**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**.



#### **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 Cmax (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

#### *Lipid as a Vehicle/Carrier for Oral Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.109672*

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,

#### *Drug Formulation Design*

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:


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

*Lipid as a Vehicle/Carrier for Oral Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.109672*

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].
