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Formulation of self-emulsifying drug delivery systems
advanced
drug delivery reviews
ELSEVIER
Advanced
Formulation
Drug Delivery Reviews 25 (1997) 47-58
of self-emulsifying
drug delivery systems
Colin W. Pouton” School
ofPharmacy and Pharmacology,
Univrrsity
ofBath, Claverton Down, Bath BA2 7AY, UK
Abstract Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils and surfactants, ideally isotropic, sometimes including cosolvents, which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastro-intestinal tract. Hydrophobic drugs can often be dissolved in SEDDS allowing them to be encapsulated as unit dosage forms for peroral administration. When such a formulation is released into the lumen of the gut it disperses to form a tine emulsion, so that the drug remains in solution in the gut, avoiding the dissolution step which frequently limits the rate of absorption of hydrophobic drugs from the crystalline state. Generally this can lead to improved bioavailability, and/or a more consistent temporal profile of absorption from the gut. Ultra-low oil-water interfacial tension and/or substantial interfacial disruption are required to achieve self-emulsification. SEDDS are usually formulated with triglyceride oils and ethoxylated nonionic surfactants, usually at surfactant concentrations greater than 25%. In practice, disruption of the oil-water interface is caused by penetration of water into the formulation or diffusion of cosolvents away from the formulation. Both of these phenomena can be studied using equilibrium phase diagrams, which in combination with particle size measurements allow the optimisation of performance of SEDDS. The precise mechanisms of emulsification remain the liquid crystal formation, oil-water subject of speculation but there is an empirical link between self-emulsification, phase-inversion temperature and enhanced solubilization of water by oily formulations, and these phenomena are indicators of the efficiency of emulsification. This article describes strategies used for formulation of SEDDS, methods used for assessment of efficiency of emulsification and practical considerations regarding the use of SEDDS for enhancement of the bioavailability of drugs from the gastro-intestinal tract. Keywords:
surfactants;
Self-emulsifying drug delivery systems (SEDDS); Self-emulsification; Phase behaviour; Liquid crystals; Triglycerides; Bioavailability
Spontaneous
emulsitication;
Nonionic
Contents 48 I. Introduction ............................................................................................................................................................................ 2. Micellar solutions, microemulsions and low-energy emulsification.. ............................................................................................ 48 52 3. Formulation of SEDDS. ........................................................................................................................................................... 52 3. I. Introduction ..................................................................................................................................................................... 3.2. Screening exercises for selection of excipients ................................................................................................................... 53 54 3.3. Assessment of the efficiency of emulsification.. .................................................................................................................. 3.4. Studies of equilibrium phase behaviour .............................................................................................................................. 55 4. Biological issues in the selection of SEDDS.. ............................................................................................................................ 57 References .................................................................................................................................................................................. SE
“Corresponding
author. Tel:
+ 44 1225 826786; fax:
+ 44 1225 8261 14; e-mail: [email protected]
0169-409X/97/$32.00 0 1997 Elsevier Science B.Y. All rights reserved P/f SO1 69-409X(96)00490-5
48
C.W. Pouton I Advanced Drug Delivery Reviews 25 (1997) 47-58
1. Introduction Self-emulsification is a phenomenon which has been exploited commercially for many years in formulations of emulsifiable concentrates of herbicides and pesticides [l]. These formulations are used to produce concentrates of crop-sprays which are diluted by the user, such as a farmer or household gardener, allowing very hydrophobic compounds to be transported efficiently. In contrast selfemulsifying drug delivery systems (SEDDS), using excipients acceptable for oral administration to humans, have not been widely exploited. There are a number of reasons why SEDDS are not in common use. Some relate to the custom and habit of pharmaceutical development laboratories, and some to genuine physicochemical issues. Most pharmaceutical companies have a commitment to tabletting machinery, which leads them to favour tablet formulation at an early stage, often before sufficient data are available on the bioavailability of the drug in question. Once the path to formulation of a solid dosage form is taken it is difficult to revert to oily formulation at a later stage, and there is the added disadvantage that the encapsulation of an oily formulation may have to be contracted out. The solvent capacities of oily formulations are not high unless the drug is very lipophilic (log P > 4), so that formulation in oils is usually limited to potent compounds. There may be a suspicion that chemically the drug will be more unstable in an oily solution than in a crystalline form, and this may be so, but at present there is insufficient data to predict chemical stability in SEDDS. The use of high concentrations of surfactants is a legitimate concern from a toxicological standpoint [2,3], and it is easy to argue in favour of formulating with tried and tested materials to prevent problems surfacing at a late stage of development of a new chemical entity. The above are issues which will tend to direct a formulator away from SEDDS, though it is now accepted that there are a group of compounds for which SEDDS is the delivery system of choice, exemplified by cyclosporin A. The development of this compound by Sandoz [4,.5] has confirmed the potential of SEDDS to bring hydrophobic compounds to the market place. There are several drugs which are poorly bioavailable from marketed tablet formulations which could have been formulated in oily systems.
But the potential of SEDDS or indeed simple oily solutions will not be realised until more human bioavailability studies have been published, and until more information is available on the chronic toxicology of SEDDS. The formulation of SEDDS remains for the most part an empirical process, though there are some useful guidelines which have emerged by characterisation of the properties of successful formulations (discussed in Section 3). An understanding of the physical chemistry of ethoxylated surfactants, and how they interact with oils and water, is necessary to interpret these observations. This is a large field and a full review is beyond the scope of this article, but there are texts and reviews which describe this field in depth [2,6,7]. The most relevant physicochemical phenomena are described below in Section 2.
2. Micellar solutions, microemulsions and low-
energy emulsification The use of the term ‘microemulsion’ in the colloid and surfactant science literature understandably causes confusion, particularly among pharmaceutical scientists. Intuitively one would assume that this term means a superfine emulsion, perhaps comprising droplets in the sub-micron range. As emulsions are thermodynamically unstable, tending always to reduce the total area of the oil-water interface, one might assume that microemulsions also should be thermodynamically unstable. However the term ‘microemulsion’ has been widely used to describe complex systems, usually consisting of oils, surfactants, cosolvents and water, which are thermodynamically stable [8-121. Often the precise morphology of complex mixtures is not fully understood, due to the role of cosolvents in providing mutual solubility. Frequently, separate oil and water phases cannot be physically defined, so that it is not possible to establish which is the continuous phase. The use of industrial, polymeric or polydisperse materials (ethoxylated surfactants, vegetable or mineral oils etc.) make such systems even more difficult to define, since attempts to characterise their morphology using spectroscopic techniques (e.g. nuclear magnetic resonance or electron spin resonance spectroscopy) or diffraction techniques (X-ray or neutron scattering) usually result in ill-defined spectra. In
C.W. Pouton I Advanced Drug Delivery Reviews 25 (1997) 47-58
practice ‘microemulsions’ are often identified by equilibrium phase studies as systems which are optically clear to the eye, yet contain a substantial mass of both oil and water. Characteristically they contain too much oil and water to be simple aqueous (or non-aqueous) micellar solutions. Whether they are thermodynamically unstable superfine emulsions or thermodynamically stable bicontinuous structures in many cases cannot be established for certain. Does this matter? Often it does not; because a thermodynamically unstable fine emulsion may be ‘metastable’ (or kinetically stable) due to the presence of a substantial interfacial film of surfactant. Pharmaceutical formulators work with a variety of interrelated systems, often without knowing their internal structure. The important characteristics are the longterm stability of the system (if it is to be used to formulate a product), and the changes that occur when the system is diluted (usually with water). In practice sufficient time should be left for a mixture (or a dilution) to equilibrate, because when working with complex mixtures of surfactants and cosolvents, first impressions can be deceptive, and a system may change considerably over periods of weeks or months if the morphology of the mixture (as first formed) was not thermodynamically stable. Stable microemulsions often have high solvent capacities for drugs making them attractive formulations for pharmaceuticals, but the utility of each system will depend on whether it is likely to be diluted on use, and whether the solvent capacity is lost on dilution. When a water-soluble cosolvent (such as polyethylene glycol or an alcohol) is an important component of the formulation, dilution with water will usually result in substantial change in phase behaviour which may cause precipitation of the drug. The phase behaviour of ethoxylated nonionic surfactants in aqueous solution, in the presence and absence of oils, is well documented [2,6,7]. Kozo Shinoda and colleagues published a series of definitive reports beginning in the early 1960s which were adequately summarised in a text by Shinoda and Friberg in 1986 [B]. In mixtures of surfactant, oil and water, the nature of the association structures which can form is determined by the relative volume and interfacial area occupied by the hydrophilic (polyoxyethylene) and hydrophobic (hydrocarbon) domains of the surfactant. The hydrophile-lipophile balance (HLB) of the surfactant gives an indication
49
of what can be expected, by comparison with surfactants of similar HLB. Phase behaviour is highly dependent on temperature, because the level of hydration of polyoxyethylene chains is lowered by increase in temperature. Effectively the HLB decreases with temperature until at a critical temperature (the cloud point) the surfactant is no longer soluble in water. The cloud point of a surfactant is modified by the presence of other components, such as oils or drugs [7]. Therefore, the phase behaviour of each system needs to be studied as a matter of course, using the published phase diagrams as a guide. Phase behaviour of polymeric industrial surfactants generally relates well to published phase diagrams of pure surfactants (of single oxyethylene chain length), but the phase boundaries observed with polymeric materials are more diffuse, which may cause difficulties in interpretation of phase behaviour [6]. Phase behaviour of three- component systems of oil, water and surfactant are often represented by isothermal triangular phase diagrams such as that shown in Fig. 1. This diagram is a good representation of the phase behaviour which can be expected of mixtures involving very polar oils; medium chain alcohols or acids. Large areas of the
Decanol
Fig. 1. Equilibrium phase diagram for the system potassium caprylate-decanol-water at 20°C. (From [33]). L,, isotropic aqueous solution; L,, isotropic oil solution; B, lamellar phase (mucous woven type); G, lamellar phase (neat phase); C. tetragonal phase: M,, hexagonal phase (middle phase): MZ, inverse hexagonal phase; V, cubic phase (from [33]).
