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Expert Opinion on Drug Delivery

ISSN: 1742-5247 (Print) 1744-7593 (Online) Journal homepage: http://www.tandfonline.com/loi/iedd20

Self-nano-emulsifying drug delivery systems: anupdate of the biopharmaceutical aspects

Irina Cherniakov PhD , Abraham J Domb & Amnon Hoffman

To cite this article: Irina Cherniakov PhD , Abraham J Domb & Amnon Hoffman (2015) Self-nano-emulsifying drug delivery systems: an update of the biopharmaceutical aspects, ExpertOpinion on Drug Delivery, 12:7, 1121-1133

To link to this article: http://dx.doi.org/10.1517/17425247.2015.999038

Published online: 05 Jan 2015.

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1. Introduction

2. The impact of the

physicochemical properties of

SNEDDS on its in-vivo

performance

3. SNEDDS effect on solubility

4. SNEDDS effect on permeability

through biological membranes

and on transporters

5. SNEDDS effect on first-pass

metabolism

6. SNEDDS effect on oral

bioavailability

7. Candidate compound selection

8. Expert opinion

Review

Self-nano-emulsifying drugdelivery systems: an updateof the biopharmaceutical aspectsIrina Cherniakov, Abraham J Domb & Amnon Hoffman†

†Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of

Jerusalem, Jerusalem, Israel

Introduction: Thirty percent of top marketed drugs in the USA and 70% of all

new drug candidates are lipophilic and exhibit poor water solubility. With

such physicochemical properties, the oral bioavailability of these compounds

lacks dose proportionality, is very limited and extremely erratic. Different

lipid-based formulations have been explored in the past few decades to

improve the oral delivery of such compounds. In recent years, the most

popular approach is their incorporation into self-emulsifying drug delivery

systems (SEDDS), with particular emphasis on self-nano-emulsifying drug

delivery systems (SNEDDS).

Areas covered: This review offers an updated overview of SNEDDS application

from the biopharmaceutical point of view. The focus of this review deals with

the potential of SNEDDS utilization to overcome absorption barriers following

oral administration of lipophilic drugs. This includes a comprehensive description

of the primary mechanisms by which lipids and lipophilic excipients, used to

formulate SNEDDS, could affect drug absorption, bioavailability and disposition

following oral administration.

Expert opinion: The utilization of SNEDDS to augment the oral bioavailability

of poorly water-soluble drugs goes beyond improvement in drug’s solubility,

as was initially presumed. In fact, SNEDDS have a potential to increase oral bio-

availability by multi-concerted mechanisms such as reduced intra-enterocyte

metabolism by CYP P450 enzymes, reduced P-glycoprotein (P-gp) efflux

activity and hepatic first-pass metabolism bypass via lymphatic absorption.

This unique biopharmaceutical point of view, presented in this review, con-

tributes to the understanding of proper drug candidate selection and of the

approach in SNEDDS formulation design.

Keywords: intra-enterocyte metabolism, lymphatic delivery, oral bioavailability, P-gp efflux,

poorly water-soluble drugs, self-emulsifying drug delivery systems, solubilization

Expert Opin. Drug Deliv. (2014) 12(7):1121-1133

1. Introduction

The oral route is the preferred mode of drug administration due to its safety,comfort, low cost and improved patient compliance. The drug’s presence in asolution at the absorptive site of the gastro intestinal (GI) tract is a prerequisitefor oral absorption. Poor drug solubility is a significant and frequently encounteredproblem for pharmaceutical scientists. The introduction of combinatorial chemistryaccompanied by advances in in-vitro high-throughput screening methods hasresulted in the rapid identification of many highly potent but poorly water-solubledrug candidates. In fact, to date > 30% of top marketed drugs in the USA and 70%of all new drug candidates are lipophilic and exhibit poor water solubility [1,2].In addition, many other promising active compounds do not reach clinical phasesin their development process due to their poor oral bioavailability.

10.1517/17425247.2015.999038 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 1121All rights reserved: reproduction in whole or in part not permitted

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The Biopharmaceutics Classification System (BCS) dividesthese drugs into two categories called Class II and Class IV.Class II drugs are defined as being poorly water soluble andhighly permeable through biological membranes. Class IVdrugs have poor water solubility and are poorly permeablethrough biological membranes [3].Having such physicochemical properties, the oral bioavail-

ability of these drugs is very limited and is extremely erratic, insome cases, ranging from 2 to 90%. Moreover, in addition topoor water solubility, certain lipophilic drugs have beenreported to be substrates for different membrane transportersand for metabolism via CYP P450 enzymes, as detailed inthis review.A promising strategy to overcome these obstacles is the

development of suitable DDS. As the in-vivo behavior of adrug is dictated not only by the drug itself, but also by itsmode of administration and the carrier system, which shouldenable an optimal release profile according to therapy require-ments [4]. Different lipid-based formulations were explored inthe past few decades to improve the oral delivery of lipophilicdrugs. In recent years, the most popular approach is theirincorporation into self-emulsifying drug delivery systems(SEDDS) with particular emphasis on self-nano-emulsifyingdrug delivery systems (SNEDDS).SNEDDS are isotropic homogenous mixtures of an active

compound in a combination of natural or synthetic lipids,surfactants and co-solvents. These anhydrous liquid mixturesare commonly termed pre-concentrates. Upon gentle agitationin an aqueous phase, such as the upper GI lumen content,these pre-concentrates spontaneously form drug-encapsulated

O/W nano-emulsions with a particle diameter of 200 nm orless. Contrary to emulsions and suspensions, SNEDDS arehighly thermodynamically stable formulations [5,6]. SNEDDScan be filled into soft/hard gelatin capsules or hydroxypropyl-methylcellulose capsules, which results in attractive commer-cial viability and patient compliance. A key factor is that thedose volume can be restricted to meet the maximal 1 g offormulated liquid that soft gelatin capsule can contain [7].

