Preparation of Double Coated
Multiparticulate Delivery System for an Anti-ulcerative
Drug
Basini Nikunja Pati1*, Patel Jitendra1,
Qureshi Md Shamim2 and
Kumar G.S3.
1Department of
Pharmaceutics, Bharat Institute of Technology-School of Pharmacy, Mangalpally, Imbrahmpatnam, RR
Dist- 501510, AP, India.
2Anwarul Uloom
College of Pharmacy, New Mallepally, Hyderabad
-500001.
3Department of Pharmacognosy, Gitam Institute of Pharmacy, Gitam
University Gandhinagar Campus, rushikonda
Visakhapatnam-530045.
ABSTRACT:
In the
long-term management of patients suffering from peptic ulcer and Zollinger Ellison Syndrome, hig
and repeat dosing may be required. Here an antiulcerative
drug, Rabeprazole sodium was selected for research
work. Since it is largely absorbed from the upper intestine, selective delivery
of drugs into the colon may be regarded as a better method of drug deliver with
fewer side effects and a higher efficacy. The aim of this study was to prepare
and evaluate a double coated multiparticulate system
for Rabeprazole delivery using ethyl cellulose and mucoadhesive polymers as the primary and secondary polymer
respectively and studied. Ethyl cellulose microparticles
containing Rabeprazole was produced using the solvent
evaporation method. Prepared ethyl cellulose microparticle
were spherical, free flowing, non-aggregated and showed no degradation in the
acidic medium. Entrapment efficacy of microparticles
was about 68.5%. Results showed that drug release was fast and complete and is affected
by the amount of core material entrapped. Ethylcellulose
microparticles were then coated by various mucoadhesive polymers using emulsion solvent evaporation (ESE) technique. Here, two mucoadhesive
polymers (HPMC and PVP) have been selected for the study. The idea for this
approach was to prepare a mucoadhesive controlled
drug delivery system, in which, ethyl cellulose gives a controlled release of
the drug and the mucoadhesive property of the coating
polymer helps in complete drug release by its localization (ulcer sites) as
well as systemic action (in colon) resulting in more bioavailability, less
degradation of drug and relief from the adverse effects of the drug. It was
shown that this system could provide a suitable drug release pattern for
delivery of active agents.
KEYWORDS: Antiulcerative
drug, mucoadhesive polymers, Ethylcellulose, Rabeprazole sodium.
INTRODUCTION:
Peptic ulcers can lead patients to various undesirable
problems (starting from ill-health, weight loss, asthma, Zollinger
Ellison Syndrome and slowly towards cancer). It remains unidentified by the
patients for a long time due to their carelessness. For their long term
treatment the Proton Pump Inhibitors (Rabeprazole)
have been found to the efficient therapeutical agents1.
This drug is more prone to acidic degradation, has severe adverse effects
and 90% of its dose gets excreted as metabolized product. But upper intestinal
region serves the better absorption site for this drug1,2.
To prevent this as well as to have better bioavailability and efficiency,
production of these double coated microparticles has been done.
MATERIAL AND METHODS:
Materials:
Rabeprazole sodium was obtained from Cipla
(Vikhroli,India). Light
Paraffin Oil was purchased from Sd- Fine Chemicals
(Mumbai). Ethylcellulose, Hydroxy
propyl methyl cellulose and Polyvinyl
pyrollidone were obtained from Sd-
Fine Chemicals (Mumbai). Hydrochloric acid, potassium dihydrophosphate,
n-hexane, acetone, ethanol, methanol, sodium hydroxide, and span 80 were
purchased from Universal laboratory (Mumbai).
Preparation of ethyl cellulose core microparticles:
Drug loaded microparticles
by o/o emulsion solvent evaporation technique, were produced as follows. Ethyl
cellulose was dissolved in 20ml of acetone with continuous stirring. The drug
was then dissolved into the polymeric solution. To produce an emulsion of this
solution containing drug molecules in the second oil phase, the drug-polymeric
solution was dispersed in light paraffin oil (containing 1% w/w span80) using a
mechanical stirrer and left stirring for at least 2hrs, 30 min at 600 rpm. When
microspheres appeared in the solution (detected by optical microscope), the
stirring has to be stopped. Subsequently the excess n-hexane was added to the
system to facilitate separation and hardening of the prepared microparticles as well as the removal of paraffin oil.
