FORMULATION DEVELOPMENT – Understanding CBD Formulation Versus Dosage Format
There are many misconceptions when it comes to considering the best way or format to consume cannabidiol (CBD) and get the maximum benefit. Formulation scientists need to consider several factors when developing new formulations of nutraceutical ingredients, especially botanical ingredients and natural materials from various sources. One of the first considerations is the purity of the ingredient along with its physicochemical properties, such as solubility, density, flowability, and stability. Botanicals and naturally sourced ingredients are complex and often can contain multiple chemical components, not to mention several classes of compounds. The physical, chemical, and sensorial properties of botanical extracts from different sources can be remarkably variable, making it difficult to directly substitute one source for another in a finished formulation.
The properties of the botanical active can have a direct bearing on the type of dosage form into which it can be formulated. For example, if the ingredient is an oil or wax versus a water-soluble material, it may not be easy to formulate into tablets or capsules. Similarly, ingredients with a large serving size may have to be delivered as a powder that is mixed into water for easy consumption. Hemp extracts are a good example of botanical ingredients, where along with the major cannabinoid CBD, there may be some THC (<0.3%) and minor quantities of many other cannabinoids as well as terpenes and flavonoids. The lipophilic extracts pose significant formulation challenges that must be addressed so that a safe, efficacious, and palatable product is available for consumers. The efficacy of any supplement is based on a sound understanding of its bioaccessibility and, more importantly, bioavailability.
HEMP EXTRACTION & PURIFICATION
Cannabinoids are extracted from the hemp plant biomass in a series of steps involving solvent extraction, filtration, and finally distillation to arrive at CBD distillate. The distillate is then further processed to produce either full spectrum, broad spectrum, or isolated single cannabinoids. Reproducibility of the whole plant extracts or full spectrum products may be challenging because of the difficulty to control variables, such as harvest to harvest variation and extraction process or formulation differences.
So called “THC-free extracts” may contain some minor cannabinoids, terpenes, flavonoids, and other trace ingredients. Broad spectrum CBD has no THC but may comprise some minor cannabinoids and terpenes; however, there is no rigorous definition of what the composition should contain. Lastly, there is pure CBD often referred to as CBD isolate. Pure CBD is a white to off-white crystalline powder. CBD in its unpurified form (full spectrum or broad spectrum) may exist as a resin, wax, or oil, depending on what other plant constituents are present. From a consumer perspective, the unpurified CBD is typically dissolved in oils, such as medium chain triglycerides or other vegetable oils.
Recently, it has been reported the THC (a psychoactive cannabinoid) content of many CBD tinctures is much higher than expected. This can place consumers in the precarious position of being unexpectantly intoxicated or potentially failing drug tests.
BIOACCESSIBILITY & BIOAVAILABILITY
Understanding how the physicochemical attributes may affect the bioaccessibility and hence the bioavailability is also critical to developing and delivering a safe and effective dietary supplement.1,2 Water-soluble components are easier to work with and can fit with a variety of delivery formats. Conversely, poorly soluble or insoluble ingredients present a significant challenge.3,4 A particularly challenging subset of ingredients are fat-soluble or lipophilic materials that must be formulated carefully to attain optimal absorption. Bioaccessibility is the first step in the process of a compound or nutrient becoming bioavailable. In this step, the compound or nutrient is first released from the delivery system, which can be a food matrix such as a gummy, or a swallowed dosage form, for example, a capsule or tablet. Many digestive steps from chewing to mixing with acid and enzymes in the gastric juice are involved in the process of making bioactives and nutrients bioaccessible. Once released from the delivery format, the bioactive or nutrient should then be available to the body in a form suitable for absorption.
The oral bioaccessibility and bioavailability of lipophilic bioactives has been shown to be enhanced when the waxy or oily ingredient is formulated into an emulsion. The composition of said emulsion, ie, lipid and emulsifier types used, as well as the key physicochemical attribute of emulsion droplet size have a direct impact on the release from the dosage form. These attributes also have a bearing on the ultimate solubilization, transport, metabolism, and absorption in the gastrointestinal tract (GI) and can affect distribution to the lymphatic system.
