RESEARCH PAPER
`
`Received 4th February, 1997.
`Accepted 26th July, 1997
`• Indian J. Pharm. Scl., 1997, 59(5) pp. 232-235
`
`In-Vitro studies on Buccal strips of Glibenclamide using Chitosan •
`
`R. ILANGO*, S. KAVIMANI, A. R. MULLAICHARAM AND B. JAYAKAR.
`Dept of Pharmaceutics, Periyar College of Pharmaceutical Sciences for Girls, Trichy, Tamil Nadu - 620 021.
`
`As glibenclamide is metabolised completely in the liver, the principal metabolite being only very weakly
`active, buccal strip glibenclamide may be very useful for the treatment of diabetes more efficiently. The
`objective of this work Is to Investigate the possibility of obtaining a slow release, relatively constant
`effective levels of glibenclamide from buccal strips using chitosan. Here attempts were made to develop
`suitable chitosan- based buccal strips and to characterise it using different in vitro methods. Chitosan-
`based strips of glibenclamide showed suitability over Eudragit-based glibenclamide buccal strips for
`controlled release behaviour.
`
`LIBENCLAMIDE is a Sulphonylurea group of
`ri drug, used in the treatment of maturity onset
`diabetes as an oral hypoglycaemiC1" 2, Glibenclam-
`ide, chemically is 1-(p-(2-(5-chloro-O-anisamido),
`ethyl), phenyl), sulfonyI)-3-cyclohexyl urea. The
`plasma half life is about 5-10 h. In the present work
`an attempt has been made to develop a buccal
`mucodhesive dosage form" of glibenclamide for
`improving and enhancing bioavailability. It may also
`be possible to bypass the hepatic first pass effect
`by administering it through the buccal mucosa, which
`is richly perfused with blood vessel and offers greater
`permeability than the skin4. The required therapeutic
`plasma concentration of glibenclamide can possibly
`be achieved more rapidly by using such buccal dos-
`age forms. Chitosan is (1-4)-2-amino-dexoy-p-
`glucan. It has similar structural characteristics as
`that of glycosamino glycans. It is tough, biodegrad-
`able and non- toxic".
`
`METHODS
`
`Glibenclamide (I.P), chitosan, Eudragit L 100,
`Eudragit S 100, Polyvinylpyrrolidone (Kollidone), pro-
`pyleneglycol, acetic acid were the chemicals used.
`
`*For correspondence
`
`Polyvinylpyrrolidone was used as a mucoadhes-
`ive polymer. Propylene glycol (5% v/v) was used as
`a plasticizer and penetration enhancer. One percent
`w/v of chitosan was prepared in 5% v/v of acetic
`acid. Glibenclamide in concentration of 1% and 2%
`were used. The chitosan buccal strips were prepared
`by casting technique."). Mixed quantity of chitosan
`that was required to produce 1% w/v of its solution
`with 5% v/v of acetic acid. Allowed to stand for one
`and half weeks with moderate stirring for the first
`3-4 days. The solution was then filtered through a
`muslin cloth to remove debris and suspended
`particles. Polyvinylpyrrolidone was accurately
`weighed and dissolved in ethanol alongwith accu-
`rately weighed quantity of chitosan solution and pro-
`pylene glycol (5% v/v) were added to obtain a viscous
`solution. The drug was then dispersed uniformly in
`the viscous solution with continous stirring. The re-
`sulting mass was then poured into glass moulds
`lined with Aluminium foil. The solvent was evaporated
`at room temperature for about 24 hours. The dried
`strip thus obtained was cut into required size con-
`sisting of required amount of the drug and stored
`in a dessicator. Strips having an oval form of 4 cm
`length and 3 cm width, 40 micron thickness and
`density 1.2031±0.5 were used for the studies.
`
`232 (cid:9)
`
`Indian Journal of Pharmaceutical Sciences (cid:9)
`
`September — October 1997
`
`Par Pharm., Inc., et al.
`Exhibit 1005
`Page 001
`
`

