Trilayer Mucoadhesive Gastro Retentive Tablets: Formulation and In vitro Evaluation

Abstract

The present study deals with drug release enhancement of Metformin HCl using mucoadhesive technology by optimization of mucoadhesive agent to improve the mucoadhesion time. Metformin HCl is an oral antihyperglycemic agent of biguanide class used in treatment of type 2 Diabetes. It is hydrophilic drug which absorbed slowly and not completely from the gastrointestinal tract. The absolute bioavailability is reported to be 50-60%. The sustained release trilayered mucoadhesive tablets of Metformin HCl were formulated by direct triple compression method using various mucoadhesive polymers. First and third layer (mucoadhesive layers) was comprises a blend of polymers such as Carbopol 940 and HPMC K100M. The second layer which is sandwiched between first and third layer contained 250 mg Metformin HCl along with release retardant Ethyl Cellulose. Batches F1, F2 and F3 were formulated. The formulated tablets were evaluated for weight variation, hardness, thickness and friability. Tablets were also evaluated for swelling index, mucoadhesive force, mucoadhesion time and in vitro drug release study. All the tablets were hydrated rapidly, mucoadhesive time were found highest in batch F2 which comprises of 1:2 ratio of Carbopol 940 and HPMC K100M in both first and third layer. The 83.80% drug released was observed in batch F2 within 8 hrs.

Full text

Journal of Pharmacy Research Vol.5 Issue 5.May 2012
Uddhav S. Bagul et al. / Journal of Pharmacy Research 2012,5(5),2463-2466
2463-2466
Research Article
ISSN: 0974-6943 Available online through
www.jpronline.info
*Corresponding author.
Uddhav S. Bagul
STES’s Sinhgad Institute of Pharmacy,
Narhe, Pune – 41,Maharastra,India
Trilayer Mucoadhesive Gastro Retentive Tablets: Formulation and In vitro Evaluation
Uddhav S. Bagul,1* Ramakant V. Patil,1 Niranjan V. Patil,1 Kishor N. Gujar2
1STES’s, Sinhgad Institute of Pharmacy, Narhe, Pune - 41, Maharastra,India
2STES’s, Smt. Kashibai Navale College of Pharmacy, Kondhava, Pune - 48,Maharastra,India
Received on:11-01-2012; Revised on: 17-02-2012; Accepted on:19-04-2012
ABSTRACT
The present study deals with drug release enhancement of Metformin HCl using mucoadhesive technology by optimization of mucoadhesive agent to
improve the mucoadhesion time. Metformin HCl is an oral antihyperglycemic agent of biguanide class used in treatment of type 2 Diabetes. It is hydrophilic
drug which absorbed slowly and not completely from the gastrointestinal tract. The absolute bioavailability is reported to be 50-60%. The sustained release
trilayered mucoadhesive tablets of Metformin HCl were formulated by direct triple compression method using various mucoadhesive polymers. First and
third layer (mucoadhesive layers) was comprises a blend of polymers such as Carbopol 940 and HPMC K100M. The second layer which is sandwiched
between first and third layer contained 250 mg Metformin HCl along with release retardant Ethyl Cellulose. Batches F1, F2 and F3 were formulated. The
formulated tablets were evaluated for weight variation, hardness, thickness and friability. Tablets were also evaluated for swelling index, mucoadhesive force,
mucoadhesion time and in vitro drug release study. All the tablets were hydrated rapidly, mucoadhesive time were found highest in batch F2 which comprises
of 1:2 ratio of Carbopol 940 and HPMC K100M in both first and third layer. The 83.80% drug released was observed in batch F2 within 8 hrs.
Keywords:Trailayer tablets, gastroretention, mucoadhesion, metformine HCl
INTRODUCTION:
Despite tremendous advancement in the drug delivery system, oral route
remains the preferred route for the administration of therapeutic agents and
because of low cost therapy and ease of administration leads to higher levels
of patient compliance. Conventional oral dosage forms such as tablets and
capsules provide specific drug concentration in systemic circulation without
offering any control over drug delivery and also cause great fluctuations in
plasma drug levels. The design of oral controlled drug delivery system should
be primarily aimed to achieve more predictable and increased bioavailability.[1]
Conventional tablet have limitation of low residence time at absorption site
and so repetitive administration of drug to obtain required bioavailability
leading to poor patient compliance and hence loss of therapeutic efficacy.[2]
An incomplete release of the drug and shorter residence time of the dosage
forms in the upper GIT, which is a prominent site for the absorption of many
drugs, leads to decreased bioavailability.[3] Drug absorption from gastrointes-
tinal tract is a complex procedure and is subject to many variables. It has been
reported that the extent of GIT drug absorption is related to contact time
with the small intestinal mucosa. Gastro retentive systems can remain in the
gastric region for several hours and therefore significantly prolong the gastric
residence time of drugs.[4]
Many approaches have been reported in the literature for the formulation of
gastroretentive drug delivery systems viz. mucoadhesion, floatation, sedi-
mentation, expansion, modified shape systems or by the simultaneous ad-
ministration of pharmacological agents which delay gastric emptying. Both
single unit systems (tablets or capsules) and multiple unit systems (multi
particulate systems) have been reported in the literature.[5] The major ab-
sorption zone, stomach or upper part of intestine, can result in incomplete
drug release from the drug delivery system leading to diminished efficacy of
the administered dose. Therefore, localizing the drug delivery in a specific
region of the gastrointestinal tract due to its mucoadhesiveness increases the
intimacy and duration of contact between the drug containing polymer and
the mucous surface.[6] Metformin HCl is an orally administered biguanide
derivative widely used in the treatment of non-insulin dependent diabetes
mellitus. It improves glycaemic control by enhancing insulin sensitivity in
the liver and muscles. The drug has also exhibited beneficial effects on several
cardiovascular risk factors such as dyslipidemia, elevated plasma plasmino-
gen activator inhibitors, other fibrinolytic abnormalities, and hyperinsulinemia
and insulin resistance.[7] Metformin HCl is an anti-hyperglycemic agent, which
improves glucose tolerance in type II diabetes. It has been reported that the
absolute bioavailability of Metformin HCl when given orally is 50–60%.
Biological half-life of Metformin HCl is 1.5–1.6 h and the main site of its
absorption is proximal small intestines.[8]
The formulation suitable for Metformin HCl, therefore, should be a gastro
retentive dosage form, which releases the drug slowly in the stomach for
gradual absorption in the intestines. The slow but complete drug release in
the stomach is expected to increase bioavailability of the drug as well its
complete utilization which may results to lower dose and GI side effects.
MATERIAL AND METHOD:
Metformin HCl was supplied as a gift sample from Centaur Pharmaceutical
Ltd., Pune. HPMC K100M was brought from Ranbaxy. Carbopol 940 was
procured from Pure Chem Laboratory and Ethyl Cellulose was supplied
from Thomas Baker hem Ltd.
Preparation of trilayer mucoadhesive compressed tablet:
Composition of the trilayer tablet is given in Table 1. In preliminary study
several batches were formulated and evaluate and the three best batches were
selected for further study. Trilayer Mucoadhesive Tablets were prepared by
direct triple compression method. Mucoadhesive layer (First & Third Layer)
HPMC K100M and Carbopol 940 while sustain release layer (Second Layer)
contains drug and Ethyl Cellulose. Tablets were prepared in three stages
using 12 mm die on CIPS Lab Press. Initially, first layer of mucoadhesive
polymer blend was compressed (first compression) for 5-10 seconds then
second layer blend was added and a second compression was performed for
20-25 seconds further third layer ingredients are added and compressed to get

