Pharmaceutical Research, Vol. 12, No. 11, 1995
`
`Review
`
`Lipid Microemulsions for Improving Drug Dissolution and
`Oral Absorption: Physical and Biopharmaceutical Aspects
`
`Panayiotis P. Constantinides1•2
`
`Received March 7, 1995; accepted June 20, 1995
`
`Purpose. This review highlights the state-of-the-art in pharmaceutical microemulsions with emphasis
`on self-emulsifying systems, from both a physical and biopharmaceutical perspective. Although these
`systems have several pharmaceutical applications, this review is primarily focused on their potential
`for oral drug delivery and intestinal absorption improvement.
`Methods. Physicochemical characteristics and formulation design based on drug solubility and mem(cid:173)
`brane permeability are discussed.
`Results. Case studies in which lipid microemulsions have successfully been used to improve drug
`solubilization/dissolution and/or intestinal absorption of poorly absorbed drugs/peptides are presented.
`Conclusions. Drug development issues such as commercial viability, mechanisms involved, range of
`applicability, safety, scale-up and manufacture are outlined, and future research and development
`efforts to address these issues are discussed.
`
`KEY WORDS: self-emulsifying systems; microemulsions; drug dissolution; membrane permeability;
`intestinal absorption; medium-chain glycerides; enhancer; peptide delivery.
`
`INTRODUCTION
`
`Much attention has been given recently to the use of
`lipid microemulsions in drug delivery, and excellent reviews
`can be found in the literature that described both physical
`properties and pharmaceutical applications (1-3) of these
`novel lipid-based drug carriers. The purpose of this review is
`not to give a comprehensive overview of the literature on
`microemulsions, but instead to focus and critically discuss
`the potential of self-emulsifying microemulsion systems as a
`novel oral dosage form for drug solubilization and intestinal
`absorption enhancement.
`Microemulsions are thermodynamically stable, isotropi(cid:173)
`cally clear dispersions of two immiscible liquids, such as oil
`and water, stabilized by an interfacial film of surfactant mol(cid:173)
`ecules (1). The surfactant may be pure, a mixture, or com(cid:173)
`bined with other additives. In the absence of water, mixtures
`of oil(s) and non-ionic surfactant(s) form clear and transpar(cid:173)
`ent isotropic solutions that are known as self-emulsifying
`drug delivery systems (SEDDS) and are recently being used
`for improving lipophilic drug dissolution and absorption (4-
`
`1 Pharmaceutical Development, UW 2921 Pharmaceutical Technol(cid:173)
`ogies, SmithKline Beecham Pharmaceuticals, P.O. Box 1539, King
`of Prussia, Pennsylvania, 19406.
`2 To whom correspondence should be addressed.
`Abbreviations: AUC, area under the plasma concentration-time
`curve; F, absolute bioavailability; GI, gastrointestinal; HLB, hydro(cid:173)
`phile-lipophile balance; i.d., intraduodenal; i.v., intravenous; MCG,
`medium-chain glycerides; MCM, medium-chain monoglycerides;
`0/W, oil-in-water; PEG, polyethylene glycol; PGG, polyglycolyzed
`glycerides; p.o., peroral; SEDDS, self-emulsifying drug delivery
`systems; W/0, water-in-Oil.
`
`6). One characteristic of these systems is their ability to form
`fine oil-in-water emulsions upon mild agitation when ex(cid:173)
`posed to aqueous media. Thus, SEDDS represent an effi(cid:173)
`cient vehicle for the in vivo administration of emulsions. It is
`for this reason that they are considered for oral delivery of
`lipophilic drugs, provided however, that the drug has ade(cid:173)
`quate solubility in the oil or oil/surfactant blend. Microemul(cid:173)
`sions are superior to simple micellar solutions in terms of
`solubilization potential and their thermodynamic stability of(cid:173)
`fers advantages over unstable dispersions, such as emulsions
`and suspensions, since they can be manufactured with little
`energy input (heat, mixing) and have a long shelf-life. How(cid:173)
`ever, the design of effective self-emulsifying microemulsion
`formulations of drugs, using well-defined and pharmaceuti(cid:173)
`cally acceptable excipients is still in its infancy. Few micro(cid:173)
`emulsion systems in marketed products or clinical evalua(cid:173)
`tion have been identified, as in the case of Cyclosporin A
`with Sandimmune (7) and Sandimmune Neoral (8) soft gel(cid:173)
`atin formulations although the former formulation is rather a
`crude emulsion and not a microemulsion. Thus, the full drug
`delivery potential of lipid microemulsions has yet to be re(cid:173)
`alized, particularly with water-soluble drugs. Oil-soluble
`drugs can be formulated in oil-in-water (o/w) microemulsions
`whereas, water-soluble ones are better suited for water-in-oil
`(w/o) systems. Phase inversion of microemulsions (9,10)
`upon addition of excess of the dispersed phase or in response
`to temperature is an interesting property of these systems
`that can affect drug release both in vitro and in vivo (1,2).
