Effect of tocopheryl polyethylene glycol succinate 1000 on solubility
enhancement, oral bioavailability enhancement and percutaneous absorption
of (S)-zaltoprofen
Pham Viet Cuong
1
, Sang-Hun Jung
1
, Cheong-Weon Cho
1
1
Department of Pharmacy, Chungnam National University, Daejeon, Korea
E-mail: [email protected]
Abstract—The solubility of (S)-zaltoprofen ((S)-
ZPF) in forty eight solvents was investigated, such
as D-alpha tocopheryl polyethylene glycol 1000
succinate (TPGS), 2-hydroxypropyl-β-cyclodextrin
(HPCD), water-soluble organic solvents and
mixtures of individual solvent. We also developed
the validated analytical method of (S)-ZPF in rat
plasma by liquid-liquid extraction, and successfully
evaluated the potential interconversion of (S)-ZPF
in plasma using a reversed and a chiral HPLC
column. The pharmacokinetics results showed oral
bioavailability of (S)-ZPF was the highest in TPGS
group among three studied groups with a strong
coefficient of correlation between solubility and
oral bioavailability of (S)-ZPF (0.97). On the other
hand, TPGS was able to enhance the solubility of
(S)-ZPF by micellar solubilization. But it was not
responsible for the enhancement of (S)-ZPF
penetration for intact and delipidized skin. Alcohol
was more effective in enhancing (S)-ZPF solubility
by increasing the free-form concentration of (S)-
ZPF and decreasing the equilibrium distribution
constant. Modification of the intact and delipidized
skin to enhance (S)-ZPF penetration by TPGS was
minimal compared to that by alcohol. The
partitioning of (S)-ZPF from all solutions into the
delipidized SC was always higher than that into
intact SC. The important role of interfacial
coverage by TPGS in hindering intact and
delipidized SC, molecular changes in SC lipids after
vehicle and chloroform/methanol solvent treatment
also supported for the result of permeation of (S)-
ZPF.
Keywords— (S)-zaltoprofen, TPGS, chiral HPLC,
oral bioavailability, percutaneous absorption.
I. INTRODUCTION
(S)-ZPF exhibited better anti-inflammatory and
analgesic activities than racemic (RS)-zaltoprofen
((RS)-ZPF) in rodents as well as a substantially higher
bioavailability compared to (R)-zaltoprofen ((R)-ZPF)
from (RS)-ZPF [1,2]. There was a report that
expressed only (S)-ZPF might be an active enantiomer
in racemic (RS)-ZPF in terms of anti-inflammatory
activity [2]. However, by far, zaltoprofen still remains
clinically used as the racemate in the market.
D- alpha tocopheryl polyethylene glycol 1000
succinate (TPGS or Vitamin E TPGS) is completely
water-soluble and it has been commonly used for
solubilizing effects, bioavailability enhancemenet on
water-insoluble drugs as well as a penetration enhancer
in transdermal/topical drug delivery systems (TDDS)
[3,4]. Moreover, TPGS has been approved by FDA as
a safe pharmaceutic adjuvant, and there are an
increasing number of commercial pharmaceutical
products containing TPGS as an adjuvant in the market
[3].
The stratum corneum (SC) has crutial role such as
host protection from pathogens or harmful substances,
water loss prevention, and body temperature regulation
[5]. While in vitro percutaneous administration studies
are typically performed on healthy skin with intact
barrier function, data on permeability of chemicals in
compromised skin are less common. Thus it is
important to obtain well-characterized models to
characterize percutaneous absorption through
compromised skin. In vitro studies utilizing
compromised skin models may be more relevant in
predicting topical drug absorption.
To best our knowledge, no studies have been
performed on the solubility, pharmacokinetic studies as
well as penetration flux of (S)-ZPF through intact and
delipidized rat skin. Hence, in this study, we focused
on evaluation of soubilization of (S)-ZPF by TPGS,
establishing the correlation between the solubility of
(S)-ZPF and its bioavailaibility, and TPGS’
mechanism of action attributed to percutaneous
absorption of (S)-ZPF through intact and delipidized
rat skin.
II. METHODS
A. Solubility of (S)-zaltoprofen
Solubility study of (S)-ZPF in 48 solvents was
performed in 72 consecutive hours to reach
equilibrium solubility, then samples measured by
reverse HPLC.
B. Validation
Linearity, sensitivity, extraction recovery, accuracy
and precision, stability studies were performed.
C. In vitro skin permeation study
Two types of skin were employed including intact
and delipidized skin. Franz diffusion cells were used.