Research in Pharmaceutical Sciences, April 2010; 5(1): 33-43 School of Pharmacy & Pharmaceutical Sciences

Received: Nov 2009 Isfahan University of Medical Sciences

Accepted: Feb 2010
Original Article

Development of theophylline floating microballoons using cellulose

acetate butyrate and/or Eudragit RL 100 polymers with different
permeability characteristics
M. Jelvehgari1,2, M. Maghsoodi1,2,* and H. Nemati1
1
Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, I.R.Iran.
2
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, I.R.Iran.

Abstract
The objective of the present investigation was to design a sustained release floating microcapsules of
theophylline using two polymers of different permeability characteristics; Eudragit RL 100 (Eu RL) and
cellulose acetate butyrate (CAB) using the oil-in-oil emulsion solvent evaporation method. Polymers were
used separately and in combination to prepare different microcapsules. The effect of drug-polymer
interaction was studied for each of the polymers and for their combination. Encapsulation efficiency, the
yield, particle size, floating capability, morphology of microspheres, powder X-ray diffraction analysis
(XRD), and differential scanning calorimetry (DSC) were evaluated. The in vitro release studies were
performed in PH 1.2 and 7.4. The optimized drug to polymer ratios was found to be 4:1 (F2) and 0.75:1 (F'2)
with Eu RL and CAB, respectively. The best drug to polymer ratio in mix formulation was 4:1:1
(theophylline: Eu RL: CAB ratio). Production yield, loading efficiencies, and particle size of F2 and F'2 were
found to be 59.14% and 45.39%, 73.93% and 95.87%, 372 and 273 micron, respectively. Microsphere
prepared with CAB showed the best floating ability (80.3 ± 4.02% buoyancy) in 0.1 M HCl for over 12 h.
The XRD and DSC showed that theophylline in the drug loaded microspheres was stable and in crystaline
form. Microparticles prepared using blend of Eu RL and CAB polymers indicated more sustained pattern
than the commercial tablet (P<0.05). Drug loaded floating microballoons prepared of combination of Eu RL
and CAB with 1:1 ratio were found to be a suitable delivery system for sustained release delivery of
theophylline which contained lower amount of polymer contents in the microspheres.

Keywords: Theophylline; Eudragit RL100; Cellulose acetate butyrate; Microparticles; Emulsion-solvent

evaporation

INTRODUCTION Conventional oral dosage forms do not offer

any control over drug delivery and cause great
Floating systems are low-density systems fluctuations in plasma drug concentrations.
having sufficient buoyancy to float over the Single unit dosage forms have the disadvan-
gastric contents and remain in the stomach for tage of a release all-or-nothing emptying
a prolonged period of time. While the system process, while the multiple unit particulate
floats over the gastric contents, the drug is systems pass uniformly through the GIT to
released slowly at the desired rate, which avoid the variation of gastric emptying and
results in increased gastro-retention time and thus release the drug more uniformly (3-5).
reduced fluctuation in plasma drug The uniform distribution of these multiple unit
concentration (1). Gastric emptying of dosage dosage forms along the GIT could result in
forms is extremely variable process to the more reproducible drug absorption and
extent that prolonging and controlling the reduced risk of local irritation; this gave rise to
emptying time is considered as a valuable oral controlled drug delivery and led to
asset of dosage forms which can reside in the development of gastro-retentive floating
stomach for a long period of time (2). microspheres (5).

*Corresponding author: Maryam Maghsoodi

Tel. 0098 411 3392608, Fax. 0098 411 3344798
Email: mmaghsoodi@ymail.com
M. Jelvehgari et al. / RPS 2010; 5(1): 33-43

To prepare floating microspheres both method, spraying-drying method and extrusion

