“DESIGN AND OPTIMIZATION OF FLASH RELEASE ORAL STRIPS OF TRIPROLIDINE HYDROCHLORIDE”
MASTER OF PHARMACY DISSERTATION PROTOCOL
SUBMITTED TO THE
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE.
BY
PATEL RITESHKUMAR KAUSHIKBHAI
M.PHARM – I
Under The Guidance of
Mr. VIRESH K. CHANDUR M. Pharm
DEPARTMENT OF PHARMACEUTICS.
SRINIVAS COLLEGE OF PHARMACY, VALACHIL, MANGALORE – 574143
2011-2013
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the Candidate and Address: / Mr. PATEL RITESHKUMARKAUSHIKBHAI
1stYEAR M.PHARM, DEPT. OF
PHARMACEUTICS,
SRINIVAS COLLEGE OF PHARMACY,
VALACHIL, MANGALORE-574143.
2. / Name of the Institution: / SRINIVAS COLLEGE OF PHARMACY,
VALACHIL, FARANGIPETE POST, MANGALORE-574143.
3. / Course of Study and Subject: / MASTER OF PHARMACY
(PHARMACEUTICS)
4. / Date of Admission: / 31/10/2011
5. / Title of the Project:
“DESIGN AND OPTIMIZATION OF FLASH RELEASE ORAL STRIPS OF TRIPROLIDINE HYDROCHLORIDE”
6.
7.
8. / Brief Resume of the intended work:
6.1 Need of the study:
Oral route is the most popular route of drug administration to produce systemic effect. Most of pharmaceutical dosage form; the conventional tablet seems to be most popular because of its ease of transportation and comparatively low manufacturing cost. But also having some drawbacks i.e. hepatic first pass metabolism, local GI toxicity, enzymatic degradation, poor bioavailability, dysphasia in case of geriatric patients, the problem of swallowing are the common phenomenon which lead to poor patient compliance.
Nearly 35-50% of the general population, especially the elderly and children suffer from dysphasia or difficulty in swallowing, which results in high incidence of non-compliance and ineffective therapy. One such relatively new dosage form is oral strip, a thin film that is prepared using hydrophilic polymer that rapidly dissolves on the tongue or buccal cavity. Recently fast dissolving drug delivery system is becoming popular as they are easy to administer and lead to better compliance. These delivery systems either dissolve or disintegrate in mouth rapidly, without requiring any water to aid in swallowing1.
The drug administered via the oral mucosa gain access to the systemic circulation through a network of arteries and capillaries. The major artery supplying the blood to the oral cavity is the external carotid artery. The venous backflow goes through branches of capillaries and veins and finally taken up by jugular vein2.
Advantages of fast dissolving oral strip over the conventional tablet.
- Availability of larger surface area that leads to rapid disintegration and dissolution in the oral cavity and promote the systemic absorption of APIs.
- The drug enters the systemic circulation with reduced hepatic first pass effect.
- Destructive acidic environment of stomach can be avoided.
- Site specific action.
- The oral or buccal mucosa being highly vascularised, drugs can be absorbed directly and can enter the systemic circulation without undergoing first-pass hepatic metabolism3.
Limitations:-
- Drugs which have large/high dose cannot be incorporated into the strips.
- Expensive packaging of oral strip3.
Recently fast dissolving drug delivery system has started gaining popularity and acceptance as new oral delivery of the drugs4. 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 ingredient5.
Triprolidine hydrochloride is a H1 antihistamine class of drug that blocks the H1 receptor. Antihistamines drugs diminish or abolish the main action of histamine in the body via a competitive, reversible blockade of histamine receptor site on the tissues. Triprolidine hydrochloride is the drug given by oral administration, three or four time a day to treat allergic rhinitis, urticaria, and allergic drug reaction6. It has a biological half life of 4-6 hrs and its oral bioavailability was found to be 4%.
Hence in the present work an attempt will be made to design and optimization of flash release oral strips of triprolidine hydrochloride for the effective management of allergenic rhinitis and stop runny nose.
6.2 – Review of literature:
· Kunte S, Tandale P prepared fast dissolving strips of verapamil by solvent casting method with the help of HPMC E6 and maltodextrin. The strips were evaluated for film thickness, folding endurance, surface pH study, drug content uniformity, in-vitro disintegration time, in-vitro dissolution studies and palatability study. In-vitro disintegration time of all formulations was found to be in the range of 20.4-28.6 sec. Based on the evaluation parameters, strips containing 2% HPMC E6 and 3.5% maltodextrin showed optimum
performance compare to all other formulations7.