`An increasing number of reports in the literature suggest
`that lipid-based microemulsions (o/w and w/o) can be used to
`enhance the oral bioavailability of drugs, including peptides
`(3,11,12). Drug delivery advantages offered by microemul(cid:173)
`sions include improved drug solubilization and protection
`
`1561
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`0724-8741/95/1100-1561$07.50/0 © 1995 Plenum Publishing Corporation
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`1562
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`Constantinides
`
`against enzymatic hydrolysis, as well as the potential for
`enhanced absorption afforded by smfactant-induced mem(cid:173)
`brane fluidity and thus permeability changes (13).
`In this review, the structure, formulation and physical
`properties of microemulsions for oral drug delivery are con(cid:173)
`sidered first, followed by case studies where lipid micro(cid:173)
`emulsions have been used successfully to improve drug dis(cid:173)
`solution and/or absorption. In this section, SEDDS together
`with o/w and w/o microemulsions for lipophilic and hydro(cid:173)
`philic drug/peptide delivery, respectively, will be discussed
`and key factors will be identified that are considered to con(cid:173)
`tribute to the improved absorption from these lipid formula(cid:173)
`tions. Finally, drug development issues and approaches to
`address these issues are discussed with the hope that this
`review will stimulate further interest in this important area of
`drug delivery.
`
`FORMULATION
`DESIGN/DEVELOPMENT CONSIDERATIONS
`
`Excipient Selection
`
`Although several microemulsion systems have been de(cid:173)
`scribed in the literature, the challenge for the pharmaceutical
`formulator is to predict which oil(s) and surfactant(s) to se(cid:173)
`lect for a particular application, taking into consideration
`their acceptability due to potential toxicity (13). The forma(cid:173)
`tion of w/o and o/w microemulsions usually involves a com(cid:173)
`bination of three to five basic components, namely, oil, wa(cid:173)
`ter, surfactant, cosurfactant and electrolyte. However, the
`use of cosurfactant in microemulsions is not mandatory and
`alcohol-free self-emulsifying microemulsion systems have
`
`been described in the literature (14,15). The tendency toward
`a w/o or an o/w microemulsion is dependent on the proper(cid:173)
`ties of both the oil and surfactant and the oil-to-water ratios.
`The hydrophile-lipophile balance (HLB) is an empirical for(cid:173)
`mula that is used to select surfactants for microemulsions
`(1,2). For both non-ionic and ionic surfactants, the HLB
`value generally varies from 1-45, with the range being 1-20
`for non-ionics. Non-ionic or zwitterionic surfactants are of(cid:173)
`ten considered for pharmaceutical applications and micro(cid:173)
`emulsion formulation since are less toxic (13,14) and less
`affected by pH and ionic strength changes (15). Water-in-oil
`microemulsions are formed using emulsifiers within the
`HLB range of 3 to 8 while o/w microemulsions are formed
`within the range of 8-18. The choice of emulsifiers is deter(cid:173)
`mined by the average HLB requirement of the proposed
`microemulsion. Some of the oils and surfactants used to for(cid:173)
`mulate microemulsions for oral drug delivery along with
`their HLB values and manufacturer's name are listed in Ta(cid:173)
`ble 1. In most cases, it is the right blend of a low and high
`HLB surfactant that leads to the formation of a stable mi(cid:173)
`croemulsion in the absence of a cosurfactant (14,15).