Journal of Pharmacy Research Vol.5 Issue 5.May 2012
Uddhav S. Bagul et al. / Journal of Pharmacy Research 2012,5(5),2463-2466
2463-2466
trilayer tablet.
Evaluation of Tablet:
1. Tablet weight variation:[9]
Twenty tablets were randomly selected and accurately weighed and were
evaluated for weight variation.
2. Tablet thickness:[9]
A vernier caliper was used to determine thickness of 10 randomly selected
tablets.
3. Drug content uniformity:[10]
For drug content uniformity, 20 tablets were weight and crushed. An accu-
rately weighed 0.05 g drug equivalent powder was transferred to 100 ml of
0.1 N HCl. This suspension was stirred on a magnetic stirrer for 5 h. The
suspension was then filtered and the drug content was determined at 233 nm
by making suitable dilutions.
4. Tablet friability:[11]
According to the BP specifications, 10 tablets were randomly selected and
placed in the drum of a tablet friability test apparatus (Electrolab). The drum
was adjusted to rotate 100 times in 4 min. The tablets were removed, dedusted
and accurately weighed. The percent weight loss was calculated.
5. Swelling index:[12]
Swelling index were determined for each formulation batch, one tablet was
weighed and placed in a beaker containing 200 ml of 0.1 N HCl. After each
interval the tablet was removed from beaker and weighed again up to 6 hours.
The swelling index was calculated using following formula,
Swelling Index (S.I.) = (Wt – Wo)/Wo
Where,
S.I. = Swelling index
Wt = Weight of tablet at time t
Wo = Weight of tablet before placing in the beaker
Fig. 1: Apparatus for measurement of mucoadhesive strength.
6. Exvivo Bioadhesion Studies:[13]
The exvivo adhesion studies were conducted using a modification of a test
assembly described by Madgulkar et al. The sheep stomach mucosa was
kept frozen in 0.1 N HCl and thawed to room temperature before use. The
membrane was excised by removing the underlying connective and adipose
tissue and was equilibrated at 37±0.5°C for 30 min in 0.1 N HCl before the
study. The tablet was placed on mucosa under constant weight of 5 g for a
total contact period of 1min. Bioadhesive strength was assessed in terms of
weight (grams) required for detaching the tablet from the membrane.(Fig. 1)
7. Exvivo mucoadhesion time:[14]
The fundus tissues of the sheep were fixed on internal side of beaker with
cyanoacrylate glue. Each tablets previously wetted 0.1 N HCl was attached
to the fundus tissue by applying a light force with fingertip for 20 seconds.
The beaker was filled with 900 ml of 0.1 N HCl and kept at 370C after 2 min.
stirring rate of 50 was applied until complete detachment occurred.
8. In Vitro drug release studies:[9]
Drug release studies of the prepared trilayer mucoadhesive tablets were
performed, in triplicate, in a USP Dissolution Tester Apparatus, type- II
(Paddle method) (Electrolab TDT -06P) at 37 ± 0.5 0C. The paddles rotated
at a speed of 50 rpm. The tablets were placed into 900 mL of 0.1 N HCl (pH
1.2). Aliquots of 10 mL were withdrawn from the dissolution apparatus at
different time intervals and filtered through a 0.45µm membrane. The drug
content was determined spectrophotometrically at a wavelength of 233 nm,
as mentioned before. At each time of withdrawal, 10 mL of fresh medium was
replaced into the dissolution basket.
RESULT AND DISCUSSION:
Physical evaluation:
The prepared mucoadhesive tablets were evaluated for various physical
parameters such as weight variation, hardness, friability and drug content.
All the batches were produced under conditions to avoiding processing vari-
ables. Physical evaluation of compressed matrix tablets showed all physical
parameters to be within specifications. Tablet weights varied between 699
and 702 mg; thickness, between 4 mm and 5 mm; and hardness, between 8-9
kg/cm2. The assay content of Metformin HCl varied between 90.2% and
97.8%, and the friability ranged between 0.3% and 0.6%.
Swelling ability:
Swelling index for all the formulations was carried out in the 0.1N HCl.
Graphical representation swelling index of all the batches are shown in Fig. 2.
Exvivo bioadhesion strength determination:
Results concur with observed facts that increase in concentration of Carbopol
940 increased bioadhesion. The HPMC K100M, because of its ability to
take up water, causes polymers to swell and interpenetrate quickly and to a
greater extent. The water uptake reduces glass transition temperature below
ambient conditions; hydrogels become progressively rubbery due to coiling
of polymer chains; and subsequently, mobility of polymer chains is in-
creased. Table-3 indicates bioadhesive strength in grams for all formulations.
The value of bioadhesive strength ranged between 13.44, 15.14 and 17.73 g
for batches F1, F2 and F3 respectively. The bioadhesion is highest when
Carbopol 940 concentration is maximum.
In vitro release studies:
In vitro dissolution studies were performed for all the formulations using

