“PREPARATION ANDEVALUATION OF BUCCAL FORMULATION FOR

AN ANTIANXIETY DRUG”

DISSERTATION PROTOCOL

SUBMITTED TO

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES

BANGLORE-85, KARNATAKA

BY

PATEL KRUNAL KUMAR SHAMBHUBHAI

M.PHARM, PART-I

DEPARTMENT OF PHARMACEUTICS

NARGUNDCOLLEGE OF PHARMACY

BANGALORE-85

(2011-2013)

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE-85,KARNATAKA.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME OF THE CANDIDATE
AND ADDRESS (IN BLOCK LETTERS) / PATEL KRUNAL KUMAR SHAMBHUBHAI
NARGUND COLLEGE OF PHARMACY,
DATTATREYANAGAR, II MAIN,
100 FEET RING ROAD,
BSK III STAGE,
BANGALORE-85,
KARNATAKA.
2. /

NAME OF THE INSTITUTION

/ NARGUND COLLEGE OF PHARMACY,
DATTATREYA NAGAR, II MAIN,
100 FEET RING ROAD,
BSK III STAGE,
BANGLORE-85,
KARNATAKA.
3. /

COURSE OF STUDY AND SUBJECT

/ MASTER OF PHARMACY IN PHARMACEUTICS
4. / DATE OF ADMISSION OF COURSE / 8th DECEMBER2011.
5. /

TITLE OF TOPIC

/ "PREPARATION AND EVALUATION OF BUCCAL FORMULATION FOR AN
ANTI ANXIETY DRUG ”
6.
7.
8. / BRIEF RESUME OF THE INTENDED WORK:
6.1 NEED FOR THE STUDY:
Many therapeutic agents have been reportedly subjected to extensive presystemic elimination by gastrointestinal degradation and/or hepatic metabolism, when administered by oral route. Oral route, many times, results in low systemic bioavailability and short duration of therapeutic activity.
Delivery of drugs via the absorptive mucosa in various easily accessible body cavities, like the ocular, nasal, buccal, rectal and vaginal mucosa, has the advantage of bypassing the hepato- gastrointestinal metabolism.
Anxiolytics(Also Anti-panic or Anti Anxiety agent) are the drugs which are used for the treatment of anxiety and its related psychological and physical symptoms.These have been shown to be useful in the treatment of anxiety disorder and are also known as minor tranquilizers, neuroleptics and anti-psychotics.Anti-anxiety drugs are classified into fourcategories, like Benzodiazepines, Azapirones , Sedative anti-histaminic, Beta-blocker.
Benzodiazepines:
  • Benzodiazepines hypnotics: drugs like Diazepam,Oxazepam.
  • Non-Benzodiazepines hypnotics:drugs like Zopiclone,Zaleplon.
Azapirones: drugs like Buspirone,Ispapirone,Gepirone.
Sedative antihistaminic: drugs like Hydroxyzine.
Beta blockers: drugs like Propranolol.
The pharmacokinetic properties of few Anxiolytics drugs are as follows:
Buspirone:-
  • It’s bioavailability is 5%.It’shalf life is 2-3hrs.It’s dose is 14-30mg thrice daily.
Haloperidol:-
  • It’s bioavailability is 50-60%.It’s half life is 10-30hrs.It’s dose is 3-5mg twice or thrice daily.
Zaleplon:-
  • It’s bioavailability is 30%.It’s half life is 1hr.It’s dose is 10mg right before bedtime.
Midazolam:-
  • It’s bioavailability is 36%.It’s half life is 2-6hrs.It’s dose is 10-15mg.
The above mentioned drugs are having low bioavailability because of first pass metabolism. Doses are ranging from 4-30mg. With an intention to improve the bioavailability, a buccal formulation was planned for an anti-anxiety drug.
6.2 REVIEW OF LITERATURE:
Varinder kumar, et al., preparedVenlafaxine buccal patches using the solvent casting method.The patches were evaluated for their physical characteristics like weight variation,drug content uniformity,folding endurance,surface pH and in-vitro drug release,in-vivo buccal permeation study,ex-vivo bioadhesion strength,ex-vivo mucoadhesion time.Patches exhibited controlled release and release the entire contents with a period of 10 hrs. [1]
