The Skin and Natural Cannabinoids–Topical and Transdermal Applications

Abstract

1. Introduction

For over two millennia, the Cannabis plant has been used for both recreational and therapeutic purposes [1,2], with various archaeological discoveries confirming that it has been cultivated across most of the known world. Ancient Chinese medicine, for example, used the plant for musculoskeletal conditions and to relax and harmonize the mind and body [3], while the Greeks and Romans used it for recreational consumption and medical use [4]. The plant’s psychoactive and analgesic qualities were used by Indians to treat various types of pain [5,6]. In the first Chinese Pharmacopeia, Cannabis seeds were recommended for the treatment of skin diseases and disorders, such as eczema, psoriasis, and other inflammatory conditions [7]. Nowadays, due to the increasing interest in sustainability and ecological issues, the use of plant-based natural products in dermatology has become a valuable method for improving therapies with respect to acute and chronic skin diseases and disorders, with lower costs for patients and healthcare systems [7]. Cannabis, a representative genus of the Cannabaceae family [8], is an annual herbaceous plant, which includes the Cannabis sativa L. (hemp and marijuana), C. ruderalis Janisch, and C. indica Lam. species [9]. Cannabis is a genus characterized by dioecy [10], producing male and female inflorescences on different individuals that are obligatory out-crossers [11]. The plant is naturally occurring and is part of the local flora in the Indian Peninsula and Central Asia; however, in the rest of the world, it is cultivated for a variety of purposes. Cannabis is used in its unprocessed state as dried flower bulbs, known as marijuana, and as pieces of resin, known as hashish [12].

What makes each variety or strain of the Cannabis plant unique in its own way is the presence of three different classes of chemical compounds that exhibit biological activity: phytocannabinoids (pCBs), flavonoids, and terpenes/terpenoids [13]; they may act either individually and/or synergistically [14]. Depending on the plant content in each of these molecules, various modulatory or potentiation pharmacological effects have been observed [15,16]. A recent classification of Cannabis plant constituents identified 545 entities divided into chemical classes based on their structural similarities [17]. Thus, more than 100 Cannabis constituents belong to the pCB class, which is mostly extracted from female plants, with the most well-known being tetrahydrocannabinol (THC) with its two derivatives Δ8-tetrahydrocannabinol (Δ8-THC) and Δ9-tetrahydrocannabinol (Δ9-THC); cannabidiol (CBD); and cannabigerol (CBG) [18,19]. The rest of the natural compounds are classified into seven other main classes: cannabinol (CBN), cannabielsoin (CBE), cannabichromene (CBC), cannabicyclol (CBL), cannabinodiol (CBND), cannabitriol (CBT), and other types of cannabinoids [20].

The pharmacokinetics and metabolism of natural cannabinoids depend on the route of administration [13]. pCBs are known to have high lipophilicity, low aqueous solubility, rapid metabolism, poor bioavailability, and erratic pharmacokinetics [21], being temperature-, light-, and auto-oxidation-sensitive [22]. For example, the oral bioavailability of CBD ranges between 13% and 19% [23] due to its incomplete oral absorption and high hepatic clearance [2], while its bioavailability increases at 34–46% when it is absorbed intranasally [24]. Also, after topical in vivo gel applications, CBD provided significant plasma levels [24]. Consequently, pCB formulations emphasize a low oral bioavailability that led to the necessity of other administration routes to improve pCBs’ bioavailability and efficacy, such as the local (topical), transcutaneous (transdermal), pulmonary, and transmucosal routes [25] that include intranasal and rectal routes, with the last one demonstrating double the rate of bioavailability compared to the oral route [22]. Topical and transdermal administration demonstrated several advantages, such as a higher bioavailability rate, prolonged steady-state plasma concentration, and a reduction in psychoactive impacts of the drug due to its passive diffusion in the main barrier of the skin, stratum corneum [22]. To evaluate the efficacy of pCB topical applications, a plethora of studies emphasizing the mechanisms of action at the molecular level, redox transformation, electronic structure, and stability; and the cytotoxic, phototoxic, and UVA or UVB photoprotective effects of pCBs have been performed [26]. To emphasize the mechanisms of action of pCBs at the molecular level, it has been demonstrated that CBD inhibits nuclear factor kappa B (NF-κB) and the genes involved in the expression of molecules with pro-inflammatory roles, such as cytokines and metalloproteinases [27]. Clinical studies emphasized that topical treatment with CBD-enriched ointment significantly improved skin parameters and disease symptomatology, proving that the topical application is a safe and non-invasive alternative for improving the quality of life in patients with various skin disorders [28].

Outside of clinical studies, to investigate the potential roles of pCBs for the treatment and alleviation of skin diseases and disorders, many types of cell lines have been used in various in vitro studies: inflamed human keratinocytes (HaCaT cells) [29], human SZ95 sebocytes [30], human eccrine-sweat-gland-derived immortalized NCL-SG3 model cells [31], human healthy and stress-induced premature senescent (SIPS) CCD-1064Sk dermal fibroblasts [32], or My-La and HuT-78 cutaneous T-cell lymphoma lines [33].

