You are on page 1of 8

http://informahealthcare.

com/drt
ISSN: 1061-186X (print), 1029-2330 (electronic)
J Drug Target, 2014; 22(2): 8794
! 2014 Informa UK Ltd. DOI: 10.3109/1061186X.2013.839686

REVIEW ARTICLE

Advances in the formulations of non-injection administration


of docetaxel
Haiqun Zhang1, Jinfeng Dou1, Yingjie Zhai1, Anchang Liu2, and Guangxi Zhai1
Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan, China and 2Department of Pharmacy, Qilu Hospital of Shandong
University, Jinan, China
Abstract

Keywords

Docetaxel is one of the most important anti-tumor drugs and has shown powerful therapeutic
activity against breast cancer, non-small cell lung cancer, prostate cancer and so on. Owing to
its poor water solubility and the efflux by P-glycoprotein (P-gp) and metabolism by CYP3A4
enzymes, it is generally administered as an injection form, the only manner for the current
clinical application. However, the injection bearing polysorbate 80 and ethanol may cause
adverse events such as severe hypersensitivity reactions, neutropenia, neurotoxicity, musculoskeletal toxicity and cumulative fluid retention, these adverse events limit clinical application
and commercialization of docetaxel. Recently, various kinds of non-injection delivery systems
for docetaxel have been developed to eliminate the polysorbate 80-based vehicle and increase
the drug solubility. In this review, the non-injection delivery formulations of docetaxel for oral
route, transdermal delivery, lung and rectal administration were discussed for future study and
clinical application.

Docetaxel, liposomes, nanoparticles,


non-injection administration

Introduction
Docetaxel (Figure 1) as an antineoplastic drug [1], belonging
to the second generation of the taxoid family, shows a
potential efficacy for the treatment of breast cancer [2],
ovarian cancer [3], lung cancer [4], prostate cancer [5], gastric
cancer [6], melanoma, soft tissue sarcomas, and head and
neck carcinomas. It is well-known for its antimitotic activity
that promotes the progress of tubulin polymerization and
inhibiting regeneration of cells through the cell cycle via
either monotherapy or combination therapy to kill malignant
tissues/cells [7]. Compared to the paclitaxel, docetaxel
exhibits a variety of unique preclinical characteristics, such
as a longer half-life, higher cytotoxicity, less schedule
dependence [8] and lower side effects [9], longer retention
time and higher accumulation in tumor cells in vivo [10],
more potent capability of inducing BCL-2, an inner mitochondrial membrane protein which blocks programmed cell
apoptosis, phosphorylation and death [11].
However, owing to its low water solubility [12] and the
efflux by P-gp and metabolism by CYP3A4 enzymes,
commercial product of docetaxel (Taxotere) is only the
injection. And the clinical injection administration of

Address for correspondence: Guangxi Zhai, PhD, Professor, Department


of Pharmaceutics, College of Pharmacy, Shandong University, 44
Wenhua Xilu, Jinan 250012, China. Tel: (86) 531 88382015. E-mail:
professorgxzhai@126.com
Anchang Liu, PhD, Associate Professor, Department of Pharmacy,
Qilu Hospital of Shandong University, Jinan, China. E-mail:
1069277305@qq.com

History
Received 28 May 2013
Revised 20 August 2013
Accepted 25 August 2013
Published online 7 October 2013

docetaxel frequently causes several side effects including


hypersensitivity reactions, febrile neutropenia, cumulative
fluid retention and nail changes [13], which is partly
attributed to the presence of polysorbate-80 or ethanol in
the formulation. In addition, injection administration is
responsible for inconvenience, pains and high costs for
patients during long period of treatment. Meanwhile,
non-injection administration has many advantages over the
injection means. In detail, oral administration is the most
popular route for the convenience, low costs, ease of use,
adaptability administration at home and appealing commercial potential. The advantages of transdermal delivery include
its non-invasive administration and gentle delivery. Lung
administration can deliver drug directly into the deep lung
by the patients respiratory action thus avoiding the first
pass hepatic metabolism and gastric digestion. And rectal
administration makes up for shortages of oral delivery and
can bypass the first-pass elimination of liver to improve
bioavailability with aiming directly at the systemic circulation. Thus, it is desirable to develop novel and effective
non-injection formulations that deliver docetaxel to tumor
sites and lower the adverse effects. And the polysorbate
80-free formulations are of particular interest.
In this article, we presented an overview of recent
advances in the formulations of docetaxel for non-injection
delivery. Many detailed examples including nanoparticles
(NPs), microemulsion, liposomes, solid dispersion for oral
route, transdermal delivery, lung administration and rectal
administration (Table 1) are discussed for future study and
clinical application.

20
13

Journal of Drug Targeting Downloaded from informahealthcare.com by Nyu Medical Center on 10/08/14
For personal use only.

88

H. Zhang et al.

J Drug Target, 2014; 22(2): 8794

OH
O

O OH

HN
O

H
OH

OH

Figure 1. Chemical structure of docetaxel.

Journal of Drug Targeting Downloaded from informahealthcare.com by Nyu Medical Center on 10/08/14
For personal use only.

Table 1. The recently studied or developed non-injectable formulations.