C.W. Pouton I Advanced Drug Delivery Reviews 25 (1997) 47-58
50
and restricted when the oil is non-polar (hexane). Optically clear ‘microemulsion’ formulations can be obtained by adding a fourth component which acts as a cosolvent for both water and oil. There is a large literature on the formation of microemulsions using alcohols such as butanol, hexanol or octanol [S-lo], which can help solubilize large quantities of oil and water, but these agents are not relevant to pharmaceutical formulators. Unfortunately they cannot be replaced adequately by polyethylene glycol, glycerol or other pharmaceutically acceptable materials. Nevertheless, it is possible to produce microemulsions with lower concentrations of solubilized oil and water and this field has been reviewed recently by Attwood [ 121. As the cloud point (temperature) is approached nonionic surfactant micelles in aqueous solution become swollen with oily solubilizates, the micelle particle size increases considerably, and at the cloud
phase diagram are occupied by mixtures which form pure phases of swollen micellar solutions, microemulsions or liquid crystalline phases (Fig. 1). If the oil is less polar the incidence of association structures formed as a single phase is reduced, so that large areas of the phase diagram are multiphasic, and full characterisation would be too labour-intensive to justify. The phase diagram for ternary systems containing carbon tetrachloride, caprylate and water are comparatively devoid of pure single phases, and those containing mineral oils are intermediate in character [2]. The polarity of the mineral ester is closest to those of triglycerides, giving an impression of the behaviour which can be anticipated for pharmaceutical systems. A series of phase diagrams for oil-Brij 96-water systems [13] is shown in Fig. 2. The areas occupied by ‘microemulsion phases’ (E or L2) are clearly larger when the oil is more polar (e.g. benzene, hexanol, cyclohexanone)
S
S
Aus!?& Cyclohexanc
Isopropyl myristate
W
(b) S
(d)
Dccalin w cc)
Ethyl okate
Benzene
W (h)
Fig. 2. Phase diagrams
Xylene
W
Cyclohexanone (i)
for Brij 96-oil-water
systems.
(From [13]).
point the curvature of the oil-water interface is lost. Further increase in temperature in the presence of oil is associated with phase inversion; the oil becomes the continuous phase with water solubilized in nonaqueous micelles (Fig. 3). Thus, for mixtures which contain a comparable proportion of oil and water, the cloud point becomes synonymous with the emulsion phase-inversion temperature (PIT) which was first explained by Shinoda and colleagues (61. Fig. 4 illustrates the region of enhanced solubilization of oil which is observed close to the cloud point of the surfactant in aqueous solution, and Fig. 5 shows how this relates to phase inversion of an emulsion. Shinoda and colleagues observed that at the PIT, when the volumes of oil and water are comparable, a large proportion of the oil and water is solubilized by a planar structure rich in surfactant, which was termed the ‘surfactant phase’ (represented as the planar structure in Fig. 3). Typically for an emulsion system there is excess oil and water which cannot be solubilized. so that at the PIT a three phase system exists. A relationship between PIT and low-energy emulsification was clear in Shinoda’s early work
I
/
I
5
IO
15
Amount
of
n-Heptone
I
(gr/Il
Fig. 4. The effect of temperature on the solubilization of heptane m
19
aqueous
solutions
nonylphenylether phenylether.
0,
and
of
II
-
I
-
polyoxyethylene(9.2).
polyoxyethylene(9.0)dodecyl-
cloud point: 0,
solubilization
limit (For 3 full
explanation see 161).
100
I I
I
0.2
0.4
I
1
0.6
0.8
w/o
-I
20 0
wt.
H20
i-RNXH40KH2CH20b.7H
fraction
1.0 C-CeH12
7wt x/system
Fig. 5. The effect of temperature and compoGtion on the dispersion
types
of
water/cyclohexane/polyoxyethylene(9.7)nonyl-
phenylether (7% w/w).
Phase
Volume
Fig. 3. Schematic diagram of the change in curvature and phase volume ratio during phase inversion. (For a full explanation
[61X
see
(For a full explanation \ee [h]).
when he realised that the surfactant was extremely mobile at the PIT and the oil-water interfacial tension reached a minimum 161. Therefore emulsification is easier because the force required to increase the interfacial area is lower. Others have observed that each oil has a ‘required HLB’ for emulsification (Fig. 6) [ 141. What underlies this observation is that surfactants can be blended so that the temperature of emulsification is close to the PIT of the system.
52
C.W. Pouton I Advanced
I--
W/Q-+
-
Drug Delivery Reviews 25 (1997) 47-58
o/w__c 8
0.07
0.06
t
1Span 2OlTween 20 2 Span 65ITween 20
Fig. 6. Optimum
HLB for emulsification
of liquid paraffin. (From
[141).
However it should be noted that for crude emulsions, such as pharmaceutical lotions, ease of emulsification is not related to emulsion stability. Rather, emulsions formed at the PIT may be unstable since the surfactant is not stably anchored at the oil-water interface [6]. In fact kinetically stable emulsions require that storage temperature is well away from the PIT. Another phenomenon which links lowenergy emulsification to the PIT is the empirical observation by Lin [15] that enhanced water solubilization is linked to ease of emulsification and low droplet size (Fig. 7). This observation can be explained satisfactorily by Shinoda’s work describing the enhanced solubilization of both oil and water which occurs at the PIT. Although the examples described above relate to size reduction of conventional emulsions with relatively low concentrations of surfactant, these concepts appear to explain the mechanism of action of some (but not all) SEDDS. It is important to emphasise that the effects of a change in temperature of only lo-20°C can have a dramatic affect on the phase behaviour of systems containing ethoxylated surfactants, and thus there ability to form microemulsions or self-emulsifying systems. Typical changes in ternary phase behaviour close to the phase inversion region are shown in Fig. 8, which clearly shows how the region of enhanced solubiliza-
0 Span 20 Weight I
8.6
0.2 fraction
1
0.6
0.4
of hydrophilic I
1
10
0.8
H LB
I
1 Tween
20
surfoctant 8
1
15
7
16.7
Fig. 7. Shift of optimum emulsification by addition of lauryl alchohol to produce a more polar oil. Dotted lines are for pure mineral oil. Solid lines are for an oil consisting of mineral oil/lauryl alchohol (8:2). (From [15]).
tion or microemulsion temperature is raised.
formation
contracts
as the
3. Formulation of SEDDS
3.1. Introduction With a large variety of liquid or waxy excipients available, ranging from oils through biological lipids, hydrophobic and hydrophilic surfactants, to watersoluble cosolvents, there are many different combinations which could be formulated for encapsulation in hard or soft gelatin. Recent interest has focused on mixtures which disperse to give fine colloidal emulsions. This broad area is the subject of a recent survey by Constantinides [16]. The present article focuses on isotropic mixtures which emulsify to produce fine oil-in-water emulsions under conditions
C.W. Pouton I Advanced Drug Delivery Reviews 25 (1997) 47-58
n
A A
E
Ms.
w
n
W
0
H.S.
Fig. 8. Typical behaviour of nonionic surfactants with temperature. The area for surfactant phase (black in A) coalesces with the hydrocarbon/emulsifier solution forming a w/o microemulsion area (B). Further increase in temperature caused reduction in the size of the microemulsion and liquid crystalline areas until at high temperature (E) only a two-phase region remains. (See [6] for a full explanation).
of gentle agitation. Isotropic liquids are preferable to waxy pastes because if one or more excipient(s) crystallise(s) on cooling to form a waxy mixture it is very difficult to determine the morphology of the materials, and most importantly the morphology of the drug within the wax. The earliest reports of self-emulsifying systems using pharmaceutical materials were of pastes, based on waxy alcohol ethoxylates [17]. These systems do disperse to form fine oil-in-water emulsions but since there is no need for or advantage of waxy pastes, use of such formulations is not advised. As a general rule it is sensible to use the simplest effective formulation, restricting the number of excipients used to a minimum. Screening studies have established that it is possible to formulate isotropic SEDDS using medium-chain tri-
53
glycerides and one of a small group of nonionic surfactants (most are ethoxylated oleate esters) [ 18,191. Why look any further than these formulations? One motivation for using alternative materials is the toxicological status of the above surfactants. There is no reason to suspect that they are likely to be more toxic than polysorbate 80, but only limited data is available on their acute and chronic toxicity. A second issue is the solvent capacity of the formulation, which may not be high enough for the drug in question. This encourages the use of more hydrophilic materials which may then require solubilization, leading to a three or four component formulation. Such a strategy can fundamentally change the mechanism of action of the SEDDS and the fate of the drug (see below). If the formulation includes a substantial proportion of hydrophilic components (and possibly water) the undiluted formulation may well be a ‘microemulsion’ itself, and could be used to solubilize hydrophilic drugs (see the accompanying article by New and colleagues [20]), though solvent capacity may well be lost on dilution. When the solubility of the drug in vegetable oil is not a problem the simplest formulation, and most desirable, may well be a simple oil solution which will itself be emulsified in the gut during digestion (see the accompanying reviews on lipolysis [21,22]).