Skin conditions affect between 30% and 70% of people worldwide and more than 3000 acute and chronic skin diseases that significantly reduce the patients’ quality of life have been described [34]. Traditional systemic treatments used in dermatology are based on topical agents (corticosteroids, vitamin D analogues, moisturizers, retinoids, and calcineurin inhibitors), phototherapy, systemic immunotherapy, systemic antibiotics and hormones, antifungals, biological agents, or small molecule inhibitors. These classic treatments may emphasize several limitations, including poor responses to treatment, potential drug interactions, hepatic and renal toxicity, and even a significant risk of skin malignancy and teratogenicity [28]. The most significant adverse effects of current drug-based therapies applied in the most frequent skin diseases, such as psoriasis, atopic dermatitis, allergic contact dermatitis, asteatotic eczema, acne, and seborrhea, are listed in Table 1: xerosis; erythema; purpura; rosacea or alteration in skin pigmentation; photoaging; skin atrophy; itching; burning sensation; folliculitis; actinic keratosis; allergic reactions; hair loss or hypertrichosis; hyper-lipidaemia; hypertension; metabolic and nutritional disorders; headache; bone marrow suppression; leukopenia; bone growth stimulation; decreased bone density; the inhibition of the hypothalamic–pituitary–adrenal axis in children; herpes simplex reactivation; and delayed wound repair [35,36,37,38,39,40,41,42,43,44]. In dermatology, pCBs have demonstrated anti-inflammatory [27,30], anti-oxidative [45], anti-aging [32], anti-acne [30], and anti-UVA/UVB radiation damage proprieties [46]. Moreover, several pCBs emphasized potent antimicrobial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) that may cause serious infection on the skin and other organs [47], which is possible due to the inhibition of Staphylococci adhesion to keratinocytes [48]. Interestingly, Luz-Veiga et al. have unveiled that CBD and CBG may be promising topical antimicrobial agents for different skin conditions without a negative impact on skin microbiota [48]. Feldman et al. have shown that CBD can be considered an alternative treatment against fungal infection due to its anti-biofilm activity against Candida albicans [49], which resides on the skin surface and may cause infections [50].

Consequently, Cannabis plant-derived compounds have been recommended for the treatment of many skin disorders and diseases, such as dry/seborrheic skin and acne [30]; atopic dermatitis (or eczema); psoriasis and resulting outcome scars [28,51]; pruritus, including neuropathic itch [52]; pain [53]; and mycosis fungoides, the most common type of cutaneous T-cell lymphoma (CTCL) [33]. An international cross-sectional survey study demonstrated that cannabinoid-based medicine (CBM) may alleviate pain and pruritus and improves wound healing and well-being in patients with epidermolysis bullosa (EB), a group of clinically and genetically heterogeneous genetic skin conditions that express fragile skin and mucosae [54]. In vivo studies demonstrated that, individually or combined, cannabinoids may reduce tumor growth or tumor cell proliferation and promote apoptosis and autophagy in melanoma cells, emerging as potential agents for the treatment of cutaneous melanoma [55]. Lichen simplex chronicus and multiple cutaneous squamous cell carcinoma (SCC) lesions have completely regressed with the topical application of 20% CBD oil [56]. Psoriasis, which emphasizes two clinical manifestations, psoriasis vulgaris and psoriatic arthritis, is the most common autoimmune skin disease that currently affects about 4% of the population [51]. pCBs are known as candidate drugs in the treatment of psoriasis due to their effects of inhibiting the proliferation of keratinocytes and modulating the associated inflammatory response [57]. Acne vulgaris (acne) affects 9.4% of the world’s population and 85% of adolescents [58]. CBD is well known for its anti-inflammatory effects on acne [58]. Both CBG and cannabigerovarin (CBGV) exert potential in the treatment of skin dryness, while CBC, cannabidivarin (CBDV), and Δ(9)-tetrahydrocannabivarin (THCV) have been proposed as novel anti-acne agents due to their efficacy [30]. In regions where cannabis use is legal, there are reported clinical cases where topical formulations including phytocannabinoids (CBD and THC), self-initiated by patients or prescribed by certain dermatologists and prepared by pharmacists, have been shown to be effective in treating a variety of skin conditions [59,60,61].

Cannabinoids work on the endocannabinoid system (ECS) [62]. The endocannabinoid receptors and their endogenous ligands were discovered and identified after the first compounds in the class were isolated and characterized. The endogenous endocannabinoid system (ECS) is represented by a molecular signaling network consisting of endocannabinoids, specific G-protein-coupled receptors (GPCRs), cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), and specific enzymes responsible for the synthesis, transport, and degradation of endocannabinoids [59]. Various studies have also identified non-CB1/CB2 receptors modulated by endocannabinoids, such as GPCRs (GPR18, GPR55, and GPR119), transient potential vanilloid receptors (TRPV1 and TRPV3), transient receptor potential ankyrin 1 (TRPA1), nuclear hormone receptors like peroxisome proliferator-activated receptors (PPARs), and others [2,63]. ECS plays a critical role in a number of physiological processes, including immune modulation, vasomotion and vasodilation, motor control, muscle fiber formation, cognitive memory, learning, anxiety, appetite, gastro-intestinal motility, sleep, fertility, lipogenesis, and the formation of insulin and muscle fibers, as well as intestinal and bronchial motility [15,64,65,66,67,68]. It also plays a key role in pathological processes like pain, inflammation, and cancer [69,70,71]. Minor pCBs, such as CBG, CBC, THCV, and cannabigerolic acid (CBGA), exert their anti-inflammatory effect in human keratinocytes via the molecular deregulation of endocannabinoid (ECB) signaling and the mitogen-activated protein kinase (MAPK) pathway [29].

Cannabinoids’ beneficial or harmful effects are determined by how they act on the CB receptors and by their affinity for a particular receptor. The cannabinoids can also interact with a multitude of other receptors, which explains the variety of effects encountered in these compounds [20]. Being fully represented in the skin, the ECS contributes significantly to the body’s homeostasis [59]. By controlling, among other things, cell growth, differentiation, and survival; immune and inflammatory responses; and sensory phenomena, the ECS is also involved in the physiology and pathology of skin functions [72].

