Permeation Enhancer-Containing Water-In-Oil Nanoemulsions as Carriers
for Intravesical Cisplatin Delivery
and Jia-You Fang
Received May 12, 2009; accepted July 20, 2009; published online August 4, 2009
Purpose. In the present work, we developed water-in-oil (w/o) nanoemulsions for the intravesical
administration of cisplatin.
Methods. The nanoemulsions were made up of soybean oil as the oil phase and Span 80, Tween 80, or
Brij 98 as the emulsiﬁer system. α-Terpineol and oleic acid were incorporated as permeation enhancers.
The physicochemical characteristics of droplet size, zeta potential, and viscosity were determined.
Nanoemulsions were administered intravesically for 1~4 h to rats in vivo. Animals were subsequently
sacriﬁced, and the bladders were harvested to examine drug accumulation and histology.
Results. Ranges of the mean size and zeta potential were 30~90 nm and −3.4 to −9.3 mV, respectively.
The addition of enhancers further reduced the size of the nanoemulsions. The viscosity of all systems
exhibited Newtonian behavior. The cisplatin-loaded nanoemulsions were active against bladder cancer
cells. The nanoemulsions with Brij 98 exhibited the complete inhibition of cell proliferation. The
encapsulation of cisplatin and carboplatin, another derivative of cisplatin, in nanoemulsions resulted in
slower and more-sustained release. The amount of drug which permeated into bladder tissues
signiﬁcantly increased when using carriers containing Brij 98, with the α-terpineol-containing formulation
showing the best result. The nanoemulsion with α-terpineol prolonged the duration of higher drug
accumulation to 3~4 h. At the later stage of administration (3~4 h), this system increased the bladder
wall deposition of cisplatin and carboplatin by 2.4~3.3-fold compared to the control solution. Histological
examination of the urothelium showed near-normal morphology in rats instilled with these nano-
emulsions. α-Terpineol possibly caused slight desquamation of umbrella cells.
Conclusions. The nanoemulsions are feasible to load cisplatin for intravesical drug delivery.
KEY WORDS: bladder; cisplatin; intravesical delivery; nanoemulsion; sustained release.
An estimated 261,000 new cases of bladder cancer are
diagnosed worldwide each year (1). Bladder cancer is the
fourth most common malignancy among men, but the high
recurrence rates likely make it the most prevalent malignancy
among all cancers, and certainly the most expensive per
patient treated (2,3). More than 70% of bladder cancers
present as non-muscle-invasive bladder cancer (NMIBC) (4).
The current treatment consists of transurethral resection
(TUR) of visible tumors, followed by intravesical chemo-
therapy to reduce disease recurrence and progression (5).
The rationale for intravesical therapy is to maximize the
exposure of tumors located in the bladder cavity to ther-
apeutic agents while limiting the systemic exposure and
thereby limiting toxicity to the host. However, intravesical
delivery has to overcome its own set of challenges, and most
prominent among them is the low residence time of a drug in
the bladder, which necessitates frequent instillation (6).
Nanosystems with a well-deﬁned particle size and shape have
immense potential for intravesical delivery, as they can
enhance the ability of drugs to cross the urothelium. A higher
surface-to-volume ratio may also be responsible for increased
absorption of encapsulated drugs (7).
Cisplatin is widely used for treating bladder cancer (8).
Given the toxicity and mortality associated with cisplatin-based
chemotherapy, intravesical administration would signiﬁcantly
reduce the systemic side effects, thus improving its therapeutic
index (5-10). Cisplatin is a hydrophilic molecule with an n-
octanol/water partitioning coefﬁcient (logP
The efﬁcacy of intravesical therapy for bladder cancer is in part
limited by the poor permeation of hydrophilic drugs into the
urothelium. Developing a formulation for intravesical cisplatin
delivery not only for higher concentrations in the bladder wall
but also for longer retention with reduced side effects would be
very beneﬁcial. Water-in-oil (w/o) nanoemulsions, a class of
nanosystems with droplet sizes of 20~200 nm, are considered
to be enhanced, prolonged-release systems for hydrophilic
Cell Pharmacology Laboratory, Graduate Institute of Natural
Products, Chang Gung University, Kweishan, Taoyuan, Taiwan.
Department of Pathology, College of Medicine, Taipei Medical
University, Taipei, Taiwan.
Pharmaceutics Laboratory, Graduate Institute of Natural Products,
Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan,
Taoyuan 333, Taiwan.
To whom correspondence should be addressed. (e-mail: fajy@mail.
Pharmaceutical Research, Vol. 26, No. 10, October 2009 (
2009 Springer Science + Business Media, LLC