Prepared microspheres were then collected by filtration, further washed with
n-hexane and dried at room temperature. Microparticles
of drug to polymer ratios of 1:8 were obtained at this stage3,4.
Microparticles coating method:
Drug loaded ethylcellulose
micropartcles were used as a core material for the
preparation of double-coated system. An O/O Emulsion Solvent Evaporation method
was applied for this step. First, A known amount of the microparticles
having particle size of 100-250 µm was dispersed in an in light paraffin oil
(40ml). This mixture was agitated for 5 min at 400 rpm. Then a mucoadhesive polymer (twice the weight of taken weight of microparticles) was dissolved in a suitable organic
volatile solvent and a polymeric solution is made. The polymer solution was then added
slowly to the microparticles dispersion by means of a
burette. The medium was
stirred for 60 min until the
organic solvent (i.e., polymer solvent) evaporated to complete the process of microparticles coating. Coated microspheres were then
washed with an excess of n-hexane, filtered and dried at room temperature4.
Microsphere morphology and particle size
determination:
The morphology of prepared microparticles was evaluated by optical microscopy.
Particle size range and distribution of
microspheres were determined using standard sieves8.
Drug content and efficacy measurement:
To determine drug entrapment within the microparticles, 100 mg of microparticles
was dissolved in 100 ml of HCl (0.1 N). After
complete dissolution, the amount of drug was quantified using a
spectrophotometric method at 292 nm in the presence of a blank prepared from microparticles containing all materials except the drug.
Drug loading was determined as the percentage of the amount of the drug
obtained to the applied amount9,10.
Efficacy of the microspheres preparation method was determined by dividing the
amount of the prepared microspheres to the initial amount of the applied
material. Drug entrapment within the double coated microparticles
was determined by dissolving 100mg of microparticles
in 100ml of HCl. The amount of drug was measured
spectrophotometrically11,12.
Release studies:
Profiles of drug release from the prepared microparticles were studied using a USP (Apparatus I)
dissolution tester.100 mg of microparticles was
incubated in 900 ml 0.1N HCl. The media were agitated
at 50 rpm, while maintaining the temperature at 37°C. 5 ml samples were
withdrawn from the dissolution medium at regular time intervals and replaced
with fresh medium. Concentration of the withdrawn samples was measured spectrophotometrically as mentioned above.13-15 In
order to investigate the influence of EC and mucoadhesive
polymer on the release profiles of microparticles,
two dissolution tests (one of ethyl cellulose core microparticles
and other after double coating with the mucoadhesive
polymer) were set in hydrochloric acid (as the gastric medium) for 2 h and then
Phosphate buffer as intestinal medium for 22 hours16,17.
RESULTS AND DISCUSSION:
Development of microparticulate
drug delivery systems using a combination of polymers has significant
advantages over the homogenous polymeric systems. Through these systems by the
selection of an appropriate combination of core and coat polymers, a microparticulate system for simultaneous entrapment of
hydrophilic and hydrophobic drugs can also be achieved. Indeed, the drug could
be entrapped in the core material using the proper characteristics of the core
polymer while it properties are improved by the desirable properties of the
coating material18-20.
Ethyl cellulose is an interesting rate
controlling polymer for drug delivery. It also provides an enteric coating
property for the advantage of the drug. However, for increasing the efficacy of
the drug, the mucoadhesive polymer aids in its
localized as well as systemic action. The purpose of this study was to present
an approach for the preparation of double coated microparticles
having mucoadhesion property suitable for oral
application. These double coated microparticles were
prepared using different mucoadhesive polymers and
various ratios of core and coat materials ethyl cellulose. Rabeprazole
was used as the model drug to investigate the ability of the system for
entrapment and controlling drug release in the gastrointestinal medium21,22.