Non-injection administration
Oral administration

Transdermal administration
Lung administration
Rectal administration

Formulation

Reference

Nanoparticles
Microemulsion
Solid dispersion
Conjugate
Nanocapsules
Liposome
Dry powder inhaler
Suppository

[28]
[36]
[39]
[42,43]
[47]
[50,53]
[58]
[62]

The preparations for the oral administration


of docetaxel
In addition to these advantages of oral administration
mentioned above, chemotherapy of oral administration can
maintain an appropriate drug concentration in the circulation
to prolong exposure to the tumor tissues and tumor cells,
which can lower the side effects and enhance the therapeutic
efficiency [14,15]. However, in the pharmaceutical field,
docetaxel is a challenging molecule for delivery due to its
poor water-solubility and limited absorption in the gastrointestinal (GI) tract that result in low oral bioavailability less
than 10% [16,17]. Moreover, it is easy to be cleared by the
CYP3A4-dependent gut metabolic processes [18] and drained
mediated by P-gp. Thus, an effective oral formulation of
docetaxel is required urgently. Indeed, many formulations
of docetaxel for oral delivery have received growing attention
in recent years.
Nanoparticles
Among the various formulations for anti-cancer drugs, selfassembled NPs have been investigated for achieving sustained
and controlled release for hydrophobic drug and the feasibility
of encapsulation [19,20]. It has also been proved that NPs
have great potential for oral chemotherapy to cross the GI
barrier due to their small size, adhesion and interaction
with cells via several possible mechanisms, including endocytic uptake, lymphatic uptake and paracellular [2123].
Additionally, suitable surface coatings (including poly(ethylene glycol), TPGS, a water-soluble form of vitamin E derived
from natural sources, polyvinyl alcohol, etc.) allow NPs to
avoid recognition by CYP3A4 enzymes/P-gp, which promotes
oral drug delivery across biological membranes [19,2427].

As for oral delivery of docetaxel, a good example can be


found from four systems of biodegradable polymeric NPs
prepared by a modified solvent extraction/evaporation
method: poly(lactic-co-glycolic acid) NPs (PLGA NPs), the
poly(lactide)-vitamin E TPGS NPs (PLA-TPGS NPs), the
poly(lactic-co-glycolic acid)-montmorillonite NPs (PLGA/
MMT NPs) and the poly (lactide)-vitamin E TPGS/montmorillonite NPs (PLA-TPGS/MMT NPs) [28] (Figure 2). As an
excellent emulsifier, TPGS is able to greatly improve the
performance of NPs, resulting in increased encapsulation
efficiency and oral bioavailability by high cellular adhesion
and uptake [26,27]. And, MMT [29] a medicinal clay, can
weaken some drug side effects and increase the negative
zeta potential of NPs to enhance adhesion to the GI mucosal
membrane [30]. The size, zeta potential and entrapment
efficiency of PLA-TPGS/MMT and PLA-TPGS NPs were
234 nm and 201 nm, 38.7 mV and 29.0 mV, 80.40% and
83.40%, respectively. In vitro cell viability studies showed
that judged by IC50 value, after incubation with MCF-7 cells
for 24 h, 48 h and 72 h, the PLA-TPGS NPs were 1.77-, 2.58and 1.58-fold more effective and the PLA-TPGS/MMT NPs
were 2.89-, 3.98- and 2.12-fold more effective than Taxotere,
respectively. During in vivo pharmacokinetics experiment
with Sprague-Dawley (SD) rats revealed that oral administration of the PLA-TPGS NPs and the PLA-TPGS/MMT
NPs could achieve 20.6- and 26.4-times longer half-life,
respectively, than intravenous administration of Taxotere at
the same 10 mg/kg dose. Moreover, one oral dose of this NPs
formulation could realize the sustained effect for 21 days in
comparison of 22 h of the injection administration of Taxotere
at the same dose. And oral bioavailability of PLA-TPGS/
MMT NPs and PLA-TPGS NPs was 78.00% and 91.30%,
which both were far higher than that of Taxotere (3.59%).
In addition, Cmax of all NP formulations synthesized in this
study ranged stably in therapeutic window. These data proved
that NPs made of biodegradable polymers for oral delivery
were a promising platform in enhancing the oral absorption
of docetaxel.
Microemulsion
Microemulsion also has been considered as one of valuable
candidates of the oral delivery for poor hydrophilic drugs
[3133]. This formulation has a great deal of advantages, such
as thermodynamic stability, ideal dissolution of hydrophobic
drugs, high solubilization potential and permeability enhancement coming from surfactant, that improve the oral absorption
together [34,35]. And some excipients, such as Cremophor,
Labrasol and Transcutol, used in microemulsion systems
could inhibit the efflux by P-gp, also impel microemulsion as
a promising approach for oral delivery of docetaxel. Yin et al.
[36] prepared a microemulsion system of docetaxel with
Cremophor EL as surfactant, Transcutol as co-surfactant and
Capryol 90 as oil phase, and evaluated the oral bioavailability
of this formulation. The mean droplet size of the prepared
microemulsion formulation was about 30 nm highly conducive to enhanced permeability and retention (EPR) effect.
This formulation was diluted 20 times with normal saline, and
could maintain soluble state for 24 h. Compared to Taxotere
(0.025 mg/cm2), the transport of docetaxel across Caco-2 cell

DOI: 10.3109/1061186X.2013.839686

Non-injection delivery formulations of docetaxel

89

Journal of Drug Targeting Downloaded from informahealthcare.com by Nyu Medical Center on 10/08/14
For personal use only.