`Medium-chain glycerides derived from coconut oil are
`particularly attractive for formulating orally active micro(cid:173)
`emulsions since, a) they are stable food grade products and
`generally recognized as safe by the Food and Drug Admin(cid:173)
`istration agency (US FDA Code of Federal Regulations, Ti(cid:173)
`tle 21, Sections 172 and 184, Interpharm Press, 1989), b)
`microemulsions incorporating these excipients can be for(cid:173)
`mulated at ambient temperature over a wide range of com(cid:173)
`positions (15), c) medium-chain glycerides (mono-, di-, and
`triglycerides) are reported to improve the intestinal absorp(cid:173)
`tion of co-formulated drugs (3,5,6,8,ll-13,16-18) and, d)
`
`Table 1. Some of the Common Excipients Used to Formulate Lipid Microemulsions for Oral Drug Delivery
`
`Excipient
`(HLB)
`
`Arlacel 80 (4.3)
`Arlacel 186 (2.8)
`Capmul MCM (5.5-6.0)
`Captex 200 (oil)
`
`Captex 355 (oil)
`Centrophase 31 (4.0)
`Cremophor EL (13.5)
`Labrafac CM IO (10)
`
`Labrafil M 1944 CSD (3-4)
`
`Labrafil M 2125 CS (3-4)
`
`Labrasol (14)
`
`Miglyol 812 (oil)
`Myvacet (oil)
`Myverol 18-92 (3.7)
`
`Soybean Oil
`
`Thgat TO (I 1.3)
`Tween 80 (15.0)
`
`Chemical Definition
`
`Manufacturer
`
`sorbitan oleate
`monoolein: propylene glycol (90: IO)
`C8/C 10 mono-/diglycerides from coconut oil
`C8/C 10 diesters of propylene glycol from coconut
`oil
`C8/C 10 triglycerides from coconut oil
`Liquid Lecithin
`polyoxyethylene glycerol triricinoleate 35 DAC
`C8/C 10 polyglycolyzed glycerides from coconut
`oil
`primarily oleic acid (C 18, 1) polyglycolysed glycer(cid:173)
`ides from apricot kernel oil
`primarily linolek: acid (C 18,2) polyglycolyzed glyc(cid:173)
`erides from com oil
`CsfC 10 polyglycolyzed glycerides from coconut
`oil
`CsfC 10 triglycerides from coconut oil
`distilled acetylated monoglycerides
`distilled sunflower oil monoglyceride (90% glyc(cid:173)
`eryl linoleate)
`primarily oleic (25%) and linoleic (54%) triglycer(cid:173)
`ides
`polyoxyethylene (25) glycerol trioleate
`polyoxyethylene (20) sorbitan oleate
`
`ICI Americas (Wilmington, DE)
`ICI Americas (Wilmington, DE)
`Abitec (Columbus, OH)
`Abitec (Columbus, OH)
`
`Abitec (Columbus, OH)
`Central Soya (Fort Wayne, IN)
`BASF (Parsippany, NJ)
`Gattefosse (Westwood, NJ)
`
`Gattefosse (Westwood, NJ)
`
`Gattefosse (Westwood, NJ)
`
`Gattefosse (Westwood, NJ)
`
`Huls, America (Piscataway, NJ)
`Eastman Chemicals (Kingsport, TN)
`Eastman Chemicals (Kingsport, TN)
`
`Croda (Mill Hall, PA)
`
`Goldschmidt Chem. (Hopewell, VA)
`BASF (Parsippany, NJ)
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`Lipid Microemulsions for Oral Drug Delivery
`
`1563
`
`Miglyol 812, a mixture of C8/C 10 triglycerides (Table 1), is
`present in a marketed soft gelatin capsule of Vitamin D3 (19).
`Recently polyglycolyzed glycerides (PGG) with varying
`fatty acid and polyethylene glycol (PEG) chain lengths and
`thus varying HLB, in combination with vegetable oils have
`been used to solubilize poorly water-soluble drugs and im(cid:173)
`prove their bioavailability (6). According to the manufac(cid:173)
`turer, these products are derived from selected, high purity,
`food grade vegetable oils which are reacted with pharmaceu(cid:173)
`tical grade PEG and therefore expected to be well tolerated
`by the body. The work by Shah et al. (6) where factors con(cid:173)
`trolling lipophilic drug release and absorption from SEDDS
`with polyglycolyzed glycerides have been thoroughly inves(cid:173)
`tigated, should serve as a useful reference in properly select(cid:173)
`ing polyglycolyzed glycerides for similar drug delivery ap(cid:173)
`plications.
