RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA
4th ‘T’ Block, Jayanagar, Bangalore - 560 041
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1.0 / Name of the Candidateand Address: / THAKKAR SAPAN BHARATKUMAR
E/ 101, Sector- II,
Suncity, Bopal
S.P.Ring Road
Ahmedabad-380 058
Gujarat.
2.0 / Name of the Institution: /
Al-Ameen College of Pharmacy,
Hosur Road, Bangalore – 560 027.
3.0
4.0 / Course of Study and Subject:
Date of Admission: / M. Pharm – Pharmaceutics
1st June – 2010
5.0 / Title of the Topic:
“Design and Evaluation of Mucoadhesive Buccal Drug Delivery System of Granisetron Hydrochloride’’
6.0 / Brief resume of the intended work:
6.1 – Need for the study:
Ever since the first chemotherapy was delivered to a lymphoma patient, nausea and vomiting has remained a concerning side effect of cancer therapy. It is estimated that one million new cancer patients are diagnosed each year. Nausea and vomiting can be significant and severely debilitating side effect of cytotoxic chemotherapy that may significantly interfere with the quality of patient’s life.1
After administration of anti-neoplastic agent, free radicals are generated, leading to localized exocytotic release of 5 – Hydroxytryptamine3 (5- HT3) receptor on vagal afferent terminals in the wall of the bowel. Receptor for a number of neurotransmitters with potentially important roles in the emetic response are present in the dorsal vagal complex. These includes the neurokinin – 1, 5- HT3, and dopamine-2 receptors, which bind to substance P, 5-HT, and dopamine, respectively. Efferent fibers project from the dorsal vagal complex to the final effecter of the emetic reflex, the central pattern generator, which is an anatomically indistinct area occupying a more ventral location in the brain stem. Receptors for other locally released mediators, such as substance P, cholecystokinin, and prostaglandins, are also present on the vagal afferent terminals. Antineoplastic agents may also induce emesis through an interaction with the area postrema within the dorsal vagal complex.2
A wide range of drugs has been shown to have effect on nausea and vomiting. These includ anti- histamines, anti- cholinergic, dopamine receptor antagonists, 5 – HT3 receptor antagonists and gastroprokinetic agent. Each of these drug affects different receptor and some act at different sites.3 Granisetron is selective 5 – HT3 receptor antagonist has more potent and longer acting properties than Ondensetron and has been used for the treatment of emesis induced by cytotoxic drugs.4 It exhibit only 60% oral bioavailability because of first pass metabolism and has a relative short half – life of 3 Hours.5
The main problem with the conventional oral dosage forms is that they have to be swallowed along with water and many patients find it difficult to swallow tablets, especially in geriatric and paediatric patients because of the physiological changes associated with these groups.
Due to this dysphagic condition, they do not comply with prescription, which results in patient non-compliance. Thus buccal drug delivery system are beneficial to patients who find it difficult to swallow tablets, moreover some of the drugs which are soluble in saliva are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into stomach, which enhances bioavailability by avoiding first pass metabolism.6
The design of mucoadhesive buccal drug delivery system includes - ease of administration, termination of therapy is easy, permits localization of the drug to the oral cavity for a prolonged period of time, it can be administered to unconscious patients, offers an excellent route for the systemic delivery for drugs with high first pass metabolism, thereby offering a greater bioavailability. A significant reduction in dose can be achieved, thereby reducing dose dependent side effects, drugs which show poor bioavailability via the oral route can be administered conveniently, it offers a passive system for drug absorption, the oral mucosa lacks prominent mucus secreting goblet cells and therefore there is no problem of a diffusion limited mucous build
up, beneath the applied dosage form, the presence of saliva ensures relatively large amount of water for drug dissolution unlike in case of rectal and transdermal route. The mucoadhesive drug delivery system is one of the approaches to increase the bioavailability and to increase consumer acceptance by virtue of rapid disintegration, self administration without water or by chewing.7
Thus there is need to design mucoadhesive drug delivery system of Granisetron Hydrochloride which attempts to overcome variable bioavailability and design better formulation to achieve quick onset of action.