Journal of Pharmacy Research Vol.5 Issue 5.May 2012
Uddhav S. Bagul et al. / Journal of Pharmacy Research 2012,5(5),2463-2466
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Fig 2: Swelling index curve of Metformin HCl tablet.
Sr. No. Name of Ingredient Batch Code (Qty in mg)
Layer1 F1 F2 F3
1HPMC K100M 50 66.6 33.3
2Carbopol 940 50 33.3 66.6
Layer2
1Metformin HCl 250 250 250
2Ethyl cellulose 250 187.5 125
Layer 3
1HPMC K100M 50 66.6 33.3
2Carbopol 940 50 33.3 66.6
Table 1: Composition for trilayer mucoadhesive tablet.
Table 2: Physicochemical parameter of tablet
Batches Hardness Weight Friability %Drug Swelling index
( Kg/cm2)(mg) (%) Content (%) in 6 hrs
F1 8.09 700 0.5 90.2 162.8
F2 8.95 699 0.3 97.8 179.1
F3 9.05 702 0.6 95.1 141.1
Batch No Mucoadhesion Mucoadhesion
Time (Hrs) Strength (Gram)
F1 > 12 13.44
F2 > 12 15.14
F3 > 12 17.73
Table 3: Parameters of mucoadhesion.
USPXXII Tablet dissolution tester employing paddle type at 50 rpm using
900 ml of 0.1N HCl as dissolution medium. The samples withdrawn were
analyzed by using UV spectrophotometer. As per the results of dissolution
study formulations F1, F2 and F3 showed 71.68%, 83.80% and 81.12%
respectively. This showed that the drug release from the tablet was sustained
for 8 hr. Graphical representation drug release profile of all the batches were
shown in Fig. 3.
CONCLUSION:
The Metformin HCl trilayer mucoadhesive tablets formulated with HPMC
and /carbopol were shown a variable mucoadhesion strength depending on
the ratio of concentration of the polymers used. The release of Metformin
HCl from the prepared trilayer tablet was slow and spread over 8 hr and
depended on concentration of ethyl cellulose in the tablet. Formulation F3
showed better sustained release than the other formulations. This approach
can also be useful to overcome formulation problems associated with BCS
class II drugs along with BCS class I drugs.
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Source of support: Nil, Conflict of interest: None Declared
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