3.2. Screening
exercises for selection
of excipients
A range of industrial nonionic surfactants were screened using subjective visual assessment by Pouton [23] and Wakerly [18,19] for their ability to form self-emulsifying systems with medium-chain and long-chain triglycerides. The most efficient systems were formed by surfactants with predominantly unsaturated acyl chains. Amongst these the most efficient were oleates with HLB values of approximately 11. Sorbitan esters (e.g. Polysorbate 85) or ethoxylated triglycerides (e.g. Tagat TO) were usually more efficient than fatty acid ethoxylates, probably because the latter are more polydisperse since they usually contain mono- and di-esters. A range of related excipients have been used to formulate SEDDS by other authors [24-261; a list of materials and some example formulations are tabulated by Constantinides [ 161.
C.W. Pouton / Advanced Drug Delivery Reviews 25 (1997) 47-58
54
3.3. Assessment
of the efficiency
of emulsification
An early attempt to quantify the efficiency of emulsification of various compositions of the Tween 85 /medium-chain triglyceride system [28], utilised a rotating paddle to promote emulsification in a crude nephelometer. This allowed an estimation of the time taken for emulsification (Fig. 9). Once emulsification was complete samples were taken for particle sizing by photon correlation spectroscopy and self-emulsified systems were compared with homogenised systems (Fig. 10). The most rapid emulsification occurred at an optimum surfactant content of 35% w/w, though it was concluded that all systems
100
’
0
I
10
1
20
30
40
50
60
mixture composltion (%wiw Tween 55)
Fig. 10. Apparent particle size of self-emulsified and homogenised emulsions of Miglyol 840/Tween 85 mixtures formed in water at 25°C. 0, self-emulsified; 0, homogenised. (From [28]). 40
IO a 6 4 2 0 0
10
20
30
40
50
60
mixture composition (Xulu Tveen 85) Fig. 9. Self-emulsification times of Miglyol 840/Tween 85 mixtures in distilled water at 25°C. 0, t,; 0, t,,,; n , t,,; 0, t,,, (a,b and c were polydisperse systems). (From 1281).
containing between 20-50% w/w Tween 85 emulsified very rapidly, so that this was not a crucial issue for formulation. The particle size was considered to be more important and there was a narrower window between 2540% w/w Tween 85 which produced fine homogeneous dispersions. The process of self-emulsification was observed using light microscopy. It was clear that the mechanism of emulsification involved erosion of a fine cloud of small particles from the surface of large droplets, rather than a progressive reduction in droplet size. When the surfactant content was above 50% the formation of viscous gels appeared to retard self-emulsification, though these systems produced very fine dispersions if more energy for dispersion was provided by homogenisation (Fig. 10). In a later study Wakerly and colleagues [l&19] identified a similar, but more efficient system, comprising of mixtures of Tagat TO with (polyoxyethylene-25-glyceryl trioleate) medium-chain triglycerides. These were sized using laser diffraction as well as photon correlation spectroscopy (Fig. 11) showing more clearly that there was a critical concentration between 20-25% w/w Tagat TO beyond which self-emulsification became highly efficient. Low particle size was maintained over the range 30-65% surfactant. The emulsification time was not determined formally during the
C.W. Pouton I Advanced Drug Delivey
500
50 I
a
I
oJ Surfaetant
Concentration
(5)
b
:
30
35
40
Surfactant
45
50
55
Concentration
60
65
70
(* ~1”)
.... ... 45.C -*-WC 34o"c
+ 25'C .... ... 30" C -*4O‘C Fig.
55
Reviews 25 (1997) 47-S8
I I. Mean emulsion droplet diameter versus surfactant concentration after self-emulsification Sizer; (b) photon correlation spectroscopy). (From [l 81).
of Tagat TO-Miglyol
812 mixtures
((a)
Laser Diffraction
latter studies but was observed visually. At concentrations above 50% Tagat TO emulsification was retarded by the high viscosity at the interface between droplet and water. Both the Tween 85/MCT oil and Tagat TO/MCT oil systems have been studied over a range of temperatures. Both systems are efficient between 5-40°C but are adversely affected if the temperature is raised above 60°C. This has been linked with the dehydration of the surfactant which gives rise to an inappropriate lower effective HLB [ 18,19,23,29]. The inclusion of drugs within SEDDS will affect their performance if the drug is able to compete with water for hydrogen bonding interactions with the ethoxy chains of the surfactant [18,23,30]. For instance, the model drug benzoic acid had a significant enhancing affect [30]. If, however, the drug is very hydrophobic and is less likely to interact with the surfactant, there may be little or no difference in performance, even in the presence of high concentrations of the drug [31].
3.4. Studies of equilibrium phase behaviour Equilibrium phase behaviour cannot reveal the true nature of the interfacial disruption which gives rise to spontaneous emulsification, but at least such studies enable prediction of the phases which are likely to form on dilution of SEDDS with water. Phase studies have suggested a role for liquid crystal formation in self-emulsification, and have also indicated that good formulations are usually operating close to a phase inversion region and in a region of enhanced aqueous solubilization [ 19,231. The enhanced solubilization is assumed to play a role in permitting more rapid penetration of water. Fig. 12 shows part of the phase diagram for dilution of an efficient SEDDS in water over a range of temperature. A number of typical features are shown. The phase inversion region is at approximately 40°C for this system (30% w/w Tween 85170% w/w MCT oil), and the system works well at ambient tempera-
C.W. Pouton I Advanced Drug Delivery Reviews 25 (1997) 47-58
56
20
25 3o%w/w water
mixture
15
lb
j
1 cehw/w POE(?O)-S-trioleott 30% Miglyol 812 7cP/&
composition
Fig. 12. Part of the phase diagram of water and the mixture 30% Tween 85/70% Miglyol 812. Roman numerals denote the number of phases present; o, oil continuous; w, water continuous; LC, liquid crystalline. (From [23]).
ture upto 60°C above which water-in-oil emulsions tend to form [23]. The region labelled LC, is equivalent to what was later referred to as LCa by Wakerly and colleagues when the Tagat TO system was studied (Fig. 13) [29]. This phase appears visibly clear, is distinctly birefringent when viewed between crossed polarising filters, as long as the light path is sufficiently long. Liquid crystal content is
70
clear when a 0.5-l cm diameter test tube is used but not when a thin film is viewed by polarising microscopy. The most likely interpretation of this result is that the mixture consists of liquid crystal dispersed in oily liquid. However, the density and refractive indices of the oil and liquid crystal regions are similar enough that they cannot be discerned as a separate phases, nor do they separate by gravity. This phase would be formed when a SEDDS made contact with as aqueous phase, and is thought to be an important factor in penetration of water into the bulk oil, causing massive interfacial disruption and ejection of droplets into the bulk aqueous phase. Nonyl phenol-5ethoxylate has a similar HLB but the equivalent phase diagram shows a clear distinctly two-phase region (L2 + LC) on dilution with water (Fig. 14). The two phases separate quickly by gravity. This latter system has no tendency to selfemulsify and requires homogenisation for droplet dispersion. This is typical of a large number of mixtures studies during screening studies [ 18,231. Whenever good self-emulsification was observed for binary mixtures of ethoxylates with MCT oil, the phase diagram always revealed the formation of LC, /LCa on dilution with water. The efficiency also correlated with high levels of solubilization. A good illustration is provided by Fig. 15 which shows that when benzoic acid was included in the SEDDS, the result was a lowering of the phase inversion region
65
10
IS T
SO T e
45 ; e r 4Oa I ” 35 r e 30 CC) 2s
7.0 IS
14
13
12
11
10 9 8 7 w w,vJ water Cordm,
6
5
4
3
2
1
0
Fig. 13. Part of the phase diagram of water and the mixture 30% Tagat T0/70% Miglyol 812. L,, aqueous; L,, oil continuous; LC, liquid crytsal (From [ 181).
ul~ P e I 35 a t ” 30 :
‘,
30
28
26
24
(0 25
zll
22
20 18 16 14 % w/w Wats Conteat
12
10
8
6
4
2
0
Fig. 14. Part of the phase diagram of water and the mixture 30% nonyl phenol-5-ethoxylate/70% Miglyol 812. L,, aqueous; L,, oil continuous; LC, liquid cry&al (From [IS]).
57
C.W. Pouton I Advanced Drug Delivery Reviews 25 (19971 47-58
I
’
0
30 3%w/w
water
25 mixhe
20 cmpaiticn
I5
IO
5
Ioo%w/w S%w/w knroicacid in POE(20)-S-triolea* Miglyol 812
becomes too dilute to fully solubilize the oil. This causes the water insoluble oil to separate as a second phase forming an oil droplet. There are then at least two mechanisms operating to cause emulsification and there may be others. The ‘diffusion and stranding’ mechanism can certainly lead to very fine emulsions or microemulsions, the disadvantage of such systems being that the solvent capacity of the system may be lost on migration of the cosolvent. This effect can be expected to be most pronounced when the log P of the drug is comparatively low (perhaps in the range log P = 2-3).
