A modern pharmaceutical approach to administration may start from the use of the cannabis plant for medical use, and then move on to the development of quality controlled extracts, the complete evaluation of their analytical profiles, and studies to assess the delivery of the correct dosage for optimal therapeutic effect. Cannabinoids are highly lipophilic molecules (log P 6–7) with very low aqueous solubility (2–10 μg/mL) [49
], that are susceptible to degradation, especially in solution, via the action of light and temperature as well as via auto-oxidation [50
]. Formulation can thus play a crucial role in increasing the solubility and physicochemical stability of the drugs. Commonly used strategies in marketed products include salt formation (i.e., pH adjustment), cosolvency (e.g., ethanol, propylene glycol, PEG400 etc.), micellization (e.g., polysorbate 80, cremophor ELP etc.), (nano)-(micro)-emulsification, complexation (e.g., cyclodextrins), and encapsulation in lipid-based formulations (e.g., liposomes) and nanoparticles [52
Various administration and delivery forms have been tested for therapeutic use. Cannabis products are commonly either inhaled by smoking/vaporization, or taken orally. The oromucosal, topical-transdermal and rectal routes are minor, but interesting, administration routes. The pharmacokinetics and dynamics of cannabinoids vary as a function of the route of administration with absorption showing the most variability of the principal pharmacokinetic steps. Absorption is affected both by intrinsic product lipophilicity and by inherent organ tissue differences (i.e., alveolar, dermal vs. gastric). A variety of factors, such as recent eating (for oral), depth of inhalation, how long breath is held for and vaporizer temperature (for inhalation) all affect cannabinoid absorption, which can vary from 20–30% for oral administration and up to 10–60% for inhalation. A reference review detailing the pharmacokinetic and pharmacodynamic aspects of cannabinoids has been written by Grotenhermen [49
]. The following sections explore the principal administration routes for cannabinoids, available products and the principal strategies (extracted from scientific literature and patents) that can be applied to improve cannabinoid efficacy and stability. Treatment indications and their level of evidence are also reported while the principal characteristics of the formulations have been summarized in Table 1
3.1. Oral Route
The primary advantages displayed by the oral administration of cannabinoids include the existence of pharmaceutical-grade compounds, standardized concentrations/doses and a non-complicated administration route. Oils and capsules currently allow for more convenient and accurate dosing than juices or teas from the raw plant. Nevertheless, absorption is slow, erratic and variable. Maximal plasma concentrations are usually achieved after 60–120 min, although this can take even longer (up to 6 h) and can be delayed. Furthermore, metabolism produces psychoactive metabolites. Extensive first-pass liver metabolism further reduces the oral bioavailability of THC, while effect duration varies from 8 to 20 h. Numerous (nearly 100) metabolites have been identified as being produced, primarily in the liver and, to a lesser degree, in other tissues, such as the heart and lungs [49
There are three oral, and one oromucosal, cannabinoid pharmaceutical preparations that are currently available.
from Abbvie Inc., Chicago, IL, USA) is a semi-synthetic form of THC, which is available in capsule form and as a solution, that has been approved by the FDA for appetite stimulation and the treatment of chemotherapy-induced nausea in patients with AIDS. Oh et al. have published a PK study that compares the oral solution and capsule forms of dronabinol under fasting and fed conditions. The solution formulation showed lower inter-individual absorption variability than the capsule formulation, especially in fed conditions, and this fact may be an important consideration in the selection of an appropriate dronabinol product for patients [56
]. Dronabinol exerted a modest, but clinically relevant, analgesic effect on central pain in the pain treatment of patients with multiple sclerosis. Although the proportion of patients that showed adverse reactions was higher in dronabinol-treated than in placebo-treated patients, it decreased over the drug’s long-term use [57
from Bausch Health Co., Laval, QC, Canada) is a synthetic cannabinoid derivative that differs structurally from THC as its C-ring is saturated and contains a C-9 ketone group (Figure 2
