Zhijun Liu

Although it is pretty easy to swallow medications in tablet or capsule form, it is not so easy to have them soluble after that. This is an important issue because drugs need to be soluble in the small intestines to be absorbed into the bloodstream and take effect. Many drug molecules are soluble or made soluble to meet this absorption need. However, more than 40 percent of new chemical entities emerging from drug discovery are not water soluble. Hundreds, if not thousands, of active pharmaceutical ingredients have been shelved from development because of poor solubility. Lack of solubility has been and continues to be a major roadblock to better medicines. An excellent molecule for a particular disease may be abandoned because of its poor solubility and unmet solutions. Major pharmas and various specialty formulation companies possess numerous tools to tackle the solubility issues, but each of these brings along substantial limiting factors related to toxicity and formulation. Solubility remains unsolved.

It is highly unexpected that a solution to poor solubility would come from the research of medicinal plants in an agricultural setting, such as the LSU AgCenter. Indeed, the medicinal plant research program was not set up to find solutions for poor solubility. Rather, it was established to understand how trees responded to environmental stresses such as drought or flooding and how fiber production could be maximized to provide sufficient and high-quality forest products.

After a brief but intensive cultivation research of medicinal plants, the direction of the research program changed into natural drug discovery to identify bioactive compounds and their potential synergism from plants, joining hundreds of other such laboratories in the world. Despite changes in research directions, each experience accumulates to back up creativity and innovation. For example, studying the mysterious ability of a plant to mobilize water-insoluble defense chemicals (e.g., antimicrobial) in their aqueous systems when herbivores attack led to careful observations and ultimately the discovery of several natural solubilizers. For example, steviol glycosides are better known for their sweetening properties, but when used with other water-insoluble compounds, they showed capabilities of holding them in water from otherwise precipitation. In numerous feasibility experiments, it was shown water-insoluble compounds were solubilized by the use of steviol glycosides by a minimum two-fold to as high as one-million-fold.

Poor solubility is easily seen by the naked eye. Curcumin, a pungent compound found in the curcuma root or more commonly curry spice, has poor water solubility and precipitates out easily. Etoposide, an old chemotherapeutic agent, is poorly soluble, and precipitation takes place as soon as it is mixed in water. Oil, such as vitamin E, is water-insoluble and forms the top layer when mixed with water. There are literally tens of thousands of poorly soluble compounds from natural and synthetic sources. To name a few, they include the anesthetic propofol, the anti-inflammatory celecoxib, the anti-fungal amphotericin B and nystatin, the anti-bacterial roxithromycin, azithromycin and erythromycin, the antiviral ritonavir, the immunosuppressant cyclosporine, the chemotherapeutic agents paclitaxel and etoposide, and many natural active agents including silybin, gingerol, tanshinones, coenzyme Q10, rutin, podophyllotoxin, capsaicin, artemisinin, resveratrol, genistein, quercetin, icariin, and oleandrin. AgCenter scientists have conducted experiments with all of these in the medicinal plant lab.

To illustrate the effect of solubility enhancement, curcumin is mixed with a steviol glycoside rubusoside and processed together. Without rubusoside, only a small amount of the curcumin remained in water, and the rest precipitated to the bottom (Figure 1 left). With rubusoside, all the curcumin was in water solution (Figure 1 right). By visualizing the intensity of yellowish color of the two water solutions, the solubility enhancing effect by some 5,000 fold is evident.

Solubility enhancement is one thing, whereas usefulness for medical research is another. Countless efforts have been undertaken to prove this utility. Since the discovery, more than 10 grant applications have been submitted to the National Institutes of Health (NIH) with little success. The skepticism is due to the lack of credentials and track record, lack of interest in pharmacological mechanisms-driven review, and the ever fierce competition for competitive federal grants. The good news is a two-year NIH grant award has finally come to the AgCenter team to study the use of this technology for converting an intravenous Taxol drug to an oral for cancer patients. This will not only allow the scientists to examine the potential in improving medications but also an opportunity to create a brand new chemotherapy that has the potential to help millions of new and ex-cancer patients in their fight against primary cancer or the threat of recurrence. Moreover, the success of this project could support expansion to other promising chemotherapy regimens that perform poorly in the clinical stages or are prevented from even entering the human studies as a result of unsolved poor solubility.

The LSU AgCenter has filed three patent applications. Because of the potential of broad applications, the AgCenter has taken the strategy of multiple licenses to allow industries to develop certain products in separate markets. The solubility enhancement technology so far has been licensed to a local food and beverage startup company to focus on food and beverage products. It has just been licensed by a Louisianabased medical food company to develop improved versions of existing products and create some new products primarily for the medical food market. A Chicago-based cancer treatment center has been sponsoring research projects performed in the medicinal plant lab to develop about two dozen bioavailable formulations for its existing dietary supplements. The average survival of the center’s patients has doubled so far, but the center plans on achieving an even higher rate. AgCenter technology could enable that goal and expand to other clinics in the United States and around the world. A license discussion has been ongoing and, if signed, would be the third license for this technology.

Outside the health arena, the solubility technology has been considered for agrochemical and agricultural uses. Many potential and new fungicidal, insecticidal and bactericidal agents are discovered, but poor solubility has been a major obstacle, in addition to much stricter environmental requirements. The AgCenter’s natural approach and the use of nontoxic solubilizing agents could be the perfect solution to these needs.

The medicinal plant lab’s search for new and more effective natural solubilizing agents is currently on hold because we have been busy developing those already discovered into proof of concept applications such as the NIH project and several sponsored research projects. Consequently, the medicinal plant lab has been re-geared to conduct bioavailability assessments using cellular and animal models with the goal of solving poor bioavailability encountered in many developmental projects. Continued internal and external support in terms of expertise and funding would facilitate the discovery of new and natural solubilizing agents at a much faster pace. This would indeed be very welcomed.

Zhijun Liu is a professor in the School of Renewable Natural Resources and leader of the Medicinal Plant Laboratory.

(This article was published in the fall 2012 issue of Louisiana Agriculture magazine.)