During the past decade several reviews covered the formu-lation design process and the physico-chemical characteriza-tion of SNEDDS; however, the biopharmaceutical aspectswith emphasis on oral drug absorption from SNEDDS wereonly briefly addressed.

In 2012 Khan et al. have published an excellent review cov-ering a summary of the lipid formulation classification systemproposed by Pouton in 2000, advantages of SNEDDS overmicro/nano-emulsions and a detailed discussion concerningthe selection of excipients for SNEDDS development. Addi-tionally, an overview of phase behavior diagrams, mechanismof self-emulsification and in-vitro SNEDDS characterizationwas also provided in great detail. Thus, these physico-chemical aspects of SNEDDS are not addressed in thecurrent review.

This review offers a comprehensive and updated overviewof SNEDDS utilization from the biopharmaceutical point ofview. The focus of this review is on the potential in SNEDDSutilization to overcome absorption barriers following the oraladministration mainly of BCS Class II compounds. Thisincludes an inclusive description of the primary mechanismsby which lipids and lipophilic excipients, used to formulateSNEDDS, can affect drug absorption, bioavailability and dis-position following oral administration. Current reports onSNEDDS effects on: i) pre-enterocyte level (alteration of thecomposition and character of the intestinal milieu andincreased solubilization); ii) intra-enterocyte level (interactionwith enterocyte-based transport processes such as permeabilitythrough the cell membrane and effects on intra-enterocytemetabolism and drug transporters); and iii) post-enterocytelevel (recruitment of intestinal lymphatic drug transport) arebroadly detailed.

2. The impact of the physicochemicalproperties of SNEDDS on its in-vivoperformance

2.1 Particle sizeIn the case of peroral administration the accurate estimationof the particle size of SEDDS is extremely important as itcan have a direct impact not only on the in-vitro evaluatedparameters (e.g., stability and release kinetics) but also onin-vivo performance [4]. It has been reported that smallerdroplet size measured in-vitro has a favorable effect on thebioavailability of the drug incorporated into SEDDS. Tarrand Yalkowsky assessed the bioavailability of cyclosporine

Article highlights

. Lipids and lipophilic excipients, used to formulateSNEDDS, can affect the oral absorption, bioavailabilityand disposition of mainly poorly water-soluble andhighly metabolized drugs.

. Aside from enhanced oral bioavailability, SNEDDS havebeen reported to reduce intra- and inter-patientvariability in the drug plasma concentration profile.

. The size and the charge of the particles formed,following introduction of SNEDDS to the water phase,can affect not only stability and release kinetics, butmay also dictate the extent of absorption of theincorporated drug.

. As SNEDDS are administered as a pre-concentrateformulation, which forms nano-dispersion only uponexposure to the fluids of the GI milieu, their long-termstability properties are not of a crucial importance.

. To date, there are only a few approved commercial self-emulsifying products available on the pharmaceuticalmarket due to: difficulty in incorporation of a lipophiliccompound into SNEDDS, precipitation of the drugfollowing dispersion of SNEDDS in aqueous media of theGI tract milieu and absence of proper guidelines onformulation design of lipid-based formulations.

This box summarizes key points contained in the article.

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A (CsA) in rats by administrating the drug in micro-emul-sions, forming particles of different sizes. Upon reduction ofthe size of the droplets, enhanced oral absorption of CsAwas observed [8]. It should be noted that in that study theformulations were prepared using the same ingredients anddiffered only by the method of preparation. Thus, other influ-ences on the bioavailability of the drug can be ruled out; thesole applicable factor on CsA bioavailability is the effect ofthe size of the particles [9]. Findings of a study published in2004 by Bekerman et al. corroborate the results described byTarr and Yalkowsky. This study evaluates several SNEDDSformulations incorporating CsA in healthy volunteers. Therange of the particle size formed upon introduction of theseSNEDDS into aqueous phase varied between 25 and400 nm. This study result demonstrates an inverse correlationbetween the particle size of the studied SNEDDS and the oralbioavailability of the incorporated CsA [10]. A similar trendwas observed and reported by several other researches investi-gating versatile lipid-based formulations [11-13].

Thus, it is reasonable to deduce that particle size distribu-tion can be of great importance on the oral bioavailability ofa drug incorporated into SNEDDS.

2.2 Zeta potentialHigh values of zeta potential (± 30 mV) exhibit strong electro-static repulsive forces, thus ruling out the possibility of floccu-lation indicating formation of stable SNEDDS [14]. However,as SNEDDS are administered as a pre-concentrate formula-tion, which forms nano-dispersion only upon exposure tothe fluids of the GI milieu, this characteristic is not of crucialimportance. Therefore, the long-term stability of the obtainednano-emulsion in-vitro is less relevant.

Nonetheless, the charge of the particles formed can have aninfluence on the oral bioavailability of the drug incorporatedinto SNEDDS. Charge-dependent interactions with humanintestinal cells with respect to absorption enhancement havebeen reported [15].

The apical surface of the intestinal epithelial cells is nega-tively charged with respect to the mucosal solution in thelumen [16]. Gershanik et al. developed SEDDS incorporatingprogesterone, which form positively charged particles upondilution with the aqueous phase. They hypothesized that thepositively charged particles can interact with the negativelycharged mucosal surface of the GI tract and increase the cellu-lar uptake of the incorporated drug. Indeed, oral administra-tion of this formulation results in an increased bioavailabilityof progesterone in female rats [17]. This hypothesis is furtherconfirmed by the administration of SEDDS incorporatingCsA in the perfused rat model. Higher blood concentrationsfollowing administration of positively charged SEDDS com-pared to corresponding negatively charged SEDDS areobserved [18]. Though, the impact of the differences in theexcipients may cause this effect via (yet) unknown mecha-nism(s).

