cbd delivery systems

December 15, 2021 By admin Off

Areas covered: This review summarizes scientific reports on cannabidiol advanced delivery systems (CBD-ADSs) that have been (i) developed, and (ii) applied therapeutically; reports published in the main scientific databases until January 2020 were included. Studies without experimental data and/or published in languages other than English were excluded. Moreover, pharmaceutical technology tools in CBD therapeutic use have been discussed, emphasizing the clinical translation of CBD carrier use.

Introduction: Cannabidiol (CBD), a phytocannabinoid from Cannabis sativa , has several therapeutic properties. However, its high lipophilicity, metabolization, and instability impair its bioavailability and translational use in clinical settings. Several advanced drug delivery systems (ADDSs) have been evaluated as CBD carriers to overcome these drawbacks. These systems can improve the CBD dissolution profile, protect it against metabolization, and produce a site-specific release, increasing its bioavailability and making CBD administration clinically effective.

Expert opinion: Studies reporting CBD-ADS use for medicinal applications were reviewed and revealed multifaceted systems that can overcome the physicochemical drawbacks of CBD and improve its biological activities. Therefore, researchers concluded that the developed CBD-ADS can be used as an alternative to traditional formulations because they show comparable or superior effectiveness in treatment protocols. Although several criteria remain to be met, our findings emphasize the potential of CBD-ADSs for translational therapeutics, particularly for neurological-disorders.

Keywords: Nanolipospheres; conjugates; ethosomes; inclusion complex; microparticles; nanocrystals; nanoparticles.

To enhance the bioavailability of cannabinoids, the alkaloid piperine has been combined with SNEDDS and orally administered to rats. The results showed an approximate 2.5-fold increase in the oral bioavailability of CBD with piperine dissolved in SNEDDS (once-daily dose) compared to CBD-SNEDDS alone. Nevertheless, there was no significant difference in CBD absorption with acute or chronic administration of piperine [150].

Furthermore, this administration route has been explored for the development of promising delivery systems that also use nanotechnology approaches [300].

Pacher P, Kogan NM, Mechoulam R. Beyond THC and endocannabinoids. Annu Rev Pharmacol Toxicol. 2020;60:637–59.

Nanotechnology-Based Approaches for Oral Delivery.

Sheriff T, Lin MJ, Dubin D, Khorasani H. The potential role of cannabinoids in dermatology. J Dermatol Treat. 2020;31(8):839–45.

Manns D, Norwig J, Reh K. Cannabis für medizinische Zwecke: Entwicklung von Arzneibuchmonographien als Qualitätsstandard. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2019;62(7):806–10.

Schindler EAD, Schnakenberg Martin AM, Sewell RA, Ranganathan M, DeForest A, Pittman BP, et al. In an exploratory randomized, double-blind, placebo-controlled, cross-over study, psychoactive doses of intravenous delta-9-tetrahydrocannabinol fail to produce antinociceptive effects in healthy human volunteers. Psychopharmacology (Heidelberg, Ger). 2020;237(10):3097–107.

Stinchcomb AL, Banks SL, Golinski MJ, Howard JL, Hammell DC, inventors; AllTranz Inc., USA . assignee. Cannabidiol prodrugs in topical and transdermal administration with microneedles patent WO2011026144A1. 2011.

The most common route of administration for cannabis-derived medicines is by inhalation, or smoking. The intrapulmonary administration of cannabinoids is regarded as an effective mode of delivery as it results in the fast onset of action (5–10 min), rapid delivery to the central nervous system and high systemic bioavailability. Furthermore, this route of administration is useful for patients who are not in the condition to take oral medications (e.g., in the case of serious nausea and vomiting). To avoid the production of toxic by-products via combustion, vaporisation, which is a technique by which cannabis is heated to the temperature of cannabinoid vaporisation, but below the point of combustion, has been proposed since the 1990s. Different types of vaporiser devices have been marketed; from larger desktop devices, such as the Volcano ® or the Arizer Extreme Q ® , to more portable models, such as the Arizer Solo ® , Crafty ® or Mighty ® Medic portable vaporisers (Storz-Bickel GmbH, same producer as the Volcano ® ) or the Syqe Inhaler, developed by Syqe Medical (IL).

Ballan E, Borochov I, inventors; Cannabics Pharmaceuticals Inc., assignee. Cannabinoid compositions, methods of manufacture and use thereof patent WO2017145160. 2017.

Less-Explored Delivery Routes for Cannabinoids and Other Preliminary Studies.

