The U.S. government’s classification of marijuana as a Schedule I drug in 1970 restricted R&D efforts to work with cannabis compounds by requiring all cannabis research that was not funded by the government to go through a Public Health Service (PHS) review. Later, in June 2015, the U.S. Department of Health and Human Services (HHS) agreed to support research into the therapeutic properties of cannabis by lifting the PHS review requirement, thus allowing research to expand and consider the benefits of cannabis, instead of focusing mainly on its harmful effects.
A major breakthrough, pioneered by Professor Raphael Mechoulam from the Hebrew University of Jerusalem, came with the discovery that not only humans, but all mammals, have an endocannabinoid system that is activated by cannabinoids, and affects a number of different areas in the body, including memory, appetite, pain sensation, stress response, energy balance and metabolism, anxiety, immune functions, thermoregulation and sleep.
Cannabinoid receptors have been discovered throughout the body and are believed to be more numerous than any other receptor type.1 Researchers have identified two types of cannabinoid receptors: CB1 and CB2. CB1 receptors are considered to be among the most widely expressed G protein-coupled receptors in the brain and are particularly abundant in areas of the brain concerned with movement and postural control, pain and sensory perception, memory, cognition, emotion, and autonomic and endocrine function.2 They are also found in peripheral tissues including peripheral nerves and non-neuronal tissues such as muscle, liver and fat.
CB2 receptors are expressed almost exclusively in cells and organs connected with the immune system and cardiovascular system, their highest concentration being found in the spleen. Many parts of the body contain both CB1 and CB2 receptors.
The use of cannabis as an analgesic, muscle relaxant, anticonvulsant, antiemetic and appetite stimulant was documented more than a century ago by William O’Shaughnessy, a British doctor working in India. More recently, interest in developing cannabis-based therapies for conditions as diverse as cancer, multiple sclerosis, some forms of epilepsy, HIV, arthritis and type II diabetes, is being discussed.
Cannabis can be complicated as it is a mixture of many components. As many as 100 cannabinoid compounds have been identified so far. [Delta]-9 Tetrahydrocannabinol (THC) is the main psychoactive component with activity at both of the cannabinoid receptors CB-1 and CB-2.3
Cannabis activity is further complicated by what is known as the ‘entourage effect’, where non-cannabinoid components of marijuana, such as terpenes, ketones, esters, lactones, alcohols, fatty acids, etc. may interact with the cannabinoids to produce a synergy of effects. For example, terpenes, the molecules responsible for marijuana’s smell, have been shown to block some cannabinoid receptor sites in the brain, while promoting cannabinoid binding in others.4
Initial research into cannabinoids focused almost exclusively on THC, but, more recently, has moved to include other cannabinoids—particularly cannabidiol (CBD)—and identifying their potential therapeutic applications. CBD has been reported to have anti-inflammatory, anticonvulsant, antipsychotic, antioxidant, neuroprotective, and immunomodulatory effects.5 CBD pharmacology differs from THC in that it does not display the same psychotropic effects as THC.6
There is also a distinction between cannabis-based products developed for medicinal use, and cannabis-driven pharmaceuticals. Medicinal cannabis products generally promote the medicinal properties of marijuana through use as dietary supplements. The products are generally botanical extracts and plant materials derived from specific strains that can be smoked, vaporized, ingested or topically applied. They may lack quality control and standardization required for pharmaceuticals that would assure users of a reliable and reproducible dose, and they may also contain levels of pesticides and other substances typically not allowed in pharmaceuticals. The delivery methods used for these products include tablets, capsules, elixirs, tinctures, topical, edibles, ingestible oils, cigarettes, vaping and dabbing.
Pharmaceutical cannabis products, in contrast, undergo full regulatory review to ensure their efficacy and safety. The cost and time required to develop these products is much greater than for nutraceutical medicinal cannabis products.
The natural variability of the constituents and concentrations of cannabinoids within plant extracts makes it difficult to standardize dosing from extracts. The plant cultivars as well as the growing conditions play into this variation. Therefore, there are advantages in isolating or synthesizing individual active ingredients. These can then be dosed as single entities, as specific combinations of active pharmaceutical ingredient (API), or as an API plus entourage materials. However, this flexibility can lead to potential complexities when developing delivery platforms, as one must consider the activity and interactions of all the components when justifying their inclusion into the formulation.
A number of possible delivery routes have been considered for pharmaceutical delivery, including ophthalmic, nasal, buccal, sublingual, transcutaneous, rectal, gastrointestinal (GI) and pulmonary.7 However, oral delivery is often preferred for its convenience and acceptance in the regulatory approval process.
