The domain of nanomedicine has brought forth several promising drug delivery technologies using diverse nano-scale carriers through diverse routes of administration. Oral drug delivery systems (DDS) find the widest acceptance among patients and manufacturers for treating diverse pathological ailments.

Development of such products poses major challenges to pharmaceutical development scientist, as more than one-half of new molecular entities exhibit poor and inconsistent bioavailability. Ostensible causes for these bioavailability issues encompass poor aqueous solubility, extensive hepatic first-pass effect, acid-lability in gastric fluid, restricted intestinal permeability, gut wall metabolism by cytochrome P450 (CYP450) family of isozymes and high P-glycoprotein (P-gp) efflux (Figure 1).

Popular formulations approaches like, micronization, co-crystals, inclusion complexes and solid dispersions primarily improve dissolution performance of the drugs only. The potential of lipid-based nanostructured DDS for oral intake has been explored for the purpose owing to their stellar merits like reduced gut wall metabolism by CYP450 group of enzymes, circumnavigation of extensive hepatic first-pass effect, reduced P-gp efflux and lowering intra/inter-subject inconsistencies in gastrointestinal absorption, besides the remarkable increase in dissolution performance, solubility and permeability.

Nanostructured systems for oral drug delivery
Nanostructured DDS primarily include a variety of non-vesicular and vesicular systems, as categorized in Figure 2.

These lipid-based nanoformulations encompass a plethora of diverse functional and nonfunctional excipients like lipids, surfactants, cosurfactants, and at times, cosolvents, where drug(s) solubilizes in the vicinity of lipidic excipients, leading to substantial increase in the drug absorption, with reduced variability and elimination of food-effects. Moreover, the lipid-based systems can easily be prepared at larger industrial and/or commercial scale with excellent dug loading, and high stability characteristics. Due to their numerous merits, there are several nanostructured systems available in the global market for oral intake today (Table 1).

Lipids are considered as one of the safe and ultimately biocompatible materials for drug delivery. Conventional lipidic systems, consisting of lipidic emulsions and microparticles, possess low stability related to particle size distribution, high degradation under extreme temperature conditions and toxic effects imposed by high concentration of surfactant. Formation of stable nano-lipidic systems can, therefore, be achieved by judicious selection, variation in the lipid-to-surfactant-ratio and optimization of the process parameters involved.

Types of lipid-based nanostructured DDS Vesicular systems
Vesicular systems are a novel means of drug delivery that can enhance bioavailability of encapsulated drug and provide therapeutic activity in a controlled manner for a prolonged period of time. Such systems invariably contain phospholipids as the integral part of the carrier along with cholesterol and surfactants for vesicle stabilization. Liposomes are the most promisingly vesicular carriers composed of lipidic bilayer, surfactants and are prepared by disrupting biological membranes using sonication. Niosomes are vesicles composed of non-ionic surfactants, which are biodegradable, relatively non-toxic, more stable and inexpensive alternative to liposomes. Similarly, bilosomes as novel bile salt stabilized vesicles acting as envelopes to protect their contents from the harsh environment of the gut enabling oral administration, have proved effective in the delivery of vaccines, biologicals and traditional small molecules. Transferosomes are the flexible membrane vesicles containing high amount of edge activator and provides enhanced permeation characteristic for delivery of loaded cargo through oral route.

Non-vesicular systems Self-emulsifying drug delivery systems (SEDDS)
These are relatively newer lipid-based technological innovations with immense promise in oral bioavailability enhancement of drugs. The formulations of SEDDS encompass oils, surfactants, co-surfactants and/or co-solvents. These are optically stable isotropic mixtures, easy to manufacture and for subsequent scale-up. Depending upon the globule size and the low free energy of the system, the SEDDS can be categorized as self-microemulsifying drug delivery systems (SMEDDS; ranging between 150 and 200 nm) or self-nanoemulsifying drug delivery systems (SNEDDS; less than 100 nm).

Besides the pivotal advantages of SNEDDS like ease of production, enhanced solvent capacity, increased stability, and easier scalability in industrial milieu another remarkable feature of SNEDDS is the resilience and amenability to adopt changes in the supramolecular structure and composition. Hence, technological innovations can encompass special type of lipid(s), emulgents(s), or process(es) leading to various newer and advanced modification in the SNEDDS to handle diverse type of process and issue with the drugs (Figure 3).