Cannabinoids, indeed, have poor oral bioavailability (estimated to be as low as 6% of a similar dose administered intravenously). Pure THC and CBD show similar plasma concentration-time profiles, with a delay of 120 min before reaching peak concentration [42]. Bioavailability increases when it is co-administered with food lipids. A cannabis formulation in sesame oil (a vehicle with long chain triglycerides [LCT], containing 42% oleic, 40% linoleic and 16% palmitic acids) significantly improved the bioavailability of cannabinoids [82].

da Silva AJ, dos Santos ES. Energetic and thermodynamical aspects of the cyclodextrins-cannabidiol complex in aqueous solution: a molecular-dynamics study. Eur Biophys J. 2020;49(7):571–89.

Pain is the result of a series of ample interactions (nervous system, metabolic, immunological responses), modulated by various factors (environmental, cultural, physical, affective), that are capable of generating specific characteristics for each individual.

Furthermore, the potential role of cannabinoid metabolites, especially active metabolites such as 7-hydroxy-CBD, should be considered, as outlined in recent studies in subjects with renal or hepatic impairments [85,86,87].


Bonn-Miller M, Tich N, Gutterman D, Messenheimer J, Sebree T, inventors; Zynerba Pharmaceuticals, Inc., assignee. Treatment of fragile X syndrome with cannabidiol patent US10213390. 2019.

Office of Medical Cannabis, MoH, Welfare and Sport, Netherlands. Information for pharmacists and healthcare professionals; 2021. https://english.cannabisbureau.nl/doctor-and-pharmacists. Accessed 15 Mar 2021.

Professional organisation guidelines, documents from international medicine institutions (Food and Drug Administration [FDA] European Medicines Agency [EMA], Government of Canada), and academic websites were also utilised, as appropriate.

Stinchcomb AL, Nalluri BN, inventors; Alltranz, LLC, USA. assignee. Transdermal delivery of cannabinoids patent US20050266061A1. 2005.

Bernkop-Schnürch A, Müllertz A, Rades T. Self-emulsifying drug delivery systems (SEDDS)—the splendid comeback of an old technology. Adv Drug Deliv Rev. 2019;142:1–2.

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.

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.

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.

The endocannabinoid system’s contribution to the regulation of such a variety of processes makes phytocannabinoid pharmacological modulation a promising therapeutic strategy for many medical fields, including the studies of analgesic, neuroprotective, anti-inflammatory and antibacterial activity [13,14].

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.

Table 2.

Overall, seven different endogenous ligands have been identified as acting within the endocannabinoid system to date. The first two endocannabinoids are the derivatives of arachidonic acid N -arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol [12]. A third endocannabinoid, 2-arachidonoyl glyceryl ether (noladin ether) was discovered in 2001. N -arachidonoyl dopamine, O -arachidonoyl-ethanolamide (virodhamine), docosatetraenoylethanol-amide, lysophosphatidylinositol and oleoylethanolamide have since been described as ligands of endocannabinoid receptors [7].

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 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].

Nabiximols (Sativex ® 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].

Cannabis ( Cannabis sativa ) is a dioic plant that belongs to the Cannabaceae family (Magnoliopsida, Urticales). Knowledge of the medical and psychoactive properties of cannabis dates back to 4000 B.C. All of the different varieties of cannabis, including the one known as Cannabis indica , belong to the same species. All C. sativa plants produce active compounds, but each variety produces these compounds in different concentrations and proportions, which do not only depend on genomic background, but also on growing conditions and climate, meaning that they can be referred to as chemical varieties or chemovars, rather than strains [1]. Each chemovar contains varying concentrations of cannabinoids, a class of mono- to tetracyclic C21 (or C22) meroterpenoids. While more than 100 different cannabinoids can be isolated from C. sativa , the primary psychoactive compound is Δ 9 -tetrahydrocannabinol (THC), which was first isolated in its pure form by Gaoni and Mechoulam in 1964 [2]. Other pharmacologically important analogues are cannabidiol (CBD), cannabinol, cannabinoid acids, cannabigerol, and cannabivarins. In addition to cannabinoids, other components, such as the monoterpenoids myrcene, limonene, and pinene and the sesquiterpenoid β-caryophyllene, can also mediate the pharmacological effects of C. sativa [3].

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 [69,70,71]. 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.

Paudel et al. have prepared a variety of formulations (CBD in PEG 400 alone and CBD in a 50:35:15 ( v / 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 (T max ≤ 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.

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 [129,130]. 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 [131,132]. 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).

Pain and inflammation are the body’s physiological responses to tissue injury, infection and genetic changes [24]. These responses can be divided into two phases: acute and chronic. The acute phase is the early, non-specific phase and is characterized by local vasodilatation, increased capillary permeability, the accumulation of fluid and blood proteins in the interstitial spaces, the migration of neutrophils out of the capillaries, and the release of inflammatory mediators (e.g., cytokines, lymphokines and histamine). Pain is produced by all these pro-inflammatory agents, that also lead to hyperalgesia through the activation of the corresponding receptors, which are expressed by nociceptive terminals ( Figure 1 ). If the condition that causes the damage is not resolved, the inflammatory process progresses towards subacute/chronic inflammation, which is characterized by immunopathological changes, such as the infiltration of inflammatory cells, the overexpression of pro-inflammatory genes, the dysregulation of cellular signalling and the loss of barrier function.