It can thus be concluded that the size and the charge of theparticles formed, following introduction of SNEDDS to thewater phase, can affect not only stability and release kinetics,but may also dictate the extent of absorption of theincorporated drug.

3. SNEDDS effect on solubility

Only after the drug molecule is presented in its dissolved statecan it partition into the enterocyte and finally cross it. Thebioavailability of BCS class II compounds is significantlyhampered due to their poor water solubility. The primarymechanism by which lipid-based formulations enhance drugsolubilization is by delivering the entire dose as a solution.Thus, the limiting step in drug absorption, that is, the slowdissolution from the crystalline state is avoided [19].

The digestion of lipid-based formulations includingSNEDDS induces changes in lipid composition within theGI tract. Thus, the solubilized phase is not obtained directlyfrom the administered lipid-based formulation, but mostlikely from the intra-luminal processing to which lipids aresubjected prior to absorption [20]. A review of the physiologyof the GI lipid absorption is, therefore, a key to understandingthe role of lipids and the mechanism by which lipid-based for-mulations enhance drug solubilization.

The presence of lipid and lipid-digestion products in theduodenum stimulates secretion of endogenous biliary-derivedsolubilizing components such as bile salts and biliary lipids(cholesterol and phospholipids). Bile increases the solubilityof lipid digestion products (i.e., 2-monoglyceride and fattyacids) in the aqueous intestinal lumen by their incorporationinto micellar and mixed-micellar structures. The polar groupof micells projects into the aqueous phase, whereas the nonpo-lar hydrocarbon chain forms the center [21,19]. The formationof the aqueous mixed micellar phase significantly expands thesolubilization capacity of the small intestine. When a poorlywater-soluble drug is administered with dietary lipids orwith lipids present in the formulation, the drug is distributedbetween these colloidal species. This process prevents drugprecipitation and leads to an increase in effective aqueoussolubility of the co-administered poorly water-solublecompound. Moreover, SNEDDS utilization provides a largeinterfacial area for partitioning of the incorporated lipophilicdrug between oil and the GI fluid [22].

Numerous studies report increased dissolution of variouspoorly water-soluble compounds by their incorporation intoSNEDDS. For example, incorporation of a poorly water-soluble lacidipine into SNEDDS significantly increases itsin-vitro solubility [23]. It should be kept in mind, however,that promising results observed in in-vitro models are oftennot corroborated by in-vivo studies. Thus, further in-vivoevaluation is necessary to investigate whether SNEDDSformulations, which successfully increase drug’s in-vitrosolubility, can promote enhanced oral bioavailability.

SNEDDS: an update of the biopharmaceutical aspects

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The micellar solubilization has another important role inovercoming a further barrier to effective uptake of lipophiliccompounds. This is diffusion across the unstirred water layer(UWL). UWL separates the brush-border membrane of theenterocyte from the bulk fluid phase in the intestinallumen [24]. The UWL, as the name implies, mixes poorlywith the bulk phase in the intestinal lumen. As the solubilityof lipophilic compounds in an aqueous medium is extremelylow, very few molecules gain access to the brush-border mem-brane [25]. Solubilization of fatty acids, monoglycerides andlipophilic drugs in micellar and mixed-micellar structures,however, can greatly enhance their transport across theUWL, thereby enhancing lipid and drug absorption [19].

4. SNEDDS effect on permeability throughbiological membranes and on transporters

It was proposed that increased transcellular permeability couldbe a possible cause of improved oral bioavailability by SNEDDSutilization. One of the proposed mechanisms behind this phe-nomenon is attributed to the association of SNEDDS compo-nents with the enterocyte membrane, leading to an increase inits fluidity and thus enhanced passive permeability [26-28].Other studies have pointed out that the alteration in the

membrane fluidity by SNEDDS components can alter the con-formation of membrane-bound transporters and promote theinhibition of membrane-bound efflux transporters. Thus, theincrease in drug permeability is a result of a reduced efflux [29,30].These may be two different and isolated mechanisms inde-

pendent from one another. It is also possible that theenhanced permeability of the drug by SNEDDS utilizationcould result from the combination of the mechanismsdescribed above, that is, increased passive transcellular trans-port together with efflux inhibition.

4.1 SNEDDS effect on efflux transportersAn increasing body of evidence has shown that certain non-ionic surfactants used to formulate SNEDDS can reducedrug efflux pumps activity.An efflux transporter of particular interest in regard to drug

absorption is the MDR 1 gene product P-glycoprotein (P-gp).This plasma membrane-bound protein is mainly distributedin drug-eliminating organs [31,32]. In the apical membrane ofthe intestinal epithelial cells, its role is to efflux compoundsback into the intestinal lumen. It can, therefore, act as abarrier to the oral absorption of P-gp substrates.Tweens, Spans, Cremophors (EL and RH40) and vitamin

E TPGS are examples of non-ionic surfactants, which havebeen reported to inhibit the P-gp efflux activity [33-36].Zhang et al. report an increased maximal concentration ofdrug in plasma (Cmax) and area under the curve (AUC)of a well-known P-gp substrate digoxin when it was orallyadministered with Tween 80 to rats. Moreover, their findingsindicate that P-gp efflux inhibition is produced in a dose-dependent manner [37].