). Nabilone is available, in a polyvinylpyrrolidone carrier, as a capsule (1 mg of drug). It displays antiemetic properties and is used for the control of the nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetics [59
Nabilone has higher bioavailability than dronabinol (95% vs. 10–20%) and presents a higher duration of action. Nabilone has recently proven itself to be a suitable and safe therapeutic option with which to aid in the treatment of cancer patients diagnosed with anorexia. An enriched enrolment, randomised withdrawal design trial (26 patients) assessed the efficacy of nabilone, in the treatment of diabetic peripheral neuropathic pain [60
]. Nabilone has an interesting range of applications (e.g., quality of life in lung cancer patients) although larger trials are still necessary if more robust conclusions are to be drawn [61
Epidiolex (from GW Pharmaceuticals plc, Cambridge, UK), is a liquid formulation of a CBD solution that has recently been approved in the US as an adjuvant treatment in Dravet syndrome, Lennox-Gastaut syndrome and severe myoclonic epilepsy in infancy. Results from double-blind, placebo controlled trials have recently been published [62
Furthermore, other improved oral-dosage formulations and therapeutic applications have been presented in a number of patents. Clinical considerations of the oral administration of a solid-dosage, CBD-containing form for the treatment of inflammatory bowel disease have been published in a patent by Robson (GW patent) [65
]. A small cohort of patients (8 patients) reported an improvement in Crohn’s disease. Furthermore, oral administration also led to another small cohort of patients being able to reduce steroid dose when treating inflammatory and autoimmune diseases [66
]. Based on this research, a CBD therapeutic formulation is being developed by Kalytera Therapeutics (Novato, CA, USA) for the prevention and treatment of graft-versus-host disease. Kalytera initiated a randomised, open-label, dose-response and comparator-controlled phase IIb trial in December 2017 to evaluate the pharmacokinetic profile, safety and efficacy of multiple doses of CBD for the prevention of graft-versus-host-disease following allergenic haematopoietic cell transplantation (NCT02478424).
The manufacture, specifications, pharmaceutical tests and preliminary pharmacokinetics of CBD-containing, compressed tablets and granulates for peroral delivery have been reported in a patent by De Vries et al. [67
Self-emulsifying drug delivery systems (SEDDS) can be significant in improving the dissolution, stability and bioavailability of THC and other cannabinoids. SEDDS, which are isotropic mixtures of oils, surfactants, solvents and co-solvents/surfactants, can be used in the design of formulations to improve the oral absorption of highly lipophilic drug compounds [68
]. Murty et al. have described self-emulsifying drug delivery systems for per os
administration in a number of patents, with the aim of improving the dissolution, stability and bioavailability of THC and other cannabinoids [69
]. The solubility of the selected drug, in oils (soybean and sesame oils, oleic acid) and surfactants (Oleoyl polyoxyl-6 glycerides, medium-chain mono- and di-glycerides and propylene glycol esters, PEG hydrogenated castor oil) was assessed.
A CBD therapeutic formulation is being developed by Kalytera Therapeutics for the prevention and treatment of graft-versus-host disease. Kalytera initiated a randomised, open-label, dose-response and comparator-controlled phase IIb trial in December 2017 to evaluate the pharmacokinetic profile, safety and efficacy of multiple doses of CBD for the prevention of graft-versus-host-disease following allergenic haematopoietic cell transplantation (NCT02478424).
Vitality Biopharma (Los Angeles, CA, USA) have proposed an invention that has led to several cannabinoid glycoside prodrugs (cannabosides) being obtained and characterized [72
] (Figure 2
). This method grants the gastro-intestinal targeting of THC, while avoiding narcotic effects. Vitality Biopharma have released data from independent clinical trial case studies which demonstrate that cannabinoids induced the remission of drug-resistant inflammatory bowel disease after eight weeks of treatment (Vitality Biopharma web site).
3.2. Administration through Mucosa
Drugs, such as cannabinoids, that are metabolized by liver and gut enzymes (first-pass hepatic metabolism), have specific pharmacokinetic requirements, demonstrate poor gastrointestinal permeability and cause irritation and therefore require alternatives to systemic oral delivery. Transdermal, nasal, inhaled-pulmonary and oral transmucosal delivery formulations enable drug uptake directly into the blood, thereby eliminating first-pass metabolism.
