DEVELOPMENT OF MOUTH DISSOLVING DOMIPERIDONE STRIPS
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED
TO
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA
BY
MALIPEDDU BHARATH KUMAR
Ι M.PHARM(2011-2012)
DEPARTMENT OF PHARMACEUTICS
M.S.RAMAIAHCOLLEGE OF PHARMACY
BANGALORE - 560 054
KARNATAKA
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR P.G. DISSERTATION
1. / NAME OF THECANDIDATE AND
ADDRESS
(IN BLOCK LETTERS) / Mr. MALIPEDDU BHARATH KUMAR
S/o M C SUBRAMANYAM
BHARATH GENERAL STORES
NEAR OLD BUS STAND
JAMMALAMADUGU
KADAPA (DIST) –516434
ANDHRA PRADESH.
2. /
NAME OF THE INSTITUTION
/ M.S.RAMAIAHCOLLEGE OF PHARMACYM.S.R.NAGAR
M.S.R.I.T POST
BANGALORE-560 054.
3. /
COURSE OF STUDY AND SUBJECT
/MASTER OF PHARMACY
INPHARMACEUTICS
4. /DATE OF THE ADMISSION
/ 16/6/20115. /
TITLE OF THE TOPIC
“ DEVELOPMENT OF MOUTH DISSOLVING DOMIPERIDONE STRIPS”6. BRIEF RESUME OF THE INTENDED WORK
6.1 NEED FOR THE STUDY
Oral route of drug administration is the most important method for systemic effect. Among the pharmaceutical dosage form, the conventional tablet seems to be most popular because of its ease of transportation and comparatively low manufacturing cost.However hepatic first pass metabolism, local GI toxicity and enzymatic degradation, poor bioavailability, hand tremors, dysphagia in case of geriatric patients, underdeveloped muscular and nervous system in infant and non-cooperative patient, the problem of swallowing are the common phenomenon which lead to poor patient compliance.
Buccal mucosa and sublingual region is highly vascularised and it gives rapid absorption of drugs than oral route. Drugs that are absorbed through the buccal mucosa and sublingualroute directly enter the systemic circulation bypassing the first-pass metabolism in the liver. The buccal mucosa provides a readily accessible route for transmucosal delivery.
A quick dissolving tablet is also known as a fast dissolving, fast-dissolving multiparticulate,rapid-dissolving, mouth-dissolving, fastmelting, or orodispersible tablets that disintegrate within 60 seconds when placed in the mouth without drinking or chewing . The active ingredients are absorbed through mucous membranes in the mouth and GIT and enter the blood stream. Advantages of fast dissolving tablets are
- Ease of administration to patients who cannot swallow, such as the elderly, stroke victims and bedridden patients; patients who should not swallow, such as renal failure patients; and who refuse to swallow, such as pediatrics, geriatric and psychiatric patients.
- Convenience of administration and accurate dosing as compared to liquid formulations.
- More rapid drug absorption from the pre-gastric area i.e. mouth, pharynx and esophagus which may produce rapid onset of action.
But due to certain disadvantages like their physical solid form, psychological fear of swallowing, chewing or choaking , friability of wafer like porous and low pressure molded tablet fabricated by various manufacturing processes and expensive packaging cost to protect the dosage form, a new technology was developed as mouth dissolving film.
Orally fast-dissolving film is new drug delivery system for the oral delivery of the drugs. It can be placed on the tongue or any oral mucosal tissue, instantly wet by saliva the film rapidly hydrates and adheres onto the site of application. It then rapidly disintegrates and dissolves to release the active ingredient1.
Domperidone is a class of drug that blocks the action ofdopamine. It has strong affinities for theD2andD3dopamine receptors,which are found in thechemoreceptor trigger zone, located just outside the blood brain barrier, which regulates nausea and vomiting.Domperidone is a first choice antiemetic in some countries.It can be used in patients withParkinson's diseasebecause unlikemetoclopramide, domperidone does not cross theblood-brain barrier. It has also been found effective in the treatment ofgastroparesis,a stomach motility condition, and forpaediatricgastroesophageal reflux(infant vomiting). It has a biological half life of 7h. and its oral bioavailability was found to be 13-17% because it undergoes hepatic and intestinal (first pass) metabolism.
