European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 48–54

www.elsevier.com/locate/ejpb

Research paper

Encapsulation of ketoprofen for controlled drug release

a,* b
Adi I. Arida , Moawia M. Al-Tabakha
a
Faculty of Pharmacy, Philadelphia University, Jordan
b
Faculty of Pharmacy and Health Sciences, Ajman University of Science and Technology Network, Al-Fujairah, United Arab Emirates

Received 17 March 2006; accepted in revised form 20 September 2006

Available online 1 October 2006

Abstract

Ketoprofen particles were encapsulated with polyions and gelatin to control the release of the drug in aqueous solutions. Charged
linear polyions and gelatin were alternatively deposited on 6 lm drug microcrystals through layer-by-layer (LbL) assembly. Sequential
layers of poly(dimethyldiallyl ammonium chloride) (PDDA) and poly(styrenesulfonate) (PSS) were followed by adsorption of two to six
gelatin/PSS bilayers with corresponding capsule wall thicknesses ranging from 41 to 111 nm. The release of Ketoprofen from the coated
microparticles was measured in aqueous solutions of pH 1.4, 4.1, and 7.4. The release rate has changed at these different pH values. At
pH 7.4 the release rate of Ketoprofen from the encapsulated particles was less by 107 times compared to uncoated Ketoprofen. The
results provide a method of achieving prolonged drug release through self-assembly of polymeric shells on drug crystals.
Ó 2006 Elsevier B.V. All rights reserved.

Keywords: Ketoprofen; Encapsulation; Controlled release

1. Introduction still need to be resolved before the method can be used clin-
ically. Important issues include the biocompatibility and
A trend in NSAID development has been to improve biodegradability of the nanocapsules, cytotoxicity tests,
therapeutic efficacy and reduce the severity of upper GI optimization of release in different parts of the gastrointes-
side effects through altering dosage forms of NSAIDs by tinal tract, targeting of the capsules, and the possibility of
modifying release of the formulations to optimize drug turning drug release on or off by an external influence. In
delivery. These formulations are designed to increase this study gelatins were used because they are biocompati-
patient compliance through a prolonged effect and reduce ble, but other materials, such as different polysaccharides,
adverse effects through lowered-peak plasma concentra- specifically synthesized polypeptides, and DNA, could be
tions. Indeed, enteric coated (EC) and sustained release used to produce more specialized capsules. Previously, it
(SR) formulations of several NSAIDs have resulted in a has been demonstrated that it is possible to assemble an
reduction in endoscopic findings in the stomach and duo- outermost microshell layer of antigen and antibody and
denal bulb as these formulations are intended to release that such shells can be used for targeted drug delivery [4].
NSAIDs in the intestine [1–3]. The use of magnetic nanoparticles on the outer shell allows
In this work the chemical principles for a new type of focused targeting to specific areas for localized action and
polymer micro-vehicle for sustained drug release were provides a means by which the capsules can be opened with
investigated. A large number of biopharmaceutical issues a high-gradient localized magnetic field [5].
Microencapsulation of drug microparticles is a useful
technique for prolonging release. Polymer-based and lipo-
*
some-based systems have been used for drug encapsula-
Corresponding author. Faculty of Pharmacy, Philadelphia University,
P.O. Box 1, 19392 Jerash, Jordan. Tel.: +962 777207171; fax: +962
tion, mostly as unordered drug/polymer conjugates [6–8].
65159912. Layer-by-layer (LbL) self-assembly technique based on
E-mail address: arida@go.com.jo (A.I. Arida). alternate adsorption of oppositely charged components

0939-6411/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejpb.2006.09.010
 A.I. Arida, M.M. Al-Tabakha / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 48–54 49

