Vol 3 - Cont J Pharm Sci - Wilolud Journals

Continental J. Pharmaceutical Sciences 3: 1 - 6, 2009
©Wilolud Online Journals, 2009.
EFFECT OF NATURAL BIODEGRADABLE AND SYNTHETIC POLYMER FOR GASTRIC DISEASE BY
FLOATING MICROSPHERES
A. K. Jain 1 , C. P. Jain 1 , K. Gaur 2 , A. Kakde 3 , M. Meena 4 , R. K. Nema 5
1 Department of Pharmaceutical Sciences, M.L.S. University, Udaipur, Rajasthan, India
2 Geetanjali College of Pharmaceutical Studies, Manwa Kheda, Udaipur, Rajasthan, India
3 Vinayaka mission university, Selam, Tamilnadu, India
4 I C M R, Delhi, India, 5 Rishiraj College of Pharmacy, Indore, Madhya Pradesh, India
ABSTRACT
The present study involves preparation and evaluation of floating microspheres with
famotidine as model drug for prolongation of gastric residence time. The microspheres were
prepared by the solvent evaporation method using polymers acrycoat S100 and chitosan. The
shape and surface morphology of prepared microspheres were characterized by optical and
scanning electron microscopy, respectively. In vitro drug release studies were performed and
drug release kinetics was evaluated using the linear regression method. Effects of natural
biodegradable polymer chitosan and another acrycoat S 100 polymer on the size of
microspheres, incorporation efficiency and in-vitro drug release were also observed. The
prepared microspheres exhibited prolonged drug release more than 18 h, incorporation
efficiency was change due to increase concentration of poly vinyl alcohol solution but
remained buoyant for more than 12 h because clumping of polymers on surface of
microspheres. The mean particle size increased and the drug release rate decreased at higher
polymer concentration. In vitro studies demonstrated diffusion-controlled drug release from
the prepared floating microspheres.
KEYWORDS: Floating microspheres, famotidine, in vitro release, bioavailability
INTRODUCTION
Floating drug delivery systems developed to increase the gastric residence time of dosage forms for gastric disease
(Seth, 1984; Moes, 1993; Deshpande et al., 1996). The multiple unit system has been developed to identify the merit
over single unit dosage form because the single-unit floating systems are more popular but have a disadvantage
owing to their ‘all-or-nothing’ emptying process leading to high variability of the gastrointestinal transit time
(Whitehead et al., 1998; Talukder and Fassihi, 2004). Still, the multiple-unit dosage forms may be better suited
because they are claimed to reduce the intersubject variability in absorption and lower the probability of dose
dumping (Rouge et al., 1997). Such a dosage form can be distributed widely throughout the gastrointestinal tract,
affording the possibility of a longer lasting and more reliable release of the drug from the dosage form (Sato et al.,
2003). The synthetic polymers have been used to prepare floating microspheres. Kawashima et al. prepared hollow
microspheres or microballoons of ibuprofen by the emulsion-solvent diffusion method using acrylic polymers
(Kawashima et al., 1992). The microspheres exhibited good in vitro floatability and drug release decreased
drastically with increasing polymer concentration. Floating microspheres of cellulose acetate loaded with three
different drugs were prepared using the solvent diffusion-evaporation method (Soppimath et al., 2002). The
microspheres remained buoyant for more than 12 h. Methylcellulose and chitosan micropellets loaded with
lansoprazole had a lower density than gastric contents and exhibited better encapsulation efficiencies (Muthusamy et
al., 2005). Other polymer solution systems that have been used to prepare floating microspheres are
polycarbonate/dichloromethane (Thanoo et al., 1993; Joseph et al., 2002), cellulose acetate butyrate/Eudragit RL100
mixture in acetone (Stithit et al., 1998) and Eudragit S100/i-propanol (Lee et al., 1999). Famotidine was used as
model drug. It is an antihistaminic drug that has been widely used in treating gastric and duodenal ulceration and
also in zollinger ellison syndrome and reflux esophagitis (Gladiziwa and Klotz, 1993). It is poorly absorbed from the
lower gastrointestinal tract and has a short elimination half life (3 h). The objective of the present study was to
develop floating microspheres of famotidine in order to achieve an extended retention in the upper gastrointestinal
tract, which may result in enhanced absorption and thereby improved bioavailability. The prepared microspheres
were evaluated for particle size, in vitro release, buoyancy and incorporation efficiency. The effect of various
formulation variables on the size of microspheres, incorporation efficiency and drug release was investigated.
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A. K. Jain et al: Continental J. Pharmaceutical Sciences 3: 1 - 6, 2009
EXPERIMENTAL
Materials and Apparatus
Famotidine was obtained as a gift sample from Intas Pharmaceutical, Ahmedabad. Polyvinyl alcohol was obtained
from S.D. Fine Chemicals Ltd. Mumbai. Dichloromethane, ethyl acetate, acetone, acrycoat S100, chitosan were
obtained from Central Drug House (Pvt) Ltd. Delhi. All other chemicals/reagents were used of analytical grade.