The development of the transmucosal dosage form has provided a non-invasive method of administration that has proven itself to be significantly superior to oral dosage in the relief of pain (e.g., oral morphine vs transmucosal fentanyl) [74
from GW Pharmaceuticals plc), is an oromucosal spray that contains a roughly 1:1 ratio of THC and CBD, as well as specific minor cannabinoids and other non-cannabinoid components (β-caryophyllene). It is administered at a dose that is equivalent to 2.7 mg THC and 2.5 mg CBD in each 100 μL ethanol spray. THC and CBD may reciprocally interact either by interfering with each other’s pharmacokinetics, or, at the cellular level, within the complex endocannabinoid signalling network. However, a study involving nine cannabis smokers reported that no significant pharmacokinetic differences were found in the similar oral THC and Sativex®
doses that were administered [75
]. Furthermore, studies have suggested that the adverse effects of THC can be antagonized by CBD [76
Nabiximols is used as an adjunctive treatment for the symptomatic relief of moderate to severe multiple sclerosis-caused spasticity in adults who have not responded adequately to other therapies, and who show clinically significant improvements in spasticity-related symptoms during an initial therapy trial. It may also be of benefit as an adjunctive analgesic treatment for the symptomatic relief of neuropathic pain in adult patients with multiple sclerosis. This same preparation is also used as an adjunctive analgesic treatment in adult patients with advanced cancer who have moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain [77
]. Although not superior to placebo in terms of the primary efficacy endpoint, nabiximols provided multiple secondary endpoint benefits, particularly in patients with advanced cancer who receive a lower opioid dose, such as individuals with early intolerance to opioid therapy.
Nabiximols has now received marketing authorization in EU countries for the treatment of spasticity and FDA investigational new drug (IND) status for the treatment of cancer pain. Some clinical trials into the use of Sativex for the treatment of neuropathic pain in multiple sclerosis patients have been successful [78
], leading to the drug gaining approval in Israel and Canada. However, further work is still required to define the best responder profile for nabiximols and to explore its full potential in this field is still required.
Transmucosal formulations of CBD with Poloxamer 407, carboxymethyl cellulose and starch have been reported by Temtsin-Krayz et al. Nanoscale-range powders have been produced using the spray drier technique. Crossover bioavailability comparisons of this formulation and Sativex have also been reported [79
A controlled-release chewing gum, made up of a (1:1) combination of CBD and THC, which provides oromucosal adsorption is being developed by Axim Biotech. Inc., (New York, NY, USA). The product is currently in clinical trials for the treatment of several diseases (pain, multiple sclerosis-associated spasticity, Parkinson’s disease, post-herpetic neuralgia, dementia etc.) [80
]. More recently, Axim have also proposed chewing gums that are formulated to provide the controlled release of microencapsulated cannabinoids, opioid agonists and/or opioid antagonists during mastication [81
The intranasal mode of administration (in which drugs are insufflated through the nose) has several advantages; the nasal cavity is covered by a thin mucosa that is well vascularised, meaning that a drug can be transferred quickly across the single epithelial cell layer directly into systemic blood circulation and avoid first-pass hepatic and intestinal metabolism, producing a fast effect. Bypassing the oral route may be more acceptable for patients who experience nausea, vomiting, oral mucositis and impaired gastrointestinal function. Furthermore, intranasal delivery is superior to iv injection because it is a non-invasive pain-free treatment that can improve patient compliance. The development of a nasal formulation of CBD could potentially aid in the treatment possible breakthrough pain and nausea attacks.
Paudel et al. have prepared a variety of formulations (CBD in PEG 400 alone and CBD in a 50:35:15 (v
) PEG: saline:ethanol solvent system both with and without the following permeation enhancers: 1% sodium glycocholate or 1% dimethyl-beta-cyclodextrin) for the investigation of the intranasal permeation of CBD in an anesthetized rat nasal absorption model [82
]. The intranasal application of CBD formulations resulted in the significant and relatively rapid absorption of CBD from the nasal cavity. The nasal absorption of CBD from all the formulations was rapid (Tmax
≤ 10 min), while the absolute CBD bioavailability achieved by the different nasal formulations was in the 34–46% range. Bioavailability decreased when the PEG content of the formulation was lowered from 100% to 50%, while the addition of permeation enhancers did not lead to AUC enhancements.
Bryson has described both semi-solid and liquid nasally administered cannabinoid compositions and a device to provide precise nasal administration [83
]. A range of different formulations were described in the patent.