`Lecithin-based microemulsions, both o/w and w/o, are
`recently being considered as alternative drug delivery sys(cid:173)
`tem that avoids problems of toxicity associated with some of
`the non-ionic surfactants (2). However, since lecithin is too
`lipophilic (HLB = 4.0) and has a tendency to form lamellar
`liquid crystalline phases, short-chain alcohols are often in(cid:173)
`cluded to alter the HLB and aid emulsification by destabi(cid:173)
`lizing the liquid-crystalline phases (20). Thus far, phospho(cid:173)
`lipid microemulsions have primarily been used for topical
`drug delivery (2) and their potential for oral drug delivery
`needs to be determined.
`
`Microemulsion Formulation and Drug Incorporation
`
`Phase Diagrams
`
`Microemulsion existence fields can be identified from
`ternary phase diagrams of systems containing oil-surfactant(cid:173)
`water. Fig. 1 shows a hypothetical pseudo-ternary phase di(cid:173)
`agram that represents schematically conventional micelles
`(Ll Phase), reverse micelles or w/o microemulsions (L2
`Phase), o/w microemulsions and coarse emulsions. In the
`absence of water, oil-surfactant mixtures can be either clear
`and isotropic solutions (SEDDS) or oily dispersions (Fig. 1)
`depending on the nature of the oil and surfactant and their
`mixing ratio. Since water-in-oil microemulsions are also
`known as reverse micelles or L2 phase, tnese two phases are
`represented by the same field on the phase diagram (Fig. 1).
`Coarse emulsions which are thermodynamically unstable
`two-phase dispersions are represented on the right side of
`the phase diagram and along the oil-water line (Fig. 1). In
`mixtures of oil, water and surfactant several other associa(cid:173)
`tion structures are formed, such as lamellar, hexagonal and
`cubic phases and detailed phase diagrams describing these
`phases can be found in the literature (1,2). These phases,
`however, although of interest to drug delivery, are beyond
`the scope of this review article. In terms of their microstruc(cid:173)
`ture, o/w and w/o microemulsions are very complex and
`dynamic ;ystems with intermediate bicontinuous structures
`being present between the o/w and w/o regions (Fig. 1).
`These phases are also referred to as type I, II or III Winsor
`microemulsions and represent microemulsions in equilib(cid:173)
`rium with excess water, excess oil or both (1). Much of the
`interest in multiphase microemulsion systems is focused on
`
`oil
`
`SEDDS (clear, isotropic)
`or
`oily dispersion~
`
`surfactant(s)
`
`bicontinuous
`microemulsion
`
`water
`
`\
`@
`
`micelle
`(L1 Phase)
`
`o/w microemulsion
`
`~ High HLB sulfactant
`Ov'-- Low HLB sulfactant or cosulfactant
`Fig. 1. A hypothetical pseudo-ternary phase diagram of an oil/
`surfactant/water system with emphasis on microemulsion and emul(cid:173)
`sion phases. Within the phase diagram, existence fields are shown
`where conventional micelles (LI phase), reverse micelles or w/o
`microemulsions (L2 phase) and o/w microemulsions are formed,
`along with the bicontinuous microemulsion and coarse emulsion
`phases. Outside the phase diagram, surfactant microstructures in
`various phases are schematically indicated. In the absence of water,
`oil-surfactant blends can be either clear isotropic solutions (SEDDS)
`or oily dispersions depending on the nature of the oil and surfactant
`and the oil-to-surfactant ratio.
`
`their applications in enhanced oil recovery and biotechnol(cid:173)
`ogy (1).
