Guo Vit E TPGS RV EJPS 2013

European Journal of Pharmaceutical Sciences 49 (2013) 175–186
Contents lists available at SciVerse ScienceDirect
European Journal of Pharmaceutical Sciences

journal homepage: www.elsevier.com/locate/ejps
Review
The applications of Vitamin E TPGS in drug delivery

Yuanyuan Guo a,b, Jun Luo c, Songwei Tan a,b, Ben Oketch Otieno a,b, Zhiping Zhang a,b,⇑
a
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, PR China
b
National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, PR China
c
MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o a b s t r a c t
Article history: D-a-Tocopheryl polyethylene glycol 1000 succinate (simply TPGS or Vitamin E TPGS) is formed by the
Available online 26 February 2013 esterification of Vitamin E succinate with polyethylene glycol 1000. As novel nonionic surfactant, it
exhibits amphipathic properties and can form stable micelles in aqueous vehicles at concentration as
Keywords: low as 0.02 wt%. It has been widely investigated for its emulsifying, dispersing, gelling, and solubilizing
Vitamin E TPGS effects on poorly water-soluble drugs. It can also act as a P-glycoprotein (P-gp) inhibitor and has been
P-glycoprotein served as an excipient for overcoming multidrug resistance (MDR) and for increasing the oral bioavail-
Oral bioavailability
ability of many anticancer drugs. Since TPGS has been approved by FDA as a safe pharmaceutic adjuvant,
Drug delivery systems
Multidrug resistance
many TPGS-based drug delivery systems (DDS) have been developed. In this review, we discuss TPGS
properties as a P-gp inhibitor, solubilizer/absorption and permeation enhancer in drug delivery and
TPGS-related formulations such as nanocrystals, nanosuspensions, tablets/solid dispersions, adjuvant
in vaccine systems, nutrition supplement, plasticizer of film, anticancer reagent and so on. This review
will greatly impact and bring out new insights in the use of TPGS in DDS.
Ó 2013 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
2. TPGS properties in drug delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
2.1. P-gp inhibitor and inhibition mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
2.2. Solubilizer/absorption enhancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
2.3. Permeation enhancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
3. TPGS formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
3.1. Fabricating nanocrystals/nanosuspensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
3.2. Fabricating SMEDDS system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
3.3. TPGS in solid dispersion/tablet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
3.4. Adjuvant for vaccine system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
3.5. Nutrition supplement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
3.6. Anticancer reagent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
3.7. TPGS micelles and liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
3.8. TPGS emulsified nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
3.9. TPGS based prodrug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
3.10. TPGS based copolymer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
3.11. Other applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
4. Conclusion and perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
⇑ Corresponding author. Address: Tongji School of Pharmacy and National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology,
Wuhan 430030, PR China. Tel./fax: +86 27 83601832.
E-mail address: zhipingzhang@mail.hust.edu.cn (Z. Zhang).
0928-0987/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ejps.2013.02.006
176 Y. Guo et al. / European Journal of Pharmaceutical Sciences 49 (2013) 175–186
1. Introduction In our previous review (Zhang et al., 2012), we discussed TPGS

