Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
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
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.
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
History
Received 28 May 2013
Revised 20 August 2013
Accepted 25 August 2013
Published online 7 October 2013
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.
OH
O
O OH
HN
O
H
OH
OH
Journal of Drug Targeting Downloaded from informahealthcare.com by Nyu Medical Center on 10/08/14
For personal use only.
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]
DOI: 10.3109/1061186X.2013.839686
89
Journal of Drug Targeting Downloaded from informahealthcare.com by Nyu Medical Center on 10/08/14
For personal use only.
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.
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.
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
91
92
H. Zhang et al.
Journal of Drug Targeting Downloaded from informahealthcare.com by Nyu Medical Center on 10/08/14
For personal use only.
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
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.
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.