The objective of the present research work is to formulate and evaluate the fast releasing oral thin films of Domperidoneto achieve a safe, rapid and effective dosage form with enhanced drug dissolutionand oral bio availability.
6.2 REVIEW OF LITERATURE
A mucoadhesive drug delivery system for systemic delivery of nitrendipine, a calcium channel blocker through buccal route was formulated. Mucoadhesive polymers like hydroxypropylmethylcelluloseK-100,hydroxylpropylcellulose,sodiumalginate, sodium carboxtmethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidoneK-30 and carbopol-934P were used for film fabrication. The films were evaluated for their weight, thickness, percentage moisture absorbed and lost, surface pH, folding endurance, drug content uniformity, in-vitro residence time, in-vitro release and ex-vivo permeation2.
Mucoadhesive buccal films was developed for systemic administration of carvedilol in the oral cavity using two different mucoadhesive polymers, hydroxypropyl methylcellulose, and hydroxypropyl cellulose. The formulations were tested for in-vitro drug permeation, buccal absorption, in-vitro release, moisture absorption and in-vitro bioadhesion studies. The physicochemical interactions between carvedilol and polymers were also investigated. They have got desired permeability and good buccal absorption and increased bioavailability when compared to that of oral solution3.
Development of fast dissolving tablet of domperidone with Avicel PH 102 and Sodium Starch Glycolate by direct compression method were prepared. All formulations were evaluated for characteristics such as hardness, friability, disintegration time and dissolution rate. An optimized formulationamongst all formulations was found to have a good hardness of 3 kg/cm2, disintegration time of 27 seconds andin-vitro drug release of not less than95% within 30 minutes4.
Fast dissolving films of levocetrizine were prepared by solvent casting method using different grades of methocel K3, E3, E5, and E15 as film former and PG, PEG 400 and tween 80 as plasticizer. Bitterness of levocetirizine was masked by forming inclusion complex with HP-ßCD. The complex was evaluated by XRD, DSC and FT-IR. Optimized films were evaluated for mechanical properties, drug content and dissolution characteristics. The combination of methocel E15 and PEG 400 exhibited excellent mechanical properties, uniformity in drug contentand in-vitro dissolution characteristics5.
Bilaminated patches composed of mixture of drug methotrexate and sodium alginate alone or in combination with sodium carboxymethylcellulose, polyvinyl pyrrolydine, Carbopol 934 and backing membrane ethyl cellulose were designed. The patches were fabricated by solvent casting technique and evaluated for In-vitro and Ex-vivo drug release. The patches were also evaluated for film weight uniformity, thickness, swelling index, surface pH, mucoadhesive strength, mucoadhesive time and folding endurance. A polymer combination of sodium alginate with carbopol 934 and glycerol as plasticizer, gave promising results6.
Development of triclosan containing fastdissolving films for local delivery to oral cavity were formulated. Various film forming agents, film modifiers andpolyhydric alcohols were evaluated for optimizing the composition of fast dissolving films. The potentialof poloxamer 407 and hydroxypropyl-β- cyclodextrin to improve solubility of drug wasinvestigated. Fast dissolving films containing TC-HPBCD complex and TC-Poloxamer 407 wereformulated and evaluated for the in-vitro dissolution profile and in-vitro microbiological assay. Films containing TC-Poloxamer 407 exhibited better in-vitro dissolution profile and in-vitro antimicrobial activity as compared to the films containing TC-HPBCD complex. Eugenol containing films improved the acceptability of TC-Poloxamer 407 films with respect to taste masking and mouth freshening without compromising the in-vivo dissolution time7.