`SEDDS are formulated in the absence of water by mix(cid:173)
`ing an oil with a non-ionic surfactant or polyglycolyzed glyc(cid:173)
`eride (4-6) and a lipid-soluble drug to form an isotropic oily
`solution. Upon dilution or in vivo administration they formed
`fine o/w emulsions. In order to formulate self-emulsifying
`o/w and w/o microemulsions, however, an oil, a blend of two
`surfactants and an aqueous phase (water or saline) is used,
`that is, a total of four basic components. These systems can
`best be described by pseudo-ternary phase diagrams where,
`a constant ratio of two of the components is used, and the
`other two are varied (1,2,15). For example, the mixture of
`the oil and the oil-soluble low HLB surfactant can be held
`fixed and titrated with known amounts of the high HLB
`surfactant and water (11,15). Since the formation of the mi(cid:173)
`croemulsion is thermodynamically favored, the order of ad(cid:173)
`dition of the components should not have any effect on the
`final size and stability of the particle.
`For preparing microemulsions incorporating long-chain
`glycerides, such as soybean oil and monoolein, the various
`components are added and mixed at temperatures between
`40-60 °C in order to reduce viscosity. For components which
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`1564
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`Constantinides
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`are solid at room temperature, such as monolein, premelting
`at the appropriate temperature is necessary before mixing
`with the oil and other surfactants. For these systems, further
`equilibration of the resulting microemulsion at 40-50°C for
`about 24 hrs was found to improve stability (15). Microemul(cid:173)
`sions incorporating medium-chain glycerides can be formed
`spontaneously at room temperature over a wide range of
`compositions (11, 15) when their components are brought
`into contact, that is without the application of high energy or
`the inclusion of short-chain alcohols that are known to cause
`tissue irritation (14). Formulation at ambient temperature is
`particularly advantageous for thermolabile drugs, particu(cid:173)
`larly peptides. The formation and stability of microemul(cid:173)
`sions consisting of non-ionic components (oil plus surfac(cid:173)
`tants) is not affected by the pH and/or ionic strength of the
`aqueous phase in the pH range between 3 and 10. This prop(cid:173)
`erty can be beneficial for drugs and other molecules exhib(cid:173)
`iting higher solubility and/or stability at low or high pH.
`
`Drug Incorporation into Microemulsions
`
`In properly selecting a suitable microemulsion system
`for drug solubilization and delivery it is important to have
`some pre-formulation data, particularly aqueous and/or oil
`solubility or even better oil/water partition coefficients
`(11, 17) along with in vitro membrane permeability data
`across different regions of intestinal tissues (21). The drug
`classification by Amidon et al. (22) based on drug solubility
`and intestinal permeability best described some of the fac(cid:173)
`tors controlling the drug dissolution and absorption process.
`This new biopharmaceutical drug classification is adapted in
`Table 2 of this review article along with the recommended
`microemulsion systems to address drug dissolution and ab(cid:173)
`sorption for each of the four drug classes (22). It should be
`emphasized, however, that in order to design efficient mi(cid:173)
`croemulsion system(s) to address specific drug delivery
`needs, computational modelling along with physicochemical
`studies of both the drug and the microemulsion system(s) are
`necessary to better understand drug structure/micro(cid:173)
`emulsion composition/permeability correlations.
`For SEDDS and o/w microemulsions the drug is solubi(cid:173)
`lized in the oil or the oil/surfactant blend whereas, for w/o
`microemulsions the drug is preferably solubilized in the
`aqueous phase followed by the addition of oil/surfactants.
`
`The amount of drug incorporated into a given microemulsion
`is dependent on its relative solubility in the various compo(cid:173)
`nents of the system, particularly on its oil/water partition
`coefficient. Preformulation data that includes aqueous solu(cid:173)
`bility, as well as solubility in selected microemulsion excip(cid:173)
`ients (Table 1) is useful and it should preceed any micro(cid:173)
`emulsion formulation work. In addition, it is necessary to
`investigate what effect the drug has on the formation and
`stability of the microemulsion particle using some of the
`physicochemical methods that are described in the next sec(cid:173)
`tion. Phase diagrams should be constructed in the presence
`of a particular drug, particularly if the drug is surface active
`and thus expected to significantly affect the microemulsion
`region.
