Lipid as a Vehicle/Carrier for Oral Drug Delivery

Abstract

The drug administered by an oral route has to withstand a harsh environment of gastrointestinal media, absorb through intestinal epithelium and circumvent first-pass metabolism in liver before reaching portal blood circulation. Moreover, hydrophobic drug molecules offer challenges for formulation with respect to their solubility and hence bioavailability. Various approaches have been developed to overcome this barrier. One of them is the use of lipids in formulation. Incorporation of the drug in lipids can result in increased solubility, absorption and thereby enhanced bioavailability. Intestinal lymphatic route of absorption has also been explored for increasing bioavailability of hydrophobic drug moieties. In this chapter, we have discussed the pathway of lipid digestion in the human body as well as the mechanism of lipid particles upon oral administration. The various lipid formulations developed and the excipients used in the formulations have also been described. The importance of lipid chain length and the effect of food in increasing the bioavailability of drug is discussed. The lymphatic pathway of lipid carriers has also been discussed.

1. Introduction

Although many advancements occur in other routes, the oral route pathway of drug administration still remains the most preferred route. It is because of its cost-effectiveness, safety and convenience of administration, ease of production, suitability for long-term or life-long use and does not require sterilization and flexibility in dose adjustment [1, 2]. Intravenous administration delivers the drug directly to blood circulation, but there is the possibility of extravasation of blood or drug, thrombosis and catheter infections [3]. So, oral route has always remained the first preference for drug administration. However, there are certain limitations of this route which need to be circumvented. It includes poor solubility of drug, poor permeability, instability, first-pass metabolism, intestinal metabolism and slow commencement of action compared to intravenous route. Additionally, drug absorption starts from stomach, but it has short residence time of 2 h. So, only weakly acidic and neutral drugs are absorbed efficiently from stomach lining. Thus, major drug absorption after oral administration, thus occurs from intestine as it imparts a high absorptive surface area and greater residence time [1, 4, 5]. The common mechanism of absorption includes passive diffusion and enterocyte-mediated active transport through stomach and intestine [6, 7]. BCS Class I drugs, having high solubility and permeability are absorbed efficiently by oral route. However, the drug molecules that are being discovered belong to BCS Class II having poor aqueous solubility and good permeability [8]. This leads to their poor oral bioavailability. Many advancements to increase bioavailability have been made including size reduction, recrystallization, complexation, solid dispersion and use of solubility enhancers [9].

Use of lipid as an excipient to enhance oral bioavailability has been widely explored. They are majorly derived from dietary oils and/or fats and are biocompatible, biodegradable in nature and non-toxic [10]. Further, they not only help in increasing the solubility of drug in gastrointestinal media but various lipids have been shown to decrease proteolytic degradation [11], increase lymphatic absorption [12] and modulate various mechanisms including P-gp activity [13]. It has also been shown to enhance transcellular absorption of drug molecules [14]. The various lipid-based formulations have been developed so far are described in this chapter. Since the lipids have varied properties, their appropriate selection and design of formulation affect the success of the formulation [15]. Moreover, absorption of drug through the lymphatic system greatly affects the bioavailability of formulation and its efficacy. In general, the drug upon oral administration is either absorbed via intestinal epithelium to portal blood circulation, or is taken up by lymphatic vessels to the lymphatic system. The drug entering portal blood circulation has to pass through liver before reaching heart thus chances of metabolism are high. While the drug entering into the lymphatic system is directly get drained to heart avoiding first-pass metabolism. Hence, the lymphatic system can be an alternate and a safe route to enhance drug delivery [16]. Since this system mainly transports lipids and fats, the lipidic drug delivery systems have greater chances of absorption through this route [17]. In particular, for selective lymphatic uptake, high lipophilicity (log P > 5) and the presence of triglycerides having long carbon chains are desired [18]. The possible parameters of lipid-based drug delivery system to enhance lymphatic absorption are described in this chapter. Moreover, the in vivo lysis lipid in the human body has also been discussed. Another pathway of absorption exclusively to the lymphatic system is through Microfold cells (M-cells) present in intestinal epithelium [19, 20]. It uptakes lipid nanoparticles as well. Hence, this route becomes important for nanosized lipid drug delivery system. The mechanism of absorption of nanoparticles through this route has been described in this chapter.

