Opportunities and challenges in developing orally administered cannabis edibles

Accepted Manuscript Title: Opportunities and Challenges in Developing Orally-Administered Cannabis Edibles Authors: Peter Chen, Michael A Rogers PII: DOI: Reference:

S2214-7993(18)30064-X https://doi.org/10.1016/j.cofs.2019.02.005 COFS 434

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Please cite this article as: Chen P, Rogers MA, Opportunities and Challenges in Developing Orally-Administered Cannabis Edibles, Current Opinion in Food Science (2019), https://doi.org/10.1016/j.cofs.2019.02.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Opportunities and Challenges in Developing Orally-Administered Cannabis Edibles

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Peter Chen1, Michael A. Rogers1,*

Department of Food Science, University of Guelph, Guelph, Ontario, Canada, N1G2W1

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Corresponding Author: 519-824-4120 ext. 54327, [email protected]

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Graphical abstract

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Highlights

Unpredictable bioavailability of THC in edible products needs to be addressed with further research into the effects of food matrix and carrier oils. Standard methods need to be established on assessing bioavailability, pharmacokinetics and toxicity. Legislation around formulation of edibles and infused beverages needs to be driven by research, which at this time does not exist in great depth. 1

Abstract The legalization of cannabis in Canada and in other jurisdictions around the World, will lead to increased demand for alternative forms of consumption including edible cannabis products.

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Cannabis research from a food science perspective has largely been absent. Existing processing methods commonly used in the pharmaceutical and food and beverage industries such as homogenization, ultrasonic cavitation and microfluidization can be applied in the production of cannabis edibles but special considerations must be taken in order to preserve the bioactive cannabinoids. The use of different surfactants must also be taken into account in order to improve

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cannabinoid solubility and enhance oral bioavailability. This review aims to summarize the latest

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information about technologies used to obtain cannabis products for oral consumption.

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1. Introduction Cannabis (Cannabis sativa L.) was originally intended as medicine, consumed orally in the form of tinctures, oils and beverages [1, 2]. More than 500 phytochemicals are identified in

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cannabis with over 100 different phytocannabinoids. The term phytocannabinoids distinguishes between exogenous compounds and naturally occurring, lipid-derived neurotransmitters found in the body which act on the endocannabinoid system [3]. Biological compounds-of-interest include: tetrahydrocannabinol (THC), its acid metabolite, 11-nor-9-carboxy-THC (THC-COOH), cannabidiol (CBD), cannabinol (CBN), terpenes, flavonoids, and several cannabinoid analogues

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and modulators of the endogenous cannabinoid system [4, 5].

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Currently, the standard method of administration is inhalation via the pyrolysis of cannabis

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flower [5, 6]. Upon inhalation, pulmonary absorption of THC causes immediate psychotropic

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effects, reaching peak plasma concentrations in roughly 6 – 10 minutes and plateaus within 2-3

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hours [7]. Furthermore, pyrolyzing cannabis simultaneously decarboxylate the inactive

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cannabinoid acids to their biologically-active phenolic form (Figure 1). However, this method has inherent health risks associated with the production of toxins and carcinogens produced by

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combustion of organic matter [8]. Vaporization albeit safer than smoking, still produces toxins and carcinogens [9, 10]. The primary advantage of inhalation is the rapid onset of psychoactive effects

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making it attractive for recreational use. Medical patients may benefit from a gradual sustained

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release and may prefer to ingest cannabis orally in the form of “edibles” (foods and drinks infused with cannabinoids). However, oral administration suffers significant shortcomings and challenges. For example, psychotropic effects are delayed 30-90 minutes after oral ingestion and reach a peak plasma concentration 2 – 6 hours with effects lasting 4-12 hours [7, 11].

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Oral administration has not only delayed onset times but also have greater unpredictability, and significantly reduced bioavailability compared to inhalation. Bioavailability refers to the amount of bioaccessible compound that is first released from the food matrix and can be absorbed

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in the gastrointestinal tract [12]. Oral ingestion of a drug will reduce its bioavailability owing to incomplete absorption by the gastrointestinal tract and/or first pass metabolism by liver enzymes. Early studies on the main psychoactive compound, THC, showed only 6% bioavailability following the oral ingestion of a cookie containing 20 mg of THC and measuring plasma THC concentration using gas chromatography/mass spectrometry (GC/MS) (Ohlsson, Lindgren et al.