In the present research work an effort will be made to formulate, optimize and evaluate mucoadhesive drug delivery system of Granisetron Hydrochloride for anti-emetic activity in the form of buccal films/buccal tablets.
6.2 REVIEW OF LITERATURE
· Matti Apro et al. has optimized 5 HT3 – receptor – antagonist based anti- emetic therapy for cancer patients, particularly during the first 24 hrs after receiving chemotherapy, based on knowledge of the chemotherapeutic regimen, comorbidity, polypharmacy, dosing convenience and age – related health. Choosing a 5 HT3 – receptor – antagonist with a long duration action, low risk of drug- drug interaction and once daily dosing is important to ensure effective prophylaxis against nausea and vomiting in the elderly and simplify and comorbidity.1
· Shaila Lewis et al. have been reported that mucoadhesive nicotine tablets for buccal administration were prepared by using polymers like HPMC K4M and Carbopol. It has been proved that the buccal tablet remained stationary at the buccal mucosa, hence it is able to provide good bioavailability and has potential clinical usefulness.8
· R K Arya et al. have investigated that mucoadhesive tablet of salbutamol sulphate were prepared by non aqueous granulation of polymers HPMC K4M (Hydroxypropyl Methyl Cellulose) and EC (Ethyl Cellulose) in different ratios 1:1, 1:2, and 2:1. The tablets were evaluated for weight variation, hardness, thickness, drug content uniformity, mucoadhesion and swelling index. In-vitro bioadhesion strength studies showed that tablets containing more HPMC K 4M were great bioadhesive in nature.9
· Basani Gavaskar et al. stated that oral dissolving film Technology (ODFT) can be administrated in the buccal cavity for a shorter period of time in seconds and gives better therapeutic action. ODFT offers an alternate platform for molecules that undergoes first pass metabolism and also to improve patient compliance.10
· Mona Semalty et al. have been reported that mucoadhesive buccal films of Glipizide were prepared by solvent casting technique using Hydroxypropyl Methyl Cellulose, Sodium CMC, Carbopol – 934P and Eudragit RL- 100. Prepared films were evaluated for weight, thickness, surface pH, swelling index, In - vitro residence time, folding endurance, In-vitro release, permeation studies and drug content uniformity. The optimized formulation showed that HPMC with Sodium CMC combination has shown good swelling, a convenient residence time and promising controlled drug realese.11
· S. Singh et al. studied that buccal bioadhesive films were designed to release the drug at a concentration above the minimum inhibitory concentration for a prolonged period of time so as to reduce the frequency of administration of the available conventional dosage forms. The films were prepared by solvent casting method using Sodium CMC, and Carbopol 974P(CP 974P). In - vitro drug release from the film was determined using a modified Franz Diffusion Cell while bioadhesiveness was evaluated with a modified two – arm balance using rabbit intestinal mucosa as a model tissue. Films containing 5% CP 974P of the total polymer were found to be the best with moderate swelling along with favourable bioadhesion force, residence time and In - vitro drug release.12
· A. Semalty et al. showed that Mucoadhesive buccal film of diltiazem hydrochloride were prepared by solvent casting technique using sodium CMC, polyvinyl pyrrolidone K30 and polyvinyl alcohol. Prepared films were evaluated for their weight, thickness, surface pH, swelling index, In - vitro residence time, folding endurance, In - vitro release, permeation studies and drug content uniformity. From this study shows that formulation in polyvinyl alcohol and polyvinyl pyrrolidone showed moderate swelling, a convenient residence time and promising drug release.13
· S. Kunte, P. Tandale have investigated the possibility of developing verapamil fast dissolving strips allowing fast, reproducible drug dissolution in the oral cavity; thus bypassing first pass metabolism. The fast dissolving strips were prepared by solvent casting technique using HPMC E6 and maltodextrin and evaluated for drug content uniformity, film thickness, folding endurance, in - vitro disintegration time, in - vitro dissolution studies, surface pH study, and palatability study. HPMC E6 and maltodextrin showed optimum performance and solvent casting technique with enhanced dissolution rate, taste masking, and hence better patient compliance and effective therapy.14
