FORMULATION AND EVALUATION OF BUCCAL TABLETS OF

KETOTIFIN FUMARATE

M.PHARM DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

By

SACHIN S. SHABADI

Under the guidance of

DR. S.B.SHIRSAND

M.Pharm, Ph.D.

DEPARTMENT OF PHARMACEUTICALTECHNOLOGY

H.K.E.S’s MATOSHREE TARADEVI RAMPURE INSTITUTEOF PHARMACEUTICAL SCIENCESGULBARGA-585105

2013-14

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES, KARNATAKA

BANGALORE

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name of the candidate
(In block letters) / SACHIN S. SHABADI
Permanent address / SACHIN S/o SHIVAKUMAR SHABADI
H.NO 3-1023\11 SIDDESHWAR NAGAR GAZIPUR
GULBARGA
DIST: GULBARGA - 585 101.
2. / Name of the institution / H.K.E.S’s MATOSHREE TARADEVI RAMPURE INSTITUTE OF PHARMACEUTICAL SCIENCES,
SEDAM ROAD,
GULBARGA-585105.
3. / Course of study and subjects / M.PHARM
(PHARMACEUTICAL TECHNOLOGY)
4. / Date of admission to the course / 31.07.2013
5. / Title of the topic / FORMULATION AND EVALUATION OF
BUCCAL TABLETS OF KETOTIFIN FUMARATE
6 / Brief resume of the intended work
6.1 / Need for the study:
The oral route is the most popular and convenient route of drug administration available. However maximum bioavailability for many of the drugs cannot be achieved by oral administration because of rapid hepatic or extra hepatic first pass metabolism, which may lead to the formation of therapeutically inactive drug molecule. Among the different approaches to avoid first pass metabolism, Buccal route seems to be more convenient and beneficial. Buccal cavity has wide variety of functions and it acts as an excellent site for absorption of drugs.1
Extensive efforts have recently been focused on targeting a drug or drug delivery system in a particular region of the body for extended period of time and better control of systemic drug delivery.2 The buccal region of the oral cavity is an attractive target for administration of the drug of choice. Advantages associated with buccal drug delivery have rendered this route of administration useful for a variety of drugs.3 The unique
Environment of the oral cavity offers its potential as a site for drug delivery. Because of the rich blood supply and direct access to systemic circulation, the oral mucosal route is suitable for drugs, which are susceptible to acid hydrolysis in the stomach or which are extensively metabolized in the liver(First pass effect).4
Ketotifin fumarate is used for the management of asthma and allergic conditions such as rhinitis and conjunctivitis, and has half life of 3 to 5 hours.Mol.Wt is 425.50.The bioavailability is 50-60% very low because it under goes first pass metabolism5.
Therefore, the present study is aimed to prepare and evaluate buccal tablets of Ketotifin fumarate in order to overcome bioavailability related problems, to reduce dose dependent side effects and frequency of administration.
6.2 / Review of Literature
Literature review shows that no work has been published on the mucoadhesive buccal tablets of Ketotifin fumarate . Some of the published reports of similar work for various medicinal agents are:
Minghetti P, Colombo A, Montanari L, Gaeta GM, Gombos F.Have designed acitretin two layer tablets, represents a good alternative to topical gel or ointment for the buccal administration of acitretion for local therapy, as the acitretin was maintained in the salivary compartment for at least 5 hrs and good clinical results were obtained.6
Chowdary KPR, Sundari GB. Have developed Matrix tablets of glipizide, using two mucoadhesive polymers namely sodium carboxymethylcelluse and HPMC with or without EC and the tablets were evaluated, tablets shows diffusion controlled and followed zero order kinetics after a lag time of 1 hr and release 90% of the drug.7
Saini M, Jain S, TiwariAK, Kaur G. Have developed in vitro and in situ kinetics of Chitosan based buccoadhesive tablets of Ketotifin fumarate and observed an increase in bioadhesive strength in combination of chitosan and sodium carboxymethylcellulose.8
Lewis S, Subramanian G, Pandey S, Udupa N. Have designed and evaluated pharmacokinetics study of mucoadhesive buccal tablets of nicotine for smoking cessation using two mucoadhesive components (HPMC/K4M/sodium alginate) has been reported. Pharmacokinetics studies are conducted in smokers, which suggests potential clinical utility in nicotine replacement therapy.9
Surapaneni MS, Das SK, Das NG. Have prepared mucoadhesive sublingual tablets of pentoxifyllin which shows controlled release of drug, 100% drug release within a reasonable period of time, measurable mucoadhesive properties and lack of drug-excipient interactions.10
Yamsani VV, Gannu R, Kolli C, Rao ME, Yamsani MR. Have prepared buccoadhesive carvedilol tablets and reported that 75.3% of carvidilol penetrated through the porcine buccal epithelium in 3 hrs and 60.2% of drug was absorbed from buccal patches in 16 min through the buccal cavity in healthy human volunteers.11
Nakhat P, Kondawar A, Babla I, Rathi L, Yeole P.Have developed buccoadhesive bilayered tablets comprising of drug containing bioadhesive layer to release the drug for extended period of time with reduction in dosing frequency.12
