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Tirupati M. Rasala et al.

/ Journal of Pharmacy Research 2010, 3(7),1531-1534


Research Article
ISSN: 0974-6943 Available online through
www.jpronline.info
Comparative Study of Ionotropic Gelation Technique To Entrap Diltiazem HCl In Mucoadhesive
Microparticulate System.
Tirupati M. Rasala.*, Govind K. lohiya, Vinita V. Kale., Jasmine G. Avari
Gurunanak College of pharmacy, Nagpur
Received on: 12-04-2010; Revised on: 126-05-2010; Accepted on:19-06-2010

ABSTRACT
The aim of present investigation was to compare the ionotropic gelation techniques for entrapping water soluble drug Diltiazem HCl in mucoadhesive
microparticulate system. Mucoadhesive polymers HPMC K15 and Carbapol 934 were used in combination with sodium alginate which provides gastric
retention for prolonged time. Diltiazem HCl microcapsules were formulated by orifice-ionic and emulsification-ionic gelation technique. The formulated microcapsules
of Diltiazem HCl were evaluated for the following parameters viz. Particle size, entrapment efficiency, in-vitro drug release and percent mucoadhesive strength.
FT-IR and SEM were used to characterize microcapsules. The results of both techniques were compared. It was evident from study that, the entrapment
efficiency of Diltiazem HCl was improved (46% - 61%) in emulsification-ionic gelation technique, as compared to orifice-ionic gelation technique (<15%). Thus
it was concluded that emulsification-ionic gelation technique is superior to orifice-ionic gelation technique to entrap water soluble drug Diltiazem HCl. The drug
release from the microcapsules were found to be slow and spread over extended period of time, drug release depends on the percent of coat material, wall thickness
and size of microcapsule. Microcapsule with a coat comprised sodium alginate, HPMC and carbapol exhibited good mucoadhesive properties as observed in in-
vitro wash-off test.

Key words:Mucoadhesion, Microcapsule, Ionotropic-gelation method, DDS, DEE,

INTRODUCTION
Oral bioavailability of certain drug can be limited by the residence India). Sodium alginate was gift sample from TIC Gums (USA), HPMC K15
time of the pharmaceutical formulations in the upper gastrointestinal tract. (Colorcon Asia PVT, LTD. Goa India), Carbapol (Noveon USA) and all other
Gastric emptying plays an important role in the dynamics of drug absorption chemicals used were of analytical grade.
and can lead to variable and unpredictable availability. The ability to maintain an
oral delivery system at the target absorption location for an extended period of METHODS:
time has great appeal for treatment of both local conditions as well as for
sustained systemic absorption. Several strategies have been proposed to modify preparation of mucoadhesive microcapsule of diltiazem hcl by
the GI transit of oral pharmaceutical formulations such as floating, high-density orifice- ionic gelation method
system, expandable, swelling system etc. Mucoadhesive drug delivery is one of
the approaches to design a formulation, which can adhere to the lining of the Microcapsules were prepared by orifice-ionic gelation method. So-
stomach, thus retaining the drug at the target absorption site for a prolonged dium alginate and mucoadhesive polymer such as HPMC K15 and Carbopol
period. This approach involves the use of bioadhesive polymers, which can 934 were dissolved in purified water to form a homogeneous polymer solution.
adhere to the epithelial surface in the stomach [1, 2]. The core material as fine powder was passed through mesh no. 120, added to
the polymer solution and mixed to form a smooth viscous dispersion. This
Drug delivery systems (DDS) that can precisely control the release dispersion was added drop wise into 10%w/v CaCl2 solution through a syringe
rates or target drugs to a specific body site had an enormous impact on the with a needle of diameter 0.55mm. The added droplets were retained in CaCl2
healthcare system. Carrier technology offers an intelligent approach for drug solution and allowed to cure for 20 minutes at 200 rpm to produce spherical
delivery by coupling the drug to a carrier particle such as microspheres, rigid microcapsules. The microcapsules were collected and dried in an oven at a
nanoparticles, liposomes, etc. which modulates the release and absorption char- temperature 450 C for 12 h.
acteristics of the drug. Bioadhesive microspheres include microparticles and
microcapsules (having a core of the drug) of 1–1000µm in diameter and consist- preparation of mucoadhesive microcapsule of diltiazem hcl by emulsifi-
ing either entirely of a bioadhesive polymer or having an outer coating of it, cation ionic gelation method. [4,5,6].
respectively. Microparticles constitute an important part of these particulate
DDS by virtue of their small size and efficient carrier characteristics. However, The microcapsules were formulated as per the same formulation
the success of these novel DDS is limited due to their short residence time at the compositions as described in the previous method. The dispersion of drug and
site of absorption. It would, therefore, be advantageous to have means for polymer with sodium alginate was added dropwise into 300 ml of olive oil
providing an intimate contact of the DDS with the absorbing membranes. It can containing 1.5% span with stirring at 200 rpm. Stirring was continued for 5 min
be achieved by coupling bioadhesion characteristics to microparticle and devel- to emulsify droplets. The droplets were cured for 20 min in calcium chloride
oping novel delivery systems referred to as “bioadhesive microparticle” [1,3]. (10% w/v) solution. Finally, the microcapsules were filtered, washed and dried
at 45ºC for 12 h.
MATERIALS:
Diltiazem HCl was a generous gift sample from ZIM Labs (Nagpur, Comparative evaluation of formulated microcapsules

