**2. Classification of lipid carriers**

Lipid carriers can be classified into various categories depending mainly on their method of preparation as well as their physicochemical properties. They include liposomes, niosomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), micro and nanoemulsions, self-emulsifying drug delivery systems (SEDDS), and lipid-drug conjugates [2, 4].

Liposomes are uni- or multilamellar spherical vesicles which are composed of cholesterol and other natural or synthetic phospholipids enfolding an aqueous compartment [6]. They were first introduced by Bangham et al. in 1965 [7]. Thus, liposomes have been considered as biocompatible and biodegradable carriers that possess efficient delivering capability of hydrophilic and hydrophobic drugs. Advantages of liposome-based drug delivery systems include reduction of systemic and of target toxicities as well as targeting potential to achieve the desired outcome [8]. Thus, many liposome formulations have been approved for commercial use such Ambisome® (amphotericin B), Depocyt® (cytarabine), DepoDur® (morphine sulfate) and many others. However, their poor stability and rapid elimination by reticuloendothelial system limit the widespread applicability of liposomal formulations [4].

Niosomes are first described by Handjani-Vila et al. in 1979 [9]. They are nonionic surfactant-based vesicles in which the hydrophilic surfactant heads are oriented toward the exterior and the interior of the bilayer while, the hydrophobic tails are enclosed inside the bilayer. Therefore, like liposomes, niosomes have the ability to encapsulate hydrophilic or lipophilic molecules [10]. Niosomes also have cholesterol in their structure which enhances the rigidity of bilayer and reduces premature drug release [11]. Niosomes are superior carriers to liposomes in terms of production cost, chemical and physical stability, and loading capacity [12].

SLNs and NLCs are the most widely described solid-core lipid-based nanocarriers in the scientific literature [3]. SLNs were first described in 1991 to replace the liquid oil of O/W emulsions by a single solid lipid or mixture of solid lipids [2]. SLNs are composed of either solid lipid or mixture of lipids, that do not melt at room or physiological temperature, in an aqueous dispersion stabilized with the help of nonionic surfactants [3].SLNs offer the advantage of avoiding the use of organic solvents during preparation, effective delivery of both hydrophilic and lipophilic drugs, feasibility of surface functionalization with specific moieties to enhance their targeting potential, possibility of extended or controlled drug release, long shelf-life, biocompatibility, lower acute or chronic toxicity and effective largescale production [2, 13, 14]. On the other hand, efficient drug delivery by SLNs is challenged by low drug loading capacity due to lipid crystalline nature, expulsion of loaded drug due to perfect crystalline lattice formation of the lipid and erratic gelation tendency that results in particle aggregation during storage [4, 14].

NLCs were developed to overcome the problem of drug expulsion during phase transition or crystallization of lipids comprising SLNs [15]. They also exist as a solid lipid matrix at temperature up to about 40°C. However, they are composed of solid lipid mixed with an oil which in turn reduces the lipid crystallization capacity and enhances the drug loading efficiency [16].

Nanoemulsions are kinetically stable heterogeneous systems composed of ultrafine oil droplets dispersed in aqueous media and stabilized by the aid of surfactants

**49**

*Self-Emulsifying Drug Delivery Systems: Easy to Prepare Multifunctional Vectors for Efficient…*

and cosurfactants. Nanoemulsions have gained increasing attention as promising drug delivery systems due to their multiple advantages including high surface area for drug absorption, biocompatibility, increasing drug solubility and improving mucosal permeability. Further, many FDA approved nanoemulsion-based products of water insoluble drugs are now available for clinical use including Restasis®, Estrasorb® and Flexogan®. Microemulsions also offer favorable characteristics such as thermodynamic stability, ease of production being formed spontaneously without the need for high energy input and high penetration due to the large surface

Lipid-drug conjugates (LDCs) are lipid nanoparticle formulations which are characterized by the conjugation ability of the lipid matrix with the hydrophilic drug moieties, and thus provide novel pro-drugs to achieve many therapeutic outcomes in oral drug delivery [18]. Like other lipid-based nanocarrier systems, LDCs possess several advantages including biocompatibility, being solid at body and room temperature, high capacity for loading hydrophilic drugs, high permeation through GI tract, enhanced drug absorption through lymphatic uptake, improving stability and bioavailability loaded drugs, and feasibility of large scale production [19].