30% 70%
Fig. 15. Part of the phase diagram of water and the mixture 30% Tween 8.5/70% Miglyol 812 in the presence of 5% benzoic acid. Roman numerals denote the number of phases present; o, oil continuous; w, water continuous; LC, liquid crystalline. (From [231).
and a enhancement of solubilization. This system had improved efficiency at ambient temperature when compared to the basic SEDDS formulation (Fig. 12). What then is the explanation for the ease of emulsification? It is likely that the mechanism involved in the Tween 85 or Tagat TO systems involves dynamic formation of liquid crystalline units at the oil-water interface which allow penetration of water down aqueous channels, causing an increase in surface pressure, and interfacial instability (191. It is important to note that these formulations are water insoluble. There may be a small fraction of the surfactant which is soluble but this will be a minor component. Thus, the majority of the surfactant remains with the oil or is dispersed as a separate emulsion phase. This situation contrasts significantly with the behaviour of SEDDS, which include a cosolvent, such as the ternary or quatemary mixtures [5,25-271 reviewed by Constantinides [16]. Where a cosolvent is present there will be a significant migration of material which partitions and becomes diluted into the bulk aqueous phase. This can lead to a rapid emulsification by a mechanism which could be described as ‘diffusion and stranding’. The cosolvent dissolves the water-insoluble component into the aqueous phase as a solubilized system, until on further migration the concentration of cosolvent
4. Biological
issues in the selection
of SEDDS
Very few biophatmaceutical studies have been performed with SEDDS (see the accompanying review [32]), and there is a need for more comparative studies, particularly against simple oils and solid dosage forms. However, it is worth speculating at this stage on the issues which will influence the absorption from SEDDS. The rate of gastric emptying of SEDDS is similar to solutions, so that they are particularly useful where rapid onset of action is desirable [31]. Conversely if the therapeutic index of the drug is low, the rapid onset and accompanying high T,,, may lead to undesirable side-effects. With regard to bioavailability there are differences between formulations which contain water-soluble surfactants or cosolvents, and those which do not. The former systems may produce emulsions or micellar solutions with lower capacity for solubilization of drugs, which may result in precipitation of drugs in the gut. SEDDS formed with relatively hydrophobic surfactants (HLB < 12) such as Tween 85 or Tagat TO, which do not migrate into the aqueous phase, tend to have lower solvent capacities for drugs unless log P (drug) > 4. However these SEDDS should be preferable if the drug can be dissolved to an adequate extent. Another important consideration, though, will be the toxicity of the surfactants, particularly if the indication for the therapy is chronic. If the drug is sufficiently oil soluble a good case can be made for avoiding SEDDS completely and formulating the drug as a simple triglyceride solution, making use of lipolysis to aid dispersion of the formulation.
C.W. Pouton I Advanced Drug Delivery Reviews 25 (1997) 47-58
58
Cl91 Wakerly, M.G, Pouton, C.W., Meakin, B J. and Morton, F.S.
References [ll Groves, M.J. (1978) Spontaneous
emulsification. Chem. Industry, pp. 417-419. PI Attwood, D. and Florence, A.T. (1983) Surfactant systems: their chemistry, pharmacy and biology. Chapman and Hall, London. [31 Swenson, ES., Milisen, W.B. and Curatolo, W. (1994) Intestinal permeability enhancement: efficacy, acute local toxicity and reversibility. Pharm Res. 11, 1132- 1142. R. and Burckart, G.J. [41 Ptachcinsky, R.J., Venkataramanan, (1986) Clinical pharmacokinetics of cyclosporin. Clin. Pharmacokinet. 11, 107-l 32. 151 Kovarik, J.M., Mueller, E.A., van Bree, J.B., Tetzloff, W. and Kutz, K. Reduced inter- and intraindividual variability in cyclosporin pharmacokinetics from a microemulsion formulation J. Pharm. Sci. 83, 444-446. [61 Shinoda, K. and Friberg, S. (1986) Emulsions and Solubilization. John Wiley and Sons, Chichester. [71 Schick, M.J. (1977) Nonionic Surfactants. Marcel Dekker, New York. PI Robb, I.D. (Ed.) (1982) Microemulsions. Plenum Press, New York.
[91 Friberg, S.E. and Botherel, P. (Eds.) (1987) Microemulsions: structure
and dynamics.
CRC Press, Boca Raton, Florida. R.S. (1988) Microemulsions and related systems. Marcel Dekker, New York. In: J. Swarbrich [ill Eccleston, G.M. (1992) Microemulsions. and J.C. Boylan (Eds.), Encyclopedia of Pharmaceutical Technology, Marcel Dekker, New York, 9, 375-421. In: J. Kreuter (Ed.) [I21 Attwood, D. (1994) Microemulsions. Colloidal Drug Delivery Systems, Marcel Dekker, New York, pp. 31-71. [I31 Lo, I., Madsen, F., Florence, A.T., Treguier, J-P., Seiller, M. and Puisieux, F. (1977 j The influence of surfactant HLB and the nature of the oil phase on the phase diagrams of nonionic surfactant-oil-water systems. J. Colloid Interface Sci. 59, 3 19-32.5. [I41 Boyd, J., Parkinson, C. and Sherman, P. (1972) Factors affecting emulsion stability and the HLB concept. J. Colloid Interface Sci. 41, 359-363. [I51 Lin, T.J., Kurihara, H. and Ohta, H. (1977) Prediction of optimum o/w emulsification via solubilization measurements. J. Sot. Cosmet. Chem. 28, 457-479. P.P. (1995) Lipid microemulsions for im[I61 Constantinides, proving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm. Res. 12, 1561-1572. 1171 Groves, M.J. and de Galindez, D.A. (1976) The self-emulsifying action of mixed surfactants in oil. Acta Pharm. Suet. 13, 361-372. drug delivery sys[I81 Wakerly, M.G. (1989) Self-emulsifying tems based on nonionic surfactant-oil mixtures. Ph.D. Thesis, University of Bath.
[lOI Bourell, M. and Schechter,
(1986) Self-emulsification of vegetable oil-nonionic surfactant mixture: a proposed mechanism of action. Am. Chem. Sot. Symposium Series 311, 242-255. WI New et al. (1997) Solubilisation of hydrophilic drugs in oily formulations. Adv. Drug Delivery Rev. 25, 59-70. [211 Embleton, J. and Pouton, C.W. (1996) Structure and function of gastro-intestinal lipases. Adv. Drug Delivery Rev., this Issue. WI MacGregor, K.J., Embleton, J.K., Perry, E.A., Solomon, L.J., Seager, S. and Pouton, C.W. (1996) Influence of lipolysis on drug absorption from the gastro-intestinal tract. Adv. Drug Delivery Rev., this issue. V31 Pouton. C.W. (1982). A study of self-emulsifying oil/surfactant mixtures. Ph.D. thesis, University of London. ~241 Shah, N.H., Carvajal, M.T., Patel, CL, Infeld, M.H. and Malick, A.W. (1994) Self-emulsifying drug delivery systems with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. Int. J. Pharm. 106, 15-23. ~251 Constantinides, P.P. and Yiv, S.H. (1995) Particle size of phase inverted water-in-oil microemulsions under different dilution and storage conditions. Int. J. Pharm. 115, 225-234. P-61 Constantinides, P.P., Scarlat, J.P., Lancaster, C., Marcello, J., Marks, H., Ellens, H. and Smith, P.L. (1994) Formulation and intestinal absorption enhancement evaluation of waterchain medium in-oil microemulsions incorporating glycerides.
Pharm. Res. 11, 1385-l 390. P.P., Lancaster, C., Marcello, J., Chiossone, D., Omer, D., Hidalgo, I, Smith, P.L., Sarkahian, A.B., Yiv, S.H. and Owen, A.J. (1995) Enhanced intestinal absorption of an RGD peptide from water-in-oil microemulsions of different composition and particle size. J. Control. Release 34, 109-l 16. WI Pouton, C.W. (1985) Self-emulsifying drug delivery systems: assessment of the efficiency of emulsification. bit. J. Pharm. 27, 335-348. P91 Pouton, C.W., Wakerly, M.G. and Meakin B.J. (1987) Selfemulsifying systems for oral delivery of drugs. Proc. Int. Symp. Control. Release Bioactive Mater. 14, 113-l 14. I301 Pouton, C.W. ( 1985) Effects of the inclusion of a model drug on the performance of self-emulsifying formulations. J. Pharm. Pharmac. 37, IP. [311 Charman, S.A., Charman, W.N., Rogge, M.C., Wilson, T.D., Dutko, F.J. and Pouton, C.W. (1992) Self-emulsifying systems; formulation and biological evaluation of an investigative lipophilic compound. Pharm. Res. 9, 87-94.
