RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA



RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA

4TH ‘T’ BLOCK, JAYANAGAR, BANGALORE - 560 041

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

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|1. |Name of the Candidate and Address |YASMEEN TAJ |

| | | |

| | |#418, NEW LINES, LINDEN STREET, |

| | |YELLAGUNDA PALLIYAM, |

| | |AUSTIN TOWN, |

| | |BANGALORE-560047. |

| | |KARNATAKA, INDIA. |

| | | |

|2. |Name of the Institution |AL-AMEEN COLLEGE OF PHARMACY, |

| | |HOSUR ROAD, |

| | |OPP. LALBAGH MAIN GATE, |

| | |BANGALORE – 560 027. |

| | |KARNATAKA. |

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|3. |Course of Study and Subject |M. PHARM – PHARMACEUTICS |

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|4. |Date of Admission |JUNE-2009 |

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|5. |Title of the Topic: |

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| |“FORMULATION AND EVALUATION of Taste Masked Orally Disintegrating Tablets for Paediatric Population”. |

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|6.0 |Brief resume of the intended work: |

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| |6.1 – Need for the study |

| |Bronchitis is a respiratory disease in which the mucous membrane of the bronchial passages in the lungs become inflammed. As the irritated|

| |membrane swells and grows thicker, it narrows or shuts off the airways in the lungs, resulting in coughing spells accompanied by thick |

| |phlegm and breathlessness. The disease occurs in two forms; acute (lasting less than 6 weeks) and chronic (reoccurs frequently for more |

| |than 2 years). Acute bronchitis is very common in children and is generally caused by lung infection.[1] |

| | |

| |Bronchiectasis is a persistent irreversible dilation and distortion of medium sized bronchi. It is a lung condition that usually develops |

| |after a series of lung problems, a lot of mucous collects in the lungs causing discomfort and needs to cough it up. The mucous (phlegm) |

| |also collects bacteria, which can add to breathing difficulties. Patients diagnosed with bronchiectasis frequently have difficulty in |

| |expectorating the infected sputum.[2] |

| | |

| |People with chronic bronchitis may experience recurrent exacerbations with worsening symptoms or greater volume or purulence of sputum. |

| |These exacerbations contribute to poorer health. Bronchitis is most common disease of childhood. |

| | |

| |The drugs commonly used to treat bronchitis and bronchiectasis are called as mucolytics and expectorants. A mucolytic agent or expectorant|

| |is any agent which dissolves thick mucous and is usually used to help relieve respiratory difficulties. |

| | |

| |The drugs include Dextromethorphen, Guiafenesin, Dexbrompheniramine, Pseudoephedrine, Bromhexine, Ambroxol hydrochloride, acetylcysteine, |

| |carbocisteine. |

| | |

| |An allergy is a condition characterized by a level of sensitivity greater than normal to a specific substance or a group of substances. |

| |These substances are called as allergens, trigger a response in susceptible individuals. These produce powerful chemicals like histamine, |

| |which cause inflammation. These chemicals act on tissues in various parts of the body, such as the respiratory system and cause symptoms |

| |of allergy like sneezing often with running and clogged nose, coughing and postnasal drip, itching eyes, nose and throat.[3] |

| | |

| |Anti-histaminic drugs like cetrizine dihydrochloride are commonly used for treatment of allergy. Cetrizine is a potent H1 receptor |

| |antagonist without any significant anticholinergic and antiserotonin effects. It inhibits the histamine mediated early phase of allergic |

| |reactions, also provides a protective effect from bronchospasm induced by inhaled histamine in asthamatics. |

| | |

| |Combination approach of Ambroxol hydrochloride and Cetrizine dihydrochloride is carried out as taking one tablet is preffered over two, |

| |also it reduces the symptoms of allergy and cough at once and improves patient compliance especially in case of paediatric population. |

| | |

| |More than 50 percent of the pharmaceutical products are orally administered as it is the most convenient route of administration and |

| |undesirable taste is one of the important formulation problem encountered with oral products. The taste of oral pharmaceutical product is |

| |an important parameter for governing compliance. Thus, taste masking of oral pharmaceutical products is important tool to improve patient |

| |compliance and quality of treatment especially in paediatrics.[4] |

| | |

| |Most of the drugs used as Mucolytic and Anti-histaminics are bitter in taste, therefore are not favourable as oral dosage form especially |

| |for paediatric population. Undesirable taste is one of the several important formulation problems that are encountered with certain drugs.|