`
`Physical Characterization of Microemulsions
`
`Once the construction of the phase diagram is complete
`and the microemulsion existence field has been identified,
`simple tests, such as dye solubilization, dilutability by the
`excess of the dispersed phase and conductance measure(cid:173)
`ment (23) are employed to identify the structure of water(cid:173)
`containing microemulsions. Oil-in-water microemulsions
`where the external phase is water are highly conducting,
`whereas w/o are not, since water is the internal or dispersed
`phase. Likewise, o/w microemulsions are dilutable with wa(cid:173)
`ter, whereas w/o are not and undergo a phase inversion into
`o/w micro-emulsions (9,10) a property that may have in vivo
`implications. Finally, a water-soluble dye is solubilized
`within the aqueous phase of the w/o particle but is dispers(cid:173)
`able in the o/w particle. Non-aqueous microemulsions
`(SEDDS) can easily be identified as clear and transparent
`oil-surfactant blends in the absence and presence of a li(cid:173)
`pophilic drug. Further physical characterization of micro(cid:173)
`emulsions involves measurement of the interfacial tension
`(1), determination of density, refractive index and viscosity
`(11,15,24) and particle size (2,10,25). A thorough review by
`Kahlweit et al. (26) is focused on different experimental tech(cid:173)
`niques used to study microemulsions and it should serve as
`useful reference for those interested in obtaining further in(cid:173)
`sight into the dymamics of microemulsion structure. Thble 3
`summarizes some of the physical properties of representa(cid:173)
`tive w/o microemulsions incorporating long- vs medium(cid:173)
`chain glycerides and saline as the aqueous phase (15). Major
`
`Table 2. Potential Microemulsion Systems for Oral Drug Delivery Based on Aqueous Solubility and
`Membrane Permeability Considerationsa
`
`Aqueous
`Solubility
`
`Membrane
`Permeability
`
`Potential
`Microemulsion
`System
`
`Anticipated Drug Delivery Benefits
`
`High
`
`High
`
`Low
`
`Low
`
`High
`
`Low
`
`High
`
`Low
`
`W/0
`
`W/0
`
`SEDDS, 0/W
`
`SEDDS, 0/W
`
`stabilization and protection against chemical and
`enzymatic hydrolysis
`stabilization and protection against chemical and
`enzymatic hydrolysis, increased bioavailabilityb
`improved solubilization and dissolution, increased
`bioavailabilityb
`improved solubilization and dissolution, increased
`bioavailabilityb
`
`a Adapted from ref. 22.
`b Increased rate and/or extent of absorption.
`
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`Lipid Microemulsions for Oral Drug Delivery
`
`1565
`
`Table 3. Comparison of the Physical Properties of Self-Emulsifying
`Water-in-Oil Microemulsions Incorporating Long- vs Medium(cid:173)
`Chain Glycerides (ref. 15)
`
`Physical Propertya
`
`Long-Chainb
`
`Medium-Chainc
`
`Density (gr/cm3)
`Refractive Index
`Viscosity (cP)
`Conductance (µmhos/cm)d
`Droplet Diametere (nm)
`(mean± sd)
`Polydispersitye
`
`0.9010
`1.471
`125.l
`0.177
`
`0.9677
`1.449
`56.7
`0.540
`
`10.3 ± 2.5
`0.114
`
`15.2 ± 4.1
`0.153
`
`a Determined at room temperature.
`b Soybean oil/Arlacel 186/Tween SO/Saline (65/22/10/3, % w/w).
`c Captex 355/Capmul MCM/Tween 80/Saline (65/22/10/3, % w/w).
`d The conductance of saline alone was 13,400 µmhos/cm.
`e Both expressed as particle number results; a polystyrene beads
`standard of 63 nm produced a particle with a mean droplet diam(cid:173)
`eter of 64.2 ± 15.1 nm and a polydispersity of0.031.
`
`differences in density, refractive index and viscosity can be
`seen whereas, similar conductance and particle size were
`obtained. The extremely low conductance and particle size
`of these microemulsions is characteristic of a thermodynam(cid:173)
`ically stable w/o particle. Interestingly, saline alone had a
`conductance of 13,400 µmhos/cm (Table 3).