· Soad A. Yehia et al. studied fluconazole mucoadhesive buccal films were prepared using film forming polymers namely; Hydroxypropylmethyl Cellulose (HPMC), hydroxyethyl cellulose (HEC), chitosan, Eudragit and sodium alginate either alone or in combination with bioadhesive polymers. The bioadhesive polymers studied were sodium carboxymethylcellulose (SCMC), Carbopol 974P, and polycarbophil (AA-A). The prepared films were characterized by means of film thickness, surface pH, swelling capacity, in vitro adhesion, In - vivo residence time, In vitro drug release and in - vivo drug release to determine the amount of drug release from selected film formulae using microbiological assay and HPLC. Optimum release behavior, convenient bioadhesion and acceptable elasticity were exhibited by film containing 2% HPMC and 1% SCMC (fresh or stored for 6 months).15
· Abul Kalam Lutful Kabir et al. showed that mouth dissolving tablets constitute an innovative dosage forms that overcome the problems of swallowing and provides a quick onset of action. Tablets were prepared by direct compression technique using super disintegrating agent (Croscarmellose sodium). The granules were evaluated for angle of repose, bulk density, tapped density, bulkiness, compressibility index and hausners ratio. The tablets were evaluated for hardness, thickness, uniformity of weight, friability, wetting time, water absorption ratio, disintegration time and drug content. In - vitro release studies were performed using USP-II (paddle method) in 900m1 of pH 1.2 at 50rpm. Tablets prepared with pharmaburst B2 and Croscarmellose sodium showed a lesser disintegration time and wetting time of 27±0.10 and 38±0.13 seconds respectively. The best formulations were subjected to stability studies at 40°C/75% RH.16
6.3 OBJECTIVE OF STUDY
In this research work, an attempt has been made to Formulate buccal drug delivery system of Granisetron Hydrochloride to improve its bioavailability and enhance patient compliance, Hence two dosage forms i.e. Bioadhesive films/tablets for buccal administration will be prepared, optimized and evaluated and compared with marketed formulation.
SPECIFIC OBJECTIVES
· To develop mucoadhesive buccal Films / tablets.
· To evaluate the optimized mucoadhesive buccal drug delivery.
· To carry out stability studies for the best formulation.
· To compare the best formulation with the available marketed formulations.
Materials and Methods
7.1 Source of Data:
1) Review of Literature from
a) Journals - such as
· AAPS PharmSciTech.
· International Journal of Pharmaceutical Sciences.
· J-Gate@HELINET
· Indian Journal of Pharmaceutical Sciences
· Pharmaceutical development and technology
· Science Direct.
b)Internet Browsing.
www.google.com
www.wikipedia.org
7.2 - Method of Collection of Data:
1) Literature survey
2) Preformulation studies.
· Solubility studies and Partition co- efficient
· Permeation studies.
· Compatibility studies.
3) Screening of Polymers like sodium CMC, HPMC, Carbopol and PVA alone or
in combination for the formulation development.
4) Formulation of mucoadhesive buccal Tablets/Films of a Granisetron Hydrochloride.
5) Evaluation
A) Physicochemical parameters
· Thickness, Weight variation
· Folding endurance
· Surface pH
B) Measurement of swelling index
C) Tensile strength of buccal film
D) Percentage elongation for buccal film
E) Percentage moisture absorption (PMA) and Loss
F) Uniformity of Drug Content
G) In - Vitro Drug release
H) In - vivo Mucoadhesive time
I) Stability studies as per ICH Guidelines
5). Comparison with marketed formulation of Granisetron Hydrochloride.
7.3 - Does the study require any investigations or interventions to be conducted on patients or other humans or animals? If so, Please describe briefly.
NO
7.4 – Has ethical clearance been obtained from your Institution in case of 7.3?
NOT APPLICABLE
/
Bibliography
1. Matti A, Judi J. Chemotherapy – induced Emesis in Elderly Cancer Patients: The role of 5 –HT3 Receptor Antagonist in the first 24 Hours. Int J Exp Clinical, Behavioral and Gerontology 2005;51:287-96.
