Accepted Manuscript

Title: Lipid-based formulations for oral administration of
poorly water-soluble drugs
Author: Huiling Mu Ren´e Holm Anette M¨ullertz
PII:
DOI:
Reference:

S0378-5173(13)00284-6
http://dx.doi.org/doi:10.1016/j.ijpharm.2013.03.054
IJP 13234

To appear in:

International Journal of Pharmaceutics

Received date:
Revised date:
Accepted date:

27-1-2013
28-3-2013
28-3-2013

Please cite this article as: Mu, H., Holm, R., M¨ullertz, A., Lipid-based formulations
for oral administration of poorly water-soluble drugs, International Journal of
Pharmaceutics (2013), http://dx.doi.org/10.1016/j.ijpharm.2013.03.054
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1
Lipid-based formulations for oral administration of poorly water-soluble drugs

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Huiling Mu a*, René Holma,b, and Anette Müllertza,c

Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen,

Biologics and Pharmaceutical Science, H.Lundbeck A/S, Ottiliavej 9, DK-2500 Valby,

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b

Denmark.

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Bioneer:FARMA, Danish Drug Development Center, Department of Pharmacy, Faculty of

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c

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Universitetsparken 2, DK-2100 Copenhagen, Denmark.

Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100

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Copenhagen, Denmark.

*Correspondence: Dr. H. Mu, Department of Pharmacy, Faculty of Health and Medical Sciences,
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University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. E-mail:
huiling.mu@sund.ku.dk

Page 1 of 45

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Abstract
Lipid-based drug delivery systems have shown great potentials in oral delivery of poorly water25

soluble drugs, primarily for lipophilic drugs, with several successfully marketed products. Pre-

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dissolving drugs in lipids, surfactants, or mixtures of lipids and surfactants omits the

dissolving/dissolution step, which is a potential rate limiting factor for oral absorption of poorly

cr

water-soluble drugs. Lipids not only vary in structures and physiochemical properties, but also in

30

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their digestibility and absorption pathway; therefore selection of lipid excipients and dosage form
has a pronounced effect on the biopharmaceutical aspects of drug absorption and distribution

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both in vitro and in vivo. The aim of this review is to provide an overview of the different lipidbased dosage forms from a biopharmaceutical point of view and to describe effects of lipid

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Key words: Lipids, lipid-based drug delivery systems, lipid digestion, lymphatic transport, in
vitro lipolysis, poorly water-soluble drug

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dosage forms and lipid excipients on drug solubility, absorption and distribution.

Page 2 of 45

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1. Introduction
Oral drug administration is desirable due to good patient convenience and consequently better
compliance. To be absorbed from the gastrointestinal (GI) tract, a drug needs to be dissolved in
the GI fluids; this is a problem for the increasing number of poorly water-soluble drug candidates

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40

that are in development in the pharmaceutical industry. However, it seems that a high

cr

permeability is maintained for most of these compounds, rendering them class II drugs in the

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Biopharmaceutics Classification System (BCS) (Amidon et al., 1995; Lipinski 2000; Lipinski et

45

limiting step for the absorption of these drugs.

an

al., 1997; Yu et al., 2002). Thus the solubility and/or dissolution rate in the GI tract often is the

M

The interests on lipid-based drug delivery systems (LBDDS) have increased over the past two

d

decades as a function of identification of these pharmaceutically difficult candidates, and

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increased even further after successful launch of lipid-based oral pharmaceutical products,
including in particular cyclosporine A, marketed as SandimmuneTM and NeoralTM. One of the

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advantages of LBDDS is that drug molecules are pre-dissolved in lipid excipients, avoiding a
potentially rate limiting dissolution step in the GI tract, thereby achieving an increased and
consistent bioavailability (Chakraborty et al., 2009; Drewe et al., 1992; Gershanik and Benita
2000; Hauss D.J. 2007; Kohli et al., 2010; Porter et al., 2008; Strickley 2004).
55

To develop LBDDS, several complex biological processes have to be taken into account, such as
digestion of lipid excipients, formation of different colloid phases during lipid digestion, and
transfer of the drug between these colloid phases. Several reviews of lipid-based formulations are
available, each focusing on different aspects of lipids in drug delivery (Chakraborty et al.,2009;

Page 3 of 45

. 2011.2007) and application of phospholipids in oral drug delivery has been reviewed by Fricker et al. Shukla et al. Singh et al. 2011... with emphasis on the formulation forms from a biopharmaceutical point of view. (2010). Yanez et al.. This review presents the recent progress on liquid lipid-based dosage forms. Hauss D. 2011). In a recent review a rational strategy for the development of lipid and surfactant based drug delivery system was suggested (Müllertz et al.2008. and an overview 80 of different lipid-based dosage forms. Pouton 2000. 2011.2010. Pouton 2006.2011). 2009a...4 60 Fricker et al. Porter et al. 2007. Rahman et al. In connection to this the LFCS 75 Ac ce p proposed by Pouton was evaluated and considerations suggested in particular reflecting the differences between triglycerides (TG) and partial glycerides. M 70 d Singh et al.2007).. Gursoy and Benita 2004. Porter et al.. Lipid excipients have been reviewed by Hauss in context of their applications in lipid-based formulations (Hauss D.2010).. Porter and colleagues summarised lipid delivery systems with focus on self-emulsifying delivery cr 65 us system (SEDDS) and assessment of lipid-based formulations using in vitro lipolysis (Porter et al. 2010. Kohli et al. This includes simple considerations on drug selection and lipid digestion related with lipid structure..J..2007.J.. Page 4 of 45 . Müllertz et al. ip t Pouton (2006. Kuentz 2011.2008). 2010. have made a general review covering SEDDS and solid dispersions (Singh et te al. from simple lipid solutions to advanced SEDDS and solidifying lipid formulations. and provided a good overview on lipid digestion and drug solubilisation in the small an intestine as well as lymphatic transport (Porter et al.. Singh et al.. 2000) proposed a Lipid Formulations Classification System (LFCS) and categorized lipid-based formulations into four different types according to their compositions.