natural and synthetic polymers have been method (17).
used. Kawashima et al. prepared hollow In current study, an emulsion-solvent
microspheres or microballoons of ibuprofen diffusion/evaporation technique was used to
using acrylic polymers by the emulsion- prepare a floating sustained-release system of
solvent diffusion method (6). Popular polymer theophylline. The influence of several factors
solution systems that have been described in on various physical characteristics, including
previous works to prepare floating micros- particle size, drug loading, dissolution and
pheres are polycarbonate/dichloromethane floating properties of the resulting micro-
(7,8), Eudragit S100/i-propanol (9) and spheres were investigated.
CAB/Eu RL mixture in acetone (10).
Moreover, methylcellulose and chitosan MATERIALS AND METHODS
micropellets loaded with lansoprazole showed
better encapsulation efficiencies with a lower Theophylline (Merck, Germany), Eudragit
density than gastric contents (11). RL 100 (RÖhm Pharma GMBh, Weiterstadt,
Srivastava et al. reported cimetidine-loaded Germany), cellulose acetate butyrate (17%
floating microspheres of hydroxypropyl butyryl, 29% acetyl and 1.5% hydroxyl
methylcellulose and ethyl cellulose (12). The contents, Aldrich, USA), Sucrose stearate
prepared microspheres exhibited prolonged (Crodesta F70) (Croda GmbH, Mettelal,
drug release (~8 h) and remained buoyant for Germany), Span 80 (sorbitan monolaurate),
>10 h (13). Sato et al. developed hollow Tween 80 (polysorbate 80), methanol, acetone,
microspheres or microballoons of riboflavin, liquid paraffin, n- hexane, n- heptanes,
aspirin, salicylic acid, ethoxybenzamide and hydrochloric acid, potassium dihydrogen
indomethacin using Eudragit S100 as enteric phosphate, sodium hydroxide (Merck,
polymer (14). Streubel et al. used polypro- Germany). All solvents and reagents were of
pylene foam powder as porous carrier for the analytical grade.
development of verapamil HCl-loaded floating
microparticles (15). Development and compa- Preparation of microparticles with Eu RL
rative study of Eu RL and CAB microspheres Microspheres were prepared by oil-in-oil
containing theophylline with/without the (O1/O2) emulsion solvent evaporation method
addition of surfactant to the internal phase using different ratios of theophylline to Eu RL
have been described in previous works (9). ratios (3:1, 4:1, and 5:1 as shown in Table 1).
Eu RL is a water-insoluble polymer and has A mixed solvent system consisting of acetone
been widely used in the microencapsulation as and methanol in a 2:1 ratio and light liquid
an enteric coating for tablets and capsules. paraffin were chosen as primary and secondary
Recently several workers have described using oil phases, respectively. Span 80 was used as
of Eu RL as a polymer employing aqueous or the surfactant for stabilizing the secondary oil
non- aqueous medium (16). The phase. The drug suspension was emulsified in
microencapsulation of drugs with CAB has a liquid paraffin/Span 80 solution under
been carried out successfully in either an stirring at 900 rpm (Model RZR-2000;
aqueous or an organic vehicle. The high Heidolph Electro, Kelheim, Germany) for 2 h.
permeability of Eu RL gives the initial burst Then 50 ml of n-hexane (non-solvent) was
release, which is desirable from therapeutic added to harden the microspheres and stirring
point of view. CAB polymer exhibit slower was continued for a further 1 h and the
rate of in vitro drug release initiated by lag hardened microspheres were collected by
time, which reduces the plasma drug filtration and washed with three portions of 50
fluctuations, as seen in conventional tablet ml of n-hexane and purified water air dried for
dosage forms. There are several methods 12 h. All microsphere formulations were
available which may be employed in the prepared in triplicate.
microencapsulation with CAB and Eu RL:
they include coacervation-phase separation

34
 Development of theophylline floating microballoons...

Table 1. Theophylline microsphere containing Eudragit RL formulations prepared by solvent evaporation method
(o1/o2)
Emulsion (O1/O2)
Drug: Internal organic phase (O1) External oily phase (O2)
Formulations Polymer
methyl Liquid
ratio Theophylline Eudragit RL100 acetone Span 80
alcohol paraffin
(g) (g) (ml) (%w/w)
(ml) (ml)
F1 3:1 1.5 0.5 7 3.5 70 1
F2 4:1 2 0. 5 7 3.5 70 1
F3 5:1 2.5 0.5 7 3.5 70 1

Table 2. Theophylline microsphere containing cellulose acetate butyrate formulations prepared by solvent evaporation
method (o1/o2)
Emulsion (O1/O2)
Drug: Internal organic phase (O1) External oily phase (O2)
Formulations Polymer Cellulose acetate
ratio Theophylline acetone Liquid paraffin Ester sucrose
butyrate
(g) (ml) (ml) (%w/w)
(g)
F'1 0.5:1 0.5 1 15 125 1.5
F'2 0.75:1 0.75 1 15 125 1.5

