The Formulation Complex

Why is the industry moving towards more complex formulation strategies?

Thomas Tice: In one sense, it is the drug substances themselves that drive formulation advances. At the moment, the industry is very interested in developing peptide drugs, but these cannot be taken orally because of poor absorption and stability. Daily injections, however, tend to have low patient compliance. It is very important not to forget the patient; everything we do as drug developers should be designed to improve patient outcomes. To this end, there is a greater focus on developing more advanced complex formulations, such as extended-release parenteral drugs, where a single injection can last for a week, a month or even longer. In particular, I’m seeing a lot of growth and opportunity with bioabsorbable formulations, such as injectable microparticles, as well as implants.

Firouz Asgarzadeh: My main area of focus is on oral delivery and here too, there is also an increasing trend towards more complex formulations. Fifty years ago or so, there was a lot more opportunity to develop drugs, but with so many products already on the market, we are at the limits of discovery. Today, many small molecules suffer from poor solubility and poor permeability – and these issues cannot always be solved with traditional formulation techniques. More complex drug delivery formulations, such as liposomes, solid solutions and targeted delivery, are now helping to bring previously unfeasible drugs to the market. 

Norbert Maurer: The pharmaceutical industry is struggling with high failure rates and enormous costs, and is in urgent need of new approaches to drug development. If you look at a conventional drug, the disposition of the drug in the body and its effects on the body (desired and undesirable) are both dependent on the drug’s molecular structure. This means that one cannot change one property without also changing the other, and one therefore usually ends up with a compromise of some sort and a drug candidate that is not ideal; for example, lower activity in an attempt to reduce side effects.

Using drug delivery technology can make a big difference, because where the drug goes in the body will no longer be dependent on the molecular structure, but on the properties of the carrier, which allows us to change one property independent of the other. The association with a carrier can protect the drug from degradation, deliver more drug to a disease site or reduce toxicity by sequestering the drug away from drug-sensitive organs. Take Doxil (a liposome formulation of the anticancer agent doxorubicin) as an example, which was one of the first nano-drugs approved by the FDA. Doxorubicin can have significant cardio toxicity, but incorporation into a liposome drug delivery system keeps it away from the heart and reduces toxicity. This allows development of drug candidates that are not ideal. One can take it even a step further and specifically design drugs for use with a particular drug delivery technology.

A second reason for this move is that many successful drugs on the market are coming off patent. The use of drug delivery technology can improve existing successful drugs and give them new patent life.  
Finally, the development of many new classes of therapeutics is only possible by using drug delivery technologies. A lot of our work at Evonik is focused on therapeutic messenger RNA (mRNA), which holds great potential for new treatments, but mRNA is easily degraded in vivo and cannot enter cells by itself – so it is relies on a good, effective drug delivery system.

Anthony Hickey: The number of potent new drugs that have poor physico-chemical properties for conventional drug delivery has led to interest in alternative drug delivery strategies. Concurrently, the evolution of biotechnology-based products requires greater attention to stability in the dosage form as well as unique approaches to overcome biological barriers to target site delivery.

Which drug delivery technologies are you most excited by and why?

TT: I am enthusiastic about the potential to target drugs, which can be as simple as putting a drug where you need it and delivering it there over a long period of time. For example, formulations are being developed for the knee to reduce inflammation. These formulations maintain efficacious levels of drug in the knee and minimize side effects from circulating drug. It is possible to target drugs to many areas of the body – and many such products are already on the market, particularly in the eye, sinus and periodontal area. Eventually, I think we’ll be able to achieve local delivery within the brain, to bone, and around the spine, and perhaps even provide drug delivery in conjunction with stem cells and tissue regeneration. In the future, we may also see products that can rebuild cartilage in the knee. We’ll be responding to these new drugs and the delivery changes as they occur.

FA: With regards to oral applications, I think the technology of the future is solid dispersions and solid solutions, combined with targeted delivery. If you have a drug with poor solubility and poor bioavailability, increasing the solubility alone may not solve all your problems, but delivering the now soluble drug to the right area of the GI tract may be able to boost bioavailability. There is also growing interest in delivering peptides orally, which is a much larger challenge than working with small molecules, but not an impossible task. By using platforms like our EUDRATEC® PEP, it is possible to go beyond incremental improvements and to deliver a drug that would otherwise not be bioavailable. For example, EUDRAGIT® polymers make it possible to protect the peptide and other actives from stomach acidity and to deliver them to the area, stick them to the intestinal wall, and then deliver the drug.