was developed in the 1990s to coat nanometer-thick films St. Louis, USA. Solutions of 3 mg/ml PSS, 2 mg/ml
on any surface [9–14]. The film thickness could be con- PDDA, and 2 mg/ml gelatin type A were prepared in
trolled within an accuracy of a few nanometers. LbL 20 mM acetic buffer at pH 4. Aqueous 0.1 M NaCl was
assembly has been applied to produce nanoshells on added to increase thickness of adsorbed polyion layers. A
micro/nanotemplates such as cells [4], fluorescein, and ibu- phosphate buffer solution of pH 7.4 was prepared accord-
profen microparticles [15,16]. Charged materials, including ing to USP 24.
linear polyelectrolytes, enzymes, antibodies, and inorganic The size of most of Ketoprofen microcrystals observed
nanoparticles, are used in the microencapsulation process under a microscope was 6 lm. Ketoprofen is practically
[4,15–18]. For controlled release systems, micron-scale insoluble in water at 20 °C. Consequently, Ketoprofen par-
cores of material are encapsulated with an outer shell. ticles were dispersed in water at 20 °C to prevent the drug
The core must be insoluble under some condition, such crystals from dissolving and losing their original shapes
as low pH, and soluble under the conditions at which con- during the coating procedure.
trolled release is to take place. The release rate generally
depends on the thickness of the encapsulating shell and 2.2. Instrumentation
the material used in the coating. Thicker shells lead to long-
er release times. Instrumental techniques used to study and characterize
Encapsulation of ibuprofen also resulted in prolonged ketoprofen particles and LbL assembly included a 9-MHz
release at different pH values [16]. The ibuprofen dissolu- quartz crystal microbalance (QCM, USI-Systems, Japan),
tion time from capsules with walls built from 15 bilayers a Zeta-Plus photon correlation and microelectrophoresis
of chitosan/dextran was 40 s at pH 7.4, compared to 10 s instrument (Brookhaven Instruments), a UV–visible spec-
with no coating. Therefore, prolongation of the release trophotometer (Milton Roy Company, USA), a USP pad-
was minimal. dle dissolution apparatus (Hanson Research Corporation,
To determine whether encapsulation by LbL assembly Chats Worth, California USA), and an Eppendorf 5804R
can substantially increase the drug release time, the tech- centrifuge.
nique was used to assemble polypeptides and polyions on
microcrystals of ketoprofen. Ketoprofen is a nonsteroidal 2.3. Experiment protocol
anti-inflammatory drug that relieves the pain, tenderness,
inflammation (swelling), and stiffness caused by arthritis Prior to polyion multilayer formation on ketoprofen
[19]. Frequent dosing of Ketoprofen is required for thera- crystals at pH 4, the coating procedure was elaborated
peutic maintenance because of its fairly fast elimination on the gold-electrode resonators of a 9-MHz quartz crystal
from the body [20,21]; it usually is taken three or four times microbalance. The resonators were immersed in a polyion
a day for arthritis or every 6–8 h as needed for pain. Expo- solution for 15 min, removed, and dried. The added mass
sure of the stomach to high levels of ketoprofen can cause and the coating thickness (DL) were calculated from the
gastric damage such as ulceration or bleeding [22]. To frequency shift (DF), according to the Sauerbrey equation,
improve this disadvantage, sustained release or enteric- using a special scaling [25,26]. For the instrument used in
coating dosage forms have been developed, resulting in less this study, the calibration was DL (nm) = 0.017 DF (Hz).
frequent dosing and less gastrointestinal disturbance [23]. Several coating configurations were studied initially to
Ketoprofen release from the LbL assembly was mea- determine the most appropriate conditions for the drug-re-
sured under three physiological pH conditions, pH 1.4 lease application. These optimized assembly conditions
(stomach), pH 4.1, and pH 7.4 (blood). By optimization were applied to the LbL shell assembly on microcrystals.
of microcapsule wall thickness and composition, ketopro- After each polyion coating, the zeta-potential of the cap-
fen release time was controlled in simulated physiological sules was calculated as the average of 10 measurements
environment. with a Zeta-Plus photon correlation spectroscopy and
microelectrophoresis instrument. All measurements were
2. Materials and methodology performed in air-equilibrated 1 mM KCl solution.
The coating procedure was carried out as follows: a neg-
2.1. Reagents and materials atively charged PSS solution was added to 200 mg of the
ketoprofen particles in pH 4 acetic acid solution (saturated
Ketoprofen (MW: 254.29) was obtained from APM with ketoprofen) and kept for 30 min, which was sufficient
Company (Sult, Jordan) and finely ground by using a mor- time to ensure that all crystals were coated. A pH of 4 was
tar and a pestle (before coating). Cationic poly(dimethyl- used because the low solubility of ketoprofen at this pH
diallyl ammonium chloride) (PDDA, MW 200,000, [24] ensured that the particle shapes and sizes were not
Aldrich), poly(ethyleneimine) (PEI, MW 50,000, Aldrich), altered. Negative polyions were used as the first layer
and anionic sodium poly(styrenesulfonate) (PSS, MW because the electric potential measurements showed that
70,000, Aldrich) were selected for the LbL assembly. A the surface of ketoprofen is positively charged at this pH.
positively charged polypeptide, gelatin type A (MW The chemical name for ketoprofen is 2-(3-benzoylphenyl)-
50,000–100,000), was obtained from Sigma Chemical Co., propionic acid. Its empirical formula is C12H12O2, with a
50 A.I. Arida, M.M. Al-Tabakha / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 48–54