It is clear from the work of Gershkovich et al that the lymphatic absorption of CBD is critical to attaining superior blood levels.5-7 This is not unexpected given how other oily nutrients have been formulated.3
The absorption of many lipophilic nutrients and bioactives are affected by food intake, this is called a food-effect-related absorption factor. In multiple food-effect studies, it has been reported the amount of CBD absorbed increased approximately four-fold when it was consumed with a high-fat meal, compared to fasting conditions.8
FORMULATION OF CBD TO IMPROVE BIOAVAILABILITY
As previously mentioned, CBD, THC, and other minor cannabinoids are lipophilic compounds and hence need to be formulated appropriately to achieve reasonable levels of absorption especially via the gastrointestinal tract. This is important as most consumer CBD offerings are formulated as oral products either as tinctures, gummies, capsules, tablets, softgels, or in beverages. It has been shown that unformulated CBD has extremely low bioavailability (less than 5%), while dissolving CBD in oils such as the MCT or sesame oil can increase bioavailability to between 6%-13%.9 The most significant increase in the bioavailability of CBD has been achieved when the cannabinoid has been formulated into a system in which the lipophilic material is encapsulated by hydrophilic ingredients. These formulations can involve various technical approaches, such as micro- or nano-emulsions, self-emulsifying systems, liposomes, micelles, or other complexes, such as those with beta cyclodextrins.10 This may be achieved using natural ingredients and emulsifiers while some methods require inclusion of synthetic materials, such as some SEDDS (self-emulsifying drug delivery system) formulations. The CBD formulations with enhanced bioavailability are often referred to as water-soluble or water-miscible formats. There has been a considerable amount of preclinical and clinical research on how these emulsified formats enable superior cannabinoid absorption.10-13 However, there is still work to be done to better understand the effect of emulsion droplet size and formula constituents on the bioavailability of CBD.10,15
INCORPORATION OF WATER MISCIBLE CBD INTO FINISHED DOSAGE FORMS
Once the CBD or hemp extract has been successfully formulated to be more bioavailable, it must then be incorporated into a consumer-friendly delivery format consumers are familiar with, such as gummies, capsules, tablets, and powders.
It is important to recognize that oil-based CBD formulations, while normally being synonymous with tinctures or softgels, may also be incorporated into gummies and other edible formats. So, one should not equate the finished delivery format with any expected level of performance in terms of bioavailability. What is critical to achieving the optimal bioavailability is that the lipophilic cannabinoid material is first formulated into a composition that lends itself to being absorbed within the human GI tract. Some absorption-enhancing technologies are more flexible than others, ie, they are available in both liquid and solid formats, enabling the formulation of a wide variety of finished dosage forms.
When it comes to having confidence in the bioavailability of a CBD formulation, there is no substitute for human bioavailability data. There have been several human pharmacokinetic studies completed on commercially marketed consumer CBD products.11,13,14,16
LEARNINGS FROM RECENT HUMAN PK STUDIES
In the past 3 years, several pharmacokinetic studies on commercial CBD formulations have been carried out by independent academic researchers.13,14,16 The pharmacokinetic learnings from these studies are several. First, pure CBD powder or CBD dissolved in oils are significantly less bioavailable that emulsified CBD formulations, see Figure 1 taken from the recent pharmacokinetic study.16 Second, for CBD emulsions the choice of the natural emulsifier as well as the emulsion droplet size can affect the bioavailability. Finally, it was found there is a noticeable increase in the bioavailability of emulsified CBD formulations when taken with food, see Figure 2 taken from the same pharmacokinetic study.16 This outcome is not dissimilar to the food effect observed with oil-based solutions of CBD.17,18
CBD FORMULATION & DOSAGE FORM MISCONCEPTIONS
There are several misconceptions around CBD and the formats best suited to its administration; some of the major ones are discussed here. First, CBD is not an oil as has been widely reported in the media, rather it is a crystalline powder as mentioned earlier. Because of CBD’s lipophilic property, it is soluble in many oils but not in water; this led to early formulations, such as oil-based tinctures or softgel capsules.