2. In vivo lysis of lipid in human body

Lipid digestion begins in the gastrointestinal tract from oral cavity in the presence of lingual lipase enzymes secreted by Ebner’s gland present on the tongue [21]. Further physical breakdown occurs due to gastric emptying, antral contraction and retropulsion. Stomach acts as the core site for the emulsification of fat molecules into coarse emulsion droplets of size approximately 0.5 μm [22, 23] followed by the enzymatic degradation of triglyceride to form a mixture of fatty acids and monoglycerides [24]. The coarse emulsion droplets when entering the small intestine stimulate the secretion of bile salts and bile lipids from the gallbladder which stabilizes the surface of droplets leading to the formation of fine droplets upon entering the intestine and further gets homogenized with bile and pancreatic juice. In general, the chain length of triglycerides determines its absorption pathway. The short- and medium-chain length fatty acids (having carbon chain length of less than 12) are able to diffuse through enterocytes, taken up by blood vessels, enter liver and then to blood circulation. On the other hand, long-chain fatty acids (having chain length greater than 12) undergoes re-esterification and are converted back to triglyceride form. These triglycerides are taken up by the chylomicrons which are absorbed by lymph vessels and drained to the blood circulation via the thoracic duct. When these chylomicrons reach any tissue, they activate the lipoprotein lipase present on the surface of BCECs to generate fatty acids. The fatty acids so formed enter muscles and adipose tissues for use or otherwise get stored. The lipids are transported in the body through lipoprotein vehicles like chylomicrons. These vehicles remain in the circulatory system until their triglycerides are consumed. They are also taken up by liver and digested. Among lipoproteins, the chylomicrons are the largest produced by intestinal wall. Other lipoproteins include high-density lipoproteins (HDL), low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL). The HDL is synthesized by liver and intestinal wall (enterocytes), VLDL by the liver and LDL partly through the metabolism of VLDL in plasma and partly by liver [25].

3. Various lipid-based formulations

Lipid nanocarriers comprise of solid lipid matrix which exists in solid form at room temperature and leads to phase transition upon physiological temperature. They are of two categories: solid lipid nanocarriers (SLNs) and nanostructures lipid carriers (NLCs). They have possessed low toxicity, a solvent-free system, inexpensive, stable during sterilization and manufacturing, can entrap both hydrophilic and lipophilic drug candidates, can prolong the drug release and easy industrial scale-up. Due to the presence of these properties, they are gaining the researchers attention. Various lipid-based systems for oral drug delivery as listed in Table 1.

Type of carriers	Merits	Demerits
SLN	Unique structure with nano size, protect drug from harsh gastric environment, by achieving effective concentration at the receptor location and bypassing the apical transporter protein improves drug absorption	Low drug loading as drug might undergo partition or expulsion while stored.
NLC	Use of liquid lipids tends to form a less ordered structure which improve drug loading and stability compared to SLNs	Excipient-based cytotoxicity, irritation and sensitization
Lipid drug conjugates (LDCs)	Alteration in physicochemical properties of drug molecules, minimizing toxicity	Drug expulsion, particle growth, unpredictive gelation
Liposomes	improved stability, a faster absorption rate due to increment in aqueous solubility	Elasticity and leaching of drug during transport, degradation of phospholipid during storage, reproducibility in the quality of final preparation
Phytosomes	High drug loading due to enhancement of complexation rate, improve stability, inhibit drug expulsion, improve absorption and bioavailability.	Rapid elimination of phytoconstituents from the formulation
NLCs	high drug encapsulation compared to conventional nanoparticles, no drug partition in oily compartments, two or more drugs can be encapsulated, inhibit degradation, non-toxic to healthy cells	Surfactant dependent toxicity
SEDDS	Improves permeation, ideal carrier for lipophilic and sensitive drug delivery, simplicity of manufacturing at industrial scale also.	In vitro models available are not reliable.; Concentration of surfactant used is high (up to 60%)
Emulsion	Minimize non-selective spread, more affinity for tumor cells, shows controlled payload drug release behavior, minimize irritation of gut wall, ease of manufacturing	Costly due to the use of micronization and reproducibility in droplet.

Table 1.

Comparison of various lipid carrier systems.