molecular weight of 254.29. Ketoprofen is a white or off- of ketoprofen from the capsules was conducted in a
white, odorless, nonhygroscopic, fine to granular powder, quartz cuvette by monitoring UV absorbance at
melting at about 95 °C. It is freely soluble in ethanol, chlo- 256 nm. The peak UV absorbance remains the same at
roform, acetone, ether, and soluble in benzene and strong different pHs used in this study. As ketoprofen has
alkali, but practically insoluble in water at 20 °C, and at low solubility at low pHs, and to ensure sink conditions
low pH [24]. Zeta-potential measurements demonstrated for different samples, concentrations of ketoprofen in
that the surface charge of a ketoprofen particle was positive the dissolution media were kept below 2 mg%. Record-
at pH 4. Referring to the chemical structure of ketoprofen ing time intervals varied from seconds to hours for
(Fig. 1) we believe that due to the high electron-withdraw- different samples. All release studies were performed at
ing abilities of the oxygen atoms in the two aromatic struc- room temperature (25 °C). After encapsulation the
tures of the compound, and because of their high microcrystals were kept in a saturated ketoprofen solu-
electronegativities, this will create a high positively charged tion. Before each release study, the capsules were rinsed
center around the carbon–carbonyl from one side and the in water for 10 s.
carbon–carbonyl atom from the other acidic side. In addi- The dissolution rates of the coated ketoprofen particles,
tion to that we believe that the two aromatic structures of commercially available ketoprofen tablets (Profenid
the compound and their highly conjugated abilities 100 mg film-coated tablets, Aventis) and ketoprofen con-
through the entire molecule, this might increase the proba- trolled release tablets (Profenid SR 200 mg, Aventis) were
bility of creating positive charges to the drug particles. measured using Method 2 of the United States Pharmaco-
The coated ketoprofen microcrystals were separated peia (USP 24) [27]. The paddles were rotated at 50 rpm and
from the polyion solution by 5 min centrifugation in an 5 mL samples were withdrawn from the dissolution medi-
Eppendorf 5804R centrifuge at 1000g. Recovered micro- um at regular intervals and extending as long as 8 h. Sam-
crystals were washed twice with acetic acid solution satu- ples taken were compensated with the same amount of the
rated with ketoprofen before further assembly. The dissolution media, taken at the same temperature from a
procedure was then repeated with polycation PDDA, a sec- control vessel of the dissolution apparatus. Initial concen-
ond PSS layer, and a second PDDA layer to form a (PSS/ tration levels which were below 30 s were extrapolated.
PDDA)2 precursor layer. This layer of strongly charged For each test, 5 mg of the dried coated particles was placed
polyions forms a stable foundation for further coating. in 500 ml of either 0.1 M aqueous hydrochloric acid solu-
Next, four layers of (PSS/gelatin) were deposited by the tion or 0.2 M aqueous acetate buffer (pH 4.1). The medium
same method. Negatively charged PSS was chosen for this was degassed and kept at 37 °C. The concentration of keto-
step because, with an isoelectric point near pH 8, gelatin is profen in solution was calculated from the UV absorbance
positively charged at pH 4. Gelatin layers strongly decrease of withdrawn samples. The pH 7.4 solution was a phos-
the drug release and are biocompatible. The coated parti- phate buffer prepared according to USP as all other buffers
cles were removed from the solvent and air dried on a filter in the work.
paper before performing dissolution test. This capsule wall
composition was the most effective for ketoprofen because 3. Results and discussion
capsules composed of other linear polyions, such as
poly(ethyleneimine), chitosan, and poly(allylamine), were In the first stage, PEI, PDDA, PSS, and gelatin were
found to have high permeability. assembled onto quartz crystal microbalance electrodes.
Gelatin is insoluble in ethanol, and to calculate its encap- Assembly of (PDDA/PSS)2(PSS/gelatin)4 multilayers was
sulation rate, 20 mg of encapsulated ketoprofen particles, monitored by QCM frequency shift measurements
which were prepared by the usual LbL technique as before, (Fig. 2). Additional NaCl was added to the solution
was gently stirred into 100 ml ethanol and left to settle freely because the film thickness of each polyion layer varies with
for 10 min. Samples from the supernatant solution were the ionic strength of the solutions [10], with higher ionic
withdrawn and analyzed through a calibration curve of strength solution generating thicker polyion films. As
ketoprofen. The absorbancies of triplicate samples were tak- shown in Fig. 1, 0.1 M NaCl in acetic acid buffer provided
en and through the calibration curve a recovery of about a 2-nm thick PDDA/PSS bilayer. Assembly steps for gela-
1.25% of ketoprofen was noted. Therefore encapsulation tin were easily monitored with QCM frequency shifts
rate can be assumed to be more than 98% which is quite high. because the film thickness sharply increased. The averaged
Drug release before and after encapsulation was frequency shift for each gelatin layer was 479 Hz, which
monitored with a UV–visible spectrometer. The release corresponds to a thickness (DL) of 8 nm. This thickness
indicates that each polypeptide layer included more than
one gelatin monolayer. This feature probably led to the
drastically decreasing permeability of the capsule walls.
The PSS layers were much thinner than the gelatin layers,
having a thickness of 0.8 nm. Finally, the total thickness
of the 11-layer coating composed of [PDDA + (PSS/
Fig. 1. The molecular structure of ketoprofen. PDDA) + (PSS/gelatin)4] was 38 nm.
 A.I. Arida, M.M. Al-Tabakha / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 48–54 51

