Pharmaceutical Research, Vol. 17, No.

6, 2000 Research Paper

Various approaches have been used in an attempt to over-

Preparation of Biodegradable Insulin come these barriers and increase the oral bioavailability of such
Nanocapsules from Biocompatible bioactives including the use of polymeric particulates (2). It
Microemulsions has been demonstrated that encapsulation within particulate
delivery systems can protect peptides from proteolytic enzymes
(3,4). Further, it has been suggested that if the size of the
particles is sufficiently small (,1 mm), they may pass across
Suchat Watnasirichaikul,1 Nigel M. Davies,1,2 the intestinal mucosa and hence facilitate the absorption of
Thomas Rades,1 and Ian G. Tucker1 peptide drugs from the gut lumen (5–7). Under such circum-
stances, the polymer used for the preparation of the particulate
carrier must be biodegradable.
Received November 30, 1999; accepted March 8, 2000
Biodegradable, aqueous cored nanocapsules suitable for
Purpose. To prepare poly(ethyl 2-cyanoacrylate) nanocapsules con- the entrapment of proteins and peptides can be prepared by
taining insulin by interfacial polymerization of spontaneously forming, interfacial polymerization of water-in-oil dispersions using
biocompatible microemulsions. alkylcyanoacrylates. However, to obtain a dispersed aqueous
Methods. A pseudo-ternary phase diagram of a mixture of medium phase having a suitably small particle size from kinetically
chain glycerides (caprylic/capric triglycerides and mono-/diglycerides),
stabilised water-in-oil coarse emulsions, a high input of energy
a mixture of surfactants (polysorbate 80 and sorbitan mono-oleate) and
water was constructed. Polarizing light microscopy was used to identify in the form of either ultrasonication (8) or vigorous stirring (9)
combinations forming microemulsions. Microemulsions were charac- is required. Even then, it is difficult to obtain a disperse phase
terized by conductivity and viscosity to select systems suitable for the having a uniform particle size below 200 nm.
preparation of poly(ethyl 2-cyanoacrylate) nanocapsules by interfacial The requirement of a high input of energy may be over-
polymerization. Nanocapsules were prepared by addition of 100 mg come by the use of microemulsions. Microemulsions are sponta-
of ethyl 2-cyanoacrylate to a stirred water-in-oil microemulsion con- neously forming, thermodynamically stable, dispersed systems
taining 1 g of water, 7.6 g of oil, and 1.4 g of surfactant. The nanocap- having a uniform droplet size of less than 200 nm. As such,
sules formed were characterized by photon correlation spectroscopy, they represent a novel system that may be exploited for the
freeze fracture transmission and scanning electron microscopy. Insulin preparation of poly(alkylcyanoacrylate) nanocapsules by
nanocapsules were prepared by using an aqueous solution of insulin
interfacial polymerization. If biocompatible oils and surfactants
(100 units/ml) as the dispersed phase of the microemulsion. The entrap-
ment and the release of insulin from the nanocapsules were determined. are used to formulate the microemulsions, the necessity of
Results. Three regions were identified in the pseudo-ternary phase isolating the nanocapsules from the reaction matrix following
diagram; a microemulsion region, a region in which liquid crystalline polymerization is removed.
structures were present and a coarse emulsion region. All systems in The in situ formation of nanocapsules in an oily microe-
the microemulsion region were water-in-oil dispersions. Poly(ethyl 2- mulsion matrix may also prove beneficial for the delivery of the
cyanoacrylate) nanocapsules having a mean particle size of 150.9 nm encapsulated bioactive as the oral bioavailability of a number of
were formed upon interfacial polymerization of the microemulsion. peptides has been increased by administration in lipid-based
Nanocapsules were found to have a central cavity surrounded by a microemulsions (10–14). The mechanism by which microemul-
polymer wall. In excess of 80% of the insulin present in the microemul- sions enhance the absorption of peptides may be a result of
sion was encapsulated upon interfacial polymerization.
their effect on membrane structure and fluidity (11–14). Lipid-
Conclusions. Interfacial polymerization of spontaneously forming
water-in-oil microemulsions represents a convenient method for the based delivery systems may also promote uptake by lymph
preparation of poly(alkylcyanoacrylate) nanocapsules suitable for the thereby overcoming hepatic first-pass metabolism (14–17).
entrapment of bioactive peptides. The aim of the current study was to investigate whether
dispersions of poly(ethyl 2-cyanoacrylate) nanocapsules having
KEY WORDS: nanocapsules; microemulsions; interfacial polymer-
ization; insulin; peptides. a narrow size distribution and capable of efficiently encapsulat-
ing a model peptide can be prepared from biocompatible
INTRODUCTION microemulsions in a simple one step process that requires only
minimal input of energy and no need for subsequent separa-
The convenience and acceptability of the oral route for tion procedures.
drug administration has meant that it has received much atten-
tion for the delivery of macromolecules, such as proteins and
peptides. However, oral delivery of these bioactives is associ- MATERIALS AND METHODS
ated with low bioavailability due to proteolytic degradation and
poor membrane permeability (1). Materials