· Kulkarni AS, Deokule HA, Mane MS and Ghadge DM reported exploration of
different polymers for the use in the formulation of oral fast dissolving strips, the different type of hydrophilic polymers used for the formulation of strip were HPMC E-15, HPMC E-5K, HPMC K4M, gelatine, eudragit, PVA, PVP, RL100, and pullulan with different excipients. Compare to all polymer strips, pullulan containing strips shows least disintegration time8.
· Renuka M, Avani A reported formulation and characterization of rapidly dissolving film of cetirizine hydrochloride using pullulan as a film forming agent. Pullulan polymer is highly hydrophilic in nature. The pullulan films were evaluated for, film thickness, in-vitro disintegration time, disintegration time, in-vitro dissolution studies, measurement of mechanical properties, taste evaluation. The in vitro and in vivo disintegration time of the optimized batch PA3 was found to be 30 seconds and 20 seconds respectively9.
· Gujan JP, Darshan AM have worked on formulation optimization and evaluation of levocetirizine dihydrochloride oral thin strip. HPMC E15, PVA and propylene glycol was used. The resulted strips evaluated for weight variation, content uniformity, folding endurance, thickness, surface pH, in-vitro disintegration and in-vitro dissolution. The optimized strips with was reported disintegration time less than 30 sec and releasing 85-98% of drug with in 2 minute. The percentage release was varying with concentration of plasticizer and polymer. The strips made with HPMC: PVA (1:2) released 96% of drug with in 1 min, which was the best release amongst all10.
· Sandeep DJ, Rahul NK, Chetan MJ, Bharat WT, Vijay RP reported on formulation and evaluation of fast dissolving oral film of levocetirizine dihydrochloride by using film forming polymer like HPMC, Sodium CMC. Levocetirizine dihydrochlorid films were evaluate for thickness, folding endurance, in-vitro dissolution time. The optimized formulation F1 was found superior than other 8 batches. Formulation F1 released the complete drug in 360 sec11.
· Shirsand SB, Suresh S, Swamy PV have reported on formulation design and optimization of fast dissolving clonazepam tablets. A 32 full factorial design was applied to investigate the combined effect of two formulation variable; amount of crospovidone and microcrystalline cellulose. The tablets were evaluated for hardness, friability, thickness, drug content uniformity, in-vitro dispersion time, wetting time and water absorption ratio. Formulation F3 was selected as the best formulation compares to all other formulations12.
· Kiran KS, Senthil KS, Sundaramoorthy K, Shanmugam S, Vetrichelvan T have done formulation and in-vitro evaluation of rizatriptan benzoate rapi melt tablets and oral thin film. Using hydroxy propyl methyl cellulose E5 LV, Aspartame. The solvent evaporation technique was applied. The prepared films were evaluated for different parameters like thickness, content uniformity, folding endurance, in-vitro disintegration, in-vitro drug release studies and drug-polymer compatibility studies (DSC). The results obtained hydroxy propyl methyl cellulose E5 LV (FF3) showed the good formulation13.
· Moharana R, Kawathekar N, Chaturvedi SC have done Simultaneous spectrophotometric estimation of triprolidine hydrochloride and pseudophedrine hydrochloride in pharmaceutical dosage form. Estimate the amount of drug present in the each tablet. Making suitable dilution of drugs and estimating the drug content by using spectrophotometric14.
· Prabhakara P, Ravi M, Marina K, Vijaynaranyana K, Ullas D, Haris NM, Shastry CS have developed formulation and evaluation of fast dissolving film of levocetrizine dihydrochloride. The films of levocetirizine dihydrochloride were prepared by using HPMC and PVA, as either single polymer or in combinations of two by solvent casting method. They were evaluated for physical characteristics such as uniformity of weight, thickness, folding endurance, drug content uniformity, surface pH, percentage elongation, and tensile strength. The formulations were subjected to disintegration, in-vitro
drug release tests and in-vivo studies. From all the prepared 9 formulations of levocetirizine F7, F5, F1 were found to be the best formation in term of drug release15.
· Aditya D, Mangal N have developed of triclosan containing fast dissolving films for local delivery to oral cavity. The potential of poloxamer 407 and hydroxypropyl-β-cyclodextrin to improve solubility of drug was investigated. Fast dissolving films containing TC-HPBCD complex and TC-Poloxamer 407 were formulated 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 time16.
· Francesco C, Irma EC, Paola M, Susanna B, Francesca S, Chiara GM, Lusia M have prepared nicotine fast dissolving film made of maltodextrins. Nicotine films were prepared by using hydrophilic polymer. Prepared films were evaluated for different parameter like stickiness determination, drug content, tensile properties, disintegration test, in-vitro dissolution test, taste evaluation. All formulation were disintegrated within 15s, the molecular weight of maltodextrins did not affect the film disintegration time17.