e. demonstrating that the simple classification into grease-balls and “brick-dust” is not always predictive in the selection of the type of lipid-based formulations. another group of compounds 90 us possesses high lipophilicity (logP) and much lower melting points. it typically has a low solubility in all compounds with poor aqueous solubility and/or a high log P will have a good solubility in Ac ce p excipients that are suitable for LBDDS. solubility enhancement through the use of surfactant and/or lipid based excipients lipids. belonging to the BCS class II and IV. At present. therefore it can be helpful to identify the etiology of the poor solubility. a continuum exists between these two simplified classes of poorly soluble an compounds. i. Obviously. the so-called “grease-balls”. Of 100 the 25 formulations classified 13 were LFCS class I. A number of poorly water-soluble compounds are regarded as “brick dust” and cannot cr be formulated as LBDDS because of their tight crystal lattice. but may have considerable higher solubility in surfactants and co-solvents. If the compound is a “brick-dust” molecule. Compounds may fall into BCS II and IV for different ip t physical chemical reasons. Selection of compounds for lipid based formulations Compounds with a low aqueous solubility. with most drug molecules not fitting either extreme. three were class III. and nine were class IV. Müllertz and co-workers (2010) recently summarised a number of commercial formulations. no model is capable of predicting the Page 5 of 45 . A few simple descriptors for the compounds and their melting points are presented in Table 1. If the molecule has the characteristics of a grease-ball and traditional formulation approaches do not provide adequate M bioavailability.5 2. are 85 frequently discussed in relation to LBDDS. Rane and Anderson (2008) recently provided a review of the different theoretical models developed to predict the solubility 105 of compounds in lipids or lipid mixtures. Therefore not te 95 d may be useful.

and TG are classified as class I polar lipids because they possess some surface solubility and can form stable monolayers on the surface (Small1968). 2006a). but if new theories can be developed that takes the specific and non-specific interactions between the compounds and the lipid excipients into the 110 ip t consideration. and in the case of SEDDS droplet size of the formed emulsion. Shimada and Page 6 of 45 . diglycerides (DG).. Mu 2005). Output parameters often include drug solubility. Monoglycerides (MG) and phospholipids are classified as class II polar lipids. colloid us structures of the aqueous dispersions. Small (1968) has classified lipids based on their interactions in aqueous systems and their behaviour in the water–air 125 interface. Therefore preformulation te measurements of solubility in excipients and mixtures hereof are the most useful parameters to 120 Ac ce p determine if lipid-based formulation is a feasible strategy for a given compound. even though drug solubility in lipid mixtures can be estimated as a simple weighted average of the M drug solubility in individual ingredients (Sacchetti and Nejati 2012). Castera 1995. When defining the formulation space for LBDDS the use of Design of Experiments (DoE) is a cr good and systematic approach. When incorporating the solubility as an output in DoE. the solubility should generally be screened. higher solubility may be 115 an achieved in the formulation mixtures than in individual excipients (Holm et al.6 solubility of a drug molecule in lipids. they may hold potential for future predictions. Physicochemical properties of lipids Lipids are generally defined as compounds containing fatty acids and can be separated into different classes (Cast and Hamilton 1999. If the solubility of a d compound is low. 3. Free fatty acids (FFA). which can form well-defined liquid crystalline phases in the bulk (Small1968).

TG and DG are also digested and absorbed differently. Even though MG. which further confirms that MG is different from TG in classified as neutral lipids in food science and lipid chemistry (Christie 1985.2(2.7 Ohashi (2003) studied the interfacial and emulsifying properties of DG and MG. Smith et al.. The high Page 7 of 45 . Watanabe and Tokimitsu (2004) investigated the digestion and absorption of TG and DG in rats by duodenal infusion of 14C-labeled lipids. 28% of 2-MG and 37% of FFA. Mu and Høy 2004. 2000a). Digestion of lipids already starts in the stomach. pre- Ac ce p duodenal lipases partially hydrolyse TG to 1. 1.3)-DG and FFA.3)-DG are further digested in 145 the small intestine by other lipases such as pancreatic lipase to 2-MG and FFA (Christophe 2004. depending on the fatty acid composition of the TG (Armand 2007.2(2. their us 135 cr the formation of microstructures in aqueous media. DG.3-DG. and MG (Christie1985. Tso 1985).3)-DG. DG. Hamosh 1979. Hamosh and Scow 1973. DG and MG are also different.. Heinz 2012). The intramolecular structure of TG affects lipid digestion and absorption (Mu and Porsgaard 2005). and TG are normally polarity is increasing in the order of TG. with up to 30% of TG being digested in the stomach. but also different in their In addition to the differences of their physiochemical properties. DG and MG are different not only in their structures. the in vivo digestion processes d 140 M surface activities and polarities. Ten min after infusion of TG and 1. Pitzalis et al. an Therefore TG. te of TG. whereas the lipolytic products of 1. 1986). Mu et al.2(2. (2000) characterised the ip t ternary phase diagrams of MG and DG in water and found that MG formed a lamellar phase and two types of bi-continuous cubic phases. the 150 lipolytic products of TG contained 10% of 1. and addition of MG to TG had a more profound effect in the reduction of the interfacial tension. they found that 130 addition of DG to TG reduced the interfacial tension.3-DG contained 26% of 1(3)-MG and 51 % of FFA.