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1980). When THC is dissolved in sesame oil, contained in gelatin capsules, bioavailability

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improved to between 10 and 20% [13]. The absorption of dietary lipids, such as sesame oil (i.e.,

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long chain triglycerides (LCT)), requires the formation of chylomicrons to serve as a carrier for

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THC and CBD through the epithelial layer to the intestinal lymphatic system thus avoiding hepatic first-pass metabolism and achieving higher bioavailability compared to lipid-free formulation

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(Figure 2) [14]. Currently, the Food and Drug Administration (FDA) approved cannabis-based

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drugs have slow, unpredictable and low absorption [15]. Dronabinol, trade names Marinol and

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Syndros, is a synthetic form of THC dissolved in sesame oil approved for use as an appetite stimulant. More recently, the FDA approved Epidiolex, a strawberry-flavored syrup containing

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cannabidiol (CBD), a non-psychoactive constituent of cannabis, dissolved in sesame oil [16]. The majority of formulations contain LCT, such as sesame oil, or medium chain triglycerides (MCT),

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such as coconut oil. The lipophilic nature of cannabinoids requires the use of a lipid carrier to solubilize the bioactives. When patients self-medicate with cannabis, the vast majority of the edible formulations involve the use of dietary lipids such as whole milk, heavy cream, butter and/or

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vegetable oil [17]. This article focuses on the concepts and methods to produce edible cannabis products. 2. Decarboxylation

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Cannabis sativa L. primarily synthesizes the carboxylic acid forms of THC and CBD known as tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA). These acidic cannabinoids typically are undesirable, as they have no psychotropic effects. Recent evidence, however, suggest that THCA and CBDA may be more potent anti-emetic and anti-nausea

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properties compared to their neutral counterparts, THC and CBD [18-20]. For the edible market,

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decarboxylation conditions need to be closely optimized because if THC is exposed too to high of

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heat it will oxidize producing cannabinol (CBN) in the presence of oxygen and light (Figure 1)

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[21].

Optimal decarboxylation time/temperatures have yet to be agreed on as the mode of analysis

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may influence the outcomes. Gas chromatograpy (GC) suffers from incomplete analysis and

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efficiency issue because it is optimized for low molecular weight neutral cannabinoids and requires

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decarboxylation or derivatization [21-23]. Liquid chromatography (LC) detects both neutral and acidic cannabinoids without decarboxylation or derivatization. Veress et al. showed maximum

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THC formation was achieved between 5-10 min at 145 ⁰ C [24]. Dussy et al. heated pure THCA for 15 min observing complete conversion of THCA to THC at 160⁰ C; however, CBN was also

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produced at 160⁰ C and 180⁰ C [21]. High performance liquid chromatography/diode array detector (HPLC/DAD) has low molar absorptivity of acidic and neutral cannabinoids resulting in high detections limits. An ultra-high-performance supercritical fluid chromatography/photodiode array-mass spectrometry (UHPSFC/PDA-MS) method successfully determined phytocannabinoid

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content, their decarboxylation and degradation products [25]. Kinetic data showed decarboxylation rate constants for THCA were twice the values for CBDA. Maximum THC production occurred at 10, 15, and 20 min at 145⁰ C, 130⁰ C, and 110⁰ C, respectively [25]. Maximum CBD

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concentration was achieved at approximately 10, 30, and 50 min at 145⁰ C, 130⁰ C, and 110⁰ C, respectively [25]. 3. Liquid Formulations

Aromatic terpenoids, such as THC, have low water solubility (e.g. 0.0028 mg/mL) [26].

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Similarly, CBD has a predicted water solubility value of 0.0126 mg/mL according to ALOGPs

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algorithms [27]. Being poorly water soluble and highly metabolized, THC and CBD are considered

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Class II drugs according to the Biopharmaceutical Classification System (BCS). Cannabis extracts

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have a resinous, oil-like consistency and are soluble in organic solvents, lipids and alcohols. Liquid formulations of various edible oils containing THC and/or CBD can be produced by solubilizing

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the extract into MCT or LCT oils [28]. However, further processing is required to obtain a miscible

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liquid in water. Liquid formulations, where the oil phase is encapsulated and dispersed in an aqueous phase, improve water solubility and reduces oxidative susceptibility [29, 30].

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Encapsulation technologies requires appropriate surfactants or emulsifiers acting to reduce the

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interfacial tension between the continuous water and oil core. High-energy, top-down approaches, generating disruptive forces to break down the coarse dispersion (i.e., high-pressure

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homogenization and sonication); while low-energy, bottom-up approaches, exploit environmental conditions to spontaneously form small oil droplets (self nano-emulsifying drug delivery systems (SNEDDS) [31]. 3.1. Cannabis Oil-Water-Emulsion

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Oil-in-water emulsions containing cannabis is often used to formulate in products such as tinctures, soft-gel capsules, lotions, e-cigarette vape cartridges and beverages. To overcome the poor immiscibility of cannabinoids in water, cannabis extracts are suspended in an edible oil (i.e.,

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coconut, olive and vegetable oils) prior to homogenization [14, 32]. Emulsions require the use of surface-active molecules (i.e., surfactants/emulsifiers) and include: polysaccharides, proteins, and natural or synthetic small molecule surfactants that include phospholipids. Surfactant selection is dependent on the nature of the emulsion (i.e., water-in-oil vs. oil-in-water), molecular composition of the oil and the ionic strength of the water phase. Natural biopolymer-based emulsifiers, such as

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proteins and polysaccharides, have attracted considerable attention due to the consumers desire to

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clean labels [33, 34]. Biosurfactants such as phospholipids have also been shown to be effective

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for low-molecular weight compounds such as THC and CBD [35, 36].