Prasanth V.V. et al., prepared mucoadhesivebuccal patches of Aceclofenac using different polymers like hydroxypropyle methylcellulose,carbopol 934-P,polyvinyl alcohol,polyvinyl pyrrolidone K-30,eudragit L-100 in various proportion and combination by solvent casting mathod.The prepared patches were smooth,elegant in appearance,uniform thickness,mass and drug content.In-vitro drug release and in-vivo drug permeation study showed that,from the formulation F10,the drug is released and permeated fastly. 2
Nikolaos AP et al., proposed that the primary goal of bioadhesive controlled drug delivery is to localise a delivery device within the body to enhance the drug absorption process in a site specific manner. Bioadhesion is affected by the synergistic action of the biological environment, the properties of the polymeric controlled release device and the drug itself. Five theories have been suggested to play a major role in bioadhesion, namely, adsorption, diffusion, electronic, fracture, and wetting theories.3
Eouani C et al., compared the polymers using texture analyzer TA-TX2i. Polymersof different chemical nature, molecular weight, as well as hydration status were used. They are namely Carbopol 971P > Polycarbophil > Carrageenan type > Na-CMC. The swelling state as well as tensile strength of polymeric films were used as measuring parameters of mucoadhesive interaction.4
Swamy PV et al., evaluated bilayer buccal tablets of Granisetron Hydrochloride, in order to overcome bioavailability problems to reduce dose dependent side effects and frequency of administration. This tablets prepared by direct compression method using combination of polymer(Sodium alginate, HPMC 50 cps, Carbopol 934P) and Ethyl cellulose as an impermeable backing layer to release drug in unidirectional way towards the mucosa thus avoiding loss of drug due to wash out by saliva.5
Miller NS et al.,reviewed use of mucoadhesive polymers in buccal drug delivery. Starting with oral mucosa, mechanism of drug permeation and characteristics of the desired polymers, this article then proceeds to cover the theories behind the adhesion of bioadhesive polymers to mucosal epithelium. Additionally, they focused on new generation of mucoadhesive polymers such as Thiolated polymers, followed by the recent mucoadhesive formulations for buccal drug delivery.6
Marina K et al., formulated buccal films of Ondansetron Hydrochloride from mucoadhesive polymers, Chitosanand PVP K30, for the purpose of prolonging drug release and improving its bioavailability. All fabricated film formulations were smooth and translucent, with good flexibility. The weight and thickness of all the formulation were found to be uniform. The inclusion of PVP K30, significantly reduce the bioadhesive strength and invitro mucoadhesion time of films, although the degree of swelling increased.7
Kapil K. Purohit et al. prepared Timolol Maleate buccal mucoadhesive patches. Timolol maleate is a non-selective beta-adrenergic blocker, and having short biological half-life and low oral bioavailability. The present investigation is concerned with the development of the buccal mucoadhesive patches to prolong the residence time and to improve the bioavailability of the drug. Various formulations were developed by using release rate controlling and gel forming polymers like HPMC K 100M, Eudragit RL100 and Ethyl cellulose by solvent casting method. In addition to this glycerol and tween 80 was used as plasticizer and permeation enhancer respectively. All the formulations had good physical appearance and physicochemical properties. From among all the developed formations, since formulation F9 retarded the drug release in a controlled manner for prolonged period of more than 7 h, gave satisfactory bioadhesion for maximum duration of 6.9 h and drug diffusedup to the 80%, so it was selected as the best formulation.8