Lipid-based drug delivery systems an 160 us digestibility is therefore an important part of formulation considerations for LBDDS.. Kaukonen et al. M which are presented separately below. Ac ce p Partially digested lipids from the stomach are solubilised in the GI fluids in the presence of both bile and pancreatic juice.. as well as the absorption and bioavailability of drugs.. supporting the further hydrolysis of 1(3)-MG (Kristensen et al. and both the lipid and drug molecules are subsequently absorbed.8 ratio of FFA/1(3)-MG in the lumen infused with DG suggested that substantial amounts of 1(3)MG were further converted to FFA and glycerol (Watanabe et al. LBDDS encompass a range of formulations. A study in cannulated pigs also showed increased portal transport of glycerol after intake of DG oil. from simple lipid solutions to advanced SEDDS. 2006). the difference of lipid digestion in the GI tract cr will affect the solubility of drug molecules in the GI fluids. Singh et al. 2012. The 170 dispersion of lipids in the GI fluids affects the kinetics of lipid digestion and absorption (Armand2007.. but also the solubilisation of drugs in the GI tract during lipid 165 te digestion. Since 1(3)-MG is often used as lipid ip t 155 excipients alone or as mixtures with DG and TG. as well as solubility and absorption of drugs from lipidbased formulations (Kaukonen et al. Understanding lipid structures and 4. Tso 1994). Selection of lipid excipients does not only affect drug d solubility in the formulations. These particles deliver digested lipids and drug molecules to enterocytes. Page 8 of 45 .. Figure 1 is a simplified illustration of digestion of lipid-based formulations and formation of micelles in the GI tract. fine emulsions are further converted to bile salt micelles and lamellar vesicles (Müllertz et al. 2009b). 2004a..2004). 2004b).

2012c.. Figure 3 shows the similar tendency for the increased lymphatic transport of lipids and halofantrine solubilised in lipids with the increasing chain-length of fatty acids. Zangenberg et al. Drug precipitation may affect its te found later in this section.. an liquid. 2010b). 2000. 2001b). Zangenberg et al. Mu et al. Lipolysis samples can be separated by ultracentrifugation into at least two phases.. The chain-length of fatty acids affects the distribution of lipids between the lymphatics and the portal vein (Mu and 195 Høy 2000b).. illustrating Page 9 of 45 . 2007. Sassene et al.. Gershkovich et al. The lipolysis is and the lipid-based formulation. (2012b). the pellet-phase can contain both calcium soaps of fatty acids and precipitated drugs (Figure 2B). Mu and Hoy 2001) as well as lipophilic compounds (Caliph et al. Kalogeris et al. lipid hydrolysis is initiated by addition of pancreatic lipases us 180 cr typically carried out in a thermo-controlled reaction vessel containing simulated intestinal fluids (Figure 2A).... In the case of targeting drugs to intestinal lymphatic transport. Larsen et al. Porter et al. More details about the in vitro lipolysis model and its application in Ac ce p the characterisation of LBDDS can be found in a recent review by Thomas et al.. long-chain fatty acids will be a 190 better choice because they can stimulate formation and secretion of chylomicrons and improve lymphatic transport of lipids (Holm et al.and pellet-phase.2008. 2007.2005. 2012). ip t 2010.. Thomas et al.2007). Different biorelevant media have been used for in vitro lipolysis (Kleberg et al. 2011.. Charman and Stella 1986b. Kleberg et al. And the composition of excipients can affect drug distribution absorption and more discussions about drug precipitation from lipid-based formulations can be d 185 M between the different phases (Figure 2C) (Ren et al... 1996... as well as characterisation of lipolysis products formed (Fatouros et al.. Larsen et al. 2001a. 2008.9 In vitro lipolysis is often used for the evaluation of LBDDS and the impact of lipid digestion on 175 drug solubilisation.. 2006b. Porter et al. 2010a. Charman and Stella 1986a.

7% of the M absorbed dose.5. (2011)... Lipid excipients.9 and 95. This is in agreement with a previous study d of lymphatic transport of hexachlorobenzene and 1.. The solubility of Dexanabinol and PRS-211.2003). respectively (Holm et al. The an 205 intestinal lymphatic transport of dexanabinol and PRS-211.1 Lipid solutions 215 Lipid solutions are the simplest lipid-based formulation and several products are already on the market (Müllertz et al. Holm et al. They compared the lymphatic transport of halofantrine in cannulated canines after administration SEDDS containing either TG8:0/18:2/8:0 or ip t 200 TG18:2/8:0/18:2 and found that the extent of lymphatic transport via the thoracic duct was 18% cr and 27% of the dose for TG8:0/18:2/8:0 and TG18:2/8:0/18:2. for instance medium-chain Page 10 of 45 . The lipids are either based upon long-chain fatty acids or medium-chain fatty acids. respectively. used in this type of formulations. These studies demonstrate that drug solubility in lipids is one of the determining factors for lymphatic drug transport.10 that the selection of lipid excipients is one of the key factors for lymphatic transport. respectively (Gershkovich et al.. vary in their physicochemical properties and their abilities to be digested.2007).2 and 8.2010). The solubility of the drug molecules in the selected lipid excipients is a critical factor for the success of the formulation.220 in long-chain TG was 7.220 was 7.1986b). us Gershkovich et al (2007) investigated the role of lymphatic transport in the oral bioavailability of two structurally similar lipophilic drugs with similar logP values.5 and 60. 8.1-bis(p-chlorophenyl)-2.2.8 mg/g. 4. (2003) also demonstrated the importance of intramolecular structure of TG for lymphatic transport of poorly water-soluble drugs. Lymphatic transport and metabolic enzymes as Ac ce p well as transporters involved in intestinal lymphatic transport have recently been comprehensively reviewed by Yanez et al.2-trichloroethane 210 te (Charman et al.