The fast dissolving strips of verapamil were prepared by solvent casting technique with the help of HPMC E6 and maltodextrin. The strips were evaluated for drug content uniformity, film thickness, folding endurance, in-vitro disintegration time,in-vitro dissolution studies, surface pH study, and palatability study. Official criteria for evaluation parameters were fuifilled by all formulations. Disintegration time of all formulations was found to be in the range of 20.4-28.6 sec. Based on the evaluation parameters, the formulation containing 2% HPMC E6 and 3.5% maltodextrin showed optimum performance against other formulations8.
Formulation of fast dissolving films containing ondansetron hydrochloride for sublingual administration were designed. The films were prepared from polymers such as polyvinylalcohol, polyvinyl pyrrolidone, Carbopol 934P in different ratios by solvent casting method. Propylene glycol or PEG 400 as plasticizers and mannitol or sodium saccharin as sweeteners were also included. The IR spectral studies showed no interaction between drug and polymer or with other additives. Ex-vivodrug permeation studies were carried out using porcine membrane model.Drug permeation of 66-77% was observed through porcine mucosa within 40 min. Higher percentage of drug release was observed from films containing the sweeteners. The stability studies conducted for a period of 8 weeks showed no appreciable change in drug content, surface pH, andin-vitrodrug release9.
Salbutamol sulfate patches were preparedusing Eudragit L-100, HPMC, PVA and Carbopol 934 in various proportions and combinationsusing PEG-400/Propylene glycol as plasticizers. Patches were laminated on one side with a waterimpermeable backing layer for unidirectional drug release. The thickness of medicated patches wereranged between 0.23 ± 0.008 and 0.59 ± 0.007 mm and mass varied between 65.23± 3.3 and117.92± 4.2 mg. Patches showed an increase in mass and swelling index with PEG-400 when comparedwith propylene glycol. The surface-pH of patches ranged between 6 and 7. Residence time of the tested patches ranged between 101 and 110 min. The maximum in-vitro release was found to be 99.93% over a period of 120 min from the optimized formulation10 .
Preparation of fast dissolving oral thin film containing dexamethasone and base materials including microcrystalline cellulose, polyethylene glycol, hydroxypropylmethyl cellulose, polysorbate 80 and low-substituted hydroxypropyl cellulose were made. The film was disintegrated within 15 s after immersion into distilled water. The dissolution test showed that approximately 90% of dexamethasone was dissolved within 5 min.This preparation showed excellent uniformity and stability, when stored at 400C and 75% in humidity for up to 24 weeks11.
The patches containing hydrochlorothiazide (HCTZ) were prepared using ethylcellulose and hydroxypropyl methylcellulose interpolymer complexes of different ratios by casting method and thereafter evaluated using the following parameters: diameter, thickness, swelling behaviour, buccoadhesive strength, drug content analysis and in-vitrorelease studies. An adapted Lecomte Du Nouy tensiometer was used to assess the buccoadhesion of the patches on freshly excised buccal mucosa of a pig. The result of the study indicated that 1:2 ratio of EC and HPMC gave the highest buccoadhesive strength. Higuchi’s analysis of the release mechanism indicated that the release of HCTZ from the patches formulated with 1:1 and 2:1 ratios of EC and HPMC predominantly occurred by a diffusional process12.
Pimozide patches were prepared using Hydroxypropyl methyl cellulose (15 & 47 cps), carbopol 934, poly vinyl alcohol, and poly vinyl pyrolidone. FTIR and UV spectroscopic methods revealed that there is no interaction between pimozide and polymers. In-vitrorelease studies of pimozide loaded patches in phosphate buffer (pH: 6.6) exhibited drug release in the range of 55.32 % to 97.49 % in 60 min13.
Fast dissolving films of piroxicam were prepared using maltodextrins (MDX) with a low dextrose equivalent as film forming material. The suitable plasticizer and its concentration were selected on the basis of flexibility, tensile strength and stickiness of MDX films, and the MDX/plasticizer interactions were investigated by ATR-FTIR spectroscopy. Flexible films were obtained by using 16–20% w/w glycerine14.