3.1 Solid lipid nanoparticles (SLNs) and nanostructured lipid nanocarriers (NLCs)

SLNs are the first generation of lipid nanocarrier introduced in 1991. The main solid lipids used in the development of nanocarriers are fatty acids, steroids, triglycerides, partial glycerides and waxes. Physically, SLNs are colloidal dispersion having different size of particles like smaller (<100 nm), medium (100–300 nm) and larger (300–1000 nm). Structurally, they comprise of APIs and solid lipid (0.1–30%) with coating of emulsifiers in the concentration limit of 0.5–5% [26, 27]. The method of preparation is opted based on physical parameters like particle size, shape, charges, stability of formulation, drug loading and drug release manner. The different solid lipids like tripalmitin, stearic acid, tristearin, glyceryl behenate, cetyl palmitate and glyceryl monostearate are generally used to form core-shell and surfactant like tyloxapol, poloxamer 188, soybean lecithin and tween 80 are used to form monolayer coating for the stabilization of lipid particles [28]. Structurally, SLNs possess highly organized crystal lattices with small space for the entrapment of the therapeutic molecules. On the basis of the spatial arrangement of the therapeutics in the SLNs, they have been classified into three different types: API is (i) homogeneously distributed throughout the SLN—homogeneous matrix arrangement; (ii) dispersed in the periphery of the core-shell-drug enrich core model and (iii) concentrated at the centre of the core-shell-drug enrich core model.

Aziz Unnisa et al. developed dapagliflozin solid lipid nanoparticles for controlling hyperglycaemia. SLNs were formulated by hot homogenization followed by probe-sonication. They utilized lipid-compritol 888 ATO; tween 80 as an emulsifier and poloxamer 188 as a co-surfactant. Prepared SLNs were of spherical shape and nano-size in range. The in vivo pharmacokinetic studies in diabetes-induced rat model showed a rise in C_max (1258.37 ± 1.21 mcg/mL), AUC (5247.04 mcg/mL) and oral absorption (twofold) of the dapagliflozin compared to its marketed formulation [29]. Huma Rao et al. formulated compritol-based alprazolam solid lipid nanoparticles. Prepared formulation shows quick onset of action and sustained release of drug. Hence alprazolam SLNs would relieve early symptoms of anxiety and depression, along with long-lasting control of symptoms in patients. They optimized the formulation and optimized formulation has 92.9 nm with narrow size distribution which demonstrate desired level of homogeneity and stability. Entrapment efficiency and drug loading capacity were found to be about 89% and 77% with smooth spherical morphology. In vitro drug release data demonstrates the 24 h sustained release of alprazolam from the SLNs. Based on their finding, they have made conclusion for promising sustained release formulation of short-acting alprazolam with decreasing dosing frequency and improves patient compliance [30].

NLCs are advanced lipid nanoparticles comprised blend of solid and liquid lipids in particle form stabilized by water base surfactants. Appropriate blend of these produces unorganized or poor crystalline lipid matrix. These provide high drug loading and prevent leaking of APIs throughout their storage. SLNs have low loading capacity because of their crystalline behavior and there is always possibility of drug expulsion during storage since solid lipids might undergo phase transition. This problem is overcome in NLCs as liquid lipid is present in it that does not allow drug to expulse [31].

Jittakan Lertpairod and Waree Tiyaboonchai prepared curcumin-loaded NLCs for targeting colon. First, NLCs were prepared using micro-emulsion method. Prepared NLCs entangled in EudragitS100, a pH-sensitive polymer, by ionotropic gelation method. The formulated MLCs are of 227 nm size, negative surface charge with high drug loading (>90%). NLCs embedded in polymeric matrix inhibit the drug release in stomach. They followed sustained released behavior in the intestine and colon [32].

3.2 Lipid drug conjugates (LDCs)

As lipids are derived from the natural sources like dietary supplements or oil/fat, they show excellent biodegradability and biocompatibility. These lipids are conjugated with the drug molecules via chemical bonds like esters, amides, disulphides, etc., and form lipid drug conjugates. LCDs have potential to alter physicochemical properties like improving the lipophilic performance, improving the drug permeation through biological membrane and brain, improving bioavailability, minimizing the toxicity, improving drug loading and altering the drug release patterns [33]. Atiđa Selman et al. formulated hybrid oral liposomes for selenium nanoparticles (Lip-SeNPs) using thiolated chitosan. Lip-SeNPs liposomes were prepared by microfluidics-assisted chemical reduction and assembling process followed by covalent conjugation with chitosan-N-acetylcysteine. Thiolated Lip-SeNPs were of 250 nm size and possessed positive charge improving adhesion to mucus layer without penetrating the enterocytes [34].