Figure 2. Schematic representation of composition of PLGA, PLGA/MMT, PLA-TPGS,


PLA-TPGS/MMT nanoparticles encapsulating docetaxel (DTX).

monolayer from microemulsion formulation significantly


increased to 0.624 mg/cm2 with the weight ratio of
Cremophor EL/Transcutol/Capryol 90 at 24.9: 12.4: 29.4.
Meanwhile, the oral bioavailability of this formulation in rats
was 34.42%, which was probably attributed to the enhancement of permeability, the inhibition of P-gp and the increased
solubility. These results proved that microemulsion would be
one of the promising delivery systems for docetaxel.

premixed solution of docetaxel. Besides, the lower interindividual variability (about 44%), the more accurate dosage without reagents of polysorbate and ethanol and well
endurable taste were also achieved. Additionally, when
docetaxel was administrated with ritonavir in the phase I
clinical trial, the oral bioavailability of docetaxel could be
improved to 131  90%. All these findings indicated that solid
dispersion formulation could potentially effective in improving oral bioavailability of docetaxel.

Solid dispersion
Solid dispersion form has many advantages such as the
enhanced solubility in an amorphous state, large surface area
of dispersive particles that can improve the oral bioavailability of hydrophobic drug [37]. Compared with conventional
oral formulations such as capsule and tablet formulations,
solid dispersion is kept away from the limitation of low
dissolution rate caused by original particle size. And in the
process of drug dissolution from solid dispersion, some
mix with the GI fluid, and the rest separates out as clear
colloidal particles or oily globules under micron size level
to guarantee a high bioavailability [38]. Hence, in chronic oral
chemotherapeutic field, the solid oral dosage form is one
of the best choices. Moes et al. [39] used docetaxel, polyvinylpyrrolidone (PVP)-K30 and sodium lauryl sulphate (SLS)
at the weight ratio of 1:9:1 to obtain a ternary oral solid
dispersion of docetaxel prepared by feeze-drying method.
As pharmacokinetic booster, ritonavir was combined with
the novel solid dispersion to inhibit the metabolism caused by
CYP3A4 enzymes. And the formulation was further filled
into one hard gelatin capsules (ModraDoc001 15 mg capsules)
to achieve a desirable exposure of docetaxel. In this study, this
oral solid dispersion form of docetaxel showed a higher
solubility (200 mg/ml), better stability at 28  C and at 25  C/
60% RH for at least 2 years and greater dissolution rate
compared to parent drug or other physical mixture. In clinical
study of six patients, the drug encapsulated in the capsules
exhibited the similar pharmacokinetic parameters to the

Conjugate
Recently, great efforts have been devoted to covalent combination of docetaxel with biodegradable materials to overcome minimal water solubility, poor stability and low
bioavailability [40]. As a biodegradable carrier, low molecular
weight chitosan (LMWC) shows higher water-solubility and
lower toxicity. One of the most significant advantages of
LMWC is to open the tight junctions between Caco-2 cells,
which is a highly useful property for oral drug delivery [41].
Lee and his colleagues attached covalently docetaxel to
LMWC via a cleavable linker, succinic anhydride, and
evaluated its antitumor efficacy in vivo and subacute toxicity
[42] (Figure 3). In simulated gastric fluid, only 24% of DTX
was released from the conjugate within 3 h, while 85  0.4%
of docetaxel was released in simulated intestinal fluid within
72 h. After injection administration, the free docetaxel rapidly
disappeared from the circulation due to its short half-life.
In contrast, the conjugate showed a much longer circulation
time for more than 72 h after oral administration. Moreover,
the half-life of this conjugate was about 614-fold longer
than that of Taxotere (3.4 h of low dose and 8.2 h of high dose
of the conjugate against 0.6 h for Taxotere). And the maximum concentration (Cmax) of conjugate (2.1  0.27 mg/ml)
was higher than that of Taxotere (0.82  0.16 mg/ml).
Meanwhile, owing to improved lipotropy from docetaxel, the
muco-adhesive property of this prodrug was 3.45.6 times
higher than pure LMWC with lower dissociation tested on

H. Zhang et al.

J Drug Target, 2014; 22(2): 8794

Journal of Drug Targeting Downloaded from informahealthcare.com by Nyu Medical Center on 10/08/14
For personal use only.

90

Figure 3. Schematic representation of docetaxel covalently attached to LWMC to form LWMC-DTX conjugate.

small intestinal brush border membrane surfaces. Compared to


docetaxel solution (10 mg/kg i.v.), the LMWC-docetaxel
conjugates (DTX 10 mg/kg p.o.) could more significantly
inhibit tumor growth and reduce tumor volume without any
apparent body weight loss. Thus, LMWC-based docetaxel
conjugate showed a great potential to be a prodrug with the
higher therapeutic effects and higher safety than Taxotere.
In addition, Khatun et al. had synthesized taurocholic acid
(TCA)-linked heparin-docetaxel (HDTA) conjugates to form
a novel nanoparticle, which could achieve an excellent oral

delivery of docetaxel [43]. On one hand, heparin could avoid


the coagulation cascade to facilitate higher uptake of conjugate and act as an anti-thrombosis, anti-angiogenesis [44,45]
and anticoagulant agent. On the other hand, bile acid could
enhance the oral absorption of conjugated drugs by interacting with its transporters that exist in the small intestinal
membrane [44]. Meanwhile, the TCA can weaken high
negative charges of heparin to reduce some side effects such
as bleed or thrombocytopenia symptom [46]. Khatun et al.
prepared this ternary biomolecular conjugates with different

Journal of Drug Targeting Downloaded from informahealthcare.com by Nyu Medical Center on 10/08/14
For personal use only.

