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A floating-type oral dosage form for piroxicam based on hollow

polycarbonate microspheres: In vitro and in vivo evaluation in rabbits

Article in Journal of Controlled Release · March 2002

DOI: 10.1016/S0168-3659(01)00507-7 · Source: PubMed

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 Journal of Controlled Release 79 (2002) 71–79
www.elsevier.com / locate / jconrel

A floating-type oral dosage form for piroxicam based on

hollow polycarbonate microspheres: in vitro and in vivo
evaluation in rabbits
N.J. Joseph, S. Lakshmi, A. Jayakrishnan*
Polymer Chemistry Division, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology,
Satelmond Palace Campus, Trivandrum 695 012, India

Received 9 May 2001; accepted 12 September 2001

Abstract

A floating type dosage form (FDF) of piroxicam in hollow polycarbonate (PC) microspheres capable of floating on
simulated gastric and intestinal fluids was prepared by a solvent evaporation technique. Incorporation efficiencies of over
95% were achieved for the encapsulation. In vitro release of piroxicam from PC microspheres into simulated gastric fluid at
378C showed no significant burst effect. The amount released increased with time for about 8 h after which very little was
found to be released up to 24 h. In intestinal fluid, the release was faster and continuous and at high drug payloads, the
cumulative release reached above 90% in about 8 h. In vivo evaluation of different dosage forms of piroxicam such as free
drug, drug-encapsulated microspheres and microspheres along with a loading dose of free drug in rabbits showed multiple
peaking in the plasma concentration–time curve suggesting enterohepatic recirculation of the drug. Pharmacokinetic analysis
showed that the bioavailability from PC microspheres alone was about 1.4 times that of the free drug and it was about 4.8
times for the dosage form consisting of the microspheres plus the loading dose. The elimination half life was increased by
about three times for the microsphere preparation alone and nearly about six times for the dosage form comprising of
microspheres and a loading dose in comparison to the free drug. Data obtained in this study demonstrated that FDF of
piroxicam in PC microspheres was capable of sustained delivery of the drug for longer periods with increased bioavailability.
 2002 Elsevier Science B.V. All rights reserved.

Keywords: Hollow microsphere; Polycarbonate microsphere; Floating type dosage forms (FDFs); Piroxicam; Sustained release; Rabbits;
Oral delivery

1. Introduction of drug delivery have been receiving much attention

in recent years [1]. Although the oral route is the
Oral dosage forms capable of having prolonged most convenient and commonly employed form of
retention time in the stomach to extend the duration drug delivery, an oral sustained release formulation
is subjected to frequently changing environments in
*Corresponding author. Tel.: 191-471-340901; fax: 191-471- the gastrointestinal (GI) tract. During its transit, it
341814. passes from the strongly acidic gastric part to the
E-mail address: [email protected] (A. Jayakrishnan). weakly alkaline intestinal part of the digestive sys-

0168-3659 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved.
PII: S0168-3659( 01 )00507-7
72 N. J. Joseph et al. / Journal of Controlled Release 79 (2002) 71 – 79