*Corresponding author. The microcapsules formulated by both techniques were subjected to


Tirupati M. Rasala. various evaluation tests like particle size, drug content, Percentage entrapment
Gurunanak College of pharmacy, Nagpur efficiency, % drug release and mucoadhesive test.
Tel.: + . 0712-2633855, 26595623, 09975321358
Telefax: +91- 0712-2633851
E-mail:tirupati_rasala@yahoo.co.in
Journal of Pharmacy Research Vol.3.Issue 7.July 2010 1531-1534
Tirupati M. Rasala et al. / Journal of Pharmacy Research 2010, 3(7),1531-1534
Table1: Core coat ratio and coating composition of microcapsules. perform in-vitro dissolution study.
Batch code Core (w/w) Coat In-vitro drug release studies for diltiazem hcl prepared by emulsifica-
Coat (w/v) Ratio Composition (w/v)
tion ionic-gelation method
MH1 1:1 Na Alginate: HPMCK15 (1:1)
MH2 1:2 Na Alginate: HPMCK15 (2:1) In vitro release rate studies were carried out using USP dissolution
MH3 1:3 Na Alginate: HPMCK15 (3:1)
MC1 1:1 Na Alginate: Carbopol 934 (1:1) apparatus Type I (Veego Scientific, 6 ST). Simulated gastric fluid of pH 1.2
MC2 1:2 Na Alginate: Carbopol 934 (2:1) with SLS (1%W/V) was used as dissolution medium (900 ml) and was main-
MC3 1:3 Na Alginate: Carbopol 934 (3:1) tained at 37o C ± 0.5o C. The basket speed was controlled at 100 rpm. Aliquots
of 10 ml were withdrawn at different time intervals up to 12 h and a 10 ml of
Table 2: Values of physical parameters and drug content for mucoadhesive fresh medium was added to replace the sample that was withdrawn. Drug
microcapsule of diltiazem HCl prepared by orifice- ionic gelation method. content of the microcapsule was determined by UV spectroscopy at 236 nm,
after suitable dilution of the samples. Dissolution studies were performed three
Batch code Particle size Drug content (Diltiazem) of %Microencapsulation times and the mean values were taken.
microcapsules Efficiency
Theoretical Practical
Measurement of percent mucoadhesive strength [5,6,9]
MH1 806.95± 5.51 50.0 3.35 6.7
MH2 844.45 ± 4.43 33.33 3.71 11.13 The mucoadhesive properties of the microcapsules were evaluated
MH3 886.56 ± 5.44 25.0 2.71 10.80
MC1 901.13 ± 8.39 50.0 6.3 12.60
by in-vitro wash off test as reported by Lehr et al. A 1cm by 1cm piece of rat
MC2 921.03 ± 7.67 33.33 5.61 16.83 stomach mucosa was tied onto a glass slide (3 inch by 1 inch) using thread.
MC3 927.73 ± 8.49 25.0 3.92 15.68 Microcapsules were spread (50) onto the wet, rinsed, tissue specimen and the
prepared slide was hung onto one of the groves of a USP tablet disintegrating
Table 3: Values of physical parameters and drug content for mucoadhesive test apparatus. The disintegrating test apparatus was operated such that the
microcapsule of diltiazem HCl prepared by emulsification- ionic gela- tissue specimen was given regular up and down movements in a beaker contain-
tion method ing 1.2 pH and pH 6.8 buffer solution. At the end of every hour the number of
Batch code Particle size Drug content of % Microencapsulation
microcapsules still adhering onto tissue was counted.
( Mean+ SD) µm ( Diltiazem) Efficiency
Diltiazem HC MC3 microcapsules RESULTS AND DISCUSSION:
Theoretical Practical
MH1 803.59 ± 4.51 50.0 23.04 46.08 Morphological characteristics of microcapsules:
MH2 812.43 ± 3.43 33.33 18.12 54.36
