DEVELOPMENT OF BILAYERED UNIDIRECTIONAL BUCCAL TABLETS USING NATURAL POLYMER

SYNOPSIS FOR

M.PHARM DISSERTATION

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA

BY

PATEL MITUL JAYPRAKASH

M.PHARM

DEPARTMENT OF PHARMACEUTICS

MARATHA MANDAL’S COLLEGE OF PHARMACY

BELGAUM

(2010-2011)

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE.

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1 / NAME OF THE CANDIDATE AND ADDRESS / PATEL MITUL JAYPRAKASH
MARATHA MANDAL’S COLLEGE OF PHARMACY,
BELGAUM -590016, KARNATAKA.
2 / NAME OF THE INSTITUTION / MARATHA MANDAL’S COLLEGE OF PHARMACY,
BELGAUM-590016, KARNATAKA.
3 / COURSE OF THE STUDY AND
SUBJECT / MASTER OF PHARMACY IN
PHARMACEUTICS
4 / DATE OF ADMISSION / JULY 2010
5 / TITLE OF THE PROJECT:- “ DEVELOPMENT OF BILAYERED UNIDIRECTIONAL BUCCAL TABLETS USING NATURAL POLYMER”
6
6.1 / BRIEF RESUME OF INTENDED WORK:-
NEED FOR THE STUDY:-
Buccal route is an alternative to oral route. The buccal drug delivery allow the drug to be delivered across the oral mucous membrane through a diffusion process(passive diffusion) where the drug enters the blood stream directly through oral cavity [1].
Buccal drug delivery can increase the therapeutic value of many drugs by avoiding specific problems associated with the drug such as gastro intestinal irritation, GIT pH problems, low absorption, decomposition due to first pass effect and short half life necessitating frequent dosing. This therapy can be terminated at any point of time after administration of tablet. The simplified medication regimen leads to improved patient compliance and reduce inter and intra patient variables [2].
Transmucosal routes of drug delivery offer distinct advantages over peroral administration for systemic drug delivery. Drug delivery via buccal route using bioadhesive dosage forms offers a novel route of drug administration, providing a safe and easy method of removing the dosage form from the buccal cavity.3 This route has been used successfully for the systemic delivery of number of drug candidates. An ideal buccal dosage form must have following properties. It must (i) maintain its position in the mouth for few hours, (ii) release the drug in controlled fashion, and (iii) provide the drug release in a unidirectional way toward 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 be achieved. The third objective can be fulfilled by preparing a system having uniform adhesiveness and an impermeable backing layer [3].
Conventional therapy requires frequent administration of thetherapeutic agent to the patient. Systemic administration of the drug often requires high concentration to maintain therapeutic effect because of dilution effect. Hence transmucosal route are used to avoid this type of toxic effect and to enhance the bio availability [4].
During the past decade, bioadhesive polymers have received considerable attention because of their ability to localize the dosage form in specific regions to enhance drug bioavailability. Bioadhesive polymers along with mucoadhesion and also act as release rate regulators. Examples of bioadhesive polymers include chitosan, sodium alginate, sodium carboxymethyl cellulose etc[2,5].
Biopolymer or natural polymers are an attractive class of biodegradable polymers since they are: derived from natural sources, easily available, relatively cheap, qualified for a number of chemical modification. The natural polymers can be proteins and polysaccharides in chemical origin. The modified the natural polymers altered to improve their biodegradation profile. Generally labile polar functionalities are added to the polymer to enhance the degradability of the polymer. The extent and nature of polymers modification is vital as excess modification can hamper the biodegradation and the added functional groups may be converted to toxic degradation product. This modification of natural polymers is achieved by chemical modification or enzymatic alteration . there are many natural polymers used as a bioadhesive polymers such as sodium alginate, chitosan, guar gum etc [19].
6.2 / REVIEW OF LITERATURE:-
·  Akbari et al (2010), developed mucoadhesive chlorehexidine tablets by direct compression using blend of HPMC and chitosan and their dissolution properties are assessed according to USP paddle method. In order to determine the mode of drug release from the tablet, the release data were subjected to various release kinetic models. The bioadhesive strength of the tablet was also evaluated. The results showed that the proportion of HPMC in the blend increased, the drug release rate decreased with a lowest release rate observed when HPMC was used alone as bioadhesive polymer. The chlorhexidine formulation showed promise as a bioadhesive delivery system for drug [6].
·  Ramana et al (2010), formulated metoprolol tartrate tablets by using carbopol. 934; HPMC, HEC and CMC by direct compression. The formulations were characterized for physiochemical parameters, In vivo release studies and in vitro placebo studies, Mucoadhesive performance, In vitro drug release with metoprolol. This product was more comfortable to the user due to absence of erosion, faster hydration rate and less viscosity of the surrounding environment, in vivo placebo studies did not shows any side effect [7].
