Advanced Drug Delivery Reviews 45 (2000) 1–4

Preface
L
www.elsevier.com / locate / drugdeliv

Places of emulsions in drug delivery

Masahiro Nakano*
Department of Pharmacy, Kumamoto University Hospital, 1 -1 -1 Honjo, Kumamoto 860 -8556, Japan

1. Introduction employed to deliver drugs parenterally by dissolving

drugs in soybean oil. Thus soybean oil emulsions are
Microparticulate drug delivery systems, which one type of oil-in-water emulsions, in which soybean
include liposomes, suspensions (drug particles, oil is used as an oil and lecithin is employed as a
microspheres, nanospheres, microcapsules, nanocap- surfactant. Oil-in-water emulsions containing drugs
sules), and emulsions, have been used widely for are called lipid microspheres by some scientists but
delivery of drugs. Liposomes have been described in lipid emulsions would be a more appropriate term for
a few volumes in this review journal [1–3]. these dosage forms.
We try to cover areas of emulsions which have not So far lipid emulsions (microspheres) containing
been covered in this series of the review journal. dexamethasone palmitate, flurbiprofen axetil or al-
Since lipid emulsions (microspheres) have already prostadil (prostaglandin E1) have been marketed in
been reviewed in an issue on lipid microspheres Japan.
(emulsions) [4] published in 1996, this topic is not
reviewed in the present issue.

4. Water-in-oil emulsions
2. Oil-in-water emulsions
Although water-in-oil emulsions can serve as
Oil-soluble drugs are enclosed in an oil phase of carriers for water-soluble drugs by dissolving drugs
oil-in-water emulsions and these emulsions serve as in a dispersed phase (water), their use is limited
carriers of many oil-soluble drugs. Fukushima et al. because of high viscosity of a dispersion medium
review their works on antitumor prostaglandins in (oil).
this issue. Use of large-droplet water-in-oil emulsions limited
lung uptake and increased tumor uptake of iodized
oil after intra-arterial hepatic injection in rabbits
3. Lipid emulsions (microspheres) bearing VX2 tumors in the liver [5].

Emulsions of soybean oil, originally used for

supplying a vegetable oil parenterally, have been 5. Self-emulsifying drug delivery systems

*Tel.: 1 81-96-373-5820; fax: 1 81-96-373-5906. Self-emulsifying drug delivery systems are mix-
E-mail address: nakano@kaiju.medic.kumamoto-u.ac.jp (M. tures of oils and surfactants, ideally isotropic, some-
Nakano). times including cosolvents, which emulsify under

0169-409X / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved.
PII: S0169-409X( 00 )00096-X
2 M. Nakano / Advanced Drug Delivery Reviews 45 (2000) 1 – 4

conditions of gentle agitation, similar to that which ment with water showed the presence of a solid
would be encountered in the gastrointestinal tract. emulsion. A multiple solid emulsion was shown for
Formulations of self-emulsifying drug delivery films containing 60% polyethylene glycol 20 000
systems have been reviewed by Pouton [6] in 1997 [14].
and by Lawrence and Rees in this issue of review
journal.
A spontaneous emulsification process has been 9. Multiple emulsions
used for a preparation of injectable lipid emulsions
[7]. Among water-in-oil-in-water type and oil-in-
water-in-oil type multiple emulsions, the former has
wider areas of applications than the latter and
6. Lipid nanoemulsions (nanospheres) therefore more studies have been reported on the
former.
Lipid nanoemulsions (nanospheres) are prepared
from purified soybean oil and purified egg yolk 9.1. Water-in-oil-in-water emulsions
lecithin. Their structures and compositions are simi-
lar to those of lipid emulsions (microspheres) but Since water-soluble drugs are enclosed in an inner
their sizes (25–50 nm) are smaller than those of lipid water phase of water-in-oil-in-water emulsions, and
emulsions (microspheres) (200 nm) [8]. The an- therefore these emulsions serve as carriers of water-
tifungal activity of lipid nanoemulsions (nanos- soluble drugs, much effort has been made to study
pheres) incorporating amphotericin B has been ex- methods of preparation and application to thera-
amined in mice [9] and rats [10]. In view of efficacy peutics. Examples include multiple emulsions con-
and toxicity, lipid nanoemulsions (nanospheres) are taining an antibiotic for injection, multiple emulsions
concluded to be the best among deoxycholate am- for arterial embolization therapy, development of a
photericin B (Fungizone), liposomal amphotericin B new membrane emulsification technique for multiple
(AmBisome) and lipid nanoemulsions (nanospheres) emulsions and clinical application of multiple emul-
incorporating amphotericin B. sions prepared by the membrane emulsification
Nanoemulsions have also been studied as one of technique which reviewed by Okochi and Nakano,
ocular drug carriers [11]. Hino et al., Nakashima et al. and Higashi and
Setouchi, respectively, in this issue.
Use of multiple emulsions as targetable delivery
7. Microemulsions systems has been reviewed previously [15].
Areas of applications of multiple emulsions covers
Microemulsions contain high percentages of both not only delivery of drugs but also delivery of
oil and water and high concentrations of surfactants vaccines for immunization [16].
[12]. Their size range is 8–80 nm. They are essen-
tially swollen micellar systems. Oral preparation of
cyclosporin A in microemulsions has been developed 10. Emulsions employed for preparations of
and has been widely used recently [13]. microspheres
Lawrence and Rees extensively review some of
recent developments as well as historical develop- 10.1. Microspheres containing fat-soluble drugs
ments in this issue.
Microspheres containing fat-soluble drugs have
been prepared through formation of oil-in-water
8. Solid emulsions emulsions [17–19]. When small droplets of organic
solvent containing drug and polymer dispersed in
Films of Eudragit RS, a hydrophobic polymer, water are subjected to vacuum, organic solvent is
containing polyethylene glycol 14 000 after treat- evaporated and solid microspheres are formed in
 M. Nakano / Advanced Drug Delivery Reviews 45 (2000) 1 – 4 3