respectively cr 225 us (Grove et al.7 mg/g. (2005) investigated the bioavailability of seocalcitol in rats after oral administration its lipid solutions and reported a twofold increase of the bioavailability an when seocalcitol was dissolved in lipids compared with a reference formulation containing propylene glycol.. whereas no difference was observed for the MCT and the LCT solutions..3 and 1. te were no significant differences between lipid solutions of short-chain TG (SCT).8) improved the oral absorption of anethol trithione in rats. whereas another drug (LU 28-179) was solubilised better when it was formulated as LCT solution. 2005). The solubility of seocalcitol in water is only 20 ng/g. whereas long-chain TG (LCT) such as sesame oil has been used in Marinol (dronabinol) and One-Alpha (alfacalcidol). No difference was observed for solubilisation of probucol when it was formulated as MCT or LCT solutions.11 220 TG (MCT) has been used to solubilise efavirenz (SustivaTM). Dahan and Hoffman (2007) also observed that the properties of drugs can affect their solubilisation during in vitro lipolysis as well as the bioavailability. Grove et al. (2004) studied the in vitro solubility of poorly water-soluble drugs during lipolysis of their lipid solutions containing either MCT or LCT and found different effects of fatty acids on solubilisation of drugs in the aqueous phase. suggesting that 240 the properties of drugs can affect their distribution between the different phases during lipolysis (Christensen et al. but there 235 Ac ce p (Han et al. For instance lipid solutions of M 230 d anethol trithione (log P=3.2004).8. 2009). ip t Dissolving drugs in lipids can significantly improve the bioavailability of poorly water-soluble drugs. Similar results have been reported for other lipophilic drugs. Lipophilic Page 11 of 45 . Seocalcitol is a lipophilic drug with a log P value 4.. whereas its solubility in MCT and LCT is 5. MCT. and LCT Christensen et al.

5mg/mL digestion medium). when comparing MCT and LCT containing LBDDS.2004). LCT = MCT = SCT for dexamethasone and MCT > LCT > SCT for griseofulvin (Dahan et al. the in vitro performance of the different formulations for dexamethasone was similar. Ac ce p After 60 min in vitro lipolysis.e. it seems possible to assess the rank order of in vivo performance of lipid solutions by the amount of drug solubilised during in vitro lipolysis. whereas 21-36% of an fenofibrate were solubilised in the aqueous phase after digestion of the formulation containing M soybean oil. Recently lipid cr solutions of fenofibrate were subjected to in vitro digestion aiming at predicting the fate of the 250 us drug in the GI tract (Mohsin 2012). of oral lipid solutions of halofantrine in beagle dogs and found that in vitro drug solubilisation te 255 d Porter et al. LCT formulations provided improved 260 solubilisation capacity.12 drug dexamethasone and griseofulvin were dissolved in SCT.2007). The in vivo ip t bioavailability of both drugs correlated well with the in vitro data. i.. 25 mg TG/mL digestion medium) were solubilised in the aqueous medium. The in vitro digestion and solubilisation data at lower lipid masses were consistent with the in vivo date where the bioavailability of halofantrine after oral administration of LCT solution was higher than MCT solutions (Porter et al. however. 265 Page 12 of 45 . more halofantrine from the MCT formulations with high lipid loads (ca... only 5-7% of fenofibrate were carried in the aqueous phase. Therefore. (2004) tried to use the in vitro lipid digestion data to explain the in vivo performance profiles were markedly dependent on the mass of lipid employed in lipid digestion experiments. whereas at low lipid concentrations (ca. MCT or LCT. whereas a 245 performance rank order of MCT > LCT > SCT was observed for griseofulvin. MCT was almost completely hydrolysed after 30 min.

a poor solubility in aqueous media is not necessarily equal to a good us solubility in pharmaceutically relevant lipids.2. Larsen and co-workers investigated the bioavailability of danazol solubilised or suspended in the PEG based surfactant Page 13 of 45 . As an alternative. but a suspension of the micronized compound in oil increased it even further. In support of this. a clear trend towards a higher bioavailability of phenytoin was seen when administered in a corn oil Ac ce p 280 suspension compared to an aqueous suspension. (1989) evaluated the influence of particle 285 size and vehicle on the absorption of propesterone in humans. and the mass of lipid employed in lipid digestion experiments.even after thorough excipient screening. including lipid excipients. M 275 an suspension of the drug in lipids can be used. a limited attention. (1978) reported a higher absorption of a lipophilic steroid from a sesame oil solution when compared to an aqueous suspension. In a more recent study. The in vitro drug solubilisation profiles can be affected by many factors. Lipid suspensions cr As discussed above. though an emulsion performed even better (Chakrabarti and Belpaire 1978). lipid solutions can be used to improve the bioavailability of lipophilic drugs. Abrams et al. the 270 ip t properties of drugs.13 All in all. a formulation approach that has only received d Carrigan and Bates demonstrated for more than 35 years ago that griseofulvin suspended in corn te oil resulted in a significantly higher bioavailability compared to administration in an aqueous suspension. hence it is not always possible to dissolve the needed drug dose in the excipients . Hargrove et al. but similar to suspensions in sesame oil. Micronisation of the compound increased the absorption of the compound significantly. when dosed orally to rats (Carrigan and Bates 1973). 4.