·  Patel et al (2007), established mucoadhesive buccal devices of propranolol HCL in the forms of bilayered and multilayered tablets were prepared by using sodium CMC, and carbopal-934 as bioadhesive polymer and ethyl cellulose to act as backing layer. Tablets were evaluated by weight uniformity, content uniformity, thickness, hardness, surface pH, swelling index, ex vivo drug release and in vivo drug permeation etc. As compared with bilayered tablets, multilayered tablets showed slow release rate of drug with improved ex vivo bioadhesive strengths and enhanced ex vivo mucoadhesion time. The mechanism of drug release was found to be non fickian diffusion for both the buccal device were found to be stable in natural saliva. The study could be good way to bypass the extensive first pass metabolism and improved the bioavailability of propranolol HCL [8].
·  Goundanavar et al (2010), developed mucoadhesive buccal tablets of glibenclamide by using carbopol 934, HPMC K4M and sodium CMC as polymers. The tablets were evaluated for different physiochemical parameters and subjected to graphical treatment according to Higuchi’s equation and Peppa’s equation and the formulation confirmed that the release mechanism is diffusion, the rate of release following first order kinetic model.[9]
·  Athawale et al (2010), designed buccodhesive microspheres by cross linking method and determine the suitability of the formulation in nicotine replacement therapy. The microspheres were evaluated for various physicochemical parameters like appearance, particle size distribution, DSC studies, angle of repose, drug content, mucoadhesion time, in vitro release and ex-vivo drug permeation studies. The release kinetic was further explored by using Korsmeyer-peppas equation. Stability studies of microspheres were carried out as per ICH guideline. Thus the developed microsphere will be very effective buccal drug delivery system for the treatment of nicotine, addiction just because of ex-vivo permeation studies of microspheres showed 88.99% drug permeation through the buccal mucosa in 8 hr with good correlation coefficient 0.99 with in vitro dissolution studies [10].
·  Aditya et al (2010), designed and evaluated controlled release of mucoadhesive buccal tablets of lisinopril with goal to increase bioavailability, reduced dosing frequency and improve patient compliance. The tablets were prepared using carbopol 934, HPMC, HEC as polymers. The tablets were evaluated for hardness, weight variation, thickness, drug content, in vitro study etc. The FTIR studies showed no evidence on interaction between drug and polymer. The results indicates that the mucoadhesive buccal tablets of lisinopril may be good choice to bypass the first pass metabolism with improvement in the bioavailability of lisinopril through buccal mucosa [11].
·  Asha et al (2010), studied mucoadhesive bilayered tablets of atorvastatin calcium using bioadhesive polymers such as carbopol 934P, sodium CMC,HEC, sodium alginate along with ethyl cellulose as an backing layer. The tablets were prepared by direct compression techniques and characterised by as exactly other tablets evaluation with bioadhesive strength, surface pH and permeability study. All the formulations gave the satisfactory results in terms of bioadhesive performance, physical and mechanical properties and surface pH. The chosen tablets of atorvastatin calcium performed 6 hr sustained drug release with desired therapeutic concentration [12].
·  Semalty et al (2008), improved bio availability in controlled release fashion and avoided first pass metabolism of glipizide, The films of glipizide were prepared by solvent casting technique using HPMC, sodium CMC, carbopol 934P and eudragit RL 100. Film were evaluated for their weight, thickness, surface pH, swelling study, in vitro residency time, folding endurance, in vitro release studies etc, The film exhibited controlled release over more than 6 hr, It was concluded that the formulations exhibited satisfactory swelling index, an optimum residence time and promising drug release thus proved to be potential candidate for development of buccal films of glipizide [13].