Nanoparticulate systems
Lipid-based nanoparticulate systems include a diverse variety of DDS, including lipidic nanoparticles, solid lipid nanoparticles (SLNs), nanostructured lipidic carriers (NLCs), lipid-drug nanoconjugates and nanomixed micelles, widely explored for oral bioavailability enhancement of drugs.

Lipidic Nanoparticles (LNPs)
Since decades, LNPs and lipidic nanopellets have been successfully employed for oral drug delivery as first and second generation nano-structured lipidic systems containing lipid matrices, respectively.

Solid lipid nanoparticles (SLNs)
SLNs are the third generation nanostructured colloidal carriers ranging in size between 1 and 1000 nm, frequently used as an alternative over traditional polymeric nanoparticles. Their colloidal dimension provides high drug pay load, controlled drug release, drug targeting, drug protection and stability. Upon peroral delivery, SLNs are readily taken up by intestinal lymphatics owing to their lipidic nature and nanosized structure to enhance the oral bioavailability. The increasing attention in SLNs is due to their combined biodegradable and bio-acceptable nature coupled with efficient drug delivery characteristics and hassle-free method of preparation vis-à-vis polymeric nanoparticles.

Nanostructured lipidic carriers (NLCs)
NLCs, another third generation of nanoparticles, size ranging between 10 and 1000 nm, consist of mixture of solid and liquid lipids. Incorporation of liquid lipid can improve the loading capacity of drugs in the NLCs. Such NLCs tend to overcome the limitations of SLNs such as risk of gelation, uncontrolled release, decreased chemical stability and drug leakage during storage due to polymorphism of lipids. Commonly employed methods to produce NLCs are high pressure homogenization or hot melt-emulsification. Figure 4 portrays the morphological layout depicting the drug distribution in lipid nanoparticles, SLNs and NLCs, respectively.

Based upon the variegated formulation strategies to optimize their nanostructures, the NLCs are categorized as type I, II, III or IV. In imperfect type I, NLC’s are prepared by mixing spatially different lipids which provide imperfections in the crystal order of lipidic nanoparticles (Figure 5a). Mixing small amounts of chemically quite different liquid lipids (oils) with solid lipids in order to achieve the highest incompatibility leads to the highest drug payload. While amorphous type II NLC’s can be achieved by mixing solid lipids with special lipids (Figure 5b). However, in multiple type III NLC’s oil in fat in water (O/F/W) is present where drugs can be accommodated in the solid, but at increased solubility in the oily parts of the lipid matrix (Figure 5c). Nevertheless, in Type IV NLC’s, water-soluble drugs are conjugated by salt formation or covalent linkage with a lipid, thus forming a water-insoluble lipidic conjugate. Drug release from lipid particles takes place by diffusion and by lipid particle degradation in the body.

Comparative physicochemical and drug delivery characteristics of SLNs and NLCs with other promising colloidal nanocarriers like lipid drug conjugates (LDCs) liposomal drug poducts (LDPs), dendrimers (DMs), nanoemulsions (NEs) and Polymeric nanoaprticles (PNs) presented in (Table 2).

 Other lipidic nanosystems
The utility of lipidic systems have paved the way for delivery of diverse pharmaceutical agents possessing problems of erratic oral bioavailability.  Lipidic nanomixed micelles (Figure 6) have been increasingly used for augmenting the oral bioavailability of drugs marked with poor aqueous solubility owing to their nano globule size, higher biocompatibility and biomimetic characteristic.

Besides, lipidic nanovectors and nanocapsules have also been recently identified as relatively novel systems for oral delivery, especially the biomolecules like proteins, peptides and nucleic acids. These nanocarriers are made up of lipids dispersed in the nonionic surfactant to form a hollow shell-like structure with size ranging between 2 and 100 nm. These exhibit promising features for delivery of drugs through systemic route and excellent physicochemical stability ostensibly owing to the presence of nonionic surfactants imparting them with the “stealth” characteristics.

Of late, assortment of lipid-based nanostructured drug delivery systems has stimulated enormous global interest for the oral usage by the pharma industry. The SNEDDS, SLNs and NLCs, in this context, possess immense promise to be commercialized for meeting the patients needs owing to their simple technology and regulatory excipient status, coupled with straight forward scale-up and validation. Besides, these systems offer much more flexibility in drug loading, modulation of drug release and improved performance in producing final dosage forms such as tablets, capsules, creams and injectables. Notwithstanding their stellar benefits in nanomedicine, the potential toxicity, economics and federal compliance of such nano-technological products are the major concerns for the pharmaceutical scientists to address.