1271 Constantinides,
[32] Humberstone, A.J. and Charman, W.N. (1996) Lipid-based vehicles for the oral delivery of poorly water-soluble drugs. Adv. Drug Delivery Rev., this issue. [33] Ekwall, P., Mandell, L. and Fontell, K. (1969) Ternary systems of potassium soap, alcohol, and water. J. Colloid Interface Sci. 31, 508-512.
drug delivery reviews
ELSEVIER
Advanced
Formulation
Drug Delivery Reviews 25 (1997) 47-58
of self-emulsifying
drug delivery systems
Colin W. Pouton” School
ofPharmacy and Pharmacology,
Univrrsity
ofBath, Claverton Down, Bath BA2 7AY, UK
Abstract Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils and surfactants, ideally isotropic, sometimes including cosolvents, which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastro-intestinal tract. Hydrophobic drugs can often be dissolved in SEDDS allowing them to be encapsulated as unit dosage forms for peroral administration. When such a formulation is released into the lumen of the gut it disperses to form a tine emulsion, so that the drug remains in solution in the gut, avoiding the dissolution step which frequently limits the rate of absorption of hydrophobic drugs from the crystalline state. Generally this can lead to improved bioavailability, and/or a more consistent temporal profile of absorption from the gut. Ultra-low oil-water interfacial tension and/or substantial interfacial disruption are required to achieve self-emulsification. SEDDS are usually formulated with triglyceride oils and ethoxylated nonionic surfactants, usually at surfactant concentrations greater than 25%. In practice, disruption of the oil-water interface is caused by penetration of water into the formulation or diffusion of cosolvents away from the formulation. Both of these phenomena can be studied using equilibrium phase diagrams, which in combination with particle size measurements allow the optimisation of performance of SEDDS. The precise mechanisms of emulsification remain the liquid crystal formation, oil-water subject of speculation but there is an empirical link between self-emulsification, phase-inversion temperature and enhanced solubilization of water by oily formulations, and these phenomena are indicators of the efficiency of emulsification. This article describes strategies used for formulation of SEDDS, methods used for assessment of efficiency of emulsification and practical considerations regarding the use of SEDDS for enhancement of the bioavailability of drugs from the gastro-intestinal tract. Keywords:
surfactants;
Self-emulsifying drug delivery systems (SEDDS); Self-emulsification; Phase behaviour; Liquid crystals; Triglycerides; Bioavailability
Spontaneous
emulsitication;
Nonionic
Contents 48 I. Introduction ............................................................................................................................................................................ 2. Micellar solutions, microemulsions and low-energy emulsification.. ............................................................................................ 48 52 3. Formulation of SEDDS. ........................................................................................................................................................... 52 3. I. Introduction ..................................................................................................................................................................... 3.2. Screening exercises for selection of excipients ................................................................................................................... 53 54 3.3. Assessment of the efficiency of emulsification.. .................................................................................................................. 3.4. Studies of equilibrium phase behaviour .............................................................................................................................. 55 4. Biological issues in the selection of SEDDS.. ............................................................................................................................ 57 References .................................................................................................................................................................................. SE
“Corresponding
author. Tel:
+ 44 1225 826786; fax:
+ 44 1225 8261 14; e-mail: [email protected]
0169-409X/97/$32.00 0 1997 Elsevier Science B.Y. All rights reserved P/f SO1 69-409X(96)00490-5
48
C.W. Pouton I Advanced Drug Delivery Reviews 25 (1997) 47-58
1. Introduction Self-emulsification is a phenomenon which has been exploited commercially for many years in formulations of emulsifiable concentrates of herbicides and pesticides [l]. These formulations are used to produce concentrates of crop-sprays which are diluted by the user, such as a farmer or household gardener, allowing very hydrophobic compounds to be transported efficiently. In contrast selfemulsifying drug delivery systems (SEDDS), using excipients acceptable for oral administration to humans, have not been widely exploited. There are a number of reasons why SEDDS are not in common use. Some relate to the custom and habit of pharmaceutical development laboratories, and some to genuine physicochemical issues. Most pharmaceutical companies have a commitment to tabletting machinery, which leads them to favour tablet formulation at an early stage, often before sufficient data are available on the bioavailability of the drug in question. Once the path to formulation of a solid dosage form is taken it is difficult to revert to oily formulation at a later stage, and there is the added disadvantage that the encapsulation of an oily formulation may have to be contracted out. The solvent capacities of oily formulations are not high unless the drug is very lipophilic (log P > 4), so that formulation in oils is usually limited to potent compounds. There may be a suspicion that chemically the drug will be more unstable in an oily solution than in a crystalline form, and this may be so, but at present there is insufficient data to predict chemical stability in SEDDS. The use of high concentrations of surfactants is a legitimate concern from a toxicological standpoint [2,3], and it is easy to argue in favour of formulating with tried and tested materials to prevent problems surfacing at a late stage of development of a new chemical entity. The above are issues which will tend to direct a formulator away from SEDDS, though it is now accepted that there are a group of compounds for which SEDDS is the delivery system of choice, exemplified by cyclosporin A. The development of this compound by Sandoz [4,.5] has confirmed the potential of SEDDS to bring hydrophobic compounds to the market place. There are several drugs which are poorly bioavailable from marketed tablet formulations which could have been formulated in oily systems.
But the potential of SEDDS or indeed simple oily solutions will not be realised until more human bioavailability studies have been published, and until more information is available on the chronic toxicology of SEDDS. The formulation of SEDDS remains for the most part an empirical process, though there are some useful guidelines which have emerged by characterisation of the properties of successful formulations (discussed in Section 3). An understanding of the physical chemistry of ethoxylated surfactants, and how they interact with oils and water, is necessary to interpret these observations. This is a large field and a full review is beyond the scope of this article, but there are texts and reviews which describe this field in depth [2,6,7]. The most relevant physicochemical phenomena are described below in Section 2.
2. Micellar solutions, microemulsions and low-
energy emulsification The use of the term ‘microemulsion’ in the colloid and surfactant science literature understandably causes confusion, particularly among pharmaceutical scientists. Intuitively one would assume that this term means a superfine emulsion, perhaps comprising droplets in the sub-micron range. As emulsions are thermodynamically unstable, tending always to reduce the total area of the oil-water interface, one might assume that microemulsions also should be thermodynamically unstable. However the term ‘microemulsion’ has been widely used to describe complex systems, usually consisting of oils, surfactants, cosolvents and water, which are thermodynamically stable [8-121. Often the precise morphology of complex mixtures is not fully understood, due to the role of cosolvents in providing mutual solubility. Frequently, separate oil and water phases cannot be physically defined, so that it is not possible to establish which is the continuous phase. The use of industrial, polymeric or polydisperse materials (ethoxylated surfactants, vegetable or mineral oils etc.) make such systems even more difficult to define, since attempts to characterise their morphology using spectroscopic techniques (e.g. nuclear magnetic resonance or electron spin resonance spectroscopy) or diffraction techniques (X-ray or neutron scattering) usually result in ill-defined spectra. In
C.W. Pouton I Advanced Drug Delivery Reviews 25 (1997) 47-58
practice ‘microemulsions’ are often identified by equilibrium phase studies as systems which are optically clear to the eye, yet contain a substantial mass of both oil and water. Characteristically they contain too much oil and water to be simple aqueous (or non-aqueous) micellar solutions. Whether they are thermodynamically unstable superfine emulsions or thermodynamically stable bicontinuous structures in many cases cannot be established for certain. Does this matter? Often it does not; because a thermodynamically unstable fine emulsion may be ‘metastable’ (or kinetically stable) due to the presence of a substantial interfacial film of surfactant. Pharmaceutical formulators work with a variety of interrelated systems, often without knowing their internal structure. The important characteristics are the longterm stability of the system (if it is to be used to formulate a product), and the changes that occur when the system is diluted (usually with water). In practice sufficient time should be left for a mixture (or a dilution) to equilibrate, because when working with complex mixtures of surfactants and cosolvents, first impressions can be deceptive, and a system may change considerably over periods of weeks or months if the morphology of the mixture (as first formed) was not thermodynamically stable. Stable microemulsions often have high solvent capacities for drugs making them attractive formulations for pharmaceuticals, but the utility of each system will depend on whether it is likely to be diluted on use, and whether the solvent capacity is lost on dilution. When a water-soluble cosolvent (such as polyethylene glycol or an alcohol) is an important component of the formulation, dilution with water will usually result in substantial change in phase behaviour which may cause precipitation of the drug. The phase behaviour of ethoxylated nonionic surfactants in aqueous solution, in the presence and absence of oils, is well documented [2,6,7]. Kozo Shinoda and colleagues published a series of definitive reports beginning in the early 1960s which were adequately summarised in a text by Shinoda and Friberg in 1986 [B]. In mixtures of surfactant, oil and water, the nature of the association structures which can form is determined by the relative volume and interfacial area occupied by the hydrophilic (polyoxyethylene) and hydrophobic (hydrocarbon) domains of the surfactant. The hydrophile-lipophile balance (HLB) of the surfactant gives an indication
49
of what can be expected, by comparison with surfactants of similar HLB. Phase behaviour is highly dependent on temperature, because the level of hydration of polyoxyethylene chains is lowered by increase in temperature. Effectively the HLB decreases with temperature until at a critical temperature (the cloud point) the surfactant is no longer soluble in water. The cloud point of a surfactant is modified by the presence of other components, such as oils or drugs [7]. Therefore, the phase behaviour of each system needs to be studied as a matter of course, using the published phase diagrams as a guide. Phase behaviour of polymeric industrial surfactants generally relates well to published phase diagrams of pure surfactants (of single oxyethylene chain length), but the phase boundaries observed with polymeric materials are more diffuse, which may cause difficulties in interpretation of phase behaviour [6]. Phase behaviour of three- component systems of oil, water and surfactant are often represented by isothermal triangular phase diagrams such as that shown in Fig. 1. This diagram is a good representation of the phase behaviour which can be expected of mixtures involving very polar oils; medium chain alcohols or acids. Large areas of the
Decanol
Fig. 1. Equilibrium phase diagram for the system potassium caprylate-decanol-water at 20°C. (From [33]). L,, isotropic aqueous solution; L,, isotropic oil solution; B, lamellar phase (mucous woven type); G, lamellar phase (neat phase); C. tetragonal phase: M,, hexagonal phase (middle phase): MZ, inverse hexagonal phase; V, cubic phase (from [33]).
