C. Yiyun, X. Tongwen / European Journal of Medicinal Chemistry 40 (2005) 1188–1192
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soluble salts were carried out and to enhance dissolution and
absorption rate, increasing the wettability and micronization
of drug particles has often been used to increase the bioavail-
ability of poorly water-soluble NSAIDs [8–10], However
methods mentioned above have not always been sufficient to
achieve this goal.
The aim of the present work was (1) to investigate the
potential of PAMAM dendrimers as solubility enhancers of
NSAIDs; (2) to study effect of molecular size and hydropho-
bic nature of NSAIDs on their solubility in the presence of
PAMAM dendrimers.
Many macromolecular drug delivery systems have been
developed to enhance the solubility of NSAIDs and limit their
side effects, which promise to be safer than their traditional
NSAID counterparts over the years [11–13].A macromolecu-
lar drug delivery system is a complex material in which a
drug is attached to a carrier molecule such as a synthetic poly-
mer, antibody, hormone or liposome. As the absorption and
distribution of the drug in such a system depended on the
properties of the macromolecular carrier, parameters such as
site specificity, protection from degradation and minimiza-
tion of side effects can be altered by modifying the properties
Dendrimers are hyperbranced, monodisperse, three-
dimensional macromolecules, having defined molecular
weight and host-guest entrapment properties. They allow the
precise control of size, shape and placement of functional
groups and combine typical characteristics of small organic
molecules and polymers that result in special physical and
chemical properties [15–18]. Accordingly, dendrimers have
attracted increasing attention for their applications in many
fields. Among them the use of dendrimers as a drug carrier in
delivery systems has been of great intreset.
Polyamidoamine (PAMAM) with an ellipsoidal or sphe-
roidal shape is one of the most-studied starburst macromol-
ecules. Due to specific synthesis PAMAM dendrimers have
some interesting properties, which distinguish them from clas-
sical linear polymers, e.g. PAMAM has a much higher amino
group density comparing with conventional macromol-
ecules, a third generation PAMAM prepared from ammonia
core has 1.24×10−4 amine moieties per unit volume (cubic
Angstrom units) in contrast to the 1.58×10−6 amine moieties
per unit volume of a conventional star polymer [18]; Also,
PAMAM Dendrimers possess empty internal cavities and
many functional end groups which are responsible for high
solubility and reactivity. These specific properties make den-
drimers suitable for drug delivery systems [19–21]. Drugs or
other molecules can either be attached to dendrimers’ end
groups or encapsulated in the macromolecule interior [22].
The high density of amino groups and special structure in
PAMAM dendrimers may be expected to have potential appli-
cations in enhancing the solubility of the low aqueous solu-
bility drugs and as delivery systems for bioactive materials
[23]. Drugs bound to dendrimers are at early stages of devel-
opment and data on them are limited. Here, we focus on using
PAMAM dendrimers as potential drug carriers, which are
emerging as a promising group of safer and perhaps more
effective alternatives to traditional NSAIDs. This study uses
PAMAM dendrimers (G2-G4) to investigate the potential of
PAMAM dendrimers to increase the solubility of NSAIDs as
exemplified by Ketoprofen, Ibuprofen, Diflunisal and
Naproxen.
2. Experiments
2.1. Materials
Ketoprofen was purchased from Hubei Wuxue Xunda
Pharmaceutical Co. (Hubei, China). Ibuprofen and Diflunisal
were obtained from Juhua Group Pharmaceutical Factory
(Zhejiang, China). Naproxen was a gift from Chetou Phar-
maceutical Factory (Zhejiang, China). Ethylenediamine,
methyl acrylate, methanol (HPLC grade) were obtained from
Shanghai Chemical Co. (Shanghai, China). Double distilled-
deionized water was used throughout.
2.2. Synthesis of star polymers
PAMAM dendrimers were synthesized by the following
method [18]. Ethylenediamine (10.0 g, 0.166 mol) was dis-
solved in 100 ml methanol in a 1-liter round-bottomed flask.
Methyl acrylate (94.6 g, 0.751 mol) was added at 40 °C and
the system stirred for 24 h under nitrogen. Excess methyl acry-
late was removed under vacuum at room temperature. A
Michael addition between the amine and the acrylate yielded
a product bearing four terminal methyl ester groups, defined
as the G0.5 PAMAM. Subsequently, ethylenediamine (120 g,
2.00 mol) was dissolved in methanol and added to the
G0.5 PAMAM and, after stirring for 48 h under nitrogen and
removing excess reactants by vacuum distillation, a product
bearing four terminal amino groups were obtained, defined
as the G1 PAMAM. By repeating the above cycle, higher gen-
eration PAMAM dendrimers (up to G5) were synthesized.
For sample preparation, 1-2 wt% PAMAM/ethyl acetate solu-
tion was repeatedly filtrated through a 0.1 um nylon filter.
Purity of the amine-terminated PAMAM dendrimers were
characterized via FT-IR (MAGNA-IR 750, Nicolet Instru-
ment Co., U.S.A), H and 13C NMR (DMX-500, German),
Mass spectral analysis (BIFI EXTM 3, German) and Ele-
ment analysis (VARIO EL 3, Elementar Instrument Co., Ger-
man).
1
2.3. Solubility testing experiments
Excess NSAIDs drugs was added to 5 ml of each test solu-
tion to ensure the drug solution reaching saturation. The solu-
tion was mechanically shaken for 24 h at 37 °C and then cen-
trifuged at 5000 rpm for a minute. The absorbances of
NSAIDs test solutions at their characteristic wavelengthes
(260 nm for Ketoprofen and Naproxen, 221 nm for Ibuprofen
and 250 nm for Diflunisal) were tested using the Varian Cary
VIII spectrophotometer. Three repeats were conducted.
Yiyun, Cheng