tem. Also, since the stomach emptying time varies released within 10 days [16]. The encapsulation of
from patient to patient, there is variation in the piroxicam in liposomes produced an increase in
amount of drug absorbed. Such drawbacks put topical anti-inflammatory effect, suggesting that the
constraints on the development of a sustained release inhibition of inflammation can be obtained with
oral drug delivery system. Many approaches have lower drug concentrations [17]. Pectin microspheres
been investigated to prolong GI transit of oral dosage as delivery system for piroxicam was evaluated for
forms. The development of bioadhesive polymers ocular delivery and in vivo tests in rabbits indicated
that adhere to the mucin-epithelial surface of the GI a significant improvement of drug bioavailability in
tract as drug carriers is one such approach to prolong the aqueous humor when compared with commercial
the GI transit time [2–4]. piroxicam eyedrops [18]. Positively charged submic-
Another approach to increase the gastroretention ron emulsion formulation of piroxicam has been
has been to employ floating type dosage forms reported to have a pronounced effect on both the
(FDFs) which remain buoyant due to their having a ulceration rate and epithelial defects in the manage-
lower density than the gastric and intestinal fluids. ment of corneal alkali-burning [19]. This study was
Both single and multiple unit systems have been undertaken in order to examine the potential of
developed [5–11]. Multiple unit systems such as hollow polycarbonate microspheres as a FDF for
microspheres capable of floating on the gastric fluid piroxicam.
have the advantage they are not subjected to ‘all or
nothing’ gastric emptying nature of single unit
systems [9]. Drug-loaded polymeric microspheres 2. Materials and methods
and ion-exchange beads capable of floating on the
gastric fluids have therefore been examined as FDFs 2.1. Materials
[9–11]. In an earlier communication [12], we
showed that microspheres prepared by a solvent Piroxicam U.S.P. was obtained from IPCA Lab-
evaporation method from a dichloromethane solution oratories (P) Ltd. (Mumbai, India). Polycarbonate
of biocompatible Bisphenol A-carbon dioxide-based (PC) based on Bisphenol A-carbon dioxide and
polycarbonate are capable of floating on the gastric poly(vinyl alcohol) (PVA, MW 125 000 Da) were
fluids. It was shown that the rapid evaporation of from BDH (Poole, UK). All other chemicals and
dichloromethane from the dispersion produces reagents were of the highest purity available from
cavities and pores in the microspheres which render local sources. Simulated gastric and intestinal fluids
them hollow and floating in nature. were freshly prepared according to the US Phar-
Nonsteroidal anti-inflammatory drugs (NSAIDs) macopoeia.
are well known for their gastrotoxic and duodenotox-
ic effects [13]. A growing proportion of elderly 2.2. Methods
patients require NSAID therapy for the treatment of
osteoarthritis or rheumatoid arthritis. Piroxicam ex- 2.2.1. Preparation of piroxicam-loaded PC
hibits better toleration than indomethacin, naproxen, microspheres
and enteric-coated acetylsalicylic acid [14]. Pirox- Floating type PC microspheres loaded with pirox-
icam has been encapsulated in poly(lactic acid) icam were prepared by the method reported earlier
microspheres by a solvent evaporation method and a [12]. Briefly, 4 ml of a 25% PC solution in dichloro-
spray-drying method [15,16]. The in vitro release of methane was mixed well with the required amount of
the drug from the microspheres prepared by the the drug and the pasty flowable mass was introduced
solvent evaporation method was reported to be into 50 ml of 20% sodium chloride solution con-
biphasic in nature and rapid with a burst effect [15]. taining 0.04% PVA and 5% methanol while the
On the other hand, microspheres prepared by the system was stirred using a half-moon paddle stirrer
spray-drying technique showed very slow release at 300 (610%) rev. / min at room temperature.
profile with less than 10% of the incorporated drug Stirring was continued till all the solvent evaporated
being released in the first 50 h and less than 20% (|2 h) and the floating drug-loaded particles were
 N. J. Joseph et al. / Journal of Controlled Release 79 (2002) 71 – 79 73