3.3. Pulmonary Administration
The intrapulmonary administration of cannabinoids is regarded as an effective mode of delivery as it results in the fast onset of action and high systemic bioavailability. Cannabis-related effects generally begin within a few minutes of the first inhalation (smoked or vaporized) and these effects can increase [84
]. A peak value is reached after 10 min, and is maintained at a steady state for 3–5 h, which is in accordance with the plasma levels of THC [85
]. Interestingly, the PK profile of inhaled cannabis is similar to that of intravenously administered THC, although it displays a lower AUC. The PK profile of CBD is very similar to that of THC, whether it is administered orally, intravenously or inhaled. These pharmacokinetics (rapid onset, short time peak effect and intermediate lasting effects) occur because first passage metabolism is avoided and are thus virtually impossible to replicate with the oral administration of cannabis or cannabinoids. The major limitation of inhaling is the variability in inter-patient efficiency that is caused by differences in inhalation techniques, respiratory tract irritation during inhalation, etc. In fact, improved methods with which to standardise dosage have been proposed for these very reasons.
A protocol to deliver CBD and THC via vaporisation has been described by Solowij et al. Crystalline-form CBD (preliminary experiments), and ethanolic solutions of CBD (4 or 200 mg) and THC (4 or 8 mg) were separately loaded onto a vaporiser filling chamber via a liquid pad (a removable disc made of tightly packed stainless steel wire mesh) as supplied by the manufacturer of the Volcano®
vaporizer device [86
A system, which combines method, devices and systems, for the controlled pulmonary delivery of active agents has also been reported; a metered dose inhaler to vaporize precise amount of agent (cannabinoids or other plant oils), a system for the evaluation of the PK value obtained after one or two puffs and an interface for the control of the profile of the drug administered have been provided by Davidson et al. [87
Several patents have presented systems for vaporisation and nebulisation, from a variety of containers [88
], at a selected temperature to form a precise amount of vapour with THC and CBD [89
]. Improved drug-delivery devices that can separate and release active cannabis substances have been disclosed in another patent [90
]; drug delivery cartridges, which include a substrate coated with at least one of either THC or CBD, are configured to allow for the passage of air through the cartridge to volatilise the agent for inhalation by a user.
3.4. Topical and Transdermal Route
Transdermal administration delivers drugs through the skin via patches or other delivery systems. Although comparable to oral-dosage forms in term of efficacy, transdermal patches provide numerous advantages. Transdermal administration avoids the first-pass metabolism effect that is associated with the oral route and thus improves drug bioavailability. Furthermore, transdermal administration allows a steady infusion of a drug to be delivered over a prolonged period of time, while also minimising the adverse effects of higher drug peak concentrations, which can improve patient adherence. Topical administration is potentially ideal for localised symptoms, such as those found in dermatological conditions and arthritis but also in peripheral neuropathic pain for which capsaicin patches have been proposed as a second line treatment after high quality of evidence was provided [91
]. However, there are some disadvantages to consider, such as the possibility of local irritation and the low skin penetration of drugs with a hydrophilic structure. Indeed, drugs that are slightly lipophilic (log P 1–4), have a molecular mass of less than 500 Da and that show efficacy at low dosage (less than 10 mg/day for transdermal administration) are ideal for administration via this route. Enhancers may also be also added to transdermal formulations to increase the penetration of permeants by disrupting the structure of the skin’s outer layer, i.e., the stratum corneum, and increasing penetrant solubility.
The evaluation stages for the transdermal administration of cannabinoids range from early preclinical phases and mouse models, to self-initiated topical use and randomized, double-blind controlled studies.