| |The problem of bitter and obnoxious taste of drugs is a challenge in the present scenario. |

| | |

| |There always exists a difference between adult and paediatric taste preferences. Children are found to be objectionable to bitterness, |

| |hence before formulating a paediatric medicine one should be aware of children’s taste preferences. Its quiet obvious that the oral dosage|

| |forms expose the drug in the mouth, a bad tasting formulation has poor patient compliance. Thus the product taste directly influences the |

| |willingness of a child to take medicine repeatedly. To deal with these taste issues, taste masking of the bad tasting active ingredient |

| |has become utmost important factor in paediatric formulations.[5] |

| | |

| |The active pharmaceutical ingredient chosen for the present study are Ambroxol hydrochloride which has a daily dose of 60-120mg in 2 or 3 |

| |divided doses and Cetrizine dihydrochloride, given in 10mg dose. |

| | |

| |Literature reveals that Ambroxol hydrochloride is a highly bitter molecule and even cetrizine dihydrochloride is bitter in taste. Also |

| |only one syrup dosage form is available with the combination of Ambroxol hydrochloride and Cetrizine dihydrochloride. Thus there is a need|

| |to develop an efficiently taste masking formulation of this combination. Moreover it is observed that along with commonly used taste |

| |masking and sweetening agents, Eudragit polymers are gaining importance in masking the taste of drugs. Eudragit EPO is used for effective |

| |taste masking of few drugs like Quinine sulphate, Ondansetron hydrochloride, Lornoxicam, Valdecoxib. |

| | |

| |Over the past three decades, Orally Disintegrating Tablets (ODT) have gained much attention as a prepared alternative to the conventional |

| |oral dosage forms such as tablets and capsules. Generally, the ODT’s are formulated to disperse rapidly in the mouth, enabling medication |

| |to be swallowed without water, thereby increasing convenience and compliance across the broad range of indications and patient types. |

| |Orally Disintegrating tablets are gaining popularity as paediatric formulation. |

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| | |

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| |The most significant issue with the Orally Disintegrating Tablet is the bitterness of the drug that can be exposed as the tablet breaks |

| |apart. Poor taste can negate the benefits of the Orally Disintegrating Tablet and lead to patient non compliance as the tablet dissolves |

| |or disintegrates in the mouth in close proximity to the taste buds. Hence to deal with these taste issues, masking of bad tasting drug is |

| |very important in an Orally Disintegrating Tablet formulation. |

| | |

| |By designing these commonly used molecules( Ambroxol hydrochloride and Cetrizine dihydrochloride) in combination into an effectively taste|

| |masked Orally Disintegrating Tablet formulation, an attempt will be made to obtain the most acceptable dosage form for paediatric |

| |population. |

| |6.2 REVIEW OF LITERATURE |

| |Ambroxol is a clinically proven systemically active mucolytic agent. When administered orally onset of action occurs after about 30 |

| |minutes. The breakdown of acid mucopolysaccharide fibers makes the sputum thinner and less viscous and therefore more easily removed by |

| |coughing.[1] |

| |Ambroxol is an active substance with a long history that influences parameters considered to be the basis for the physiological production|

| |and the transport of the bronchial mucus. Therefore Ambroxol’s indication ‘secretolytic therapy in an acute and chronic pulmonary disease |

| |associated with abnormal mucous secretion and impaired mucous transport.[2] |

| |Gawade RS, Ravinder k. Cetrizine is used in commercial products as a dihydrochloride salt. It is a piperazine derivative and a metabolite |

| |of hydroxyzine, is an orally active, selective H-1 receptor antagonist and useful as non-sedating antihistaminic. Cetrizine |

| |dihydrochloride is bitter in taste and is reported to long acting, used for symptomatic relief of allergic conditions.[3] |

| |Basak SC,.et al. reviewed that ambroxol, a metabolite of bromhexine is used as an expectoration improver and a mucolytic agent. It is |

| |used in the treatment of acute and chronic disorders characterized by the production of excess of mucous. It is been successfully used for|

| |decades in the form of its hydrochloride salt as a secretion releasing expectorant in a variety of respiratory disorders.[6] |

| |Venkatesh DP, Geetha Rao CG. presented that amroxol hydrochloride, is a potent mucolytic capable of inducing bronchial secretion. It is |

| |used the treatment of asthma, bronchitis and cough, but it is very bitter and slightly soluble in water, therefore its taste masking is |

| |important to omprove patient compliance and the quality of treatment especially in paediatrics.[7] |