filtered and washed with distilled water and dried in male albino rabbits weighing 2.2–2.5 kg. Nine
an air oven at 608C overnight. rabbits were divided into three groups and were
fasted for 24 h. One batch was fed with 20 mg
2.2.2. Entrapment efficiency of piroxicam in PC piroxicam powder in a gelatin capsule, the second
microspheres batch was given 67% piroxicam-loaded PC micro-
In an Erlenmeyer flask, 10 mg of piroxicam- spheres equivalent to 20 mg of piroxicam and the
loaded PC microspheres was accurately weighed and third batch was given 7 mg of piroxicam powder
dissolved in 2 ml of dichloromethane following along with 67% piroxicam-loaded microspheres
which 50 ml of 2 M hydrochloric acid was intro- equivalent to 20 mg. Water was given ad libitum
duced, the flask stoppered and stirred magnetically during fasting and throughout the experiment. Blood
for 6 h. After evaporation of dichloromethane com- samples, 2 ml were collected from the marginal ear
pletely at 608C, the solution was filtered and the vein into heparinized centrifuge tubes just before
absorbance of the filtrate was read at 354 nm [20] at dosing and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10 and 24 h
appropriate dilution using 2 M HCl as blank in a during the study. Blood samples were centrifuged at
UV–visible spectrophotometer (Milton-Roy, Gen- 1500 rev. / min and the plasma was separated. One
esys 2, USA). undosed plasma sample was kept as blank. To 1 ml
each of the other plasma samples, 5 ml of acetoni-
2.2.3. Size distribution of microspheres trile was added. The tubes were then centrifuged at
Size distribution of the microspheres was deter- 2500 rev. / min for 15 min, 4 ml of the supernatant
mined using standard test sieves (Filterwel, Mumbai, was pipetted out to which 0.2 ml of 1.47 M
India). Particles which passed through one sieve but perchloric was added and drug concentration was
were retained on the other were collected and determined by UV spectroscopy at 330 nm as
weighed and the distribution was analyzed based on validated by earlier workers [21]. The blank con-
the weight fraction on each sieve. sisted of 1 ml of undosed plasma, 4 ml of acetonitrile
and perchloric acid.
2.2.4. Surface morphology The calibration curve for piroxicam was con-
Surface morphology of the microspheres was structed as follows. Piroxicam solutions in acetoni-
examined by scanning electron microscopy in a trile were prepared at concentrations of 1, 2, 4, 6 and
Hitachi instrument (Model S-2400, Japan) after 8 mg / ml. One milliliter of this solution was made up
vacuum sputtering the particles with gold. to 5 ml using acetonitrile. To each of these solutions,
1 ml of plasma from undosed rabbit blood was added
2.2.5. In vitro dissolution studies and the contents centrifuged at 2500 rev. / min for 15
In vitro dissolution studies were carried out in a min. Supernatant 4 ml was then pipetted out to
USP paddle type dissolution assembly. Piroxicam- which 0.2 ml of 1.47 M perchloric acid was added
loaded PC microspheres, 50 mg was introduced into and the absorbance was measured at 330 nm. The
900 ml of the dissolution medium and stirred at 100 blank was prepared using plasma from the undosed
rev. / min at 378C. At different time intervals, 1 ml of animal, acetonitrile and perchloric acid in exactly the
the solution was withdrawn and was made up to 5 ml same way. The calibration curve for piroxicam
and the absorbance was read at 354 nm. An equal plotted as absorbance at 330 nm versus concentration
volume of the medium was introduced into the was linear over the range of 1–8 mg / ml with a
container after each withdrawal to maintain a con- correlation coefficient of 0.9996.
stant volume. The dissolution studies were repeated
three times in simulated gastric and intestinal fluids. 2.2.7. Pharmacokinetic analysis
The mean values are plotted as percent cumulative Pharmacokinetic parameters were derived from the
release versus time. plasma concentration versus time plot. The area
under the curve (AUC), the peak concentration
2.2.6. In vivo studies (Cmax ) and the time to attain peak concentration
The in vivo studies were conducted in healthy (T max ) were obtained from such plots. The elimina-
74 N. J. Joseph et al. / Journal of Controlled Release 79 (2002) 71 – 79

tion rate constants k el for the different dosage forms medium, the amount of stabilizer employed, etc.
were determined from the semi-logarithmic plot of Therefore, it would be possible to prepare hollow PC
plasma concentration versus time. k el was calculated microspheres of desired size by varying some of
from the terminal linear portion of the curve using these parameters.
linear regression analysis. Elimination half-lives t 1 / 2 Fig. 3 shows the cumulative release of piroxicam
were calculated by dividing 0.693 by the elimination from PC microspheres of three different loadings
rate constant [22]. into simulated gastric fluid at 378C. There is no
significant burst effect from any of the preparations.
Guiziou et al. have reported significant burst release
3. Results and discussion of the drug from poly(lactide) microspheres prepared
by solvent evaporation [15]. The release is faster
Piroxicam-loaded PC microspheres prepared by from microspheres having a higher drug payload.
the solvent evaporation method were predominantly The drug / polymer ratio of microspheres having high
spherical in appearance, although some were found drug payloads is large and therefore the hindrance to
to be elongated. The particles floated on both simu- diffusion of the drug from the polymer matrix would
lated gastric and intestinal fluids. The porous nature be rather low making the diffusion facile at high
of the microspheres was evident by SEM examina- loadings which is reflected in the faster release. At
tion (Fig. 1a). As can be seen in the micrograph, all loadings tested, the amount released with respect
there were many large pores and cavities in the to time increases for about 8 h after which very little
microspheres which made them float on the simu- is found to be released up to 24 h. In the case of
lated fluids. The pores and cavities in the micro- intestinal fluid, the release is faster in comparison to
spheres were formed by the rapid evaporation of the release in the gastric fluid and at 59 and 67%
dichloromethane. Fig. 1b shows the surface morphol- loadings, the cumulative release reached above 90%
ogy of the microsphere at a higher magnification in about 8 h (Fig. 4). Release from the microspheres
after the incorporated drug has been completely having only 38% drug was found to be slow in this
washed off. The rough and porous nature of the medium although there appears to be continuous
microsphere matrix is evident from the photomicrog- release up to 24 h unlike in gastric fluid. Piroxicam
raph demonstrating that the diffusion of the incorpo- has poor aqueous solubility. Being a weakly acidic
rated drug will be highly facile from the microsphere drug having a pKa of 6.3, at the pH of simulated
matrix. gastric fluid (pH 1.2), the extent of ionized drug is of
The incorporation efficiency of piroxicam was the order of 2.5310 26 . At the pH of intestinal fluid
found to be good at all loadings. Table 1 gives the (pH 7.5), the ratio of ionized to unionized is of the
incorporation efficiency at the three different load- order of 15.1. The poor ionization in gastric fluid
ings examined. The high entrapment efficiency of the would account for the incomplete release seen in this
drug is believed to be due to its poor aqueous medium as opposed to intestinal fluid. The solubility
solubility. Fig. 2 shows the particle size distribution of piroxicam is known to increase rapidly with pH
of piroxicam-loaded PC microspheres. The extent of values above the pKa of the drug [23].
loading appears to influence the particle size dis- Fig. 5 shows the release profile of piroxicam from
tribution of microspheres. When the loading is high, 67% loaded PC microspheres for 3 h in simulated
the proportion of larger particles formed is also high. gastric fluid followed by release in intestinal fluid.
With 67% loading, most of the particles were in the This experiment was performed because multiple-
size range of 600–1200 mm suitable for oral ad- unit FDFs are known to have prolonged residence
ministration. The viscosity of the polymer solution at time in the stomach. For instance, it is reported that
such high drug loadings is very high and is respon- floating alginate beads have a residence time of 5.5 h
sible for the formation of large microspheres. The vis-a-vis 1 h for their non-floating counterparts [9]. If
size of the microspheres formed is however, a one were to presume that the residence time is
function of many factors such as stirring speed, increased by three times, this experiment gives some
viscosity of the dispersed phase and dispersion idea of the extent of release that takes place in the
 N. J. Joseph et al. / Journal of Controlled Release 79 (2002) 71 – 79 75