as a molecular biomaterial for nanomedicine, including TPGS-
D-a-Tocopheryl polyethylene glycol 1000 succinate (TPGS or based prodrug, micelles and liposomes, as a surfactant or additive
Vitamin E TPGS, Fig. 1) is a water-soluble derivative of natural Vita- in fabricating nanoparticles and TPGS-related polymeric nanopar-
min E, which is formed by esterification of Vitamin E succinate ticles for drug delivery. In this review, we discuss the original
with polyethylene glycol (PEG) 1000. It has an average molecular applications of TPGS in DDS and its properties as a P-gp inhibitor
weight of 1513, an amphiphilic structure of lipophilic alkyl tail (including inhibition mechanisms), solubilizer/absorption enhan-
and hydrophilic polar head with a hydrophilic/lipophilic balance cer and permeation enhancer. The TPGS formulations are focused
value of 13.2 and a relatively low critical micelle concentration on nanocrystals, nanosuspensions, tablets/solid dispersions, adju-
(CMC) of 0.02% w/w. It is a waxy solid (m.p. 37–41 °C) and com- vant in vaccine systems, nutrition supplement, plasticizer of film,
pletely dissolves in water (Wu and Hopkins, 1999). anticancer reagent and so on. It will have great indication in the
As one of the novel nonionic surfactants, TPGS has been widely use of TPGS in DDS and give an overview of the applications of
used in wetting, emulsification, solubilization, spreading, and TPGS in DDS.
detergency (Sadoqi et al., 2009). TPGS displayed significant surface
activity and notable effect on the lipid model membrane (Shah and
2. TPGS properties in drug delivery
Banerjee, 2011). It can solubilize a variety of both water-soluble
and water-insoluble compounds. As the water content increases,
The special amphiphilic structure of TPGS, especially the D-a-
TPGS forms lamellar reverse micellar phase, hexagonal phase,
tocopheryl succinate part, gives it many interesting properties. As
and normal micellar phase. TPGS is also miscible with oils, such
a result, TPGS was widely used in DDS (Dintaman and Silverman,
as soybean oil and medium chain triglyceride, other surfactants,
1999; Eastman, 2000; Fischer et al., 2002; Yu et al., 1999).
and cosolvents such as propylene and polyethylene glycols. It is
stable at pH 4.5–7.5 and less than 10% hydrolyzed when kept for
3 months in neutral aqueous buffer. However, it degrades in alka- 2.1. P-gp inhibitor and inhibition mechanism
line environment (Eastman, 2000; Wu and Hopkins, 1999). The
stability is still high even at lower pH, 3.4% of TPGS degraded with- P-gp is an ATP-dependent drug efflux pump, also known as mul-
in 8 h at pH 1.0 and 37 °C. The stability of the ester bond between tidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-
D-a-tocopherol and succinic acid has also been demonstrated family B member 1 (ABCB1). It is extensively distributed and ex-
(Christiansen et al., 2011b). pressed in the intestinal epithelium, hepatocytes, renal proximal
The TPGS safety has been reported and the oral LD50 is >7 g/kg tubular cells, adrenal gland and capillary endothelial cells compris-
for young adult rats of both sexes (Beilman et al., 1988a,b; Krasav- ing the blood-brain and blood-testis barrier. It transports a wide
age and Terhaar, 1977; Shepard, 1989; Topping, 1987). In recent variety of substrates across extracellular and intracellular mem-
years, TPGS has been applied in drug delivery systems (DDSs) since branes. It can decrease drug accumulation in cells and mediate
it is an FDA approved pharmaceutically safe adjuvant. On Jan 27 MDR to cancer cells. Many anticancer drugs such as paclitaxel, eto-
2005, FDA approved Tocosol emulsion formulation of paclitaxel poside, doxorubicin, vinblastine, etc. are P-gp-substrates. P-gp can
(Sonus Pharmaceuticals, Inc.) for use in the treatment of nonsuper- affect the drug distribution and bioavailability, limit the drug pas-
ficial urothelial cancer. In the formulation, TPGS is used to create sage across the blood brain barrier and remove toxic metabolites
small high-drug loading nanoparticles. and xenobiotics from cells into urine, bile and the intestinal lumen
TPGS has been used as an absorption enhancer, emulsifier, sol- (Hoffmeyer and Brinkmann, 2001). Dintaman and Silverman were
ubilizer, additive and permeation enhancer, stabilizer, nutrition the first people to investigate the relationship between TPGS and
supplement, etc. (Dintaman and Silverman, 1999; Yu et al., P-gp in 1999. They found out that below its CMC of 0.02 wt%, TPGS
1999). It can increase the solubility of drugs such as cyclosporines, could act as an inhibitor of P-gp. This resulted in inhibition of P-gp
taxanes, steroids, and antibiotics (Constantinides et al., 2002; mediated drug transport and multidrug resistance (Akhtar et al.,
Fischer et al., 2002; Illum et al., 1997; Liu et al., 2000; Nielsen 2011; Collnot et al., 2006; Lo, 2003). Besides TPGS, other nonionic
et al., 2001). TPGS has served as the excipient for overcoming mul- surfactants such as Tween 80, PluronicÒ, Cremophor EL, are also
tidrug resistance (MDR) and an inhibitor of P-glycoprotein (P-gp) capable of inhibiting P-gp activity. Among them, TPGS was most
for increasing the oral bioavailability of anticancer drugs (Collnot effective. Rhodamine 123, P-gp-mediated transporter, was inhib-
et al., 2010; Constantinides et al., 2006; Dintaman and Silverman, ited in a concentration-dependent manner for the following surfac-
1999; Varma and Panchagnula, 2005). It can increase the cytotox- tants in the order; TPGS > Pluronic PE8100 > Cremophor
icity of doxorubicin, vinblastine, paclitaxel and colchicine in the EL > Pluronic PE6100. These surfactants exhibited a transporter-
G185 cells by inhibiting P-gp activity (Dintaman and Silverman, specific interaction, rather than non-specific membrane permeabi-
1999). It has exhibited oral absorption enhancement in cyclospor- lization (Bogman et al., 2003; Hugger et al., 2002; Johnson et al.,
ine A, vancomycin hydrochloride and talinolol in animals (Bogman 2002).
et al., 2005; Boudreaux et al., 1993; Prasad et al., 2003; Sokol et al., TPGS was found to inhibit the P-gp mediated talinolol transport
1991). TPGS can also act as an anticancer agent to induce apoptosis by Caco-2 model study. In healthy volunteers, TPGS increased AUC
and develop a synergistic effect with other anticancer drugs (Mi (area under concentration) and Cmax of talinolol by 39% and 100%,
et al., 2011). respectively after coadministration. This may be attributed to TPGS
inhibition of the P-gp activity and resultant increase of talinolol
bioavailability (Bogman et al., 2005). TPGS was found to enhance
the cytotoxicity of doxorubicin, vinblastine, paclitaxel and colchi-
cine in the human MDR1 cDNA (G185) cells which were 27–135
fold more resistant to these drugs than the parental NIH3T3 cells.
However, TPGS did not increase the cytotoxicity of 5-FU (not a P-
gp substrate) in the G185 cells (Dintaman and Silverman, 1999;
Traber et al., 1986).
The transporter inhibition activity of three nonionic surfactants
Fig. 1. Chemical structure of TPGS. (TPGS, Tween 80 and Cremophor EL) was investigated on P-gp, the
Y. Guo et al. / European Journal of Pharmaceutical Sciences 49 (2013) 175–186 177
human intestinal peptide transporter, and the monocarboxylic acid demonstrated that TPGS was neither a substrate nor a competitive
transporter in Caco-2 cell monolayers. The role of membrane fluid- inhibitor in P-gp efflux transport. The P-gp ATPase inhibition was
ity and protein kinase C in surfactant-induced transporter inhibi- due to the allosteric modulation that TPGS binds to the nontrans-
tion was also evaluated. Tween 80 and Cremophor EL were found port active binding site and not the Cis(Z)-flupentixol binding site
to significantly increase the apical-to-basolateral (AP-BL) and de- (Collnot et al., 2010, 2007). The commercially available TPGS1000
crease the basolateral-to-apical (BL-AP) permeability. TPGS exhib- is so far the most potential efflux pump inhibitor as studied by Lehr
ited a reduction in the BL-AP permeability of rhodamine 123 in et al. As shown in Figs. 2 and 3, Collnot et al. demonstrated that the
Caco-2 monolayers. Compared to these two surfactants, TPGS rigi- PEG length (200–6000) of Vitamin E succinate derivatives can af-
dized lipid bilayers of cell membrane, and did not inhibit the pep- fect the inhibition activity on the efflux pump and the promising
tide transporter. Tween 80 inhibited the peptide transporter and TPGS derivatives could be TPGS with PEG 1100–1500 (Collnot
only Cremophor EL inhibited the monocarboxylic acid transporter. et al., 2006).
It seems that TPGS can inhibit the P-gp activity without affecting TPGS also showed inhibitory effects on cytochrome P450 3A
the membrane fluidity (Rege et al., 2002; Yamagata et al., 2007). (CYP3A) (Christiansen et al., 2011a; Johnson et al., 2002). It can
P-gp ATPase (P-gp energy source of active transport) inhibition act as in vitro inhibitor for CYP-mediated metabolism and has the
caused by TPGS is the main reason for this (Collnot et al., 2007). potential for modifying the pharmacokinetics when coadminis-
Monoclonal CD243 P-gp antibody (UIC2) shift assay results tered with CYP substrates (Christiansen et al., 2011a). However,
Fig. 2. Rhodamine 123 transport across Caco-2 monolayers in the absence and presence of TPGS analogs possessing different PEG chain lengths; (A) absorptive transport Ap-
Bl; (B) secretory transport Bl-Ap; mean ± SD, n = 18; bars marked with are significantly different from negative control. (P < 0.05) and are very significantly different
(P < 0.001) (Collnot et al., 2006). Reproduced with permission.
Fig. 4. TPGS concentration-dependent solubility of paclitaxel. Inset shows total