DOI: 10.3109/1061186X.2013.839686

coupling ratios of DTX in HTA and selected HDTA3


(the coupling ratio being 3.0  0.5) and HDTA4 (the coupling
ratio being 4.7  0.3) for further evaluation. The results showed
that this HDTA conjugate could form NPs in water with
diameters in 100120 nm, spherical shape, good stability
in vitro up to 30 days in 10% FBS solution at 37  C. In oral
absorption experiments, the AUCs of HDTA3 and HDTA4
presented 256 mg/(ml/min) and 338 mg/(ml/min) at the dose
of 5 mg/kg, 349 mg/(ml/min) and 361 mg/(ml/min) at the dose of
10 mg/kg, respectively. Moreover, the bioavailability, half-life
and volume of distribution of HDTA4 were 9.08%, 6.1  0.1 h
and 0.28  0.1 L/kg, respectively. In anti-tumor effect study,
optical imaging signals of HDTA4 NPs were detected only in
the tumor site at 24 h after oral administration. After treatment
with HDTA4, the tumor volume decreased to 54% within 24
days compared to that of normal saline group treatment. This
result suggested the improved oral absorption and effective
tumor treatment of HDTA4. Further, more significant effect of
HDTA4 was obtained in MDA-MB231 tumor-bearing mice. It
can be predicted that the novel conjugates will be an attractive
platform for oral delivery system of docetaxel to realize high
bioavailability, great oral absorption and effective cancer
targeting therapy.
Nanotransporter
To address the active efflux by P-gp and metabolism in the
gut wall by CYP3A4 enzymes [18], many efforts are desirable
to focus on finding diverse formulations for oral delivery.
What is more, it will be of particular interest to design these
new formulations with special features, such as penetrating
the enterocytes, bypassing P-gp and gut metabolism,
accumulating in the lymphatic system and being uptake to
kill malignant cells. Nassar et al. [47] developed the
poly(lactic-co-glycolic acid) (PLGA) nanocapsules (NC)loading docetaxel, and embedded the NC in entero-coated
microparticles. They prepared nano oil droplets incorporated
in a thin polymeric membrane with 23 nm thick by a spraydrying technique. The blank and two identical batches
I and II NCs showed average diameter in 304, 293 and
352 nm, and zeta potential values in 54.4  2.3, 60.1  4.3 and
37.7  3 mV, respectively. In pharmacokinetic evaluation,
the NCs in microparticles displayed higher bioavailability
(5754.5  1338.8 ng/(mL/h) for AUC) after oral administration than the docetaxel solution (2080  81.2 ng/(mL/h)
for AUC) and docetaxel NCs (1441.9  485.6 ng/(mL/h)
for AUC) after injection administration. Reversely, the T1/2
(1.9  0.7 h) and clearance values (0.9  0.2 L/h/kg) of
NCs in microparticles were significantly lower than those
of docetaxel solution (2.9  0.4 h and 2.4  0.1 L/h/kg) and
docetaxel NCs (4.7  0.1 h and 3.8  1.3 L/h/kg). The organ
distribution study revealed that the circulating fluorescent
NCs obviously accumulated in the lymphatic system. After
incubation with WRC 256 cells for 72 h, docetaxel-loaded
NCs embedded in microparticles exhibited increased cytotoxicity compared with blank microparticles and the docetaxel solution. The innovative formulation that could retain
intrinsic activity and significantly improve the oral bioavailability of docetaxel without markedly affecting P-gp would
be a good choice for further study.