Mucoadhesive buccal films of glipizide were prepared by solvent casting technique using hydroxypropylmethylcellulose, sodium carboxymethylcellulose, 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 films exhibited controlled release over more than 6 h15.
Bilayered mucoadhesive buccal patches for systemic administration of domperidone (DOM), a dopamine-receptor (D(2)) antagonist, were developed using hydroxy propyl methyl cellulose and PVPK30 as a primary layer and Eudragit RLPO and PEO as a secondary layer. Optimized formulation was associated with 99.5% drug release with a higuchi model release profile and 53.9% of the drug had permeated in 6 h. with a flux of 0.492 mg/h/cm2through porcine buccal membrane16.
6.3 OBJECTIVES OF THE STUDY
The present research work has been aimed for:
Formulation of fast dissolving domperidone oral thin films using ideal polymers by suitable methods.
Evaluation of formulated film strips using different parameters like surface pH, swelling studies ,drug content, film thickness, folding endurance of the film, in-vitrobioadhesive studies, in-vitrodrug release studies, ex-vivopermeation studies etc.
Compatibility studies between the drug and carrier by FTIR and DSC.
Statistical analysis of all the results.
To conduct stability studies as per the ICH guidelines and predict the shelf life of the dosage form.
7. MATERIALS AND METHOD
7.1 SOURCE OF DATA
- Library of M.S.RamaiahCollege of Pharmacy.
- e-Library of M.S.RamaiahCollege of Pharmacy.
- The data will be collected from official books such as IP,BP,USP.
- Internet source.
- International and National Pharmaceutical Journals.
7.2 MATERIALS
Drug:Anti-emetic drug: Domperidone.
Polymers like Hydroxy propyl methyl cellulose, Hydroxy propyl cellulose, Hydroxy ethyl cellulose,Microcrystalline cellulose, Polyvinylpyrrolidine, Polyvinylalcohol, Maltodetrins, Polaxomers etc.
Plasticizers like glycerol, polyethylene glycol, dibutyl phthalate, castor oil etc.
Saliva stimulating agents such as citric acid, malic acid, lactic acid, ascorbic acid, tartaric acid etc.
Organoleptic additives like coloring, flavoring and sweetening agents.
All the chemicals, excipients and solvents used will be of laboratory grade and
analytical grade procured from reliable sources.
7.3 METHODS OF DATA COLLECTION
- PRE-LABORATORY WORK
literature survey using Internet and from Scientific Journals.
- LABORATORY WORK
Preformulation studies
The drug-polymer compatibility determination using thermal analysis such as FTIR and DSC techniques.
Plot of standard calibration curve for pure drug Domperidone.
Formulation studies
Formulation of fast dissolving thin film strips of Domperidone using ideal polymer blends in varied combination ratios by suitable methods.
Evaluation studies
Evaluation of the formulated films using different parameters like Surface pH, Swelling studies ,drug content, film thickness, Folding endurance of the film, in-vitro Bioadhesive studies,, ex-vivo Permeation studies.
In-vitro drug release and kinetics studies of the dosage forms.
Stability studies of the optimized formulation as per the ICH guidelines and to predict the shelf life.
7.4 Does the study require any investigation or intervention to be conducted on patients or other human or animals?
-NO-
7.5 Has ethical clearance been obtained from your institute?
-NOT APPLICABLE-
8. LIST OF REFERENCES
1.Vishwkarma DK, TripathiAK, Yogesh P, Maddheshiya B.Review article on mouth dissolving film.J Global Pharm Tech.2011; 3(1):1-8.
2.Nappinnai M, Chandanbala R, Balaijirajan R. Formulation and evaluation of nitrendipine buccal films. Ind J Pharm Sci. 2008; 70(5):631-635.
3.Rao M, Vamshi Vishnu Y, Ramesh G, Chandrasekhar K. Development of mucoadhesive patches for buccal administration of carvedilol. Current Drug Delivery. 2007;4:27-39.