The topical anti-inflammatory activity of phytocannabinoids in a roton oil mouse ear dermatitis assay has been described by Tubaro et al. [92
], while preclinical evaluations of the transdermal administration of CBD, via gel application, has been further tested on a rat complete Freund’s adjuvant-induced monoarthritic knee joint model [93
]. In this latter study, CBD was found to demonstrate therapeutic potential for the relief of arthritic pain-related behaviour and to exert an anti-inflammation effect without any evident high-brain-center psychoactive effects. Results showed that a dose of 6.2 mg/day reduced knee-joint swelling and that increasing the dose to 62 mg/day failed to yield additional improvements. The transdermal administration of CBD has also been observed to provide better absorption than the oral administration route in same arthritic model [30
Ethosomal carriers are mainly composed of phospholipids, (phosphatidylcholine, phosphatidylserine, phosphatidic acid), with a high concentration of ethanol and water [94
]. An ethosomal formulation for CBD, which consisted of 3% CBD and ethanol in a carbomer gel, has been prepared by Lodzki et al. [95
], and its anti-inflammatory effect was tested on carrageenan-induced aseptic paw oedema in a mouse model. The results demonstrated that the carrageenan-induced development of an oedema was only prevented in its entirety in the CBD-pretreated group of mice. The in vivo occluded application of CBD ethosomes to the abdominal skin of nude mice resulted in high accumulation of the drug in the skin and the underlying muscle.
A topical transdermal gel containing a proprietary and patent-protected CBD formulation is being developed by Zynerba Pharmaceuticals (Devon, PA, USA) and is currently in clinical development for the treatment of epilepsy, developmental and epileptic encephalopathy, fragile-X syndrome and osteoarthritis [96
]. The gel is designed to be applied once or twice daily. Permeation profiles of a range of formulations have also been reported [99
A particularly interesting, although anecdotal, result has recently been published by Chelliah et al., who described the benefits that CBD provided as anti-inflammatory agent in three patients affected by epidermiolysis bullosa. Paediatric patients benefited from the use of topical CBD (applied as an oil, cream and spray by their parents) leading to a reduction in pain and blistering as well as rapid wound healing [100
]. There were no adverse effects reported, either by the patients or their families, of this topical use of CBD.
The release of cannabinoids from a microneedle formulation that is administered transdermally has been reported by Brooke [101
], while a patent by Weimann has more recently focused on CBD delivery [102
]. In this latter work, a solution of CBD 10% in ethanol with modified cellulose gave a thixotropic preparation that was placed in a reservoir. Diffusion through the skin occurs and is measured using hydrophilic and hydrophobic membranes. A monolithic version, also containing penetration enhancers (oleic acid and propylene glycol), was also prepared for comparison purposes. Linear release was observed for 24 h and cumulative amounts exceeded 200 µg/cm2
A range of patents for the topical administration of CBD, mixed with other well-known anti-inflammatory phyto-derived products, will also be summarised here, as will their adsorption and effect on pain relief.
Siukus has presented an oleo gel composition made up of non-psychoactive Cannabis sativa
components for the treatment and/or reduction of deep tissue joint and muscle inflammation caused by mechanical skeletal muscle trauma and arthritis/osteoarthritis. The oleo gel composition is based on phytocannabinoids (2% of total mass) mixed with an extract of Olea europaea
(Olive) (82%), Mentha arvensis
leaf oil (0.5%), and anhydrous colloidal silica (8.2%) [103
]. Preclinical evidence was reported.
The same author has more recently published a patent that describes a topical composition made up of an essential combination of synergistically acting phytoactive materials and non-psychotropic phytocannabinoids in combination with a Calendula
flower extract (Calendula officinalis
L.) and the base formulation to provide anti-inflammation, anti-oxidation, emollient and bactericidal activity [104
Jackson et al. [105
] have proposed a topical administration of CBD with silicon fluids, coupled with hyaluronic acid. This system is claimed to enhance application methods and improve absorption into the skin to help ease pain.
The use of cannabinoids, in combination with odorous volatile compounds and emu oil has also been proposed as a method to improve the effectiveness of cannabinoid transdermal delivery to areas in the hypodermis [106
The application of CBD with argan oil for the treatment of the pain and swelling associated with inflammation, in arthritic and rheumatic diseases, has been described by Shemanky et al. [107
]. Gel, cream and emulsion formulations were tested.
Improved anti-inflammatory effects can be obtained from a composition containing boswellic acids, either isolated from Boswellia family plants (Buseraceae) or in the form of an extract, and either CBD or a Cannabis sativa
In order to complete this overview of topical CBD, we should note that CBD exerts interesting sebostatic and anti-inflammatory effects on human sebocytes [109
], (data obtained from in vitro evaluations). Indeed, CBD has been shown to inhibit the proliferation of hyperproliferative keratinocytes [54
], and to possess remarkable antibacterial activity [55
]. The authors also demonstrated the potent local activity of CBD as an anti-acne agent. Furthermore, its high lipophilicity means that CBD is expected to preferentially enter the skin via the transfollicular route and to accumulate in the sebaceous gland.