Caprylic/capric triglycerides (Crodamol GTCCE), poly-

sorbate 80 (Crillet 4E) and sorbitan mono-oleate (Crill 4E)
1 were supplied by Croda Surfactants NZ (Auckland, NZ).
Formulation and Drug Delivery Group, School of Pharmacy, Univer-
sity of Otago, P.O. Box 913, Dunedin, New Zealand. Caprylic/capric mono-/diglycerides (Capmul MCME) was a
2
To whom correspondence should be addressed. (e-mail: nigel.davies@ gift from Abitec Corp. (Columbus, OH). Ethyl 2-cyanoacrylate
stonebow.otago.ac.nz) was purchased from Sigma (St. Louis, MO). Human insulin
ABBREVIATIONS: PCS, photon correlation spectroscopy; TEM, (Humulin RE) was obtained from Eli Lilly (Auckland, NZ).
transmission electron microscopy; SEM, scanning electron microscopy. Acetonitride (HPLC grade) and chloroform (AR grade) were

0724-8741/00/0600-0684$18.00/0 q 2000 Plenum Publishing Corporation 684

Preparation of Nanocapsules from Microemulsions 685

purchased from BDH (Poole, Dorset), UK. Distilled water was point dried using a Bal-Tec 030 critical point dryer. Samples
used throughout. were then sputter coated with gold/palladium (BioRad coating
system) prior to viewing. For freeze fracture TEM, nanocap-
Methods sules were sandwiched between two copper grids, snap-frozen
by immersion in liquid propane (21808C) and freeze fractured
Construction of Pseudo-Ternary Phase Diagram using a Balzers BAF 300. Fractured samples were shadowed
with platinum (458) and carbon (908). The replica was then
Pseudo-ternary systems of oil (Crodamol GTCC and Cap- washed in chloroform, methanol and finally distilled water.
mul MCM, 3:1 weight ratio), surfactant (Crillet 4 and Crill 4, Dried replicas were viewed at an accelerating voltage of 80 kV.
3:2 weight ratio) and water of various weight ratios were pre- The particle size and distribution of the nanocapsules was
pared and left overnight at room temperature to equilibrate. The measured by PCS (Zetasizer 3000, Malvern Instruments Ltd.).
weight ratio of the two surfactants used was chosen according to For analysis, nanocapsules were washed repeatedly following
the combination which solubilized the greatest amount of water synthesis and dispersed in a 0.2% w/w polysorbate 80 solution
in an oil system containing 20% w/w total surfactant. Visual in ethanol. Measurements were carried out at 258C.
observation, phase-contrast and polarizing light microscopy
(Optiphot Nikon PFX microscope) were used to identify combi- Determination of Encapsulated Insulin
nations forming microemulsions, liquid crystalline structures
or coarse emulsions. Colloidal systems showing birefringence 1.6 g of the polymerized insulin microemulsion was diluted
when viewed by cross-polarized light microscopy were desig- to 10 ml with water adjusted to pH 2.5 by addition of hydrochlo-
nated liquid crystalline whereas clear, non-birefringent, iso- ric acid. An acidic medium was chosen for dilution to inhibit
tropic systems were designated microemulsions. A pseudo- polymer hydrolysis and thus prevent release of entrapped insu-
ternary phase diagram for the components was constructed and lin. 300 ml of this dispersion was thoroughly mixed with 300
the phase boundaries identified. ml of 80% v/v methanol in water (pH 2.5). Nanocapsules and
oil were separated from the methanolic aqueous phase by cen-
trifugation (12,000 g for 12 minutes at room temperature). The