F'3 1:1 1 1 15 125 1.5

Preparation of microparticles with CAB solidify the microspheres and was stirred for 1
Microspheres were prepared by oil-in-oil more h to allow complete evaporation of
(O1/O2) emulsion solvent evaporation method acetone. Microspheres were separated by
using different ratios of theophylline to CAB filtration and washed thrice with 50 ml of n-
(0.5:1, 0.75:1 and 1:1) as shown in Table 2. hexane and purified water and air dried for 12
Theophylline was dispersed in acetone h. All microsphere formulations were prepared
(polymer solvent) containing CAB. The drug in triplicate.
suspension was emulsified in a liquid
paraffin/ester sucrose solution under stirring at Buoyancy percentage
400 rpm (Model RZR-2000; Heidolph Electro, The amount of 200 mg microspheres were
Kelheim, Germany) for 1 h in an ice bath. spread over the surface of a USP dissolution
Then microspheres were collected, washed apparatus (type II) filled with 900 ml 0.1 M
three times with 30 ml n-heptane to remove acidic solution (HCl) containing 0.02% Tween
any remaining oily phase, air-dried for 12 h to 80 (18). The medium was agitated with a
obtain discrete microspheres. All microsphere paddle rotating at 100 rpm for 12 h. The
formulations were prepared in triplicate. floating and the settled portions of micro-
spheres were recovered separately. The
Preparation of microparticles with CAB:Eu microspheres were dried and weighed. The
RL combination buoyancy percentage was calculated by the
Microspheres were prepared using oil-in-oil following formula:
(O1/O2) emulsion solvent evaporation method % buoyancy of microspheres = (weight of
using theophylline to CAB and Eu RL ratio floating microspheres/initial weight of floating
(4:1:1). The drug polymer dispersions microspheres) × 100
completely dissolved in 10 ml acetone and
were then slowly introduced into 75 ml liquid Determination of percent loading efficiency
paraffin previously added with 1% Span 80, and production yield
while stirring at 900 rpm for 2 h. Then, 50 ml To 20 mg of each sample was added 10 ml
of n-hexane (non-solvent) was added to methanol, stirred at 500 rpm for 30 min. The

35
M. Jelvehgari et al. / RPS 2010; 5(1): 33-43

drug concentration was determined spectro- the dissolution medium containing 900 ml of
photometrically (UV-160, Shimadzu, Japan) at hydrochloric acid (0.1 M) buffer solution (pH
286 nm. All experiments were done in 1.2). After 2 h, 17 ml of 0.2 M phosphate
triplicate. Loading efficiency was calculated buffer stock, pre-equilibrated at 37 °C, were
according to the following equation: added to the dissolution vessel. The pH was
Loading efficiency (%) = (actual drug content immediately adjusted, if necessary, with 0.2 N
in microparticles/theoretical drug content) × HCl or 0.2 N NaOH to pH 7.4 (19). A quantity
100 (3 ml) of the dissolution medium was sampled
The prepared microspheres were collected at predetermined time intervals and fresh
and weighed. The measured weight was dissolution medium was simultaneously used
divided by the total amount of all non-volatile to replenish the dissolution medium on each
components which were used for the occasion to keep the volume constant. The
preparation of the microspheres. All of the sample was filtered through filter disc (0.45
experiments were performed in triplicate. µm), and the drug concentration in the samples
% Yield = (Actual weight of product/Total was assayed spectrophotometrically at 271 nm
weight of excipient and drug) × 100 for both the acidic and enteric buffers. Each
experiment was repeated three times.
Frequency distribution analysis
Samples of microspheres were analyzed for RESULTS
frequency distribution with calibrated optical
microscope fitted with a stage and an ocular Effect of drug-polymer ratios on the physical
micrometer. Small quantities of microsphere properties of the microparticles
were spread on a clean glass slide and the One of the features of this process was the
average size of 50 particles and the frequency use of two solvents (termed as 'mixed solvent
distribution was determined in each batch. system' or MSS here) (20) as a dispersed
medium and suitable non-aqueous processing
Differential Scanning Colorimetry (DSC) medium to enable formation of O1/O2
The physical state of drug in the emulsion. Components of the MSS can be
microspheres was analyzed by Differential selected from any of the commonly available
Scanning Calorimeter (Shimadzu, Japan). The organic solvents such as dichloromethane,
thermo grams of the samples were obtained at ethyl acetate, acetone, acetonitrile, methanol,
a scanning rate of 10 °C/min conducted over a etc (21,22). Having chosen oil as the
temperature range of 25-300 °C. processing medium, it is imperative that
solvent for polymer be immiscible with oil.
X-ray Powder diffractometry (X-RPD) Acetone is a unique organic solvent which is
X-RPD of the theophylline microspheres polar, water-miscible and oil-immiscible. All
were performed by a diffractometer using other organic solvents like methanol, ethyl
model (Siemens D5000, Munich, Germany) alcohol, ethyl acetate, acetone, dimethyl
equipped with a graphite crystal mono- sulphoxide and tetrahydrofuran are oil-
chromator (CuKα) (a voltage of 40 KV and a miscible and do not form emulsions of the
current of 20 mA) radiations to observe the polymer solution in oil (19,21). When the drug
physical state of drug in the microspheres at has some solubility in the acetone: ethanol
voltage of 40 KV and a current of 20 mA. solution, prolonged mixing caused an increas-
ed amount of aggregation to occur. The range
Dissolution studies of surfactant concentration used was between
Drug release on the microspheres were carried 0 and 1%. Higher concentration promoted
out using a USP basket method for 24 h at a aggregation of the microcapsules. With oil as a
stirring speed of 100 rpm and temperature of processing medium, use of acetone alone as a
37 ± 0.5 °C. An amount of the microspheres dispersing medium did not ensure formation of
equivalent to 200 mg of theophylline filled in a a stable emulsion. Liquid paraffin containing
hard gelatin capsule (Size no.0) were placed in 1% surfactant (Span 80/ester sucrose) and

