Lipid carriers are interesting for the transport of lipophilic drugs and, to some extent, hydrophilic drugs [18,49]. Some limitations of specific lipid carriers commonly investigated, such as nanoparticles produced only from solid lipids, and also nanostructured lipid carriers, include their low capacity to incorporate hydrophilic drugs due to the effects of stability during the production process. Only poorly water-soluble drugs can be conveniently incorporated into the solid lipophilic matrix. To overcome this limitation, lipid-drug conjugates have been developed, and up to the present loading capacities of up to 33% have been achieved [50,51]. The first search on cannabidiol and lipid nanoparticles resulted in the bibliometric map shown in Figure 2, showing the high amount of work done in the field of drug delivery and drug formulation for a range of applications (e.g., antidiabetic, anticancer, and anti-inflammatory actions, for multiple sclerosis and Alzheimer’s disease), including in clinical trials.

When compared to other lipid carriers (e.g., solid lipid nanoparticles and nanostructured lipid carriers), lipid-drug conjugates can exceed the minimal loading capacity for hydrophilic drugs, typically below 0.5% [52,53]. This is sufficient for highly potent peptides and proteins, such as eosinophil peroxidase (EPO) and interferons, as these can be solubilized in the fused lipid matrix, using mixtures of surfactants or acyl and diacylglycerols present in the lipid [49]. Lipid-drug conjugates have numerous advantages, namely: (i) protection against enzymatic and chemical degradation of drugs [50]; (ii) an increase in the lipophilicity of the hydrophilic compound [49,50,54]; (iii) easier passage through the blood–brain barrier [50]; (iv) an increase in the load capacity for hydrophilic drugs [49,50,54]; (v) increased stability in vivo, reducing solubility and subsequently accessibility by enzymes [49,51]; and (vi) an improvement in the permeability of the lipophilic molecule across membranes [51,55].

The principle of lipid-drug conjugates lies in transforming drugs with hydrophilic characteristics into a more lipophilic and consequently a more insoluble molecule by conjugation with a lipidic compound (Figure 3) [49]. Thus, the conjugation can be carried out by forming a salt with a fatty acid, for example, the reaction of the functional groups of the drugs with the carboxylic groups of the fatty acids [51,54] or alternatively by covalent bonding (for example, ether, ester) [49,51].

Obtaining the formulation of cannabidiol-loaded lipid nanoparticles is difficult because of the low water solubility of CBD. However, several studies have already proven the successful and efficient production of CBD-high-loaded lipid carriers for parenteral or oral application. Lipid carriers allow parenteral administration in therapy with CBD, which could be of interest due to the broad field of pharmacological effects. Francke et al., (2021) [43] have shown that a higher drug loading in emulsions and self-dispersing mixtures than in liposomes emphasizes an advantage of oil-containing carrier systems for CBD formulation. For oral therapy, phospholipids as natural emulsifiers and solubilizers can generate self-dispersing lipid formulations. Due to mild agitation, these formulations can be filled into hard capsules and dispersed in gastrointestinal fluids [43]. Figure 4 shows that cannabidiol has been reported for skin infection and the treatment of acne vulgaris, in combination with other synthetic drugs, and also formulated as lipid nanoparticles to improve its bioavailability.

The poor bioavailability of drugs, when administered topically, is mainly due to two reasons: (i) low dissolution rate and (ii) poor permeability [16,49,51,54,56]. This can be explained by the Noyes–Whitney Equation, which describes the dissolution rate (dc/dt), which is proportional to the concentration gradient (cs − cx/h), where the cs factor is the total concentration of drugs in the liquid (solubility saturation). The h factor is the diffusion distance above the surface of the drugs particle. The dissolution rate is given as a function of the surface area: where D is the diffusion coefficient and A is the surface area. The higher the stirring speed in the dissolving medium, the lower the value of h and, consequently, the higher the dissolving rate of the drugs. The ideal situation is when h tends to zero and, simultaneously, dc/dt tends to infinity (Figure 5) [57,58].