Fig. 3. Influence of Vitamin E, Vitamin E succinate and PEG 1000 on rhodamine 123 solubility of paclitaxel vs micellar concentration of TPGS. Each bar represents
transport across Caco-2 monolayers; mean ± SD, n = 9; bars marked with are very mean ± S.D. (n = 3) of equilibrium solubility at 48 h (Varma and Panchagnula, 2005).
significantly different from control (P < 0.001) (Collnot et al., 2006). Reproduced Reproduced with permission.
with permission.
to cyclosporine saline solution. The half-life and MRT were in-
creased by 44% and 24%, respectively (Wacher et al., 2002b). Boud-
another study exhibited that TPGS has hardly any direct inhibitory reaux et al. (1993) reported a twofold AUC increase when
effect on CYP3A but has a significant inhibitory effect on P-gp in rat cyclosporine A was co-administered with Liqui E, a glycerol and
intestinal mucosa (Mudra and Borchardt, 2010). In vitro cell exper- TPGS. Sokol et al. (1991), Chang et al. (1996) also reported a 71%
iments demonstrated that CremophorÒ EL, TPGS and high concen- and 61% AUC increase on CsA, respectively. Pan et al. (1996) re-
trations of polysorbate 80 could inhibit the efflux transporters, ported a 32% decrease in CsA daily dosage after coadministration
ABCB1 (P-gp) and ABCC2 (MRP2). These two transporters play an with TPGS and 26% decrease on the CsA cost. This may be
essential role in the limitation of oral bioavailability of drugs (Han- attributed to the fact that TPGS can form micelles with improved
ke et al., 2010). Thus the oral bioavailability of CYP substrates could
be improved by including TPGS in the formulation. However an-
other study showed no significant inhibition of MRP2-mediated ef-
flux in Madin-Darby canine kidney/MRP2 cells from the
surfactants (Bogman et al., 2003).
2.2. Solubilizer/absorption enhancer
Solubilizers/absorption enhancers are functional excipients in-