C.W. Pouton I Advanced Drug Delivery Reviews 25 (1997) 47-58
50
and restricted when the oil is non-polar (hexane). Optically clear ‘microemulsion’ formulations can be obtained by adding a fourth component which acts as a cosolvent for both water and oil. There is a large literature on the formation of microemulsions using alcohols such as butanol, hexanol or octanol [S-lo], which can help solubilize large quantities of oil and water, but these agents are not relevant to pharmaceutical formulators. Unfortunately they cannot be replaced adequately by polyethylene glycol, glycerol or other pharmaceutically acceptable materials. Nevertheless, it is possible to produce microemulsions with lower concentrations of solubilized oil and water and this field has been reviewed recently by Attwood [ 121. As the cloud point (temperature) is approached nonionic surfactant micelles in aqueous solution become swollen with oily solubilizates, the micelle particle size increases considerably, and at the cloud
phase diagram are occupied by mixtures which form pure phases of swollen micellar solutions, microemulsions or liquid crystalline phases (Fig. 1). If the oil is less polar the incidence of association structures formed as a single phase is reduced, so that large areas of the phase diagram are multiphasic, and full characterisation would be too labour-intensive to justify. The phase diagram for ternary systems containing carbon tetrachloride, caprylate and water are comparatively devoid of pure single phases, and those containing mineral oils are intermediate in character [2]. The polarity of the mineral ester is closest to those of triglycerides, giving an impression of the behaviour which can be anticipated for pharmaceutical systems. A series of phase diagrams for oil-Brij 96-water systems [13] is shown in Fig. 2. The areas occupied by ‘microemulsion phases’ (E or L2) are clearly larger when the oil is more polar (e.g. benzene, hexanol, cyclohexanone)
S
S
Aus!?& Cyclohexanc
Isopropyl myristate
W
(b) S
(d)
Dccalin w cc)
Ethyl okate
Benzene
W (h)
Fig. 2. Phase diagrams
Xylene
W
Cyclohexanone (i)
for Brij 96-oil-water
systems.
(From [13]).
point the curvature of the oil-water interface is lost. Further increase in temperature in the presence of oil is associated with phase inversion; the oil becomes the continuous phase with water solubilized in nonaqueous micelles (Fig. 3). Thus, for mixtures which contain a comparable proportion of oil and water, the cloud point becomes synonymous with the emulsion phase-inversion temperature (PIT) which was first explained by Shinoda and colleagues (61. Fig. 4 illustrates the region of enhanced solubilization of oil which is observed close to the cloud point of the surfactant in aqueous solution, and Fig. 5 shows how this relates to phase inversion of an emulsion. Shinoda and colleagues observed that at the PIT, when the volumes of oil and water are comparable, a large proportion of the oil and water is solubilized by a planar structure rich in surfactant, which was termed the ‘surfactant phase’ (represented as the planar structure in Fig. 3). Typically for an emulsion system there is excess oil and water which cannot be solubilized. so that at the PIT a three phase system exists. A relationship between PIT and low-energy emulsification was clear in Shinoda’s early work
I
/
I
5
IO
15
Amount
of
n-Heptone
I
(gr/Il
Fig. 4. The effect of temperature on the solubilization of heptane m
19
aqueous
solutions
nonylphenylether phenylether.
0,
and
of
II
-
I
-
polyoxyethylene(9.2).
polyoxyethylene(9.0)dodecyl-
cloud point: 0,
solubilization
limit (For 3 full
explanation see 161).
100
I I
I
0.2
0.4
I
1
0.6
0.8
w/o
-I
20 0
wt.
H20
i-RNXH40KH2CH20b.7H
fraction
1.0 C-CeH12
7wt x/system
Fig. 5. The effect of temperature and compoGtion on the dispersion
types
of
water/cyclohexane/polyoxyethylene(9.7)nonyl-
phenylether (7% w/w).
Phase
Volume
Fig. 3. Schematic diagram of the change in curvature and phase volume ratio during phase inversion. (For a full explanation
[61X
see
(For a full explanation \ee [h]).
when he realised that the surfactant was extremely mobile at the PIT and the oil-water interfacial tension reached a minimum 161. Therefore emulsification is easier because the force required to increase the interfacial area is lower. Others have observed that each oil has a ‘required HLB’ for emulsification (Fig. 6) [ 141. What underlies this observation is that surfactants can be blended so that the temperature of emulsification is close to the PIT of the system.
52
C.W. Pouton I Advanced
I--
W/Q-+
-
Drug Delivery Reviews 25 (1997) 47-58
o/w__c 8
0.07
0.06
t
1Span 2OlTween 20 2 Span 65ITween 20
Fig. 6. Optimum
HLB for emulsification
of liquid paraffin. (From
[141).
However it should be noted that for crude emulsions, such as pharmaceutical lotions, ease of emulsification is not related to emulsion stability. Rather, emulsions formed at the PIT may be unstable since the surfactant is not stably anchored at the oil-water interface [6]. In fact kinetically stable emulsions require that storage temperature is well away from the PIT. Another phenomenon which links lowenergy emulsification to the PIT is the empirical observation by Lin [15] that enhanced water solubilization is linked to ease of emulsification and low droplet size (Fig. 7). This observation can be explained satisfactorily by Shinoda’s work describing the enhanced solubilization of both oil and water which occurs at the PIT. Although the examples described above relate to size reduction of conventional emulsions with relatively low concentrations of surfactant, these concepts appear to explain the mechanism of action of some (but not all) SEDDS. It is important to emphasise that the effects of a change in temperature of only lo-20°C can have a dramatic affect on the phase behaviour of systems containing ethoxylated surfactants, and thus there ability to form microemulsions or self-emulsifying systems. Typical changes in ternary phase behaviour close to the phase inversion region are shown in Fig. 8, which clearly shows how the region of enhanced solubiliza-
0 Span 20 Weight I
8.6
0.2 fraction
1
0.6
0.4
of hydrophilic I
1
10
0.8
H LB
I
1 Tween
20
surfoctant 8
1
15
7
16.7
Fig. 7. Shift of optimum emulsification by addition of lauryl alchohol to produce a more polar oil. Dotted lines are for pure mineral oil. Solid lines are for an oil consisting of mineral oil/lauryl alchohol (8:2). (From [15]).
tion or microemulsion temperature is raised.
formation
contracts
as the
3. Formulation of SEDDS
3.1. Introduction With a large variety of liquid or waxy excipients available, ranging from oils through biological lipids, hydrophobic and hydrophilic surfactants, to watersoluble cosolvents, there are many different combinations which could be formulated for encapsulation in hard or soft gelatin. Recent interest has focused on mixtures which disperse to give fine colloidal emulsions. This broad area is the subject of a recent survey by Constantinides [16]. The present article focuses on isotropic mixtures which emulsify to produce fine oil-in-water emulsions under conditions
C.W. Pouton I Advanced Drug Delivery Reviews 25 (1997) 47-58
n
A A
E
Ms.
w
n
W
0
H.S.
Fig. 8. Typical behaviour of nonionic surfactants with temperature. The area for surfactant phase (black in A) coalesces with the hydrocarbon/emulsifier solution forming a w/o microemulsion area (B). Further increase in temperature caused reduction in the size of the microemulsion and liquid crystalline areas until at high temperature (E) only a two-phase region remains. (See [6] for a full explanation).
of gentle agitation. Isotropic liquids are preferable to waxy pastes because if one or more excipient(s) crystallise(s) on cooling to form a waxy mixture it is very difficult to determine the morphology of the materials, and most importantly the morphology of the drug within the wax. The earliest reports of self-emulsifying systems using pharmaceutical materials were of pastes, based on waxy alcohol ethoxylates [17]. These systems do disperse to form fine oil-in-water emulsions but since there is no need for or advantage of waxy pastes, use of such formulations is not advised. As a general rule it is sensible to use the simplest effective formulation, restricting the number of excipients used to a minimum. Screening studies have established that it is possible to formulate isotropic SEDDS using medium-chain tri-
53
glycerides and one of a small group of nonionic surfactants (most are ethoxylated oleate esters) [ 18,191. Why look any further than these formulations? One motivation for using alternative materials is the toxicological status of the above surfactants. There is no reason to suspect that they are likely to be more toxic than polysorbate 80, but only limited data is available on their acute and chronic toxicity. A second issue is the solvent capacity of the formulation, which may not be high enough for the drug in question. This encourages the use of more hydrophilic materials which may then require solubilization, leading to a three or four component formulation. Such a strategy can fundamentally change the mechanism of action of the SEDDS and the fate of the drug (see below). If the formulation includes a substantial proportion of hydrophilic components (and possibly water) the undiluted formulation may well be a ‘microemulsion’ itself, and could be used to solubilize hydrophilic drugs (see the accompanying article by New and colleagues [20]), though solvent capacity may well be lost on dilution. When the solubility of the drug in vegetable oil is not a problem the simplest formulation, and most desirable, may well be a simple oil solution which will itself be emulsified in the gut during digestion (see the accompanying reviews on lipolysis [21,22]).