Patel MV, Prajapati GB, Patel MK. Have prepared Mucoadhesive bilayer tablets of propranolol hydrochlorideand observed in vitro permeation studies showed 68.65% ± 3.69% drug release of the sustained dosage form andbuccal bilayer tablets showed a mucoadhesion time of more than 12 hours.13
Emami J, Varshosaz J, Saljoughian N. Havedeveloped and evaluated controlled release buccoadhesive verapamil hydrochloride tablets,the Buccoadhesive verapamil tablets containing 53% CP and 13.3% HPMC showed suitable release kinetics and adhesive properties and did not shown any interaction between polymers and drug.14
Nakhat PP, kondawar AA, Yeole PG.Have prepared buccoadesive tablet of metoprolol tartrate which shows optimized formulation containing carbopol 934 P and methocel K4M in the ratio of 1:1 which showed surface pH values in the range of 6 to 7 and 91.50% cumulative release in 10 hours.15
Singh S, Jain S, Muthu MS, Tilak R.Have prepared buccal bioadhesive tablets of clotrimazole which markedly prolong the duration of the antifungal activity and may prove to be a viable alternative to the conventional local oral medication.16
Patel RS, Poddar SS.Have prepared mucoadhesive buccal patches of salbutamol sulphate. The study conclude that the combination of polymer PVA, chitosan and PVP showed good mucoadhesive and swelling characteristics.17
Derle D, Joshi O, Pawar A, Patel J, Jagadale A. Have prepared the mucoadhesive buccal tablet of propranolol hydrochloride,help to bypass extensive hepatic first pass metabolism and hence improve bioavailability. Also concluded that buccal bi-layer tablets showed a mucoadhesion time of more than 12 hours.18
Madgulkar A, Kadam S, Pokharkar V. Have prepared buccoadhesive tablets of miconazole nitrate which markedly prolong the duration of antifungal activity.19
Arya RK, garud A, Jain NK, garud N.Have developed and evaluated of mucoadhesive buccal tablets of salbutamol sulphate. It concludes thatastheratioofHPMCintablets increasesthehardnessof tablet also increase and when the ratio of ethylcelluloseisdouble as comparetoHPMC,showsminimum hardness of3.0kg.20
Senthil V, Gopalakrishnan S, Sureshkumar R, Jawahar N, Ganesh GNK.Have designed and evaluated mucoadhesive slow-release tablets of theophylline.This conclude that natural adhesive agent(caesalpinia pulcherrima)exhibit considerable mucoadhesive property and mean residence time values when compared with tablets of carbopol, HPMC and chitosan.21
Deshmane SV, Joshi UM, Channawar MA, Biyaani KR, Channawer AV. Have prepared buccal compact containing propranolol. This concludes that ratioof carbopol and HPMC have rate controlling effect over the time.22
Pandey S, Gupta A,Yadav J S, Shah D R.Have prepared bilayered buccal tablets of carvedilol.This conclude that mucoadhesive tablet formulation containing 5-6% carbopol 934p,65-68%HPMC K4M and 30% lactose showed 82.7% drug release.23
Velmuragan S, Nagaraju K, Deepika B,Sundar V. Have prepared Buccal tablets of Metaprolol Tartarate.This conclude that mucoadhesive tablet formulation containing Metoprolol (50mg), HPMC K4M (25mg),Carbopol (37.5mg),Mannitol (98.7mg)showed the drug release for extended period of time through buccal mucosa.24
Shirsand SB, Swamy PV, Keshavshetti GG. Have prepared Atenolol Bilayer Buccal Tablets.This conclude that Atenolol with controlled drug release can be
successfully prepared by direct compression method usingHPMC 15 cps, HPMC 50 cps and Carbopol 934p asmucoadhesive polymers and ethyl cellulose as backing layer exhibited well controlled and delayed release pattern.25
Swamy PV, Kinagi MB, Biradar S S, Gada SN, Shilpa H. Have prepared bilayer Buccal tablets of Granisetron. This conclude thatbilayer buccal tablets ofGranisetron HCL containing Granisetron HCL,Sodium alginate (47% w/w), Carbopol 934p (3% w/w), PVP K-30 (binder, 30% w/w) and mannitol showed 94% drug release for a period of 8 hours.26
Prakash Rao. Have developed the controlled release buccoadhesive tablets containing pantoprazoleusing locust beangum, HPMC and sodium CMC.It was found that locust bean gum gave higher mucoadhesive strength than HPMC and sodium CMC27.
Lodhi M.Have prepared buccal films of Ivabradine HCl for the treatment of angina pectoris to avoid repeated administration and release of drug in more controlled fashion, thereby to improve the bioavailability28.
6.3 / Objectives of the study
In the present work, studies will be carried out on the design and evaluation of buccal tablets of KETOTIFIN FUMARATES in order to,
  1. Overcome bioavailability related problems (bypass the first-pass effect) with a possible reduction in the overall dosage of the drug.
  2. To reduce dose dependent side effects and frequency of administration.
  3. To facilitate administration to those patients sufferingwith upper gastrointestinal tract disease or surgery this affects GIT absorption or those patients who have difficulty in swallowing per oral medications.
  1. In the proposed research work, we will prepare buccal tablets with the aim to achieve:
  • Greater therapeutic efficacy.
  • Avoidance of gastrointestinal disturbances, first pass effect and
Abdominal or stomach pain.
  • Improve patient compliances.
  • These prepared buccal tablets may fulfill the need of present work.