Self-emulsifying drug delivery systems (SEDDS) are lipid-based formulations that encompass isotropic mixtures of natural or synthetic oils, solid or liquid surfactants and co-surfactants [20]. When they are exposed to aqueous media (e.g., gastrointestinal fluids), they undergo self-emulsification to form O/W nanoemulsions or microemulsions with a mean droplet size between 20 and 200 nm [21]. Consequently,

SEDDS are usually referred to as self-nanoemulsifying drug delivery systems

the nature of the resulting dispersions formed following their dilution [20].

soluble drugs particularly those belonging to class II of the Biopharmaceutics Classification System by multiple underlying mechanisms [22]. Among these mechanisms, the enhanced drug solubilization was the most widely investigated. Lipidic components of SEDDS stimulate lipoprotein/chylomicron production thus promoting drug absorption [23]. The ultrafine droplet size range of the resulting emulsion provides a large surface area of interaction with gastrointestinal (GI) membranes [24]. Importantly, the bioactive effects of various ingredients employed in SEDDS formulation have significantly contributed to the enhanced oral bioavailability of the loaded drugs. These bioactive effects include tight junction opening and increasing membrane fluidity by the high surfactant content employed in SEDDS formulation [25]. Furthermore, stimulation of the intestinal lymphatic pathway as well as inhibition of intestinal drug efflux pumps such as P-glycoprotein (P-gp) and intestinal cytochrome P450 3A4 (CYP3A4) are considered promising strategies for enhancing the oral delivery of P-gp substrates and bypassing intesti-

(SNEDDS) or self-microemulsifying drug delivery systems (SMEDDS) depending on

SEDDS have been reported to enhance the oral bioavailability of poorly water-

P-gp is an energy-dependent membrane bound protein and the most abundantly distributed ATP-binding cassette transmembrane transporter throughout the body [27]. P-gp prevents the accumulation of endogenous substances and xenobiotics in cells by transporting them back to the extracellular space [28]. Unfortunately, intestinal P-gp transporters hamper the intestinal uptake of substrate drugs thus, reducing their oral bioavailability. Additionally, overexpression of P-gp transporters is involved in the development of multidrug resistance (MDR) in numerous human tumor types [29]. Hence, many strategies have been developed to inhibit P-gp

*DOI: http://dx.doi.org/10.5772/intechopen.88412*

**3. Self-emulsifying drug delivery systems**

nal and hepatic first pass metabolism [26].

area of internal phase [17].

*Self-Emulsifying Drug Delivery Systems: Easy to Prepare Multifunctional Vectors for Efficient… DOI: http://dx.doi.org/10.5772/intechopen.88412*

and cosurfactants. Nanoemulsions have gained increasing attention as promising drug delivery systems due to their multiple advantages including high surface area for drug absorption, biocompatibility, increasing drug solubility and improving mucosal permeability. Further, many FDA approved nanoemulsion-based products of water insoluble drugs are now available for clinical use including Restasis®, Estrasorb® and Flexogan®. Microemulsions also offer favorable characteristics such as thermodynamic stability, ease of production being formed spontaneously without the need for high energy input and high penetration due to the large surface area of internal phase [17].

Lipid-drug conjugates (LDCs) are lipid nanoparticle formulations which are characterized by the conjugation ability of the lipid matrix with the hydrophilic drug moieties, and thus provide novel pro-drugs to achieve many therapeutic outcomes in oral drug delivery [18]. Like other lipid-based nanocarrier systems, LDCs possess several advantages including biocompatibility, being solid at body and room temperature, high capacity for loading hydrophilic drugs, high permeation through GI tract, enhanced drug absorption through lymphatic uptake, improving stability and bioavailability loaded drugs, and feasibility of large scale production [19].

## **3. Self-emulsifying drug delivery systems**

Self-emulsifying drug delivery systems (SEDDS) are lipid-based formulations that encompass isotropic mixtures of natural or synthetic oils, solid or liquid surfactants and co-surfactants [20]. When they are exposed to aqueous media (e.g., gastrointestinal fluids), they undergo self-emulsification to form O/W nanoemulsions or microemulsions with a mean droplet size between 20 and 200 nm [21]. Consequently, SEDDS are usually referred to as self-nanoemulsifying drug delivery systems (SNEDDS) or self-microemulsifying drug delivery systems (SMEDDS) depending on the nature of the resulting dispersions formed following their dilution [20].