Small1968).. i. Porter et al. as an there is a need for continuous focus on sedimentation and physical stabilization of the suspension. Trull et al... 310 Pouton and Porter 2008. from which it was concluded that lipid ip t suspension vehicles may perform just as well as lipid solutions for some compounds. in the case of SNEDDS.2008.. also from a the situations where the solubility in lipids is insufficient. SEDDS/SNEDDS preconcentrates are isotropic mixtures of oils.3. Drug molecules are dissolved in SEDDS/SNEDDS preconcentrates in these formulations. Tuleu et al. Emulsions and nanoemulsions often contribute to an uniform and reproducible oral bioavailability of the drug in both the fasted and fed state (Mueller et al. The lipid part of the SNEDDS forms Page 14 of 45 . and co-solvents (Müllertz et al. The authors reported that a suspension of danazol led 290 to the same oral bioavailability as a lipid solution. surfactants. From an industrial point of view. additionally that this relative unexplored formulation type may be an option in however. Alternatively a small capsule containing the drug molecule plus disintegrants can be included in M a capsule containing the lipid. us 295 cr lipid suspension. Self-Emulsifying Drug Delivery Systems SEDDS and Self-NanoEmulsifying Drug Delivery Systems (SNEDDS) are type II and type III Ac ce p formulations in the LFCS. capsule in a capsule. Development of SNEDDS has received most attention in recent years and will therefore be the focus of this section. 1994.. 2004). this is a nanoemulsion.2008).. Altogether this demonstrates that the physical form is important for the absorption.14 Labrafil® M2125CS (Larsen et al. lipid based suspensions are slightly more difficult to manufacture than the solutions..e. Upon dispersion of the preconcentrates in the GI fluids an emulsion is 305 formed. 1994) and not least also lead to an improved bioavailability (Julianto et al. d 300 te 4.2010. 2000.

Page 15 of 45 . Lipophilic surfactants are employed in SNEDDS to ease the emulsification process. and found that the most significant factor in influencing the droplet size of nanoemulsions upon dispersing SNEDDS preconcentrate was the co-surfactant MaisineTM 35-1.2006a).2006a... A number of recent publications have shown the advantages of DoE in the optimization of SEDDS/SNEDDS (Basalious et al. Constantinides 1995. 2005). Wang et al. Small 1968).... Ren et al. an 320 us excipients may play individual or synergistic roles of dissolving lipophilic compounds in the Several SNEDDS containing poorly water-soluble drugs have been developed and evaluated for M their in vivo performance (Date and Nagarsenker 2007...15 the core of the emulsion droplet.. Furlanetto et al.. Pouton et al. 2010. Recently. investigated the influence of different excipients and their interactions on formulation characteristics of SNEDDS using DoE for a model drug fenofibrate.. as well as predicting optimized formulations with the desired profile (Holm et al. Dixit and d Nagarsenker 2008a. 1986). Gershanik et al. Holm et al. 2010. Dixit and Nagarsenker 2008b. 1993. and is often lacking a systematic approach for evaluating impact of excipients on the performance of formulations as well as the fate of drugs. 2009). Ac ce p DoE enables evaluating effects of multiple factors. The preconcentrate and solubilising them into the GI fluids. Development of SNEDDS is often driven by empiric.2000.2000. 2011. Liu et al. hydrophilic surfactants enable the spontaneous emulsifying process upon dispersing the preconcentrates in aqueous media under mild agitation by forming a fluidal interfacial film between oil and water phases (Gershanik et al. The utilisation of DoE may also improve the understanding on the influence of different 330 excipients and their interactions... Wakerly et al. alone or in combination. Taha et al. ip t 315 Addition of co-solvent can lead to a faster dispersion of preconcentrates to nano-emulsions cr (Craig et al. 325 te pseudo-ternary diagrams and solubility of drugs.2008.

presumably resulting from solubilisation of the vesicular lipids by the additional bile salt and a structural change to a micellar system. The fate of drugs during the transit in the GI tract may be affected by many factors. For 355 this reason it was speculated that the physical form of drug precipitates during digestion might be important for the bioavailability of the drug.2010. Page 16 of 45 . The lipolytic products together with bile salts and phospholipids form micelles and other colloidal structures (Kleberg et al.2011). (2004)..2012). The te importance of the vesicular species for their drug solubilisation capacity has been investigated by Porter et al.16 335 which functions as co-surfactant to improve the emulsification of oil.. A significant reduction in droplet surface activity of fenofibrate and improved self-emulsifying process. For both cinnarizine and danazol a continuous recipitation of drugs was observed during the in vitro lipolysis process (Sassene et al. cinnarizine precipitated amorphous (Figure 4).. If the solubilisation capacity of micelles is M 345 d lower than that of the initial fine emulsions. probably due to the us mentioned above. which resulted in a fast redissolution (Larsen et al. 1976. which has a much lower capacity for drug solubilization. However. meanwhile it also works as the oil phase and results in larger droplets (Ren et al. They found that dilution with buffer alone resulted in relatively little drug 350 Ac ce p precipitation. fine emulsions are formed upon dispersing SNEDDS preconcentrates in the GI fluids. Cordle and Lowe 1998..2010a. drug compounds may precipitate in the GI tract. Sémériva and Desnuelle 1979).. which facilitates lipid hydrolysis by co-lipase dependent pancreatic lipase on the oil/water an interface (Chapus et al.. Müllertz et al.2012).2011). Larsen et al.. As cr 340 ip t size was interestingly observed when fenofibrate was loaded in the vehicles. whereas dilution with a bile salt solution resulted in extensive precipitation.