3.2. Screening
exercises for selection
of excipients
A range of industrial nonionic surfactants were screened using subjective visual assessment by Pouton [23] and Wakerly [18,19] for their ability to form self-emulsifying systems with medium-chain and long-chain triglycerides. The most efficient systems were formed by surfactants with predominantly unsaturated acyl chains. Amongst these the most efficient were oleates with HLB values of approximately 11. Sorbitan esters (e.g. Polysorbate 85) or ethoxylated triglycerides (e.g. Tagat TO) were usually more efficient than fatty acid ethoxylates, probably because the latter are more polydisperse since they usually contain mono- and di-esters. A range of related excipients have been used to formulate SEDDS by other authors [24-261; a list of materials and some example formulations are tabulated by Constantinides [ 161.
C.W. Pouton / Advanced Drug Delivery Reviews 25 (1997) 47-58
54
3.3. Assessment
of the efficiency
of emulsification
An early attempt to quantify the efficiency of emulsification of various compositions of the Tween 85 /medium-chain triglyceride system [28], utilised a rotating paddle to promote emulsification in a crude nephelometer. This allowed an estimation of the time taken for emulsification (Fig. 9). Once emulsification was complete samples were taken for particle sizing by photon correlation spectroscopy and self-emulsified systems were compared with homogenised systems (Fig. 10). The most rapid emulsification occurred at an optimum surfactant content of 35% w/w, though it was concluded that all systems
100
’
0
I
10
1
20
30
40
50
60
mixture composltion (%wiw Tween 55)
Fig. 10. Apparent particle size of self-emulsified and homogenised emulsions of Miglyol 840/Tween 85 mixtures formed in water at 25°C. 0, self-emulsified; 0, homogenised. (From [28]). 40
IO a 6 4 2 0 0
10
20
30
40
50
60
mixture composition (Xulu Tveen 85) Fig. 9. Self-emulsification times of Miglyol 840/Tween 85 mixtures in distilled water at 25°C. 0, t,; 0, t,,,; n , t,,; 0, t,,, (a,b and c were polydisperse systems). (From 1281).
containing between 20-50% w/w Tween 85 emulsified very rapidly, so that this was not a crucial issue for formulation. The particle size was considered to be more important and there was a narrower window between 2540% w/w Tween 85 which produced fine homogeneous dispersions. The process of self-emulsification was observed using light microscopy. It was clear that the mechanism of emulsification involved erosion of a fine cloud of small particles from the surface of large droplets, rather than a progressive reduction in droplet size. When the surfactant content was above 50% the formation of viscous gels appeared to retard self-emulsification, though these systems produced very fine dispersions if more energy for dispersion was provided by homogenisation (Fig. 10). In a later study Wakerly and colleagues [l&19] identified a similar, but more efficient system, comprising of mixtures of Tagat TO with (polyoxyethylene-25-glyceryl trioleate) medium-chain triglycerides. These were sized using laser diffraction as well as photon correlation spectroscopy (Fig. 11) showing more clearly that there was a critical concentration between 20-25% w/w Tagat TO beyond which self-emulsification became highly efficient. Low particle size was maintained over the range 30-65% surfactant. The emulsification time was not determined formally during the
C.W. Pouton I Advanced Drug Delivey
500
50 I
a
I
oJ Surfaetant
Concentration
(5)
b
:
30
35
40
Surfactant
45
50
55
Concentration
60
65
70
(* ~1”)
.... ... 45.C -*-WC 34o"c
+ 25'C .... ... 30" C -*4O‘C Fig.
55
Reviews 25 (1997) 47-S8
I I. Mean emulsion droplet diameter versus surfactant concentration after self-emulsification Sizer; (b) photon correlation spectroscopy). (From [l 81).
of Tagat TO-Miglyol
812 mixtures
((a)
Laser Diffraction
latter studies but was observed visually. At concentrations above 50% Tagat TO emulsification was retarded by the high viscosity at the interface between droplet and water. Both the Tween 85/MCT oil and Tagat TO/MCT oil systems have been studied over a range of temperatures. Both systems are efficient between 5-40°C but are adversely affected if the temperature is raised above 60°C. This has been linked with the dehydration of the surfactant which gives rise to an inappropriate lower effective HLB [ 18,19,23,29]. The inclusion of drugs within SEDDS will affect their performance if the drug is able to compete with water for hydrogen bonding interactions with the ethoxy chains of the surfactant [18,23,30]. For instance, the model drug benzoic acid had a significant enhancing affect [30]. If, however, the drug is very hydrophobic and is less likely to interact with the surfactant, there may be little or no difference in performance, even in the presence of high concentrations of the drug [31].
3.4. Studies of equilibrium phase behaviour Equilibrium phase behaviour cannot reveal the true nature of the interfacial disruption which gives rise to spontaneous emulsification, but at least such studies enable prediction of the phases which are likely to form on dilution of SEDDS with water. Phase studies have suggested a role for liquid crystal formation in self-emulsification, and have also indicated that good formulations are usually operating close to a phase inversion region and in a region of enhanced aqueous solubilization [ 19,231. The enhanced solubilization is assumed to play a role in permitting more rapid penetration of water. Fig. 12 shows part of the phase diagram for dilution of an efficient SEDDS in water over a range of temperature. A number of typical features are shown. The phase inversion region is at approximately 40°C for this system (30% w/w Tween 85170% w/w MCT oil), and the system works well at ambient tempera-
C.W. Pouton I Advanced Drug Delivery Reviews 25 (1997) 47-58
56
20
25 3o%w/w water
mixture
15
lb
j
1 cehw/w POE(?O)-S-trioleott 30% Miglyol 812 7cP/&
composition
Fig. 12. Part of the phase diagram of water and the mixture 30% Tween 85/70% Miglyol 812. Roman numerals denote the number of phases present; o, oil continuous; w, water continuous; LC, liquid crystalline. (From [23]).
ture upto 60°C above which water-in-oil emulsions tend to form [23]. The region labelled LC, is equivalent to what was later referred to as LCa by Wakerly and colleagues when the Tagat TO system was studied (Fig. 13) [29]. This phase appears visibly clear, is distinctly birefringent when viewed between crossed polarising filters, as long as the light path is sufficiently long. Liquid crystal content is
70
clear when a 0.5-l cm diameter test tube is used but not when a thin film is viewed by polarising microscopy. The most likely interpretation of this result is that the mixture consists of liquid crystal dispersed in oily liquid. However, the density and refractive indices of the oil and liquid crystal regions are similar enough that they cannot be discerned as a separate phases, nor do they separate by gravity. This phase would be formed when a SEDDS made contact with as aqueous phase, and is thought to be an important factor in penetration of water into the bulk oil, causing massive interfacial disruption and ejection of droplets into the bulk aqueous phase. Nonyl phenol-5ethoxylate has a similar HLB but the equivalent phase diagram shows a clear distinctly two-phase region (L2 + LC) on dilution with water (Fig. 14). The two phases separate quickly by gravity. This latter system has no tendency to selfemulsify and requires homogenisation for droplet dispersion. This is typical of a large number of mixtures studies during screening studies [ 18,231. Whenever good self-emulsification was observed for binary mixtures of ethoxylates with MCT oil, the phase diagram always revealed the formation of LC, /LCa on dilution with water. The efficiency also correlated with high levels of solubilization. A good illustration is provided by Fig. 15 which shows that when benzoic acid was included in the SEDDS, the result was a lowering of the phase inversion region
65
10
IS T
SO T e
45 ; e r 4Oa I ” 35 r e 30 CC) 2s
7.0 IS
14
13
12
11
10 9 8 7 w w,vJ water Cordm,
6
5
4
3
2
1
0
Fig. 13. Part of the phase diagram of water and the mixture 30% Tagat T0/70% Miglyol 812. L,, aqueous; L,, oil continuous; LC, liquid crytsal (From [ 181).
ul~ P e I 35 a t ” 30 :
‘,
30
28
26
24
(0 25
zll
22
20 18 16 14 % w/w Wats Conteat
12
10
8
6
4
2
0
Fig. 14. Part of the phase diagram of water and the mixture 30% nonyl phenol-5-ethoxylate/70% Miglyol 812. L,, aqueous; L,, oil continuous; LC, liquid cry&al (From [IS]).
57
C.W. Pouton I Advanced Drug Delivery Reviews 25 (19971 47-58
I
’
0
30 3%w/w
water
25 mixhe
20 cmpaiticn
I5
IO
5
Ioo%w/w S%w/w knroicacid in POE(20)-S-triolea* Miglyol 812
becomes too dilute to fully solubilize the oil. This causes the water insoluble oil to separate as a second phase forming an oil droplet. There are then at least two mechanisms operating to cause emulsification and there may be others. The ‘diffusion and stranding’ mechanism can certainly lead to very fine emulsions or microemulsions, the disadvantage of such systems being that the solvent capacity of the system may be lost on migration of the cosolvent. This effect can be expected to be most pronounced when the log P of the drug is comparatively low (perhaps in the range log P = 2-3).