·  Kumar et al (2006), developed and characterized controlled release buccoadhesive core-in cup systems of the terbutaline sulphate by direct compression method with polymers like cardopol ,HPMC K4M . Buccoadhesive films were prepared by solvent evaporating technique using chitosan , HPMC K4M and HPMCP. The preformulation studies of TBS like solubility , partition coefficient and compatibility studies with polymers using DSC and FTIR were carried out. The systems were evaluated for tablets as like others. In addition buccoadhesive films were evaluated with regard to their tensile strength, folding endurance and water vapour transmission rate. Preformulation studies showed that TBS had sufficient solubility in phosphate buffer pH 6.6 and was found to be compatible with selected polymers. Maximum bioadhesive strength was observed for BCC systems formulated with carbopol-934 alone. The swelling index increased with the HPMC K4M content of the systems. In vitro dissolution studies showed that all the buccoadhesive systems followed first-order release kinetics. Stability studies revealed that TBS was stable at buccal pH and in human saliva. Buccoadhesive film formulations containing chitosan and HPMC K4M exhibited greater release than formulations containing HPMCP and HPMC K4M. The films also exhibited greater folding endurance. The tensile strength was higher for formulations containing HPMCP and HPMC K4M which suggests that the films were tough and hard, whereas films containing chitosan and HPMC K4M were more soft and flexible [14].
·  Derle et al (2009), formulated and evaluated mucoadhesive bilayered tablets of propranolol hydrochloride using bioadhesive polymers such as sodium alginate and carbopol 971P along with ethyl cellulose as backing layer .The tablet were evaluated for weight variation thickness , hardness, friability, surface pH, mucoadhesive strength, swelling index, in vitro. drug release. The surface pH of all tablets was found to be satisfactory, close to neutral pH Hence no irritation would observe with these tablets. The mechanism of drug release was found to be zero order kinetics [15].
·  Hirlekar et al (2009), investigated Carvedilol as the buccal drug delivery system. In that improved the dissolution rate of carvedilol by metlyl beta- cyclodextrin . The tablets were prepared by direct compression method. It is characterised by the FT-IR, DSC, and x-ray diffractometry studies and then it was evaluated dissolution rate, drug release, mucoadhesive strength and ex-vivo permeability study with Carvediol. The characterization of binary system revealed solubility and dissolution rate. Buccal tablets containing complex drug showed increased dissolution rate indicating higher concentration of drug in solution form as well as increased permeability through buccal mucosa. Thus it can be concluded that improvement in solubility by complexation along with avoidance of first pass metabolism by incorporation of complex in to buccal tablets would lead to increased bioavailability of carvedilol [16].
·  Shanker et al (2009), formulated tizanidine HCL tablets by direct compression using bioadhesive polymers such as HPMC K4M, sodium CMC and a combination of two polymer. It was improved the permeation of drug by permeation enhancer such as beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, sodiumdeoxycholate. It characterized by bioadhesion strength, ex vivo residence time, swelling and in vitro dissolution studies, permeation studies, stability studies in the natural saliva, in vivo mucoadhesion on human volunteers. The development of bioadhesive buccal drug delivery of tizanidine HCL tablets was one of the alternative route to avoid first pass effect and proved prolonged release . In addition, these formulation reduce the need of frequent administration and enhanced patient compliance. A combination of sodium CMC and HPMC K4M results strongly suggest that increase in the permeation due to the effect of sodium deoxycholate on paracellular and transcellular .From human volunteers, subjective parameters and mucoadhesive parameters were found to be satisfactory [17].
·  Perioli et al (2007), designed a sustained release bilayered tablets of flurbiprofen by using different polymers and in organic matrix like HPMC K15M, HEC, carbomer 940 etc. It was prepared by direct compression method. Tablets were evaluated in terms of swelling, mucosal adhesion, organolaptic studies, in vivo release studies were performed as well. The results were obtained from tablets containing 20 mg of flurbiprofen which allowed to good anti inflammatory sustained released in the buccal cavity for 12 hr, ensuring efficacious salivary concentration and led to no irritation [18].
6.3
7.
7.1
7.2
7.3
7.4
7.5
8. / OBJECTIVES OF THE STUDY:-
The objective of the study is as follows:
1) Formulation of bilayered tablet by any suitable method.
2) To improve the oral bioavailability of drug.
3) To overcome the first pass metabolism of drug.
4) Evaluation of bilayered tablet for their physicochemical studies.
5) Stability studies for selected formulations.
MATERIALS AND METHODS:-
SOURCES OF DATA:-
•  Review of literature from:
Journals such as:
•  Indian Journals and International journals
Web sites :
•  Word wide web.
•  J-Gate@Helinet
•  Science Dir
MATERIALS:-
Proposed Drugs:- Suitable drug for the buccal drug delivery will be selected from the following
classes
Anti asthmatic drugs or
Anti hypertensive drugs
Polymers:- Polymers from naturals and synthetics sources can be used.
METHODS OF PREPARATION:-
1) Preparation of bilayered tablets by direct Compression Technique or any other method.
2) Evaluation:-[6,7,8,13,16,17,18]
A) Precompression:-
a) Bulk density
b) Tapped density
c) Angle of repose
d) Carr’s index
e) Hausner’s ratio
B) Postcompression:-
a) Thickness
b) Weight Variation