Fig. 1. SEM of polycarbonate microspheres containing 67% piroxicam showing pores and cavities in the matrix (a) and surface morphology
of the microsphere after washing off the incorporated drug (b).

poorly absorbed gastric tract. Of course, the exact the intestinal tract. The total absorptive area of the
residence time of the present dosage form in the small intestine is about 200 m 2 while the estimates
gastric and intestinal regions has not been deter- for stomach are only about 1 m 2 [22]. The absorption
mined, but the data demonstrate that only about a of drugs is therefore maximum in the intestinal
quarter of the drug incorporated would be released in region. There is a continuous increase in the release
the gastric tract depending on the gastric emptying of the entrapped drug in the intestinal fluid and it
time and the rest would be available for release in took 5 h for almost all of the remaining 75% of the
76 N. J. Joseph et al. / Journal of Controlled Release 79 (2002) 71 – 79

Table 1
Incorporation efficiency of piroxicam in hollow polycarbonate
microspheres
Drug Theoretical Actual Incorporation
content (%) content (%) efficiency (%)
Piroxicam 40 38.6 96.6
60 59.1 98.0
70 67.2 96.0

drug to be released into this medium. Determination

of the dissolution rate of piroxicam powder in
simulated intestinal fluid showed that the dissolution
was rapid with over 80% dissolving in 30 min. The
sustained release seen from the microsphere formula-
tion lasting up to 5 h is therefore noteworthy. Since
the floating microspheres are not expected to be
emptied into the small intestine from the stomach in
a single event, the time available for absorption in
the intestine could even be prolonged beyond 5 h as
seen in vitro.
The in vivo evaluation of the different dosage
forms of piroxicam was conducted in rabbits. Rabbit
has been chosen as the model since there have been
many bioavailability studies of piroxicam using this Fig. 3. Cumulative release of piroxicam from polycarbonate
animal model [24]. Fig. 6 shows the plot of plasma microspheres of three different loadings into simulated gastric
concentration of the drug versus time for different fluid at 378C: 38% loaded (m), 59% loaded (.) and 67% loaded
dosage forms with values listed in Table 2. The peak (j).
plasma concentration (Cmax ) for piroxicam powder
was found to be 3.9 mg / ml and time to attain the peak concentration (T max ) was 6 h. In the case of PC
microspheres, the Cmax was 2.7 mg / ml and T max was
8 h. In the case of microspheres given along with the
loading dose of 7 mg of piroxicam powder the Cmax
and T max were 4.3 mg / ml and 8 h, respectively. As
can be seen from the plot, there is dose dumping in
the case of free drug as well as from the dosage form
consisting of microspheres and loading dose. With
microspheres alone, the mean plasma concentration
is well below 3 mg / ml throughout the study period.
As expected, the microspheres given along with the
loading dose show a higher plasma concentration
compared to the microspheres alone. The fall in
concentration in the case of piroxicam powder after
peaking is rather sharp whereas the other two dosage
forms exhibit fairly steady release rates and the fall
in concentration is less rapid. Multiple peaking in the
Fig. 2. Particle size distribution of piroxicam-loaded polycarbo- plasma concentration–time curve suggests en-
nate microspheres: 38% loaded (A), 59% loaded (B) and 67% terohepatic recirculation of the drug. Although,
loaded (C). continuous release is seen in both fluids in vitro,
 N. J. Joseph et al. / Journal of Controlled Release 79 (2002) 71 – 79 77