water. Dry microspheres are obtained after filtration 12.3. Coating of multiple emulsion with a
of particles, washing with water and drying. palmitoyl derivative of mannan

10.2. Microspheres containing water-soluble drugs The water-in-oil-in-water multiple emulsion sys-
tem was coated with a palmitoyl derivative of
Microspheres containing water-soluble drugs have mannan to assess its toxicity in vitro and its dis-
been prepared through formation of water-in-oil-in- tribution behavior in vivo. A significant enhancement
water multiple emulsions [20] When water-soluble in lung uptake and a decreased internalization by
drugs such as peptides are wanted to be enclosed in a spleen was noticed [23].
matrix of polymers, water-soluble drugs are dis-
solved in water and the solution is dispersed in
dichloromethane solution containing a polymer to 13. Conclusion
form a water-in-oil dispersion. The water-in-oil type
dispersion is subsequently dispersed in water to form As reviewed above, a variety of emulsions can be
a water-in-oil-in-water multiple emulsion. When the prepared depending on use. Thus emulsions offer
organic solvent is removed by vacuum, microspheres wide areas of applications not only to drug therapy
in which drug is dispersed in a polymer suspended in but also to prevention of diseases by means of
water are obtained. The solid particles are filtered, immunization by delivery of vaccines.
washed and dried.

References
11. Fates of emulsions and drugs in emulsions
in the body
[1] S. Hirota, Theme editor, New liposome developments, Adv.
Drug Deliv. Rev. 24 (1997) 121–366.
Studies on dispositions of emulsions themselves [2] P.R. Cullis, A. Chonn, Theme editors, Interaction of lipo-
and drugs administered in emulsions are important somes with serum proteins in relation to clearance properties,
topics and are covered by Kawakami et al. in this Adv. Drug Deliv. Rev. 32 (1998) 1–152.
[3] H. Kiwada, Theme editor, The pharmacokinetics of lipo-
issue.
somes for tumor targeting, Adv. Drug Deliv. Rev. 40 (1999)
1–127.
[4] Y. Mizushima, Theme editor, Lipid microspheres, Adv. Drug
12. Modified emulsions
Deliv. Rev. 20 (1996) 113–266.
[5] T. de Baere, X. Zhanf, B. Auber, G. Harry, C. Lagrange, J.
In order to achieve efficient targeting of emulsions Ropers, J. Dufaus, J. Lumbroso, P. Rougier, M. Ducreus, A.
to sites of action of each drug, surface structures of Roche, Quantification of tumor uptakes of iodized oils and
emulsions are modified. emulsions of iodized oils: experimental study, Radiology 201
(1996) 731–735.
[6] C.W. Pouton, Formulations of self-emulsifying drug delivery
12.1. Electronically charged submicron emulsions systems, Adv. Drug Deliv. Rev. 25 (1997) 47–58.
[7] W. Yu, E.S.T. do Egito, G. Barratt, H. Fessi, J.P. Devissaguet,
Possible usefulness of positively and negatively F. Puisieux, A new approach to the preparation of injectable
charged submicron emulsions for enhanced topical emulsions by a spontaneous emulsification process, Int. J.
Pharm. 89 (1993) 139–146.
delivery of antifungal drugs have been studied
[8] J. Seki, H. Sasaki, M. Doi, H. Yoshikawa, Y. Takahashi, S.
recently [21]. Yamabe, H. Fukui, S. Sonoke, H. Yamamoto, M. Hirose, Y.
Ezure, T. Ando, K. Ushimaru, M. Sugiyama, Lipid nano-
12.2. Lectin-functionalized multiple emulsions for sphere (LNS), a protein-free analogue of lipoproteins, as a
improved cancer therapy novel drug carrier for parenteral administration, J. Control.
Rel. 28 (1994) 352–353.
[9] M.A. Hossain, S. Maesaki, H. Kakeya, T. Noda, K. Yanagi-
Lectin-functionalized multiple emulsions have hara, E. Sasaki, Y. Hirakata, K. Tomono, K. Tashiro, S.
been examined for improvement of cancer therapy Kohno, Efficacy of NS-718, a novel lipid nanosphere-en-
[22]. capsulated amphotericin B, against Cryptococcus neofor-
4 M. Nakano / Advanced Drug Delivery Reviews 45 (2000) 1 – 4