| | |

| |Jacob S, Shirwaikar A. studied that taste masking is an important developmental challenge in the fast dissolving drug delivery system |

| |since it dissolves or disintegrates in the mouth in close proximity to the taste buds. Fast dissolving dosage forms is one that |

| |disintegrates rapidly in the saliva without the need for water. Sometimes they are designed to be absorbed through the buccal and |

| |oesophagesl mucosa as the saliva passes into the stomach.[8] |

| |Bhatia MN, et al. suggested that a simple, rapid, accurate, precise and reproducible simultaneous equation method has been developed for |

| |simultaneous estimation of ambroxol hydrochloride and cetrizine hydrochloride in tablets. Ambroxol hydrochloride has absorbance maxima at |

| |243 nm, while cetrizine hydrochloride has absorbance maxima at 229 nm in glass-distilled water. The method developed involves no |

| |separation or extraction process. The proposed methods were successfully applied to the determination of ambroxol hydrochloride and |

| |cetrizine hydrochloride in tablets, with high percentage of recovery, good accuracy, and acceptable precision.[9] |

| |Kayumba C, et al. developed a taste-masked quinine sulphate dosage form as a flexible pediatric formulation. Quinine sulphate pellets were|

| |produced via extrusion-spheronisation. The pellets were coated using Eudragit® EPO to obtain a taste-masked formulation. Using 15% dibutyl|

| |sebacate (based on polymer weight) as a plasticizer in the formulation caused rapid pellet. 20% (w/w) Eudragit® EPO was required to obtain|

| |a homogeneous film and to delay quinine sulphate release, sufficiently to mask the bitterness after drug administration.[10] |

| |Khan S, et al. carried out a research to mask the intensely bitter taste of ondansetron HCl and to formulate a rapid disintegrating tablet|

| |(RDT) of the taste-masked drug. Taste masking was done by complexing ondansetron HCl with aminoalkyl methacrylate copolymer (Eudragit EPO)|

| |in different ratios by the precipitation method.[11] |

| |Okuda Y, Osawa T. designed a new orally disintegrating tablet (ODT) that has high tablet hardness and a fast oral disintegration. To |

| |obtain rapid disintegration granules (RDGs), a saccharide, was spray-coated with a suspension of corn starch using a fluidized-bed |

| |granulator. When tabletting these RDGs, it was found that the RDGs increased tablet hardness by decreasing plastic deformation and |

| |increasing the contact frequency between granules.. Tablets could disintegrate immediately in the oral cavity regardless of the tablet |

| |hardness and were considered to be appropriate for ODTs.[12] |

| |Eudragit EPO is very suitable for excellent taste masking even at low film thickness. It is also used to coat difficult dosage forms, such|

| |as multiparticulate fast disintegrating tablets.[13] |

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| |6.3 OBJECTIVE OF STUDY |

| |To formulate orally disintegrating tablets of Ambroxol hydrochloride and cetrizine dihydrochloride in combination with better taste |

| |masking effect as they are bitter in taste. To improve the patient compliance with the use of these paediatric formulations having |

| |efficient taste masking properties. |

| | |

| |SPECIFIC OBJECTIVES: |

| |To screen the best taste masking agent for Ambroxol hydrochoride and Cetrizine dihydrochloride. |

| |To design and develop taste masked orally disintegrating tablets of Ambroxol hydrochoride and Cetrizine dihydrochloride. |

| |To evaluate the tablets for physicochemical properties. |

| |To evaluate the tablets for extent of taste masking achieved in human volunteers |

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| |7.0 Materials and Methods |

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| |7.1 Source of Data: |

| |I. Review of Literature from |

| |a. Journals - such as. |

| |International Journal of Pharmaceutics. |

| |European Journal of Pharmaceutics and Biopharmaceutics. |

| |American Association of Pharmaceutical Scientists. |

| |Indian Journal of Pharmaceutical Sciences. |

| |Asian Journal of Pharmaceutical sciences. |

| |b. Internet Browsing. |

| |Web sites: |

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| |7.2 - Method of collection of data: |

| |1. From Literature |

| |2. Preformulation studies: |

| |a. 1. Standardization of method of estimation. |

| |2.Solubility studies. |

| |3.Drug and excipient interaction study – FTIR. |

| |3. Formulation: |

| |a. Development of taste masked orally disintegrating tablets. |

| |b. Evaluation of the tablet for |

| |- Physical appearance |

| |- Weight variation |

| |- Drug content |

| |- In-vitro Disintegration studies. |

| |- In-vitro Dissolution studies. |

| | |

| |-In-vivo disintegration time, sensory evaluation of Roughness and taste in human volunteers. |

| |4. Comparision with marketed paediatric formulations. |

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| |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. |

