MUCOADHESIVE BUCCAL DRUG DELIVERY SYSTEMS …

Basanta Kumar Behera et al. World Journal of Pharmaceutical research
MUCOADHESIVE BUCCAL DRUG DELIVERY SYSTEMS
CONTAINING ROSIGLITAZONE MALEATE FOR TREATMENT OF
TYPE II DIABETES: FORMULATION DESIGN AND IN -VITRO
EVALUATION
Basanta Kumar Behera*1, Ranjit Mohapatra1, Sunit Kumar Sahu1, Vikram Viswajit
Mishra2, Akula Santosh Kumar2
2Jeypore College of Pharmacy, Rondapalli, Jeypore, Koraput,Odisha
ABSTRACT
were fabricated with objective of avoiding extensive first pass
metabolism and to prolong its duration of action with reduction in
dosing frequency. The mucoadhesive polymers used in the
formulations were Carbopol 934P and HPMC. Tablets were prepared
by direct compression method using polymer in different ratios. The
tablets were evaluated for thickness, hardness, weight variation,
uniformity of content, surface pH study, in-vitro swelling study,
matrix erosion study, Mucoadhesive strength and mucoadhesion time,
in-vitro drug release study and subjected to stability study. The
stability studies shown that all the formulation were stable as there
was no significant change in any values under study. Formulation (F4)
containing Carbopol 934P and HPMC in the ratio of (0.28571:1)
shown good buccoadhesive force and maximum drug release of
99.0219% in 8 hours. The surface pH of all tablets was found to be satisfactory (pH= 5.13 –
6.19), close to buccal pH, hence no irritation would observe with these tablets. It was
observed that the best formulation F4 shown surface pH 6.12 and follows release kinetics
First order >Higuchi order>Korsemeyer-Peppas >zero order>Hixson Crowell order.
Although majority of the formulations followed non-fickian (anomalous) diffusion mediated
World Journal of Pharmaceutical research
Volume 1, Issue 3, 689-704. Research Article ISSN 2277 – 7105
Article Received on 17 May 2012, Revised on 06 June 2012, Accepted on 22 June 2012
*Correspondence for Author:
* Basanta Kumar Behera
University Department of
drug release, the release exponent ‘n’ for formulation F8 is 0.964 (i.e., > 0.89) , which
indicates that when the Carbopol 934P and HPMC ratio is 0.8, the release mechanism is
undergoing a change from non-Fickian to Case II transport. The results indicate that the
mucoadhesive buccal tablets of Rosiglitazone maleate may be a good choice to bypass the
extensive hepatic first pass metabolism with an improvement in the bioavailability of
Rosiglitazone maleate through buccal mucosa for the treatment of type II Diabetes Mellitus.
Key words: Mucoadhesive drug delivery, buccal tablets, rosiglitazone maleate
INTRODUCTION
Much attention has been focused, recently on targeting a drug delivery system to a particular
region of the body for extended period of drug release, not only for local targeting of drugs
but also for the better control of systemic delivery. The concept of mucoadhesion was
introduced into controlled drug delivery in the early 1980s. Mucoadhesives are synthetic or
natural polymers, which interact with the mucus layer covering the mucosal epithelial surface
and mucin constituting a major part of the mucus. Drug delivery using mucoadhesive dosage
form via transmucosal route, bypasses hepato-gastrointestinal first pass elimination
associated with oral administration, thereby increases the bioavailability and produces longer
therapeutic effect .[1-2]
From a technological point of view, an ideal buccal dosage form must have three properties.
It must maintain its position in the mouth for a few hours, release the drug in a controlled
fashion and provide the drug release in a unidirectional way towards the mucosa. In regard to
the first requirement, strong adhesive contact to the mucosa is established by using
mucoadhesive polymers as excipients. If the mucoadhesive excipients are able to control drug
release, the second requirement can also be achieved. The third objective can be fulfilled by
preparing a system having uniform adhesiveness and impermeable backing layer. Various
mucoadhesive devices such as include tablets, film, patches, discs, strips, ointment and gel
have been recently developed.[3-14]
Rosiglitazone - a potent, novel antidiabetic agent is used in management of type-II diabetes
mellitus. After 8 to 12 weeks of Rosiglitazone monotherapy, the dose may be doubled in case
of insufficient response and this leads to higher incidence of dose dependent side effects such
as gastro-intestinal disturbances, headache, altered blood lipids, oedema, hypoglycaemia.