Non-injection delivery formulations of docetaxel

91

Formulation for transdermal administration


of docetaxel
Transdermal delivery is popular with its non-invasive administration and gentle delivery, with three stages of process
including release, penetration and absorption into the blood
circulation. However, there are still many shortcomings
and deficiencies existing in transdermal delivery, such as
the barrier to penetrate across the stratum corneum (SC)
of skin, the outer skin with several microns, the incompatibility
of drugs to the physicochemical properties of cell membrane,
and lacking feasible designs that facilitate transdermal transport [48], all of which limit its further development. On one
hand, because the SC layer is lipophilic, hydrophobic molecules can diffuse through the SC layer easily. On the other
hand, the drugs need to be hydrophilic to arrive in deep
dermis across aqueous viable epidermis and finally arrive at
the blood circulation smoothly [48]. So, for an ideal designed
formulation, it is necessary to have both appropriately hydrophilic and hydrophobic properties. Liposome is a fine choice.
Owing to the failure of conventional liposomes to penetrate
deeply through the natural barrier of skin, a new class of
deformable (elastic or ultraflexible) liposomes has received the
growing interest [49]. Cevc et al. [50] introduced one elastic
liposome to overcome the limitation from skin barriers, which
showed highly deformability as drug carrier. These novel
liposomes with mean diameter ranging from 70 to 136 nm,
were made up of lipids and biocompatible membrane softner.
They could drive themselves following intracellular sealing
lipids into cell of the stratum corneum, as the ultradeformable
delivery vehicles [51] to achieve higher entrapment efficiency,
better steady-state flux, shorter lag time, greater effect for
transdermal delivery compared to traditional liposomes. Based
on that, Qiu and Gao used docetaxel as model drug via the
co-administration of microneedle pretreatment and elastic
liposome [52] to increase its skin permeation. Being pressed
into skin surface layer through a force of about 10 N,
microneedles with the advantages of both conventional
injection needles and transdermal patches perform short
microscopic conduits to enhance delivery of docetaxel across
SC dramatically. Once the drug through the SC, it can
distribute rapidly in deeper tissue and be absorbed into the
underlying capillaries and then into systemic circulation
(Figure 4). Compared with conventional liposomes, the
developed elastic liposomes showed smaller particle size
(43 nm) and lower polydispersity index (0.08). In addition,
higher cumulative concentration (approximately 38 mg/cm2),
larger steady-state flux (1.9  0.4 mg/cm2/h) and shorter lag
time (3.8  0.5 h) were also achieved owing to the driving force
from transdermal hydration gradient by occlusive method.
Importantly, the lag time (3.8  0.5 h) obtained following
the application of elastic liposomes through microneedletreated skin was decreased by nearly 70% relative to that
obtained from conventional liposomes.
Shortly after using phospholipids, sodium cholate as
surfactant, they prepared a surfactant-ethanolic liposomal
(SEL) system [53] to facilitate the transdermal delivery
of docetaxel. The docetaxel-loaded SEL formulation bearing
optimal composition (phospholipid-sodium cholate, 85:15,
20% ethanol, w/w) provided the improved solubility of

92

H. Zhang et al.

J Drug Target, 2014; 22(2): 8794

Journal of Drug Targeting Downloaded from informahealthcare.com by Nyu Medical Center on 10/08/14
For personal use only.

Figure 4. Schematic diagram of increasing


skin permeation of docetaxel via the
co-administration of microneedle
pretreatment and elastic liposome.

docetaxel (110.3  3.9 mg/ml), small mean size (81 nm)


and high encapsulation capability (84%). In addition, the
highest cumulative permeation amount of docetaxel was
31.1  3.6 mg/cm2 in non-occlusive administration and
100.3  5.4 mg/cm2 in occlusive administration, and the lag
time in SC layer was decreased to 7.1  0.7 h from 9.0  0.0 h
of ethanolic solution. These results proved that the surfactantethanolic elastic liposomes was a penetration enhancer
and well suitable to enhance the transdermal delivery of
docetaxel.

Preparation for lung administration of docetaxel


Lung cancer is described as excessive growth of cell in lung
tissues resulting in metastasis, invading neighboring tissue
and even out of the lungs. It was reported that lung cancer was
responsible for over 0.22 million new cancer cases and 0.16
million deaths in the US in 2012, and non-small cell lung
carcinoma made up about 80% of whole total lung cancers.
Even worse, owing to the effect of anti-apoptotic cell defense
system mediated by BCL-2 protein family, pump-out caused
by P-gp/other multidrug resistance pumps and the dysfunction
of cell apoptotic mechanism caused by inactive or mutant p53
gene, previous chemotherapeutic agents for treating lung
cancer showed defective or weak therapeutic effect [54].
Docetaxel, one of the most effective drugs for NSCLC
treatment, has drawn great attention. And dry powder inhaler
(DPI) as an available approach for delivering medicinal
aerosols to lung, exhibits its unique superiority [55,56].
Currently, the research on DPI are extensive and profound,
and it can deliver drug directly into the deep lung by the
patients respiratory action [57], thus avoiding the first pass
hepatic metabolism and gastric digestion. Besides, non-viral
gene vectors as liposome has been an appealing strategy for
treating lung cancer with non-immunity, great safety and
targeting ability via suitable ligand. According to these,
Jinturkar et al. [58] developed liposome formulation of
docetaxel and p53, a gene suppressing tumor and inducing
apoptosis, to realize direct targeting delivery and reverse drug
resistance. The novel DTX-loaded liposomes composed of
DOTAP, DOPE, cholesterol and DPPC were prepared by
thin film hydration method, and further combined with p53

to form lipoplexes. DOTAP, DOPE and cholesterol could


promote p53 gene transfection and drug release, and cholesterol was helpful to rigidize this liposome form. In this study,
the optimized liposomes showed some favorable characteristics, such as small mean size (200350 nm), zeta potential
(2532 mV), higher encapsulation efficiency (72.36%) and
drug loading (4.34%), and sustained effect up to 1624 h.
In intracellular uptake studies, when 6-Coumarin was
encapsulated in the developed liposomes, the level of
coumarin fluoroscence emission signal from the cells was
improved by 2530% than that of coumarin suspension. And
cytotoxicity of the liposomal form was enhanced by 1020%.
After pretreatment of p53, the cytotoxicity was improved
further by 4060% relative to drug solutions. The improved
cell cytotoxicity was probably attributed to great cellular
sensitivity to drug, which was caused by the inhibition
on anti-apoptotic cellular defense and regain of apoptotic
function. Finally, this developed formulation was lyophilized
to form dry powder inhaler formulation.

