical and Phase I development. We’re also proud of progress made within the Non-invasive Macromolecule Delivery Consortium (NMDC). We’re very interested in how we can improve the adherence for these large-molecule injectable drugs. How do you make administration as easy and painless as possible, so that patients don’t see taking the drug as such a hurdle? There is real enthusiasm from our collaborators in the consortium, including founding co-sponsors Takeda Pharmaceuticals, Genentech, 3M and Allergan. The more we talk to each other the more we find that the challenges we face are very similar, so it makes sense to work together rather than solve the same problem five times at different companies. We now have working groups set up to address oral, pulmonary/nasal, transdermal and ocular delivery, and efforts are continuing to spread the word and get more and more organizations participating.

What are your plans for the future?

We’re particularly enthusiastic about doing more on the education front, and about working to accelerate new technologies (see “Tech Incubator”). We’re also really excited about our work with the Lung Cancer Alliance. We want to see patients brought into the development process earlier, so that all the features that lead to maximum adherence can be included in the first generation product, rather than after commercialization. That can only happen when there is data on what patients need, so getting involved with that research is a logical next step for the Institute.

 For more information, visit www.drugdeliveryinstitute.com