RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE,
KARNATAKA.
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1. / Name of the candidate and address(in block letters) / SHIVAKUMAR K.
BAPUJI PHARMACY COLLEGE
S.S. LAYOUT, SHAMANUR ROAD
DAVANGERE – 577 004
2. / Name of the institution / BAPUJI PHARMACY COLLEGE
3. / Course of study and subject / M. PHARM
(INDUSTRIAL PHARMACY)
4. / Date of admission to course / 07-07-2010
5. / Title of the topic / DESIGN AND EVALUATION OF RANITIDINE HYDROCHLORIDE CHEWABLE TABLETS WITH SUPPRESSED BITTERNESS AND IMPROVED ORAL FEELING
6.
7.
8. / BRIEF RESUME OF THE INTENDED WORK
6.1 Need for the study
The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site of the body, to achieve promptly and then maintain the desired therapeutic drug concentration that elicits the desired pharmacological action and to minimize the incidence and the severity of unwanted adverse effects.1
For many decades, treatment of an acute disease or a chronic illness has been mostly accomplished by delivering drugs using various pharmaceutical dosage forms, including tablets, capsules, pills, suppositories, ointments, creams, liquids, aerosols, and injectables as carriers. Amongst various routes of drug delivery, oral route is perhaps the most preferred to the patients.2 The oral route of drug administration is the most important method of administering drugs for systemic effects. Nevertheless, it is probable that at least 90% of all drugs used to produce systemic effects are administered by oral route. It is the very popular and successfully used for delivery of drugs because of convenience and ease of administration, greater flexibility in dosage form design, and ease of production and low cost of such a system.3
Chewable tablets are intend to be chewed in the mouth prior to swallowing and are not intended to be swallowed intact. The purpose of chewable tablet is to provide a unit dosage form of medication which can be easily administered to children or to the elderly, who may have problem in swallowing a tablet intact. It is also recommended to achieve rapid onset of action. Chewable tablets are preferred for the drugs having high dose, the tablets of which cannot be swallowed.
Dose of most of the antacids is large, so that the typical antacid tablet would be too large to swallow. The activity of antacid is related to its particle size. If the tablet is chewed prior to swallowing, better acid neutralization may be possible from a given antacid dose.4 A survey of the literature indicates that extensive work was conducted in the development of chewable tablet. The drugs studied are aluminium hydroxide, acetaminophen, antibiotics, and caffeine.5
The proposed ranitidine HCl chewable tablets contain ranitidine HCl which acts as an anti ulcer agent and it also contains calcium carbonate and magnesium hydroxide which act as antacids. A disintegrant such as microcrystalline cellulose may be added to give the patient the option of dispersing the tablet in water. It is made possible because of water solubility of ranitidine HCl.
Ranitidine hydrochloride is a H2-receptor antagonist and is widely used. Ranitidine HCl is a white to pale yellow crystalline solid with melting point 70oC and is freely soluble in water, where as calcium carbonate and magnesium hydroxide are insoluble in water. Chemically ranitidine HCl is 1,1-ethenediamine, N-[2-[[[5-[(dimethylamino) methyl]-2-furanyl] mehyl]thio]ethyl]-N1-methyl-2-nitro, HCl. It is widely prescribed in active duodenal ulcers, gastric ulcers, Zollinger-Ellison syndrome, gastro esophageal reflux disease, and erosive esophagitis. The recommended adult oral dosage of ranitidine is 150 mg twice daily or 300 mg once daily. The effective treatment of erosive esophagitis requires administration of 150 mg of ranitidine 4 times a day.6 A conventional dose of 150 mg can inhibit gastric acid secretion up to 5 hours.7 Ranitidine is absorbed only in the initial part of the small intestine and has 50% absolute bioavailability. The half life is 2.5 to 3 hrs.8
6.2 Review of the study
Chewable tablet dosage forms continued to draw attention in the search for improved patient compliance and decreased incidence of adverse drug reaction. Many drugs exhibit bitter taste when orally administered and the bitter taste often causes non-compliance of patients because of the discomfort. Therefore, suppression of the bitter taste has been an important subject for chewable tablets with simultaneous improvement in oral feeling.