3.3 Liposomes

Liposomes are spherical vesicular systems mimic the cell plasma membrane structure. The main lipid used is phospholipid like eggs or soybean phosphatidylcholine, which for the bilayer with amphiphilic nature comprising a head (hydrophilic in nature) and a tail (hydrophobic in nature). For minimizing the fluidity in the bilayer, cholesterol is added for enhancing its in vitro and in vivo stability. Both hydrophilic and lipophilic drugs can be entrapped in the vesicles. Lipophilic drugs get entrapped in the lipid portion while hydrophilic drugs get entrapped in the aqueous portion. Based on the size of the vesicles and layers, they have been classified as (i) multilaminar vesicles that are composed of around 5–20 concentric bilayers of lipid and (ii) unilamellar liposome vesicles.

Oral administration is challenging for the liposomes due to degradation by acids, enzymes like lipase and bile salts present in gastric media. To overcome this problem, new technologies including engineering of polymers or ligands have been developed [5]. The strategies that are performed to improve the stabilization and disruption in the gastric environment are as follows:

1. Bilosomes: Incorporation of bile slats like sodium taurocholate, sodium glycocholate and sodium deoxycholate. They act as a permeation enhancer, enhance absorption, prevent premature release of drug and protect liposomes against the bile salts of the intestinal media [35].

2. Surface modification by polymer coating: Use of enteric coating polymers for the protection from the gastric environment due to stearic hindrance; mucoadhesive polymers for enhancing the drug absorption by prolonged retention in the intestinal mucosa and polymeric conjugation for improving stability and promoting receptor-mediator endocytosis [36, 37].

3. Use of lipids with higher phase transition temperature like dipalmitoylphosphatidylcholine, distear-oylphosphatidylcholine and sphingomyelin along with cholesterol. They are resistant to hydrolysis and oxidation and provide stability owing to their higher rigidity and packing [38].

Thuan ThiDuong et al., developed Berberine-loaded liposomes using air-suspension coating (layering) method for reduction in exogenous cholesterol and production of anti-hyperlipidaemia therapeutic effects. The prepared formulation was in narrow size distribution with nano-size range, possess good drug entrapment and spherical morphology. The lipid-lowering activity was evaluated using rats and mice. 628% increment in oral bioavailability was obtained in comparison to plain drug. Moreover, reduction in low-density lipoprotein, total cholesterol, triglycerides and low-density lipoprotein cholesterol were in hyperlipidemic mice [39].

Shabari Girinath Kala and Santhivardhan Chinni prepared d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) liposomes of nintedanib esylate. It is a kinase inhibitor used to treat lung cancer. It suffered from first-pass metabolism and hence has low oral bioavailability (~4.7%). The liposomes were prepared using the thin-film hydration method. They have applied the design of experiments to check the influence of process and formulation parameters like phospholipids: cholesterol ratio, drug loading and sonication time. Prepared TPGS liposomes had a particle size of 125 ± 6.7 nm, entrapment efficiency of 88.6 ± 4.1% and zeta potential of + 46 ± 2.8 mV. Morphologically they were spherical in a state with partial amorphization. In vitro drug release follows Higuchi kinetics with sustained drug release of 92% in 36 h in vitro cytotoxicity test was performed using A-549 cells and C-6-labeled liposomes revealed more effective than the marketed formulation. The preparation was found stable in stability chamber and simulated fluids. Based on the pharmacokinetic data prepared liposomal shows bout 6% times greater oral bioavailability compared to marketed formulation. Hence the prepared formulation shows prolonged drug release with improved bioavailability [40].

Shuang Liu et al. prepared chitosan-coated nanoliposomes (CC-NLs) of betanin using soya lecithin and cholesterol by a reverse-phase evaporation method. The physicochemical properties of chitosan-coated material were compared with uncoated nanoliposomes. They have found lower values of absolute zeta potentials and larger particle sizes than uncoated NLs. Moreover, stability and target release rate was improved in CC-NLs compared to uncoated NLs. Further, betanin delivered by CC-NLs had higher in vitro and cellular antioxidant activities than free betanin and betanin delivered by uncoated NLs [41].

Chen Yanga et al. developed alpha-linolenic acid nanoliposomes (ALA-NLs) decorated with carboxymethyl chitosan for improving the oral bioavailability of linolenic acid. Upon comparison with CMC-coated liposomes with uncoated liposomes, they have observed layer formation with spherical morphology, improved physicochemical properties and encapsulation efficiency of about 79% of ALA. Further release of ALA in a simulated gastrointestinal environment would be regulated in CMC-coated nanoliposomes. Moreover, in vivo testing found that greater area under the curve ALA concentration and its absorption of CMCS-ALA-NLs compared to ALA-NLs and ALA-emulsion. The absorption of ALA was improved by CMCS-ALA-NLs [42].