Finally, the topical (ocular) administration of THC prodrugs has been proposed as a treatment to reduce intraocular pressure in glaucoma [110
]. THC appears to be especially attractive in this case as, in addition to its intra ocular lowering activity, the presence of cannabinoid receptors in ocular tissues has recently been confirmed [111
]. Hydrophilic THC prodrugs have been obtained by linkage with valine, with dipeptides and amino acid-dicarboxylic esters (Figure 2
). Among them the best corneal permeability and intraocular pressure-lowering activity shown by these prodrugs were observed in the THC-Val-HS emulsion and micellar solution formulations.
3.5. Nano-Technological Approaches
Pharmaceutical nanotechnology is widely used in drug delivery as it can develop devices that are specifically adapted to improving the therapeutic efficacy of bioactive molecules. Indeed, nanocarriers, such as nanoemulsions, dendrimers, micelles, liposomes, solid lipid nanoparticles and nanoparticles of biodegradable polymers for controlled, sustained and targeted drug delivery, are popular and present possible alternatives to traditional formulation approaches. Nanovectors for drug delivery potentially offer a number of advantages: more efficient delivery of highly lipophilic drugs at high doses, protection from aggressive environments (e.g., acidic pH in the digestive tract), as well as targeted and controlled delivery to achieve precise administration to a specific tissue over a determined period of time (e.g., pegylation [113
], coating with polysaccharides [114
], etc.). Even though the use of nanocarriers as drug-delivery systems offers many advantages, there are still some drawbacks that need to be addressed: instability during blood circulation, low renal clearance, limited accumulation in specific tissues and low uptake by target cells. Physico-chemical aspects, such as surface charge, size, shape and deformability, modulate uptake and interactions with host cells as well as influencing uptake by immune cells, the subsequent immune responses and nanovector biodegradation [115
]. An interesting work on the limitations, opportunities and concerns in this field has recently been published by Park [116
]. Significant research effort has been dedicated to the development of nanocarriers for the treatment of cancer, neurological diseases, cardiovascular diseases and use as antimicrobial agents, for which the principal route is systemic administration.
Their high lipophilicity and low stability (degradation via the effects of temperature, light and auto-oxidation can occur) mean that cannabinoids benefit greatly from nanotechnology approaches [51
]. Indeed, recent years have seen micellar, liposomal and nanosized formulations being proposed for use in topical and systemic preparations. A brief description of the approaches presented in patents and in the literature, follows, while principal formulation data are reported in Table 2
3.5.1. Lipid Carriers
Although liposomes are one of the most frequently studied and used market-approved drug delivery systems [55
], only a few patents involving cannabinoids have been published. The main disadvantage for liposomes in the encapsulation of lipophilic compounds is their reduced ability to locate such compounds in their phospholipid bilayer. Low encapsulation efficiency, or drug loading (ratio of encapsulated drug/sum of all components), is normally obtained for this reason. Rapid bioavailability and onset in the pulmonary administration of loaded-THC liposomes has been reported by Hung [117
]. The formulation was composed of dipalmitoylphosphatidylcholine and cholesterol, giving liposomes with an average size of 300–500 nm containing 0.3 mg/mL THC. Pharmacokinetic data described slow and prolonged release that continued for more than 5 h after administration.
Micellar and liposomal preparations have also been proposed by Winniki et al. [118
]. Micelles of 1 μm diameter were obtained via solvent injection in water and rapid solvent removal, while liposomes were produced using phosphatidylcholine ~52%, phosphatidylethanolamine 20%, phospholipids 26% and other compounds in a 2% mixture, via film hydration and solvent injection, ultrasonication and calcium alginate encapsulated liposomal suspension. Stability ranged from a few days (micelles) to several months (liposomes).