. drug precipitation occurred ip t very fast during in vitro lipolysis. but further studies are required to clarify and confirm the hypothesis of the physical form of drug precipitates during digestion is important for the bioavailability of the drug.2012a). DoE can be used in the optimisation of SEDDS/SNEDDS to simplify the optimisation process and predict the optimised 375 formulations.2012a).4. 4. studied supersaturated SNEDDS containing halofantrine (Thomas et al. te 370 d should also be considered and addressed for the strategy to be useful in improving absorption Ac ce p The increased interest on SEDDS/SNEDDS is closely related with the uniformed and reproducible oral bioavailability of drugs in both the fasted and fed state. but more studies need to be performed in this area in order to get a better M understanding on the phenomena and the mechanism. However. When the concentration of halofantrine in the 360 SNEDDS preconcentrate was 150% of the equilibrium solubility. The enhanced dissolution of the amorphous halofantrine 365 us was also reflected in vivo where two capsules of conventional SNEDDS were required to achieve similar AUC and Cmax as obtained after dosing of a single capsule of supersaturated SNEDSS an (Thomas et al. Transformation of liquid lipid systems into solid oral dosage forms Page 17 of 45 . Supersaturated SNEDDS may be used to improve the bioavailability of poorly water-soluble drugs.. The stability of supersaturated SNEDDS and bioavailability..17 Recently. Therefore drug precipitations are not necessarily a problem during the dispersion of SNEDDS. subsequent dissolution studies of the precipitates demonstrated enhanced dissolution of halofantrine.2012c).. which was suggested to be due to an cr amorphous form (Thomas et al. 2012a) and simvastatin (Thomas et al. Thomas et al.

Dry emulsions containing poorly water-soluble drugs have been prepared by drying o/w emulsions containing a solid carrier. Dollo et al. in vivo evaluation in Page 18 of 45 . 2008). but the maximum absorption was retarded by the solid SNEDDS (Yi et al. Dixit and Nagarsenker (2008c) studied self-nanoemulsifying granules 400 containing ezetimibe. O/w emulsions can be reconstituted from dry emulsions upon addition of an aqueous an phase. More recent advances in the study of solid SNEDDS with focus on solidification te techniques have been summarized by Tang et al. followed with drying in a desiccators. 1991).18 380 In order to achieve better physicochemical stabilities of LBDDS and ease commercialisation. The oldest solidification techniques include spray drying.. a lot of efforts have been devoted to transformation of liquid lipid systems into solid oral dosage forms. developed a solid SNEDDS by dispersing SNEDDS preconcentrates containing nimodipine in a dextran solution followed by spray drying. which encapsulates the dispersed lipid phase when the aqueous phase is removed by spray drying (Christensen et al. in vivo or in vitro.... by lyophilisation (Corveleyn and Remon 1998).. 2001. With the development of lipid-based formulations. 395 Ac ce p Yi et al. lyophilisation. The ratio of solid carrier to lipid phase influences the reconstitution properties (Christensen et al. The oral bioavailability of nimodipine was investigated in rabbits and similar AUC and Cmax values were observed from both SNEDDS.2001). 1996). Dissolution studies revealed two to three fold increases in the dissolution rate compared to plain drug. Takeuchi cr 385 us et al... no difference was observed in the droplet size of the reconstituted emulsions from liquid and solid SNEDDS (Yi et al.2008). such as M 390 d SNEDDS. 2003. by mixing SNEDDS preconcentrates with colloidal silicon dioxide. (2008). spray drying technique has also been used to solidify other kind of lipid-based formulations. and rotary ip t evaporation. a cholesterol absorption inhibitor. or by rotary evaporation (Porter et al.

Tan et al. (1991).. Recently. Cmax. te 415 d bioavailability of danazol from solidified formulation in rats was 50% lower than the liquid Ac ce p solid carriers as well as solidification process should be carefully considered. signifying the potential of such kind of formulation in improving delivery of lipophilic 405 drugs (Dixit et al. and the formulations due to incomplete desorption of SEDDS. The in vivo study in dogs showed similar 410 us bioavailability of cyclosporine from SNEDDS containing capsules and SNEDDS loaded LLT. when LLT contained a tablet disintegrant (Sander et al.. a 420 conventional oil. No significant differences were observed in the pharmacokinetic parameters (AUC. Van Speybroeck et al.. Recently. which were prepared by direct compression of porous magnesium aluminometasilicate. More recently silica-lipid hybrid (SLH) microcapsule systems have been used to improve the bioavailability of poorly water-soluble drugs (Simovic et al. who compared the oral bioavailability of vitamin E acetate from a silica encapsulated drug emulsion. or Tmax).. an (2012) studied the effect of solidification of SEDDS on drug release in vitro and absorption in vivo when SEDDS were adsorbed onto Neusilin US2 powder.. They found that the release of M danazol during in vitro lipolysis was 35% lower for the adsorbed formulation. 2011).2009). 2010. Page 19 of 45 . SLH microcapsules composed of MCT.2008c). Therefore selection of lipid excipients. Effects of silica encapsulation has been investigated by Takeuchi et al. Sander and Holm investigated the possibility to solidify ip t SNEDDS using liquid loadable tablets (LLT).19 rats also showed significant decrease in the total cholesterol levels as compared to positive control. and a liquid emulsion. 2009. Tan et al. SNEDDS containing cyclosporine were loaded by a cr simple absorption method (Sander and Holm 2009). lecithin and silica nanoparticles resulted in improved AUC (250-270 min g/ml) of 425 celecoxib compared to a lipid solution (170 min g/ml) and an o/w emulsion (197 min g/ml).