R.S.Hirlekar et al., designed of a buccal drug delivery system for a poorly soluble drug.Carvedilol is an antihypertensive drug used in the treatment of congestive heart failure, cardiac arrhythmias and angina pectoris. It exhibits poor bioavailability of 25-30% which is attributed to its poor solubility and high first pass metabolism. The present work was aimed at overcoming these two limitations. Drug-Methyl-β-cyclodextrin complex was prepared by kneading method and characterized by Fourier Transformation Infrared spectroscopy, Differential Scanning Calorimetry and powder X-Ray Diffractometry studies. Dissolution rate of complex was compared with plain drug and physical mixture. The complex was incorporated into buccal tablet. The buccal tablets were evaluated for drug release, mucoadhesive strength and ex-vivo permeability.9
Hariprasanna R.C. et al., prepared Loratadin mucoadhesive tablets.The aim of present work is to prepare buccal tablet of Loratadine to increase the bioavailability by avoiding first pass metabolism. Three different types of formulation were prepared Carbopol 934P as a primary polymer and Chitosan or Sodium alginate as a secondary polymer. The buccal tablets were prepared with varying the concentration of polymer by direct compression method. The prepared tablets were evaluated in terms of weight variation, hardness, thickness, friability, swelling index, surface pH,in-vitrodrug release, mucoadhesion test, stability studies and FTIR studies. Estimation was carried out spectrophotometricaly at 248nm.10
Santosh Kumar Mishra et al,. preparedmucoadhesive buccal patches of Flurbiprofen (FBN). Solubity enhancement was attempted by making solid dispersion of drugwith β-CD (cyclodextrin). Initially preformulation were carried out using reported methods. Buccal patcheswere prepared by solvent casting technique using polymers like polyvinyl alcohol (PVA), sodium carboxymethylcellulose (SCMC), and hydroxypropyl methylcellulose (HPMC). The prepared patches were evaluatedfor their weight variation, thickness, folding endurance, surface pH, swelling index, in vitro residencetime, in vitro permeation studies, drug content uniformity and bioadhesion test.11
Ashwini RM et al., have employed buccoadhesives to improve the bioavailability of drugs undergoing significant hepatic first pass metabolism. Domperidone has low bioavailability due to extensive first pass effect. Buccoadhesive hydrophilic matrices containing domperidone and polymer like Carbopol 934P & Methocel K100LV were taken as the formulation variable for optimizing bioadhesion and kinetics of dissolution. A suitable combination of two polymers provided adequate bioadhesive strength and fairly regulated the release profile up to 4hr.12
Vishnu M. Patel et al., prepared mucoadhesive buccal patches containing Propranolol hydrochloride using solvent casting method. Chitosan was used as bioadhesive polymer and different ratios of chitosan to PVP K-30 were used.The patches were evaluated for their physical characteristics like weight variation,drug content uniformity, folding endurance, ex-vivo mucoadhesion strength, ex-vivo mucoadhesion time, surface pH, in-vitro drug release and in-vitro buccal permeation sudy.Patches exhibited controlled release for a period of 7 hrs. 13