`
`ORAL DRUG DELIVERY APPLICATIONS OF
`MICROEMULSION SYSTEMS/CASE STUDIES
`
`SEDDS and 0/W Microemulsions
`
`Early work by Pouton (4) on the physical chemistry of
`SEDDS was very useful and has led to the establishment of
`these systems for the oral administration of lipophilic drugs
`that are subject to dissolution rate limited absorption. An
`efficient SEDDS should, a) be able to form a fine emulsion
`having particle size of less that 5 µm upon dilution with
`aqueous media under mild agitation (4-6), and, b) produce oil
`droplets of appropriate polarity which permit a faster drug
`release to the aqueous phase (6). In a subsequent study,
`Charman et al. (5) showed that a self-emulsifying formula(cid:173)
`tion of a lipophilic drug WIN 54954 (5-[5-[2,6-dichloro-4-
`( dihydro-2-oxazolyl) phenoxy ]pentyl]-3-methylisoxazole)
`that consisted of a medium-chain triglyceride (Neobee M5)/
`non-ionic surfactant (Thgat TO)/drug (40/25/35, % w/w), can
`be emulsified rapidly upon gentle agitation in 0.1 N HCl at 37
`~C producing emulsions with mean droplet diameter of less
`than 3 µm. When the absolute bioavailability of the drug in
`fasted dogs from a soft gelatin capsule of the self-emulsifying
`formulation was compared to that produced from a PEG 600
`solution in a capsule, no significant differences in bioavail(cid:173)
`ability from these two formulations were observed (5). The
`SEDDS however, improved the reproducibility of the plasma
`profile in terms of the maximum plasma concentration
`(Cmax) and the time to reach the maximum concentration
`(tmax).
`Although several non-ionic surfactants can be used in
`combination with vegetable oils to produce SEDDS, poly-
`
`glycolyzed glycerides (Thble 1) are effective emulsifiers. It
`has been shown (6) that the molecular weight of PEG in
`glyceride, the fatty acid chain length and degree of unsatur(cid:173)
`ation, as well as, the concentration of glyceride in the
`SEDDS play a crucial role in optimizing the performance of
`the SEDDS (6). Monitoring the release of a lipophilic drug,
`Ro 15-0778, which is a naphthalene derivative (6), from sev(cid:173)
`eral SEDDS using different polyglycolyzed emulsifiers, it
`has been found that Labrafac CM 10 with an HLB of 10
`(Thble 1) produced the highest release rate. Furthermore,
`both the dissolution of Ro 15-0778 and pharmacokinetic pa(cid:173)
`rameters upon oral administration to non-fasted dogs from a)
`SEDDS, b) drug solution in PEG 400, (control) c) capsule
`formulation of wet-milled spray dried powder, and d) tablet
`formulation of micronized drug, were determined and com(cid:173)
`pared and Fig. 2 and Table 4 summarize these data (6). As
`can be seen from Fig. 2 and Table 4, the use of the SEDDS
`resulted in both improved dissolution and absorption (in(cid:173)
`creased Cmax and AUC) as compared to the other oral dos(cid:173)
`age forms.
`Self-emulsifying formulations of new lipophilic benzo(cid:173)
`diazepine compounds which can be filled into hard or soft
`gelatin capsules for oral administration have been recently
`patented (27). These formulations contain propylene glycol,
`polyglycolyzed glycerides, such as, Labrafil M 2125 CS or M
`1944 CS or Labrasol in combination with Tween 80 (Thble 1)
`and are claimed to be useful for the treatment of pain, panic
`or anxiety.
`Improved dissolution and oral absorption of lndometh(cid:173)
`acin in the rat from a self-microemulsifying drug delivery
`system (SMEDDS) incorporating polyglycolyzed glycerides
`as compared to an aqueous suspension of the drug has also
`been recently reported (28). This SMEDDS is similar to
`SEDDS and consists of an oil, surfactant and co-surfactant
`mixture which emulsifies spontaneously when diluted with
`water under gentle stirring (28). Its applicability to other
`lipophilic drugs/peptides need to be determined.