7.0 / Materials and Methods
7.1 / Source of Data:
  • Internet
  • GulbargaUniversity Library, Gulbarga
  • International Pharmaceutical Abstract
  • HKE’s College of Pharmacy Gulbarga

7.2 / Materials:
Drug: Ketotifin fumarate .
Polymers: Hydroxypropyl methyl cellulose(HPMC) different grades, Sodium
Alginate, Sodium carboxymethyl cellulose, Carbopol and Ethyl cellulose.
Equipments:
  • UV-visible spectrophotometer (Shimadzu 1700).
  • PH-meter (systronics335).
  • Electronic Balance.
  • Single Pan electronic balance.
  • Monsanto hardness tester.
  • USP XXIII tablet dissolution test apparatus-II.
Preparation of Ketotifin fumarate buccal tablet:
In the present study, buccal tablets of Ketotifin fumarate will be prepared by direct compression method using different grades of HPMC and carbopol as mucoadhesive polymers.
Buccal tablets with varying concentration of polymer and drug will be prepared. The prepared buccal tablets will be evaluated for various physicochemical characteristics such as:
  • Hardness test
  • Friability test
  • Uniformity of Weight
  • Uniformity of drug contents
  • Surface pH study
  • Swelling index
  • Mucoadhesive strength
  • In vitro drug release study