2500 40 50.0
40.0
35
30.0

Zeta-Potential (mV)
2000

Film Thickness (nm )

Frequency Shift (Hz )

30 20.0
10.0
1500 25
0.0
20 -10.0 0 2 4 6 8 10 12
1000 15 -20.0
-30.0
10
500 -40.0
5 Adsorption Steps

0 0 PSS Zeta-Potential (mV) PDDA Zeta-Potential (mV) Gelatin Zeta-Potential (mV)

1 2 3 4 5 6 7 8 9 10 11 12
Adsorption Layers Fig. 3. Zeta-potential of the coated ketoprofen microcrystals versus the
number of adsorption steps for shell compositions of (PSS/
Gelatin PDDA PSS
PDDA)2 + (PSS/gelatin)4.
Fig. 2. Frequency shift and film thickness of each assembly layer for
PDDA + (PSS/PDDA) + (PSS/gelatin)4 adsorption on QCM electrodes.
tin layers tended to have zeta-potentials with lower magni-
The first three-layer precursor [PDDA + (PSS/PDDA)] is 4 nm thick.
The averaged frequency shift of every gelatin layer is 479 Hz, correspond- tudes, averaging +5 mV. The surface potential of the PSS
ing to a thickness of 8 nm. layers slightly decreased with each application from
28 mV after the first layer to 15 mV at the 11th layer.
Probably, in some regions PSS did not completely over-
The QCM assembly data were used as a guide for selec- come the more bulky gelatin layer. This decline could limit
tion of polyion capsule formation conditions (i.e. the com- total thickness of the shell after another five to six bilayers
ponent concentration, solution pH, and deposition time) of gelatin/PSS. The alternating surface charge of coated
on the particles. It was difficult to directly measure shell drug particles was strong evidence that the layer-by-layer
thickness on particles, but in a previous study it was found assembly of the oppositely charged components was
that the layer thickness coated on QCM electrodes was half successful.
the shell thickness on microtemplates [15,17,28]. The QCM The amount of drug released from microcapsules with
measurements indicated that a single gelatin layer coated different numbers of gelatin layers was quantified (mini-
on drug microcrystals was 16 nm thick, taking into mum of 95% of the sample tested for dissolution by mea-
account the doubling of the layer thickness for a swollen suring the absorbance of the solution containing the
polyion multilayer compared with dry multilayer [12]. microencapsulated particles. These data are shown as a
The nano-shell thickness ranged from 41 to 111 nm for function of time in Fig. 4. At pH 1.4 (close to stomach
two to six gelatin/PSS bilayers, as estimated from QCM pH), the half-release times (t1/2) were 0.30, 0.60, and
data. The corresponding swollen wall thickness was 0.80 h for two-, four-, and six-layer gelatin coatings,
122 nm for a two-block shell with the composition respectively. The t1/2 of the unmodified drug particles was
[(PDDA/PSS) + (PSS/gelatin)6]. Therefore, the polymer 0.15 h. After encapsulation, the t1/2 was two, four, and
wall/ketoprofen core mass ratio is 0.20. 5.33 times longer compared to the uncoated ketoprofen
Ketoprofen is available in the market by prescription as particles. The total release times were 1.8, 3.2, and 6.4 h
25, 50, 75, 100, 150, and 200 mg capsules. Some of its for two, four, and six gelatin bilayers, respectively. The
brand names in the USA are Orudis and Oruvail. Orudis four- and six-layer coatings are thick enough to provide
capsules contain 25, 50, or 75 mg of ketoprofen. While, slow release in a gastric environment (pH 1.4). Ketoprofen
each Oruvail 100, 150, or 200 mg capsule contains ketopro- coated with four to ten PSS/PDDA bilayers did not dem-
fen in the form of hundreds of coated pellets. In this work, onstrate a significant increase in release time.
and upon addition of gelatin layers, particles have At pH 7.4, the half-release times were 0.006, 0.03, and
increased in their size and this was checked with micro- 0.25 h for two, four, and six layers of gelatin, respectively
scope after addition of every layer and after measuring (Fig. 5). The half-release time for unmodified ketoprofen
charges by QCM. This would tell that the addition of gel- particles was estimated to be 0.0005 h (1.8 s). The total
atin has been done physically. release times were 0.05, 0.32, and 0.75 h for two, four,
Surface electrical potentials (zeta-potential) for the and six gelatin layers, respectively. The uncoated ketopro-
encapsulated ketoprofen particles at each step of the alter- fen particles dissolved in 0.007 h (25 s). Thus, the release
nate adsorption process are shown in Fig. 3. The uncoated time was 7, 46, and 107 times longer after encapsulation
drug is positively charged with potential +51 mV. The first with two, four, and six layers, respectively.
PSS layer converted it to negative 31 mV. The first At pH 7.4, the drug half-release time ratio of the
PDDA coating gave positive charge at +32 mV. The gela- six-layer coating/zero-layer coating was much higher
52 A.I. Arida, M.M. Al-Tabakha / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 48–54

1.0
0.9

Frac tion of Drug Releas ed

0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1 2 3 4 5 6 7 8
Time (Hours)

Fraction of Drug Released (Ketoprofen Crystals) Fraction of Drug Released (2 Gelatin Layers)
Fraction of Drug Released (4 Gelatin Layers) Fraction of Drug Released (6 Gelatin Layers)

Fig. 4. Release profiles of ketoprofen before and after encapsulation at pH 1.4.

1.0
0.9
Frac tion of Drug Releas ed

0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
Time (Hours)

Fraction of Drug Released (Ketoprofen Crystals) Fraction of Drug Released (2 Gelatin Layers)
Fraction of Drug Released (4 Gelatin Layers) Fraction of Drug Released (6 Gelatin Layers)

Fig. 5. Release profiles of ketoprofen before and after encapsulation at pH 7.4.