P-gp and intra-enterocyte metabolizing enzymes (mainlyCYP3A4, which are elaborated in great detail in the nextsection) share numerous substrates and inhibitors; they proba-bly work coordinately as a protective mechanism and areresponsible for the poor bioavailability mainly of class IIdrugs [38]. Thus, when conducting studies to investigate theSNEDDS mechanism of action responsible for enhanced oralbioavailability, it is difficult to distinguish between these twoabsorption barriers. Bearing this in mind, the authors haveincorporated into SNEDDS an exclusive P-gp substrate talino-lol, which is not subjected to intra-enterocyte metabolism [39].The results of this study demonstrate a threefold increase intalinolol relative oral bioavailability following administrationof talinolol-SNEDDS compared to a free drug (Figure 1) [40].Once finding an exclusive P-gp substrate, the authors wereable to isolate the effect of their SNEDDS on the P-gp activity.

It is worth noting that for BCS Class II compounds, whichare commonly formulated into SNEDDS, poor permeabilityis not a limiting factor in their absorption pathway [3]. How-ever, the effect of efflux transport by P-gp can significantlylimit their oral bioavailability [41]. Thus, the increased perme-ability of BCS Class II compounds by SNEDDS should beattributed to diminished efflux of the compound, ratherthan to the increased passive transcellular transport.

4.2 SNEDDS effect on uptake transportersUsually, when investigating SNEDDS effects on intestinaltransporters, the research is focused on the efflux transport, asdescribed above. Recently a surprising issue was raised. It wasreported that surfactants could also affect uptake intestinaltransporters. This new insight implies that surfactant oraladministration may lead to reduced or increased permeability,depending on the contribution of the individual event [36].

Several uptake transporters including organic anion trans-porting polypeptide (OATP) are expressed in the apical mem-brane of enterocytes. These transporters were reported to beinvolved in the oral absorption of many endogenic com-pounds and xenobiotics [42,43]. Dresser et al. report that grape-fruit, orange and apple juices’ administration to humanvolunteers significantly reduces the uptake of an OATP sub-strate fexofenadine and decreases its AUC and Cmax [44].Additionally, in-vitro studies conducted by Engel et al. indi-cate that polyethylene glycol, Solutol HS and CremophorEL inhibit some of the OATP family transporters [45].

To date, there is a significant lack in comprehensive under-standing of the possible SNEDDS effect on uptake transport-ers and its clinical relevance to drug bioavailability. Thus, thissubject should be further evaluated.

It should be pointed out, though, that in the case of BCSclass II drugs, which are highly permeable compounds, intes-tinal uptake transporters most probably do not have animportant influence on their absorption. Some drugs, how-ever, especially low permeable compounds depend on uptaketransporters in the intestine to achieve effective systemic con-centrations. In this case, the administration of surfactants

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alone or by SNEDDS utilization could have an unfavorableeffect on their oral bioavailability.

5. SNEDDS effect on first-pass metabolism

It was generally assumed that the liver exerted the dominanteffect in the first-pass metabolism process, whereas the intestinalwall was presumed to function as a physical barrier to drug per-meability. This traditional point of view was based on the obser-vation that the protein levels of drug-metabolizing enzymes inthe small intestine were found to be generally significantly lowerthan those in the liver [46,47]. Nonetheless, enzymes of theCYP3A sub-family were found to be highly expressed in themature villus tip enterocytes of the small intestine [48,49]. TheCYP3A sub-family of enzymes is considered to have a majorrole in Phase I metabolism in human beings. In fact, theCYP3A sub-family is responsible for the oxidative metabolismof ~ 50% of currently marketed drugs [50]. It was shown thatenzymes of the CYP3A family constitute > 70% of the smallintestinal CYP P450s, whereas CYP3A constitute only 30% oftotal human hepatic CYP [47,51]. Thus, the perception that theliver is the only major organ responsible for the first-pass effectwas replaced by the realization that the intestinal wall can alsosignificantly contribute to the drug metabolism process.

Research conducted in the past two decades confirms thishypothesis. The most prominent example of intestinalPhase I metabolism was reported by Benet et al. Their clinicalpharmacokinetic studies demonstrate the substantial role ofthe intestinal metabolism on the oral bioavailability of CsAin healthy volunteers. The study results reveal that 14% ofthe orally administered CsA is unabsorbed, due to either irre-versible efflux by P-gp or degradation in the GI, 51% (of theabsorbed dose) is metabolized in the enterocytes and only 8%is lost due to hepatic first-pass metabolism [52]. Moreover,intestinal Phase I first-pass metabolism has been shown tobe clinically relevant for several other drugs, among them

are midazolam, tacrolimus, nifedipine, felodipine and verapa-mil [53,54]. Thus, these observations of the past two decades ledto greater credence to the preeminence of intestinal enzymesin the first-pass metabolism process. Therefore, the impactof intestinal, Phase I first-pass metabolism on oral drug bio-availability, should not be overlooked or underestimated.

It is worth noting that intestinal first-pass metabolism andhepatic first-pass metabolism are two different processes. Thisfact is sometimes overlooked, which can lead to some miscon-ceptions in the drug development process. These metabolicroutes should be distinguished, because for some drugshepatic first-pass metabolism is the main barrier in theabsorption process, whereas for others intestinal first-passmetabolism predominates. This is important to realize,because the means to bypass hepatic first-pass metabolismare different from those that can be applied to evade metabo-lism by the intestinal wall.

5.1 Reduced intra-enterocyte metabolism by SNEDDSAn increasing body of evidence has shown that certain compo-nents used to formulate SNEDDS can affect the disposition ofdrugs by inhibiting CYP enzymes in cellular microsomes of theenterocytes. Shen et al. report that the oral bioavailability of aCYP3A4 substrate atorvastatin is significantly increased uponincorporation into SEDDS containing Cremophore [55]. Inthe study by Ren et al., 22 pharmaceutical excipients weretested for their ability to inhibit the activity ofCYP3A4 enzymes [56]. Fifteen of the tested excipients, amongstwhich are Tween 20, Cremophore 35, lecithin and CremophorRH40, inhibit the activity of CYP3A4 by at least 50% in-vitro.Similar results were obtained in their in-vivo midazolam(a CYP3A4 substrate) study. Ren et al. [57] also indicate thatnon-ionic surfactants inhibit midazolam metabolism in aconcentration-dependent manner and meet the criteria for amixed competitive inhibitory model.