cluded in formulations to increase the solubility of a substance
or improve the absorption of a pharmacologically active drug. To
solubilize water-insoluble drugs for oral and parenteral adminis-
tration, there are many techniques such as pH adjustment, cosol-
vents, complexation, microemulsions, self-emulsifying DDSs,
micelles, liposomes, and emulsions (Kuentz, 2011; Strickley,
2004). TPGS was found to increase the apparent solubility and sta-
bility for some unstable drugs by incorporation into TPGS micelles
(di Cagno et al., 2012). TPGS significantly enhanced the aqueous
solubility of paclitaxel in a linear relationship when TPGS concen-
tration was higher than 0.1 mg/mL as seen in Fig. 4. The oral bio-
availability of paclitaxel was enhanced 4.2-fold and 6.3-fold for
[C-14]paclitaxel coadministered with verapamil (25 mg/kg, 19.9%
oral bioavailability) and TPGS (50 mg/kg, 29.9% oral bioavailabil-
ity), respectively, compared to TaxolÒ (4.7% oral bioavailability)
as seen in Fig. 5 (Varma and Panchagnula, 2005). TPGS was also
used as solubilizer for celecoxib, corticosteroids, capuramycin ana-
log SQ641 and propofol (Cianetti et al., 2010; Fulzele et al., 2006;
Momot et al., 2003; Nikonenko et al., 2009; Saidi and Boris,
2001; Varma and Panchagnula, 2005).
TPGS has been shown to increase the absorption flux of a HIV
protease inhibitor, amprenavir (Yu et al., 1999), enhance the bio-
availability of cyclosporine in human volunteers (Chang et al., Fig. 5. Plasma concentration–time profile of [14C]paclitaxel in rats after (a)
2005) and of colchicine in rats. Colchicine formulation containing intravenous administration (2 mg/kg); (b) after oral administration (25 mg/mL) of
TPGS significantly increased the systemic exposures, twofold in- [14C]paclitaxel alone and in combination with verapamil or TPGS. Data points
crease of AUC, as compared to the aqueous reference vehicle (Bitt- represent mean and error bars show S.E.M. (n = 4). ⁄P < 0.05 and P < 0.01,
significantly different when compared to oral paclitaxel alone. #P < 0.05 and
ner et al., 2002). After oral coadministration with cyclosporine, ##P < 0.01, significantly different when compared to oral paclitaxel in combination
TPGS (50 mg/kg) increased the Cmax and AUC0–1 from 1.3 to with verapamil (Pcl, [14C]paclitaxel; Ver, verapamil) (Varma and Panchagnula,
2.9 lg/mL and from 28.5 to 59.7 lg h/mL, respectively, compared 2005). Reproduced with permission.
solubilization of CsA and also interact with P-gp in the intestines. example, Pluronic F-127 and co-solvent, TPGS formulation pro-
Tocopheryl polypropylene glycol succinate 1000 (TPPG1000), duced the highest drug permeation rate and the longest crystalliza-
whose structure is similar to TPGS, was also found to enhance tion time (Ghosh et al., 2012). TPGS may also alter intestinal
the oral bioavailability of raloxifene (Wempe et al., 2009). TPGS en- permeability, at least in vitro, via inhibition of drug transporter
hanced intestinal absorption of hydrophilic macromolecular drug, function (Yu et al., 1999). However, the permeation enhancement
vancomycin with Labrasolin rats. The Cmax and AUC0–6h of vanco- due to P-gp interaction may be depressed by the micelle-associa-
mycin were increased 2.2 and 2.4 times, respectively after the tion during the inclusion of poorly soluble drugs in micelles. Poorly
addition of 12.5% of TPGS and 50% Labrasol during formulation soluble drugs have a high tendency to nucleate immediately after
(Prasad et al., 2003). It has also been found to significantly enhance formulation or even during storage because of thermodynamic
the intestinal absorption of Berberine chloride (BBR). At a concen- challenges. The use of surfactant is indeed effective in reducing
tration of 2.5%, TPGS achieved around 2.9 and 1.9-fold improve- drug loss and improving mass balance and also brings about
ment on Cmax and AUC0–36 of BBR, respectively after oral changes in thermodynamic activity (Katneni et al., 2008). This ef-
administration (Chen et al., 2011). fect was owed to the reduced thermodynamic activity of the drug
Although there is a lot of data demonstrating TPGS effects on which is due to micellar association or complexation, and/or the
oral absorption, solubility or permeation enhancement, some stud- fact that the micelle-bound fraction of drug is not readily perme-
ies show contrary results. It has no significant effects on both able. This leads to changes in the free concentration of drug avail-
enterocyte-based metabolism and P-gp efflux of verapamil in ex- able for transport or diffusion across the membrane (Katneni et al.,
cised rat intestine experiment at a concentration of 0.01 wt% (John- 2006). The micellar fraction and permeability depression of drug
son et al., 2002). The inclusion of the TPGS did not result in correlated with the surfactant concentration (Fischer et al.,
absorption enhancement of antiviral agent UC-781 in the intestinal 2011a). Other studies have confirmed these results. In the presence
perfusion technique (Deferme et al., 2002). It was found to increase of poloxamer 188, the drug permeability was also found to be de-
the solubility of estradiol through micellar solubilization but it pressed in a concentration-dependent manner. However, micellar
only had an insignificant influence on the skin (Sheu et al., 2003). association was one important but not the only factor affecting
It did not improve oral bioavailability of R1481 which is a potential drug permeability, especially in the case of hydrophilic compounds
agonist for the treatment of overactive bladder and has poor oral (Fischer et al., 2011b). Inclusion of poorly soluble drugs in micelles
bioavailability. R1481 can be metabolically stable due to low intes- may reduce the drug’s thermodynamic activity and subsequently
tinal permeability, and P-gp efflux mechanism (Ramsay-Olocco impair its passive diffusion, which results in a delicate balance be-
et al., 2004). TPGS can modify the pharmacokinetics of orally tween permeation inhibition due to micelle-association and per-
administered P-gp substrates without increasing the AUC (Cornaire meation enhancement due to P-gp interaction (Buckley et al.,
et al., 2004). It has no effect on oral absorption of sirolimus in rats 2012). In paclitaxel formulation with TPGS, paclitaxel exhibited a
and no significant effect on P-gp substrates digoxin and celiprolol 26-fold higher BL-AP permeability than AP-BL direction for trans-
in vitro and in vivo (Wacher et al., 2002a). PEG400 accelerated port across rat ileum. TPGS exhibited a concentration-dependent
the small intestinal transit but TPGS did not do so when used as increase in AP-BL permeability and decreased BL-AP permeability.
a solubility-enhancer in hard gelatin capsules (Schulze et al., At a concentration of 0.1 mg/mL, TPGS demonstrated the maxi-
2006). It has no significant effect on the gastrointestinal transit mum efflux inhibition activity. The maximum paclitaxel perme-
and drug absorption in beagle dogs as the combination of two ability at 0.1 mg/mL TPGS may be attributed to the interplay of
model drugs, ampicillin (200 mg) and antipyrine (100 mg) with concentration dependent P-gp inhibition and the micellar forma-
various excipients, PEG 400, propylene glycol, TPGS and Labrasol tion (Varma and Panchagnula, 2005). The similar maximum surfac-
in capsules (Schulze et al., 2005). tant concentration for poor soluble drugs was also demonstrated in
the formulation with polysorbate 80 (Katneni et al., 2006).
2.3. Permeation enhancer
3. TPGS formulations
Permeation enhancers can be incorporated into formulations to
promote their permeation through the skin or intestinal walls. 3.1. Fabricating nanocrystals/nanosuspensions
TPGS as an excipient in the formulation of amprenavir, a poorly
water-soluble substrate of P-gp, was found to enhance the intralu- Drug nanocrystals and submicron-sized drug crystals, have re-
minal drug concentration and affect the permeability in a concen- cently become a mature drug delivery strategy for oral delivery.
tration-dependent way (Brouwers et al., 2006). TPGS was also The nano-sizes of the particles can increase the drug dissolution
found to be a profound enhancer for the penetration flux of minox- rate and improve oral absorption. Surfactants are usually used as
idil and its retention in the skin from topical minoxidil formula- stabilizers in this system. TPGS-paclitaxel nanocrystals were fabri-
tions of water/alcohol/polyethylene glycol 400 at concentrations cated by Liu et al. (2010). TPGS and the drug were dissolved in
higher than 5% (Sheu et al., 2006). The penetration enhancement chloroform and evaporated under nitrogen atmosphere. The film
of estradiol by TPGS was not as significant as ethanol/TPGS cosol- formed was hydrated and sonicated for 10–15 min using a bath
vent system (Liou et al., 2009). A microemulsion formulation of sonicator to form nanocrystals. The nanocrystals exhibited moder-
temozolomide acid hexyl ester (TMZA-HE) was constructed with ate uniform particle sizes with the rod width being 40 nm and
oil phase and TPGS as a surfactant. The formulation demonstrated length around 150 nm and could realize controlled release phe-
increased solubility and significantly increased permeation. It may nomena for the payload. In P-gp overexpressing cells, NCI/ADR-
be used as a potential formulation for transdermal delivery of RES, the TPGS nanocrystals exhibited significant antiproliferation
TMZA-HE (Suppasansatorn et al., 2007). effect compared with other formulations. In xenograft experiment
TPGS was found to significantly increase the apparent perme- after inoculating NCI/ADR-RES cells in nude mice, only 10 mg/kg of
ability of P-gp substrate, colchicine, without a change in the colo- TPGS/drug nanocrystals exhibited obvious tumor regression, as
nic tissue integrity. TPGS has the potential to enhance drug seen in Fig. 6. From the report, TPGS may act as surfactant, stabi-
permeability in colonic tissue (Bittner et al., 2008). It also acted lizer of the nanocrystals and drug resistance inhibitor to reverse
as skin permeation enhancer of diclofenac sodium and temozolo- MDR (Liu et al., 2010).
mide hexyl ester prodrug by microemulsion systems (Mohammed, TPGS acted as surfactant/stabiliser and showed the best results
2001; Suppasansatorn et al., 2005). Compared to other systems, for on stability of nanosuspension among 13 different stabilizers from
Fig. 6. TPGS/paclitaxel nanocrystals formulated. Transmission electron microscope images of PTX formulations, tumor growth inhibition effect of PTX/TPGS nanocrystals,
Taxol and TPGS alone in the NCI/ADR-RES xenograft model. Solid arrows indicate the days of intravenous administration and the structure of TPGS and paclitaxel (Liu et al.,
2010). Reproduced with permission.
screening study where TPGS concentrations were tested at 25 or 3.2. Fabricating SMEDDS system
100 wt% of the drug weight (Van Eerdenbrugh et al., 2009b). How-
ever, another investigation showed that 10 wt% was good enough TPGS was used as surfactant in fabricating a self-microemulsify-
to form nanosuspension of itraconazole (Van Eerdenbrugh et al., ing DDS (SMEDDS) to increase the solubility, dissolution rate and
2008b). TPGS-stabilized nanosuspensions (25 wt%, relative to the oral bioavailability for tacrolimus, anti HIV drug UC781 and penc-
drug weight) were produced by media milling for 9 model drug lomedine (De Smidt et al., 2004; Goddeeris and Van den Mooter,
compounds, cinnarizine, griseofulvin, indomethacin, itraconazole, 2008). The tacrolimus-loaded particle size was less than 20 nm