The skin is an accessible organ for the non-invasive or minimally invasive administration of medications [73]. However, the variability in skin permeability remains a challenge in optimizing transdermal drug delivery that targets the epidermis, dermis, deeper tissues, and systemic circulation [74]. Hence, the skin can be approached from both points of view as a therapeutic target and as a route of systemic administration.

The skin has the advantage of being an easy and convenient route of administration for a wide range of active ingredients, including natural or synthetic cannabinoids. Various techniques for the enhancement of skin permeabilization are available for the improvement of bioavailability and the efficacy of therapeutic cannabinoids, such as the use of organosilane particles as transdermal delivery vehicles [75], oleic acid and ethanol as good chemical enhancers, ethosomes and nanocryogels as controlled release strategies, and microneedle arrays for both the topical and transdermal delivery of incorporated cannabinoids [76].

Complementary and alternative medicine (CM and CAM) therapies have an increasing presence in dermatology [77], gaining popularity among patients in recent years. Natural remedies are seen as safer than conventional medications, with few if any notable adverse effects. However, dermatologists are wary of prescribing cannabinoid-based remedies due to the lack of studies regarding the formulation and standardization of extracts and safety profiles [78]. There are a few reported clinical cases of allergies related to topical cannabis contact, such as pruritus, urticaria, or angioedema, which were confirmed via specific allergy tests [79]. Similar o many other natural products or extracts, cannabis-based medicines have the potential to cause skin allergies in some individuals. However, thanks to advances in formulation techniques, exposure to some cannabis plant constituents may be significantly reduced.

The current review aims to bridge the gap between cannabinoids as traditional healing herbal extracts and the current science regarding optimal usage, including the formulation, route of administration, dosage, and frequency of use of these compounds in dermatological disorders and diseases.

2. The Topical versus the Transdermal Route of Administration for Natural Cannabinoids

2.2. The Skin as a Potential Route for Systemic Administration

The skin, which is the largest organ in the human body and serves as a barrier between the body and the outside world as well as an immunological function, is made up of three layers, the dermis, the epidermis, and the stratum corneum (SC) [145,146,147,148], as shown in Figure 2 and Figure 3.

Figure 2

The molecular members of the skin’s endocannabinoid system (ECS).

Figure 3

Particularities of skin ECS at the pilosebaceous unit level.

The skin has unique characteristics: It is permeable relative to the environment and allows the diffusion of air, heat, water, and low molecular weight molecules [145]. Skin permeability can occur in three different ways: the intercellular pathway, which involves the space between corneocytes and keratinocytes; the transcellular pathway, which involves corneocytes and the lipid matrix around them; and the appendicular pathway, which involves sweat glands and hair follicles [149]. Because of this, transdermal application can be used as an alternative method of drug administration. This is because it is simple to use and because it is administered directly into the systemic circulation, avoiding the first hepatic passage and the potential appearance of unwanted metabolites; moreover, the necessary dose and side effects can be significantly reduced [73,150,151].

The transdermal administration of cannabinoids avoids the first-pass metabolism that occurs in the liver, but because they are extremely hydrophobic, they have a limited diffusion across the aqueous layers of the skin [152]. From a physicochemical perspective, molecules with a low weight (below 500 g/mol), a melting point of less than 250 °C, and high potency (less than 10 mg/day) are suitable for transdermal administration. Because transdermal administration necessitates passing through the hydrophobic/lipophilic SC, absorption in the deep aqueous layers, and then passage into the systemic circulation, these substances also need to have a moderate lipophilicity/hydrophilicity balance (logP = 1–5) [73,150,153]. Because the molecular weight of cannabinoids is not what we want, nor is the ratio of lipophilicity/hydrophilicity, they have a log P between 5 and 7 (as seen in Table 2) and low solubility in water; their transdermal administration represents a challenge. These difficulties not only led to the use of permeability enhancers such as oleic acid and ethanol but also techniques that modify the characteristics of the molecule by using microemulsions, physical amplifiers (microneedles and electroporation), iontophoresis, ultrasound, magnetophoresis, encapsulation in micro-/nanogels, nanoparticles, and nanocarriers [25,73,76].

Table 2

Classification of the most important phytocannabinoids by their lipophilic nature.

Phytocannabinoid	LogP Octanol/Water	Chemical Structure
Cannabidiolic acid (CBDA)	4.86 [154]
Cannabidiol (CBD)	5.79 [155]
Cannabinodiol (CBND)	6.00 [156]
Δ9-trans-tetrahidrocannabinol (THC)	7.26 [157]
Δ8-trans-tetrahidrocannabinol (Δ8-THC)	7.4 [156]
Cannabigerol (CBG)	7.47 [158]
Cannabigerolic acid (CBGA)	8.31 [158]
Tetrahydrocannabinolic acid (THCA)	8.41 [158]

Open in a separate window

 

2.2.1. Why Transdermal Administration of Cannabinoids Could Be the Solution?

Modern medicine is constantly looking for therapeutic methods that bring definite improvements in the clinical condition of patients. At the same time, researchers are looking for new drugs that have a high degree of safety when administered and, last but not least, can cover a wide range of ailments.