MH3 823.52 ± 5.44 25.0 14.56 58.24
MC1 856.13 ± 7.13 50.0 23.67 47.34
The mucoadhesive microcapsules of Diltiazem HCl prepared by
MC2 867.23 ± 4.67 33.33 18.57 55.71 orifice and emulsification ionic gelation method were found to be discrete,
MC3 887.03 ± 8.49 25.0 15.37 61.48 spherical, free flowing. The microcapsules were uniform in size, with size range
of 806.9 µ to 927.7 µ and 803.5 µ to 887.03 µ respectively. The SEM Photo-
Table 4: Mechanism of drug release from optimized formulations graph indicated that the microcapsules were spherical and completely covered
Models r value n value the coat polymer (Figure 2). The microencapsulation efficiency was in the
range of 6.7-15.68 % and 46.08-61.48% respectively (Figure 1).
MH3 MC2 MC3
Korsmeyer-peppas 0.9975 0.9965 0.9975 0.9368
Zero order 0.9974 0.9962 0.9977 0.8702 In-vitro drug release studies:
Estimation of Diltiazem HCl The encapsulation efficiency of diltiazem HCl prepared by orifice
ionic gelation method was very low (6.7-15.68 %) so, in-vitro dissolution
Diltiazem HCl was estimated spectrophotometrically at 236nm us- studies were not performed on diltiazem HCl mucoadhesive microcapsules.
ing UV spectrophotometer shimadzu, 1601(Japan).
The in-vitro dissolution studies of the diltiazem HCl microcapsules
Size analysis and Percentage encapsulation efficiency: prepared by emulsification ionic gelation method were carried out in simulated
gastric fluid(0.1M HCL, pH 1.2 with SLS 1%) and simulated intestinal fluid
The microcapsules size was determined by using optical micros- (phosphate buffer 6.8) using USP type I (basket) apparatus in 900ml of disso-
copy method. The entrapment efficiency was calculated by sonicating 100 mg lution media for the 12 hours. The formulation batch MH1 has shown 98.75%
of microcapsules in 100 ml of pH 6.8 buffer for a period of 2 hours to facilitate drug release in 10 hr and MH3 has shown 97.16% in 12 hr. Batch MC2 and
the complete dissolution of the microcapsules. The drug released was spectro- MC3 released 98.14% and 94.90 % drug in 12 hr in pH 1.2 with SLS 1%
photometrically analysed. The entrapment efficiency in percentage was calcu- respectively. The batch MH2 and MH3 has shown 98.88% and 97.48% drug
lated as per the following formula. release in 8 hrs respectively. Similarly the batch MC2 and MC3 released 98.13
Practical drug content % and 93.51% drug in 8 hrs in phosphate buffer 6.8 respectively.
DEE = × 100
Theoretica l drug content
Drug release kinetics
Scanning electron microscopic analysis:
The release mechanism of diltiazem HCl from most optimized for-
The morphology and the surface texture of the microcapsules were mulations, batches MH3, MC2 and MC3 was studied by fitting the data
studied using Scanning electron microscopy (SEM). obtained from in-vitro release studies into zero order, first order, Higuchi,
Korsmeyer-peppas and Hixon-crowell models.
In-vitro drug release studies:
On the application of different release models, it was found that the opti-
The Highest encapsulation efficiency of Diltiazem HCl prepared by mized formulation of diltiazem HCl (batch MH3 and MC2) follows the
orifice-ionic gelation method was found to be 15%; so there is no significance to Korsmeyer-peppas model. The value of ‘n’ was found to be be 0.9368 which

