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 . 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. , 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 . 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 .
Ethosomal carriers are mainly composed of phospholipids, (phosphatidylcholine, phosphatidylserine, phosphatidic acid), with a high concentration of ethanol and water . An ethosomal formulation for CBD, which consisted of 3% CBD and ethanol in a carbomer gel, has been prepared by Lodzki et al. , 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 [96,97,98]. The gel is designed to be applied once or twice daily. Permeation profiles of a range of formulations have also been reported .
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 . 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 , while a patent by Weimann has more recently focused on CBD delivery . 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%) . 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 .
Jackson et al.  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 .
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. . 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 extract .
In order to complete this overview of topical CBD, we should note that CBD exerts interesting sebostatic and anti-inflammatory effects on human sebocytes , (data obtained from in vitro evaluations). Indeed, CBD has been shown to inhibit the proliferation of hyperproliferative keratinocytes , and to possess remarkable antibacterial activity . 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 . 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 . 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 , coating with polysaccharides , 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 . An interesting work on the limitations, opportunities and concerns in this field has recently been published by Park . 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 . 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.
|Type||Constituents||Drug||Size (nm)||Encapsulation Efficiency||Application||Development Stage||References|
|Lipid-based||liposomes||DPPC, cholesterol||THC||300–500||0.3 mg/mL||i.v.||Pharmacokinetics|||
|micelles||PC, PE plus phospholipids||Terpenes, hemp oil||n.d.||Stability evaluations|||
|micelles||Polyethoxylated castor oil, glycerol||Cannabis oil||100||n.d.||oromucosal||Clinical trials||[119,120]|
|NCL||tristearin/tricaprylin 2:1||Cannabinoids||100||high||Formulation study|||
|NCL||Cetyl palmitate or glyceryl dibehenate||THC||200||n.d.||nasal||Preclinical studies|||
|NCL||Glyceryl dibehenate or glyceryl palmitostearate||CB-13||120||99%||oral||Preclinical studies|||
|PNL||PTL401||THC CBD 1:1||<50||99%||oral||Preclinical studies|||
|PNL||PTL401||Plus piperine||<50||99%||oral||Clinical trials||[131,132]|
|Polymeric-based||PLGA||plus coating agents||CB-13||253–344||85%||oral||Preclinical studies|||
|PLGA||plus coating agents||THC||290–800||96%||oral||Preclinical studies|||
NCL, nanostructured lipid carrier; PNL, pro-nano-liposphere; PLGA, poly(lactic-co-glycolic acid); PCL, Poly-ε-caprolactone; PC, phosphatidylcholine; PE, phosphatidylethanolamine; EE = encapsulation efficiency calculated as (total drug added-free non-entrapped drug) divided by the total drug added; PLT401 is a proprietary formulation containing polysorbate 20, sorbitan monooleate 80, polyoxyethylene hydrogenated castor oil 40, glyceryl tridecanoate, lecithin and ethyl lactate; n.d., not defined.
3.5.1. Lipid Carriers
Although liposomes are one of the most frequently studied and used market-approved drug delivery systems , 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 . 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. . 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 [119,120].
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 . 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 . 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 . 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. .
Lipid nanoparticle formulations have been also reported, by Duran-Lobato et al. , 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 . 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 . Products, such as Sandimmune® Neoral (cyclosporin A), Fortovase® (saquinavir) and Norvir® (ritonavir), have confirmed the value of this approach . 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 . 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).
Micro and nanoemulsions of active annabis ingredients (cannabinoids and terpenes) have also been presented in a patent , 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) .
An excerpt from- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222489/