Therefore, cannabinoids are a class of compounds that seem to satisfy these needs via the multiple proven or still researched therapeutic effects, such as the following: analgesic, anti-inflammatory, antioxidant, antibacterial, and antiemetic [45,62,159,160,161]. Cannabinoids have sparked the interest of scientists due to their high therapeutic potential. For this reason, pharmacological studies address subjects that debate and analyze the methods of the administration of cannabinoids to improve their bioavailability, ease of administration, and reduction in adverse reactions. For example, the most intensively analyzed route of administration is the oral one. Additionally, recent studies have highlighted that cannabinoids have low bioavailability following oral administration. Some of the reported causes are as follows: (1) the high lipophilicity of these compounds such that low solubility in water that limits their absorption, (2) hepatic first-pass metabolism, (3) rapid metabolism, (4) irregular pharmacokinetics, (5) their instability in the presence of gastric pH, and (6) the influence of temperature [76,162,163,164]. Considering the above-mentioned reasons, it is expected that researchers will explore other routes of administration in an attempt to minimize these inconveniences. Therefore, transdermal formulations come to the aid of scientists. In other words, theoretically, problems arising from the oral administration of cannabinoids can be solved by using the skin as a way of entering the body when the pathology or symptom being treated allows it. Some disadvantages of cannabinoid oral administration are detailed in the following lines.

The effect of the first hepatic passage is manifested by the biotransformation of the drug before it enters systemic circulation. Both endogenous and exogenous cannabinoids undergo hepatic metabolism after oral administration, a fact that considerably influences the bioavailability of the drug. Specifically, cannabinoids are substrates of the CYP enzyme family [165]. For example, dronabinol (Marinol), a synthetic delta-9-THC for oral use, is primarily metabolized by hydroxylation via multiple CYPs. Both active and inactive metabolites result from this reaction [166]. An in vivo study on patients treated with CBD identified the presence of 33 different metabolites in the patients’ urine using spectrometric methods. Thus, due to the intense metabolism undergone by CBD, the study suggests that this natural compound could provide valuable information about the mechanism of several types of biotransformation [167].

What is interesting is the fact that the metabolism of cannabidiol occurs primarily due to hydroxylation, which is catalyzed by CYP2C19 and CYP3A4 enzymes [168]. In addition, CBD is a potent inhibitor of these enzymes [169]. This information is significant in the context of the simultaneous administration of the Epidiolex product (synthetic cannabidiol: GW Pharmaceuticals) as an adjuvant in patients with refractory epilepsy treated with clobazam, which is another substrate for these enzymes that belong to the CYP family. Consequently, the plasma level of the active metabolite of clobazam (norclobazam) requires frequent monitoring in patients following this treatment simultaneously with CBD [169].

Regarding the metabolism of endocannabinoids, studies have shown the existence of some inactive metabolites. In addition, research has focused on inhibiting the degradation of endocannabinoids with pharmacologically valuable results. Therefore, it is interesting to mention FAAH inhibition strategies, with this molecular target becoming extremely attractive for the anxiolytic effects observed in neuropsychiatric diseases and the antinociceptive effect in pain conditions [170]. Thus, FAAH inhibition has been intensively explored in clinical and preclinical studies [171]. For example, modulating the concentration of anandamide by inhibiting FAAH can reduce anxious behavior in rodents with chronic stress [172]. In addition, in a multicenter, double-blind, placebo-controlled study, JNJ-42165279, an FAAH inhibitor, reduced the Liebowitz Social Anxiety Scale (LSAS) by 30% and achieved an improvement in the Clinical Global Impression-Improvement (CGI-I) by the end of 12 weeks of treatment [173]. Therefore, it is easy to understand that the hepatic metabolism of orally administered cannabinoids produces qualitative and quantitative changes in the active substances. Also, the substrate–enzyme interaction increases the risk of drug interactions, to which the risk of toxicity or failed treatment is added.

Also, cannabinoids are molecules with a high degree of lipophilicity and are susceptible to degradation if they are formulated as solutions. They can undergo autoxidation reactions; thus, control over the pharmacokinetics of the administered compound is lost. In addition, exposure to light, herbal cannabis or cannabis resin, or extracts leads to significant losses in phytochemical component levels [174,175].

Their high lipophilic nature poses serious problems in cannabinoid oral administration. It is well documented that the oral bioavailability of CBD and THC is as low as 6% [175]. Also, THC under various oral formulations shows variable absorption. Moreover, THC absorption is slow, irregular, and unpredictable. Pharmacokinetic studies have noted similar oral absorption for both THC and CBD, a fact that requires the formulation of these compounds in oil to counteract the harmful effects on oral bioavailability given the low solubility of cannabinoids in water [25].

On the other hand, the variable pharmacokinetics of cannabinoids is demonstrated by a significantly different metabolic pattern depending on the oral formulation [176]. For example, in a double-blind, randomized, single-center study, nine healthy male volunteers were treated with unheated Cannabis sp. extracts, heated Cannabis sp. extracts, and dronabinol. The results of the study demonstrated the different plasma concentration levels of certain metabolites depending on the form of administration, in addition to the higher bioavailability of the heated extract compared to the unheated extract and synthetic CBD. Specifically, the authors found the highest scores of the average plasma value of the area under the plasma concentration/time curve (AUC) during the first 24 h after drug administration for THC-COOH, which is the inactive metabolite of dronabinol [177].

Consequently, the results of the oral administration of cannabinoids impose pharmacokinetic problems that are difficult to anticipate and require rigorous comparative studies on the medicinal form approached. Also, the variable bioavailability of cannabinoids requires the development of quality-controlled extracts, with a pharmacological profile that allows the administration of correct doses for optimal therapeutic effects.

That is why the transdermal administration of cannabinoids would have some advantages: the possibility to increase the therapeutic dose by avoiding the hepatic first-pass effect; direct application to the affected area, especially in dermatological conditions or the possibility to obtain an analgesic effect; and adverse effect minimization, as seen in Table 3. On the other hand, transdermal preparations allow the use of larger amounts of active substance, with controlled release for a longer period of time [178]. However, there are several difficulties and restrictions with respect to transdermal cannabinoid preparations. The physico-chemical stability of the preparation is a subject that deserves attention in this context.