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Energy intensive, top down approaches also generate nanoemulsions (i.e., droplet size < 100

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nm). Droplet size reduction occurs when the shear force applied is greater than the internal Laplace

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pressure of the dispersed phase droplet [37]. Particle size reduction can be achieved with high shear homogenizers or ultrasonic cavitation [38]. Microfluidization, ultrasonic cavitation and

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acoustic cavitation induces extensive physical shearing, resulting from the formation, growth and collapse of microbubbles caused by pressure fluctuations leading to the disruption of the coarse

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emulsion and results in the formation of nanoemulsions [39-41]. The collapse of microbubbles

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causes localized turbulence resulting in the formation of microjets generate enough shear force to facilitate droplet size reduction and mixing of the two immiscible phases [42]. Studies using ultrasonic cavitation on cannabis does not exist at the present, however, others have successfully used this method for other insoluble bioactives. Salvia-Trujillo et al. reported average droplet diameter of lemongrass oil-alginate of 4.31 nm at a frequency of 24 kHz and 400 W/mL of applied 7

energy [43]. Another study showed decrease in droplet diameter size from 57.75 to 41.15 nm following increased sonication time from 5 to 15 min in the formulation of basil oil nanoemulsions [44].

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3.2. Lipid Based Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) In an attempt to increase oral bioavailability of cannabinoids, one research group has developed a lipid based SNEDDS known as Pro NanoLipospheres (PNL) [45]. PNL consists of a liquid mixture containing the active lipophilic compounds (e.g., THC and CBD), natural or

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synthetic lipid (triglyceride, polyoxyl 40-hydroxy castor oil, etc.) and surfactants (Lecithin, Tween

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20 and Span 80). PNL is referred to as a “pre-concentrate” and spontaneously assembles into an

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oil-in-water nanoemulsions with particle size less than 200 nm when it reaches the upper

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gastrointestinal lumen. Solubility in aqueous conditions is achieved by entrapping the lipophilic compound within the triglyceride core. The addition of a solubility enhancer such as piperine

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showed 6-fold increase in the bioavailability of CBD and 9.3-fold increase in the bioavailability

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of THC [45]. Bioavailability is believed to be primarily enhanced due to the nanometric size of the particles capable of entering the inter-villus space and intestinal brush border and having

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greater surface area available for absorption. Further bioavailability enhancement in the presence

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of piperine is due to the ability of this alkaloid to inhibit first pass metabolism enzymes cytochrome P450 (CYP) as well as inhibit P-gp efflux pumps [46, 47]. It has also been reported that piperine

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can reduce phase II metabolism by inhibiting UDP-glucuronyl-transferases [6]. 4. Solid Formulations Edibles can be considered solid delivery systems for cannabinoids. However, there are currently no peer-reviewed research on the topic of cannabis edible formulations due to prohibition 8

of cannabis at the state level in the US and unclear regulations regarding cannabis edibles in Canada. Numerous challenges exist in dealing with edibles as the route of administration because it is dependent on the pharmacokinetics of the drug. Edibles delivers cannabinoids through the

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gastrointestinal tract, absorbed via the intestinal epithelial and transported into the bloodstream via the hepatic portal vein. From there circulation directs the cannabinoids to the liver where firstpass metabolism occurs [48]. It is here that liver enzymes, primarily CYP P450, hydroxylate THC into 11-hydroxytetrahydrocannabinol (11-OH-THC). 11-OH-THC is said to be equally or more potent than THC and is present at higher plasma concentrations when THC is ingested orally

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compared to smoking [2, 49]. Individual response and metabolism alter these effects making

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dosing and dose titration a significant challenge. The instruction to consumers of edibles is to “start

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low and go slow” as the effects may not manifest even after 60 min of ingestion. Currently,

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research into formulating solid doses of cannabinoids only pertains to pharmaceutical and

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4.1. Controlled Release

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medicinal applications to be delivered in the form of tablets and capsules.