Colin R. Gardner et al.,describe of the potential use of drugs modulating 5-HT activity in the treatment of Anxiety. It has been suggested that central 5-HT mediated system may be involved in modulation of Anxiety and in the Anxiolytic effect of Benzodiazepines. Buspirone is clinically active in the treatment of Anxiety and other Anxiolytic candidates, Gepirone and Isapirone may act as agonist on 5HT1A receptor. A selective 5HT2 antagonist, ritanserin has Anxiolytic effects in clinical studies but, like the 5HT1A agonist, does not show a similar profile to Benzodiazepines in models of anxiety.14
ADVANTAGES OF MUCOADHESIVE DRUG DELIVERY SYSTEMS:
Drugs administration via oral mucosa offers several advantages:
1)Ease of administration.
2)Termination of therapy is easy.
3)Permits localization of drug to the oral cavity for a prolonged period of time.
4)Can be administered to unconscious patients.
5)Offers an excellent route, for the systemic delivery of drugs with high first pass metabolism, thereby offering a greater bioavailability.
6)A significant reduction in dose can be achieved thereby reducing dose related side effects.
7)Drugs, which are unstable in the acidic environment or destroyed by enzymatic reaction can administered.
8)Drugs, which show poor bioavailability via the oral route, can be administered conveniently.
9)The presence of saliva ensures relatively large amount of water for drug dissolution unlike in case of rectal and transdermal routes.
10)Systemic absorption is rapid.
11)This route provides an alternative for the administration of various hormones, narcotic analgesics, steroids, enzymes, cardiovascular agents etc.
12)The buccal mucosa is highly perfused with blood vessels and offers a greater permeability than the skin.
6.3 OBJECTIVES OF THE STUDY:
The main objective of the present study is to formulate and evaluate a buccal drug delivery system for an anti anxiety drug by adopting following steps:-
Step I: Development of suitable analytical method for the estimation of the drug.
Step II: Preformulation studies, Drug-excipients compatibility studies for selection
of excipients.
Step III: Permeability study of the drug by using diffusion cell to check whether
the drug has enough permeability or not.
Step IV: Preparation of formulation either film/tablet using various polymers for
buccal delivery.
StepV:Evaluation of the prepared formulation by different physicochemical characterization studies such as
a)Weight variation
b)Thickness
c)Content uniformity
d)Surface pH
e)Permeability study
f)Bioadhesive strength
g)Drug release
h)Swelling study
i)In vitro residence time
Step VI: Stability study of the most satisfactory formulation
MATERIALS AND METHODS:
7.1 Materials:
Anti-anxiety drugs like, Diazepam,Lorazepam,Buspiron,Gepiron,Zaleplon,Ispapiron,
Hydroxyzine,Propranolol,Chlordiazepoxide,Alprazolam.
.Bioadhesive polymers:
Water soluble polymer:Carbopol, Na-Carboxy methyl cellulose, Hydroxyethyl cellulose,Hydroxypropyl methyl cellulose, Hydroxypropyl cellulose, Sodium alginate etc.
Water insoluble polymer:Eudragit,Polycarbophil, Ethyl cellulose etc.
Using the above materials, based on initial experimentation,a buccal formulation for an antianxiety drug will be prepared.
7.2 Source of Data:
Data will be obtained from Pub med, Science Direct, Medline, and other Internet facilities, literature search and related articles from library of Nargund College of Pharmacy.
A. Journals & Articles:
Advanced Drug Delivery Review.
International Journal of Pharmaceutical Science.
American Association of Pharmaceutical Scientists.
International Journal of Pharmaceutical Education & Research.
Research Journal of Pharmaceutics and Technology.
European Journal of Pharmaceutics and Biopharmaceutics.
Asian Journal of Pharmaceutics
Journal of Indian Medical Association.
B. Internet Browsing:




 lab.com
C.Text Books:
Hardman JG, Limbird LE. Goodman and Gilman’s the pharmacological basis of therapeutics. 10thedition.
SC. Martindale the complete drug reference. 34th ed. London, Chicago: Pharmaceutical Press; 2005.
KD Tripathi. Essentials of Medical Pharmacology. 5th edition.
7.3 Method Of Collection Of Data (including sampling procedure, if any):
  1. Spectrophotometric or HPLC method for the estimation of drug.
  2. Formulation is prepared using bioadhesive polymers.
  3. The formulations will be evaluated for the bioadhesive tensile strength, swelling studies, permeability study, thickness uniformity and content uniformity.
  4. In vitropermeation of drug from the formulation is studied using diffusion cell.
  5. Mechanism of release of drug from the formulation is evaluated.
  6. The best formulation will be selected.
  7. Stability study of the selected formulation will be carried out as per ICH guidelines.
7.4 Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly.
Experimental study is focuseduptoin vitro models only.
7.5 Has ethical clearance been obtained from your institution in case of 7.4?
-NOT APPLICABLE-
LIST OF REFERENCES:
1. Varinder K,Foziyah Z. Formulation and evaluation of buccal patches of Venlafaxin. Int J of Pharm and Biological Sci.2011 July-Sept;1(3):170-82.
2.Prasanth VV, Sam MT. Formulation and evaluation of Mucoadhesive Buccal patches of Aceclofenac.Scholars Research Library.2012;4(1):297-306.
3.Nikolaos AP, Jennifer JS. Hydrogels as mucoadhesive andbioadhesive materials.A review. Biomaterials.1996;(17):1553-61.
4.Eouani C, Piccerelle PH, Prinderre P, Bourret E, Joachim J.In-vitro comparative study ofbuccal mucoadhesive performance of different polymerfilms. EuropeanJ of pharmBiopharmaceutics.2000March;52:45-55.
5. Swamy PV, Kinagi MB, Biradar SS, Gada SN, Shilpa H. Formulation design and evaluation of bilayer buccal tablets of granisetron hydrochloride. IndianJof Pharm Education & Research.2011July-sep;45:242-7.
6. Miller NS, Chittchang M, Johnston TP. The use of mucoadhesive polymers inbuccal drug delivery. Advanced Drug Delivery Reviews. 2005Nov;57(11):1666-91.
7. Marina K, Narayana RC, Vijayanarayana K,Prabhakara P. In vitro and in vivo evaluation of Chitosan buccal films of Ondansetron Hydrochloride. Asian J of Pharm.2011;1(3):164-71.
8.Kapil K. Formulation and evaluation of Timolol Maleate buccal mucoadhesive patches. J of pharm research. 2010;3(8):2031-35.
9. Hirlekar RS. Design of buccal drug delivery system for a poorly soluble drug. Asian J of pharm and clinical research. 2009 July-Sept;2(3):49-53.
10. Hariprasanna RC, Najmuddin M, Prashant AB. Development and evaluation of mucoadhesive buccal tablet of Loratadine. J of pharm research. 2011;4(8):2066-2702.
11.Santosh Kumar M, Navneet G, Ranjit S. Development and evaluation of mucoadhesive of Flubriprofen. Polish Pharm Society. 2011;68(6):955-64.
12.Ashwini RM, Mangesh RB, Amruta SN, Nitin DW. Formulation development of domperidone buccal bioadhesive hydrophilic matrix tablet. Asian J of Pharm.2011;5 (1):21-7.
13. Vishnu PM, Bhupendra PG. Design and chericteristics of Chitosan containing Mucoadhesive Buccal patches of Propranolol Hydrochloride. Acta pharm.2007 March;57 (1):61-72.
14.Gardner CR. Potential use of drugs modulating 5-HT activity in the treatment of anxiety. General Pharmcology: The Vascular System. 1988;19(3):347-56.
9. / SIGNATURE OF THE CANDIDATE / (PATEL KRUNALKUMAR SHAMBHUBHAI)
10. / REMARKS OF THE GUIDE / RECOMMENDED FOR DISSERTATION WORK.
11. / NAME & DESIGNATION OF
11.1GUIDE
11.2SIGNATURE / RAMA BUKKA
M.PHARMACY
ASSISTANT PROFESSOR
DEPT.OF PHARMACEUTICS
NARGUNDCOLLEGE OF PHARMACY
11.3HEAD OF THE DEPARTMENT
11.4SIGNATURE / Dr. C.S.R. LAKSHMI
PROFESSOR
HEAD OF THE DEPARTMENT OF PHARMACEUTICS
NARGUNDCOLLEGE OF PHARMACY,
12. / 12.1REMARKS OF THE
PRINCIPAL
12.2 SIGNATURE. / FORWARDED AND
RECOMMENDED FOR FAVORABLE CONSIDERATION.
(DAYANAND. S. PURANIK)