loviride, mebendazole, naproxen, phenylbutazone and phenytoin with the composition of Miglyol 840: TPGS: Transcutol P as
(Ghosh et al., 2011; Van Eerdenbrugh et al., 2008a). Curcumin- 1:7.2:1.8. The formulation exhibited a significant improvement in
loaded nanosuspension with TPGS as stabilizer was found to release characteristics of tacrolimus and achieved sevenfold in-
achieve a 3.8-fold and 11.2-fold increase of AUC and MRT respec- crease in oral bioavailability compared with homemade solution
tively, as compared to curcumin solution after intravenous admin- (Goddeeris et al., 2010; Wang et al., 2011). Wei et al. (2010) pre-
istration (Gao et al., 2010). Rilpivirine nanosuspension was pared SMEDDS composed of medium-chain triglyceride oil and
fabricated by using TPGS as a surfactant for long-acting parenteral surfactant mixtures of TPGS and Tweens at different ratios. Com-
formulations for prophylactic treatment in HIV. The nanosuspen- pared with other surfactant in the composition of SEDDS, TPGS
sions were prepared by wet milling (Elan NanoCrystalÒ technol- can achieve higher inhibition effect on pancreatic lipase than poly-
ogy) in an aqueous carrier with size 200, 400 and 800 nm, sorbate 80, Cremophor EL and sucrose laurate but lower than
respectively. The suspension demonstrated over 6 month stability Cremophor RH40 (Christiansen et al., 2010).
and homogeneity. 200-nm sized nanosuspensions may act as
long-acting injectable formulation (Baert et al., 2009). TPGS was 3.3. TPGS in solid dispersion/tablet
also used as emulsifier for coenzymeQ(10) (CoQ(10)) olive oil
emulsion. The plasma concentration and AUC0–24h of TPGS emul- TPGS was added in solid dispersions to increase the drug solu-
sion were increased up to 7 and 3.7-fold compared with the ol- bility, dissolution rate and also enhance the drug oral bioavailabil-
ive-oil mixed formulation of CoQ10 (Nishimura et al., 2009). ity (Ahn et al., 2011; Moneghini et al., 2010; Schamp et al., 2006).
Paclitaxel nanoemulsion was fabricated with TPGS in labrasol TPGS combined with solutol HS-15 in solid dispersion was found to
and exhibited enhanced oral bioavailability, up to 70.2% compared enhance the solubility and dissolution of nifedipine. It may be
to 10.6% for oral TaxolÒ (Ke et al., 2005; Khandavilli and Panchagn- attributed to the fact that the micellar formulation can increase
ula, 2007). Iodine-loaded oil-in-water emulsion with 30% lipiodol the solubility of drug, enhance the separation of drug particle
and 282 mg/mL (9:1 Tween 80: TPGS) was formulated as an inter- and interaction between polymer and drug, and improve wettabil-
stitial computed tomographic lymphographic agent in a normal rat ity and partial crystalline drug transferred to the amorphous form
model. The emulsion exhibited prolonged duration, up to (Rajebahadur et al., 2006). TPGS-based-capsule was found to in-
534.0 ± 481.1 min compared with the duration for iopamidol, crease the oral bioavailability by more than 100%. The AUC was in-
8.2 ± 12.3 min (Chung et al., 2010). creased 10-fold and dissolution at 30 min was 98% compared to
47% for drug-in-capsule (Vandecruys et al., 2007). Carbamazepine formulation AquanovaÒ (TPGS 100 IU and 400 mg crystalline Vita-
(CBZ) as solid dispersions in polyvinylpyrrolidone (PVP) K30 min C) was found to increase the oral bioavailability as compared
(Sethia and Squillante, 2004b) or polyethylene glycol (PEG) (Bara- to regular fat-soluble Vitamin E formulation (Back et al., 2006).
kat et al., 2009) with either Hf:Gelucire 44/14 or TPGS were pre- Aqua-E containing TPGS significantly increased the absorption of
pared by conventional solvent evaporation and supercritical fluid c-tocopherol in malabsorbing patients with cystic fibrosis com-
(SCF) processing methods. TPGS was found to increase the dissolu- pared with an oil-based formulation (Papas et al., 2007). Oral toco-
tion rate up to 10.6-fold compared to neat CBZ. TPGS with 0.1% fersolan (TPGS formulation) was more bioavailable than water-
concentration increased the CBZ permeability and cell cytotoxicity. miscible Vitamin E formulation in children with chronic cholesta-
Solid dispersion with PEG8000 and TPGS increased the AUC up to sis. Tocofersolan may be an alternative of Vitamin E administration
2–3-fold compared to neat CBZ after oral administration of to avoid painful intramuscularly injected Vitamin E formulation in
20 mg/kg dosage (Sethia and Squillante, 2004a). TPGS was also chronic cholestasis (Jacquemin et al., 2009). TPGS was also applied
added as stabilizer in fabricating itraconazole solid dispersions as a supplement for traditional post-surgical treatment in cardiac
by co-spray-drying with AerosilÒ 200. The oral bioavailability of transplant recipients. It was found to prolong the graft survival, de-
the drug was significantly enhanced compared to the crystalline crease rejection and improve the graft fractional shortening. It also
drug with around 10-fold AUC increase (Sethia and Squillante, prevents the distention in systolic and diastolic lengths in un-
2002; Van Eerdenbrugh et al., 2009a). Solid dispersions composed treated allografts, inhibits nitrosylation in heme protein, decreases
of Eudragit E100 and TPGS were found to enhance the dissolution the expression of inducible nitric oxide protein by 50%, and inhibits
of anti-HIV drug UC 781 (Goddeeris et al., 2008a). Solid dispersions mitogen-stimulated proliferation by both rat and human lympho-
of Hf with TPGS (1:6) and Hf: Gelucire 44/14: TPGS (1:3:3 wt%) in- cytes. These activities are significant and can be exploited in its
creased the oral bioavailability of Hf up to five and sevenfold, combination with cyclosporine A therapy. This demonstrates that
respectively compared to commercially available tablet (contain- TPGS has a significant effect in limiting lymphocyte proliferation
ing 250 mg HfHCl, 8.6%) in fasted beagles (Khoo et al., 2000). and activation, extending graft survival and limiting graft rejection
The aqueous solubility and the dissolution rate of furosemide were and dysfunction (Nguyen et al., 2006). TPGS was used as a vehicle
rapidly and markedly enhanced from the 1:2 furosemide-TPGS so- for oral administration of Vitamin E and D to prevent or correct
lid dispersion. The solid dispersion changed the crystalline nature deficiency states in chronic cholestasis (Argao et al., 1992; Plauth
and the association of furosemide and TPGS which might occur et al., 1997; Socha et al., 1997; Sokol et al., 1993). It is an alterna-
in the molecular level (Shin and Kim, 2003). tive in correcting Vitamin E deficiency in children with chronic
Crowley et al. (2002), Jin and Tatavarti (2010) investigated the cholestasis who are unresponsive to other forms of oral Vitamin
feasibility of forming tablets with TPGS by conventional high shear E. All children exhibited similar response to TPGS with normaliza-
wet granulation. TPGS has a waxy nature and low melting point, tion of Vitamin E status. Neurological function was improved in 25
around 37 °C. This may limit its application in solid dosage formu- patients, stabilized in 27 patients, and worsened in only two pa-
lations. Some critical characters such as TPGS levels, binder and tients after an average treatment period of 2.5 years. No adverse ef-
extragranular filler were considered during product design. The fects have been reported and thus the dosage of TPGS (20–25 IU/
feasibility of developing monolithic and bilayer coated tablets with kg/day) appears to be a safe and effective form of Vitamin E for
up to 10% TPGS was confirmed after optimization studies (Jin and reversing or preventing Vitamin E deficiency during chronic child-
Tatavarti, 2010). TPGS was found to increase the solubility and dis- hood cholestasis (Sokol et al., 1993). TPGS enhanced Vitamin D
solution effect of carbamazepine (CBZ) tablets in a concentration- absorption by micellar structure in eight children (aged 5 months
dependent manner (Charkoftaki et al., 2011). TPGS levels in tablets to 19 years) with severe chronic cholestasis. All patients exhibited
can significantly affect the tensile strength, disintegration time and enhanced absorption of Vitamin D3 when coadministrated with
dissolution of the formulation. The fast disintegrating tablets of 25 mg/kg TPGS. The mean area under the curve for serum Vitamin
ternary solid dispersions composed of TPGS and HPMC 2910 or D3 was increased to 403.0 ± 83.1 nmolh/L compared to
PVPVA 64 have been formulated to improve the dissolution of 155.6 ± 32.1 ngh/mL for normal Vitamin D3 formulation (Argao
the anti-HIV drug UC 781 and itraconazole (Goddeeris et al., et al., 1992). Oral coadministration of TPGS and retinyl palmitate
2008b; Janssens et al., 2008). TPGS is also used as an additive to with Vitamin A was found to be a good supplement for chronic
improve wettability and dissolution rate of cilostazol and etodolac cholestatic liver disease (Feranchak et al., 2005).
in capsules (Barakat, 2006; Kim et al., 2010).
3.6. Anticancer reagent
3.4. Adjuvant for vaccine system
TPGS was found to possess similar anticancer activity to a-toc-
TPGS was used as an adjuvant for vaccines. It was admixed with opheryl succinate (TOS). It can inhibit the growth of human lung
antigens at 5 wt% and found to significantly increase the levels of carcinoma cells in vitro (Fig. 7) and in nude mice (Fig. 8). TPGS
the immunoglobulin responses after intranasal administration. was more effective at inducing apoptosis and the generation of
The IgG and IgA were increased fivefold and 100-fold, respectively reactive oxygen species compared with TOS (Youk et al., 2005). Re-
compared with vaccine formulations without TPGS (Ravichandran cent studies also reported a significant synergistic effect between
et al., 2007). TPGS blended with poly(caprolactone) for nasal TPGS2000 and docetaxel as shown from cell cytotoxicity assay in
immunisation of diphtheria toxoid exhibited enhanced immune Table 1. Up to now, there is no confirmatory data to support its
response compared with the formulation without TPGS (Somav- anticancer property (Mi et al., 2011).
arapul et al., 2005). The antigen uptake and antibody response
was increased by the addition of absorption enhancers to Vibrio 3.7. TPGS micelles and liposomes
anguillarum 02 antigen after oral vaccination (Vervarcke et al.,
2004). TPGS can formulate micelles for drug or imaging agent delivery
with a CMC of 0.02 wt%. TPGS micelles were also used to encapsu-
3.5. Nutrition supplement late other functional materials like multi-wall or single-wall car-
bon nanotubes (Xu et al., 2010), as well as C60 fullerenes or iron
TPGS can act as the alternative formulation of fat-soluble Vita- oxide (Yan et al., 2007). However, the CMC of TPGS is relatively
min E (Westergren and Kalikstad, 2011). Water soluble Vitamin E high as mentioned above and TPGS micelles may dissociate in
Fig. 7. TPGS more effectively inhibited the growth of H460 and A549 lung carcinoma cell lines in comparison with TOS. (A) Dose–growth curve for H460 and A549 cells after
treatment with TOS (d) or TPGS (s). (B) The effect of TOS, TPGS, PEG 1000, and both TOS and PEG 1000 on the growth of H460 cells. Cells were seeded at a density of 4 103/
well in 96-well plates and, starting 24 h later, were incubated for 48 h with varying doses of TOS, TPGS, PEG 1000 or both TOS and PEG 1000 and their growth and viability of
cells were determined by MTT assay. Results are expressed as percentage growth (mean ± S.D. of triplicate wells) relative to untreated cells (Youk et al., 2005). Reproduced
with permission.
and stabilizer to liposomes or lipid based formulations may bring