The oily and resinous nature of cannabis extracts render it difficult to manufacture it into a fine

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powder for tablet manufacturing which is further complicated by the instability of THC in the solid

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state. Additionally, the amorphous state of THC is also susceptible to oxidative degradation due to a lack of defined crystal lattice structure which facilitates electron transfer to oxygen [50]. To

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overcome these challenges, a lipid based formulation can be used with cross-linking and barrier forming properties [51]. One study proposes the use of compritol, a matrix-forming lipid excipient for controlled release that forms a protective barrier surrounding the active encapsulated bioactive [52, 53]. High-pressure homogenization is used to create the emulsion which can then be spraydried into a fine powder. In order to increase the tablets plasticity and resistance to fracture, precirol 9

is added to the formulation [54]. These lipids have been previously shown to produce a sustained release tablet produced via direct compression [52, 55-57]. Solid dispersion techniques can be employed to produce THC-lipid dispersions by heating the mixture and molding into slugs prior

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to cryo-milling and compression into tablets [53]. Alternatively, THC may be dissolved in hexane coated onto a filler and then dried thereby removing hexane [53]. This is then blended with other lipid excipients and compressed into tablets. These methods are used to produce THC oral tablets with chemical and physical stability for 3 months and sustained release over a period of 24 hr (Figure 3) [53].

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Lipid nanoparticles can also be produced using the emulsification-solvent evaporation method

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[58] to produce a cannabinoid formulation coated with either chitosan or polyethylene glycol

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(PEG) [59]. Precirol, lecithin and the cannabinoid were co-suspended in dichloromethane and

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added to an aqueous phase containing Tween 20 and sodium deoxycholate [59]. The mixture was

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dispersed by sonication followed by homogenization and stirred allowing dichloromethane to

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evaporate. The particles were then lyophilized to obtain a fine powder and can be compressed into tablets. Polymeric poly(lactic-co-glycolic) acid (PLGA) nanoparticle loaded with cannabis was

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also evaluated [59]. PLGA nanoparticles were prepared by dissolving PLGA, Span 60 and cannabis in acetone and subsequently added dropwise to Pluronic F68 under agitation. Following

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evaporation of the acetone, the particle suspension was centrifuged to collect the nanoparticles and

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then re-suspended in trehalose prior to lyophilization. Surface modification of these nanoparticles with chitosan and polyethylene glycol (PEG) promoted GI uptake and absorption of the particles. The resulting PLGA nanoparticle had a diameter of 320 – 420 nm while the lipid nanoparticle had a diameter of 120 – 160 nm [59]. PLGA particles display an extended release profile of the cannabis but a slightly decreased GI uptake compared to lipid nanoparticles [59]. Surface 10

modification with chitosan showed enhanced GI uptake compared to PEG [59]. It is extremely important to note that cytochrome P450 is involved in the metabolism of numerous drugs, including cannabinoids, making the potential of significant drug interactions of edibles something

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consumers and patients alike need to be acutely aware of [60]. 5. Conclusion

In Canada, where cannabis has now been legalized, legislation on cannabis edible products

remains to be defined. The unpredictable bioavailability of edible products needs to be addressed

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with further research into the effects of food matrix and carrier oils. A standardized approach

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needs to be developed to quantify and characterize cannabinoids as well as for assessing

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bioaccessibility and bioavailability. While the focus of this review has been on formulation of

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cannabis edible products, the underlying biological mechanism responsible for the many anecdotal health benefits of cannabinoids still needs to be studied. With change in policy taking

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shape in many jurisdictions, we anticipate an increase in research surrounding the topic of

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cannabis from both food and pharmaceutical perspectives.

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We have no real conflicts of interest in this area. Dr. Peter Chen has accepted employment starting in March 2019 with Hydropothecary’s research team. He has also worked part time with Beleave.

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We have no real conflicts of interest in this area. Dr. Peter Chen has accepted employment starting in April 2019 with Hydropothecary’s (HEXO Corp.) research team. He has also worked part time with Beleave Kannabis Corp.

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Figures

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Figure 1 - Decarboxylation of THCA to THC and oxidative degradation of THC to CBN

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Figure 2 – Proposed mechanism for intestinal lymphatic transport of tetrahydrocannabinol (THC)

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and cannabidiol (CBD) following oral administration with long-chain triglycerides (LCT). (1)

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Solubilisation of THC and CBD in mixed micelles following lipid digestion in the small intestine. (2) Chylomicron uptake inside the enterocytes. (3) Chylomicron carries THC and CBD to systemic

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circulation via the intestinal lymphatic system bypassing hepatic first-pass metabolism. [14].

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Figure 3 – In vitro THC release profiles from 10 mg and 20 mg tablets. THC in hexane was coated

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on the dibasic calcium phosphate anhydrous filler and blended with the other excipients including Pluronic® F68, glycerol distearate, glycerol dibehenate, Aerosil® R972 and magnesium stearate.

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The blend was directly compressed into tablets. Dissolution conditions include paddle apparatus

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operated at 100 rpm, 37⁰ C in 0.5% sodium lauryl sulfate medium [53].

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