3.4 Phytosomes

Phytosomes are also known as phytoconstituents–phospholipids complex in which bioactive phytoconstituents form a strong hydrogen bonding and Van der Waals forces with polar region of phospholipids. They are derived from a stoichiometric chemical reaction between APIs and phospholipids. Various methods such as solvent evaporation, salting out and lyophilization method are employed using non-polar solvents such as ethanol, dichloromethane and tetrahydrofuran [43]. Ravi Gundadka Shriram et al. developed Silymarin a hepatoprotective agent phytosomes for improving oral bioavailability by solvent evaporation method. The prepared phytosomes were of porous particles with smooth surface and particle size was in the range of 218.4 ± 2.54 nm. A significant enhancement in the aqueous solubility was obtained which correlates with its high drug release rate. Moreover, the in vivo studies exhibited heptatoprotective effect with good efficacy of formulation in it during the CCl₄-induced hepatotoxicity rat model [44].

3.5 Lipid nanocapsules (LNCs)

LNCs are structurally hybrid arrangements between liposomes and polymeric nanoparticles. External shell is composed of solid lipids emulsified with surfactant and semiliquid enriched central core. Three principal components of LNCs are oils and mixture of a non-ionic surfactant as well as hyrdophobic surfactant. The core is generally made of liquid lipids which act as a drug depot and about 10–25% w/w while solid lipids form the shell. NLCs are generally prepared using medium-chain triglycerides such as caprylic acid and capric acid. Lecithin, which is a complex mixture of various phosphatidyl esters such as phosphatidylinositol, phosphatidylcholine, phosphatidylserine and phosphatidylethanolamine is widely used as a lipophilic surfactant. The main sources of lecithin are eggs, sunflower, soybean, lysolecithin and rapeseed [45]. For enhancing the stability of NLCs, up to 1.5% w/w of lecithin is used. It forms a rigid shell when cooled. Hence, its concentration directly influences the rigidity and thickness of the outer shell [46]. Apart from this, non-ionic surfactants like solutol, Cremophor RH40 and RH60 are also used [47].

3.6 Nanoemulsion and microemulsion

Nanoemulsions or microemulsions are dispersion systems of two immiscible liquids possessing varying droplet sizes. They are isotropic mixture consisting of hydrophilic solvents and co-cosurfactant/surfactants that help to increase the solubility of hydrophobic APIs. Nanoemulsion is generally interchanged by microemulsion. Both have tremendous differences in structural aspects as well as thermodynamic stability. These differences are due to the presence of surfactant concentration and the method of preparations. Nanoemulsion requires exogenous energy during manufacturing like micofludization, high shear homogenization, etc., due to low concentration of surfactant while microemulsion can form spontaneously as surfactant concentration is high. Microemulsions are thermodynamically more stable than nanoemulsion [48, 49].

Onkar B. Patil et al., developed effective and stable nanoemulsion of tadalafil (TDF) and ketoconazole (KTZ) for targeting liver. They have utilized Leciva S-95 as lipid, tween 80 which is a hydrophilic surfactant, and span 80 which is a lipophilic surfactant were utilized as a surfactant while poloxamer 108 as a co-surfactant. The prepared formulation possesses a spherical shape nano-size droplet with narrow size distribution. In vitro drug released data exhibited controlled release behaviors of both drugs in the formulation. This may indicate improvement in half-life and reduced toxicity for normal tissue cells. NEs showed improvement in cytotoxicity towards HepG2 cells by increasing the drug uptake [50]. Gabriela Garrastazu Pereira et al. formulated nanoemulsion of anticancer ω-3 fatty acid derivatives for oral administration. They formulated a stable nanoemulsion comprised of Labrafac™ as a lipidic phase, span 80 and tween 80 as a surfactant having droplet size 150 nm. They prepared the formulation by employing phase-inversion emulsification process and reduction in particle size by high-pressure homogenization. Prepared nanoemulsions, during in vivo tumor study in mice, showed a significant reduction in relative tumor volume [51]. Manohar Mahadev et al. fabricated quercetin nanoemulsion for enhancing the therapeutic effectiveness and oral bioavailability in diabetes mellitus. They have used tween 80, ethyl oleate and labrasol as surfactant, oil and co-surfactant, respectively, for the formulation of nanoemulsion and optimized the formula using Box–Behnken design. The formulation had a 125.51 nm particle size with a 0.215 poly dispersibility index with a spherical shape. Formulation exhibited greater drug release in comparison to pure drug. Moreover, animal studies revealed remarkable protective and therapeutic properties in the management of diabetes [52].