Cannabis compounds tend to be highly lipophilic and poorly water-soluble. Cannabinoids typically fall into Developability Classification System (DCS) Class IIb (see Figure 1) and would be expected to show solubility limited absorption. DCS Class IIb compounds often benefit from formulation technologies that improve intrinsic solubility such as lipid-based systems, or solid dispersion systems; however, some cannabinoids exhibit extensive absorption with minimal formulation effort.
Softgel capsules can deliver cannabis in lipid-based systems. Lipid formulations use various lipids and/or surfactants to dissolve/disperse the drug. The softgel shell also provides an excellent oxygen barrier, which can be important, as some of the cannabinoids readily oxidize. Softgel capsules are also intrinsically capable of handling liquid APIs such as THC, which exists as viscous oil.
After the patient swallows the softgel capsule, the shell ruptures rapidly, in 5 to 10 minutes, and the API is released into the GI tract, allowing rapid absorption into the blood stream. Proper selection of lipid excipients gives the formulator the ability to influence the absorption process. Lipid-based formulations (LBFs) can be digested by lipases and bile salts to produce mixed micelles that are then absorbed through the enterocytes, or surfactant systems can be utilized to deliver self-microemulsifying drug delivery system (SMEDDS) to improve absorption (see Figure 2).
Although some cannabis compounds may exhibit extensive absorption, they often have poor bioavailability due to first-pass liver metabolism. In such cases, lipid-based formulations can be designed to promote lymphatic absorption. Lymphatic absorption involves the assembly of long chain fatty acids and lipids along with the cannabinoid into chylomicrons, which are then absorbed into the lymphatic system, thereby bypassing the liver. There may be an additional benefit of lymphatic absorption in immune related disease states, as the lymphatic system plays an integral role in the immune system and may help target such diseases.
Hot melt extrusion (HME) has also been used to deliver cannabinoids. HME is a solid dispersion technology that can enhance the bioavailability of poorly soluble drugs. The HME process is used to prepare an extrudate of API solid dispersions in a polymer/excipient matrix that can be then incorporated into downstream processing and solid dose form manufacture. This process allows the extrudate to be formulated into final dosage forms, such as tablets and capsules (see Figure 3).
Oral inhalants, nasal, sublingual/buccal and topical delivery platforms offer alternatives to oral delivery that bypass first-pass metabolism. These approaches usually deliver the drug into the systemic blood circulation and do not target the lymphatic system.
Pressurized metered dose inhalers (pMDIs) offer fast onset and bypass the first-pass metabolism. Factors to take into consideration when formulating for pMDIs are limitations to the size of the dose (25-100 µl), particle/droplet size control, whether the API should be in solution or suspension, and concerns about the long-term effect of delivering systemically acting drugs via the lung epithelia.
Similar to pMDIs, a nasal spray offers similar dose size limitations, rapid onset, and bypasses the first-pass metabolism. Droplet size control, irritancy and the retention of the dose in the nasal cavity need to be considered.
Transdermal delivery can also bypass the first-pass metabolism and can offer the additional benefit of extended release of the API. Because transdermal delivery usually only delivers microgram doses, this technology is best suited to potent drugs.
Cannabis-based therapies hold much promise. As studies advance our understanding of cannabis, it may become possible to treat diseases and to provide relief of symptoms that are not adequately controlled by existing medications in some patients. However, by their nature, they are complex compounds and the development of drugs that offer a consistent, reliable dose with minimal side effects is challenging. The choice and application of both the formulation and the delivery mechanism will play a key role in the product’s ultimate success.
- The Cannabis Biotech/Pharma Market Could Surpass $20 Billion by 2020; Viridian Capital Advisors; December 2015.
- Mackie K, Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength, International Journal of Obesity (2006) 30, S19–S23.
- Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002; 54: 161–202.
- Russo EB, Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects, Br J Pharmacol. 2011 Aug; 163(7): 1344–1364.
- Kogan and Mechoulam, Cannabinoids in health and disease, Dialogues Clin Neurosci. 2007 Dec; 9(4): 413–430.
- The Biology and Potential Therapeutic Effects of Cannabidiol, June 24, 2015, National Institute on Drug Abuse.
- Huestis MA, Human Cannabinoid Pharmacokinetics, Chem Biodivers. 2007 Aug; 4(8): 1770–1804.
Dr. David Fulper is Director of Technology Support, at Catalent Pharma Solutions in St. Petersburg, Florida. He joined R.P. Scherer, which later became Catalent, in 1997 and has held various positions in R&D and operations. Prior to joining Catalent he worked for Schering Plough and was Director of Liquid Filled Capsules at Patheon Pharmaceuticals. He received his master’s and doctorate in pharmaceutics from the University of Mississippi.