compared to that at pH 1.4. At pH 7.4 the release appears Dissolution profiles (Fig. 6) show that LbL coating of
to occur in three stages (Fig. 5); an initial burst occurs for ketoprofen particles with anionic PSS and cationic PDDA,
the first few seconds, followed by a slow release that is lin- followed by adsorption of gelatin, significantly slowed the
ear in time. In the final stage, release slows exponentially, dissolution rate of the drug in physiologically relevant
tending asymptotically to the saturation concentration media. The shell architecture is (PSS/PDDA)2 + (PSS/gela-
(total dissolution) of the drug. tin)4. At pH 1.4 and 4.1, respectively, as would be encoun-
Drug release in the pH 1.4 solution did not exhibit a lin- tered by the drug in the gastrointestinal tract of humans,
ear region. The total release time for the six-layer coating the release of the drug from the coated particles was three
was twice that of the four-layer coating. Additionally, the and two times slower than from the film-coated particles.
initial burst for the six-layer capsules lasted for a shorter At pH 4.1 the dissolution time of film-coated drug was
amount of time than that for the thinner coatings, and 1.9 h (114 min) compared to 3.5 h for the coated drug. At
the slow release part of the curve was nearly linear in time pH 1.4, similar to the pH of the stomach, the coated drug
(Fig. 4). Because the half-release time of the six-layer dissolved within 5 h. The release of drug from the coated
microcapsules was much longer than that for the uncoated particles (Fig. 6) was also 2.5 times as slow as that from
particles, it should be possible to use the encapsulation to a ketoprofen tablet (Profenid 100 mg film-coated tablets,
design controlled-release microdevices. Aventis) and not significantly different from that of
 A.I. Arida, M.M. Al-Tabakha / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 48–54 53

1.0
0.9

Fraction of Drug Released

0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1 2 3 4 5 6
Time (Hours)

Fraction of Drug Released (0.1 M HCl) Fraction of Drug Released (Buffer pH 4.1)

Fraction of Drug Released (Profenid Retard at pH 4.1) Fraction of Drug Released (Profenid Film-Coated at pH 4.1)

Fraction of Drug Released (Profenid Film-Coated at pH 7.4)

Fig. 6. Dissolution profiles of (PSS/PDDA)2 + (PSS/gelatin)4 coated ketoprofen microparticles compared to film-coated ketoprofen tablets and sustained
released ketoprofen commercially available tablets in physiologically relevant media.

commercially available controlled release tablets (Profenid In comparison with other traditional methods of drug
SR 200 mg). However, LbL-coated microparticles are delivery, the method described here has the following
much smaller. To elucidate the difference between the SR, advantages: (i) the wall thickness and diameter of the
LbL and the film-coated ketoprofen at pH 4.1, ANOVA microcapsule can be varied with a precision; (ii) the capsule
test was performed. The test indicated that they are signif- wall architecture can be designed in a wide variety of ways