some advantages to these systems, such as improved cytotoxicity
and overcoming MDR (Zhang et al., 2012). TPGS micelles can not
only increase the solubility of payload, may also act as antioxidant
to increase the stability of entrapped compounds which are prone
to oxidation in physiological fluids. On the contrary, the ordinarily
used solubilizer of cyclodextrin can not protect the unstable drug
from degradation. This may be attributed to the antioxidant prop-
erty of TPGS micelles (di Cagno et al., 2012).
3.8. TPGS emulsified nanoparticles

Fig. 8. TPGS suppressed the growth of human A549 lung cancer cells implanted in
nude mice. Nude mice were subcutaneously injected with A549 cells, tumors were TPGS can be used as an emulsifier or an ideal coating molecule
allowed to reach approximately 50 mm3, and the treatment was initiated. The
in fabricating drug-loaded nanoparticles which can achieve higher
asterisks denote significant differences between tumor volume of TPGS versus
vehicle-treated mice (P < 0.05) (n = 6, 6 and 8 for TOS, TPGS and vehicle treatment drug encapsulation efficiency (up to 100%) and cellular uptake of
group, respectively) (Youk et al., 2005). Reproduced with permission. the nanoparticles, and thus higher therapeutic effects compared
with polyvinyl alcohol (PVA) emulsified nanoparticles (Feng,
blood. Therefore, TPGS is usually mixed with other materials such 2006). Feng’s group showed many impressive results (Zhang
as PEG-PE, PEG-DSPE, oleic acid, Pluronic P105, Pluronic P123, et al., 2012). TPGS emulsified nanoparticles displayed a slower
PLGA-PEG-FOL and Pluronic F127/poly(butylcyanoacrylate) to release pattern than that of PVA. The content of TPGS as surfactant
form mixed micelles to increase the micelle stability and drug sol- can be as low as 0.02–0.03 wt% and has 67 times higher emulsifi-
ubilization (Zhang et al., 2012). The addition of TPGS as a surfactant cation effects than PVA. TPGS has been applied as a surfactant in
Table 1
IC50 of docetaxel formulated in TaxotereÒ, TPGS2 k micelles and FA TPGS2 k micelles after 24, 48, 72 h incubation with MCF-7 breast cancer cells at 37 °C (Mi et al., 2011).
Reproduced with permission.
Incubation time (h) IC50 (lg/ml)