SEDDS have been reported to enhance the oral bioavailability of poorly watersoluble drugs particularly those belonging to class II of the Biopharmaceutics Classification System by multiple underlying mechanisms [22]. Among these mechanisms, the enhanced drug solubilization was the most widely investigated. Lipidic components of SEDDS stimulate lipoprotein/chylomicron production thus promoting drug absorption [23]. The ultrafine droplet size range of the resulting emulsion provides a large surface area of interaction with gastrointestinal (GI) membranes [24]. Importantly, the bioactive effects of various ingredients employed in SEDDS formulation have significantly contributed to the enhanced oral bioavailability of the loaded drugs. These bioactive effects include tight junction opening and increasing membrane fluidity by the high surfactant content employed in SEDDS formulation [25]. Furthermore, stimulation of the intestinal lymphatic pathway as well as inhibition of intestinal drug efflux pumps such as P-glycoprotein (P-gp) and intestinal cytochrome P450 3A4 (CYP3A4) are considered promising strategies for enhancing the oral delivery of P-gp substrates and bypassing intestinal and hepatic first pass metabolism [26].

P-gp is an energy-dependent membrane bound protein and the most abundantly distributed ATP-binding cassette transmembrane transporter throughout the body [27]. P-gp prevents the accumulation of endogenous substances and xenobiotics in cells by transporting them back to the extracellular space [28]. Unfortunately, intestinal P-gp transporters hamper the intestinal uptake of substrate drugs thus, reducing their oral bioavailability. Additionally, overexpression of P-gp transporters is involved in the development of multidrug resistance (MDR) in numerous human tumor types [29]. Hence, many strategies have been developed to inhibit P-gp

*Current and Future Aspects of Nanomedicine*

**2. Classification of lipid carriers**

(SEDDS), and lipid-drug conjugates [2, 4].

enhances the drug loading efficiency [16].

modification due to their lipophilic nature [4]. Further, they are promising carriers for protection of therapeutic peptides against harsh GI environment [3]. Ease of preparation, cost effectiveness and possibility of large-scale production make LBDDs more attractive compared to polymeric nanoparticulate delivery systems [5].

Lipid carriers can be classified into various categories depending mainly on their method of preparation as well as their physicochemical properties. They include liposomes, niosomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), micro and nanoemulsions, self-emulsifying drug delivery systems

Liposomes are uni- or multilamellar spherical vesicles which are composed of cholesterol and other natural or synthetic phospholipids enfolding an aqueous compartment [6]. They were first introduced by Bangham et al. in 1965 [7]. Thus, liposomes have been considered as biocompatible and biodegradable carriers that possess efficient delivering capability of hydrophilic and hydrophobic drugs. Advantages of liposome-based drug delivery systems include reduction of systemic and of target toxicities as well as targeting potential to achieve the desired outcome [8]. Thus, many liposome formulations have been approved for commercial use such Ambisome® (amphotericin B), Depocyt® (cytarabine), DepoDur® (morphine sulfate) and many others. However, their poor stability and rapid elimination by reticuloendothelial

system limit the widespread applicability of liposomal formulations [4].

Niosomes are first described by Handjani-Vila et al. in 1979 [9]. They are nonionic surfactant-based vesicles in which the hydrophilic surfactant heads are oriented toward the exterior and the interior of the bilayer while, the hydrophobic tails are enclosed inside the bilayer. Therefore, like liposomes, niosomes have the ability to encapsulate hydrophilic or lipophilic molecules [10]. Niosomes also have cholesterol in their structure which enhances the rigidity of bilayer and reduces premature drug release [11]. Niosomes are superior carriers to liposomes in terms of

production cost, chemical and physical stability, and loading capacity [12].

