BIOAVAILABILITY ENHANCEMENT - A New Year for Solubility Enhancement

As we launch into 2014, I’d like to review and update some of the data that summarizes the important challenges we face, but also cover the significant progress we’ve made. Last year, contributing authors to the column gave insights into what’s driving the increase in insoluble compounds, and what excipient and solubilization technology providers are doing to innovate toward their clients’ success. Their participation itself represents a growing need for collaboration, and a willingness to work together to achieve a common goal.

THE NUMBERS & TRENDS

2013 has proven to follow the FDA-approval trend from the past 10 years. The FDA’s Center for Drug Evaluation and Research (CDER) reported 26 NME approvals as of December 16, 2013, five fewer than the same time in 2012, and well below the 2012 year-end total of 39. With the 10-year average number of yearly approved NMEs in the range of 26 compounds, one might be inclined to ponder a silver lining.

A deeper dive into the data shows that there are promising trends and that the past significant investments may well pay off in the next several years. Data from the Pharmaceutical Research and Manufacturers of America (PhRMA) show that the investment in research and development over the past 20 years has been a steady 17% of the total pharmaceutical sales (PhRMA 2013 Profile). This is a significant increase relative to the 1980s when only 9% of sales was invested. So if there has been such an increase in spending, what indication do we have that there is an improvement in productivity? This can be found in the global pipeline when during that period we have seen more than a doubling of the number of compounds in clinical stage development (Figure 1) compiled from PhRMA industry reports. If one takes into account that the average time for a compound to navigate through the pipeline is on the order of 10 years, it is not hard to imagine that these investments will take time to manifest in terms of approved drugs. All things being equal and given that the clinical pipeline has grown significantly, there is good reason to believe that we will see a corresponding increase in approvals over the next few years.

While the pipeline appears to be growing in strength, there are other trends that are at play that cannot be ignored. The nature of the compounds moving through development and entering the market place is changing, and in particular, there are numerous reports of how early phase compounds are increasingly insoluble. Estimates of the percentage of insoluble NMEs in development today (in preclinical through Phase II clinical trials) vary broadly, and have been stated at 40%, 70%, and even 90%.1-3 Regardless of the exact percentage, with over 10,000 NMEs in the combined preclinical and clinical development stages, the number of solubility-challenged compounds is extremely large.

However, one need not look only at the early phase compounds to see these trends. An Agere analysis of the approved compounds from the past 30 years shows the same trends. In Figure 2, the average of the logP and log(solubility-mg/mL) of all approved compounds in a given year is plotted against the year in which they are approved.4 As the graph clearly demonstrates, there has been a continuous rise in the lipophilicity and a corresponding decrease in the solubility of approved drugs. In fact, the average solubility of all approved drugs in 2012 was more than 10X less than those drugs approved in 1983.

In The Second Quadrant (Drug Development & Delivery, May 2013), I reported on an analysis conducted at Agere to map the solubility space of more than 1,300 marketed drugs from the past 30-plus years. We visualized this space by plotting the number of compounds with a given solubility and logP as a function of those two variables. Figure 3 compares the individual compounds approved in 2012 with this solubility space. As can be seen, the compounds of today are clearly on the edge of the averaged solubility space with a strong trend to higher logP and lower solubility.

Various reasons exist for the trend toward lower solubility and higher lipophilicity, many of them touched on by contributing authors to The Second Quadrant in 2013. Examples include the fact that diseases being addressed today are much more complex than those in the past; the nature of the binding pockets in modern drug targets favoring compounds with lower solubility; and modern methods for designing, synthesizing, and optimizing chemical libraries that have led to new chemistries with low aqueous solubility.

SIGNS OF SUCCESS

With the trends showing a clear need, platforms for delivering poorly soluble molecules continue to be a strong need in the industry. We learned about many advances in The Second Quadrant series in 2013, and evidence of these contributions manifests in a growing list of drugs that have been approved that have leveraged a broad array of solubilization technologies. More than 40 drug products have benefitted from amorphous solid dispersions, supercritical fluid processing, SMEDDS, nanocrystals, cyclodextrins, and lipid technologies (the list can be found at http://www.agerepharma.com/ collaboration/resources). This represents a small overall component of the overall number of approved compounds, but on the flip side of the coin, it also demonstrates that significant progress has been made throughout the past 15 years in the adoption of solubilization platforms.

Adoption of new drug delivery technology is not purely composed of the precedence set by approved drugs. Any vital industry that has an underlying shift in a key component of its products must also be seeing advances scientific knowledge and innovation. The pharmaceutical industry is certainly no exception. To gain more quantitative insight into how the scientific knowledge has expanded, Agere analyzed the number of journal citations that reference “solid dispersions.” This study found that literature citations referencing solid dispersions grew from 8 in 1980 to more than 1,400 per year 30 years later. This growth in the literature demonstrates that the collective knowledge base of the industry is expanding exponentially.

A consequence of a broader and deeper scientific understanding of the issues surrounding delivery of poorly soluble molecules is greater adoption of the platforms required for successful products. Arguably, one measure of the successful translation of scientific knowledge into products is patents. Patents (applications and granted) have grown in a similar exponential pattern to the literature. As an example, the number of patents referencing solid dispersions has grown from 2 in 1977 to an estimated 668 for 2013.5

In summary, there are a number of indicators that show the pharmaceutical industry is making good progress to increasing the number of marketed drugs. As compounds in the global pipeline evolve to lower solubility, drug delivery is playing an increasingly important role in the successful development of drug products. Finally, given that these trends are 30 years in the making, it appears safe to say that solubilization is not a fad but rather firmly here to stay.

NEXT ISSUE

In 2013, we gained insights from the perspectives of many companies that collaborate as part of the emerging supply chain on which pharmaceutical companies depend for overcoming poor solubility. Throughout the next few issues, we’ll explore about drugs have benefited from solubilization platforms. We hope to learn from the challenges faced, how technologies were selected, and key issues that came up and were overcome. If your company has had an experience in successfully delivering poorly soluble compounds that you would like to share, please contact me to be included. Other companies facing similar challenges and CROs supporting clients would benefit from your insights about what worked, what is still needed to simplify the process, and what could be done differently going forward.

REFERENCES

1. Maier H. Overcoming poorly soluble pharmaceutical formulations with hot-melt extrusion. Drug Development & Delivery. 2012;12(8):55-62.
2. Patel ND, Patel KV, Panchal LA, Shukla AK, Shelat PK. An emerging technique for poorly soluble drugs: self-emulsifying drug delivery system. Int J Pharmaceut Biolog Arch. 2011;2(2):621-629.
3. Benet et al. Bulletin Technique Gattefosse. 2006;9:9-16.
4. Experimental data was used when publically available. All other values were estimated via calculation. All peptide and protein therapeutics were excluded.
5. Drug Bank, Agere Analysis.