Table 3

Advanced formulations designed in order to penetrate the skin or membranes and to produce systemic effects.

Route of Absorption	Pharmaceutical Form Type	Disease	Observations	Reference
Transdermal	cannabinoids in a gel formulation using Transcutol®	increased penetration through the skin in various disease models	tested in vivo in two rat models of cocaine and alcohol addiction in the prevention of relapse to drug use	[179,180]
	ZYN001—Synthetic D-glyceryl acid ester prodrug of THC	fibromyalgia and neuropathic pain	tested by Zynerba Pharmaceuticals Inc. (USA), failed to achieve the desired blood levels of THC	[181]
	THC encapsulated in MLVs for transdermal applications.	pain treatment	tested in vitro for skin penetration by Altum Pharmaceuticals Inc. (USA)	[182]
	gel containing CBD using Transcutol®	epilepsy, developmental and epileptic encephalopathy, fragile-X syndrome, and osteoarthritis	developed and tested in vitro by Zynerba Pharmaceuticals Inc. (USA)	[183,184]
Transdermal	CBD and argan oil combination using Transcutol® to encapsulate CBD	pain and inflammation associated with rheumatic or arthritic inflammatory disorders	Shemanky et al. [97] reported the beneficial effects of this formulation in a group of ten volunteer patients.	[185]
	THC prodrugs encapsulated using Transcutol®	patients with pathologically high intraocular pressure	tested by Zynerba Pharmaceuticals Inc.	[186,187]
Transdermal	stimulus-responsive chitosan/ZnO nanoparticles for transdermal absorption of CBD	epilepsy	delivery system was tested in vitro for drug release properties and cytotoxicity	[188]
	microemulsion containing THCA and CBDA	increased penetration through the skin in various disease models	tested in vitro for permeation improvement	[189]
	CBD emulsions stabilized with chitosan/collagen peptides nanoparticles	cosmetic applications	in vitro testing demonstrated that particle is able to penetrate the stratum corneum and diffuse into deeper layers of the skin	[190]
Transmucosal (oral)	oral formulation containing one or more cannabinoid–micelle encapsulation	Alzheimer’s disease, neuropathic pain, Dravet syndrome, Lennox–Gastaut syndrome, myoclonic seizures, juvenile myoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms, tuberous sclerosis complex, West syndrome, anxiety	not tested in vivo	[191]
	oral formulation containing one or more cannabinoids formulated as encapsulated micelles in the form of mucoadhesive gel, tablet, powder, liquid gel capsule, oral solution, granules, extrudates		tested in vivo on dogs by GW Research Limited (GB)	[192]
	oral formulation comprising a combination of at least two cannabinoids (THC or analogies and CBD or analogues)—in the form of mucoadhesive gel, tablet, powder, liquid gel capsule, oral solution, granules, extrudates	pediatric epilepsy	tested in vivo on dogs by GW Research Limited (GB)	[193]
	CBD or another cannabinoid conjugates	cancer	tested by Diverse Biotech Inc.	[194]
	TurboCBD™ delivery technology capsules	increasing circulating CBD in various disease	pharmacokinetic profile in a double-blinded, placebo-controlled, cross-over study on 12 healthy volunteers	[195]
	Canemes®—solid self-emulsifying pharmaceutical compositions comprising CBD and THC combination	pain-relieving drug	not tested in vivo	[196,197]
	Canemes®—cannabinoids chewing gum containing CBD/ CBDV/ THC/ CBC/ CBG combined with other compounds.	multiple sclerosis-related pain and spasticity, Parkinson’s disease, dementia, restless leg syndrome, and post-herpetic neuralgia	not tested in vivo	[198]
Transmucosal (oral)	Canemes®—CBD in the self-emulsifying delivery system	increases bioavailability in various disease	bioavailability tests in human	[199,200]
	Canemes®—cannabinoid derivatives and conjugates	acute and chronic pain	not tested in vivo	[201]
	Canemes®—CBD cyclodextrins; cannabinoids with sulfo-alkyl-β-CD	pain, Parkinson’s disease	clinical trial	[202,203]
	BRCX014—CBD with poloxamer 407, carboxymethyl cellulose, and starch	various disease	not tested in vivo	[204]
	BRCX014—CBD sublingual formulation	cancer treatment	not tested in vivo	[108,205]
	BCT-521—Combination of CBD and THC	pain management with cancer patients, Fibromyalgia, symptom relief in patients with advanced cancer	not tested in vivo	[205]
	ZYN001—synthetic D-glyceric acid ester prodrugTHC encapsulations in multilayered lipid vesicles	fibromyalgia and neuropathic pain pain treatment	not tested in vivo	[182]
Transmucosal (nasal)	nasal pharmaceutical product containing CBD plus other cannabinoids for topical application in the nasal cavity	schizophrenia	CBD+THC formulation tested on healthy volunteers	[206]
Transmucosal (pulmonary)	Canemes®—cannabinoid derivatives and conjugates	acute and chronic pain	not tested in vivo	[201]
	CBD mucoadhesive nanostructured lipid carriers	neuropathic pain	tested in vivo on mice model of neuropathic pain produced a better antinociceptive effect than oral or nasal administration of simple CBD oil	[207]
	Canemes®—cannabinoid derivatives and conjugates	acute and chronic pain	not tested in vivo	[201]
Trans-corneal	CBD-loaded mixed polymeric micelles of chitosan	degenerative and inflammatory disease of the eye	tested in vitro on human corneal epithelial cell line	[208]
Transmucosal (rectal)	CBD stable nanosized transfersomes as a rectal colloid	various diseases in which CBD has proven efficacy	tested in vivo for CBD release and nanoparticle delivery through the rectal membrane	[209]

Open in a separate window

Abbreviations: MLVs, multi-layered lipid vesicles; THC, tetrahydrocannabinol; CBD, cannabidiol; THCA, tetrahydrocannabinolic acid; CBDA, cannabidiolic acid; CBDV, cannabidivarin; CBC, cannabichromene; CBG, cannabigerol.