Salonen and Lehto (2008) also described the fabrication and chemical modifications of porous silicon for 435 an biomedical applications. only a limited number of studies have compared the performance of different LBDDS in vivo and/or in vitro. Tanaka et al. 2010).5 min-1). and LCT... Quantification of the lipase-mediated digestion kinetics in vitro showed the lag phase duration of 5 s. respectively.2-1. Simovic et al. MCT.2009).. 2007. 5.9 min-1). te Solidification of liquid lipid systems may improve the physiochemical stabilities of LBDDS. In vitro and in vivo effects: comparison of dosage forms and lipid excipients Both selection of lipid excipients and dosage forms can be important for drug solubilisation and 445 absorption. (2010) studied the safety of nanoporous silicon carriers in vivo followed single and multiple dose intravenous administrations in mice and claimed that they d M provided evidence of safe intravenous administration. (2009) compared the performance of lipid solution and sub-microemulsion of a lipophilic drug anethol trithione both in vivo and in vitro. and 18-23 s for lipid emulsion..8 min-1) (Tan et al.20 that was suggested to be a reflection of dissolution enhancement (Tan et al. More safety studies on Ac ce p 440 solidifying carriers should also be performed. 7-10 s. However. 2012). the initial digestion rate 430 ip t constant was highest for lipid emulsions (1. and lipid solution. and the formulations were prepared using SCT. Sub-microemulsion Page 20 of 45 . This confirms the importance of cr emulsification on lipid digestion. Details about mesoporous silicon and assembling nanoparticle us coatings can be found in the recent reviews (Prestidge et al.5-0. and lowest for lipid solution (0. SLH. followed with SLH (1. Han et al. The selection of the solidification techniques and solid carriers is important to ensure sufficient desorption of drugs as well as lipid excipients from solid carriers.

2009). LCT. mixture of DG and MG.21 formulations were digested more rapidly in vitro than oil solutions. for diverse formulations including SEDD. (2007) also studied the d 460 te bioavailability of seocalcitol in minipigs. especially 470 SNEDDS. 455 us Nielsen et al. including MCT. They found that SEDDS..9) in rats using a multivariate statistical method. one Ac ce p was lipid solution and the other was SNEDDS. All LBDDS enhanced drug absorption compared to an aqueous suspension. there was a tendency (not significant) toward lower exposure when LCT was used in the formulation Page 21 of 45 . were most effective in pushing the exposure of the compound CDA.2007).. two lipid-based formulations were investigated.. similar seocalcitol bioavailability was observed from the two different formulations in both cases (Grove et al. but the drug absorption was better from cr ip t emulsions than from lipid solutions when LCT was used (Han et al. and the solubilisation 450 capacity during lipolysis was in the order of SCT<MCT<LCT. but the difference was not significant. In vitro studies on the same formulations showed that the release rate and extent of release of probucol from the M oil solution were significantly lower than that from SEDDS/SNEDDS. SNEDDS and lipid solutions. They used different lipid excipients. Grove et al. (2008) studied the bioavailability of probucol from lipid solutions and SEDDS/SNEDDS in fasted and fed minipigs and found higher bioavailability of probucol from an SEDDS/SNEDDS than from oil solutions. and the rank order of probucol released (SEDDS/SNEDDS> oil solution) was similar to the rank order of bioavailability from the in vivo study (Fatouros et al. 465 Kuentz et al (2007) investigated the role of lipid formulation parameters on the oral bioavailability of the compound CDA (log P=8. 2008). The study was carried out both in fasted and fed state.

It was concluded that maintaining drug in aqueous phase depended on the solubilisation of drug by mixed bile salt micelles and lipolytic products (Mohsin2012). It is possible to target lymphatic transport of drugs by selection of lipid excipients containing long-chain fatty acids for lipophilic drugs with good solubility in lipids.22 (Kuentz et al. especially lipophilic drugs. different LFCS type formulations were used to investigate the influence of lipid digestion on the distribution of fenofibrate between the aqueous phase and the pellet phase (Mohsin2012). it requires more Ac ce p 485 te monitoring drug solubility during the lipid digestion process. a high concentration of surfactant used in type IIIB and IV cr systems lowered the rate of digestion. even though it had lower initial digestion rate. Rational design of lipid-based formulations can be achieved by utilisation of DoE. an 480 M however. It should be noted. that no comparative in vivo studies were carried out. Type I formulations presented comparably higher amount us of fenofibrate in aqueous phase after 30 min lipolysis. In order to broaden the utilisation studies on better characterizations of lipid degradation products in vitro and correlation studies of in vitro and in vivo.2007). d In vitro lipolysis model has been increasingly used in mimicking the enzymatic degradation and of the in vitro model in understanding of how LBDDS promote drug delivery. which can also be used in prediction of optimised formulations. In a recent in vitro lipolysis study in biorelevant media. Drug precipitation during dispersing of Page 22 of 45 . However. Summary 490 LBDDS have great potentials for improving oral bioavailability of poorly water-soluble drugs. 6. As expected type II and type IIIA formulations were rapidly digested in the initial stages because of the larger ip t 475 surface area of emulsions..

