Drug development today is a long, arduous and expensive proposition. Since the first half of the 20th century, the standard of care in medicine and the pharmaceutical industry[1] [2] is developing medications using nationally standardized protocols for medication safety and efficacy along with precision dosing for any new drug. Formulation development of drugs is key to ensure standardized quality, control over precision dosing, safety, accurate quantities delivered as well as the delivery to the correct site of action.
Using botanically derived medicines with their high degree of variability is why most drugs today, despite them being derived originally from compounding natural substances from plants, are now chemically synthetic versions made in laboratories. For example, the drug digitalis (or digoxin) which was originally derived from the foxglove plant[3] is now synthetically made. Cannabis, like many botanicals presents challenges to drug development and formulation. One of the biggest challenges is the ability to fully demonstrate and prove consistency in its chemical composition due in part to its complexity.
Cannabis is composed of over 100 cannabinoids and about 500 other compounds such as terpenes and flavonoids. Additionally, there are over 550 different strains/chemovars of the plant all with differing ratios and combinations of these cannabinoids such as THC and CBD and compounds such terpenes.[4] And efficacy for one chemovar does not establish efficacy for another due to the interaction of the varied and different ratios of components in each.[5] It practically requires individual testing and proof that each particular chemovar variety of cannabis be evaluated for efficacy for a specific health conditions.
Additionally, the federal illegality of cannabis does not allow for nationally systemized controlled agricultural practices and growth conditions to guarantee more consistency in the final product. This is left to each separate state’s government requirements, therefore creating overall quality issues that make formulation development difficult but important.
When we look at cannabinoid drug development, accurate dosing is major issue. And since oral administration is usually the preferred route[6] for drug compliance and use, this is the first hurdle to overcome. All cannabinoids are lipophilic and have poor water-solubility[7]. When there is poor water solubility there is potentially slow oral drug absorption and that can cause variable bioavailability, which can become a rate-limiting step to achieve therapeutic plasma concentrations and ensuing pharmacologic response[8].
Additionally, there is a classification system called the Biopharmaceutical Classification System (BCS)[9] which differentiates potential drugs based on their solubility and permeability. Cannabinoids are class II, indicating low water solubility but high permeability due to their lipophilic nature. Therefore, in oral preparations there will be difficulties getting the compound absorbed into the systemic circulation but once inside they can be carried to the correct site of action permeable across the cell membranes.
Using lipid-based formulations is one way to address this.[10] Another technique called solid dispersion formulation, uses a mixture of drugs with water soluble carriers[11], which are compounds consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug inside it. For example, using sugar molecules called cyclic oligosaccharides which have an outer surface that is hydrophilic and an inner cavity that is hydrophobic has been used as a vehicle to deliver these lipophilic drugs in a more water-soluble form[12]. Additionally, a formulation technique called nanosuspension technology, takes poorly water-soluble drugs and breaks them down into tiny particles between 200-600nm[13] and suspends them in a colloid dispersion mixture to improve solubility, bioavailability to improve pharmacokinetics, efficacy and safety[14].
Another key issue critical in creating cannabinoid medicines is to ensure they are safe and contaminant free of molds, solvents, heavy metals, pesticides and bacterial pathogens all more likely to be found when trying to extract medication from natural botanical products.
Cannabis used as an inhaled medication already poses potential risks especially for immune compromised patients such as cancer patients[15], due to possible bacterial or fungal contaminants. Therefore, formulations of oral or sublingual formulations of cannabis are a better option, since the stomach acid in our GI tract is actually designed to kill and neutralize many potential pathogens and allergens, in addition to the first pass through our liver which neutralize many potential toxins. But regardless of delivery method, it is critical to ensure as best as possible that we mitigate any contaminants when developing cannabinoid medications.
Additionally, in many states there are requirements to grow indoors, and since plants naturally contain water content that makes them very prone to mold formation during storage and drying, so it is key to ensure moisture content analyzers[16] and hygrometers are employed to create and maintain consistency.
We also need to ensure that there are no residual solvents or heavy metals in the final products. The lipophilic nature of cannabis usually requires organic solvents to extract constituents. These solvents are all potentially harmful and maybe even carcinogenic. That is why many processors are not trying to extract with high pressure carbon dioxide[17].
Many different types of analytic chromatography techniques[18] can be used to ensure the levels of different constituent components of cannabis (such as terpene levels, THC and CBD, THCA, CBDA etc.) There are also important culture-based tests[19] to ensure sterility related to pathogenic microbiological and bacterial contamination. All of these are of major concern to ensure the consistency and safety of any medicine derived from cannabis.
Incidentally and historically, medicinal cannabis tinctures were a common treatment[20] at the end of the 19th century and beginning of the 20th century. Yet despite what we learned in our first class, cannabis which fell out of favor and was eventually taken off the US Pharmacopeia in 1942[21], wasn’t all due to the cumbersome and expensive taxation imposed by the Marijuana Tax Act of 1937[22]. The rise in precise dosing with the development of pills and tablets such as aspirin[23], as well as the lack of understanding of the active ingredients in cannabis and its mechanism of action, which were not discovered until the 1960s[24], all contributed to its initial demise as a therapeutic agent.