4.Parmar RB, Baria AH, Tank HM, Faldu SD. Formulation and evaluation of domperidone Fast Dissolving Tablets. Int J Pharm Tech Res. 2009;1(3):483-487.
5.Dhagla Ram Choudhary, Vishnu A Patel, Usmangani Chhalotiya1, Harsha V Patel, Aliasgar J Kundawala. Formulation and evaluation of fast Dissolving Film oflevocetirizine dihydrochloride using different grades of methocel. J Pharm Res.2011;4(9):2919-2924.
6.Satyabrata Bhanja, EllaiahP, Rohit Choudhury, MurthyKVR, Bibhutibhusan Panigrahi, Sudhir Kumar, Padhy. Formulation, development and evaluation of mucoadhesive buccal patches of methotrexate. J Adv Pharm Res. 2010; 1: 17- 25.
7.Aditya Dinge, Mangal Nagarsenker. Formulation and evaluation of fast dissolving films for delivery of triclosan to the oral cavity.AAPS Pharm Sci Tech.2008;9(2):349-356.
8.Kunte S, Tandale P. Fast dissolving strips: A novel approach for the delivery of verapamil. J Pharm Bioall Sci.2010; 4: 325-328.
9.Koland M, SandeepVP, Charyulu NR. Fast dissolving sublingual films of ondansetron hydrochloride: Effect of additives onin-vitrodrug release and mucosal permeation.
J Young Pharmacists. 2010; 2(3): 216-22.
10.Prasanth Viswanadhan Vasantha, Ayarivan Puratchikody , Sam Thomarayil Mathew, Ashok Kumar Balaraman. Development and characterization of Eudragit based mucoadhesive buccal patches of salbutamol sulphate.Saudi Pharm J. 2011; 19: 207–214.
11.ShimodaHet al. Preparation of a fast dissolving oral thin film containing dexamethasone: A possible application to antiemesis during cancer chemotherapy. Eur J Pharm Biopharm.2009; 73: 361-365.
12.Attama AA, Akpa PA, Onugwu LE, IgwiloG. Novel buccoadhesive delivery system of hydrochlorothiazide formulated with ethyl cellulose-hydroxypropyl methylcellulose interpolymer complex. Sci Res Essay.2008; 3(6): 343-347.
13.Biswajit Basu. Release kinetics studies of pimozide from buccal mucoadhesive patches.J Pharm Res. 2011;4(6):1806-1808.
14.Francesco Cilurzo, Irma E Cupone, Paola Minghetti, Francesca Selmin, Luisa Montanari. Fast dissolving films made of maltodextrins. Eur J Pharm Biopharm.2008; 70: 895-900.
15.Semalty M,Semalty A,Kumar G. Formulation and characterization of mucoadhesive buccal films of glipizide. Ind J Pharm Sci.2008;70(1):43-48.
16.Palem CR,GannuR,Doodipala N,Yamsani VV,Yamsani MR. Transmucosal delivery of domperidone from bilayered buccal patches: in-vitro,ex-vivo and in-vivo characterization.Arch Pharm Res.2011;34(10):1701-10.
9. / SIGNATURE OF THE CANDIDATE10. / REMARKS OF THE GUIDE / Recommended for Approval
11. / NAME AND DESIGNATION OF
11.1 GUIDE / Dr.S.BHARATH, M.Pharm.,Ph.D,ACCR
Professor and Head
Dept. of Pharmaceutics
M.S.RamaiahCollege of Pharmacy
Bangalore-560 054.
11.2 SIGNATURE
11.3 CO-GUIDE / NOT APPLICABLE
11.4 SIGNATURE
11.5 HEAD OF THE DEPT. / Dr.S.BHARATH, M.Pharm.,Ph.D.,ACCR
Professor and Head
Dept. of Pharmaceutics
M.S.RamaiahCollege of Pharmacy
Bangalore-560 054.
11.6SIGNATURE
12. / 12.1 REMARKS OF THE PRINCIPAL / Forwarded for Approval
12.2 SIGNATURE
1