Further, adverse events of clinical significance which are reported frequently with
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conventional instant release dosage forms of the drug are edema, anemia, and weight gain.
Thus, there is a need to maintain Rosiglitazone at its steady state plasma concentration.[15-17]
Hence, this study was carried out to formulate and evaluate mucoadhesive buccal dosage
form of rosiglitazone maleate as a model drug and optimize the formulation parameters to
finally get optimized formulations having sufficient bioadhesive strength, bioadhesion time,
and desired release profile.
Rosiglitazone maleate was procured from M/S Nicholas Piramal India Limited, Hyderabad as
gift sample. Carbopol 934P was procured from Loba chemie (Mumbai, India).HPMC was
received as a gift samples from Griffon Laboratories (Mumbai, India) and other chemicals
used were procured commercially and were used as received.
Development of calibration curve
Rosiglitazone Maleate equivalent to 10 mg of Rosiglitazone was weighed accurately and
added to 10 ml volumetric flask. It was dissolved in 1ml of ethanol and volume was made
with 0.1 N HCl to get a stock solution. From the stock solution 0.4, 0.8, 1.2, 1.6, 2.0 ml were
pipette out to get 4, 8, 12, 16 and 20 µg/ml solutions. Absorbance of each of these was
recorded at 228 nm. The Absorbance versus concentration (µg/ml) was plotted in Figure No -
1 as shown below.
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Composition of formulations
direct compression method. Composition of various formulations employing Carbopol 934P,
HPMC, Spray dried lactose, Mannitol, Magnesium stearate and Talc are shown in Table No-
1.
Tablet preparation[18]
The mucoadhesive buccal tablets were prepared by direct compression method using Rimek
Minipress-I rotary tablet machine to obtain the tablets of desired specification. Briefly, all the
ingredients of tablets were blended in mortar with a pestle for 15 min to obtain uniform
mixture. The blended powder was then compressed into 150 mg tablets (at 5-7 kg/cm2) on a
single stroke, 10 station rotary tablet machine (Rimek Mini Press-I, Ahmedabad, India) with
8mm round shaped flat punch.
Table-1: Compositions of Rosiglitazone maleate bucoadhesive tablets.
Evaluation of Mucoadhesive buccal tablets
Thickness
Tablets were evaluated for their thickness using Slide Callipers. The results are shown in
Table No- 2.
Weight variation and hardness
Weight variation test was conducted according to USP using an electronic digital balance
(Sartorious, BT-2245) and the average weight was calculated. The hardness was measured
with Monsanto hardness tester. The results are shown in Table No- 2.
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Content uniformity or assay
Content uniformity test was conducted according to USP using. The results are shown in
Table No- 3.
Surface pH[19]
The surface pH of the buccal tablets was determined inorder to investigate the possibility of
any side effects in vivo. An acidic or alkaline pH may cause irritation to the buccal mucosa.
The method developed by Battenberg et al was used. A combined glass electrode was used
for this purpose. The tablet was allowed to swell by keeping it in contact with 1 ml of
distilled water (pH 6.5 ± 0.05) for 2hr at room temperature. The pH was measured by
bringing the electrode in contact with the surface of the tablet and allowing it to equilibrate
for 1min.The result are shown in Table No- 3.
Mucoadhesive strength and mucoadhesion time [20-21]
Mucoadhesive strength of the tablets was measured on a modified two-arm physical balance
as described by Quadnich et al. The rabbit buccal mucosa was used as biological membrane
for the studies. The rabbit mucosa was obtained from the local slaughter house and stored in
Krebs buffer at 4ºC from the time of collection and used within 3hrs of procurement. The
membrane was washed with distilled water and then with phosphate buffer pH 6.8 at 37ºC.