`

`Table 1: Composition of glibenclamide buccal strips
`
`Ingredients
`
`Chitosan strip
`2% Drug
`1% Drug
`
`1% Drug
`
`Eudragit strip
`2% Drug
`
`Control (cid:9)
`
`.
`
`2%
`
`Glibenclamide
`Chitosan
`Eudragit
`Acetic Acid
`Ethanol
`Poly vinyl
`pyrrolidone
`Propylene Glycol
`
`1%
`1%
`
`5%
`
`2%
`1%
`
`5%
`
`1%
`
`1%
`
`2%
`
`1%
`
`500 mg
`
`500 mg
`
`5%
`500 mg
`
`5%
`500 mg
`
`5%
`500 mg
`
`5%
`
`5%
`
`5°,;
`
`5%
`
`5%
`
`Table 2 : Swelling studies of buccal strips* (in CM)
`
`Time In
`minutes
`
`Chitosan buccal strip
`2% Drug
`1% Drug
`
`Eudragit buccal strip
`2% Drug
`1% Drug
`
`0
`5
`10
`30
`60
`
`3.0
`3.2 + 0.002
`3.8 + 0.05
`4.2 + 0.03
`4.3 + 0.2
`
`3.0
`3.3 + 0.002
`3.6 + 0.04
`4.0 + 0.1
`4.2 + 0.4
`
`3.0
`3.05 + 0.002
`3.09 + 0.006
`3.15 + 0.005
`3.2 + 0.001
`
`3.0
`3.04 + 0.002
`3.08 + 0.004
`3.15 + 0.07
`3.18 + 0.06
`
`* Average of Three Trials with Standard deviation
`
`For Eudragit buccal strip preparation (1:1) ratio
`of Eudragit L 100 and Eudragit S 100 were used
`instead of chitosan solution. Ethanol was used as
`solvent for Eudragit buccal strips. Drug free strips
`were prepared for comparison.
`
`Evaluation of Buccal strips
`
`Buccal strips of 4 cm length and 3 cm width
`were placed petridishes, 50 ml water was added
`and surface diameter was measured at 0, 5, 10, 30
`and 60 minutes intervales. Four replications of each
`test were carried out. Buccal strips of equal density
`(1.203) were weighed accurately and kept immersed
`in 50 ml of water. Strips were taken out carefully at
`
`5, 10, 30 and 60 minutes intervals blotted with filter
`paper to remove the water present on their surface
`and weighed accurately. The percent swelling was
`calculated using the following formula".
`
`Percentage Swelling - (cid:9)
`
`Wet Weight-Dry Weight
`x 100
`Wet weight
`
`Density Determination of the strips was made
`employing the film thickness and by using the relation
`D=m/v
`
`Where D = Density of free strips
`M = Wt of strip samples in grams
`and V = Volume of strip sample (cm)3
`
`September — October 1997 (cid:9)
`
`Indian Journal of Pharmaceutical Sciences (cid:9)
`
`233
`
`Par Pharm., Inc., et al.
`Exhibit 1005
`Page 002
`
`