· Nidhi PS, Vaishali AK, Anwar SD, Minal NB have worked on development of fast dissolving oral thin films of ambroxol hydrochloride: effect of formulation variables. HPMC was used as a film former, tween 80 as an emulsifying agent and polyethylene glycol 4000 as a plasticizer. These three variables were studied at two levels thus, a 23 full factorial design was applied and eight different formulations were developed. Developed films were evaluated for different parameters like thickness, folding endurance, tensile strength, percentage moisture absorption, drug content uniformity,
disintegration test, in-vitro dissolution studies, and stability studies. F7 was reported as best formulation among all the formulation18.
· Shalke PV, Dumbare AS, Gadhave MV, Jadhav SL, Sonawane AA, Gaikwad DD have performed formulation and evaluation of rapidly disintegrating film of amlodipine besylate. Amlodipine besylate films were prepared by using sodium alginate as film forming agent. To decrease the disintegrating time of formulations sodium starch glycolate was used as disintegrating agent. A full 32 factorial design was applied using concentration of polymer. The formulation F6 was showing sufficient drug release after 6 min. all the nine formulation was showing approximately 70-85% drug release after 6 min19.
6.3 – Objectives of the study:
1. To prepare the fast dissolving oral strips of triprolidine hydrochloride.
ü To improve bioavailability of the drug bypassing first pass metabolism.
ü To give rapid onset of action.
ü To give more patient compliance.
2. To optimize polymer concentration in the strip.
3. To evaluate the formulations with respect to various physical parameters. (Physical appearance, thickness of strips, folding endurance etc).
4. To evaluate the strips with respect to drug estimation, in-vitro disintegration time and in-vitro dissolution rate studies.
5. Compatibility studies between the drug and carrier by FTIR and DSC.
6. To study the effect of polymer concentration on in-vitro release of drug.
7. To carry out stability studies as per ICH guidelines.
MATERIALS AND METHODS
Materials:
· Drug : Antihistamine:- Triprolidine hydrochloride
· Polymers : Hydroxy propyl methyl cellulose, Microcrystalline cellulose,
Polyvinyl pyrrolidone, Polyvinyl alcohol, Maltodextrin, Pullulan etc.
· Plasticizers : Polyethylene glycol, Glycerine, Propylene glycol etc.
· Saliva stimulating
agents : Citric acid, Malic acid, Lactic acid etc.
· Solvent : Water or organic solvent.
· Organoleptic
additives : FDA approved Colouring agents, Flavouring agents and
Sweeting agents.
All the chemicals, excipients and solvents used will be of laboratory grade and analytical grade which are obtain from reliable sources.
Method:
v The preparation of oral film is carried by any one of the following method.
Ø Solvent casting
Ø Semi solid casting
Ø Rolling
Ø Solid dispersion extrusion
Ø Hot melt extrusion
7.1 Source of data:
Review of literature from
a) Journals such as
Ø International Journal of Pharmaceutical Sciences
Ø Indian Journal of Pharmaceutical Education and Research
Ø Journal of Chemical and Pharmaceutical Research
Ø Indian Journal of Pharmaceutical Sciences
Ø Research Journal of Pharmaceutical, Biological and Chemical Sciences
Ø International Journal of Pharmaceutical Sciences Review and Research
Ø International Journal of Pharmacy and Pharmaceutical Sciences
Ø Journal of Pharma Research
Ø Indian Drug Review
Ø European Journal of Pharmaceutics and Biopharmaceutics
Ø Advances in Biological Research
Ø Journal of Pharmacy and Bioallied Sciences
Ø Journal of Current Pharmaceutical Research
Ø IJPI’s Journal of Pharmaceutics and Cosmetology
Ø Scholars Research Library
Ø Journal of Advance Pharmaceutical Research
b) Internet Browsing.
c) Laboratory based studies.
7.2 – Method of Collection of Data:
1. Study of research articles.
2. Laboratory investigation:
Preformulation studies
Ø The drug-polymer compatibility determination by using thermal
analysis such as FTIR and Differential Scanning Colorimetric techniques.
Ø Plot of standard calibration curve for pure drug of Triprolidine hydrochloride.
Evaluation of formulated Fast dissolving oral strips of Triprolidine hydrochloride which includes:
Ø Uniformity of weight
Ø Strip thickness
Ø Surface pH
Ø Folding Endurance
Ø Uniformity of Drug content
Ø In-vitro drug release studies
Ø Stability studies of the formulation as per the ICH guideline
Ø Swelling index
Ø Water absorption
Ø In-vitro disintegration time
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.