A nano-technology platform proposed by Medlab Clinical (Sydney, NSW, Australia), named NanoCelleTM
, that is made up of micelles obtained by mixing oils, glycerol and non-ionic surfactants is currently undergoing advanced trails. Micelles of nanometer size (less than 100 nm) and positive average Z potential have been observed to deliver lipophilic molecules (vitamin D3, statins, testosterone propionate, CBD) for absorption across the oral buccal mucosa, bypassing the gastrointestinal tract. Early research into their use in the treatment of pain is underway in Australia [119
Lipid nanoparticles in a solid particle matrix are produced from oil/water emulsions by simply replacing the liquid lipid (oil) with a solid lipid, i.e., one that is solid at body temperature. First generation analogues, produced from a solid lipid only, are named solid lipid nanoparticles. The second generation of nanostructured lipid carrier (NLC) particles are produced from a blend of a solid lipid and a liquid lipid, in which the partially crystallized lipid particles, with mean radii ≤ 100 nm, are dispersed in an aqueous phase containing one or more emulsifiers [121
]. NLC can be considered suitable carrier systems for THC and CBD because they make use of solid particle matrices instead of fluid matrices, such as emulsions and liposomes, meaning that NLC can better host substances and protect them from degradation. The solid particle matrix is also able to slow the diffusion of THC from inside the particle to the particle surface.
Esposito et al. have described the development of a method to encapsulate cannabinoid drugs (precisely the inverse agonist of the CB1 receptor (AM251 and Rimonabant) and the URB597 fatty acid amide hydrolase inhibitor) in NLC [122
]. In this circumstance, the lipid phase was composed of tristearin/tricaprylin 2:1 while Poloxamer 188 was added to the water phase. Nanoparticles of around 100 nm with high encapsulation efficiency were obtained.
NLC have recently been proposed for administration as a dosage form for nasal delivery. Nanospheres of 200 nm diameter, composed of either cetyl palmitate or glyceryl dibehenate and loaded with THC were obtained. In vitro mucoadhesion evaluations have revealed that cationic NLC formulations (obtained via the addition of cetylpyridinium chloride) should have high mucoadhesiveness properties [123
]. The solid matrix of the NLC was found to have a stabilizing effect on THC. Indeed, 91% of the THC was unaltered after 6 months storage at 4 °C. About 1.7 mg THC is administered with one spray of the 0.25% THC-loaded NLC formulation in each nostril. This amount was close to the THC amounts obtained from the oromucosal formulation in a study by Johnson et al. [124
Lipid nanoparticle formulations have been also reported, by Duran-Lobato et al. [125
], to incorporate and deliver CB-13, a cannabinoid drug that acts as a potent CB1/CB2 receptor agonist, and show therapeutic potential. Nanoparticles composed of either glyceryl dibehenate or glyceryl palmitostearate and stabilized with two different surfactants (polysorbate 20 and sodium deoxycholate), were produced using the emulsification-solvent evaporation method. The best formulation in terms of size (120 nm) and polydispersity was obtained using glyceryl palmitostearate as the lipid matrix, which was effective, in the presence of lecithin, in the preparation of cannabinoid-loaded particles with high EE (around 99%) and stability upon storage at 4 °C. In vitro biocompatibility was assessed and demonstrated that that this type of formulation is safe. Furthermore, neither free CB-13 nor LNP produced cytotoxic effects in three cell lines at the tested dose (250 μg/mL of each LNP formulation for 24 h). This formulation was also stable under intestinal conditions, seemingly making it suitable for the oral delivery of CB-13.