 

2.2.2. The Use of Nanotechnologies for Cannabinoid Transdermal Administration

The field of cannabinoid research is expanding its boundaries more and more. The understanding of the pharmacology of these compounds and the knowledge of their beneficial effects in the treatment of pain, post-chemotherapy emesis, neuropsychiatric conditions, and dermatological conditions, in particular, stimulated researchers to address topics related to optimal formulations. Theoretically, the most promising formulations, which exceed the limitations imposed by the physico-chemical characteristics of cannabinoids, mentioned above are those that allow their administration on the skin [154]. Among these skin administration methods, we focus on those based on nanotechnology, that have, as observed in Figure 4, better penetration through skin layers than conventional formulations.

Figure 4

The passage of substances through the layers of the skin depending on the way they are formulated. SLN, solid lipid nanoparticles; NLC, nanostructured lipid carriers.

These formulations include but are not limited to lipid-based nanocarriers (liposomes, nanostructured lipid carriers, and solid lipid nanoparticles) and vesicular nanocarriers (niosomes, liposomes, transferosomes, ethosomes, and transethosomes) [210].

Due to the high lipophilic nature of cannabinoids, creams are one of their topical administration systems with multiple advantages. The topical application of cream containing CBD and CBD:THC in various proportions allowed a reduction in the symptoms of epidermolysis bullosa simplex and psoriasis [211,212].

However, creams incorporating cannabinoids have their limitations. To increase the stability of active substances, it is necessary to ensure a slightly acidic pH. CBD, for example, degrades at pH = 6 and pH = 7. In addition, increasing the stability of the cannabinoid using alcoholic formulations, as required by the physico-chemical characteristics of these compounds, is not recommended for applications to the skin, especially in dermatological conditions [174,213]. In addition, light and temperature must be controlled so that the product can keep the properties for which it was created [91].

Another delivery system for cannabinoids through the skin, with a series of improved characteristics compared to oils and creams, is to use gels. From a mechanistic point of view, gels allow the deep penetration of cannabinoids through the skin for a systemic effect. It is interesting that researchers have tried to apply different techniques to obtain constant and controllable concentrations of cannabinoids in the plasma. In this sense, in a study on a rat model of arthritis, the gel containing CBD reduced the associated inflammation, limb posture score, and thickening of the synovial membrane in a dose-dependent manner [214].

Advanced research has allowed the improvement of these forms of administration so that both gels and creams have been proposed to improve their characteristics using nanotechnology. Thus, improving the contact time with the skin, producing a uniform dispersion of the active substance, increasing the stability and bioavailability of the active substance, and high penetration through the skin are some of the qualities of the formulations improved by nanotechnology [215].

Nanoemulsion is “a system of water, oil, and amphiphile, which is a single optically isotropic and thermodynamically stable liquid solution” [216]. This type of emulsion is a formulation option that is suitable for both lipophilic and hydrophilic substances [217]. The advantages of nanoemulsions include reduced toxicity, the ability to be administered by various routes (topical, transdermal, parenteral, and others), and an increase in the stability of incorporated active substances [215,217]. Using this release system, numerous pharmaceuticals, including analgesics, anti-inflammatories, antidepressants, anti-anginal, anti-psychotics, and anti-cancer agents, have been researched and developed [217]. Recently, nanoemulsions significantly improved the skin penetration capacity of THCA and CBDA cannabinoids. This transdermal release system potentiated the stability, permeation rates, and solubility of cannabinoids. Thus, these promising results propose nanoemulsions as a strategy to improve the stability of cannabinoids in dermal formulations [189]. On the other hand, although promising, this drug delivery system also presents a series of disadvantages. The realization of nanoemulsions requires a series of special formulation techniques, which involve considerable financial efforts. In addition, there is scientific evidence that confirms a potential disruption of the integrity of the lipids of the corneous layer of the skin, a disadvantage generated by substances that further enhance the permeation of the active substance through the skin [215]. Despite these drawbacks, the research field of nanocarriers continues to develop. Thus, other nanoparticles are created, such as liposomes, to improve drug delivery skin systems.

One or more lipid layers that incorporate an aqueous phase structurally form nanoparticles called liposomes. These vesicular nanocarriers have the advantage of allowing both the topical and transdermal administration of drugs. In addition, liposomes allow the controlled release of the active substance [215]. According to some researchers, by having a higher skin deposition than other delivery systems, liposomes have superior properties relative to oil-/water-type emulsions and solutions [218].

From a mechanistic point of view, liposomes improve the topical administration of drugs by acting as a rate-limiting barrier, which prevents systemic absorption where this is not desired. Additionally, by improving the flexibility of liposomes with the help of surfactants and adding elastic lipid bilayers, these nanocarriers can serve for the transdermal administration of drugs with promising results [219]. At the same time, this delivery system allows the incorporation of highly lipophilic substances, such as cannabinoids. A recent study on an experimental canine model of chronic pain tests the subcutaneous administration of CBD in the form of liposomes. This study demonstrates that liposomal CBD produces qualifying CBD plasma concentrations that are maintained over the tested period (28 days) [220]. Accordingly, liposomes can become a successful method of administration for cannabinoids in the future due to their proven analgesic effect. However, there are also disadvantages with respect to the use of these nanocarriers. These formulations can determine the systemic absorption of active substances through the shunt or follicular pathway. Thus, there is a risk of systemic adverse reactions. In addition, the high costs of the preparation technology used and certain stability problems can create difficulties in the clinical expansion of these types of formulations [219,221].