To obtain lipid-drug conjugates, drugs are added to an aqueous solution with an excess of sodium hydroxide. Subsequently, a precipitate forms, which is filtered through a filter paper and then washed three times with water suitable for injections. Then, it is dried at 40 °C and stored at 4 °C. The fatty acid salts of drugs are prepared by dissolving this and the fatty acids (e.g., oleic acid and stearic acid) in an appropriate solvent and consequent solvent evaporation under reduced pressure. The formulations obtained, i.e., the conjugates, are dried for 24 h [54,59]. Another method of obtaining lipid-drug conjugates includes high-pressure homogenization. Fatty acid vesicles with drugs are prepared by dispersing the residue in a surfactant (i.e., Tween^®80) [50,54] containing glycerol, forming a pre-dispersion. This pre-dispersion is subject to homogenization at high pressure, comprising 20 to 27 cycles at a pressure of 1500 bar. Some authors [50] argue that after five cycles, the samples should be placed on ice to avoid the high temperatures—temperatures well above 40 °C—of the dispersion.

Lipid-drug conjugates have been widely used for brain therapy, specifically in treating sleeping sickness caused by Trypanosoma brucei gambiense [50,54,59]. Currently, no products are available that use this technology for cutaneous application. However, this methodology presents a therapeutic advance, a new approach to transport hydrophilic drugs in a lipophilic medium, as is the case of the skin structure. Some factors that may justify the non-exploitation of this methodology at the top level may be:

• The traditional pharmaceutical formulas (e.g., creams and ointments) have responded to different pathologies as much as possible;
• Unlike many other structures and organs, the skin’s composition allows a broad absorption of hydrophilic and lipophilic drugs;
• Simply the development of other transport mechanisms, such as the phospholipid micelles.

However, if developed for a cutaneous application, this therapeutic approach would present numerous advantages: (i) bioavailability; (ii) the use of biocompatible lipids, which would lead to more significant bioavailability; (iii) the ability to deliver hydrophilic drugs to more lipophilic compartments of the skin’s constitution; (iv) a decrease in the number of drugs used; and (v) more excellent protection for drugs from degradation agents. Therefore, this therapeutic approach presents several relevant and promising aspects for a future, possible cutaneous application [49,55,56].

Micelles are colloidal dispersions (i.e., vesicles of size comprised between 10–100 nm) of amphiphilic nature; their composition is simultaneously a lipophilic portion (nucleus) and a hydrophilic portion (outer surface). These vesicles are currently used to transport lipophilic drugs, among other functionalities (Figure 6).

Micellar technology was introduced in the last decade of the 20th century [60]. Subsequently, scientists developed Novavax^®, patenting micelle technology and, later, launched the first nano-product of transdermal lotion (Estrasorb^TM) in 2003 [48]. Compounds used in Estrasorb^TM are generally recognized as safe (GRAS) as micellar vesicles are formulated based on nanotechnology that achieves an advance in transdermal therapy. The formulation represents a robust and a versatile delivery system, accommodating a range of therapeutic composts with different physical–chemical properties [60,61,62,63,64,65]. As micellar vesicles, in the form of emulsions (lotions), are attractive alternatives for delivering bioactives through topical application. The technology allows high concentrations of drugs to penetrate the skin, and it functionally creates a deposit of drugs in the stratum corneum and epidermis, avoiding the first passage effect [11]. These two formulations could be exploited for the transdermal delivery of cannabidiol.

Due to the formation of micelles and driven by the reduction of free energy in the system, the removal of two hydrophobic fragments from the aqueous environment consequently results in a network of hydrogen bonds in water. The hydrophobic fragments of the amphiphilic molecule form the nucleus of a micelle, while the hydrophilic components constitute the outer surface of the micelle [11,15]. In general terms, in the formation of phospholipid micelles, the formation of a multiphase nanoemulsion occurs (hydrophilic and lipophilic portion simultaneously). In this sense, there are five essential components for the construction of phospholipid micelles, namely (i) drugs; (ii) the solvent; (iii) a surfactant; (iv) phospholipid, and (v) the aqueous medium. When these compounds are added and subjected to a homogeneous mixing process, the drugs can have one or more conformations (Figure 7): (a) solid particles; (b) drugs associated with the micelle; (c) drugs associated with the oil; and/or (d) solubilized (micro/nanoparticles).