icantly different with actual p value equal to 0.007. Further and can include polymers, lipids, enzymes, DNA and inor-
analysis to find the differing group indicated that while ganic nanoparticles [5,15–17,26,30,31]; (iii) attachment of
Profenid film-coated are significantly different from both antibodies or antigens will allow targeting of capsules [4].
Profenid Retard (p = 0.015) and the gelatin microencapsu- Typically a polymer:drug mass ratio of 10:1 is used in the
lated ketoprofen (p = 0.0012), the latter two did not show preparation of a polymer-based drug-delivery system
significant difference from each other (p 6 0.05). [8,32], and in this work a 0.20 was obtained.
An important aspect of the current study is the use of gel-
atin for capsule formation. In previous work [10,16] it was 4. Conclusion
not possible to substantially increase the release time of ibu-
profen using dextran sulfate/chitosan capsules. In another Sustained drug release was achieved by 6-lm ketoprofen
study [15], a fluorescent compound coated with poly(allyla- particles micro-encapsulated with 41–111 nm thick gelatin/
mine)/poly(styrenesulfonate)4–8 capsules resulted in small polyanion multilayer shells. This shell composition was a
increases in release time compared with bare fluorescein substantial improvement over shells constructed from
dye microcrystals. Ai et al. [28] tried to encapsulate Furose- poly(allylamine) or chitosan, and provided up to 107 times
mide microcrystals with polyions to control the release of the slower release time, when compared with dissolution of
drug in aqueous solutions through LbL assembly. The conventional ketoprofen particles.
release rate of furosemide from the encapsulated particles
was reduced compared to uncoated furosemide. Acknowledgement
Klitzing and Mohwald [29] found that rhodamine
diffusion through (PSS/PAH)8 multilayers was much The authors gratefully acknowledge the support from
slower when the layers were deposited in the presence of the Deanship of Scientific Research and Higher education
1 M NaCl than it was when they were deposited in pure at Philadelphia University of Jordan, without which this
water which is a strongly charged polyion. Klitzing and work could not be done.
Mohwald results were similar to the finding of this work.
In this work, gelatin A was used. It is a weak polybase with References
isoelectric point around pH 8; therefore it has a small posi-
tive charge at pH 7.4. Nevertheless the multilayer capsule is [1] J.W. Hoftiezer, G.R. Silvoso, M. Burks, K.J. Ivy, Comparison of the
effect of regular and enteric-coated aspirin on gastroduodenal mucosa
stable and even less permeable at this pH than at a pH of
of man, Lancet 2 (1980) 609–612.
1.4, where both PSS and gelatin are strongly charged. Gel- [2] F.L. Lanza, G.L. Royer, R.S. Nelson, Endoscopic evaluation of the
atin B has an isoelectric point of 5 therefore it was not used effects of aspirin, buffered aspirin, and enteric-coated aspirin on
in this work. gastric and duodenal mucosa, N. Engl. J. Med. 303 (1980) 136–138.
54 A.I. Arida, M.M. Al-Tabakha / European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 48–54