5.2 Stimulation of intestinal lymphatic drug

transport to avoid hepatic FPMThe intestinal lymphatic system is a physiological pathway forthe absorption of dietary lipid digestion products, for exam-ple, long chain fatty acids (LCFA), triglycerides (TG) andcholesterol esters [58]. Within intestinal cells the LCFAs andmonoglycerides are re-esterified into TG in the endoplasmicreticulum. Before these TGs leave the enterocytes they areincorporated into chylomicrons. Chylomicrons are the largestlipoproteins found [59]; thus, they cannot enter blood capillar-ies. Instead they enter the lymphatic capillaries termed lac-teals, which are located in the villi of the enterocyte(Figure 2) [19]. This way post prandial lipids, which enter thelymph, bypass the liver at first passage. Eventually the lymphreunites with the blood at the junction of the left jugular andthe left subclavian veins [60].

The pharmaceutical community hypothesized that thisunique physiological route of lipid absorption can be exploited

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Talinolol_SNEDDS

Talinolol

Time (h)

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Figure 1. Plasma talinolol concentration vs time plot

(mean ± SD) following oral administration of talinolol and

talinolol-SNEDDS 4 mg/kg (n = 6 for each group).SNEDDS: Self-nano-emulsifying drug delivery systems.

SNEDDS: an update of the biopharmaceutical aspects

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as a potential means of DDS to circumvent hepatic first-passmetabolism. It was presumed that some lipophilic drugs mayassociate with TG of the chylomicrones in the enterocyte andenter the systemic circulation via the lymphatic rout [61].Indeed, it has been reported that lipid-based delivery systems

such as SNEDDS can be utilized to promote lymphatic drugtransport. The oil phase used in SNEDDS formulations is acomponent of great importance. Not only can it facilitate thesolubilization of a lipophilic compound; but it can also affectthe absorption pathway of the incorporated drug [62]. Severalresearchers report that the biological fate of the drug is primarilyinfluenced by long-chain triglycerides (LCTs), thus indicatingthat lipid-based delivery systems containing LCTs, such asSNEDDS, can promote the lymphatic transport of lipophilicdrugs, while bypassing the hepatic portal vein route andenhancing the oral bioavailability of the drug [19,63].Recently it has been reported that not only the oil compo-

nent of SNEDDS can promote lymphatic transport, but

certain surfactants can also produce the same effect [64,65]. Asthe concentration of surfactants in SNEDDS formulations ishigh and can reach up to 60% [66], their contribution to thelymphatic transport needs to be further explored.

It should be noted that the fluid flow rate in portal bloodis ~ 500-fold higher than that of intestinal lymph. Thus,most low-molecular-mass drugs are absorbed through the por-tal vein [19]. Therefore, to enter the lymph the targeted drugshould exhibit an intrinsic capacity for intestinal lymphatictransport. There are a number of in-vivo models to investigatedrug presence in the lymph [67-69]. For example, an in-vivomodel used is the lymphatic venous shunt. Using this modeldrug concentration in lymph can be measured for a longperiod of time by collecting a sample of the lymphaticfluid [70]. However, these models are very difficult to perform,time consuming and require high surgical skills. For thisreason, an ex-vivo model for studying intestinal lymphatictransport was developed. This model is based on the findingthat there is a linear correlation between the degree of uptakeof lipophilic molecules by plasma-derived chylomicrons andthe extent of lymphatic transport measured in-vivo(Figure 3) [71]. Thereafter, these researchers took this approacheven further, to provide in-silico estimation of the expectedlymphatic bioavailability impact of TG formulation on mole-cules prior to their synthesis [72].

Although the observed enhanced oral bioavailability issometimes hypothesized to be a result of enhanced lymphatictransport of the lipophilic drug by SNEDDS utilization, onlya limited number of studies have investigated the direct lym-photropic potential of SNEDDS using the models describedabove. An example is a study conducted by Hauss et al. [73]

and a study conducted by Wu et al. [74].It should be emphasized that drugs that are trafficked to the

systemic circulation via the intestinal lymphatic system effec-tively by-pass the liver, consequently reducing the opportu-nity for hepatic first-pass metabolism. However, it should bekept in mind that the intestinal metabolism is not bypassedand can provide significant first-pass effect prior to the enter-ing of the drug into the lymphatic system.

6. SNEDDS effect on oral bioavailability

The previous sections of this review focuses on the differentbarriers in the absorption process of mainly Class II com-pounds in the isolated manner. The current chapter providesan insight into the overall SNEDDS effect using oral bioavail-ability as the end point of the investigation.

Diverse liquid SNEDDS have been developed and haveshown superior in-vivo characteristics in terms of improvedoral bioavailability (Table 1).

Aside from enhanced oral bioavailability, SNEDDS havebeen reported to decrease the influence of food effect [75],and bile secretion on oral bioavailability. Moreover, reducedintra- and inter-patient variability in the plasma concentrationprofile by SNEDDS was reported [75,76].

Opening

Lymph

Chylomicron

Chylomicrons75 – 1200 nm

B.

A.

VLDL30 – 80 nm

LDL18 – 25 nm

HDL5 – 12 nm

Blood capillary

Figure 2. A. The figure depicts the structure of blood and

lymph capillaries and their permeability to chylomicrons.