3.7 Self-emulsifying drug delivery system (SEDDS)

These systems are made using oil, surfactant/co-surfactant mixture (ratio of oil:surfactant is generally varying from 20:30 to 20:60). Upon oral administration, spontaneous nanoemulsion form in the GIT. These systems have the capacity to penetrate the mucus layer and reach the epithelial tissue thus helping the penetration of drug molecules having less permeability in general. SEDDS have the potential to facilitate the delivery of poorly permeable drugs. Nowadays, research is going on for the combination of SEDDS with polymers in the oral absorption of peptides. Polymer can improve the mucoadhesion in the mucus membrane which may, in turn, lead to prolonged therapeutic effectiveness. Net negative charges are present in the mucus carrier due to the presence of sialic and sulphonic acid and upon ionic interaction, oily droplets exhibit positive charges and improve adhesion and absorption of drug molecules [53]. Diego A. Bravo-Alfaro et al. formulated self-nanoemulsifying drug delivery systems of betulinic acid (BA), a bioactive molecule having antineoplastic, antiviral and anti-inflammatory activity. Betulinic acid has low water solubility. They used lauroglycol FCC and caprylic acid as a lipid phase and found greater solubility of BA. By applying pseudoternary phase diagrams Cremophor EL^® and Labrafil M1944CS were selected as surfactant and co-surfactant. Prepared nanoemulsion possess approximately 22–56 nm particle size with 0.058–0.135 PDI. Moreover, they have found no changes in the particle size in the presence of simulated small intestinal phase conditions for 105 min. In vivo studies demonstrated about a 15-fold increment in the bioavailability of BA compared to free BA solution [54].

4. Mechanism of lipid nanoparticles

Regarding the typical triglyceride-based lipid nano-particles will undergo the same digestive processes as lipids consumed through food after being administered orally. Still, mechanism of oral bioavailability has now no longer been defined but some of the additives are standard for know-how the enhancement of absorption. Surface area, smaller particle size and morphology are extra suitable traits for oral absorption. Since lipids are regarded to improve oral absorption of drug and they can be prepared with less particle size, it has been concluded that this carrier system must use lipids as the excipient for greater and steady absorption through gastrointestinal pathway [55]. Additionally, solid-lipid nanoparticles (SLNs) surface area, interaction with epithelial membranes and bio adhesion to the GI wall appear to extend their absorption in the GIT, which probably improves oral absorption. There are three basic mechanisms for oral administration of lipids, lipophilic excipients and lipid-based formulation for increased absorption [56],

1. Pre-enterocyte level (solubilization of drug)

2. Intra-enterocyte level (chylomicron formulation)

3. Post-enterocyte level (lymphatic drug transport)

According to a claim that lipid nanoparticles have adhesive characteristics that allow them to adhere to the surface of enterocytes in the stomach and immediately release drugs for absorption into the cells. Parallel to this, SLN contributes significantly to the formation of micelles in the oral uptake by causing the release of bile salts and lipase/co-lipase, Additionally, the bile salts and micelles interact to form mixed micelles that facilitate the absorption of these colloidal species by enterocytes, which transport drugs inside cells, these mechanisms have been called the “Trojan horse” effect [57]. Micelles are created after absorption and present in the enterocyte, where they are re-esterified via the monoacyl glycerol or phosphatidic acid route to become chylomicrons and maintained by phospholipids. The penetration of mucus and unstirred water layer, however, is what restricts the rate of digestion. Following formation, the chylomicrons are subjected to the lymphatic transport system via mesenteric lymph before being drained by the thoracic duct [58, 59].

Following oral administration, several techniques for drug transport into the lymphatic system have been reported. These Peyer’s patches contained M cells that are used for vaccine distribution through the transcellular and paracellular mechanisms [55], as well as therapeutic drugs and nanocarriers. The transcellular approach is the most fundamental technique for lipid-based carriers to be absorbed. Enterocytes are promoted to generate chylomicron when drug is delivered using lipid-based transporters, which further emulsify and incorporate the lipophilic drug molecules into the nonpolar core. This stimulates the intestinal lymphatics to absorb drugs that are just slightly water soluble.