SLNs and NLCs are the most widely described solid-core lipid-based nanocarriers in the scientific literature [3]. SLNs were first described in 1991 to replace the liquid oil of O/W emulsions by a single solid lipid or mixture of solid lipids [2]. SLNs are composed of either solid lipid or mixture of lipids, that do not melt at room or physiological temperature, in an aqueous dispersion stabilized with the help of nonionic surfactants [3].SLNs offer the advantage of avoiding the use of organic solvents during preparation, effective delivery of both hydrophilic and lipophilic drugs, feasibility of surface functionalization with specific moieties to enhance their targeting potential, possibility of extended or controlled drug release, long shelf-life, biocompatibility, lower acute or chronic toxicity and effective largescale production [2, 13, 14]. On the other hand, efficient drug delivery by SLNs is challenged by low drug loading capacity due to lipid crystalline nature, expulsion of loaded drug due to perfect crystalline lattice formation of the lipid and erratic gelation tendency that results in particle aggregation during storage [4, 14].

NLCs were developed to overcome the problem of drug expulsion during phase transition or crystallization of lipids comprising SLNs [15]. They also exist as a solid lipid matrix at temperature up to about 40°C. However, they are composed of solid lipid mixed with an oil which in turn reduces the lipid crystallization capacity and

Nanoemulsions are kinetically stable heterogeneous systems composed of ultrafine oil droplets dispersed in aqueous media and stabilized by the aid of surfactants

**48**

activity for enhancing the oral bioavailability of P-gp substrate drugs and reversing MDR in tumor cells. Among these strategies, nanocarriers have been widely investigated [26]. Nanocarriers have the advantage of protecting P-gp substrates against premature release and interaction with the biological environment [30]. They control drug tissue distribution and favorably accumulate in tumor tissue [31, 32]. Among various nanocarriers, SEDDS have been widely explored to enhance the oral bioavailability of P-gp substrate drugs and reverse MDR in tumor cells.

Interestingly, the unique combination of SEDDS properties allows the enhancement of oral bioavailability of both hydrophobic and hydrophilic drugs [33]. The oral delivery of protein therapeutics and genetic materials represents a real challenge due to their hydrophilic nature and their large molecular weight. In this chapter, we discuss the recent progress in the application of SEDDS for enhancing the oral bioavailability of P-gp substrates, reversing MDR in tumor cells and oral delivery of protein therapeutics and genetic materials. The aim of the current discussion is to call attention to the unique combination of SEDDS properties that makes them multifunctional delivery systems acting *via* various mechanisms to enhance the oral delivery of target therapeutic agents.

#### **3.1 SEDDS overcome P-gp-mediated efflux and reverse MDR in tumor cells**

Over the past 2 decades, SEDDS have been widely investigated to overcome P-gp-mediated efflux of substrate drugs to enhance their oral bioavailability. The potential of SEDDS to inhibit P-gp activity relies mainly on the excipients with established P-gp inhibition activity that are employed in the formulation [26]. Nonionic surfactants are the most widely employed excipients and are considered the mainstays of P-gp inhibition by SEDDS [29]. Cremophor EL, Cremophor RH40, vitamin E TPGS 1000, Labrasol, Transcutol P and Tween 80 are the most frequently employed. P-gp inhibition activity of a given surfactant depends on its HLB value and the structure of its hydrophobic domain [34]. There is no obvious correlation between surfactants' HLB values and P-gp inhibition activity. Structurally, the hydrophobic moieties of the surfactant should be linked to polyoxyethylene hydrophilic side chains to inhibit P-gp activity [34].

The binding affinity of nonionic surfactants to the hydrophobic portion of P-gp molecule is different from that of ionic surfactants [35]. Nonionic surfactants can change the secondary or tertiary structure of P-gp molecule resulting in the loss of its function [36]. Additionally, non-ionic surfactants were reported to modulate P-gp activity by inhibiting P-gp ATPase activity and either membrane fluidization or rigidization [37, 38]. At concentrations below the critical micelle concentration, nonionic surfactants are most effective in reducing P-gp activity; however, surfactant micelles showed some P-gp modulation activity [26].