[3] R.I. Trondstad, E. Aadland, T. Holler, B. Olassen, Gastroscopic [19] T.G. Kantor, Ketoprofen: a review of its pharmacologic and clinical
findings after treatment with enteric-coated and plain naproxen tablets properties, Pharmacotherapy 6 (1986) 93–103.
in healthy subjects, Scand. J. Gastroenterol. 20 (1985) 239–242. [20] G.W. Houghton, M.J. Dennis, E.D. Rigler, R.L. Parsons, Compar-
[4] H. Ai, M. Fang, S. Jones, Y. Lvov, Electrostatic layer-by-layer nano- ative pharmacokinetics of ketoprofen derived from single oral doses
assembly on biological microtemplates: platelets, Biomacromolecules of ketoprofen capsules or a novel sustained-release pellet formulation,
3 (2002) 560–564. Biopharm. Drug. Dispos. 5 (1984) 203–209.
[5] M. Fang, P. Grant, M. McShane, G. Sukhorukov, V. Golub, Y. [21] K.A.E. Khodairy, A.G. Eshra, A.H. Nada, S.A.M. Mortada,
Lvov, Magnetic bio/nanoreactor with multilayer shells of glucose Preparation and in vitro evaluation of slow release ketoprofen
oxidase and inorganic nanoparticles, Langmuir 18 (2002) 6223– microcapsules formulated into tablets and capsules, J. Microencap-
6229. sulation 9 (1992) 365–373.
[6] K. Leong, B. Brott, R. Langer, Bioerodible polyanhydrides as drug- [22] R.L. Savage, P.W. Moller, C.L. Ballantyne, J.E. Wells, Variation
carrier matrices. I: Characterization, degradation, and release char- in the risk of peptic ulcer complications with nonsteroidal
acteristics, J. Biomed. Mater. Res. 19 (1985) 941–955. antiinflammatory drug therapy, Arthritis Rheum. 36 (1993)
[7] D. Spragg, D. Alford, R. Greferath, C. Larsen, K. Lee, G. Gurtner, 84–90.
M. Cybulsky, P. Tosi, C. Nicolau, M. Gimbrone, Immunotargeting [23] B. Toft, J. Christophersen, N. Christensen, G. Hesselsoe, S. Mikkel-
of liposomes to activated vascular endothelial cells: strategy for site- sen, T. Aaboe, K. Mose, T. Thorsager, G. Jakobsen, A double-blind,
selective delivery in the cardiovascular system, Proc. Natl. Acad. Sci. crossover study of a sustained-release tablet of ketoprofen and
USA 94 (1997) 8795–8800. normal ketoprofen capsules in the treatment of patients with
[8] V. Junyaprasert, A. Mitrevej, N. Sinchaipanid, P. Boonme, D. osteoarthritis, Curr. Med. Res. Opin. 9 (1985) 708–712.
Wurster, Effect of process variables on the microencapsulation of [24] G.R. Hanson, Analgesic, Antipyretic, and Anti-inflammatory Drugs,
vitamin A palmitate by gelatin–acacia coacervation, Drug. Dev. Ind. in: A.R. Gennaro, A.H. Der Marderosian, G.R. Hanson, T.
Pharm. 27 (2001) 561–566. Medwick, N.G. Popovich, R.L. Schnaare, J.B. Schwartz, H.T. White
[9] G. Decher, Fuzzy nanoassemblies: toward layered polymeric multi- (Eds.), Remington: The Science and Practice of Pharmacy, Lippincott
composites, Science 227 (1997) 1232–1237. Williams & Wilkins, USA, 2000, p. 1458.