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2011 and Sassene et al. II. 1993(Moffett et al. 5. Simplified digestion process of lipid-based formulations. 2011 and Ren et al. Figure 4. Scattered plots ( ) indicate the dissolved mass of fenofibrate (mg) in the aqueous phase.0 M NaOH throughout the lipolysis. Redrawn and adapted Ac ce p from Mu & Høy 2000b and Caliph et al. Page 38 of 45 . B) ip t 825 phase separation of lipolysis sample after ultracentrifugation. C) distribution (%) of cr fenofibrate in the aqueous phase ( ) and precipitates ( ) upon 3 min of dispersion and us 30 min of digestion of the SNEDDS preconcentrates in a lipolysis medium. 10:0/18:2/10:0. (b) Pellet from in vitro lipolysis containing precipitated cinnarizine. A) Cumulative d lymphatic transport of fatty acids after intragastric administration of structured TG 835 te 8:0/18:2/8:0. B) cumulative lymphatic transport of halofantrine after oral administration in different TG solutions. and 10% an 830 respectively. (B) Diffractogram of cinnarizine obtained using XRPD. Lymphatic transport of lipids and halofantrine solubilised in lipids. Figure 2. Redrawn and adapted from Larsen et al. M Figure 3. The black bars are the percentage of cinnarizine in the aqueous phase and the grey bars show the percentage of cinnarizine precipitated in the pellet. A) the typical set up of a lipolysis model.38 Figure captions: Figure 1. (d) blank pellet spiked with crystalline cinnarizine (Adapted from Larsen et al. 1993). The curve shows the addition of 840 1. (a) Crystalline cinnarizine. (c) blank pellet. (A) Partition of cinnarizine during in vitro lipolysis in the duodenum step.. 2000.. Redrawn and adapted from Moffett et al. The concentration of cosolvent ethanol in the formulation I. 12:0/18:2/12:0. and III is 0. 2010). 2012. In vitro lipolysis and drug precipitation.

CA .drugbank.docx cr Table 1.8 1. (Laguna Niguel.9 4. USA) and MOE.ip t Table 1_new.4 -0. Canada) for the PSA calculations Ac 2) From www.3 60. version 2008 (Chemical computing group. (2010) Page 39 of 45 .9 72. Simple descriptor for different molecules in commercial available lipid-based formulations together with the type of lipid Alfacalcidol Amprenavir Bexarotene Calcitrol Ciprofloxacin Dronabirol Efavirenz cLogP 1) 5.8 6.5 38.3 Lipid formulation class I IV I III III I I used commercially 3) ed M an Compound ce pt us formulation class 1) Calculated using clogp from Daylight inc.2 37.9 29.5 131.5 Melting point (°C) 2) 136 72-74 230-231 113 255-257 200 139-141 Hydrogen acceptors 2 6 2 3 6 2 2 Hydrogen donor 2 3 1 3 2 1 1 Polar surface area (Å) 1) 40.9 4.8 5. Montreal.ca 3) Classified by Mullertz et al.

1 145.2 I Ac ce pt used commercially 3) IV Ritomair us Compound cr Table 1 cont.8 166.8 3.5 53-54 121 Hydrogen acceptors 3 2 Hydrogen donor 0 0 Polar surface area (Å) 1) 52.8 IV I III + IV I III ed M an 5.8 2.ip t Fenofibrate Ibudilast Progesteron cLogP 1) 5.2 7.4 Lipid formulation class IV Saquinavir Tiranavir Valproic acid Cyclosporine 3. Page 40 of 45 .6 34.7 4.1 Melting point (°C) 2) 80.3 3.5 37.8 105.3 278.4 78-82 350 86-89 120-130 151 2 6 7 6 2 23 0 4 5 2 1 5 34.

an us cr i graphical abstract.pdf Drug Ac ce pt ed M In vitro lipolysis Lipid-based formulations Page 41 of 45 .

Figure 1.pdf Figure 1 Drug Ac ce p Formation of mixed micelles te d M an us cr ip t Lipid digestion Page 42 of 45 .

Figure 2.pdf Figure 2 us cr ip t (A) an (B) Lipid phase Dispersion 80 60 40 100 80 60 40 20 20 0 I II 140 120 Ac % Fenofibrate 100 Digestion ce pt 120 Mass of dissolved Fenofibrate (mg) (C) ed Pellet phase M Aqueous phase 0 III I II III Page 43 of 45 .

Figure 3.pdf Figure 3 100 8 12:0/18:2/12:0 ip t 6 4 10:0/18:2/10:0 2   0 us 8:0/18:2/8:0 cr Cumulative % of MCFA in lymph (A) 0 2 4 6 an Time (h) 8 LCT MCT SCT Lipid-free Ac ce pt ed M (B) 24 Page 44 of 45 .

Figure 4.pdf Figure 4 us cr ip t (A) Ac ce pt e d M an (B) Page 45 of 45 .