TaxotereÒ Micelles without DXLa Micelles with DXL FA Micelles with DXL
24 103.4 1.350 0.526 0.178
48 1.28 1.530 0.251 0.152
72 0.148 7.58 0.233 0.114
a
The value represents the concentration of docetaxel, that is equivalent to the concentration of TPGS2k for 50% viability.
Table 2
TPGS application as solubilizer, permeation enhancer, Vitamin E alternative, oral absorption enhancer and so on in drug delivery system.
Formulation Drug model Purpose Significant effects

Tablet Carbamazepine/UC781 Dissolution effect Increase the solubility, wettability and dissolution property (Kim et al., 2010)
Capsule/dissolution Ampicillin/antipyrine Oral absorption No effect on small intestine transit (Schulze et al., 2006), gastrointestinal
verapamil transit (Schulze et al., 2005), oral bioavailability R1481 and sirolimus (Wacher
et al., 2002a,b)
Solid dispersion Itraconazole/UC781 Oral bioavailability Enhance the AUC of drug around 2–5 fold in rat and dog TPGS/Labrasol/GL44/
Nifedipine/halofantrine 14 (Ahn et al., 2011)
Nanosuspension Curcumin/itraconzole Oral absorption stabiliser Ninefold of AUC and fivefold of C-max in TPGS nanosuspension compared to
Loviride the coarse suspension after oral administration (Baert et al., 2009; Ghosh
et al., 2011)
Surfactant/micelle Paclitaxel/cyclosporine P-gp inhibition mechanism/ P-gp inhibition from Caco-2 monolayer model; influence of ATPase activity
structure Epirubicin/raloxifene solubility enhancer/oral without membrane fluidity changement (Rege et al., 2002); inhibitor for CYP-
Nanocrystal Verapamil/quercetin absorption enhancer mediated metabolism (Christiansen et al., 2011a,b); Inhibitor of P-gp and
SEDDS Amprenavir/talinolol MRP2 (Hanke et al., 2010); increased AUC and Cmax after coadministration;
SMEDDS Colchicine/vancomycin sixfold increase on the oral bioavailability of paclitaxel after coadministrated
with 50 mg/kg TPGS (Varma and Panchagnula, 2005)
Anticancer TOGS/TPGS Anticancer mechanism Inhibit human lung carcinoma cells in nude mice and cell culture (Youk et al.,
2005)
Adjuvant Vaccine Adjuvant Fivefold of IgG and 100-fold of IgA improved (Ravichandran et al., 2007)
Alternative/nutrition Vitamin E Oral absorption In cholestasis and thoracic duct-cannulated rats; Vitamin D and E deficiency
Vitamin D/A patients and children (Feranchak et al., 2005; Jacquemin et al., 2009)
Surfactant additive Estradiol/colchicine Permeation enhancer Delivery of drug through skin and skin permeation enhancers (Mohammed,
2001); HP-b-CD/HPMC/TPGS 1000 microparticle (Sethia and Squillante,
2004a)
Surfactant/antioxidant Absorption for lung injuries Reduce the oxidative stress and partially decrease the cyclosporine A
therapy pan-capase inhibition mediated reactive oxygen species formation (Grub et al., 2002; Wolf et al.,
1997)
Film/TPGS Paclitaxel Additive/plasticizer The elongation at break was 7–20 fold for TPGS 5–15% in PLLA film (Dong
et al., 2008)
the emulsification of PLGA, PCL, PLA-TPGS, PLGA-PEG and MPEG- could also promote the drug release rate from paclitaxel-loaded
SS-PLA NP. The resulted nanoparticles exhibited higher cell cyto- PLLA films, which may be caused by TPGS hydrophilicity and large
toxicity in vitro and lower maximum tolerated drug levels, longer surface area to volume ratio from PLLA/TPGS films compared with
half life, high oral bioavailability and improved therapeutic effects PLLA film (Dong et al., 2008). The special structure of PLLA/TPGS
compared with TaxolÒ in vivo. film may make it useful as implant for localized drug delivery or
scaffold in tissue engineering.
3.9. TPGS based prodrug TPGS was found to enhance the biocompatibility of polysulfone
(Psf) hollow fiber membranes (HFMs) for acute and chronic
Polymer-drug conjugation is one of major strategies to increase hemodialysis in blood purification. They were prepared by dry
drug solubility, permeability and stability and/or circulation time. wet spinning using 5–20 wt% TPGS as an additive in dope solution
Three kinds of prodrug based on TPGS have been reported by and TPGS was successfully entrapped in Psf hollow fiber as con-
Feng’s group (Zhang et al., 2012). They synthesized TPGS-PTX pro- firmed by ATR-FTIR and TGA (Dahe et al., 2011b). TPGS modified
drug, but the in vitro experimental results were not presented. The Psf HFMs exhibited the most favorable tissue response compared
second is TPGS-DOX prodrug, which showed pH dependent re- with other HFMs (Dahe et al., 2011a). TPGS can be enzymatically
lease, much higher cellular uptake, higher cell cytotoxicity and cleaved to deliver the lipophilic antioxidant, Vitamin E, to cell
lower side effects compared with pristine DOX. The TPGS-cisplatin membranes. It has been demonstrated to act as antioxidant to par-
prodrug also enhanced the chemotherapeutic efficacy of cisplatin tially decrease the cyclosporine A (CsA) mediated reactive oxygen
against HepG2 cells (Mi et al., 2012). species formation, completely decrease thiobarbituric acid reactive
substances formation, prevent the loss of protein-bound sulphyd-
3.10. TPGS based copolymer ryl groups and completely inhibit the CsA cytotoxicity (Wolf
et al., 1997). It significantly inhibited SDZ IMM125-mediated cellu-
TPGS based copolymers can be easily synthesized by ring open- lar Ca2+ uptake, a redox-sensitive process in cell culture (Grub
ing polymerization. TPGS-PLA, TPGS-PLGA, TPGS–PCL, TPGS-PGA- et al., 2002). Similar antioxidant activity was also exhibited in
PCL and TPGS-PLA-PCL were all applied in DDS (Zhang et al., the liquid crystalline formulation of quercetin with TPGS (Anstee
2012). Among them, TPGA-PLA was mostly reported. Many drugs et al., 2010; Shah and Banerjee, 2011; Vicentini et al., 2007; Yan
or functional elements like docetaxel, paclitaxel, doxorubicin, cur- et al., 2007). Minoxidil solutions supplemented with TPGS in cosol-
cumin, supraparamagnetic iron oxide and quantum dots can be vent systems consisting of water, alcohol, and polyethylene glycol
encapsulated in TPGS-PLA nanoparticles with high encapsulation 400 were designed to evaluate the efficacy of promoting hair
efficiency, improved cellular uptake and cell cytotoxicity and growth after topical application and the safety in C57BL/6J mice.
long-circulation property (Zhang et al., 2012). TPGS was found to increase the proliferation of hair by 0.5% but
this effect deteriorated at TPGS concentration above 2% (Chen
3.11. Other applications et al., 2005).
TPGS can act as a plasticizer in film preparation, such as HPC