Table 1: Different formulations of floating microspheres
S. No. Code
Drug:
ratio
Polymer
Organic solvent system
Polyvinyl
alcohol
(%w/v)
1. C1* 1:1 Dichloromethane: Ethanol 1:1 0.25
2. C2 1:2 Dichloromethane: Ethanol 1:1 0.25
3. C3 1:3 Dichloromethane: Ethanol 1:1 0.25
3. C4* 1:1 Dichloromethane: Ethanol 1.:1 0.5
3. C5* 1:1 Dichloromethane: Ethanol 1:1 1.0
4. A1 1:1 Dichloromethane: Ethanol 1:1 2.0
5. A2 1:2 Dichloromethane: Ethanol 1:1 2.0
6. A3 1:3 Dichloromethane: Ethanol 1:1 2.0
*Formulation coded with different concentration of polyvinyl alcohol (% w/v) using same drug:
polymer ratio
Code
Buoyancy
Table 2: Various formulation parameters for microspheres
Mean Incorporation
Husner’s
size a (%) b
particle efficiency percentage b ratio
Carr’s index Angle of
repose (θ)
C1*
375.1±1.818 86.15±0.044 80.6±2.1 1.66±0.023 14.285±0.345 23.41 ° ±0.035
C2
378.7±2.914 83.15±0.011 79.01±3.3 1.146±0.059 12.79±0.421 22.43 ° ±0.581
C3
389.3±1.984 84.15±0.012 77.56±3.6 1.166±0.039 12.35±0.746 22.15 ° ±0.351
C4*
376.1±1.657 85.52±0.065 81.7±2.1 1.56±0.056 13.13±0.345 22.24 ° ±0.028
C5*
379.1±1.546 84.38±0.038 82.8±2.1 1.42±0.073 13.06±0.254 21.85 ° ±0.026
A1
380.8±2.164 83.15±0.032 76.14±2.1 1.58±0.046 13.58±0.546 22.87 ° ±0.124
A2
383.6±1.854 83.51±0.034 74.85±1.8 1.42±0.028 12.468±0.214 21.85 ° ±0.256
A3
390.6±1.931 81.35±0.016 75.56±1.9 1.35±0.075 11.845±0.587 20.85 ° ±0.428
a Mean±SD, n=10. b Mean±SD, n=3.
Preparation of microspheres
Microspheres were prepared by the solvent evaporation emulsification technique as employed by Struebel et al.
(Struebel et al., 2003). Famotidine as model drug and polymers such as acrycoat S100 (batch A1-A3) or chitosan
(batch C1-C5) was dissolved in a mixture of solvent system at room temperature to be prepare different formulation
systems (Table 1). This dispersed medium was poured into 150 mL 0.1 M acidic solution containing polyvinyl
alcohol as continuous medium at room temperature and subsequently stirred at ranging agitation speed for 2 h to
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A. K. Jain et al: Continental J. Pharmaceutical Sciences 3: 1 - 6, 2009
allow the volatile solvent evaporate. The prepared microspheres were filtered, washed with distilled water and dried
in vacuum.
Characterization of microspheres
Size and shape of microspheres: The size of microspheres was determined using a microscope (Olympus NWF 10x,
Educational Scientific Stores, India) fitted with an ocular micrometer and stage micrometer. Scanning electron
microscopy (SEM) (Philips-XL-20, The Netherlands) was performed to characterize the surface of formed
microspheres. Microspheres were mounted directly onto the sample stub and coated with gold film (~ 200 nm)
under reduced pressure (0.133 Pa).
Flow properties: It was determined in terms of carr’s index (Ic) and hausner’s ratio (H R ) using following equations:
H R =ρ t/ ρ b
I c =ρ t- ρ b/ ρ t
Figure 1: Scanning electron microscopy photographs of floating microspheres
The angle of repose (θ) of the microspheres, which measure the resistance to particle flow, was determined by fixed
funnel method by using following equation:
tan θ=2H/D
Where, 2H/D is the surface area of the free standing height of the microspheres heap that formed after making the
microspheres flow from the glass funnel.
Buoyancy percentage: Microspheres (0.3 g) were spread over the surface of a USP XXIV dissolution apparatus
(type II) filled with 150 ml 0.1 mol L –1 hydrochloric acid (USP, 2000). The medium was agitated with a paddle
rotating at 500 rpm for 12 h. The floating and the settled portions of microspheres were recovered separately. The
floated microspheres were collect by decantation and weighed.