Blood capillaries have tight intercellular junctions whereas

the lymphatic vasculature is much leakier and freely perme-

able to large particles. Chylomicrons, due to their large

dimensions, cannot enter the blood circulation. Instead, they

enter the lymphatic capillaries. B. The picture depicts the size

of chylomicrons in comparison to other lipoproteins.

chylomicrons are the largest of the lipoproteins.LDL: Low-density lipoprotein; HDL: High-density lipoprotein; VLDL: Very-low-

density lipoprotein.

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The SNEDDS effect on the oral bioavailability of tacroli-mus has been examined. Tacrolimus is a potent immunosup-pressant [77,78]; however, its clinical use is hampered by itspoor oral bioavailability and extremely high inter- and intra-patient variability. This is due to extensive pre-systemic metab-olism by intra-enterocyte CYP3A enzymes and efflux by P-gppumps [79]. Study results indicate that the relative oral bioavail-ability of tacrolimus upon incorporation into SNEDDS wassignificantly greater in comparison to free drug [80]. Moreover,reduced variability in tacrolimus plasma concentrations isobtained following tacrolimus-SNEDDS administration. Theability of SNEDDS to increase oral bioavailability and reducevariability was further corroborated in recently performedstudies. An antiarrhythmic BCS Class II [81] compound amio-darone (AM) has been incorporated into SNEDDS [40]. AM ischaracterized by erratic, unpredictable absorption and low oralbioavailability (20 -- 80%), which is mainly mediated by intra-enterocyte metabolism via CYP3A4 [82]. The oral administra-tion of AM-SNEDDS to rats results in a 1.65 and 1.54-foldincrease in Cmax and AUC, respectively (Figure 4). In addition,incorporation of AM into SNEDDS results in reduced vari-ability in the AUC and Cmax values [40].

These findings emphasize the added value of SNEDDS,that is, reduced plasma fluctuations or a more predictiveabsorption in addition to enhanced oral bioavailability.

7. Candidate compound selection

SNEDDS have been stated by many scientists to be suitableformulations for improving the oral bioavailability, mainly of

BCS Class II drugs. BCS is a drug classification scheme for cor-relating in-vitro drug product dissolution and in-vivo bioavail-ability, based on the recognition that drug dissolution and GIpermeability are the fundamental parameters controlling rateand extent of drug absorption [3]. The BCS divides drugs anddrug candidates into four principal categories based on theseparameters: Class I -- High solubility-high permeability; ClassII -- Low solubility-high permeability; Class III -- Highsolubility-low permeability; and Class IV -- Low solubility-low permeability drugs. To date, > 30% of top marketed drugsin the USA and 70% of all new drug candidates are lipophilicand consequently have poor aqueous solubility, combinedwith high permeability through the enterocyte membrane;thus they frequently fall into Class II as defined by the BCS [2].

It was traditionally believed that the extremely low and erraticbioavailability of Class II compounds is hampered mainly due totheir poor water solubility. The use of lipid-based DDS such asSNEDDS for improving the bioavailability of Class II drugswas based on the observation that co-administration of poorlywater-soluble drugs with a high-fat meal can improve their bio-availability [83]. The prevailing viewwas that SNEDDS is an effec-tive and practical solution in improving the oral bioavailability ofa lipophilic compound by its presentation and maintenance in adissolved state. This way the drug is introduced in fine oil dropletsat the molecular level, throughout the transit in the GI tract.However, there are compounds for which poor water solubilityis not the main hurdle in their oral absorption process. The caseof cyclosporine is the most prominent example demonstratedby Wu et al. For example, CsA, a BCS Class II compound, is aP-gp and CYP3A substrate. It had no permeability difficultyand is absorbed at least 86% when solubilized with corn oil in acommercially available lipid-based formulation. Its oral bioavail-ability, however, is low due to amarked intra-enterocyte first-passextraction and P-gp efflux of 60% or more [84].

In light of these data, Wu and Benet examined the BCSfrom a biopharmaceutical perspective and developed a modi-fied classification system that may be useful in predictingroutes of elimination, effects of efflux and absorptive trans-porters as well as effects of transporter-enzyme interplay onoral absorption. They suggest that it may be more useful toreplace the permeability criterion with the major route ofdrug elimination and metabolism and proposed designationof the major route of drug elimination as a part of or insteadof, permeability criteria used in the BCS classifications.According to this model termed Biopharmaceutical DrugDisposition Classification System (BDDCS), drugs classifiedas Class II compounds are those for which the influence ofpre-systemic metabolism by CYP 450 enzymes and efflux byP-gp on oral drug bioavailability predominates. This isbecause their low solubility does not enable us to facilitateadequate drug concentrations at the absorption site to pro-duce the inhibition of those barriers [85].

It is reasonable to attribute the increased bioavailability ofgriseofulvin [86,87], vitamin A [88] and other solubility-limitedcompounds to improved solubilization. However, for extensive

20 40 60 80 1000(%) of drug associated with CM ex-vivo

(%)

of

do

se a

bso

rbed

into

inte

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al ly

mp

hat

ics

0

5

10

15

20

25

Halofantrine

Vit D

Vit E

Benzo[a]pyrene

Probucol

DiazepamCSATestosterone

p,p′ DDT

Figure 3. Lymphatic availability of tested drugs (% of dose)

versus degree of association of drugs with isolated

chylomicrons (CM) in the ex-vivo model (% of amount).Reprinted from [71] with permission from Elsevier � 2005.