30% 70%
Fig. 15. Part of the phase diagram of water and the mixture 30% Tween 8.5/70% Miglyol 812 in the presence of 5% benzoic acid. Roman numerals denote the number of phases present; o, oil continuous; w, water continuous; LC, liquid crystalline. (From [231).
and a enhancement of solubilization. This system had improved efficiency at ambient temperature when compared to the basic SEDDS formulation (Fig. 12). What then is the explanation for the ease of emulsification? It is likely that the mechanism involved in the Tween 85 or Tagat TO systems involves dynamic formation of liquid crystalline units at the oil-water interface which allow penetration of water down aqueous channels, causing an increase in surface pressure, and interfacial instability (191. It is important to note that these formulations are water insoluble. There may be a small fraction of the surfactant which is soluble but this will be a minor component. Thus, the majority of the surfactant remains with the oil or is dispersed as a separate emulsion phase. This situation contrasts significantly with the behaviour of SEDDS, which include a cosolvent, such as the ternary or quatemary mixtures [5,25-271 reviewed by Constantinides [16]. Where a cosolvent is present there will be a significant migration of material which partitions and becomes diluted into the bulk aqueous phase. This can lead to a rapid emulsification by a mechanism which could be described as ‘diffusion and stranding’. The cosolvent dissolves the water-insoluble component into the aqueous phase as a solubilized system, until on further migration the concentration of cosolvent
4. Biological
issues in the selection
of SEDDS
Very few biophatmaceutical studies have been performed with SEDDS (see the accompanying review [32]), and there is a need for more comparative studies, particularly against simple oils and solid dosage forms. However, it is worth speculating at this stage on the issues which will influence the absorption from SEDDS. The rate of gastric emptying of SEDDS is similar to solutions, so that they are particularly useful where rapid onset of action is desirable [31]. Conversely if the therapeutic index of the drug is low, the rapid onset and accompanying high T,,, may lead to undesirable side-effects. With regard to bioavailability there are differences between formulations which contain water-soluble surfactants or cosolvents, and those which do not. The former systems may produce emulsions or micellar solutions with lower capacity for solubilization of drugs, which may result in precipitation of drugs in the gut. SEDDS formed with relatively hydrophobic surfactants (HLB < 12) such as Tween 85 or Tagat TO, which do not migrate into the aqueous phase, tend to have lower solvent capacities for drugs unless log P (drug) > 4. However these SEDDS should be preferable if the drug can be dissolved to an adequate extent. Another important consideration, though, will be the toxicity of the surfactants, particularly if the indication for the therapy is chronic. If the drug is sufficiently oil soluble a good case can be made for avoiding SEDDS completely and formulating the drug as a simple triglyceride solution, making use of lipolysis to aid dispersion of the formulation.
C.W. Pouton I Advanced Drug Delivery Reviews 25 (1997) 47-58
58
Cl91 Wakerly, M.G, Pouton, C.W., Meakin, B J. and Morton, F.S.
References [ll Groves, M.J. (1978) Spontaneous
emulsification. Chem. Industry, pp. 417-419. PI Attwood, D. and Florence, A.T. (1983) Surfactant systems: their chemistry, pharmacy and biology. Chapman and Hall, London. [31 Swenson, ES., Milisen, W.B. and Curatolo, W. (1994) Intestinal permeability enhancement: efficacy, acute local toxicity and reversibility. Pharm Res. 11, 1132- 1142. R. and Burckart, G.J. [41 Ptachcinsky, R.J., Venkataramanan, (1986) Clinical pharmacokinetics of cyclosporin. Clin. Pharmacokinet. 11, 107-l 32. 151 Kovarik, J.M., Mueller, E.A., van Bree, J.B., Tetzloff, W. and Kutz, K. Reduced inter- and intraindividual variability in cyclosporin pharmacokinetics from a microemulsion formulation J. Pharm. Sci. 83, 444-446. [61 Shinoda, K. and Friberg, S. (1986) Emulsions and Solubilization. John Wiley and Sons, Chichester. [71 Schick, M.J. (1977) Nonionic Surfactants. Marcel Dekker, New York. PI Robb, I.D. (Ed.) (1982) Microemulsions. Plenum Press, New York.
[91 Friberg, S.E. and Botherel, P. (Eds.) (1987) Microemulsions: structure
and dynamics.
CRC Press, Boca Raton, Florida. R.S. (1988) Microemulsions and related systems. Marcel Dekker, New York. In: J. Swarbrich [ill Eccleston, G.M. (1992) Microemulsions. and J.C. Boylan (Eds.), Encyclopedia of Pharmaceutical Technology, Marcel Dekker, New York, 9, 375-421. In: J. Kreuter (Ed.) [I21 Attwood, D. (1994) Microemulsions. Colloidal Drug Delivery Systems, Marcel Dekker, New York, pp. 31-71. [I31 Lo, I., Madsen, F., Florence, A.T., Treguier, J-P., Seiller, M. and Puisieux, F. (1977 j The influence of surfactant HLB and the nature of the oil phase on the phase diagrams of nonionic surfactant-oil-water systems. J. Colloid Interface Sci. 59, 3 19-32.5. [I41 Boyd, J., Parkinson, C. and Sherman, P. (1972) Factors affecting emulsion stability and the HLB concept. J. Colloid Interface Sci. 41, 359-363. [I51 Lin, T.J., Kurihara, H. and Ohta, H. (1977) Prediction of optimum o/w emulsification via solubilization measurements. J. Sot. Cosmet. Chem. 28, 457-479. P.P. (1995) Lipid microemulsions for im[I61 Constantinides, proving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm. Res. 12, 1561-1572. 1171 Groves, M.J. and de Galindez, D.A. (1976) The self-emulsifying action of mixed surfactants in oil. Acta Pharm. Suet. 13, 361-372. drug delivery sys[I81 Wakerly, M.G. (1989) Self-emulsifying tems based on nonionic surfactant-oil mixtures. Ph.D. Thesis, University of Bath.
[lOI Bourell, M. and Schechter,
(1986) Self-emulsification of vegetable oil-nonionic surfactant mixture: a proposed mechanism of action. Am. Chem. Sot. Symposium Series 311, 242-255. WI New et al. (1997) Solubilisation of hydrophilic drugs in oily formulations. Adv. Drug Delivery Rev. 25, 59-70. [211 Embleton, J. and Pouton, C.W. (1996) Structure and function of gastro-intestinal lipases. Adv. Drug Delivery Rev., this Issue. WI MacGregor, K.J., Embleton, J.K., Perry, E.A., Solomon, L.J., Seager, S. and Pouton, C.W. (1996) Influence of lipolysis on drug absorption from the gastro-intestinal tract. Adv. Drug Delivery Rev., this issue. V31 Pouton. C.W. (1982). A study of self-emulsifying oil/surfactant mixtures. Ph.D. thesis, University of London. ~241 Shah, N.H., Carvajal, M.T., Patel, CL, Infeld, M.H. and Malick, A.W. (1994) Self-emulsifying drug delivery systems with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. Int. J. Pharm. 106, 15-23. ~251 Constantinides, P.P. and Yiv, S.H. (1995) Particle size of phase inverted water-in-oil microemulsions under different dilution and storage conditions. Int. J. Pharm. 115, 225-234. P-61 Constantinides, P.P., Scarlat, J.P., Lancaster, C., Marcello, J., Marks, H., Ellens, H. and Smith, P.L. (1994) Formulation and intestinal absorption enhancement evaluation of waterchain medium in-oil microemulsions incorporating glycerides.
Pharm. Res. 11, 1385-l 390. P.P., Lancaster, C., Marcello, J., Chiossone, D., Omer, D., Hidalgo, I, Smith, P.L., Sarkahian, A.B., Yiv, S.H. and Owen, A.J. (1995) Enhanced intestinal absorption of an RGD peptide from water-in-oil microemulsions of different composition and particle size. J. Control. Release 34, 109-l 16. WI Pouton, C.W. (1985) Self-emulsifying drug delivery systems: assessment of the efficiency of emulsification. bit. J. Pharm. 27, 335-348. P91 Pouton, C.W., Wakerly, M.G. and Meakin B.J. (1987) Selfemulsifying systems for oral delivery of drugs. Proc. Int. Symp. Control. Release Bioactive Mater. 14, 113-l 14. I301 Pouton, C.W. ( 1985) Effects of the inclusion of a model drug on the performance of self-emulsifying formulations. J. Pharm. Pharmac. 37, IP. [311 Charman, S.A., Charman, W.N., Rogge, M.C., Wilson, T.D., Dutko, F.J. and Pouton, C.W. (1992) Self-emulsifying systems; formulation and biological evaluation of an investigative lipophilic compound. Pharm. Res. 9, 87-94.
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[32] Humberstone, A.J. and Charman, W.N. (1996) Lipid-based vehicles for the oral delivery of poorly water-soluble drugs. Adv. Drug Delivery Rev., this issue. [33] Ekwall, P., Mandell, L. and Fontell, K. (1969) Ternary systems of potassium soap, alcohol, and water. J. Colloid Interface Sci. 31, 508-512.