Although micellar technology can preferentially accommodate crystalline compounds, surprisingly, it can also be used for amorphous compounds. The formed micellar system can also accommodate poorly soluble drugs. Depending on the physical–chemical properties of the drugs and the dosage requirements, the load capacity that can be achieved through this system is up to 20% [66,67].

The solvent is generally used to assist solubilization of the drugs during processing, although it is not a prerequisite. The typical solvent used in the preparation of phospholipid micelles is ethanol. In addition, stable micelles can be obtained through other solvents, such as propylene glycol, low molecular weight polyethylene glycol, triacetin, and N-methyl pyrrolidinone. The solvent plays an essential role in controlling the solubilized fraction of drugs, critical for facilitating drug permeability. The stabilizers used are generally non-ionic. Stable micelle preparations have been prepared using hydrophilic and lipophilic stabilizers that encompass a range of products with an appropriate hydrophilic-lipophilic balance (HLB) [68]. Surfactants include sorbitan esters, glycerol esters, block copolymers, polyethylene glycol esters, and ethoxylated fatty esters. Surfactants help stereochemically stabilize oil droplets and contribute to the formation of the micellar phase [11,14,15,66]. Table 3 describes some phospholipids used to form micelles and the final particle size. The lipids are from the internal phase of the micelle. Depending on the properties of the drugs, the lipophilic phase can accommodate a fraction of the drug’s insoluble form. The aqueous medium used is generally purified water. A buffering agent can be included to maintain the pH and to maximize the stability of the drugs. The phospholipid micelles are dependent on therapeutic need as well as the physical–chemical properties of the drugs, the intended site of action (local or systemic), and the profile of the target product. For topical or transdermal administration, the micellar system can be classified as a type of micro-reservoir system of controlled dissolution that can be adapted for the release of drugs topically (where the site of action is the skin) or transdermally (systemic availability). The physical–chemical properties of the formulation can be adapted, depending on the type of administration intended [69].

The composition of a phospholipid micelle formulation is inherently antimicrobial. According to the results of the United States Pharmacopeia (USP) antimicrobial efficacy tests for a placebo formulation of phospholipid micelles, it indicates that the micellar formulation not only impedes bacterial growth but essentially presents microbicide activity. This can be attributed to the small size of the preparation (in the order of nanometers) and the nature of the composition (that is, the high concentration of non-ionic surfactant). However, a micellar formulation exhibits a good safety profile, and it is relatively dermatologically a non-irritant [11]. This property offers commercial advantages such as the possible elimination of an antimicrobial preservative (especially for a product packaged in a multidose container), or the possible synergy of the microbicidal effect of a micellar preparation when prepared with an antibacterial, antifungal, antiviral agent [11].

Transdermal administration involves the application of a pharmacologically active compound on the skin to reach the systemic circulation to reach the site of action, often away from the site of application. Since the approval of the first transdermal delivery system for drugs in 1981, Transderm-Scop^®, there has been intense research in the field of transdermal therapy for the treatment of a variety of clinical conditions [70]. Transdermal administration is particularly advantageous for drugs with a significant hepatic first-pass effect or degradation in the gastrointestinal tract.

Although lately there has been a good development of formulations at the transdermal level, there is still a low point of innovation about the vectorization and delivery of drugs at the top level [66,67]. Most dosage forms are limited to traditional creams, ointments, and gels. Some of the new commercial applications are sprays and foams. Phospholipid micelle technology can be exploited to create better dosage forms at the top level, guaranteeing efficient and effective delivery of drugs locally (at the application site). It is possible to adapt a drugs deposition, disposition, and permeability kinetics through formulation engineering (altered composition, drug charge, particle size, among others). The ever-growing interest in CBD’s health-promoting bioactivities and the benefits of lipid nanoparticles and lipid particles as delivery systems to overcome the low bioavailability of CBD has advanced in recent years. This led to the registration of various patented works for applications of CBD for skin care as well as formulations to deliver the active ingredient. In Table 4 we present several examples of patents within this scope.