36
 Development of theophylline floating microballoons...

Table 3. Effect of drug: polymer ratio on drug loading efficiency, production yield and particle size of theophylline
microspheres
Drug: Production Theorical
Formulations MADEa DLEb MPSc Buoyancy
Polymer yield drug
(٪±SD) (٪±SD) (µm ± SD) (٪±SD)
ratio (٪±SD) content (٪)
F1 3:1 42.2 ± 0.93 75 47.5 ± 0.02 63.0 ± 0.05 382.9 ± 1.73 62.3 ± 2.31
F2 4:1 59.1 ± 0.65 80 59.1 ± 0.25 73.9 ± 0.16 372.4 ± 1.70 63.8 ± 2.50
F3 5:1 73.1 ± 1.09 83 73.1 ± 0.15 88.0 ± 0.09 231.6 ± 1.71 72.9 ± 4.52
F'1 0.5:1 53.7 ± 1.34 33 11.5 ± 0.29 34.6 ± 0.86 44.28 ± 1.99 80.3 ± 4.02
F'2 0.75:1 45.4 ± 0.45 43 41.1 ± 0.40 95.9 ± 0.95 273.6 ± 1.73 75.6 ± 6.31
F'3 1:1 78.0 ± 12.26 50 27.4 ± 2.99 73.6 ± 11.6 440.8 ± 1.74 56.2 ± 5.63
Mix 2:0.5:0.5 69.1 ± 0.24 67 29.8 ± 1.11 44.5 ± 2.69 370 ± 1.72 65.5 ± 4.25

*F1 to F3 (microspheres containing Eu RL100), F'1 to F'3 (microspheres containing CAB) and Mix (microspheres
containing Eu RL100 and CAB). aMADE: Mean amount of drug entrapped, bDLE: Drug loading efficiency, cMPS:
Mean particle size

non-solvent (n-hexane) were used in the and loading efficiency of mix formulation
normal microencapsulation procedure (containing CAB and Eu RL) were 69.1 and
Microspheres were formed after a series of 44.5, respectively. A volume-based size
steps like solvent evaporation and addition of distribution of drug, polymer, and drug loaded
non-solvent. Microspheres (CAB and Eu RL) microspheres indicated a log–probability
were prepared using different drug-polymer distribution. Mean particle size of original
ratios as shown in Tables 1 and 2. The drug- theophylline, Eu RL and CAB was 429 ± 1.26
polymer ratio was varied by maintaining the µm, 590.8 ± 1.73 µm and 131.3 ± 1.69 µm,
amounts of polymer, surfactant and solvent respectively. The prepared floating micro-
constant in all preparations, and changing the spheres containing of Eu RL were found to be
amount of drug. The results of the effect of discrete and spherical (Fig. 1). The mean
drug-polymer ratio (microspheres containing diameter of microspheres composed of Eu
CAB/Eu RL) on production yield, drug RL1 and/or CAB were between 44.28 to 440.8
loading efficiency and mean particle size are µm; CAB microspheres represented the least
shown in Table 3. In all formulations, the and largest size.
mean amount of drug entrapped in the
prepared microspheres was different from Percentage Buoyancy
theoretical value. The drug loading efficiencies Good in vitro buoyancy was observed for
were in the range of 63-88% for microspheres all microsphere formulations (Table 3).
prepared with Eu RL and 34.58-95.87% for Microspheres prepared using CAB showed the
microspheres containing CAB. The highest optimized floatability (88.3 ± 4.02 buoyancy)
encapsulation efficiency (95.87%) was in 0.1 M HCl. A floating time of 12 h may be
obtained with CAB polymer. considered a satisfactory performance of the
According to Table3, increasing the drug to prepared formulations. Eu RL is more
polymer ratios in microspheres prepared with permeable than cellulose acetate butyrate. Eu
both Eu RL 100 and CAB caused an increase RL has 10% of functional quaternary
in the production yield. In the case of ammonium groups. Density of Eu RL and
microspheres containing Eu RL 100, CAB are 0.815-0.835 g/cm3 and 1.16-1.3
increasing the drug to polymer ratios from 3:1 g/cm3, respectively. Eu RL will give rise to an
to 5:1 increased the production yield from 42.2 initial burst release which is essential from
± 0.93 to 73.1 ± 1.09. Similarly, increase drug therapeutic point of view, while CAB will
to polymer ratios from 0.5:1 to 1:1 in control the drug release by maintaining the
microspheres containing CAB, the production buoyancy, which renders drug more
yield increased from 45.39 to 78.02. The yield permeable. It was evident that addition of Eu
R

