Formulation Strategy: Five Years From Now

David Elder

What would you say are the main benefits of employing early formulation testing?

Most small or virtual biopharm companies try to progress their asset as quickly as possible to a clinical decision making milestone so that they can get a rapid return on their investment.  To do this they invest minimally in formulation, using either API alone (powder in bottle), API in capsule or much less frequently, API dissolved in a suitable vehicle (if it’s a soluble API… often a big ‘if’).  This is an understandable approach if your cash constrained, but often times they run foul of poor exposure in the clinic and can’t increase the dose to effectively examine the clinical pharmacology in man. This is an obvious outcome of high throughput chemistry and combinatorial chemistry that has led to ever increasing numbers of poorly soluble APIs [1].  For these compounds which may constitute as much as 70% of the current drugs in development formulation strategies are absolutely essential to ensure adequate exposure so that they can explore the pharmacology in man.

What do you see as the most critical unmet drug delivery need?

A lot of the newer drug therapies, for example oligonucleotides, stem cells, etc offer great promise but the huge challenge is still delivery to the site of action [2]. For instance, with oligonucleotides, the issue is that whilst drugs working through the RNA interference (RNAi, sometimes called siRNAs) mechanism can indeed shut off genes (and hence offer the promise to treat difficult targets/diseases), it has been difficult to deliver such drugs to the cells where they are really needed. This is because RNA is quickly broken down in the bloodstream by exo- and endo-nuclease activity. But even if it gets to the target cells where they is required, they often have trouble entering into the cells where they will elicit their response. Chemical modification of RNA has offered increased in vivo stability and to avoid eliciting immunogenic responses. Various delivery mechanisms are being assessed. The lead approach towards delivery is liposomal particles. Liposomes naturally accumulate in the liver, hence many of the RNAi drugs under clinical development target liver-related disorders, e.g. high cholesterol, liver cancer,etc. The global head of exploratory and translational science at Merck (Dr. Alan Sachs), recently indicated that the Merck have assessed more than 300 approaches for delivery of RNAi drugs, but nothing was found that was either safe and effective enough to warrant progressing further [3].

The clear promise of RNAi is inactivation of the gene preventing troublesome proteins from being produced by the body. For example, individuals with genetic mutations rendering the protein PCSK9 inactive, have very low cholesterol and a consequent reduced risk of heart attacks. Pharma companies have designed drugs to block the action of PCSK9. However, although initially it looked as if only RNAi could down regulate PCSK9, now more conventional therapies are looking promising. Pfizer, Amgen and Regeneron s have all progressed into clinical trials with monoclonal antibodies designed to inactivate PCSK9 [3].

How do you keep up with new and emerging technologies?

I think it is a significant challenge and whereas, you can never be truly an expert in all of the myriad different fields of pharmaceutics, I do think it behoves the pharmaceutical scientist to at least know a little about a lot of different things. Networking is vital, both within your organisation and across the Industry and Academia. I try to keep up to date with the literature as much as possible.  Access to electronic libraries ensures that specific articles or journals are readily available.  I look to Advanced Drug Delivery Reviews as a journal to keep me current in the field of drug delivery.  For instance the whole of the November issue was aimed at drug delivery to the kidney and there is an article in the January issue about RNAi therapy using functionalised scaffolds. There are broad based journals covering all aspects of controlled release delivery and I like to keep current across a broad field of pharmaceutics by regularly scanning Journal of Pharmaceutical Science which has good cutting edge science.

What do you think will be the next breakthrough in your field?

It is difficult to be sure as there is so much good science going on within Academia and Industry. Stem cell therapies look very exciting, but again there is the challenge of delivery.  I think delivery of therapeutic large molecules to the brain will be a huge breakthrough [4]. The blood brain barrier is an extremely effective barrier that actively removes via efflux mechanisms (mostly PgP based) unwanted molecules from the brain. However, coupling peptides with molecules that are actively transported into the brain is a promising development area. 

How do you think formulation screening and testing will develop in the next 5-years?

I think there will be greater emphasis on understanding the bio-pharmaceutics (BCS) and related development pharmaceutics classification (DCS) of molecules as a prelude to formulation activities.  The BCS system (pioneered by Gordon Amidon) categorises drugs based on solubility and permeability characteristics into a 4-box model [5].  BCS 1 molecules (high solubility/high permeability) are easiest to formulate; whereas BCS IV molecules are the most difficult. The DCS system [6] builds on this and uses bio-relevant media e.g. FASSIF/FESSIF to get better understanding of solubility; as well as the projected dose.  The dose is really important as even drugs with very poor solubility, i.e. 10 microgram/ml will be soluble in gastric media at doses of 2.5mg or less. Once the bio-pharmaceutics information has been assessed you can quickly decide which formulation strategy is best for your drug.  Using the DCS system you can also see how your drug compares with other marketed compounds and how they were formulated.  For instance if your drug’s bio-pharmaceutics characteristics closely resembles itraconazole, then you know that some sort of solid dispersion will be required.  Then excipient compatibility screens, which will be typically automated can be utilised and prototype formulations prepared and characterised.

For anyone interesting in attending the Global Pre-Formulation and Formulation Summit, what will be the key take home messages?

I think it is the quality of the speakers that is the big bonus.  IQPC have pulled together a broad range of leading Industry experts that will provide attendees with insightful perspectives of drug development. A lot of the talks are from big pharma giving their perspective, but equally the conference is streamed and there are presentations from virtual companies allowing participants to navigate through the minefield of multiple different service providers.  I’m particularly looking forward to Marcus Brewster’s talk on Formulation Decision Trees (J&J) and Marl MacAllister from Pfizer on Selecting Formulations for Early Drug Development.  But by selecting those two I’m really doing the others are great disservice as they are all excellent speakers, with powerful messages. I’m really excited and looking forward to the conference!


[1] CA Lipinski, Drug-like properties and the causes of poor solubility, J.Pharmacol. Toxicol. Methods, 44; 235-249 (2000).

[2] CC Esau, BP Monia, Therapeutic potential of microRNA, Adv. Drug Deliv. Revs., 59; 101-114 (2007).

[3] A Pollack, Drugmakers’ fever for the power of RNA interference has cooled, New York Times, February 7th, 2011.

[4] GJ Doherty, HT McMahon, Mechanisms of endocytosis, Ann. Revs. Biochem., 78 1-46 (2007).

[5] GL Amidon, H Lennernas, VP Shah, JR Crison, A theoretical basis for a biopharmaceutical drug classification: the correlation in vitro drug product dissolution and in vivo bioavailability, Pharmaceutical Research, 12; 413-420 (1995).

[6] JM Butler, JB Dressman, The developability classification system: Application of biopharmaceutics concepts to formulation development, J. Pharm. Sci., DOI 10.1002/jps.22217 (2010).

Interview conducted by Andrea Charles.