Journal of Pharmacy Research Vol.3.Issue 7.July 2010 1531-1534


Tirupati M. Rasala et al. / Journal of Pharmacy Research 2010, 3(7),1531-1534
120

% cumulative drug
80 MH1
DIL I
% Entrapment efficiency

100
DIL II MH2
60 80

release
MH3
60 MC1
40
40 MC2
20 20 MC3
0
0 0 2 4 6 8 10
MH1 MH2 MH3 MC1 MC2 MC3 Time (hrs)
Batch Code Fig 4: Cumulative % drug release of diltiazem HCl in pH 6.8
Figure 1: Comparative entrapment efficiency of dltiazem HCl 120

% Mucoadhesion
microcapsules prepared by orifice-ionic and emulsification ionic gela- 100
tion method. 80 MH1
60 MH2
40 MH3
20 MC1
0
MC2
0 2 4 6 8 10
MC3
Time (hr)

Fig 5: Mucoadhesion behaviour of microcapsule formulations in PH 1.2


a)Spherical microcapsule with size 806.95µ (×85) b) surface texture of
120
microcapsules (×500) Diltiazem HCl microcapsules prepared by orifice-
ionic gelation method
% Mucoadhesion

100
MH1
80
MH2
60 MH3
40 MC1
MC2
20
MC3
0
0 1 2 3 4 5 6 7
Time (hr)
c)Spherical microcapsule with size 851.2 (×85) d) surface texture of Fig 6: Mucoadhesion behaviour of microcapsule formulations in 6.8
microcapsules(×1500) Diltiazem HCl microcapsules prepared by
buffer
emulsification-ionic gelation method
120 120
% Mucoadhesion

100 100
MH1
% cumulative drug

MH1 80
80 MH2
MH2 60
release

60 MH3 40 MH3
MC1 MC1
20
40 MC2
MC3 0 MC2
20 0 2 4 6 8 10 MC3
0 Time (hrs)
0 2 4 6 Time 8 10 12 14

Figure 2: Scanning electron microscopy of Diltiazem HCl microcapsules Fig 7: Mucoadhesion behaviour of microcapsule formulations in pH 1.2
prepared by ionic gelation method 120
120 100
% Mucoadhesion
% cumulative drug

MH1
100 80
MH2 MH1
80 60
release

MH3 MH2
60 MC1 40 MH3
MC1
40 MC2 20
MC2
0
20 MC3 MC3
0 2 4 6 8 10
0
Time (hrs)
0 2 4 6 8 10
Time (hrs)
Fig 8: Mucoadhesion behaviour of microcapsule formulations in pH 6.8
Fig 3: Cumulative % drug release of diltiazem HCl in pH 1.2
Journal of Pharmacy Research Vol.3.Issue 7.July 2010 1531-1534
Tirupati M. Rasala et al. / Journal of Pharmacy Research 2010, 3(7),1531-1534
indicates that it follows non-fickian diffusion. The formulation batch MC3 ACKNOWLEDGMENTS:
follows the zero order release which show constant drug release rate with time
(table 4). The authors are very much thankful to ZIM Lab, Colorcon, Noveon,
TIC gums for providing gift sample and also to UGC for providing financial
CONCLUSION: assistance.

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Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.3.Issue 7.July 2010 1531-1534

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