Characterization of Microemulsions
concentration of insulin in the aqueous supernatant representing
Oil/surfactant/water combinations forming microemul- the insulin not associated with the nanocapsules was determined
sions were characterized with regards to viscosity (Brookfield by HPLC using a C18 column (LunaE 5 m C18 (2), 250
DVIII viscometer fitted with a CP-42 cone and plate spindle) 3 4.6 mm; Phenomenex) and a mobile phase of 23.5% w/w
and conductivity (YSI 3418 conductivity cell, Yellow Spring acetonitrile in a 0.125 molar solution of sodium dihydrogen
Instruments, Yellow Springs, OH having a cell constant (K) of phosphate adjusted to pH 2.5 with orthophosphoric acid. The
0.1/cm). Samples for conductivity measurement were prepared column was maintained at 508C and the flow rate at 1.4 ml/
using 0.1 molar sodium chloride as the aqueous phase. Viscosity min. 200 ml of sample was injected and the eluent monitored
and conductivity measurements were carried out in duplicate at a wavelength of 212 nm (Spectra-Physics UV-2000). The
at 258C. amount of insulin encapsulated was estimated from the differ-
ence in concentration of insulin detected in the supernatant of
Preparation of Nanocapsules a polymerized microemulsions following processing and that
in the supernatant of an unpolymerized microemulsions to
A microemulsion was prepared at 48C by mixing 1.4 g of which an equivalent concentration of insulin had been added.
the surfactant blend, 7.6 g of the oil mixture and 1.0 g of water The extraction efficiency of insulin from an unpolymerized
(buffered to pH 7.4 with isotonic phosphate buffer). A solution microemulsion by this method was 95.19 6 2.58% (n 5 3).
containing 100 mg of ethyl 2-cyanoacrylate monomer in 300 The release of insulin from nanocapsules was carried out
mg of chloroform was slowly added to the microemulsion under by diluting 4 g of polymerized microemulsion containing insulin
mechanical stirring. The system was left for at least 4 hours to 25 ml with water (pH 2.5) which was subsequently stirred
at 48C for polymerization. Nanocapsules were collected for at 200 rpm in a water-jacketed beaker (458C). These conditions
characterization by centrifugation at 51500 g for 60 min at were chosen to obtain a time-release profile suitable for the
258C (Beckman J2/MC Centrifuge, JA20.1 rotor). For SEM investigation of the reservoir nature of the nanocapsules. The
and PCS, the product was redispersed by ultrasonication in concentration of insulin in the release medium as a function of
ethanol followed by centrifugation at 18,500 g for 10 minutes time monitored. Samples were processed and insulin analyzed
at 258C to remove residual oil and surfactant. This process was as for determination of encapsulated insulin within nanocap-
repeated to ensure complete removal of residues. sules. Under these conditions, it was found that when free
For the preparation of nanocapsules containing insulin, insulin was added to the release medium containing polymer-
the water was substituted with an aqueous solution of insulin ized microemulsions, 8% degraded in a first-order fashion over
having a concentration of 100 units/ml and a pH of 7.4 a five hour period. The results for the release of insulin from
(Humulin RT). the nanocapsules were thus compensated for this degradation.