`

`Effect of concentration on drug release
`
`Table 3 : Percentage swelling of chitosan
`buccal*Strips
`
`Time in
`Minutes
`
`Chitosan strips
`1% Drug
`
`rips
`Chitc=n (cid:9)
`2 % Drug
`
`5
`10
`
`15
`
`30
`
`60
`
`24 ± 0.02
`
`27 ± 0.05
`
`29 ± 2.3
`
`31 ± 3.2
`
`32 ± 2.21
`
`20 ± 0.02 (cid:9)
`
`26 ± 0.02 (cid:9)
`
`28.5 ± 2.5
`
`30 ± 1.6
`
`31.5 t 0.06
`
`It1
`Ul
`
`U.
`
`IA 1
`0
`-4
`(-4
`
`100
`
`90
`
`80
`
`70
`
`10
`
`40
`
`30
`
`20
`
`10
`
`* Values expressed as the mean of four readings with
`S.D.
`
`The thickness of each film was measured in the
`centre and around the periphery with a horizontal
`metroscope. All thickness and weight measurements
`were made after residual moisture has been removed
`from the samples by storing in a dessicator for
`1 week.
`
`In Vitro release study
`
`The strip was carefully pressed on to a micro-
`scopic slide. The slide was placed at an angle of 45°
`in a 250 ml beaker containing 200 ml of pH 7.4 buffer
`preheated to 37°. The beaker was kept in 37°
`waterbath. A non agitated system was selected to
`eliminate any effect of turbulence on the release rate
`as to assure that no disruption of the strip occured.
`Periodic assay samples were obtained by removing
`the slide, stirring the solution and pipetting a 5 ml
`sample with a graduated pipette, whose tip was
`covered with a piece of muslin cloth. The slide was
`quickly reinserted, making sure that the strip re-
`mained completely immersed throughout the release
`study. The beaker was kept covered through-out the
`run to prevent evaporation. All samples were an-
`alysed using an UV spectrophotometer at 226 nm.
`
`RESULTS AND DISCUSSION
`
`There is no interaction between chitosan and
`glibenclamide which was confirmed by Infrared
`
`A
`A— Chitosan Strip (1% Drug)
`B — Eudragit Strip (1% Drug)
`C— Chitosan Strip (2% Drug)
`D — Eudragit Strip (2% Drug)
`
`spectrum of physical mixture of chitosan and
`glibenclamide.
`
`Chitosan buccal strips with 1% and 2% drug and
`Eudragit buccal strips with 1% and 2% drug were
`prepared and evaluated. The content uniformity of
`glibenclamide in the prepared buccal film was found
`to be satisfactory and was within 5% variation. Poly-
`vinylpyrrolidone was used as the mucoadhesive
`polymer which have a molecular weight of 49,000.
`This is water soluble hydrocolloid, mucoadhesive by
`the dissolution kinetics of the polymeric carrier. Thus
`the polymer dissolution was the rate controlling step
`in drug release. When a swellable polymeric matrix
`was made by incorporating chitosan or Eudragit with
`the polymer solution, delay in the dissolution of poly-
`mer due to swelling of the incorporated substances
`occurs. This leads to controlled release of drug from
`mucodhesive strips.
`
`Chitosan swells more than Eudragit, which may
`lead to controlled release of drug in case of buccal
`strips prepared with chitosan. The Eudragit polymer
`solution consisting of equal proportion of (1:1) Eu-
`dragit S 100 and Eudragit L 100. Eudragit S 100
`has swelling property whereas Eudragit L 100 has
`no swelling property.
`
`234 (cid:9)
`
`Indian Journal of Pharmaceutical Sciences (cid:9)
`
`September — October 1997
`
`Par Pharm., Inc., et al.
`Exhibit 1005
`Page 003
`
`

`

`In_Y : id0 P-S:Lt..51: CC CLIELSCLAA::AL (cid:9)
`
`5.UCCAL.
`
`4-
`
`r
`
`1
`
`CHIITSA24 STRIP (2%)
`
`STRIP (1%)
`
`(111)
`
`EVr.R.C.If STRIP (CS)
`
`1
`
`9
`6 (cid:9)
`7 (cid:9)
`3 TIPE IJ HOY'S 5 (cid:9)
`2. (cid:9)
`Graph I: In Vitro studies of Glibenclamide In
`various concentrations in the Chitosan and
`Eudragit Strip system
`
`In vitro studies of glibenclamide in various con-
`centrations in the chitosan matrix showed that the
`percent telease was maximum at 1% drug concen-
`tration (80.5%) when the drug content was increased
`to 2%, the rate of drug release was decreased. The
`controlled release of drug may be by diffusion
`through the chitosan matrix.
`
`With Eudragit buccal strips also, in vitro studies
`showed that the percent release was maximum with
`1% drug concentration (78%). Here also when the
`drug content was increased to 2%, the rate of drug
`release was decreased. However when the results
`of study was compared with those obtained with
`chitosan matrix, maximum percent release of drug
`as well as the controlled rate of drug release was
`shown only in chitosan matrix. The greater swelling
`nature of chitosan may perhaps be responsible for
`
`the promising diffusion controlled drug release
`than the Eudragit- based system.
`
`ACKNOWLEDGEMENTS
`The authors gratefully acknowledge the receipt
`of gift sample of glibenclamide from Hoechst Marion
`Roussel Limited., chitosan from Central Institute of
`Fisheries Technology (Cochin), Eudragit from Rohm
`pharma, Germany. They are also thankful to K.
`Veeramani, President, Periyar Maniammai Educa-
`tional and charitable society for his encouragement
`and the college authorities for the facilities.
`
`REFERENCES
`
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`
`September — October 1997 (cid:9)
`
`Indian Journal of Pha6aceutical Sciences (cid:9)
`
`235
`
`Par Pharm., Inc., et al.
`Exhibit 1005
`Page 004
`
`