Preparation for rectal administration of docetaxel


Among the routes of pharmacotherapy in practice, oral drug
delivery is the general choice. However, if patients have the
symptoms such as nausea and vomiting or even convulsions,
oral administration is difficult and not feasible. Faced with
these undesirable situations, rectal administration provides an
ideal choice that enable absorbed drugs to bypass first-pass
elimination of liver to improve bioavailability and achieve
systemic circulation directly [59,60]. Rectal administration
depends on passive diffusion through the lipoidal membrane,
so suppository is one of the optimum choices owing to its
nonionized and lipid soluble characteristics. However, conventional suppository as a solid form melted or softened
slowly in rectum and caused foreign-body sensation of
patients after administration, bringing patients with inconvenience and even refusal feeling [61]. Also, these conventional suppositories can arrive the terminal part of the large
intestine through the peristaltic action. However, unfortunately, they cannot avoid a first-pass effect in the rectum after
administration. A large number of researchers devoted
themselves to the development of reformative convulsions

Journal of Drug Targeting Downloaded from informahealthcare.com by Nyu Medical Center on 10/08/14
For personal use only.

DOI: 10.3109/1061186X.2013.839686

and realized some new breakthrough. Choi et al. [62] invented


a novel rectal formulation named as docetaxel-loaded
thermosensitive liquid suppository which is based on two
or more poloxamers to obtain a gelation temperature of
3036  C and contains carbopol, sodium alginate or polycarbophil as a bioadhesive polymer to obtain adhesive force
and appropriate gel strength. This formulation composed
of 0.011% of docetaxel, 80.5472.99% of water, 2535% of
poloxamer and 210% of polysorbate showed many superiorities, such as enhancing water solubility of docetaxel,
offering desirable bioavailability, reducing side effects caused
by the conventional docetaxel injections and easy to prepare
and administrate. In addition, after rectal administration of the
liquid suppository, the maximum drug concentration in
plasma (Cmax) was approximately 140 ng/ml at 1 h and
the plasma drug concentration maintained a high level of
5080 ng/ml for 6 h. By contrast, after oral administration,
Cmax was only about 100 ng/ml at 0.58 h and gradually
decreased, and the drug levels of the liquid suppository form
were much greater than that of the oral solution from 6 h
to 12 h. Furthermore, the dose of the liquid suppository was
6-fold lower than that of the oral solution, while the former
showed a 1.25-fold higher AUC than the latter. The absolute
bioavailability of developed formulation by rectal administration reached to 29%, while only 2.8% for the oral solution
group. In addition, the liquid suppository was easy to be
administrated by rectal and gelled immediately into the body.
Also, it stayed in the rectum until the complete drug
absorption without arriving the terminal part of large intestine
and did not leak out from the anus, resulting in great
compliance for patients. Therefore, this docetaxel-loaded
thermosensitive liquid suppository might be a promising
rectal formulation used in the cancer treatment.

Conclusion
Docetaxel was an effective agent against multiple tumor
types. However, owing to its low water solubility and the
efflux by P-gp, it is generally administered as an injection
form, which is inconvenient, not cheap for patients, also
frequently associated with severe side effects related to the
injection excipients. Therefore, non-injection administration
means of docetaxel are necessary in improving treatment
efficacy and minimizing side effects. Some novel formulations of docetaxel for non-injection administration have been
developed, such as nanoparticle, microemulsion, solid dispersion, conjugate, capsule, liposome, freeze dry powder,
suppository. It is noteworthy that although enormous progress
has achieved in the past decades, a great many non-injection
formulations reported so far face with severe challenges, such
as first-pass effect, slow absorption and various uncertain
factors in GI for oral administration, SC barrier function for
transdermal administration, irregular and incomplete absorption from rectum administration. So, we have only found
clinical trial of solid dispersion for the oral administration
of docetaxel and introduced in Solid Dispersion section.
But, no matter how many challenges are there needed to be
faced, the non-injection formulations of docetaxel seem to be
an appealing platform and will present a new era in clinical
chemotherapy.

Non-injection delivery formulations of docetaxel

93

Declaration of interest
This work is supported by a research grant (2011HZ078)
from Department of Shandong Public Health, PR China.