Additionally, lipid-based carriers can enhance intestinal lymphatic lipid flux and lipoprotein production, both of which are regulated by the physiochemical characteristics of lipids and the presence of stabilizer. Lipid-based transcellular routes are additional. There are various transcellular mechanisms through which lipid-based drug delivery systems are transported into enterocytes, including macro-pinocytosis, caveolae-mediated, clathrin-mediated and clathrin and caveolae-independent endocytosis [60].

Griffin and O’Driscoll gave explanations for how the lipid-based formulations improved the oral absorption of lipophilic drugs specifically for peptide and protein-like drugs, in addition, to improving intestinal lymphatic transport and drug solubilization. These enclosed increased intestinal membrane permeability, fluidization of the intestinal membranes, reduce the enzymatic degradation, alteration of TJs, generation of lipid-protein interactions and alteration of enterocyte-based efflux and metabolic activities are some of these [61].

In addition to the above-mentioned factors, lipid-based formulations stimulate prolonged gastric emptying, which prolongs the stomach’s time in the stomach and increases the rates at which drug molecules dissolve at the absorptive site, hence improving drug absorption [62]. As a result, lipid-based nanoparticles increase the oral bioavailability of lipophilic drugs through bio-adhesion mechanisms in addition to endogenous lipid absorption pathways, which include absorption through M cells of Peyer’s patches, solubilization, permeability across the enterocyte, increased paracellular and transcellular transport, controlled drug release, delayed gastric emptying time, stimulation of lymphatic transport, avoidance of intestinal first-pass metabolism, etc.

The review demonstrated that due to the unique characteristics of lipid nanoparticles and its components (wide variety of lipid constituents such as P-gp inhibitor, permeability enhancer, endogenous solubilizing components, etc.) multiple mechanisms for absorption and permeation, no toxicity and its formulation opportunities including avoidance of organic solvents during production of complex and challenging formulation strategy for drugs that, when taken orally have poor water solubility [63], Drug (lipid-nano formulation) may be eliminated from the body after oral administration as a result of its lipophilicity, which is directly affected to the bioavailability of drug molecules and lipid nanoparticles. Changes in the components of lipids may affect the bioavailability of bioactive characteristics, including, such of those vaccines. However, adding the surface of lipid nanoparticles with a surface-active substance like PEG prolongs their stay in the bloodstream while preventing phagocytosis uptake.

5. Critical influencing factors

It is claimed that the type of lipid (chain lengths and saturation degree) is one of the most essential factors that affect CM transport. Lipophilicity of short, medium and long-chain fatty acids and CM binding capacity both are significantly correlated with chain length. Reports say that transport via the portal vein there is preferred short-chain fatty acid, whereas medium-chain or long-chain fatty acids are prone to be transported via the lymph. Self-nanoemulsifying drug delivery systems (SNEDSS) composed of long-chain fatty acids than medium chain-fatty acids in lymph add proof to support the dependency of chain length [64]. Halofantrine, a particularly lipophilic drug, was used in a research of lipid-based vehicles to demonstrate that the lymphatic affinity of the vehicles followed the order of C18 (15.8%) > C8–10 (5.5%) > C4 (2.22%) > C0 (0.34%) [65]. An increase in FA chain length is highly correlated with enhanced drug transport efficiency. This may be explained by higher affinity to intracellular CMs and lipoproteins by higher lipophilicity of long-chain fatty acid. Administered in oil solution of 1,3-dioctanoyl-2-linoleyl-sn-glycerol, abbreviation MLM to denote the position of “medium long medium” chains, enhances absorption of halofantrine while maintaining levels of lymphatic transport that are comparable to the level of sunflower oil solution. However, halofantrine formulation was made into SNEDSS which based on MLM and 1,3-dilinoyl-2-octanoyl-sn-glycerol, enclosed as LML to indicate “long-chain-long” chain lengths, lymphatic transport was found to be 17.9% and 27.4%, although the availability of plasma was 56.9% (MLM) and 37.2% (LML), respectively [66]. It is indicated that consideration of ratio and length of chain may be a way to change how drugs are distributed throughout various pathways.

