Overcoming Complexity

Dr. Robert Lee, President
June 2019, The Medicine Maker

There are two key drug development trends that are reshaping the industry’s approach to formulation, leading to a rise in non-traditional dosage forms, such as nasal sprays, drug-eluting implants and more complex products. Firstly, there is the issue of poor solubility, which often forces companies to use a more complicated formulation strategy. Molecular targets can be quite hydrophobic, and the therapeutic molecules intended to interact with these targets are increasingly insoluble. Around 40 percent of marketed drugs, and as many as 90 percent of drugs in the development pipeline, contain poorly water-soluble APIs that will not be effective if formulated as a standard solid oral dose. For many developers, this may be viewed as a concern or a road block; however, it is also an opportunity. There are multiple techniques available to increase the solubility or dissolution rate of drugs and improve their delivery, such as amorphous solid dispersions, lipidic-based systems, and nanoparticle suspension formulations. And there are also new benefits in terms of protecting intellectual property as a complex product often offers numerous opportunities in this area.

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Secondly, the industry is also witnessing an increase in applications made under the 505(b)(2) FDA pathway, which involves repurposing existing, marketed APIs for a different route of administration. Companies use this pathway to develop differentiated forms for approved APIs – often to improve patient preference and compliance. The generic drug market is highly saturated so developing improved products is one way of carving out a more profitable niche. 505(b)(2) approvals grew by 50 percent last year and with the rising cost of taking new chemical entities to market, I expect use of this regulatory pathway to continue to grow. The ability to leverage pre-existing safety and efficacy data results in reduced time to market, although repurposing an API into a highly optimized dosage form is a highly technical challenge.

With more and more companies adopting complex formulation strategies, either for repurposing or to solve solubility or bioavailability challenges, a number of advanced techniques are emerging. One example is nanomilling, which is increasingly being used to improve bioavailability of oral dosage forms. During the milling process, drug particles are reduced in size to below 1000 nm, and typically as low as 100-200 nm. The conversion to nanocrystals increases the surface area-to-volume ratio of the API, allowing for greater interaction with water which increases the API dissolution rate – the rate of dissolution is inversely proportional to the particle diameter.

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When looking for new formulation avenues, it is important to remember that one size does not fit all. You need to keep your eye out for new technologies but also be able to critically evaluate them to see if they will work for your drug product. I believe it is prudent to have an arsenal of several drug development technologies available so that you can evaluate all of them with your API to see which results in the target product profile. For example, if one of my company’s clients was interested in improving bioavailability and decreasing food effects for an orally administered drug, we would evaluate nanomilling, lipidic systems, and solid solutions via hot melt extrusion or spray drying (depending on the physicochemical properties of the API, of course).

In many cases, companies choose to work with a CDMO because they don’t have their own internal resources to carry complex product development projects forward and may not wish to invest in new infrastructure and technologies. In this case, however, it is important to remember that it’s not all about techniques and equipment. While several CDMOs offer nanomilling machinery, for example, not all have the requisite knowledge on stabilizing nanoparticulate suspensions and the analytical capabilities. Similarly, drug complexity can be further compounded when you’re working with DEA-controlled substances that fall under Schedule I–V, or highly potent compounds in general. These attributes add extra layers of complexity – both scientific and regulatory.

In my view, it is becoming increasingly difficult to formulate new chemical and molecular entities; many of the “easy” molecules have already been formulated and targets are commonly hydrophobic. It is clear to me that complexity is here to stay. We must also consider patients and regulators’ desires for medicines that promote compliance. The factors impacting compliance – safer formulations with less side effects, lower doses with the same therapeutic benefit, more palatable formulations, less invasive delivery devices, etc – contribute to the need for complex formulations. Personally, I find this space really satisfying and diverse to work in. You have to understand the molecules you are working with and use technology and expertise to find drug delivery systems that match their physical properties and create a dosage form that delivers the target product profile. Complex products may mean that an “off-the-shelf” solution isn’t the answer and people will be forced to think outside of the box. In turn, this will lead to more innovation through the development of proprietary technologies and inventions in the face of specific molecule or application issues. Ultimately, this can only be a good thing for the industry and for patients, who will benefit from more efficient and convenient medicines.

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