The rabbit buccal mucosa was cut into pieces and washed with phosphate buffer pH 6.8.A
piece of buccal mucosa was tied to the glass vial, which was filled with phosphate buffer. The
glass vial was tightly fitted into a glass beaker (Filled with phosphate buffer pH 6.8 at 37ºC ±
.5ºC), so that it just touches the mucosal surface. The buccal tablet was suck to the lower side
of a rubber stopper. The two sides of the balance were made equal before the study, by
keeping a 5gm weight on the right hand pan. A weight of 5gm was removed from the right-
hand pan, which lowered the pan along with the tablet over the mucosa. The balance was kept
in this position for 1 min contact time. Mucoadhesive strength was assessed in terms of
weight (gm) required to detach the tablet from the membrane. Mucoadhesive strength was
measured as force of adhesion (Newton) by using the following formula and the results are
shown in Table No- 3.
Force of adhesion (Newton) = (Mucoadhesive strength × 9.81) / 100
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For measuring mucoadhesion time a 10-gram weight was put on right side pan after raising it
and the detachment time was noted. The time period throughout which the tablet remained
attached to the mucosa is mucoadhesion time.
In vitro swelling studies[19, 22]
The degree of swelling of bio-adhesive polymer is an important factor affecting adhesion. For
conducting the study, a tablet was weighed and placed in a Petri dish containing 5ml of
phosphate buffer pH 6.8 in 12hr. at regular intervals of time (1, 2, 4, 8 & 12hrs), the tablet
was taken out from the Petri dish and excess water was removed carefully by using filter
paper. The swelling Index was calculated using the following formula and results are
summarized in Table No- 4.
Swelling Index (S.I) = (Wt – W0) × 100 / W0
Where S.I = Swelling Index.
Wo= weight of tablet before placing in the beaker.
Matrix Erosion
Each tablet weighed (W1) were immersed in a phosphate buffer pH 6.8 for predetermined
time (1, 2, 4, 8 and 12 hr). After immersion, tablets were wiped off by the excess of surface
water by the use of filter paper. The swollen tablets were dried at 60ºC for 24 hr in an oven
and kept in a desiccator for 48 hr prior to be reweighed (W2). The matrix erosion was
calculated using the following formula and the results are shown in Table No- 4.
In vitro release study
The in vitro release study for all the formulations were carried out for 12 hrs using a USP-
Dissolution Test Apparatus Type-II (DISSO 2000, Lab India, India). The temperature of the
dissolution medium (Phosphate buffer of pH 6.8, 900ml) was maintained at 37°C ± 1°C with
a stirring rate of 50 rpm. At predetermined intervals 5 ml sample was withdrawn and equal
volume was replaced to maintain sink condition. The sample was further diluted with
methanol and absorbance measured in a UV spectrophotometer (PharmaSpec UV- 1700;
Shimadzu, Japan) at 228 nm against suitable blank. The absorbance was converted to drug
concentration using a calibration curve (Absorbance = 0.043 x Concentration - 0.006; r2 =
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0.999) and then cumulative % drug released was calculated with the help of dilution factor.
The release kinetics such as zero order, first order, Higuchi, Hixson- Crowell and
Korsemeyer-Peppas were determined & the % cumulative drug release data are shown in
Table No- 5. Similarly comparative study of the formulations F1 to F8 is shown in Figure
No-2.
Mechanism of release[23-24]
The mechanism of release was determined by fitting the release data into various kinetic
equations such as Zero order, First-order, Higuchi, and Korsemeyer-Peppas and finding the
R2 values of the release profile corresponding to each model. The value of regression
correlation coefficient (R2) was evaluated for all the formulations and the result are shown in
Table No-6 and Table No-7.
Zero order: C = K0t
K0 - zero-order rate constant expressed in units of concentration/time, t - time in hrs.
First order: LogC = LogC0 – (K/ 2.303) t
Where, C0 - is the initial concentration of drug, K - first order constant, t - time in hrs.
Higuchi: Qt = K t1/2
Where Qt - amount of the release drug in time t, K -kinetic constant, t- time in hrs.
Korsmeyer- Peppas: Mt / M∞ = K tn
Where Mt - represents amount of the released drug at time t,
M∞- is the overall amount of the drug (whole dose) released after 8 hrs
K- is the diffusional characteristic of drug/ polymer system constant.
n- is a diffusional or release exponent that characterizes the mechanism of release of drug.