[1] Zineh I. & Woodcock J. Clinical pharmacology and the catalysis of regulatory science: opportunities
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[2] Gonzalez D., et. al. Precision Dosing: Public Health Need, Proposed Framework and Anticipated Impact. Clin Trans Sci. 2017; 10(6): 443-454.
[3] Digitalis, How Digitalis is Used Risks and Side-effect. Science Jrank.org. Updated 2020. https://science.jrank.org/pages/2088/Digitalis.html. Accessed February 23,2020.
[4] Mieri D., Behind the Smokescreen of Medical Cannabis. TEDX. Published June 1, 2018 https://www.youtube.com/watch?v=9ioJbVyNg08. Accessed February 23, 2020.
[5] Miller M., et. al. Cannabis and Cannabinoid Drug Development: Evaluating Botanical Versus Single Molecule Approach. Int rev Psychiatry. 2018; 30(3): 277-284.
[6] Bayliss M., et. al. Quality guidelines for oral drug candidates: dose, solubility and lipophilicity. Drug Discov Today. 2016; 21(10): 1719-27.
[7] Wall M., Sadler B., Brine D., Taylor H., Perez-Reyes M., Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women. Clinical Pharmacology and Therapeutics 1983; 34: 352–363.
[8] Sharma D, Soni M, Kumar S, Gupta GD. Solubility enhancement—eminent role in poorly soluble drugs. Research Journal of Pharmacy and Technology. 2009; 2(2): 220–224.
[9] Food and Drug Administration. The Biopharmaceutics Classification System (BCS) Guidance. Published December 22, 2017. https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/biopharmaceutics-classification-system-bcs-guidance . Accessed April 4, 2020.
[10] Salva R., et. al. Review and Analysis of FDA Approved Drugs Using Lipid-Based Formulations. Drug Dev Ind Pharm. 2017; 40(11): 1743-1758.
[11] Poutan CW. Formulation of poorly water-soluble drugs for oral administration: Physicochemical issue and lipid formulation classification system. Eur J Pharm Sci. 2006;29:278–87.
[12] Davis ME, Brewster ME. Cyclodextrin-based pharmaceutics: past, present and future. Nat Rev Drug Discov. 2004;3(12):1023
[13] Muller RH, Jacobs C, Kayer O. Nanosuspension for formulation of poorly soluble drugs. In: Nielloud F, Marti-Mesters G, editors. Pharmaceutical emulsion and suspension. New York: Marcel Dekker; 2000. pp. 383–407.
[14] Patel R., Agarwal Y., Nanosuspension : An Approach to Enhance Solubility of Drugs. J Adv Pharm Technol Res. 2011; 2(2): 81-87.
[15] Ruchlemer R., et. al. Inhaled Medicinal Cannabis and the Immune Compromised Patient. Supportive Care in Cancer. 2015; 23: 819-822.
[16] Wolffe L., Preventing Mold and Fungus in Cannabis with Data Analytics. Cannabis Industry Journal.com Published Januray 20, 2020. https://cannabisindustryjournal.com/feature_article/preventing-mold-fungus-in-cannabis-with-data-analytics/ . Accessed April 4, 2020.
[17] Krunoslav A., Supercritical CO2 Extraction of Cannabis Sativa L. Seed Oil. Indust Crops and Prod. 2015; 76: 472-478.
[18] Pellati F., New Methods for Comprehensive Analysis of Bioactive Compounds in Cannabis Sativa L. Molecules Online. Published October 14, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222702/ .Accessed April 4, 2020.
[19] Mc Kernan K., Metagenomic Analysis of Medicinal Cannabis Samples; Pathogenic Bacteria, Toxigenic Fungi, and Beneficial Microbes Grow in Culture-based Yeast and Mold tests. F100Res Online. Published October 7, 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089129/ . Accessed April 4, 2020.
[20] Bridgeman M., Abazia D., Medicinal Cannabis: History Pharmacology and Implications for the Acute Care Setting. Pharmacy & Therapeutics. 2017; 42(3): 180-188.
[21] US Pharmacopeia, Antique Cannabis Book 12th ed. Appendix C. Published 1942. http://antiquecannabisbook.com/Appendix/AppendixC.htm. Accessed February 23, 2020.
[22] Pasanti S, Bifulco B. Modern History of Medical Cannabis:From Widespread Use to Prohibitionism and Back. Trends in Pharmacologic Sciences. March 2017; 38(3):195-19
[23] Goldberg D., Aspirin Turn of the Century Miracle Drug. Science History Institute. Published June2, 2009. https://www.sciencehistory.org/distillations/aspirin-turn-of-the-century-miracle-drug . Accessed February 23, 2020.
[24] Gaoni,Y., Mechoulam,R. Isolation and structure of DELTA-tetrahydrocannabinol and other neutral cannabinoids from hashish. J Am Chem Soc. 1971;93(1):217-224.
Dr. Leigh Vinocur is a board certified emergency physician, who also has a cannabis consulting practice for patients and industry. She is a member of the Society of Cannabis Clinicians. And in the inaugural class for the first Masters of Science in the country in Cannabis Science and Therapeutics at the University of Maryland School of Pharmacy.
This blog is not written or edited by Hearst. The authors are solely responsible for the content.