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| |YES |

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| |The taste masking achieved in the developed formulations needs to be evaluated in human volunteers. As, such a study will give more |

| |appropriate and authentic results. |

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| |7.4 – Has ethical clearance been obtained from your Institution in case of 7.3? |

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| |APPLIED FOR INSTITUTIONAL CLEARANCE |

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|8.0 |Bibliography |

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| | [cited 2009 Nov 11] |

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| |Crockett A, Cranston JM, Alpers JH, Latiner KM. Mucolytics for bronchiectasis; cocrane database of systemic reviews 2001;(1).art |

| |no:CD001289. |

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| | [cited 2009 Nov 12] |

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| | [cited 2009 Nov 12] |

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| | [cited 2009 Nov 14] |

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| |Basak.SC, Reddy BMJ, Lucas mani KP. Formulation and release behaviour of sustained release ambroxol hydrochloride HPMC matrix tablets. |

| |Indian J Pharm Sci 2006;68(5):594-8. |

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| |Venkatesh DP, Geetha Rao CG. Formulation of taste masked oro-dispersible tablets of ambroxol hydrochloride. Asian J Pharm |

| |2008;2(4):261-4. |

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| |Jacob S, Shirwaikar A. Preparation and evaluation of microencapsulated fast melt tablets of ambroxol hydrochloride. Indian J Pharm Sci |

| |2009;71(3):276-84. |

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| |Bhatia NM, Ganbavale SK, More HN. Spectrophotometric estimation of ambroxol hydrochloride and cetirizine hydrochloride in tablets. Asian |

| |J Pharm 2008;2(3):159-62. |

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| |Kayumba C, Huydebaert N, Cordella C, Vervaet C, Remon JP. Quinine sulphate pellets for flexible pediatric drug dosing; formulation |

| |development and evaluation of taste masked efficiency using electronic tongue. Eur J Pharm Biopharm 2007;66(3):460-65. |

| | |

| |Khan S, Kataria P, Nakhat P, Yeole p. Taste masking of ondensetron hydrochloride by polymer carrier system and formulation of rapid |

| |disintegrating tablets. AAPS PharmSciTech 2007;8(2):E1-E7. |

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| |Okuda Y, Osawa T. A new formulation to orally disintegrating tablets using a suspension spray coating method. Int J Pharm Sci |

| |2009;382(2):80-87. |

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| | [cited 2009 nov 23] |

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| | [cited 2009 Nov 15] |

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| | [cited 2009 Nov 16] |

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| |Poole PJ, Black PN. Oral mucolytics for exacerbation of chronic pulmonary disease: systemic review. BMJ 2001;322(7297):1271. |

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|9.0 |Signature of the candidate: | |

| | |(YASMEEN TAJ) |

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|10.0 |Remarks of the Guide: |Recommended for Approval |

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|11.0 |Name and Designation of: | |

| |11.1 Institutional Guide: |Dr. (Mrs.) ROOPA S. PAI |

| | |PROFESSOR, |

| | |DEPARTMENT OF PHARMACEUTICS, |

| | |AL-AMEEN COLLEGE OF PHARMACY, |

| | |BANGALORE-560027. |

| |11.2 SIGNATURE: | |

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| |11.3 CO-GUIDE | |

| | |Dr. (Mrs) V. KUSUM DEVI |

| | |PROFESSOR AND HEAD, |

| | |DEPARTMENT OF PHARMACEUTICAL MARKETING AND MANAGEMENT, |

| | |AL-AMEEN COLLEGE OF PHARMACY, |

| | |BANGALORE-560027. |

| |11.4 Signature: | |

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| |11.5 Head of the Department | |

| | |Dr. (Mrs.) SARASIJA SURESH |

| | |Professor and Head, |

| | |Department of pharmaceutics, |

| | |Al-Ameen College of Pharmacy, |

| | |BANGALORE-560027. |

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| |11.6 Signature: | |

|12.0 |12.1 Remarks of the Chairman and Principal | |

| | |Forwarded to the University for Scrutiny |

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| |12.2 Signature of the principal | |

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| | |Prof. B. G. SHIVANANDA |

| | |Principal, |

| | |Al-Ameen College of Pharmacy, |

| | |Hosur Road, |

| | |Bangalore – 560 027. |

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