Another factor is food effect that may enhance lymphatic transport and with bioavailability of plasma. Radio-labeled cannabinoid receptor agonist CRA13 have 72–75% oral bioavailability in fed dogs vs. 8–20% in fasted ones, with 43.7% through lymphatic transport [67]. After the meal has been taken total amount of halofantrine increases from 1.3% to 54% in lymphatic transport of the administered dose. Sometimes, consumption of food may slow down the process of absorption, but not necessarily affect systemic bioavailability and AUC. Regarding the food effect, there are some exceptions which should be noted. For example, after administration of high-fat food, the AUC of DDT with high CM binding efficiency enhances by 1.5-fold, however, under identical circumstances, diazepam with low CM binding efficiency shows no significant difference, lymphatic transport is higher for DDT but not for diazepam. Stimulation of CMs may have partly affected by the food effect. Intake of not only fat but high contents of carbohydrates also affects the higher production of CM [68]. Additionally, the bile salts produced during lipid digestion help to stabilize the mixed micelles that entrap the drug molecule. This is turn help to increase the drug absorption and CM formation inside the cell enterocytes. The importance of many endogenous bile salts is demonstrated by the drastically reduced halofantrine synthesis in lymph in bile duct salt-cannulated rats.

6. Lymphatic transport of lipid carriers

There are two pathways for entry to the lymphatic system: M-cell uptake of particles and absorption of lipidic molecules through lymph vessels. The vascular region throughout the body is surrounded by specialized lymphatic vessels that absorb the molecules giving entry to a complex network of lymphatic systems [69, 70]. The pore size of blood vessels is not enough for the uptake of large molecules of triglycerides and phospholipids. However, the lymphatic capillaries are single-layer, thin-walled and non-fenestrated due to which it is easily able to permit these large molecules [71]. Upon absorption through lymph vessels, the lymph fluid containing absorbed molecules enters the thoracic duct followed by subclavian vein and finally is drained into the circulatory system. This pathway bypasses the liver before entering the blood circulatory system thus avoiding first-pass hepatic metabolism [72]. When drug reaches the circulatory system, it is in form of micelles or mixed micelles which dissociate into monomers because of dilution with the large volume of lymph/blood (the surfactant concentration decreases due to dilution and results in a concentration below its CMC value) [73]. In other cases where the drug is carried in lipid vesicle form, the release of drug becomes prolonged. It has been reported in literature that the presence of triglyceride-rich lipoproteins diverts the absorption of drug exclusively through lymphatic route. Moreover, it has been also reported that greater lipoprotein synthesis particularly after postprandial administration diverts absorption of drugs dominantly through lymphatic system [67, 74]. This indicates that lipid derived either from diet or formulation determines the transport of drug either through lymphatic system or portal blood circulation [75]. This further relates to the new era for formulation development ruling out the necessity of traditional pathways like increasing solubilization capacity. It also brings new opportunities for various excipients that are emerging as bioactive recently in the last decade [76]. Further, excipients such as Cremophor EL and pluronic polymers have been shown to decrease chylomicron production and reduce the P-gp efflux transport of drug molecules [77, 78]. One of the versatile excipients in this category is tween 80 which has been found as excellent solubilizer, inhibitor of P-gp efflux and increase chylomicron production [76, 79]. Another pathway for lymphatic absorption through M cells has also been explored in the last two decades. These cells are able to recognize pathogens due to the presence of specific ligands on their surface. The particles of formulation have thus been engineered to mimic these ligands that are recognized by M-cells. Such ligands include peptides like Arg-Gly-Asp, glucans, proteins like lectins etc. [80, 81, 82]. Another peptide ligand investigated for M-cell uptake is RGD which recognizes a5b1 integrin on M-cells. However, due to its instability in gastrointestinal tract media, its analogue RGD peptidomimetic has been developed. This new moiety has been grafted on the surface of poly(lactic-co-glycolic acid) nanoparticles and tested for M-cell uptake. It was found that the efficacy of this new molecule remained the same as compared to its parent moiety (RGD) but the stability in GI media was improved [83, 84].

7. Conclusion

In recent decades, number of innovations have been developed in lipid-based drug delivery for oral route. Moreover, the advancements in technology transfer have also been seen favoring the production of these novel systems. The in vivo performance evaluation, in vitro drug release studies have also been improved allowing us to track the amount of drug that is able to cross the gastrointestinal tract and/or lymphatic absorption. This delivery system has proved as more useful for poorly water-soluble drugs especially for potent lipophilic drugs because of their biocompatibility and non-toxicity, solubility enhancing properties. Overall, lipid-based drug delivery is one of the safest options for the oral delivery of lipophilic drugs.

Conflict of interest

The authors declare no conflict of interest.