**2.2 Lipid-based formulations**

Delivery systems with lipid-based formulations are mainly of three types—liquid, solid, and lipid as colloidal carriers (liposomes). The liquid formulations are emulsions or micro-emulsions, self-emulsifying or self-nanoemulsified drug-delivery systems, and solid in oil suspensions. The solid lipid-based systems include solid-state micro-emulsions, solid self-emulsifying drug-delivery systems for dry emulsions, microspheres, nanoparticles, and suppositories. The incorporation of the drug to the matrix or shell-core of the solid lipid nanoparticle relies on the composition and the preparation mode of the formulations [7].

The different types of lipid-based nanocarriers are solid lipid nanoparticles (SLNs), liposomes, lipid-drug conjugates, lipid nanocapsules (LNCs), and nanostructured lipid carriers. Nanocarriers fabricated using lipid biomolecules show low *in vivo* toxicity and are subject to parenteral, oral, transdermal, intranasal, and ocular administration.

SLNs are stable in biological fluids and offer a good therapeutic alternative—their size is between 80 and 100 nm, they are more efficient than polymeric nanoparticles, and have the advantage of being able to be prepared from non-toxic physiological lipids, habitually used as excipients. In Ref. [7] the authors present various advantages compared to other colloidal carriers, such as controlled drug release and targeted therapy; and they protect encapsulated compounds from degradation. Their nature is very versatile and they can be applied in chemotherapy. The solid matrix forms an o/w emulsion, it is formed by well-tolerated lipids, and it allows for the incorporation of hydrophilic and/or hydrophobic drugs. The amount of encapsulated active

compounds ranges from 1 to 5% for hydrophilic compounds and reaches 80% for lipophilic ones [16]. The lipids used as the coating can increase bioavailability, they help drug release and protect from water permeability. SLNs are most useful for the oral administration of drugs and vitamins that can solubilize in a lipid medium [17]. They have a lower cost than synthetic polymers, than PLGA for instance, and besides, can bind PEG as ligand [7].

LNCs are hybrid structures between polymeric nanoparticles and liposomes. Their size is small (between 20 and 100 nm), they are very stable, biodegradable and biocompatible, easy to manufacture, they can accommodate one or two drugs together, which can be released in a sustained manner. They show an oily liquid core surrounded by a solid or semisolid hydrophobic shell made of solid lipids and emulsifying agents. They are prepared through micro-emulsification or high-pressure homogenization. The principal components are oils, a lipophilic surfactant, and a non-ionic surfactant. Usually, fatty alcohol or acids; steroids or waxes; mono, di, or triglycerides; and phospholipids are employed [2, 18]. Triglycerides used as excipients, such as caprylic acid (Labrafat®), lauric acid, palmitic acid, oleic acid, and behenic acid, present different chain lengths; mixed glycerides and polar oils like sorbitan trioleate (span 85), and oleic acid, are also used as emulsifying agents. Vegetable oils obtained from castor, soybean, olive, argan, eucalyptus, orange, and sesame are also being tested. Lecithin obtained from egg, soybean, rapeseed, sunflower, and lysolecithin is used as a lipophilic surfactant and is available as Lipoid® and Phospholipon® brands. Phospholipon® is a mixture of nature hydrogenated lecithin and phospholipids. On the other hand, ethanol, glycerol, propylene glycol, and PEG, as well as water-soluble and insoluble (non-ionic) surfactants are used as cosolvents to improve solubility. Water-soluble surfactants have HLB numbers of 12 or more and are, for example, alkyl ether ethoxylate, cremophor RH40 and RH60 (ethoxylated hydrogenated castor oil); and water-insoluble ones have values of HLB from 8 to 12 and can adsorb on the oil-water interface, such as polyoxyethylene and sorbitan trioleate (Tween-85). Finally, anti-oxidants like α-tocopherol, β-carotene, propyl gallate, and butylated hydroxytoluene are added [7, 18]. Among hybrid lipid-polymer nanoparticles (LPNs) are polymer-core lipid shell nanoparticles, formed by a polymer inside the core that is surrounded by one or more membrane-like lipids. The space between the polymer and the lipid is filled with water or aqueous buffer. The core polymer delays drug delivery and favors lipid stability. It is possible to encapsulate lipophilic drugs easily. In the case of highly water-soluble drugs, lipid-polymer complexes can be used [7]. The anti-cancer drug salidroside is incorporated in polymer-core lipid shell NPs formed by PLGA-PEG-PLGA triblock and the lipids lecithin and cholesterol, with high encapsulation efficiency, negative charge, and 150 nm size [19].

There is a type of hollow-core/shell lipid-polymer-lipid hybrid nanoparticles where polymeric NPs and PEGylated lipoplexes are combined. They contain a layer of positively charged lipid, which forms the inner hollow core, a middle layer of PLGA, which is hydrophobic, external to the PEG, and a neuter lipid layer between them. These systems are not simple LPNs, they present the features of PEGylated lipoplexes and PLGA nanoparticles. The positively charged hollow core can accommodate anionic drugs more efficiently than a polymer alone, the polymeric layer of the medium will allow sustained release, and the PEG-lipid layer avoids the particle being recognized by a macrophage, increases stability, and slows down polymer degradation and drug release. The combination of si-RNA and small drug molecules in the hydrophobic layer of PLGA is very useful for the treatment of different diseases, including multidrug-resistant cancers [7, 20].