Evaluation of Ketotifin fumarate buccal tablet
Hardness test: The crushing strength (kg/cm2) of tablets is determined by using Monsanto hardness tester.
Friability test: It is determined by weighing of 10 tablets after dusting, placing them in the friabilator and rotating the plastic cylinder vertically at 25 rpm for 4 min. After dusting, the total remaining weight of tablets is recorded and the percentage loss in weight is calculated.
Uniformity of weight: Twenty tablets from each batch is selected at random and weighed individually. The individual weights are compared with average weight for determination of weight variation.
Uniformity of drug contents: Five tablets are powdered in a glass mortar and the powder equivalent to 5 mg of drug is placed in a stopper 100ml conical flask. The drug is extracted with 40 ml methanol with vigorous shaking on a mechanical gyratory shaker (100 rpm) for 1 hour and filtered in to 50 ml volumetric flask through cotton wool and more solvent is passed through the filter to produce 50 ml. The solution is analyzed for drug content by measuring the absorbance.
Surface pH study:The surface pH of the all buccal is determined in order to investigate the possibility of any side effects in vivo. As an acidic or alkaline pH may irritate the buccal mucosa, we sought to keep the surface pH as close to neutral as possible. A combined glass electrode is used for this purpose. The tablet is allowed to swell by keeping it in contact with 1ml of pH 6.8 phosphate buffer for 2 hour at room temperature. The pH is identified by bringing the electrode in to contact with the tablet surface and allowing the surface to equilibrate for 1 min.
Swelling index: Theswelling rate of the buccal tablets is evaluated by usingpH 6.8 phosphate buffer. The initial weight of the tablet is calculated (w1). The tablets are placed in pH 6.8 phosphate buffer(6ml) in a petridish placed in an incubator at 37±10C, tablet is removed at different time intervals (0.5,1.0, 2.0, 3.0, 4.0, 5.0, 6.0,7.0,8.0 hours) wiped with filter paper and reweighed (w2). The swelling index is calculated by the formula:
Swelling index = 100(w2-w1)/w1.
Mucoadhesive strength:Mucoadhesive strength of the tablet was measured on a modified physical balance using sheep bovine cheek pouch as model mucosal membrane.A double beam physical balance was removed. To Left arm of balance a thick thread of suitable length was hanged. To the bottom side of thread a glass stopper with uniform surface was tied. A clean glass mortar was placed below hanging glass stopper.In this mortar, place a clean 500ml beaker,within which place another glass beaker of 50ml capacity in inverted position and weighted with 50gm to prevent floating. The temperature control system involvesplacing thermometer in 500ml beaker and intermittently adding hot water in outer motar filled with water. The balance was so adjusted that right-hand side was exactly 5gm heavier than the left.
In vitro drug release study: This is carried out in USP XXIII tablet dissolution test apparatus-II (Electrolab), employing paddle stirrer at 50 rpm and 200ml of pH 6.8 phosphate buffers as dissolution medium. The release study is performed at 37±00C.The backing layer of the buccal tablet is attached to glass disk with fresh medium. The samples were filtered through 0.2 µm Whatman filter paper and analyzed after appropriate dilution by UV spectrophotometer.
7.3 / Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so please describe briefly
Not under the plan of the work
7.4 / Has ethical clearance have been obtained from your institution in case of 8.4?
Not applicable
8.0 / List of References
  1. Harris D, Robinson JR. Drug Delivery via the mucous membrane of the oral cavity. J Pharma Sci 1992; 81: 1-10.
  2. Jain NK, Khar RK, Ahuja A, Ali J. Controlled and Novel Drug Delivery. 1st edn, New delhi CBS Publishers and Distributors1997: p.353.
  3. Salamat-miller N, Chittchang M, Johnston TP.The use of mucoadhesive polymer in buccal drug delivery. Adv Drug Del Rev 2005;57(11):1666-91.
  4. Vyas SP, Khar RK. Bioadhesive and Mucoadhesive System. Controlled Drug Delivery,1st edn, Vallabh Prakshan 2002: p.292.
  5. SweetmanSC,editor.Martindale;the complete drug reference,35thedn, pharmaceutical press,London 2006; P-1009.
  6. Minghetti P, ColomboA, Montanari L, Gaeta GM, Gombos F. Buccoadhesive Slow Release Tablets of Acitretin: Design and in vivo Evaluation. Int J Pharm 1998;169:195-202.
  7. Chowdary KPR, Sundari GB. Design and Evaluation of Mucoadhesive Controlled Release Oral Tablets of Glipizide. Indian J Pharm Sci 2003;65(6): 591-94.