mans, Antimicrob. Agents Chemother. 42 (1998) 1722– [17] N. Wakiyama, K. Juni, M. Nakano, Preparation and evalua-
1725. tion in vitro of polylactic acid microspheres containing local
[10] T. Otsubo, S. Maesaki, M.A. Hossain, Y. Yamamoto, K. anesthetics, Chem. Pharm. Bull. 29 (1981) 3363–3368.
Tomoto, T. Tashiro, J. Seki, Y. Tomii, S. Sonoke, S. Kohno, [18] K. Juni, J. Ogata, M. Nakano, T. Ichihara, K. Mori, M.
In vitro and in vivo activities of NS-718, a new lipid Akagi, Preparation and evaluation in vitro and in vivo of
nanosphere incorporating amphotericin B, against Aspergil- polylactic acid microspheres containing doxorubicin, Chem.
lus fumigatus, Antimicrob. Agents Chemother. 43 (1999) Pharm. Bull. 33 (1885) 313–318.
471–475. [19] K. Juni, J. Ogata, N. Matsui, M. Kubota, M. Nakano,
[11] P. Calvo, J.L. Vila-Jato, M.J. Alonso, Comparative in vitro Modification of the release rate of aclarubicin from polylac-
evaluation of several colloidal systems, nanoparticles, tic acid microspheres by using additives, Chem. Pharm. Bull.
nanocapsules, and nanoemulsions as ocular drug carriers, J. 33 (1885) 1734–1738.
Pharm. Sci. 85 (1996) 530–536. [20] Y. Ogawa, M. Yamamoto, H. Okada, T. Yashiki, T.
[12] D. Attwood, Microemulsions in colloidal drug delivery Shimamoto, A new technique to efficiently entrap leuprolide
systems, in: J. Kreuter (Ed.), Colloidal Drug Delivery acetate into microcapsules of polylactic acid or copoly(lac-
Systems, Marcel Dekker, New York, 1994, pp. 31–71. tic / glycolic) acid, Chem. Pharm. Bull. 36 (1988) 1095–
[13] R. Arumugam, H.E. Soriano, A.O. Scheimann, B.S. Reid, 1103.
G.S. Gopalakrishna, O. Barakat, C.F. Ozaki, P.R. Wood, [21] M.P.Y. Piemi, D. Korner, S. Benita, J.-P. Marty, Positively
Immunosuppressive therapy with microemulsion cyclosporin and negatively charged submicron emulsions for enhanced
A shortens the hospitalization of pediatric liver transplant topical delivery of antifungal drugs, J. Control. Rel. 58
recipients, Clin. Transpl. 12 (1998) 588–592. (1999) 177–187.
[14] M. Lovrecich, F. Rubessa, Morphology and surface prop- [22] A.J. Khopade, K.S. Nandakumar, N.K. Jain, Lectin-function-
erties of blends of Eudragit RS with different poly(ethylene alized multiple emulsions for improved cancer therapy, J.
glycol)s, Pharmaceut. Develop. Technol. 3 (1998) 123–129. Drug Target. 6 (1998) 285–292.
[15] S.S. Davis, I.M. Walker, Multiple emulsions as targetable [23] A.J. Khopade, K.R. Mahadik, N.K. Jain, Targeting of
delivery systems, Methods Enzymol. 149 (1987) 51–64. multiple emulsions to the lungs, Pharmazie 51 (1996) 558–
[16] T.L. Hearn, M. Olsen, R.L. Hunter, Multiple emulsions oral 562.
vaccine vehicles for inducing immunity or tolerance, Ann.
NY Acad. Sci. 778 (1996) 388–389.