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pre-systemic (and especially intestinal) metabolism substrates,such as for CsA [10,89], tacrolimus [90], simvastatin and most ofthe drugs and herbal remedies as those listed in (Table 1),enhancement of solubility by SNEDDS utilization is probablynot the onlymechanism responsible for their improved bioavail-ability. Moreover, several recent studies demonstrated that thesolubilization capacity of SNEDDS decreases following thelipolysis process in the GI tract, mainly as the nano-vesicle struc-tures do not remain intact following lipolysis, but rather becomea part of mixed micelles formed by bile salts, phospholipids andother GI composites [91]. Furthermore, some of the excipientsthat compose SNEDDS undergo digestion in the GI tract,which leads to significant loss of solubilization capacity [92].As elaborated in the previous sections of this review,

SNEDDS have demonstrated potential to increase oral bio-availability by multi-concerted mechanisms such as reducedintra-enterocyte metabolism by CYP P450 enzymes, reducedP-gp efflux activity and by promoting hepatic first-pass bypassvia lymphatic absorption. It is, therefore, more than reason-able to conclude that enhancement of solubility is obviouslynot the only mechanism responsible for improved oral bio-availability by SNEDDS. Thus, in the author’s opinion a

more accurate statement is that SNEDDS can serve as adrug delivery platform for poorly soluble and highly metabo-lized drugs, that is, Class II drugs as defined by the BDDCS.

Here are some examples from the literature to support thestated hypothesis. For instance, it was generally agreed thatpoor water solubility was the main reason for the low oral bio-availability of glyburide. Liu et al. developed SNEDDS incorpo-rating this poorly soluble drug [95]. Their in-vitro studies indicatethat SNEDDS increases the solubility of glyburide and elimi-nates the influence of pH on its dissolution. Additionally, oraladministration of this formulation results in a 1.53-fold increasein the relative bioavailability. The increased oral bioavailabilitywas judged to bemainly a result of the increased drug solubiliza-tion. Poor water solubility, however, is probably not the onlybarrier to its oral absorption. A study published by Zhou et al.reveals that glyburide undergoes metabolism mainly byCYP3A4 enzymes [93]. As elaborated above in Section 5.1,some components used to produce SNEDDS (such as Cremo-phore RH-40 used in the study by Liu et al.) reportedly inhibitthe activity of metabolizing enzymes [35]. Thus, there is a possi-bility that in addition to increased solubility, the oral bioavail-ability of this antiglycemic agent is also augmented due to the

Table 1. Examples of studies reporting enhanced bioavailability of different drugs upon their incorporation into

SNEDDS.

Drug Excipients Effect on oral

bioavailability

Study model Mechanism behind

elevated bioavailability

Ref.

Glyburide Miglyol 812, CremophorRH 40, 1,2-propandiol

1.53-fold increase in oralrelative bioavailability

Beagle dogs Increased solubility [95]

Atazanavir Maisine 35 -- 1 (C21),Transcutol P

2.13 and 2.57-foldincrease in Cmax andAUC, respectively

Rats Increased solubility,increased permeability,Possible lymphatictransport and reducedmetabolism

[96]

Valsartan Triacetin or Castor oil,Tween 80, PEG 600

For triacetin-SNEDDS5 and 2.4-fold increase inCmax and AUC,respectively; for castor oil-SNEDDS 8 and 3.6-foldincrease in Cmax andAUC, respectively

Rats Increased solubility,Possible lymphatictransport

[97]

Naringenin Triacetin, Tween 80,Transcutol HP

4.9 and 2.8-fold increasein Cmax and AUC,respectively

Rats Increased solubility [98]

Quercetin Castor oil, Tween 80,Cremophore RH 40,PEG 400

Three and two-foldincrease in Cmax andAUC

Rats Increased solubility

Talinolol Triacetin, Brij-721,ethanol

1.4-fold increase in AUC Rats Increased solubility,Increased permeability

[99]

Amiodarone Trilaurin, Tween 20, Span80, Cremophore RH 40,lecithin, ethyl lactate

1.8 and twofold increasein Cmax and AUC

Rats Increased solubility,reduced metabolism

[40]

Simvastatin Labrafil, Tween 80, andTranscutol

1.55 and 1.5-foldincrease in Cmax andAUC

Human volunteers Increased solubility [100]

SNEDDS: Self-nano-emulsifying drug delivery systems.

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inhibition of CYP3A4. A similar trend was seen in a study pub-lished by Ghai et al. [99]. They have incorporated a poorly water-soluble b1-adrenoreceptor blocker, talinolol, into SNEDDScomposed of triacetin, Brij-721 and ethanol. Their in-vitro stud-ies demonstrate superior solubility properties of the compound.Additionally, oral administration of talinolol-SNEDDS to ratsresults in a 1.4-fold increase in AUC. The enhanced oral bio-availability is attributed to the increased solubility. However,several studies reported talinolol to be a potent P-gp substrate [39].Some surfactants used to formulate SNEDDS, such as Brij usedby Ghai et al. in developing talinolol-SNEDDS, have shownpotential to inhibit efflux pump activity, as elaborated above inSection 4.1. It is, therefore, possible that in addition to increasedsolubility the increased permeability and subsequent enhancedoral bioavailability of talinolol can be a result of decreasedP-gp efflux produced by SNEDDS components. Furthermore,the newer SNEDDS formulations incorporating CsA aCYP3A4 and P-gp substrate are characterized by higher andmore predictive bioavailability. The bioavailability of CsAfrom these SNEDDS formulations is up to 50% greater thanthat of the original crude emulsion formulation [10,89]. More-over, a marketed SEDDS formulation has been shown to reduceinter- and intra-patient variability on CsA absorption andabsorption of CsA from this formulation was relatively unaf-fected by food as compared to a crude emulsion formulation [76].

These examples emphasize the rationale in the applicationof SNEDDS for increasing the dissolution and oral bioavail-ability of Class II drugs as defined by the BDDCS.