Characterization of Nanocapsules RESULTS

The external and internal structure of the nanocapsules
Pseudo-Ternary Phase Diagram
was visualized by SEM (Cambridge Stereoscan 360) and freeze
fracture TEM (Philips 410LS) respectively. Samples for SEM The choice of components used for the preparation of
were dried by using a graded series of ethanol and then critical the pseudo-ternary phase diagram was based on the work of
686 Watnasirichaikul, Davies, Rades, and Tucker

Constantinides et al. (13). They demonstrated that a mixture

of medium chain glycerides similar to those used in the present
investigation formed water-in-oil microemulsions when mixed
with certain weight ratios of polysorbate 80 and water. Further,
these researchers demonstrated that a microemulsion prepared
from these components significantly increased the oral bioavail-
ability of both a water-soluble marker and a water-soluble pep-
tide. Thus, if nanocapsules could be prepared from such a
microemulsion, then a combination of nanocapsules dispersed
in the microemulsion matrix may be beneficial in the oral
delivery of water-soluble peptides. To maximize the peptide
loading and yield of nanocapsules prepared from such systems,
we investigated whether the fraction of the aqueous dispersed
phase of the microemulsions reported by Constantinides et al.
(13) could be increased. The maximum water solubilized by a
20% surfactant in oil system was therefore determined for a
series polysorbate 80/sorbitan mono-oleate mixtures (Fig. 1).
The maximum percentage water solubilized was achieved for
systems containing polysorbate 80:sorbitan mono-oleate having Fig. 2. Pseudo-ternary phase diagram for a mixture of medium chain
glycerides (Crodamol GTCC:Capmul MCM, 3:1), a mixture of surfac-
weight ratios of between 3:2 and 1:1, being approximately tants (polysorbate 80:sorbitan mono-oleate, 3:2) and water. ME:
14% w/w compared with 8% w/w when only polysorbate 80 microemulsion, LC: systems containing liquid crystals and E: coarse
was used. emulsions.
The pseudo-ternary phase diagram for the mixture of
medium chain triglycerides and mono-/diglycerides having a
weight ratio of 3:1 and a mixture of polysorbate 80 and sorbitan
mono-oleate having a weight ratio of 3:2 and water is shown Characterization of Microemulsions
in Fig. 2. The nature of the phase diagram was not altered if All microemulsions were poor conductors having specific
the water was replaced with a 0.1 molar aqueous solution of conductances in the range 0.35–5.05 mmhos/cm as compared
sodium chloride. The maximum amount of water which could to 10,420 mmhos/cm for a 0.1 molar aqueous solution of sodium
be incorporated into systems forming microemulsions following chloride. Thus all systems in the microemulsion region of the
an adequate equilibration period was found to be only 14% phase diagram are water-in-oil dispersions.
w/w. In preliminary studies, the microemulsions obtained by Microemulsions demonstrated Newtonian flow behavior.
Constantinides et al. (13) at high surfactant concentrations (50– The viscosity was found to be dependent on both the concentra-
80% w/w) and water concentrations of between 15 and 40% tion of water and surfactant (Fig. 3). Systems having a viscosity
w/w were only observed immediately following mixing of the of greater than 50 cps were considered too viscous to allow
components. However, these microemulsions were found to for good mixing upon addition of the ethyl 2-cyanoacrylate
transform to systems containing liquid crystalline structures monomer. A system containing 10% water, 76% glycerides and
upon overnight equilibration. 14% surfactant (3:2 ratio of polysorbate 80:sorbitan mono-
oleate) having a viscosity of 39 cps was therefore used for the
preparation of aqueous cored poly(ethyl 2-cyanoacrylate)
nanocapsules.