Solid lipid nanoparticles (SLNs) are lipid nanoparticles that are known for their low toxicity, ensuring biodegradability and biocompatibility for drug delivery. In addition, via topical administration, these systems potentiate the penetration of active substances through the SC of the skin, ensuring a uniform, homogeneous administration and increased adhesiveness. On the other hand, these systems have the disadvantage that they can lead to drug deposits in certain areas of the body where they were administered. The desired drug deposits, which have therapeutic importance, are at the level of hair follicles and sebaceous and sweat glands [215]. These nanocarriers are superior to nanoemulsions and are suitable candidates for the incorporation and topical administration of highly lipophilic drugs [222].

On the other hand, nanostructured lipid carriers (NLCs) are a form of nanoparticles with improved properties compared to SLN. These nanocarriers are made up of a mixture of solid and liquid lipids. These nanoparticles show promising results for topical administration. They form small-sized particles, have superior adhesion power at the level of the SC, increase the bioavailability of drugs, and improve the hydrophilic properties of the active substances. Compared to SLNs, NLCs have improved occlusive properties [223,224]. Unfortunately, the evidence for the effective transdermal administration of NLC is insufficient and inconclusive [225]. Cannabinoids have been studied in the form of NLC. For example, the intranasal administration of CBD in the form of NLC improved antinociceptive effects in chronic neuropathic pain induced by chemotherapy in a murine model. This effect was more potent for NLC compared to the CBD solution [207]. Additionally, in a recent in vitro study, it was shown that the photostability of cannabidiol extracts can be improved by their encapsulation in nanostructured lipid carriers (NLCs). In addition, in the same study, the authors managed, using this type of nanoformulation, to potentiate the anti-inflammatory activity of cannabidiol at this level [162].

In summary, drug delivery systems that use nanotechnologies present both pros and cons. Even so, lipid-based nanotechnologies are intelligent drug delivery systems and are promising for the administration of cannabinoids on the skin for topical and transdermal action.

3. Future Perspectives on the Transdermal Delivery of Cannabinoids

The undeniable development with respect to increasing cannabinoid bioavailability, whether natural or synthetic, has increased their potential of being introduced into therapy, with the ultimate objective of increasing bioavailability and efficacy and lowering toxicity and/or adverse effects. However, as the research study’s findings indicate, highlighted in Section 2 of the current work, such studies need to continue to provide feasible solutions to the issues that scientists in the field are still facing, and these issues are as follows: (i) most cannabinoids have harmful and/or psychoactive effects when administered systemically; (ii) the need for extending the pain-relieving effect; (iii) the poor ability of cannabinoids within topical formulations to cross all skin layers; (iv) overcoming the legal issues associated with the use of these substances for therapeutic purposes.

Cannabinoid study has become a mainstream discipline as a result of the growing interest in the use of cannabinoids in pharmaceutical formulations, which show promise in the treatment of a number of diseases. These studies revealed a couple of key concepts that need to be considered when designing or optimizing novel pharmaceutical formulations with the purpose of enhancing cannabinoid transport. These concepts will be further discussed in more detail. Using cannabinoid compounds with no affinity for CB1 receptors from CNS (central nervous system), which drastically limits the selection of effective solutions, or formulating them so that they cannot cross the BBB are two practical ways to avoid the psychotropic action of cannabinoid compounds. Another interesting perspective in order to avoid the psychotropic effects of common cannabinoids is represented by the design and synthesis of dualsteric/bitopic ligands that are able to selectively target CB2 receptors versus CB1, as Gado et al. reported [226].

When released into the bloodstream, cannabinoids have the ability to cross the BBB, where they will exert their undesirable effects on the CNS. The topical formulations of such substances may thus offer a unique alternative to avoid their binding to CB1 receptors at the central level by employing the structures of the epidermis as a reservoir for cannabinoids. This paradigm is obviously particularly important, as it prevents the rapid release of a large amount of substance into the bloodstream with the detrimental consequences already mentioned, but it is equally important to develop formulations that enable the controlled release of the active ingredient from these deposits as a way to extend the duration of the expected effect.

Pharmaceutical formulations for external application need to ensure effective transdermal delivery of the therapeutically relevant substance. In this regard, the oil–water partition coefficient, logP, which describes the degree of lipophilicity of a molecule or molecular assembly [227,228], is of particular interest, along with other physicochemical properties, including the melting point, aqueous solubility, pKa, and molecular weight (Mw). In order to be able to penetrate through the skin’s layers, particularly the SC, the optimal log P value of a chemical entity should be within the range of 1–3 [229,230]. Consequently, transdermal formulations of cannabinoids should reduce their log P from values of 6–7 to those within the optimum range.