Stability studies
Stability studies were performed according to ICH guidelines. Stability of each formulation
under accelerated storage conditions of temperature and humidity was studied. The samples
were taken out at intervals of 0, 1, 2, 3, 4, 5 and 6 months. Tablets were evaluated for the
different physicochemical parameters i.e. content uniformity, surface pH, mucoadhesive
strength and swelling Index. The results are presented in Table No- 8.
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RESULTS AND DISCUSSION
In order to select the best formulation, various evaluation parameters were checked and
subjected to in-vitro dissolution studies and their release profiles. Stability studies were
performed for six months as per ICH guidelines.
Thickness
The average thickness of tablets was determined and the results are presented in Table No- 2.
The average thickness of tablets ranged from 2.7mm to 2.5mm. None of the formulations
deviated from the standards.
Weight variation and hardness
The percentage weight variation of each tablet from average weight was less than 5% i.e. less
than 1.2% as shown in Table No-2, which provided good uniformity. The table No-2 shown
that hardness of all formulations was ranged from 4.8 to 5.6 Kg/cm2. None of the
formulations deviated from the standards.
Content uniformity or % drug content
The content uniformity of all tablets was evaluated and the results are presented in Table No-
3. The maximum percentage of drug content from the different formulations was found to be
99.4% and minimum percentage of drug content was found to be 96.8%. Hence it is
concluded that all the formulations are falling within the pharmacopoeial limits.
Surface pH
The surface pH of tablets of each formulation was tested and the results are provided in Table
3. The maximum and minimum pH value of the formulations were found to be 6.19 and 5.13
respectively .The acceptable pH of saliva is in the range of 5-7 and the surface pH of all
tablets are within the limits. Hence, these formulations may not produce any irritation to the
buccal mucosa.
Mucoadhesive strength and mucoadhesion time
In-vitro mucoadhesive strength study was studied as per standard protocol. The results
depicted in Table 3. The mucoadhesive strength, mucoadhesive force and mucoadhesion time
for the designed formulations ranged from 28.5 to 39.5gm, 2.79585 to 3.87495 N and 9.34 to
12.62 hours respectively. With increased in concentration of Carbopol 934P in designed
formulations, the mucoadhesive strength and mucoadhesive force as well as mucoadhesive
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time increases (F5>F4>F3>F2>F1). With decreased in concentration of HPMC in designed
formulations, the mucoadhesive strength and mucoadhesive force as well as mucoadhesive
time increases (F5>F4>F3>F2>F1).HPMC below 46% shown decreased in mucoadhesive
time (F5 =10.7 hr),but further decreased in concentration showed increase in mucoadhesive
time due to synergistic mucoadhesive action of Carbopol 934P and HPMC. Thus, it can be
concluded that the designed tablets exhibited good mucoadhesive strength. Considering the
Carbopol 934P: HPMC ratio used, mucoadhesive strength and mucoadhesive time,
formulation F4 was found to be best among various formulations. The table No-3 shown that
the mucoadhesive strength, mucoadhesive force and mucoadhesive time of F4 was 37.4 gm,
3.66894 N and 11.5 hr respectively.
Table-2: Thickness, Weight variation and Hardness of Rosiglitazone Bucoadhesive
tablets
In vitro swelling studies
The swelling index of the tablets from each formulation (F1 to F8) was evaluated and the
results are provided in Table No- 4. The results indicate that after 8 hrs the tablets from the
formulations F1 to F4 were hydrated to an extent of 85.70, 88.7, 89.4 and 90.00%
respectively. The highest hydration (swelling) was observed with the formulation F4. The
swelling index increases by increasing the contact time as the polymer gradually absorbs
water due to hydrophilic nature with resultant swelling.
Matrix Erosion
The mucoadhesive polymers used are hygroscopic and retain large amount of water. Tablets
containing HPMC polymer F1 to F3 showed the matrix erosion 12.5, 10.7 and 9.8 after 12
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hr respectively. This is because the presence of water that balanced the weight loss due to
erosion and was more evident for this group, as it showed higher hydration rate. When the %
HPMC was less than 50 % i.e. F4 to F8 then % matrix erosion as shown in Table No-4
decreases in the order F4<F5<F6<F7<F8.