37
M. Jelvehgari et al. / RPS 2010; 5(1): 33-43

a
b
c
d
e
f

271.4
A
a
b
c
e
d
f

b
c
d
e

0 100 200 300

Temperature [?C]

Fig. 1. Optical microscopic photograph of a spherical Fig. 2. DSC thermogram of (A) microspheres of Eu RL;
microspheres F1 (theo: Eu RL ratio 4:1), F'2 (theo: CAB a) physical mixture F2, b) F1 (3:1 ratio) , c) theophylline
ratio 0.75: 1) and Mix (theo: Eu RL: CAB ratio d) F2 (4:1 ratio), e) F3 (5:1 ratio), f) Eu RL ( B)
1:0.5:0.5) formulations at 10x. microspheres of CAB; a) F'1 (0.5:1 ratio) , b) F'2 (0.75:1
ratio), c) F'3 (1:1 ratio), d) physical mixture F'2, e) CAB,
f) theophylline and (C) microspheres of mixture; a) Mix
RL 100 increased the permeability of (1:0.5:0.5), b) physical mixture, c) Eu RL, d) CAB , e)
microcapsules to the surrounding dissolution theophylline.
medium due to the swelling nature of the
polymer (23). In addition to this, the porous In vitro release studies
nature of microcapsules produces an upward Fig. 4 shows the release profile of the drug
motion of the dosage form to float on the from the microparticles. The in vitro release of
gastric contents. theophylline from microspheres containing Eu
RL exhibited initial burst effect which may be
DSC due to the presence of some drug particles on
Pure theophylline exhibits a sharp melting the surface of the microspheres. The release
endotherm around 271.4 °C (Fig. 2A, f). It is profiles are illustrated in Fig. 4A. In order to
obvious from thermograms that the DSC have better comparison between the
curves of physical mixtures of drug with dissolution profiles, dissolution efficiency (the
polymers as well as the microsphere area under the dissolution curve at a given
formulations are almost the same. This time which is expressed as percentage of the
endotherm of the drug is present in most of the area of the rectangle described by 100%
thermograms at 269 to 270 °C (Fig. 2A). The dissolution at the same time), t50% (dissolution
intensity of the drug fusion peak, however, for time for 50% fractions of drug), and f2 (used to
the microsphere formulation was lower than compare multipoint dissolution profiles), Q2h
that of the pure drug and physical mixtures. and Q8h were calculated. Microspheres with
high loading efficiency or high drug
X-RPD entrapment (F3 formulations) showed faster
The X-ray diffraction patterns show that the dissolution rate. Fig. 4 and Table 4 show that
pure drug is crystalline in nature (Fig. 3A, a). the initial drugs release for some of
However, when it was incorporated into the microsphere formulations are slightly high.
polymer matrix the principal peaks of the drug Fig. 4 also shows that in most cases a biphasic
was appeared with lower intensity (Fig. 3). dissolution pattern exist. This is the point

38
 Development of theophylline floating microballoons...

c
d

e
f
g
c

h
i

Fig 3. X-ray diffraction of A) theophylline (a), F2 (4:1 ratio) (b), physical mixture F2 (4:1 ratio) (c), Eu RL100 (d), B)
CAB (e), physical mixture F'2 (f), F'2 (g), C) mix (1: 0.5: 0.5 ratio) (h), and physical mixture (i) formulations.

where pH of the dissolution medium was initial release (Fig. 4C).

altered from 1.2 to 7.4. When microspheres come in contact with
Comparing the drug release from micro- gastric fluid the gel formers, polysaccharides,
spheres containing CAB (Fig. 4B) shows that and polymers hydrate to form a colloidal gel
the release of drug from these microspheres is barrier that controls the rate of fluid
slower than the release of the drug from penetration into the device and consequent
microspheres containing Eu RL (compare F3 drug release. As the exterior surface of the
with F'3). However, no significant difference dosage form dissolves, the gel layer is
was observed between the percentages of drug maintained by the hydration of the adjacent
released at 8h (Q8h) between microspheres hydrocolloid layer. The air trapped by the
containing Eu RL or CAB (P > 0.05). swollen polymer lowers the density and
Combination of CAB and Eu RL correspon- confers buoyancy to the microspheres.
ding to lower level of the polymer with However, a minimal gastric content needed to
theophylline in the formulation (Mix) resulted allow proper achievement of buoyancy (1,5).
in a sustained fashion in the drug release rate Hollow microspheres of acrylic resins,
and reduced the initial release (Fig. 4C). Eudragit, polyethylene oxide, and cellulose
Combination of CAB and Eu RL correspon- acetate; polystyrene floatable shells;
ding to lower level of the polymer with polycarbonate floating balloons and gelucire
theophylline in the formulation (Mix) resulted floating granules are the recent developments.
in sustaining the drug release rate and reduced the