Production of microparticles
under different conditions was investigated. From these experiments it was
possible to encapsulate with various mucoadhesive
polymers (HPMC and EC+PVP), leading to the formation of particles with mucoadhesive characteristics23.
Microscopic observations (Figure 1) showed
that all the dried microparticles were almost
spherical, free flowing and non-aggregated. The microparticles
were stable at low pH values. The size of the microparticles
varied between 50 to 400 µm, while 92% of the particles had a size range
between 50 to 250 µm. However, about 60% of the microparticles
fall within the 100 to 250 µm size range. These results were not much different
for the three microparticles preparation conditions
applied. Figure 2 shows the particle size distribution of the prepared
microparticles24.
Figure 1:
Drug release data (Formulation D1) :
Figure 2:
Drug release data (Formulation D2) :
The swelling index study and in-vitro bioadhesion study were also carried out for both the
formulations to judge the mucoadhesive behavior of
the formulations as shown in the table. In the swelling index study, the
increased percentage of weight was calculated, after imbibitions of water. The microparticles of the both the formulations showed more or
less the same increase in weight after absorbing water. In the in-vitro bioadhesion study, the microparticles
of the formulation D2 (with EC+PVP)
showed more persistent sticking to the bio-tissue. Though, the formulation D1
(with HPMC) also showed an acceptable amount of bioadhesion to the tissue25.
The entrapment efficiencies and preparation
efficacy of different prepared samples consisting of various polymers are shown
in table 1. The drug entrapment was also good in all samples, being about 74%
for the primary microspheres. Furthermore, this amount did not differ for the
coated microspheres, showing negligible drug loss during the second reaction33,34,35.
Table 1: Drug
microencapsulation efficacy of mucoadhesive polymers
and ethyl cellulose (n=3)
|
Formulation |
Drug content (in 100 mg) |
Drug entrapment
efficiency (%) |
|
With HPMC (D1) |
3.715 |
88.748 ± 0.059 |
|
With EC + PVP (D2) |
2.589 |
73.436 ± 0.082 |
DISCUSSION:
The percentage yields of both the double
coated formulations were found to be satisfactory as shown in the table 3.
Though, percentage yield of the formulation D1 was more in
comparison to the formulation D2. Whereas, in the case of particle
size analysis, the double coated microparticles had
attained increased particle size than the singly coated microparticles.
The formulation D2 showed the bigger particles in comparison to the
formulation D1. But the microparticles of
the formulation D1 were more spherical and regular than that of the
formulation D2. Results are shown in Table -2.
Table 2: Particle
Size analysis
|
Formulation |
Particle size |
|
D1 |
146.23 ± 0.380 |
|
D2 |
206.43 ± 0.067 |
The drug content study showed a slight
decrease in the drug content of the final, double coated formulation in
comparison to the singly coated formulation. The drug entrapment though was
more in the case of the formulation D1 than in the formulation D2.
The drug entrapment data are shown in Table -1.