SEDDS have superior formulation efficiency and *in vivo* performance compared to their individual components [39]. Various formulation aspects of SEDDS can potentiate the P-gp inhibition activity of their ingredients. The entrapment of P-gp substrate within the ultrafine emulsion droplets provides a protection against recognition by P-gp efflux pumps at GI epithelium [33]. In addition, SEDDS allow the co-administration of several excipients which are co-localized in close proximity to GI epithelium [22]. Further, pharmaceutical excipients with established P-gp inhibition activity (e.g., curcumin) or traditional P-gp inhibitors (e.g., elacridar) could be loaded into the SEDDS formulation to further augment their P-gp inhibition activity [40, 41].

On the other hand, the efflux of chemotherapeutic agents by P-gp transporters, which are overexpressed in tumor cells, represents a major obstacle in cancer chemotherapy [42]. SEDDS are extensively investigated to overcome MDR in tumor

**51**

▪

*†*

**Table 1.**

*Absolute bioavailability.*

*Ref. [33] © Elsevier (2018).*

*Self-Emulsifying Drug Delivery Systems: Easy to Prepare Multifunctional Vectors for Efficient…*

cells which is partly attributed to the overexpression of P-gp efflux transporters. SEDDS allow the combinational delivery of multiple chemotherapeutic agents acting *via* independent pathways in the same vector to produce a synergistic anticancer activity [42]. Interestingly, SEDDS could be employed for the co-delivery of various

antioxidants for overcoming the oxidative stress in cancer cells [43].

**Protein SEDDS composition Bioavailability** 

Cremophor EL (33.3%) Transcutol HP (25%)

Cremophor EL (25%) Co-solvent (DMSO and glycerol, 1:3) (10%)

Cremophor El (32.5%) Alcohol (32.5%)

Cremophor EL (30%) Propylene glycol (10%) Captex 355 (30%)

SoyPC (9.6%) Span 80 (21.1%) Oleic acid (36.1%) MCT (12%) 0.5% gelatin solution (3%) H2O (12%) **Surfactant phase:** Tween 80 (6%)

Capmul MCM (30%) Cremophor El (30%) Propylene glycol (10%)

Labrafil 1944 (35%) Capmul PG 8 (25%) Cremophor EL (30%) Propylene glycol (10%)

*Abbreviations: DMSO, dimethyl sulfoxide; MCT, medium chain triglycerides.*

β-lactamase Lauroglycol FCC (41.7%)

Insulin Miglyol 840 (65%)

Insulin Ethyl oleate (35%)

Leuprorelin Capmul MCM (30%)

Pidotimod† **Oil phase:**

Enoxaparin Captex 8000 (30%)

*Self -double emulsifying drug delivery system.*

**3.2 SEDDS enhance the oral delivery of protein and peptide therapeutics**

Protein therapeutics have a significant role in almost every field of medicine. However, the extensive application of protein therapeutics is challenged by their route of administration, being administered by parenteral route which is associated with reduced patient compliance [44]. Consequently, there is a great interest in the development of noninvasive strategies for delivery of protein therapeutics [45]. Oral delivery systems have been extensively investigated for the administration of protein drugs [46]. Unfortunately, the oral delivery of protein and/or peptide therapeutics is challenged by several barriers including the acidic environment

**increase**

1.29-fold β-lactamase

17.2-fold Leuprolide

2.56-fold Pidotimod

2.25%▪ Enoxaparin IV

2.02%▪

*SEDDS-mediated enhancement in the oral bioavailability of various proteins. Reprinted with permission from* 

solution

3.33-fold Insulin solution Sprague–

6.5-fold Insulin solution Male Wistar

acetate solution

solution

solution

**Control Animal** 

**species**

Sprague– Dawley rats

Dawley rats

rats

Sprague-Dawley rats

Sprague– Dawley rats

Sprague-Dawley rats **Ref.**

[54]

[55]

[56]

[57]

[48]

[58]

*DOI: http://dx.doi.org/10.5772/intechopen.88412*

*Self-Emulsifying Drug Delivery Systems: Easy to Prepare Multifunctional Vectors for Efficient… DOI: http://dx.doi.org/10.5772/intechopen.88412*

cells which is partly attributed to the overexpression of P-gp efflux transporters. SEDDS allow the combinational delivery of multiple chemotherapeutic agents acting *via* independent pathways in the same vector to produce a synergistic anticancer activity [42]. Interestingly, SEDDS could be employed for the co-delivery of various antioxidants for overcoming the oxidative stress in cancer cells [43].