  8. Saini M, Jain S, TiwariAK, Kaur G. Chitosan based buccoadhesive tablets of pentazocine hydrochloride: in vitroand in situ kinetics. Indian J Pharm Sci 2005; 67(6): 743-7.
  9. Lewis S, Subramanian G, Pandey S, Udupa N. Design, Evaluation and Pharmacokinetic study of Mucoadhesive Buccal Tablets of Nicotine for Smoking Cessation. Indian J Pharm Sci 2006;68(6):829-31.
  10. Surapaneni MS, Das SK, Das NG. Effect of excipient and processing variables on adhesive properties and release profile of pentoxifylline from mucoadhesive tablets. DrugDevIndPharm 2006; 32(3):377-87.
  11. Yamsani VV, Gannu R, Kolli C, Rao ME, Yamsani MR. Development and in vitro evaluation of buccoadhesive carvedilol tablets. Acta Pharm 2007;57(2):185-97
  12. Nakhat P, Kondawar A, Babla I, Rathi L, Yeole P. Studies on Buccoadhesive Tablets of Terbutaline Sulphate. Indian J Pharm Sci 2007;69(4):505-10.
  13. Patel MV, Prajapati GB, Patel MK. Mucoadhesive bilayer tablets of propranolol hydrochloride. AAPS PharmTechSci2007; 8(3) Article 77:E1-E6.
  14. Emami J, Varshosaz J, Saljoughian N. Development and Evaluation of Controlled Release Buccoadhesive Verapamil Hydrochloride Tablets. DARU 2008;16(2):60-9.
  15. Nakhat PP, Kondawar AA, Yeole PG.Development and in vitro Evaluation of Buccoadhesive Tablets of Metoprolol Tartrate. Indian J Pharm Sci 2008; 121-3.
  16. Singh S, Jain S, Muthu MS, Tilak R. Preparation and evaluation of buccal bioadhesive tablets containing clotrimazole. Curr Drug Del 2008;5(2):133-41.
  17. Patel RS, Poddar SS. Development and characterization of mucoadhesive buccal patches of salbutamol sulphate. Curr Drug Del 2009; 6(1): 140-4.
  18. Derle D, Joshi O, Pawar A, Patel J, Jagadale A. Formulation and Evaluation of Buccoadhesive Bilayer Tablet of Propranolol Hydrochloride. Int J Pharma Pharm Sci 2009;1(1):206-12.
  19. Madgulkar A, Kadam S, Pokharkar V. Development of Buccal Adhesive Tablet With Prolonged Anti Fungal Activity: Optimization and ex vivo Deposition Studies. Int J Pharma Pharm Sci 2009;71(3):290-4.
  20. Arya RK, Garud A, Jain NK, Garud N. Development and evalution of mucoadhesive buccal tablets of salbutamol sulphate. Int J Pharma Pharm Sci 2010; 2(2): 40-2.
  1. Senthil V, Gopalakrishnan S, Sureshkumar R, Jawahar N, Ganesh GNK, Nagasamyvenkatesh.Mucoadhesive slow-release tablets of theophylline:design and evaluation.Asian J Pharm 2010; 64-8.
  2. Deshmane SV, Joshi UM, channawar MA, Biyaani KR, channawer AV.Design and characterization of carbopol-HPMC-ethyl cellulose based buccal compact containing propranolol HCL. Indian J Pharm Edu Res 2010; 44(3): 253-8.
  3. Pandey S, Gupta A,Yadav J S, shah D R. Formulation and In-vitro evalution of bilayered buccal tablets of carvedilol.Indian J Pharm Edu Res 2010; 44(3): 259-66.
  4. Velmuragan S, Nagaraju K, Deepika B,Sundar V. Formulation and In-vitroevalution ofBuccal tablets of Metoprolol Tartarate.Int J Pharm Pharm Sci2011;3(2):239-46.
  5. Shirsand SB,Swamy PV, Keshavshetti GG.Design and Evaluation of Atenolol Bilayer Buccal Tablets.RGUHS J Pharm Sci2011;1(1):4-10.
  6. Swamy PV, KinagiMB, Biradar SS, Gada SN, Shilpa H.Formulation Design and Evaluation of Bilayer Buccal Tablets ofGranisetron Hydrochloride.Indian J Pharm Edu Res 2011;45(3):242-7.
  7. Mamatha Y, Prakash Rao B, Ramesh K, Rajarajan S, Beny B, Reddy YV.
Formulation and Evaluation of bucco adhesive Buccal tablets containing pantoprazole.
RGUHS J pharma Sci 2012;2(3);69-80.
28.Lodhi M, Dubey A, Narayan R, Prabhakaran P, and Priya S .Formulation and
Evaluation of buccal films of Ivabradine Hydrochloride for the treatment of
Stable angina Pectoris. Int J pharm Investig 2013; 3(1);47-53.
9. / Signatures of candidate / SACHIN S. SHABADI
10. / Remarks of Guide / Mucoadhesive buccal tablets of drugs with extensive first-pass effect, such as Ketotifin fumarate will be definitely advantageous in improving bioavailability characteristics, ultimately resulting in a reduced dosage and dose related side effects.
11. / Name and designation of
(in block letters)
11.1 Guide / Dr. S.B.SHIRSANDM.PHARM., Ph.D.
ASST.PROFFESOR
DEPT.OF PHARMACEUTICAL TECHNOLOGY
H.K.E.S’s MATOSHREE TARADEVI RAMPURE INSTITUTE OF PHARMACEUTICAL SCIENCES
GULBARGA-585105.
11.2 Signature
11.3 Co-guide
11.4 Signature
11.5 Head of the Department / Dr. K.PURUSHOTHAM RAOM.PHARM., Ph.D.
PROFFESOR
DEPT.OF PHARMACEUTICAL TECHNOLOGY
H.K.E.S’s MATOSHREE TARADEVI RAMPURE INSTITUTE OF PHARMACEUTICAL SCIENCES
GULBARGA-585105.
11.6 Signature
12. / 12.1 Remarks of Chairman and Principal
12.2 Signature

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