39
M. Jelvehgari et al. / RPS 2010; 5(1): 33-43

F1 F2 F3 PM F2 Theophylline‐SR
100

Cumulative % Drug Released
80

60

40

20 A
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)

F'1  F'2 F'3 PM F'2 Theophylline ‐SR

Cumulative % Drug Released

100
80
60
40
20 B
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
Mix PM (Mix) Theophylline‐SR
Cumulative % drug Released

80

60

40

20 C
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)

Fig 4. Percent release of theophylline from microspheres prepared with different polymer-to-drug ratio containing
Eudragit RL (A), cellulose acetate butyrate (B), combination cellulose acetate butyrate and Eudragit RL (C), physical
mixture and commercial theophylline SR®.

Table 4. Comparision of various release characteristics of theophylline from different microsphere formulations, and
physical mixture.
b c d e
t50% DE Q2 Q8
Formulation Similarity factor
(h) (%) (%) (%)
F1 Up>24 42.22 ± 4.41 7.44±0.01 46.03±1.09 33.72
F2 <3 72.36 ± 5.52 7.41±0.03 77.97±1.17 59.63
F3 3 73.06 ± 6.24 6.58±0.06 84.73±2.61 37.71
a
PM (Eu RL) 3 79.05 ± 6.21 18.1±1.38 78.20±1.33 49.05
F'1 12 3.690±43.36 6.06±0.12 44.99±0.46 33.14
F'2 5 69.39±4.27 6.45±0.16 71.39±2.06 50.87
F'3 5 77.80±5.19 20.5±0.15 84.61±0.66 56.43
PM (CAB) 8 63.29±3.33 7.21±0.08 53.82±0.08 41.90
Mix 3 60.06±5.54 5.23±0.05 69.86±0.5 50.61

PM(CAB & Eu RL) 3 69.35±4.17 21.7±0.74 76.21±0.78 48.62

®
Theophylline SR 4 75.79±4.62 10.5±3.57 79.57±5.24 100
a b c d
PM) Physuical Mixture; t0.5%) dissolution time for 50% fractions DE) Dissolution Efficiency Q2) amount of drug
release after 2 h;eQ8) amount of drug release after 8 h

40
 Development of theophylline floating microballoons...

DISCUSSION Low intensity of peaks could be ascribed to

the crystalline state of the drug in the
The encapsulation efficiency of the drug microparticles. This confirms the results
depended on the solubility of the drug in the obtained from DSC experiments.
solvent and continuous phase. The high
entrapment efficiency of theophylline in In vitro release
microspheres may be attributed to its poor As more drugs are released from the
aqueous solubility. Encapsulation efficiency microspheres, more channels are probably
rose with increase in theophylline concen- produced, contributing to faster drug release
tration in the microspheres containing Eu RL rates. F1, F2 and F3 formulations showed the
and CAB. This could be due to the high lowest burst release in comparison with
permeability characteristics of polymer which theophylline SR and physical mixture
would facilitate the diffusion of part of the formulations and the percentage of burst
entrapped drug to the surrounding medium release reduced as the ratio of drug to polymer
during the preparation of the microparticles. in the preparation of microsphere decreased.
The reason for increased production yield at The burst release could be attributed to the
high drug-polymer ratios could be due to presence of some theophylline particles on the
decreased diffusion rate of solvents (acetone surface of microspheres. When particles are
and/or methanol) from concentrated solutions prepared by O1/O2 method, water-soluble
into emulsion. The extent of loading drugs do not have tendency to migrate to the
influenced the particle size distribution of non-polar medium, thereby concentrating on
microspheres. Decreasing of microspheres size the surface of the microspheres leading to
can be attributed to the fact that with the burst effect (28). Moreover, the burst release
higher diffusion rate of non-solvent to polymer could also be explained by the imperfect
solution the smaller size of microcapsules is encapsulation of the drug inside
easily obtained (24). The mean particle size of microparticles, resulting from the unstable
CAB microspheres was greater than that of Eu nature of the emulsion droplets during the
RL microspheres, and this may be viscosity solvent removal step. This potential instability
related. may cause a part of the loaded drug to relocate
The nature of the polymer influenced the at the microparticle surface, thereby rapidly
floating behavior of the microspheres. Micros- released (29). The first portion of the biphasic
pheres with the highest levels of CAB and Eu dissolution curves is due to theophylline
RL were least buoyant. It is likely that the dissolution which starts immediately after the
surfactant incorporated in the formulations beginning of the dissolution process. For the
would have increased their wettability and release of the drug in the second phase
hence, hydration, more than in the other combination of the diffusion of the remaining
microspheres which had lower levels of the dispersed drug into the bulk medium,
permeable Eu RL and CAB. Consequently, the formation of pores within the matrix due to the
increased amount of absorbed liquid medium initial drug dissolution and swelling which
replaced the air inside the floating micros- enhances the permeability of the polymer to
pheres, thus rendering them less buoyant the drug might be involved (30). Fig. 4
(5,12,13). illustrates that different theophylline micros-
The drug could be either dispersed in pheres exhibited different dissolution profiles.
crystalline/amorphous form or dissolved in the In order to find out which release profiles is
polymeric matrix during the process of micro- more suitable for oral administration, the
encapsulation (25,26). Any abrupt or drastic release data were compared with those of
change in the thermal behavior of rather the commercial theophylline extended release
drug or polymer may indicate a possible drug- formulations. The theophylline microspheres
polymer interaction (27). DSC thermograms prepared in this study could be embedded into
did not reveal any interaction between drug soft gelatin capsules for peroral administration.
and excipients in prepared microspheres. According to the US pharmacopoeia not less