Fig. 1. Maximum percentage water solubilized by a system containing

medium chain glycerides and mixtures of polysorbate 80/sorbitan
mono-oleate having different weight ratios. Ratio of medium chain Fig. 3. Viscosity of microemulsions as a function of surfactant and
glycerides to surfactant mixture is 4:1. water content.
Preparation of Nanocapsules from Microemulsions 687

When the rate of release of insulin from polymerized

microemulsions was measured in water (pH 2.5), an initial rapid
rate of release was observed over the first 30 minutes which was
followed by a period during which the rate remained constant
(60–180 mins) before a decline in the rate was observed after
180 minutes (Fig. 6). The initial concentration of insulin in the
release medium was found to be equivalent to 14% of the
total insulin which was in agreement with the concentration of
unencapsulated insulin present in the formulation. The concen-
tration of insulin in the medium when release was complete
was equivalent to around 80% of the total insulin added to the
microemulsion prior to polymerization.
When the release medium was maintained at 48C, retarding
the hydrolytic degradation of the polymer, no release of associ-
ated insulin was noted over a 10 hour period. Thus the method
used for processing the samples did not cause disruption of
the nanocapsules and suggests that the associated insulin is
Fig. 4. Scanning electron micrograph of poly(ethyl 2-cyanoacrylate) encapsulated within the nanoparticles.
nanocapsules.
DISCUSSION
Poly(alkylcyanoacrylates) constitute a group of biocom-
Characterization of Nanocapsules patible, biodegradable polymers, which can be prepared by a
base-catalyzed anionic polymerization of the appropriate alkyl-
Particles isolated following addition of ethyl 2-cyanoacry- cyanoacrylate monomer (18). Aqueous cored poly(alkylcyanoa-
late to the microemulsion were observed to be spherical with crylate) particulates suitable for the encapsulation of peptides
a smooth surface when viewed by SEM (Fig. 4). TEM of freeze- can therefore be prepared by the interfacial polymerization of
fractured samples showed that the particles had a central cavity the monomer using water-in-oil dispersions (9). However, to
surrounded by a polymer wall (Fig 5). The particle size of the achieve a dispersed phase having a suitably small particle size
nanocapsules as determined by PCS was 150.9 nm with a to form nanocapsules, a high input of energy in the form of
polydispersity of 0.101 representative of the narrow distribution either ultrasonication (8) or vigorous stirring (9) is usually
of the microemulsion droplets. required. This requirement can be overcome by the use of
thermodynamically stable colloidal systems, such as micelles
Nanoencapsulation of Insulin or microemulsions. The use of such systems offers further
The concentration of insulin in the supernatant of pro- advantages over kinetically stabilised dispersions in that their
cessed samples of polymerized microemulsions was found to be particle size is small and uniform, and they form spontaneously
13.9 6 2.7% (n 5 4) of that of unpolymerized microemulsions and reproducibly. These properties render them amenable to
containing an equivalent amount of insulin. Thus, 86% of the industrial scale-up.
insulin was associated with the nanocapsules. It is however unlikely that micellar polymerization can be
used to efficiently nanoencapsulate hydrophilic bioactives such
as proteins and peptides due to the aqueous nature of the contin-
uous phase, although a high association has been reported when

Fig. 5. Freeze-fracture transmission electron micrograph of poly(ethyl Fig. 6. Release of insulin from nanocapsules in water (pH 2.5). Values
2-cyanoacrylate) nanocapsules. represent means 6 SD, n 5 4.
688 Watnasirichaikul, Davies, Rades, and Tucker

insulin is adsorbed onto pre-formed nanoparticles (4). The prep- ACKNOWLEDGMENTS

aration of nanocapsules from water-in-oil microemulsions as
The authors wish to thank Mark Gould of the South Cam-
described in the present study results in a high encapsulation
pus Electron Microscope unit, University of Otago for the sam-
efficiency of insulin since the water-soluble peptide is confined
ple preparation for TEM and SEM. We acknowledge Abitec
to the aqueous phase which is in the form of nanodroplets of
corporation, Columbus, Ohio and Croda Surfactant NZ for pro-
the water-in-oil microemulsions. Polymerization at the oil/water
viding oils and surfactants. Acknowledgement is also given to
interface can therefore encapsulate a large percentage of the
the Thai Government Pharmaceutical Organization (GPO) for
water-soluble peptide. A drawback of this technique, however,
a Ph.D. scholarship to S.W.
could lie in the difficulty of isolating the nanoparticles from the
polymerization vehicle, requiring extensive washing to remove
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