`The use of o/w microemulsions, for oral drug delivery
`has centered around lipophilic peptide delivery, particularly
`of Cyclosporine. Two oral dosage forms of Cyclosporine are
`available commercially, which are marketed by the name
`Sandimmune, an olive oil-based solution that also contains
`
`120
`
`Time(min)
`Fig. 2. In vitro dissolution profile of Ro 15-0778 from different for(cid:173)
`mulations. (e) SEDDS; (T) 1.2 % PEG 400; (A) wet milled spray
`dried powder; <•> micronized drug. (Source: ref. 6 with permission)
`
`140
`
`Purdue 2017
`Collegium v. Purdue, PGR2018-00048
`
`

`

`1566
`
`Constantinides
`
`ethanol and Labrafil M 1944 CS (Table 1) and a soft gelatin
`formulation that contains, corn oil, gelatin, glycerol, dehy(cid:173)
`drated ethanol and Labrafil M 2125 CS (Thble 1). The extent
`and rate of absorption of the drug, however, from this for(cid:173)
`mation varies widely, both within-patient and between pa(cid:173)
`tient populations, with the oral bioavailability being in the
`range from about 7-90% and the time to reach peak plasma
`concentration between 1.5 to 22 hrs (7). Therefore, there has
`been a need to develop an orally effective formulation of
`Cyclosporine with more consistent absorption characteris(cid:173)
`tics and several investigators began exploring this possibility
`using different microemulsion systems.
`In a systematic study, Ritschel (3,29,30) reported on the
`gastrointestinal absorption of Cyclosporin A using a number
`of o/w microemulsion systems. Three different physical
`forms of microemulsions were employed: a) a liquid micro(cid:173)
`emulsion for in situ studies using the isolated segment rat
`model to determine absorption site, b) a microemulsion gel
`formed by the addition of silicon dioxide for rectal bioavail(cid:173)
`ability studies, and c) a microemulsion gel encapsulated into
`hard gelatin capsules for peroral administration to dogs. Re(cid:173)
`sults from a) and b) indicated that the absorption of cyclo(cid:173)
`sporin A followed the order: small intestine > rectum >
`large intestine ~ stomach. The results from c) in dogs (29)
`showed no difference in both the absolute and relative bio(cid:173)
`availability between the commercially available Sandim(cid:173)
`mune solution and an o/w microemulsion formulation (3,29).
`Similar experiments were carried out in rats (3,30) where the
`standard Sandimmune p.o. solution and two different micro(cid:173)
`emulsion formulations were administered perorally by intra(cid:173)
`gastric feeding tube and the results are shown in Table 5
`(3,30). An approximately 3-fold increase in absolute bio(cid:173)
`availability was observed with one of the microemulsions
`compared to the Sandimmune solution (Table 5). However, a
`similar microemulsion formulation in which branched chain
`fatty acid esters were substituted for long-chain fatty acid
`esters gave no significant improvement in bioavailability
`over the standard oral solution (Table 5). Although the
`smaller droplet size in the microemulsion as compared to
`that of coarse emulsion plays a role in improving absorption,
`certainly other factors need to be considered, such as, the
`type of the lipid phase and surfactants in the microemulsion
`and the digestibility of the lipid used (3). A working model
`based on a hypothesized mechanism utilizing lipid absorp(cid:173)
`tion pathways by which peptides are being absorbed from
`microemulsions given perorally has been proposed by
`Ritschel (3). However, caution should be exercised in pro(cid:173)
`posing lipid absorption pathways for the uptake of micellar
`
`lipid-based carriers (3]), such as mixed micelles and micro(cid:173)
`emulsions, since only monomeric lipid molecules are known
`to permeate intestinal epithelial cells (32).
`A new cyclosporine formulation (Sandimmune Neoral)
`has recently been developed by Sandoz (33) and is now a
`marketed product in Europe and in clinical studies else(cid:173)
`where. This new formulation is a microemulsion preconcen(cid:173)
`trate that is similar to the earlier discussed SEDDS and it
`contains cyclosporin A, along with a surfactant, a hydro(cid:173)
`philic cosolvent and a blend of lipophilic and hydrophilic
`solvents (33). Due to compositional differences in the oil and
`surfactant between the original Sandimmune and Sandim(cid:173)
`mune Neoral, the later formulation forms an o/w microemul(cid:173)
`sion upon in vivo self-emulsification (33) whereas the former
`formulation forms a crude emulsion. In clinical studies,
`Sandimmune Neoral, has shown to produce reduced inter(cid:173)
`and intrapatient variability in cyclosporine pharmacokinetics
`when compared to the marketed original Sandimmune (8).
`Representative data comparing the pharmacokinetics of
`these two cyclosporine formulations in stable renal trans(cid:173)
`plant patients is given in Table 6 (33). As can be seen from
`these data, this new ora