film (Repka and McGinity, 2000) and PLLA films (Repka and 4. Conclusion and perspective
McGinity, 2001). It was found to decrease the glass transition tem-
perature and the force of adhesion of the films, as well as the flex- We have discussed the properties of TPGS as solubilizer, oral
ibility and elongation at breaking point during tensile testing. TPGS absorption/bioavailability enhancer, micellar property as a surfac-
tant, additive or emulsifier, stabilizer in fabricating drug formula- Bogman, K., Erne-Brand, F., Alsenz, J., Drewe, J., 2003. The role of surfactants in the
reversal of active transport mediated by multidrug resistance proteins. J. Pharm.
tions, permeation enhancer and even its anticancer or antioxidant
Sci. 92, 1250–1261.
effect (see Table 2). It seems that all the applications of TPGS in Bogman, K., Zysset, Y., Degen, L., Hopfgartner, G., Gutmann, H., Alsenz, J., Drewe, J.,
drug delivery are based on its amphiphilic structure. The lipophilic 2005. P-glycoprotein and surfactants: effect on intestinal talinolol absorption.
structure of Vitamin E succinate makes it usable as Vitamin E sup- Clin. Pharmacol. Ther. 77, 24–32.
Boudreaux, J.P., Hayes, D.H., Mizrahi, S., Maggiore, P., Blazek, J., Dick, D., 1993. Use of
plement, antioxidant, and anticancer agent. The hydrophilic head water-soluble liquid Vitamin E to enhance cyclosporine absorption in children
of PEG 1000 showed the most P-gp inhibition effects and provided after liver transplant. Transplant. Proc. 25, 1875.
the micellar property for this molecular biomaterial. Until now the Brouwers, J., Tack, J., Lammert, F., Augustijns, P., 2006. Intraluminal drug and
formulation behavior and integration in in vitro permeability estimation: a case
most perspective property applied in drug delivery is based on its study with amprenavir. J. Pharm. Sci. 95, 372–383.
P-gp inhibition and great surfactant effect on formulations. In fur- Buckley, S.T., Fischer, S.M., Fricker, G., Brandl, M., 2012. In vitro models to evaluate
ther studies, there may be more modifications and related poly- the permeability of poorly soluble drug entities: challenges and perspectives.
Eur. J. Pharm. Sci. 45, 235–250.
mers for DDS. The recent TPGS-based copolymer application in Chang, T., Benet, L.Z., Hebert, M.F., 1996. The effect of water-soluble Vitamin E on
drug delivery has exhibited long-circulation and improved oral cyclosporine pharmacokinetics in healthy volunteers. Clin. Pharmacol. Ther. 59,
bioavailability in fabricated nanoparticles. The TPGS-related 1–7.
Chang, T., Benet, L., Hebert, M., 2005. The effect of water-soluble Vitamin E on
copolymer, PLA-TPGS, was found to overcome MDR in MCF-7/ cyclosporine pharmacokinetics in healthy volunteers. Clin. Pharmacol. Ther. 59,
ADR cells but further investigations may still be required to con- 297–303.
firm this. It may be applied in clinical administration of chemo- Charkoftaki, G., Dokoumetzidis, A., Valsami, G., Macheras, P., 2011. Supersaturated
dissolution data and their interpretation: the TPGS-carbamazepine model case.
therapeutic agents. Besides this, our group is harnessing the
J. Pharm. Pharmacol. 63, 352–361.
micellar property and P-gp inhibitor effect of TPGS to construct Chen, C.H., Sheu, M.T., Wu, A.B., Lin, K.P., Ho, H.O., 2005. Simultaneous effects of
stimuli-responsive prodrug. The prodrug may be cleaved in tumor tocopheryl polyethylene glycol succinate (TPGS) on local hair growth
cells by pH and/or reduced to release conjugated drug and TPGS. It promotion and systemic absorption of topically applied minoxidil in a mouse
model. Int. J. Pharm. 306, 91–98.
will combine the effects of TPGS in P-gp inhibition and stimuli- Chen, W., Miao, Y.Q., Fan, D.J., Yang, S.S., Lin, X., Meng, L.K., Tang, X., 2011.
responsive drug release. Bioavailability study of berberine and the enhancing effects of TPGS on
intestinal absorption in rats. AAPS Pharm. Sci. Tech. 12, 705–711.
Christiansen, A., Backensfeld, T., Weitschies, W., 2010. Effects of non-ionic
Acknowledgements surfactants on in vitro triglyceride digestion and their susceptibility to
digestion by pancreatic enzymes. Eur. J. Pharm. Sci. 41, 376–382.
Christiansen, A., Backensfeld, T., Denner, K., Weitschies, W., 2011a. Effects of non-
The work was financially supported by National Basic Research ionic surfactants on cytochrome P450-mediated metabolism in vitro. Eur. J.
Program of China (973 Program, 2012CB932500), NSFC (81241103 Pharm. Biopharm. 78, 166–172.
Christiansen, A., Backensfeld, T., Kuhn, S., Weitschies, W., 2011b. Investigating
and 21204024) and Hunan Provincial Science and Technology Pro- the stability of the nonionic surfactants tocopheryl polyethylene glycol
ject (No. 2012FJ3002). succinate and sucrose laurate by HPLC-MS, DAD, and CAD. J. Pharm. Sci. 100,
1773–1782.
Chung, Y.E., Hyung, W.J., Kweon, S., Lim, S.J., Choi, J., Lee, M.H., Kim, H., Myoung, S.,
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Guo Vit E TPGS RV EJPS 2013

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European Journal of Pharmaceutical Sciences 49 (2013) 175–186

Contents lists available at SciVerse ScienceDirect

European Journal of Pharmaceutical Sciences

The applications of Vitamin E TPGS in drug delivery

1. Introduction In our previous review (Zhang et al., 2012), we discussed TPGS

Fig. 4. TPGS concentration-dependent solubility of paclitaxel. Inset shows total

2.2. Solubilizer/absorption enhancer

Solubilizers/absorption enhancers are functional excipients in-

and stabilizer to liposomes or lipid based formulations may bring

3.8. TPGS emulsiﬁed nanoparticles

Incubation time (h) IC50 (lg/ml)

Formulation Drug model Purpose Signiﬁcant effects

TPGS can act as a plasticizer in ﬁlm preparation, such as HPC

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