2. URL: http://www.nejm.org/doi/full/10.1056/NEJMra0706547 [ cited on 2010 Oct 10]
3. URL: http://en.wikipedia.org/wiki/Antiemetic # classification [ cited on 2010 Oct 10]
4. Katsuya M, Yumiko T, Kahoru N, Nobuhiro M, Hidefumi O. The Antiemetic efficacy of prophylactic Granisetron in gynecologic surgery. Anesth Analg 1995;80:970-74.
5. URL: http://en.wikipedia.org/wiki/Granisetron [ cited on 2010 Oct 10]
6. Venkatalakshmi R, Sasikala C, Swathi R, Tejaswini G et al. Formulation and Evaluation of Granisetron Hydrochloride Mouth Dissolving Tablet. Int J Ph Sci 2009;1(2):336-41.
7. Khanna R, Agarwal SP, Alka A. Mucoadhesive buccal drug delivery : A potential alternative to conventional therapy. Indian J Pharm. Sci 1998;60(1):1-11.
8. Shaila L, Subramanian G, Pandey S, Udupa N. Design, Evaluation and Pharmacokinetic study of mucoadhesive buccal tablet of nicotine for smoking cessation. Indian J Pharm Sci 2006,68(6):829-31.
9. Arya R K, Akanksha G, Neetesh KJ, Navneet G. Development and Evaluation of mucoadhesive buccal tablets of salbutamol sulphate. Int J Pharmacy Pharm Sci 2010;2(2):40-42.
10. Basani G, Subash V, Guru S, Madhusudan R. Overview on fast dissolving films. Int J Pharmacy Pharm Sci 2010;2(3):29-33.
11. Mona S, Semalty A, Kumar G. Formulation and Characterization of mucoadhesive buccal films of Glipizide. Indian J Pharm Sci 2008;70(1):43-48.
12. Singh S, Jain S, Muthu MS, Tiwari S, Tilak S. Preparation and Evaluation of buccal bioadhesive films containing Clotrimazole. AAPS PharmSci Tech 2008;9(2):660-67.
13. Semalty A, Mona B, Bhatt GK, Gupta GD, Shrivastav AK. Design and Evaluation of mucoadhesive buccal films of Diltiazem Hydrochloride. Indian J Pharm Sci 2005;67(5):548-52.
14. Kunte S, Tandale P. Fast Dissolving Strips: A novel approach for the delivery of Verapamil. J Pharm Bioall Sci 2010;2(4):325-28.
15. Soad AY, Omaima NE, Emad BB. Fluconazole Mucoadhesive Buccal Films: In Vitro/In Vivo performance. Current Drug Delivery 2009;6(1):17-27.
16. Abul K, Shaikh M, Md. Arshad J, Abu S. Formulation, Development and Evaluation of mouth dissolving tablets of Loratadine. S J Pharm Sci 2009;2(2):59-65.
9.0 / Signature of the Candidate: / ( THAKKAR SAPAN BHARATKUMAR)
10.0 / Remarks of the Guide: /
Recommended
11.0 / Name and Designation of:
11.1 Institutional Guide: /
Mrs. AISHA KHANUM
Assistant ProfessorDepartment of pharmaceutics.
Al-Ameen College of Pharmacy
Bangalore- 560 027
11.2 Signature:
11.3 Institutional Co - Guide: / Mr. VINAY PANDIT
Lecturer
Department of pharmaceutics.
Al-Ameen College of Pharmacy
Bangalore- 560 027
11.4 Signature:
11.5 Head of the Department: / Dr. (Mrs.) V. KUSUM DEVI
Professor and Head
Department of Pharmaceutics
Al-Ameen College of Pharmacy
Bangalore- 560 027
11.6 Signature:
12.0 / 12.1 Remarks of the Chairman and Principal / Forwarded to the University for scrutiny
12.2 Principal / Prof. B. G. SHIVANANDA
Principal
Al-Ameen College of Pharmacy,
Hosur Road, Bangalore – 560 027
11