References
1. Walker RA, Jones JL, Chappell S, et al. Molecular pathology
of breast cancer and its application to clinical management. Cancer
Metast Rev 1997;16:527.
2. Figgitt DP, Wiseman LR. Docetaxel. Drugs 2000;59:62151.
3. Kaye SB. The integration of docetaxel into first-line chemotherapy
for ovarian cancer. Int J Gynecol Cancer 2001;11:313.
4. Belani CP, Eckardt J. Development of docetaxel in advanced nonsmall-cell lung cancer. Lung Canc 2004;46:311.
5. Petrylak DP. Docetaxel (Taxotere) in hormone-refractory prostate
cancer. Semin Oncol 2000;27:249.
6. Ridwelski K, Gebauer T, Fahlke J, et al. Combination chemotherapy with docetaxel and cisplatin for locally advanced and metastatic
gastric cancer. Ann Oncol 2001;12:4751.
7. Lavelle F, Bissery MC, Combeau C, et al. Preclinical evaluation
of docetaxel (Taxotere). Semin Oncol 1995;22:316.
8. Cortes JE, Pazdur R. Docetaxel. J Clin Oncol 1995;13:264355.
9. Diaz JF, Andreu JM. Assembly of purified GDP-tubulin into
microtubules induced by Taxol and Taxotere: reversibility, ligand
stoichiometry, and competition. Biochemistry 1993;32:274755.
10. Riou JF, Petitgenet O, Combeau C, Lavelle F. Cellular uptake
and efflux of docetaxel (Taxotere) and paclitaxel (Taxol) in P388
cell line. Proc Am Assoc Cancer Res 1994;35:385.
11. Haldar S, Basu A, Croce CM. Bcl2 is the guardian of microtubule
integrity. Cancer Res 1997;57:22933.
12. Haas H. Development of new taxane formulations. Pharm Unserer
Zeit 2005;34:11521.
13. Baker J, Ajani J, Scotte F, et al. Docetaxel-related side effects
and their management. Eur J Oncol Nurs 2009;13:4959.
14. Feng SS, Chien S. Chemotherapeutic engineering: application
and further development of chemical engineering principles for
chemotherapy of cancer and other diseases. Chem Eng Sci 2003;58:
4087114.
15. Aisner J. Overview of the changing paradigm in cancer treatment:
oral chemotherapy. Am J Health Syst Pharm 2007;64:47.
16. Gao K, Sun J, Liu K, et al. Preparation and characterization of a
submicron lipid emulsion of docetaxel: submicron lipid emulsion
of docetaxel. Drug Dev Ind Pharm 2008;34:122737.
17. Park K. Nanovehicles for enhanced oral delivery of taxanes. J Contr
Rel 2009;140:778.
18. Waterschoot RA, Lagas JS, Wagenaar E, et al. Absence of both
cytochromeP4503A and P-glycoprotein dramatically increases
docetaxel oral bioavailability and risk of intestinal toxicity.
J Cancer Res Clin 2009;69:89969002.
19. Sun P, Zhang Y, Shi L, Gan Z. Thermosensitive nanoparticles selfassembled from PCL-b-PEO-b-PNIPAAm triblock copolymers and
their potential for controlled drug release. Macromol Biosci 2010;
10:62131.
20. Hobbs SK, Monsky WL, Yuan F, et al. Regulation of transport
pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci USA 1998;95:460712.
21. Sanders E, Ashworth CT. A study of particulate intestinal
absorption and hepatocellular uptake. Exp Cell Res 1961;22:
13745.
22. Florence AT, Hillery AM, Hussain N, Jani PU. Nanoparticles as
carriers for oral peptide absorption: studies on particle uptake and
fate. J Control Release 1995;36:3946.
23. Lefevre ME, Vanderhoff JW, Laussue JA, Joel DD. Accumulation
of 2-mm latex particles in mouse Peyers patches during chronic
latex feeding. Cell Mol Life Sci 1978;34:1202.
24. Jung T, Kamm W, Breitenbach A, et al. Biodegradable nanoparticles for oral delivery of peptides: is there a role for polymers to
affect mucosal uptake? Eur J Pharm Biopharm 2000;50:14760.
25. Delie F. Evaluation of nano- and microparticle uptake by the
gastrointestinal tract. Adv Drug Del Rev 1998;34:22133.
26. Mu L, Feng SS. A novel controlled release formulation for
anticancer drug paclitaxel (Taxols): PLGA nanoparticles containing
vitamin E TPGS. J Contr Rel 2003;86:3348.

Journal of Drug Targeting Downloaded from informahealthcare.com by Nyu Medical Center on 10/08/14
For personal use only.

94

H. Zhang et al.

27. Mu L, Feng SS. PLGA/TPGS nanoparticles for controlled release


of paclitaxel: effects of the emulsifier and the drug loading ratio.
Pharm Res 2003;20:186472.
28. Feng SS, Mei L, Anitha P, et al. Poly(lactide)-vitamin E derivative/
montmorillonite nanoparticle formulations for the oral delivery of
Docetaxel. Biomaterials 2009;30:3297306.
29. Lee YH, Kuo TF, Chen BY, et al. Toxicity assessment of
montmorillonite as a drug carrier for pharmaceutical applications:
yeast and rats model. Biomed Eng-App Bas C 2005;17:1218.
30. Norris DA, Puri N, Sinko PJ. The effect of physical barriers and
properties on the oral absorption of particulates. Adv Drug Del Rev
1998;34:13554.
31. Kawakami K, Yoshikawa T, Moroto Y, et al. Microemulsion
formulation for enhanced absorption of poorly soluble drugs
prescription design. J Control Rel 2002;81:6574.
32. Araya H, Tomita M, Hayashi M. The novel formulation design of
O/W microemulsion for improving the gastrointestinal absorption
of poorly water soluble compounds. Int J Pharm 2005;305:6174.
33. Kawakami K, Yoshikawa T, Hayashi H, et al. Microemulsion
formulation for enhanced absorption of poorly soluble drugs II.
In vivo study. J Contr Rel 2002;81:7582.
34. Shah NH, Carvajal MT, Patel CI, et al. Self-emulsifying drug
delivery systems (SEDDS) with polyglycolyzed glycerides for
improving in vitro dissolution and oral absorption of lipophilic
drugs. Int J Pharm 1994;106:1523.
35. Constantinides PP. Lipid microemulsions for improving drug
dissolution and oral absorption: physical and biopharmaceutical
aspects. Pharm Res 1995;12:15672.
36. Yin YM, Cui FD, Mu CF, et al. Docetaxel microemulsion for
enhanced oral bioavailability: preparation and in vitro and in vivo
evaluation. J Contr Rel 2009;140:8694.
37. Leuner C, Dressman J. Improving drug solubility for oral delivery
using solid dispersions. Eur J Pharm Biopharm 2000;50:4760.
38. Serajuddin ATM. Solid dispersion of poorly water-soluble drugs:
early promises, subsequent problems, and recent breakthroughs.
J Pharm Sci 1999;88:105866.
39. Moes JJ, Koolen SLW, Huitema ADR, et al. Pharmaceutical
development and preliminary clinical testing of an oral solid
dispersion formulation of docetaxel (ModraDoc001). Int J Pharm
2011;420:24450.
40. Kruijtzer CM, Beijnen JH, Schellens JH. Improvement of oral drug
treatment by temporary inhibition of drug transporters and/or
Cytochrome P450 in the gastrointestinal tract and liver: an
overview. Oncologist 2002;7:51630.
41. Kean T, Thanou M. Biodegradation, biodistribution and toxicity of
chitosan. Adv Drug Del Rev 2010;62:311.
42. Lee E, Kim H, Lee IH, Jon S. In vivo antitumor effects of chitosanconjugated docetaxel after oral administration. J Contr Rel 2009;
140:7985.
43. Khatun Z, Nurunnabi M, Reeck GR, et al. Oral delivery of
taurocholic acid linked heparin-docetaxel conjugates for cancer
therapy. J Control Release 2013;170:7482.
44. Park K, Lee GY, Kim YS, et al. Heparin-deoxycholic acid chemical
conjugate as an anticancer drug carrier and its antitumor activity.
J Contr Rel 2006;114:3006.
45. Kim SK, Lee DY, Lee E, et al. Absorption study of deoxycholic
acid-heparin conjugate as a new form of oral anti-coagulant.
J Control Release 2007;120:410.

