Removing Troublesome Solubilizing Excipients from Injectables

Surfactants-or the soaps that are typically added to many injectable drugs to make drugs become more soluble in solution-can be problematic for some patients, and can induce allergic reactions and inflammatory responses once administered. In many cases, a patient can be allergic solely to the excipient in a drug, rather than to the drug’s API. Excipients such as surfactants can cause anaphylactic shock, blood clotting, hemolysis, and other serious-sometimes life-threatening-side effects.

According to the authors of a new study published on May 19, 2016 in the journal Nature Communications, 14% of approved drugs in 2015 in the DrugBank database contain hydrophobic compounds that require the help of some type of solubilizing additive. The actual drug-to-excipient ratio in these types of medicines is less than ideal; compared with the API, “the excipient in nanoscale drug-delivery vehicles represents a substantially larger component of the total injected mass, particle size, and molarity,” according to the study authors.

Corresponding author of the study, Jon Lovell, assistant professor in the Department of Biomedical Engineering, School of Engineering and Applied Sciences, at the University at Buffalo, told this publication, "Within the category of injectable drugs that don't dissolve in water, a substantial percentage-probably the majority-use surfactants or non-aqueous solvents to dissolve the drug. Some of the well-known injectable drugs that make use of surfactants include Taxol (paclitaxel), Sandimmune (cyclosporine), and Cordarone (amiodarone).”

Lovell said that a well-known biocompatible surfactant used for dissolving hydrophobic drugs for injectables is Cremophor-EL, made by BASF. Lovell said a 2010 study in Community Oncology concluded that "up to 40% of patients who receive Taxol (containing Cremophor-EL) have had hypersensitivity reactions (bronchospasm, urticaria, and hypotension) and through 2009, there were 431 cases reported of patients with anaphylaxis-and the surfactant is suspected to be implicated."

A new method to strip out the surfactants commonly used in the manufacture of injectable medications is described in the Nature paper by Lovell and his colleagues. The authors used a specific surfactant-a validated biocompatible additive called Pluronic-and exposed it to low temperatures so that it lost much of its surfactant qualities. Through the use of a low-temperature membrane processing technology (for which The State University of New York at Buffalo has filed a patent), investigators were able to remove all “free and loosely bound surfactant” from frozen drug micelles. The technique left behind some concentrated surfactant within the frozen drug micelle, which was enough additive for the drug to remain soluble and stable. Stripping out the majority of surfactants, the authors wrote, would help avoid some of the risks linked to injectable medications. They concluded, “Minimizing the amount of excipient not only holds potential to enable higher dosing due to reduced adverse side-effects, but also minimizes unexpected carrier effects that can modulate drug function.”

All said, investigators were able to produce formulations of 12 different drugs that contained 100 to 1000 times fewer excess additives than current commercial versions. “For the drugs we looked at, this is as close as anyone has gotten to introducing pure, injectable medicine into the body,” said Lovell in a University at Buffalo press release. “Essentially, it’s a new way to package drugs.”

Future work will be focused on the long-term stability of the surfactant-stripped induced frozen micelles (ss-InFroMs) and the ability of ss-InFroMs to withstand lyophilization.

Sources: Nature Communications, University at Buffalo