NM: Lipid nanoparticle technology for the delivery of therapeutic messenger RNA is very exciting and fascinating because it has the potential to enable the expression of virtually any protein in the body, allowing for the treatment of genetic diseases such as cystic fibrosis where key proteins are either defective or missing. There is also a lot of potential for the development of personalized medicines. Another application of this mRNA delivery technology is the development of new vaccines with antigens that can be directly expressed by the body (in situ synthesis), which can result in a better immune response, as it resembles a normal viral infection.

AH: Liposomal drug delivery has paved the way for unique strategies for nanoparticle production. The most exciting new technologies are those that facilitate delivery of large quantities of drug in a fashion that enhances bioavailability. Since my major interest is in pulmonary drug delivery, solid lipid nanoparticles are an exciting new development as they facilitate pulmonary delivery of large quantities of drug, with minimal excipient, to achieve local targeting within the lungs.

What are the challenges of developing and manufacturing complex formulations?

TT: I referred to injectable microparticles earlier; for these, you need a scalable, highly robust manufacturing process because within these tiny particles you are creating a specific polymer morphology along with the drug that will control drug release. Understanding the process and controlling critical process parameters is essential. To make matters more challenging, industry is developing more potent compounds – so as well as GMP requirements, you also need to take into consideration worker safety by using engineering controls, personal protective equipment and executing industrial hygiene protocols.

FA: Scale up, commercial viability and process robustness are very important – whether dealing with injectables or oral drug product. I also believe that excipients are crucial. For many years, excipients have been called “inactive ingredients”, meaning that they are just fillers to hold the drug particles together. But when dealing with complex formulations, like solid solutions, the drug will not have the same therapeutic effect without the excipients, so calling them mere fillers is not correct. As well as having to control the active, we now need precise control over excipients; to this end, quality by design is crucial.

NM: Complex formulations are more challenging because there is no direct relationship between plasma (and tissue) concentration and drug activity, particularly when dealing with injectable nanoparticle formulations. When the drug is incorporated in a delivery system, it is not bioavailable and hence it is not active. It only becomes active once the drug is released from the carrier. In contrast to conventional drugs where predictions about activity can be made based on plasma drug levels, rapid screening models that look at activity (very often in vivo) are required for the development of injectable nanoparticle formulations. Of course, the manufacturing process is also more complex and development can be more time-consuming compared to conventional formulations. Thorough characterization of every process step is important for rapid development.

AH: Challenges vary depending on the intended route of administration. In general, the availability of biocompatible and safe excipients offers potential scientific and regulatory barriers to development. In addition, due to the complexity of certain drug delivery systems, translation to production scale manufacturing can pose problems.

What advice would you give companies who want to start developing complex formulations?

TT: These formulations have many potential benefits, but one should not underestimate the development challenges. You can’t learn how to develop complex formulations overnight; you need expertise and experience, as well as substantial infrastructure investment. I recommend consulting with experts, like Evonik, who have dedicated resources towards building infrastructure and intellectual property around these complex formulations.

FA: In the oral field, our EUDRATEC®  platform gives customers access to many complex systems that can improve oral delivery of drugs, peptides and poorly permeable BCS III/IV actives. Developing a complex injectable formulation is even more challenging. In both instances, as Tom said, consulting with experts is crucial. Specialist companies will have accumulated a vast amount of knowledge and technologies that can help drugs to reach their targets more effectively. 

NM: Many companies come to us with existing formulations and processes – and time and again I have seen problems with scalability. For example, I’ve seen processes that would require 1500 liters of solvent to prepare clinical trial material for a first in man study. When developing a process or formulation, it is important to start with the end in mind. What are the material requirements for a Phase I study, how do they increase through clinical trials to commercialization? Is the manufacturing process scalable, can it satisfy these requirements? Also, thorough characterization of the formulation is important. I’ve been in the situation before where the process was not scalable and little characterization had been performed on the formulation. It is time consuming enough to have to re-design a process, but even more challenging if you do not know exactly what the end-result is. Lipid-based formulations have complex structures, which can change depending on the process used. Thorough characterization and understanding of your product can really aid the design of an effective process.

AH: I believe it is important to establish that the intended therapeutic application has a current unmet medical need in terms of efficacy or safety, and that the drug is sufficiently potent in key predictive experiments to justify exploring a delivery system approach. Additionally, it is important to propose a drug delivery approach with biocompatible and safe materials that require minimal manufacturing process controls to ensure quality and minimize expense.

About the Authors