Table 3:
In-vitro bioadhesion data:
|
Time (min.) |
Microparticles adhered to the tissue |
|
|
D1 |
D2 |
|
|
10 |
70(2.1) |
71(1.7) |
|
20 |
60(1.9) |
58(1.7) |
|
30 |
51(1.2) |
57(1.2) |
|
40 |
43(1.7) |
52(1.4) |
|
50 |
39(1.5) |
48(1.6) |
|
60 |
34(1.8) |
41(1.9) |
|
70 |
29(1.6) |
37(1.3) |
|
80 |
27(1.5) |
35(1.5) |
|
90 |
27(1.3) |
32(1.8) |
|
100 |
27(1.0) |
31(1.4) |
Table 4: Drug
release data: Formulation D1:
|
Time (hrs) |
Abs. |
Concentration (μg) |
Conc. in pipetted vol.(mg) |
Conc. in 900 ml (mg) |
CR |
%CR |
|
0.5 |
0.163 |
3.32653061 |
0.01663265 |
2.99387755 |
2.9938775 |
14.969388 |
|
1 |
0.294 |
6 |
0.03 |
5.4 |
5.41663265 |
27.083163 |
|
1.5 |
0.337 |
6.87755102 |
0.03438776 |
6.18979592 |
6.21979592 |
31.09898 |
|
2 |
0.355 |
7.24489796 |
0.03622449 |
6.52040816 |
6.55479592 |
32.77398 |
|
2.5 |
0.363 |
7.40816327 |
0.03704082 |
6.66734694 |
6.70357143 |
33.517857 |
|
3 |
0.375 |
7.65306122 |
0.03826531 |
6.8877551 |
6.92479592 |
34.62398 |
|
3.5 |
0.468 |
9.55102041 |
0.0477551 |
8.59591837 |
8.63418367 |
43.170918 |
|
4 |
0.487 |
9.93877551 |
0.04969388 |
8.94489796 |
8.99265306 |
44.963265 |
|
4.5 |
0.492 |
10.0408163 |
0.05020408 |
9.03673469 |
9.08642857 |
45.432143 |
|
5 |
0.502 |
10.244898 |
0.05122449 |
9.22040816 |
9.27061224 |
46.353061 |
|
5.5 |
0.546 |
11.1428571 |
0.05571429 |
10.0285714 |
10.0797959 |
50.39898 |
Table 5: Drug
release data:
|
Time (hrs) |
Abs. |
Concentration (μg) |
Conc. in pipetted vol.(mg) |
Conc. in 900 ml(mg) |
CR |
%CR |
|
0.5 |
0.174 |
3.55102 |
0.017755 |
3.195918 |
3.195918 |
15.97959 |
|
1 |
0.273 |
5.571429 |
0.027857 |
5.014286 |
5.032041 |
25.1602 |
|
1.5 |
0.306 |
6.244898 |
0.031224 |
5.620408 |
5.648265 |
28.24133 |
|
2 |
0.248 |
5.061224 |
0.025306 |
4.555102 |
4.586327 |
22.93163 |
|
2.5 |
0.309 |
6.306122 |
0.031531 |
5.67551 |
5.700816 |
28.50408 |
|
3 |
0.329 |
6.714286 |
0.033571 |
6.042857 |
6.074388 |
30.37194 |
|
3.5 |
0.323 |
6.591837 |
0.032959 |
5.932653 |
5.966224 |
29.83112 |
|
4 |
0.316 |
6.44898 |
0.032245 |
5.804082 |
5.837041 |
29.1852 |
|
4.5 |
0.351 |
7.163265 |
0.035816 |
6.446939 |
6.479184 |
32.39592 |
|
5 |
0.358 |
7.306122 |
0.036531 |
6.57551 |
6.611327 |
32.50561 |
|
5.5 |
0.483 |
9.857143 |
0.049286 |
8.871429 |
8.907959 |
41.13878 |
Formulation D2:
Table 6: Drug release
kinetics data:
|
Formulation (Drug:Polymer) |
Zero-Order |
First-Order |
Higuchi Model |
Korsenmeyer- Peppas Model |
Mechanism of drug
release |
||||
|
|
R2 |
K |
R2 |
K |
R2 |
K |
R2 |
n |
|
|
D1 |
0.912 |
6.022 |
0.939 |
-0.040 |
0.949 |
19.32 |
0.942 |
0.450 |
Fickian |
|
D2 |
0.392 |
4.948 |
0.925 |
-0.012 |
0.917 |
18.05 |
0.601 |
0.234 |
Fickian |
The swelling index study and in-vitro bioadhesion
study were also carried out for both the formulations to judge the mucoadhesive behavior of the formulations as shown in the
table 4 and 5 respectively. In the swelling index study, the increased
percentage of weight was calculated, after imbibitions of water. The microparticles of the both the formulations showed more or
less the same increase in weight after absorbing water. In the in-vitro bioadhesion
study, the microparticles of the
formulation D2 showed more persistent sticking to the bio-tissue.
Though, the formulation D1 also showed an acceptable amount of bioadhesion to the tissue29,30.
The rheological study of both the
formulations was also satisfactory as shown in the table 3. Both the
formulations showed a good rheological characteristic. Though, the microparticles of formulation D1 showed the
better flowing ability than the microparticles of
formulation D2.