It has also been frequently communicated that CBD tinctures are absorbed in the buccal cavity or via sublingual administration. However, it is suggested that little if any cannabidiol is absorbed through the buccal mucosa.19 The only instance in which sustained buccal delivery of a lipophilic active such as cannabidiol was achieved was using an occlusive buccal adhesive patch technology.20 The cannabidiol was reported to absorb into the buccal tissue and eventually achieved clinically relevant plasma levels; however, the rate was deemed to be relatively slow and not suitable for an immediate- release delivery system.
There has been a wide array of water-soluble or more appropriately termed water-miscible products entering the CBD market throughout the past several years. Claims that nano-emulsions or dispersions of one form or another have superior bioavailability have become commonplace. However, there is little in the way of preclinical or clinical testing in human subjects to support these claims. It may be possible there is an optimal sub-micron emulsion droplet size that results in improved bioavailable and that smaller is not always better.21
Consumers seeking benefits from CBD and other cannabinoid products should look carefully at the formulation to determine which product may be best for them. The best scenario is that the manufacturer can refer to studies carried out on its products in a human population.
Many consumer CBD products refer to the number of milligrams of ingredient, which may lead consumers to believe that higher labelled levels of CBD will address their particular concerns. Recent pharmacokinetic studies have highlighted significant variance in CBD blood levels based on product formulation in which a properly formulated product can be several times more bioavailable than a simple oil-based solution. Selecting a CBD product on the basis of proven bioavailability rather than the number of milligrams listed per serving or per container may be a more reliable approach to achieving a satisfactory outcome.
- Erin Johnson, Michael Kilgore, Shanna Babalonis, Cannabidiol (CBD) product contamination: Quantitative analysis of Δ9 -tetrahydrocannabinol (Δ9 -THC) concentrations found in commercially available CBD products; Drug and Alcohol Dependence237, 1-6 2022.
- McClements, D. J. and Xiao, H. Excipient foods: designing food matrices that improve the oral bioavailability of pharmaceuticals and nutraceuticals. Food & Function 2014, 5, 1320-1333.
- McClements, D. J. Enhanced delivery of lipophilic bioactives using emulsions: A review of major factors affecting vitamin, nutraceutical, and lipid bioaccessibility. Food & Function 2018, 9 (1), 22−41.
- Andresa Gomes, Guilherme de Figueiredo Furtado, and Rosiane Lopes Cunha, Bioaccessibility of Lipophilic Compounds Vehiculated in Emulsions: Choice of Lipids and Emulsifiers. J. Agric. Food Chem. 2019, 67, 13-18.
- A. Zgair, J.B. Lee, J.C.M. Wong, D.A. Taha, J. Aram, D. Di Virgilio, J.W. McArthur, Y.-K. Cheng, I.M. Hennig, D.A. Barrett, P.M. Fischer, C.S. Constantinescu, P. Gershkovich, Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation, Sci. Rep. 7 (1) (2017).
- Jonathan Wong, Olena Sivak, Kishor M Wasan, Peter M. Fischer, Pavel Gershkovich. Intestinal absorption of lipophilic cannabinoids: The role of lymphatic transport Conference Paper 5th World Conference on Drug Absorption, Transport and Delivery June 2013.
- Adelaide Jewell, Alice Brookes, Wanshan Feng, Marianne Ashford, Paul Gellert, James Butler, Peter M. Fischer, David J. Scurr, Michael J. Stocks, Pavel Gershkovich. Distribution of a highly lipophilic drug cannabidiol into different lymph nodes following oral administration in lipidic vehicle. Eur. J. Pharm. Biopharm. 2022, 174, 29-34.
- Perucca, Emilio, Bialer, Meir, Critical Aspects Affecting Cannabidiol Oral Bioavailability and Metabolic Elimination, and Related Clinical Implications. CNS Drugs. 2020, 34 (8), 795–800.