Table-3: Content uniformity, surface pH, Mucoadhesive strength, Mucoadhesive force
and mucoadhesive time of Rosiglitazone Bucoadhesive tablets
Table-4: In-vitro swelling study and Matrix Erosion of Rosiglitazone Bucoadhesive
tablets
In vitro release study
The drug release pattern was studied for all formulations (F1 to F8) for 8 hrs following
standard procedure and the results are provided in Table No-5 and Figure No-2, 3 and 4. The
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release was found to be influenced by the presence of both the rate limiting polymers –
Carbopol 934P and HPMC. Carbopol 934P uniformly retarded the drug release from the
matrix due to its acidic as well as hydrophobic properties and could not be leached out
quickly (Figure No- 3 & 4) so that formulations with higher Carbopol 934P content released
less (F8<F7<F1 ). On physical examination of tablets during dissolution study, it was found
that tablets were initially and slowly eroded over the period of time. The opposite trend could
be observed in case of HPMC where the drug release increased with increasing polymer
concentration < 50% (43.333%) of formulations (F5>F6>F7>F8).Further increasing in
concentration of HPMC retards the drug release due to decrease in hydration of polymer.
Table-5: % Cumulative drug release from different formulation
Figure-2: Comparative study of % Cumulative drug release from different formulation
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Figure-3: Effect of Carbopol 934P and HPMC polymer ratio on % Cumulative drug
release from different formulation
Figure-4: Effect of % HPMC polymer on % Cumulative drug release from different
formulation
Kinetic studies i.e. zero-order, first order, Higuchi, Hixson-Crowell and Korsemeyer-Peppas
were conducted for all formulations and the data are shown in Table No-6 and 7. The release
exponent ‘n’ from Korsemeyer-Peppas model and type of transport of different formulations
is shown in Table No-7.
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The R2 values of first order release as well as R2 values of Higuchi release pattern for all
formulations were near one implying a mixed order kinetics being operative. The release
exponent ‘n’ value for each formulation was above 0.5, indicating that mechanism of release
is the Non-Fickian diffusion type.23- 24Although majority of the formulations followed non-
fickian (anomalous) diffusion mediated drug release, the release exponent ‘n’ for formulation
F8 is 0.964 (i.e., > 0.89) , which indicates that when the Carbopol 934P and HPMC ratio is
0.8, the release mechanism is undergoing a change from non-fickian to Case II transport.
Table-6: Regression correlation coefficient (R2) of various models of different
formulation
Table-7: Regression correlation coefficient (R2) of Korsemeyer-Peppas models of
different formulation, release exponent (n) and type of transport of drug from
formulation
Stability studies
The stability studies were conducted on the best formulation F4 as per ICH guidelines [ICH
Q1A (R2)]. The stability studies data was recorded at intervals of 0, 1,2,3,4, 5 and 6 months.
The following parameters were investigated: drug content, surface pH, mucoadhesive
strength (gm) and swelling index .The results are presented in Table No- 8 and 9.From the
result Table No-9 it was shown that, there was no significant change in any values. Hence
the formulation F4 is considered to be highly stable.
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Table-8: Stability study of Formulation F4 (6 months of storage)
Table-9: % Change in parameters after stability study at different storage specification
CONCLUSION
It may be concluded that that formulation (F4) with a composition of 2.667% Rosiglitazone
maleate, 13.333% Carbopol 934P and 46.667% HPMC was selected as the final optimized as
well as best formulation that exhibited satisfactory bucoadhesive properties in comparison to
other formulations. The mechanism of release of Rosiglitazone maleate from the buccal drug
delivery system was following First order as well as Higuchi order. Hence, in the present
study Rosiglitazone maleate bucoadhesive delivery system could be developed with desirable
bucco-adhesion and release modulation for a once daily administration for the treatment of
Type II diabetes and may be good choice to bypass the first-pass metabolism with an
improvement of bioavailability of the drug through the buccal mucosa.
ACKNOWLEDGEMENTS
Authors are thankful to Nicholas Piramal India Limited, Hyderabad and Griffon Laboratories
Mumbai, India for donating gift sample of Rosiglitazone maleate and HPMC respectively.
Also We would like to acknowledge Director and Head of the Department of University
Department of Pharmaceutical Sciences, Utkal University,Vani Vihar, Bhubaneswar, Odisha
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and Director, Jeypore College of Pharmacy, Jeypore, India for their support during this
project.
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