In-vitro kinetics study of both the formulations was shown in
the table-6.
CONCLUSION:
From the above experimental work under double coating,
it can be concluded that the formulation containing double coated microparticles comprising of HPMC as mucoadhesive
polymer ( D1) gives the
most satisfactory results compared to the double coated microparticles
comprising of EC+PVP i.e.,(D2).
Thus this formulation with HPMC was selected for further experimental work.
REFERENCES:
1.
Ussain Altaf, Hasan
Al-Saeed Abdul Hamid, Syed Shahid Habib.
Effect of single oral dose of sodium rabeprazole on
the intragastric pH and volume in patients
undergoing elective surgery.Ind J Med Res 2008;127(2-):165-70.
2.
Ace Fabio, Pallotta Stefano, Casalini Stefania, Gabriele Bianchi Porro.
A review of rabeprazole
in the treatment of acid-related diseases. Therapeutics Clinlical Risk Management 2007;3(3):363-79.
3.
ARIET, Rabeprazole sodium (Enteric Coated Tablets) Product
Monograph, RA Approved 8/ 2008 www.janssen-ortho.com
4.
Ali Nokhodchi, Javad Farid D. Microencapsulation of Paracetamol by Various
Emulsion Techniques Using Cellulose Acetate Phthalate. Pharmaceutical Technology 2002:54-60.
5.
Hourasia MK, Jain SK. Pharmaceutical approaches to colon
targeted drug delivery systems. J. Pharm.Sci. 2003;6:33-66.
6.
Uleu C, Andrieux C, Cherbuy C et al., Colonic delivery of sodium butyrate via
oral route: Acrylic coating design of pellets and in vivo evaluation in rats.
Method Find Exp. Clin 2001;23:245-53.
7.
Fori-Kwakye K, Fell JT. Leaching of pectin from mixed films containing
pectin, chitosan and HPMC intended for biphasic drug
delivery. Int. J. Pharm 2003;250:251-57.
8.
Hrabi SF Madsen G Dyrstad K et
al., Development of pectin matrix tablets for colonic delivery of model drug ropivacaine. Eur. J. Pharm. Sci.2000;10:43-52.
9.
Li JK, Wang N, Wu
XS. Gelatin nanoencapsulation of protein/peptide
drugs using an emulsifier-free emulsion method. J. Microencapsul
1998;15(2):163-72.
10.
Turkoglu M, Ugurlu T. In vitro
evaluation of pectin-HPMC compression coated 5-aminosalicylic acid tablets for
colonic delivery. Eur. J. Pharm. Biopharm 2002;
53(1):65-73.
11.
Kim BK, Hwang SJ,
Park JB, Park HJ, Preparation and characterization of drug-loaded polymethacrylate microspheres by an emulsion solvent
evaporation method. J. microencapsulation 2002; 19(6):811-22.
12.
Pachuau L, Sarkar S, Mazumder B. Formulation and evaluation of matrix
microspheres for simultaneous delivery of salbutamol sulphate and theophylline -- Tropical Journal of Pharmaceutical Research
2008;7(2):995-1002.
13. Alex R, Bodmeier R.
Encapsulation of water-soluble drugs by a modified solvent evaporation method
and Effect of process and formulation variables on drug entrapment –Journal of Microcapsulation 1990;7(3):347-55.
14. Kim H, Cho M, Sah H. Development of New Reverse Micellar Microencapsulation Technique to Load Water-Soluble
Drug into PLGA Microspheres. Arch Pharm Res 2005;28(3):370-5.
15. Morkhade
DM, Joshi SB. Evaluation of gum damar as a novel microencapsulating material for ibuprofen
and diltiazem hydrochloride –Indian Journal of
Pharmaceutical Sciences 2007;69(2):263-68.
Received
on 02.07.2010
Accepted on 02.08.2010
© A&V Publication all right reserved
Research Journal of Pharmaceutical
Dosage Forms and Technology.
2(5): Sept.-Oct. 2010, 335-339