Fig. 6. Plot of plasma concentration of piroxicam versus time for

the three different dosage forms. Piroxicam powder 20 mg (j),
67% piroxicam-loaded microspheres equivalent to 20 mg pirox-
icam (m) and 7 mg piroxicam powder plus 67% loaded micro-
spheres equivalent to 20 mg piroxicam (n).

Fig. 4. Cumulative release of piroxicam from polycarbonate piroxicam is highly bound to plasma proteins in vivo
microspheres of three different loadings into simulated intestinal and therefore the release profile seen in vivo is
fluid at 378C: 38% loaded (n), 59% loaded (,) and 67% loaded
(h).
different. Such multiple peaking has been observed
by earlier workers in clinical studies as piroxicam is
known to be eliminated to a large extent through the
biliary route [25,26]. Piroxicam is a drug with a long
elimination half life and is rapidly and fully absorbed
in man. The recommended dose of piroxicam in
adults is 20 mg daily and the mean plasma con-
centration attained is reported to be about 2 mg / ml
after single dose and a steady state concentration of
about 6 mg / ml is sustained with 20 mg daily for
effective therapy [25]. However, elimination is im-
paired in some elderly patients, resulting in a high
interindividual variability in the steady state levels
following the standard 20 mg / daily dosage regimen
[27]. Sustained release dosage forms capable of
steady release of the drug over prolonged periods
may therefore prove beneficial to overcome such
variability due to erratic elimination of the drug. As
can be seen in the case of microspheres and par-
ticularly with the dosage form consisting of micro-
spheres with loading dose, a higher plasma con-
centration is maintained throughout the study period.
The pharmacokinetic parameters estimated are
Fig. 5. In vitro release profile of piroxicam from 67% loaded
given in Table 1. The area under the curve AUC 0 – `
polycarbonate microspheres into simulated gastric fluid for 3 h was calculated from the plasma concentration versus
followed by release into intestinal fluid at 378C. time plot using the relation,
78 N. J. Joseph et al. / Journal of Controlled Release 79 (2002) 71 – 79

Table 2
Mean pharmacokinetic parameters of piroxicam-containing floating type polycarbonate microspheres (MS) after oral administration in
rabbits
Sample Cmax T max k el AUC 0-` t1 / 2 Clearance
(mg / ml) (h) (h 21 ) (mg h / ml) (h) (ml / h)
Powder 20 mg 3.9 6 0.070 75.8 9.8 264
MS contg. 20 mg drug 2.7 8 0.024 107.3 28.9 186
MS contg. 20 mg drug17 4.3 8 0.012 364.5 56.8 74
mg powder

AUC 0-` 5 AUC 0-24 1 C /k el microspheres alone. FDFs of polymer microspheres

are not numerous in the literature unlike their non-
where C is the concentration at 24 h presuming floating counterparts and often special methods are
100% absorption since piroxicam is known to be required to produce such hollow spheres. The PC
readily and rapidly absorbed. Assessment of the area employed in this study generates hollow micro-
AUC 0 – ` showed that bioavailability was minimum spheres by the usual microencapsulation technique
for the free drug. The bioavailability of microspheres with excellent drug incorporation efficiency. There-
alone was about 1.4 times that of the free drug and it fore, multiple unit systems based on polycarbonate
was about 4.8 times for the dosage form consisting microspheres would be of significance as a FDF for
of the microspheres plus the loading dose. Elimina- sustained drug delivery by the oral route.
tion was less rapid with both microsphere dosage
forms in comparison to the free drug. The elimina-
tion half life for piroxicam powder was estimated to Acknowledgements
be 9.8 h as opposed to 28.9 h for the microspheres
alone and 56.8 h for microspheres given with the The authors thank the Director, SCTIMST for
loading dose (Table 2). This means that the elimina- permission to publish this manuscript. N.J.J. expres-
tion half life is increased by about three times for the ses his thanks to the Director for providing the
microsphere preparation alone and nearly about six necessary facilities to carry out the M. Pharm.
times for the dosage form comprising of micro- project at SCTIMST.
spheres and a loading dose in comparison to the free
drug. Estimation of clearance showed that the values
for free drug, microspheres and microspheres plus
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