3.5. Nano-Technological Approaches.

Cannabis-derivative-based medicines may be able to enrich the drug treatment arsenal for chronic pain and inflammation conditions, although this is very much open to debate at the moment. CBD, unlike THC, is not considered an abused drug and several industries are involved in the production of CBD as an active pharmaceutical ingredient with the highest quality standard. It is relevant, and expected, that regulatory agencies, other than the Medications Health Care Products Regulation Agency, will evaluate and approve CBD as a medicine after a careful study of quality, safety and efficacy data [13]. While medicinal cannabis has already entered mainstream medicine in many countries, particular care should be taken in a period in which the on-line availability of a variety of CBD-based products for therapeutic purposes, such as oils, tinctures and vapours, has rapidly expanded and, along with it, an increase in potential health risks for patients/consumers may be expected.

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].

Conclusions in studies into reducing opioid doses in the management of chronic pain, where some trials have shown clinical benefits, are sometimes not completely reliable as they inadequately report dose changes and have mixed results in analgesic effects [144]. Recent analysis has found no evidence to suggest that Cannabis can exert an opioid-sparing effect [145].

The chronic pathological pain state, including neuropathic pain, is a leading health problem worldwide as it endures beyond the resolution of the pain source and can deeply impact quality of life [26]. Unlike physiological pain, in which tissue injury and/or inflammation can induce reversible adaptive changes in the sensory nervous system leading to protective sensitization, changes in sensitivity become persistent or chronic in neuropathic pain. Furthermore, the nervous system, peripheral or central, is injured in neuropathic pain. It is characterised by pain in the absence of a noxious stimulus and may be spontaneous in its temporal characteristics or be evoked by sensory stimuli (hyperalgesia and dynamic mechanical allodynia). For example, neuropathy is still among the most common diabetes complications, affecting up to 50% of patients, despite recent advances in treatment. There is no effective treatment with which to prevent or reverse neuropathic pain [27], thus current treatment is only directed at reducing symptoms. The treatment of chronic pain is still an unmet clinical need, where adequate pain relief is obtained using drugs with adverse effects on central nervous system side [28]. The quality of life of neuropathic pain patients is often aggravated by comorbidities such as sleep disorders, depression and anxiety compromise.

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 .

There are three oral, and one oromucosal, cannabinoid pharmaceutical preparations that are currently available.

4. Critical Overview of Clinical Studies.

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.

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.

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 [96,97,98]. The gel is designed to be applied once or twice daily. Permeation profiles of a range of formulations have also been reported [99].

Cannabinoids and endocannabinoids are a hot topic in the fields of chemical and biomedical research with more than 1000 articles being published per year and the trend is for that to increase. Furthermore, research into cannabinoid delivery systems is growing and a plethora of patents have shown interest in the companies working in this field, especially when it comes to local/transdermal administration. Combining formulations may provide an opportunity to produce rapid systemic effects and long-term outcomes (e.g., analgesia). This could be achieved with intranasal cannabinoid sprays used as a low-dose adjuvant to patches in order to aid rapid absorption for systemic effects. Interesting and promising transdermal administration results can also be found in the use of terpenes (from the same source) as CBD and THC penetration enhancers, and thus improve the effectiveness of the therapeutic components. This, once again, highlights the role that quality plays in defining the composition, dosage and related safety of the components extracted from cannabis.

There is a growing body of evidence to suggest that cannabinoids are beneficial for a range of clinical conditions, including pain, inflammation, epilepsy, sleep disorders, the symptoms of multiple sclerosis, anorexia, schizophrenia and other conditions. The transformation of cannabinoids from herbal preparations into highly regulated prescription drugs is therefore progressing rapidly. The development of such drugs requires well-controlled clinical trials to be carried out in order to objectively establish therapeutic efficacy, dose ranges and safety. The low oral bioavailability of cannabinoids has led to feasible methods of administration, such as the transdermal route, intranasal administration and transmucosal adsorption, being proposed. The highly lipophilic nature of cannabinoids means that they are seen as suitable candidates for advanced nanosized drug delivery systems, which can be applied via a range of routes. Nanotechnology-based drug delivery strategies have flourished in several therapeutic fields in recent years and numerous drugs have reached the market. This review explores the most recent developments, from preclinical to advanced clinical trials, in the cannabinoid delivery field, and focuses particularly on pain and inflammation treatment. Likely future directions are also considered and reported.

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.

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.