[10] Y. Lvov, G. Decher, H. Möhwald, Assembly, structural character- [25] G. Sauerbrey, Verwendung von Schwingquartzen zur Wägung
ization and thermal behavior of layer-by-layer deposited ultrathin dünner Schichten und zur Mikrowägung, Z. Physik. 155 (1959)
films, Langmuir 9 (1993) 481–486. 206–218.
[11] S. Keller, H.-N. Kim, T. Mallouk, Layer-by-layer assembly of [26] Y. Lvov, K. Ariga, I. Ichinose, T. Kunitake, Assembly of multicom-
intercalation compounds and superlattices on surfaces: towards ponent protein films by means of electrostatic layer-by-layer adsorp-
molecular ‘beaker’ epitaxy, J. Am. Chem. Soc. 116 (1994) 8817–8821. tion, J. Am. Chem. Soc. 117 (1995) 6117–6123.
[12] J. Schlenoff, Redox-active polyelectrolyte multilayers, Adv. Mater. 10 [27] The United States Pharmacopeia 24 and National Formulary 19,
(1998) 347–351. United States Pharmacopeial Convention Inc., Rockville, MD, 2000.
[13] D. Sullivan, M. Bruening, Ultrathin, ion-selective polyimide mem- [28] H. Ai, S.A. Jones, M.M. de Villiers, Y.M. Lvov, Nano-encapsulation
branes prepared from layered polyelectrolytes, J. Am. Chem. Soc. 123 of furosemide microcrystals for controlled drug release, J. Controlled
(2001) 11805–11806. Release 86 (2003) 59–68.
[14] J. Mendelson, C. Barrett, V. Chan, A. Pal, A. Mayes, M. Rubner, [29] R. van Klitzing, H. Mohwald, A realistic diffusion model for
Fabrication of microporous thin films from polyelectrolyte multilay- ultrathin polyelectrolyte films, Macromolecules 29 (1996) 6901–
ers, Langmuir 16 (2000) 5017–5023. 6906.
[15] A. Antipov, G. Sukhorukov, E. Donath, H. Möhwald, Sustained [30] S. Moya, E. Donath, G. Sukhorukov, M. Auch, H. Bäumler, H.
release properties of polyelectrolyte multilayer capsules, J. Phys. Lichtenfeld, H. Möhwald, Lipid coating on polyelectrolyte surface
Chem. B 105 (2001) 2281–2284. modified colloidal particles and polyelectrolyte capsules, Macromol-
[16] X. Qiu, S. Leporatti, E. Donath, H. Möhwald, Studies on the drug ecules 33 (2000) 4538–4544.
release properties of polysaccharide multilayer encapsulated ibupro- [31] F. Caruso, R. Caruso, H. Möhwald, Fabrication of hollow, spherical
fen microparticles, Langmuir 17 (2001) 5375–5380. silica and composite shells via electrostatic self-assembly of nano-
[17] Y. Lvov, F. Caruso, Biocolloids with ordered urease multilayer shells composite multilayers on decomposable colloidal templates, Science
as enzymatic reactors, Anal. Chem. 73 (2001) 4212–4217. 282 (1998) 1111–1114.
[18] Y. Lvov, A. Antipov, A. Mamedov, H. Möhwald, G. Sukhorukov, [32] D. Burgess, Macromolecular Complexes, in: P. Dubin, J. Block, R.
Urease encapsulation in nanoorganized microshells, Nano Lett. 1 Davies, D. Schulz, C. Thies (Eds.), Chemistry and Biology, Springer,
(2001) 125–128. Berlin, 1995, pp. 285–324.