8. Expert opinion

The utilization of lipid-based drug delivery systems in generaland of SNEDDS in particular shows great potential inimproving the solubility, enhancing bioavailability and reduc-ing inter/intra subject variability. Although this potential has

been recognized for nearly two decades, the full impact ondrug disposition by SNEDDS and its components havebeen recognized only in the recent years. This review summa-rizes the current comprehension of the biopharmaceuticalaspects of SNEDDS. Recent mechanistic research conductedby our group and by other researchers implies that SNEDDSability to augment the oral bioavailability of poorly water-soluble drugs goes beyond improvement in the solubility ofa drug as was initially presumed. The summarized data inthe current review indicates that SNEDDS have a potentialto increase oral bioavailability by multi-concerted mecha-nisms such as reduced intra-enterocyte metabolism by CYPP450 enzymes, reduced P-gp efflux activity and by bypassinghepatic first-pass metabolism via lymphatic absorption.

It should be however noted that there is a phenomenon of‘negative results bias’, meaning that in many cases there wereno enhancement in bioavailability despite the SNEDDS utili-zation. Such negative results are rarely published; therebymask the fact that the optimized properties of the pharmaceu-tic compounding are rather specific, and need further investi-gational efforts to uncover. Thus, critical comparison betweennegative results (which are only known to the specific labora-tory where the studies were conducted) and successful formu-lations may provide important information that is beyond theavailable published data.

Nevertheless, in light of the information presented in thecurrent review, it is evident that SNEDDS have attractedincreasing attention as ameans to enhance the oral bioavailabil-ity of poorly soluble and highly metabolized drugs. Althoughmany studies have been conducted there are only few approvedcommercial self-emulsifying products available on the pharma-ceutical market. There are several reasons for this phenome-non. One of them is the difficulty in incorporation of alipophilic compound into SNEDDS. Additionally, it hasbeen reported that the fate of the drug incorporated intoSNEDDSmay be altered throughout its transit in the GI tract.Some poorly water-soluble drugs are successfully solubilized bySNEDDS; however, they fail to reach the site of absorption intheir molecular state. This is because precipitation occurs fol-lowing dispersion of SNEDDS in aqueous media of the GItract milieu [94]. As described in the third section of this review,upon dispersing SNEDDS pre-concentrates in the GI milieu,fine emulsions are formed, which facilitates lipid hydrolysisby lipase on the o/w interface. Following this process, micellestogether with other colloidal structures composed of the lipo-litic products, bile salts and phospholipids are formed. In casethe solubilization capacity of these micelles is lower as com-pared to the initial fine emulsion formed, the incorporateddrug might precipitate in the GI tract. In-vitro drug solubilityin the formulation is indeed an important characteristic inlipid-based formulation design; however, solubilization capac-ity following lipid digestion is also required to estimate in-vivoperformance. The absence of proper guidelines for lipid-basedformulations on formulation design represents difficulty indeveloping new products, as well.

0

0.1

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0.4

0.5

0.6

0.7

0.3 AM-SNEDDSAM

0 5 10 20 25 30 35 45 504015Time (h)

Co

nc

(ug

/ml)

Figure 4. Plasma amiodarone (AM) concentration--time plot

(mean ± S.E.M.) following oral administration of AM and

AM-SNEDDS, 12.5 mg/kg (n = 6 for each group).SNEDDS: Self-nano-emulsifying drug delivery systems.

SNEDDS: an update of the biopharmaceutical aspects

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This review summarizes the recent advances in the under-standing of the versatile biopharmaceutical effects ofSNEDDS. This unique biopharmaceutical point of view con-tributes to the understanding of proper drug candidate selec-tion and of the approach in SNEDDS formulation design.The selection of candidates to be formulated into SNEDDSto achieve improved oral bioavailability and reduced variabil-ity should be based on the intelligent recognition of theabsorption barriers of a drug. The understanding of the roleof certain transporters or intestinal CYP P450 enzymes onthe absorption and disposition characteristics of a specificdrug must be investigated. This knowledge will enable intelli-gent excipient selection in the SNEDDS formulation process.Optimal SNEDDS composition per individual physico-chemical properties and absorption processes of a drug will

enable the modulation of the relevant absorption barriers foreach drug candidate. In opinion of the authors, SNEDDS uti-lization can offer the most beneficial outcome in augmentingthe bioavailability of poorly soluble and highly metabolizeddrugs, that is, BDDCS Class II drugs.

Declaration of interest

The authors have no relevant affiliations or financial involve-ment with any organization or entity with a financial interestin or financial conflict with the subject matter or materialsdiscussed in the manuscript. This includes employment, con-sultancies, honoraria, stock ownership or options, expert testi-mony, grants or patents received or pending, or royalties.

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AffiliationIrina Cherniakov*1 PhD, Abraham J Domb2 &

Amnon Hoffman†3

†,*Authors for correspondence1Candidate

The Hebrew University of Jerusalem, Institute for

Drug Research, School of Pharmacy, Faculty of

Medicine, P.O.B 12065, Jerusalem 91120, Israel

Tel: +972 2 675 7667, +972 544 692 657;

E-mail: irasolodkin@gmail.com2Professor

The Hebrew University of Jerusalem, Institute for

Drug Research, School of Pharmacy, Faculty of

Medicine, Jerusalem 91120, Israel3Professor, Chairman of the Division of Clinical

Pharmacy, Head of the PharmD Program

The Hebrew University of Jerusalem, Institute for

Drug Research, School of Pharmacy, Faculty of

Medicine, P.O.B 12065, Jerusalem 91120, Israel

Tel: +972 2 6757014;

Fax: +972 2 6757246;

E-mail: amnonh@ekmd.huji.ac.il

SNEDDS: an update of the biopharmaceutical aspects

Expert Opin. Drug Deliv. (2014) 12(7) 1133

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