41
M. Jelvehgari et al. / RPS 2010; 5(1): 33-43

than 70-80% of the theophylline should be Tabriz University of Medical Sciences is

released within 8 h (21). The similarity factor greatly acknowledged.
showed that microsphere formulations F2
(containing Eu RL), F'2, F'3 (containing CAB) REFERENCES
and mix (containing Eu RL and CAB) exactly
matches the release profile of commercial 1. Gaba P. Floating microspheres: a review. 2008.
formulations (Table 4) and there was no Available from: URL:http://www.pharmainfo.net/
significant difference between these two reviews /floating-microspheres-review
2. Hirtz J. The gut absorption of drugs in man: a review
dissolution profiles (f2 = 50.61-59.63%). CAB of current concepts and methods of investigation. Br
has a low permeability to drug which results J Clin Pharmacol. 1985;19:77-83.
from its high intermolecular attraction. 3. Chien YW. Controlled and modulated release drug
Hydrogen bonding between the hydroxyl delivery systems. In: Swarbrick J, Boylan JC,
groups of the carboxylic moiety and the editors. Encyclopedia of pharmaceutical technology.
New York: Marcel Dekker Inc.1990; p. 280-285.
carbonyl oxygen of ester group increases the 4. Jain NK. Controlled novel drug delivery. 1st ed.
degree of solidity of the polymer and New Delhi: CBS Publishers and Distributors. 2002;
decreases its porosity and permeability. p.236-255.
However, Eu RL is a copolymer of acrylic and 5. Kouchak M, Badrian A. Preparation and in vitro
methacrylic acid esters with a low content of evaluation of a microballon delivery system for
theophylline. Iran J Pharm Res. 2007;6:35-42.
quaternary ammonium groups. The 6. Kawashima Y, Niwa T, Takechi H, Hino T, Itoh Y.
ammonium groups present as salts promotes Hollow microspheres for use as floating controlled
permeability and act as a channeling agent for drug delivery systems in the stomach. J Pharm Sci.
the entrance of the liquid medium through the 1992;81:35-140.
floating microsphere wall, causing it to swell. 7. Soppimath KS, Kulkarni AR, Rudzinski WE,
Aminabhavi TM. Microspheres as floating drug-
This facilitates the diffusion of the dissolved delivery systems to increase gastric retention of
drug out of the microsphere into the drugs. Drug Metab Rev. 2002;33:149-160.
dissolution medium. Thus, by varying the ratio 8. Muthusamy K, Govindarazan G, Ravi TK.
of CAB and Eu RL in the theophylline Preparation and evaluation of lansoprazole floating
microspheres, the rate of release of micropellets. Ind J Pharm Sci. 2005;67:75-79.
9. Thanoo BC, Sunny MC, Jayakrishnan A. Oral
theophylline can be controlled. sustained-release drug delivery systems using
polycarbonate microspheres capable of floating on
CONCLUSION the gastric fluid. J Pharm Pharmacol. 1993;45:21-24.
10. Joseph NJ, Lakshmi S, Jayakrishnan A. A floating-
Theophylline microspheres were prepared type oral dosage form for piroxicam based on
hollow polycarbonate microspheres: in vitro and in
using the solvent evaporation method. This vivo evaluation in rabbits. J Control Release.
method has been applied for the preparation of 2002;79:71-79.
microballoons system with other polymers and 11. Stithit S, Chen W, Price JC. Development and
drugs (5). The high permeability of Eu RL characterization of buoyant theophylline
gives the initial burst release, which is microspheres with near zero order release kinetics. J
Microencaps. 1998;19:725-737.
desirable from therapeutic point of view. CAB 12. Lee JH, Park TG, Choi HK. Development of oral
polymer exhibit slower rate of in vitro drug drug delivery system using floating microspheres. J
release initiated by lag time, which reduces the Microencaps. 1999;16:715-729.
plasma drug fluctuations, as seen in conven- 13. Srivastava AK, Ridhurkar DN, Wadhwa S. Floating
tional tablet dosage forms. In the present microspheres of cimetidine: formulation,
characterization and in vitro evaluation. Acta Pharm.
study, controlled release without initial peak 2005;55:277-285.
level achieved with these formulations may 14. Jain AK, Jain CP, Tanwar YS, Naruka PS.
reduce dose frequency and side effects as well Formulation, characterization and in vitro evaluation
as improve patient compliance. of floating microspheres of famotidine as a gastro
retentive dosage form. 2009;3:222-226.
15. Sato Y, Kawashima Y, Takeuchi H, Yamamoto H.
ACKNOWLEDGMENT Physicochemical properties to determine the
buoyancy of hollow microspheres (microballons)
The financial support of research office of prepared by the emulsion solvent diffusion method.

