Pharma and Health from Ingredients to Pills: Botanical Drug Formulations

Plant based medicinal remedies date back to the dawn of mankind.  Today, botanical medicines have found a niche primarily amongst those who want a more natural remedy without the potential side-effects found in many modern medicines.  The FDA classifies botanical products as foods, dietary supplements, drugs, medical devices, or cosmetics, depending on their intended use. (1) The designation relies solely on the marketed and labelled intended use of the product.  Over the past 10 years, research and development efforts have been escalated into the potential uses of botanical formulations to treat a plethora of conditions, spurred on by the sudden rise and approval of the use of CBD to treat a variety of symptoms.  While there is quite a bit of hype which surrounds modern botanical remedies, it is important to note that currently there are very limited clinical trials studying such compounds. Botanical medicines are currently viewed, skeptically, as their effectiveness in treating many of the conditions they are marketed to treat have not been scientifically proven. Nevertheless, it is important to note that in this realm of pharmacology, there is much potential for research and development of novel botanical compounds.

Botanical Drug Market

Plant-derived drugs as a segment have been forecasted to grow from $29.3 billion in 2017 to around $39.2 billion by 2022 with a CAGR of 5.9% for the period of 2017-2022. Botanical drugs are suggested to see a growth from $57.0 million to $425 million with a CAGR of 49.5% for the same period. (2) The botanical drug category is still finding its niche with big pharma companies, as they are often hesitant to make large investments without intellectual property protection. However, many players continue to investigate the potential for commercialization, with larger pharmaceutical companies typically acquiring startups after their innovative products have reached the final stages of successful clinical development or showed great potential as a new drug.

The first botanical drug approved by the FDA was Veregen, (a treatment for genital and perianal warts) which is derived from the green tea plant. Later, the FDA approved another New Drug Application (NDA) for the drug Fulyzaq (an indicator drug for HIV-associated diarrhea) extracted from the blood-red latex of the croton tree found in South America. (3)  Epidiolex (GW Pharma) is a CBD derived medicine approved for the treatment of seizures. Probably the most striking example of a successful botanical medicine is Oseltamivir (branded Tamiflu) which was discovered from star anise, a native plant to China, with worldwide sales exceeding $3 billion. While the previously stated medicines have been approved and are being marketed, it is only 4 of over 2000 such NDAs submitted to the FDA over the past 10 years.  This trend has left a gap in large investors due to the uncertainty of such compounds actually making it to market.  Nevertheless, many startups have formed recently to provide vital R&D activities.

Formulations

Botanical formulations can be quite an undertaking in scientific research.  With the efficacy of such compounds under question, the burden of proof requiring early evidence in the pipeline processes. Many botanical compounds have been isolated, generally through high pressure liquid chromatography (HPLC), selecting key molecules from the whole plant.   Once the botanical compound has been extracted, usually in a liquid or oil form, it is generally difficult to run through the standard pre-formulation/formulation testing. Many of these compounds do not readily form salts and/or polymorphs. This tends to make crystallization into an active pharmaceutical ingredient (API) either difficult or cost prohibitive.  However, due to their complex chemistry, direct precipitation can be accomplished through the use of an anti-solvent.   

While single source compounds have shown promise as of late, a meta-analysis of published reports by a Brazilian group suggests that the whole plant preparations were as much as 5 times more efficacious than single source products.(4) Formulation efforts on whole plant products will likely spend the near future in in vitro testing or used in oral suspensions.  These types of formulations are generally simple from a compounding point of view.  The part of the plant (oil, crushed leaves, etc.) is incorporated with a binding agent and dispensed.  FDA approval for such materials is generally more difficult as the FDA requires evidentiary proof of a particular compound’s efficacy. Thus, testing these materials in clinical studies is reserved only for the most promising cases.

However, testing during the formulation and pre-formulation steps is generally confined to spectroscopic, HPLC and thermal analysis.  Nuclear magnetic resonance (NMR) would be possible, but cost prohibitive for any group other than large medical supplies manufacturers and pharma. Clinical studies for FDA approval, significant evidentiary documentation must exist. The limited testing available for such compounds has proven to be one of the larger hurdles in the advancement of a compound or complex from the formulation and preformulation stages.

Advances in nanotechnology have aided in the formulation and development of botanical medicines.  For instance, many constituents of the herbal drugs will lose their bioavailability in the highly acidic pH of the stomach before reaching the blood, while other constituents are metabolized by the liver. Thus, the optimum dosage of the herbal drugs is unlikely reach the blood. If the drug does not function in the optimum dosage to the target region at "minimum effective levels," then the therapeutic effect of the drug cannot be verified. Nanocarriers applied to herbal remedies will carry optimum dosages of the drug to their target site, bypassing all the barriers such as acidic pH of stomach and liver metabolism, while increasing the prolonged circulation of the drug in the blood due to their small size. Nano-sized delivery systems are advantages due to the following reasons:

1. Ability to deliver high concentrations of drugs to disease sites because of their unique size and high loading capacities.

2. Deliver the drug in the small particle size that enhances the entire surface area of the drugs allocating quicker dissolution in the blood.

3. The concentration seems to persist at the sites for the longer periods.

4. Exhibits passive targeting to the disease site of action without the addition of any particular ligand moiety.

5. Decrease in the side effects.

6. Decrease in the dose of the drug formulation. (5)

Conclusion

While the use of botanical medicines dates back to pre-history, its use as effective remedies to targeted medical treatment has been a topic of increasing R&D efforts over the past decade.  While the efficacy of such compounds is still under scrutiny by the scientific community, new promising materials are being discovered frequently.  Isolating both single source and complex whole plant ingredients is generally a simple process, either by using ground plant parts, or separating key compounds through HPLC. Formulating these compounds can be a little trickier as normal formulation and preformulation steps end in no result as crystallizing many of the newer components proves difficult to repeat consistently.  Advances in nanotechnology have greatly increased the bioavailability of botanical medicines.  With a projected market growth over the next couple years, the funding is certainly not in short supply.  Thus, while large pharma has been slow to join in the research efforts of emerging compounds, they are more than happy to buy up startups who have performed the preliminary research and development. Briefly, this good strategy allows most pharmaceutical companies to speed the new product development process.

References:

1. US FDA Guidance: Botanical Drug Development, December 2016

2. ReportLinker: https://www.prnewswire.com/news-releases/botanical-and-plant-derived-drugs-global-markets-300563001.html. November 2017,

3. BMB Rep. 2017，50(3): 111-116.

4. Pharmaceut Reg Affairs, 2019， 8:2.

5. J Adv Pharm Technol Res. 2012，Jul-Sep; 3(3): 142146.

Date: April 15, 2020

About the Author:

Lin Zhang, M.D., senior director of a health care industry company in the United States. With the experience in clinical medicine, biotechnology, health industry and other fields, he is responsible for the research and development of plant medicine, functional food and health products. He was a clinician and worked for the National Cancer Institute, FDA and the National Cancer Center of Japan for many years.

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