As revealed in Section 2.1, the ongoing research with respect to obtaining appropriate solutions for the use of cannabinoids for therapeutic purposes has resulted in the development of a wide range of formulations, with each one having its advantages and disadvantages. The most promising outcomes from the perspective of therapeutic efficacy which don’t cause significant discomfort for the patient and at a competitive production price, should serve as a basis for the further development of technologies envisioned for introduction the of new cannabinoid therapeutic agents into the clinic. Nanotechnology allowed the encapsulation of cannabinoids in nanocarriers, improving their physical–chemical stability and bioavailability while also preventing degradation. In this regard, several nanotechnology-based formulation strategies have been developed, of which lipid-based nanoparticles have proven to be the most attractive for transdermal delivery. As shown in Figure 4, such formulations can be tailored in various approaches, and these range from simple micro- or nanoemulsions to complex architectures, such as liposomes, solid lipid nanoparticles (SLNs), lipid nanocapsules (LNCs), or self-emulsifying drug delivery systems (SEDDS) [22,231]. Despite the fact that they exhibit obvious benefits over conventional topical formulations, typical liposomes are believed to be unsuitable as transdermal delivery systems of drugs. Unmodified liposomes have been retained in the SC because of their rigid structure, which prevents diffusion into the deeper skin layers. In addition, the use of regular liposomes is limited by their poor stability, poor encapsulation efficiency, and decreased loading capacity [232]. To develop an innovative class of liposomal formulations with enhanced properties, several approaches have therefore been evolved, with one of them being focused on deformable liposomal formulations including transfersomes, ethosomes, invasomes, mentosomes, and niosomes. Ogunsola and colab. have depicted a method for the preparation and characterization of flexible liposomes, also named transfersomes, and they are able to pass through the small intercellular spaces between SC cells (20–40 nm) [233]. This study has established the dependence between the degree of skin permeability and the ratio between phosphatidylcholine (PC) and Tween 80 (a non-ionic surfactant), the main constituents in the composition of the liposomes prepared by the research group. To be included in transdermal formulations, future research should focus on optimizing the preparation method of this type of liposomes to counteract their main weaknesses, such as instability against oxidative degradation [234].

Sermsaksasithorn and colab. have approached the transdermal administration of CBD from Cannabis sativa with the help of a transdermal patch, aiming to alleviate the effect on psoriasis, within a randomized double-blind controlled trial [235]. The authors thought out the benefits of employing transdermal patches, which are similar to those of any other transdermal delivery system; however, the patches also provide better dose control. The most suitable substances for such delivery systems are lipophilic molecules with low molecular weight, and they also have lower melting points and higher volatility, characteristics associated with excellent skin penetration and relatively simple formulation [236]. Isaac and Holvey emphasized the impact of using transdermal patches in psychiatric medication, through which the legal concerns of the use of drugs with psychotropic action are overcome, preventing the possibility of drug abuse and facilitating the least restrictive affordable administration of prescribed medication as well. From an economic point of view, the cost of a transdermal formulation, particularly in the form of patches, has always been a subject of debate as the costs are much higher compared to the same treatment administered orally.

Nevertheless, the formulation of cannabinoids with the help of nanotechnology, along with many other drugs, is in continuous progress, allowing unique solutions to numerous challenges that would otherwise have remained unsolved. Future strategies in the field should provide at the same time accessible, reproducible, and cost-reduced solutions.

4. Conclusions

Cannabis-based products intended for administration on the skin should be developed by keeping the final target of the pharmacological action of compounds in mind. On one hand, those that target local actions in the upper layers of the skin can be formulated as conventional topical formulations (creams, gels, or ointments) by simply incorporating the compounds or natural extracts in the formulation’s base. On the other hand, for systemic actions, advanced transport systems that allow passage through all skin layers into systemic circulation should be developed.

Studies focusing on major dermatologic pathologies assess the potential of cannabinoids as a therapeutic alternative to conventional treatments, not only underlining their efficacy but also their good safety profile. Topical formulations containing natural cannabinoids have shown local analgesic, antipruritic, anti-inflammatory, cicatrizing, or antibacterial actions, demonstrating their benefits in the treatment of conditions such as psoriasis, atopic dermatitis, allergic contact dermatitis, eczema, lichen simplex, varicose ulcer, or epidermolysis bullosa. For millennia, the traditional use of natural cannabinoids has provided empirical evidence that they may have considerably fewer adverse events than current synthetic pharmacological agents. Because they are of natural origin, phytocannabinoids circumvent the drawbacks of synthetic compounds, which require significant resources both for production and for the removal of byproducts or solvents that are typically toxic or have undesirable effects. For these formulations, developing standardized products with an exact content of cannabinoids or standardized Cannabis extracts is required, and they should be clinically tested.

The treatment of conditions that involve the modulation of specific receptors, whether they are endocannabinoid receptors or other types of receptors, requires advanced processing to allow the systemic absorption of cannabinoids. In an attempt to develop such an advanced cannabinoid transport system, it would be ideal to consider the following aspects: (i) Only compounds of known purity can be used to prepare advanced delivery systems, while the active principle content from formulations based on plant extracts is difficult to optimize; (ii) the methods of loading active compounds need to be optimized to obtain precisely dosed products that release a well-defined quantity of the substance; (iii) controlled release systems that can maintain an effective plasma concentration as long as possible should be developed; (iv) cannabinoids exhibiting psychotropic effects should be preferably encapsulated in certain transport systems that prevent their passage through the BBB, and only peripheral CB receptors should be modulated; (v) production technologies have to be improved to circumvent excessively high costs that limit the access to such products.

Abbreviations

Funding Statement

This work was supported by a grant from the Ministry of Research, Innovation, and Digitization, CNCS/CCCDI—UEFISCDI, project number PN-III-P4-ID-PCE-2020-1247, within PNCDI III.

Author Contributions

Conceptualization, W.B., B.-I.T., A.-N.N., C.M.U. and S.-I.F.; writing—original draft preparation, S.-I.F., W.B., B.-I.T., A.N.N., C.M.U., L.-E.F., I.M.T., A.N.B., M.F.H. and V.P.; supervision, W.B., B.-I.T., C.M.U. and A.-N.N. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Footnotes

References