Formulations that are based on self-(nano)emulsifying drug delivery technology (SEDDS) have been proposed as a means of improving the oral bioavailability of drugs that show poor aqueous solubility [126
]. The base formulation, which is an isotropic mixture of an active compound in combination with lipids, surfactants and a co-solvent, has been called a pro-nano-liposphere (PNL) pre-concentrate and is ingested as a soft gelatine capsule. When it reaches the aqueous phase of the gastrointestinal tract, the PNL spontaneously forms a drug-encapsulated oil/water micro-emulsion with a particle diameter of less than 60 nm. The clinical usefulness of SEDDS, which stems from their ability to increase the solubility and oral bioavailability of poorly soluble drugs, have led to them attracting considerable interest [127
]. Products, such as Sandimmune®
Neoral (cyclosporin A), Fortovase®
(saquinavir) and Norvir®
(ritonavir), have confirmed the value of this approach [128
]. PTL401 is the proprietary PNL-based formulation of THC and CBD. The PTL401 formulation is composed of THC-CBD (1:1) in a formulation with polysorbate 20, sorbitan monooleate 80, polyoxyethylene hydrogenated castor oil 40, glyceryl tridecanoate, lecithin and ethyl lactate [129
]. The CBD-THC PNL formulation also allows absorption enhancers, such as curcumin, resveratrol and piperine, to be incorporated. PK evaluations in a rat model have indicated that only piperine enhanced the oral bioavailability of CBD in-vivo [130
]. Moreover, the enhanced oral bioavailability can be attributed to the inhibition of intestinal processes, rather than those of hepatic first-pass metabolism, while additional increases in the AUC of CBD prove that piperine-PNL also has an effect on phase II, and not on just phase I, metabolism. THC-CBD-piperine-PNL demonstrated higher absorption rates than Sativex®
in human volunteers, with peak values of 1 h for both THC and CBD, versus 3 h for THC and 2 h for CBD, respectively. Furthermore, the incidence and severity of reported adverse events were similar in both groups [131
]. Nevertheless, regarding the role of piperine, it is important to remember that it is able to alter the metabolism of many drugs, being a cytochrome and glucuronyl transferase inhibitor. In addition, piperine demonstrates non-negligible toxicity (it is Generally Recognized as Safe only up to 10 mg/day).
Micro and nanoemulsions of active annabis ingredients (cannabinoids and terpenes) have also been presented in a patent [133
], which proposes rectal-vaginalC and solid oral dosage forms.
A proprietary CBD nanotherapeutic formulation (CTX01) for subcutaneous administration is being developed by Cardiol Therapeutics (Oakville, ON, Canada) the treatment of heart failure with preserved ejection fraction. Preclinical studies are currently under way (Cardiol web site) [134
3.5.2. Polymeric Carriers
Polymers have played an integral role in the advancement of drug delivery technology and this field has grown tremendously. Polymers are currently used in pharmaceutical formulations and show a wide range of safety and biodegradation variables. Developments in responsive polymers, polymer therapeutics and advanced systems for molecular recognition or for the intracellular delivery of novel therapeutics have more recently appeared [135
]. Polymeric drug delivery systems are able to protect drugs from degradation and control drug release.
The poly (lactic-co-glycolic acid) (PLGA) polymer is one of the most commonly used materials for the encapsulation of drugs, as it is mechanically strong, hydrophobic, biocompatible and degrades into toxicologically acceptable products that are eliminated from the body.
PLGA nanoparticles, loaded with CB-13 for oral delivery, have been coated with a variety of agents (chitosan, Eudragit RS, vitamin E and lecithin) [137
]. The nanoparticles exhibited particle sizes of 253–344 nm and high entrapment efficiency values (around 85%). Higher release rates were obtained with vitamin E and lecithin surface modification. Biodistribution evaluations revealed that none of the proposed surface modifications prevented the opsonisation process (liver and spleen uptake). Nonetheless, CB-13, which is highly lipophilic and displays low water solubility, can be absorbed well when it is included in these surface-modified polymeric carriers.
Biocompatible polymer PLGA was preferred by Martin-Banderas for the preparation of THC-loaded nanoparticles for use as an anticancer agent [138
]. Nanoparticles, with sizes ranging from 290–800 nm, were obtained with PEG, chitosan and PEG-chitosan being used as coating agents. Encapsulation efficiency and drug loading (around 96% and 4.8%, respectively) were not affected by the type of coating used and sustained drug release, of up to 10 days, was obtained. Surface modification with PEG reduced protein adsorption and thus, most likely, the in vivo opsonisation processes.
Poly-ε-caprolactone (PCL) is another polymer that is widely used in drug delivery systems. This is a biocompatible, biodegradable, FDA-approved, semi-crystalline aliphatic polyester that degrades slowly. Hernán Pérez de la Ossa has developed a formulation in which CBD is loaded into PCL particles. Spherical microparticles, with a size range of 20–50 μm and high entrapment efficiency (around 100%), were obtained. CBD was slowly released over within ten days when dissolved in the polymeric matrix of the microspheres in an in vitro test [139