J Drug Target, 2014; 22(2): 8794

46. Nurunnabi M, Khatun Z, Moon WC, et al. Heparin based


nanoparticles for cancer targeting and noninvasive imaging.
Quant Imaging Med Surg 2012;2:21926.
47. Nassar T, Qadri SA, Frenkel OH, et al. High plasma levels
and effective lymphatic uptake of docetaxel in an orally
available nanotransporter formulation. Cancer Res 2011;71:
301828.
48. Naik A, Kalia YN, Guy RH. Transdermal drug delivery: overcoming the skins barrier function. Pharm Sci Technolo Today
2000;3:31826.
49. Elsayed MMA, Abdallah OY, Naggar VF, Khalafallah NM.
Lipid vesicles for skin delivery of drugs: reviewing three decades
of research. Int J Pharm 2007;332:116.
50. Cevc G, Blume G. Lipid vesicles penetrate into intact skin owing to
the transdermal osmotic gradients and hydration force. Biochim
Biophys Acta 1992;1104:22632.
51. Mishra D, Garg M, Dubey V, et al. Elastic liposomes mediated
transdermal delivery of an anti-hypertensive agent: propranolol
hydrochloride. J Pharm Sci 2007;96:14555.
52. Qiu YQ, Gao YH, Hu KJ, Li F. Enhancement of skin permeation
of docetaxel: a novel approach combining microneedle and elastic
liposomes. J Contr Rel 2008;129:14450.
53. Qiu YQ, Li S, Li F, et al. Enhancement of transdermal delivery of
docetaxel by surfactantethanolic liposomes. J Chin Pharm Sci 2011;
20:46672.
54. Saad M, Garbuzenko OB, Minko T. Co-delivery of siRNA and
an anticancer drug for treatment of multidrug-resistant cancer. Int J
Nanomed 2008;3:76176.
55. Timothy M, Crowder TM, Rosati JA, et al. Fundamental effects
of particle morphology on lung delivery: predictions of Stokes
Law and the particular relevance to dry powder inhaler formulation
and development. Pharm Res 2000;19:23945.
56. Telko MJ, Hickey AJ. Dry powder inhaler formulation. Resp Care
2005;50:120927.
57. Islam N, Gladki E. Dry powder inhalers (DPIs) a review of device
reliability and innovation. Int J Pharm 2008;360:111.
58. Jinturkar KA, Anish C, Kumar MK, et al. Liposomal formulations of Etoposide and Docetaxel for p53 mediated enhanced
cytotoxicity in lung cancer cell lines. Biomaterials 2012;33:
2492507.
59. Chiang LM, Wang HS, Shen HH, et al. Rectal diazepam solution is
as good as rectal administration of intravenous diazepam in the
first-aid cessation of seizures in children with intractable epilepsy.
Pediatr Neonatol 2011;52:303.
60. Hoogdalem E, de Boer AG, Breimer DD. Pharmacokinetics of
rectal drug administration, Part I. Clin Pharmacokinet 1991;21:
1126.
61. Yuan Y, Cui Y, Zhang L, et al. Thermosensitive and mucoadhesive
in situ gel based on poloxamer as new carrier for rectal administration of nimesulide. Int J Pharm 2012;430:11419.
62. Choi HG, Yong CS, Yeo WH. Docetaxel-loaded thermosensitive
liquid suppository composition for rectal administration. WIPO,
2011. Available from: http://patentscope.wipo.int/search/en/detail.
jsf?docId=WO2011129627&recNum=191&docAn=KR20110026
62&queryString=evaporators&maxRec=179088 [last accessed
20 Oct 2011].