Buoyancy % = Floated mass of prepared microspheres / Total mass of prepared microspheres
Incorporation efficiency: To determine the incorporation efficiency, prepared microspheres were taken, thoroughly
triturated in pestle mortar equivalent as drug used in formulation and suspended in a 5 ml of dichloromethane as
dissolving medium. The suspension was suitably diluted with water and filtered to separate shell fragments. Drug
content was analyzed spectrophotometrically at 265 nm.
In-vitro drug release: A USP basket apparatus has been used to study in vitro drug release from microspheres (Singh
and Kim, 2000; Dinarvand et al., 2002; Abrol et al., 2004). In the present study, drug release was studied using a
modified USP XXIV dissolution apparatus type I (basket mesh # 120, equals 125 µm) at 100 rpm in distilled water
and 0.1 mol L –1 hydrochloric acid (pH 1.2) as dissolution fluids (900 ml) maintained at 37 ± 0.5 °C. Withdrawn
samples (10 ml) were analyzed spectrophotometrically as stated above. The volume was replenished with the same
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A. K. Jain et al: Continental J. Pharmaceutical Sciences 3: 1 - 6, 2009
amount of fresh dissolution fluid each time to maintain the sink condition. All experiments were performed in
triplicate. Linear regression was used to analyze the in vitro release mechanism.
Statistical analysis: Experimental results were expressed as mean ± SD. Student’s t-test and one-way analysis of
variance (ANOVA) were applied to check significant differences in drug release from different formulations.
Differences were considered to be statistically significant at P< 0.05.
RESULTS AND DISCUSSION
Floating microspheres were prepared by the solvent evaporation method by using acrycoat S100 and chitosan (Table
1). The SEM photographs showed that the fabricated microspheres were spherical with a smooth surface and
exhibited a range of sizes within each batch (Fig. 1). The microspheres floated for prolonged time over the surface
of the dissolution medium without any apparent gelation. Buoyancy percentage of the microspheres was shown in
Table 2.
Figure 2: Effect of chitosan polymeric concentration on in vitro drug release from floating microspheres (bars
represents mean±SD; n=3)
Microspheres were prepared using different polymers with gradually increasing polymer concentration and same
polymer with variability in concentration of PVA in combination with a fixed concentration of drug to assess the
effect of polymer concentration on the size of microspheres. The mean particle size of the microspheres significantly
increased with increasing cellulose acetate concentration (p < 0.05) and was in the range 375.1±1.818 to
389.3±1.984 µm (Table II). The viscosity of the medium increases at a higher polymer concentration resulting in
enhanced interfacial tension (Reddy et al., 1990; Ishizaka, 1981). The size of prepared microsphere was change due
to variability in concentration of PVA, as concentration of PVA increase size of microspheres increase but
incorporation efficiency was reduced. The same concentration of polymer with changing concentration of PVA,
buoyancy percentage and period was increase till to 18 h. In vitro FM release studies were performed in 0.1 mol/L
hydrochloric acid for 18 h. The cumulative release of FM significantly decreased with increasing polymer
concentration (p < 0.05, Fig. 2, 3) because of clumping of polymer on surface of microspheres. The increased
density of the polymer matrix at higher concentrations results in an increased diffusional path length. This may
decrease the overall drug release from the polymer matrix because higher gelation of surface. Furthermore, smaller
microspheres are formed at a lower polymer concentration and have a larger surface area exposed to dissolution
medium, giving rise to faster drug release. The data obtained for in vitro release were fitted into equations for the
zero-order, first-order and Higuchi release models (Costa and Lobo, 1987; Wagner, 1969; Schefter, 1963). The
interpretation of data was based on the value of the resulting regression coefficients. The in vitro drug release
showed the highest regression coefficient values for Higuchi’s model, indicating diffusion to be the predominant
mechanism of drug release. in-vivo floating behavior will be discussed in future for in-vitro and in-vivo co-relation.
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A. K. Jain et al: Continental J. Pharmaceutical Sciences 3: 1 - 6, 2009
CONCLUSIONS
In vitro data obtained for floating microspheres of famotidine showed excellent floatability, good buoyancy and
prolonged drug release. Microspheres of different size and drug content could be obtained by varying the
formulation variables. Diffusion was found to be the main release mechanism. Thus, the prepared floating
microspheres may prove to be potential candidates for multiple-unit delivery devices adaptable to gastric disease.
ACKNOWLEDGEMENTS
The authors acknowledge the Director, Bhupal Noble’s College of Pharmacy, Udaipur, Rajasthan.
Figure 3: Effect of acrycoat S100 polymeric concentration on in vitro drug release from floating microspheres (bars
represents mean±SD; n=3)
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Received for Publication: 27/04/2009
Accepted for Publication: 12/05/2009
Corresponding Author:
Abhishek K. Jain
1 Department of Pharmaceutical Sciences, M.L.S. University, Udaipur, Rajasthan, India
E-mail address: akjainmlsu@gmail.com
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