42
 Development of theophylline floating microballoons...

Eur J Pharm Biopharm. 2003;55:297-304. 24. Bhardwaj SB, Shukla AJ, Collins CC. Effect of
16. Streubel A, Siepmann J, Bodmeier R. Floating varying drug loading on particle size distribution and
microparticles based on low density foam powder. drug release kinetics of verapamil hydrochloride
Int J Pharm. 2002;241:279-292. microspheres prepared with cellulose esters. J
17. Joseph W, Nairn JG. Some factors affecting the Microencapsul. 1995;12:71-81.
microencasulation of pharmaceuticals with cellulose 25. Herrmann J, Bodmeier R. Biodegradable,
acetate phthalate. J Pharm Sci. 1986;75:573-78. somatostatin acetate containing microspheres
18. Wan LSC, Chui WK. Deviation of the ratio of drugs prepared by various aqueous and non-aqueous
in a two-component mixture encapsulated in solvent evaporation methods. Eur J Pharm
cellulose phthalate microspheres. J Micro- Biopharm. 1998;45:75-82.
encapsul.1995;12:417-23. 26. Bodmeier R, Chen H. Preparation and charac-
19. The United States Pharmacopoeia. 24th ed. Vol. 1. terization of microspheres containing the anti-
Rockville: United States Pharmacopoeial inflammatory agents, indomethacin, ibuprofen, and
Convention. 2000; p. 1941-1943. ketoprofen. J Control Release. 1989;10:167-175.
20. Kilicarslan M, Baykara T. The effect of the 27. Jones DS, Pearce KJ. Investigation of the effects of
drug/polymer ratio on the properties of verapamil some process variables on microencapsulation of
HCL loaded microspheres. Int J Pharm. propranolol HCl by solvent evaporation method. Int
2003;252:99-109. J Pharm. 1995;118:199-205.
21. Viswanathan NB, Thomas PA, Pandit JK, Kulkarni 28. Jameela SR, Suma N, Jayakrishnan A. Protein
MG, Mashelkar RA. Preparation of non-porous release from poly(ε-caprolactone) microspheres
microspheres with high entrapment efficiency of prepared by melt encapsulation and solvent
proteins by a (water-in-oil)-in-oil emulsion evaporation techniques: a comparative study. J
technique. J Control Release. 1999;55:9-20. Biomater Sci Polym. 1997;8:457-466.
22. Kim BK, Hwang SJ, Park JB, Park HJ. Preparation 29. Lu W, Park TG. Protein release from poly(lactic-
and characterization of drug-loaded poly- coglycolic acid) microspheres: protein stability
methacrylate microspheres by an emulsion solvent problems. J Pharm Sci Technol. 1995;49:13-19.
evaporation method. J Microencapsul. 2002;19:811- 30. Pignatello R, Consoli P, Puglisi G. In vitro release
822. kinetics of tolmetin from tabletted Eudragit
23. Nath B, Nath LK, Mazumdar B, Sharma N, Sarkar microparticles. J Microencapsul. 2000;7:373-383.
M. Design and development of metformin HCl
floating microparticles using two polymers of
different permeability characteristics. Int J Pharm
Sci Nanotech. 2009;2:627-637.

43