- Millar, S.A., Stone, N.L., Yates, A.S., O’Sullivan, S.E. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans, Frontiers in Pharmacology, 2018, Article 1365.
- Millar S.A., Maguire R.F., Yates A. S., O’Sullivan, S.E. Towards Better Delivery of Cannabidiol (CBD). Pharmaceuticals, 2020, 13, 219.
- Knaub, K.; Sartorius, T.; Dharsono, T.; Wacker, R.; Wilhelm, M.; Schön, C. A novel self-emulsifying drug delivery system (SEDDS) based on Vesisorb® formulation technology improving the oral bioavailability of cannabidiol in healthy subjects. Molecules 2019, 24, 2967.
- Nakano, Y.; Tajima, M.; Sugiyama, E.; Sato, V.H.; Sato, H. Development of a Novel Nano emulsion Formulation to Improve Intestinal Absorption of Cannabidiol. Med. Cannabis Cannabinoids 2019, 2, 35–42.
- Williams, N.N.B.; Ewell, T.R.; Abbotts, K.S.S.; Harms, K.J.; Woelfel, K.A.; Dooley, G.P.; Weir, T.L.; Bell, C. Comparison of Five Oral Cannabidiol Preparations in Adult Humans: Pharmacokinetics, Body Composition, and Heart Rate Variability. Pharmaceuticals 2021, 14, 35.
- Hobbs, J.M.; Vazquez, A.R.; Remijan, N.D.; Trotter, R.E.; McMillan, T.V.; Freedman, K.E.; Wei, Y.; Woelfel, K.A.; Arnold, O.R.; Wolfe, L.M.; et al. Evaluation of pharmacokinetics and acute anti-inflammatory potential of two oral cannabidiol preparations in healthy adults. Phytother. Res. 2020, 34, 1696–1703.
- Francke, N.M.; Schneider, F.; Baumann, K.; Bunjes, H. Formulation of Cannabidiol in Colloidal Lipid Carriers. Molecules 2021, 26, 1469.
- Abbotts, K.S.S.; Ewell, T.R.; Butterklee, H.M.; Bomar, M.C.; Akagi, N.; Dooley, G.P.; Bell, C. Cannabidiol and Cannabidiol Metabolites: Pharmacokinetics, Interaction with Food, and Influence on Liver Function. Nutrients 2022, 14, 2152.
- Taylor, L.; Gidal, B.; Blakey, G.; Tayo, B.; Morrison, G. A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects. CNS Drugs 2018, 32, 1053–1067, Correction in CNS Drugs 2019, 33, 397.
- Crockett, J.; Critchley, D.; Tayo, B.; Berwaerts, J.; Morrison, G. A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects. Epilepsia 2020, 61, 267–277.
- Itin, C.; Domb, A.J.; Hoffman, A. A meta-opinion: cannabinoids delivered to oral mucosa by a spray for systemic absorption are rather ingested into gastro-intestinal tract: the influences of fed / fasting states, Expert Opinion on Drug Delivery, (2019), DOI: 10.1080/17425247.2019.
- Itin, C.; Barasch, D.; Domb, A.J.; Hoffman, A. International Journal of Pharmaceutics, 581 (2020) 119276.
Dr. Gerry McNally is a seasoned consumer healthcare R&D executive with more than 25 years of experience as an R&D leader in the consumer healthcare industry. During his tenure at McNeil Consumer Healthcare and Johnson & Johnson, he was instrumental in leading the development of numerous innovative and highly successful products and launching multiple novel drug delivery technologies. He was involved in creating unique formulations for Imodium® Multi-Symptom Relief, and Pepcid® Complete and novel formats, such as Tylenol® Rapid Release Gels. He earned his PhD and BSc Hons. in Chemistry from University College Dublin, Ireland. He holds more than 30 patents in the field of drug delivery/pharmaceutical formulation, has authored several papers, and delivered presentations at industry conferences.
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