Swati J et al., designed and evaluated chewable tablet of levamisole (used in treatment of worm infestations). As an anthelmintic, it probably works by targeting the nematode nicotinergic acetylcholine receptor. In the market, levamisole tablets are available in the form of tablets. The chewable tablets of levamisole were prepared by using lactose or mannitol along with sodium starch glycolate in concentration ratios especially for paediatric use. Sodium saccharin and vanilla were used as sweetening agent and flavouring agent respectively. It was observed that the formulation containing lactose shows less disintegration time than formulation containing mannitol.9
Kanaka et al., formulated and evaluated montelukast sodium chewable tablets by different techniques. Montelukast sodium is used for prophylaxis and chronic treatment of asthma. Montelukast sodium chewable tablets (5 mg) were prepared and evaluated for the parameters such as average weight, hardness, tensile strength, friability, in vitro dissolution, and assay. The study on the dissolution profile revealed that product prepared from direct compression method had faster dissolution rate while compared to remaining batches and marketed product. Assay values were within the limits of 95 to 105%.10
Kathiresan K et al., formulated and evaluated 5 batches of loratadine chewable tablets. Loratadine, H1 receptor antagonist used in the treatment of allergic rhinitis and urticaria. Results showed that thickness, weight variation, friability, hardness, and content uniformity of all 5 formulations were within the acceptance limits. But in the in-vitro dissolution study, formulations 1, 2, and 5 demonstrated better cumulative drug release than formulations 3 and 4. However, cumulative drug release of formulation 5 was comparable with innovator than formulations 1 and 2. Hence the study concludes that loratadine chewable tablet formulated using avicel CE 15 and starch paste showed better characteristics of chewable tablets.11
Hiroyuki S et al., developed oral acetaminophen chewable tablets with inhibited bitter taste. Various formulations with some matrix bases and coregents’ were examined for development of oral chewable tablets which suppressed the bitter taste of acetaminophen, often used as an antipyretic for infants. Corn starch/lactose, cacao butter and hard fat (Witepsol H-15) were used for matrix bases, and sucrose, cocoa powder and commercial bitter-masking powder mixture made from lecithin (Benecoat BMI-40) were used for corrigents against bitter taste. The bitter taste intensity was evaluated using volunteers by comparison of test samples with standard solutions containing quinine at various concentrations. For the tablets made of matrix base and drug, Witepsol H-15 best inhibited the bitter taste of the drug, and the bitter strength tended to be suppressed with increase in the Witepsol H-15 amount. When the inhibitory effect on the bitter taste of acetaminophen solution was compared among the corrigents, each tended to suppress the bitter taste; especially, Benecoat BMI-40 exhibited a more inhibitory effect. Further, chewable tablets were made of one matrix base and one corrigent, and of one matrix base and two kinds of corrigents, their bitter taste intensities after chewing were compared. As a result, the tablets made of Witepsol H-15/Benecoat BMI-40/sucrose, of Witepsol H-15/cocoa powder/sucrose and of Witepsol H-15/sucrose best masked the bitter taste so that they were tolerable enough to chew and swallow. The dosage forms best masking bitter taste showed good release of the drug, indicating little change in bioavailability by masking.12
Maddi SS et al., designed sodium fluoride chewable tablets for dental caries. Chewable tablets containing low dosage fluoride content were prepared using two varities of celluloses and their in vitro parameters were evaluated. An eighteen month clinical trial revealed that both these formulations were effective in controlling the caries. However, ethyl cellulose is proved to be superior to methylcellulose as a controlled release matrix material in controlling caries. Thus this study recommends ethyl cellulose matrix tablets containing low fluoride content is an efficacious and cost effective drug device in controlling dental caries.13
6.3 Objective of the study
The objectives of present investigation are:
1. To develop analytical method for the estimation of ranitidine hydrochloride in a suitable solvent system.
2. Preparation of ranitidine hydrochloride chewable tablets using different organoleptic agents.
3. To evaluate the dosage forms (chewable tablet) for the integrity and stability.
4. In vitro evaluation of ranitidine hydrochloride chewable tablets for the release characteristics.
MATERIALS AND METHODS
7.1 Source of data
The physicochemical properties of drug will be collected from the national and international journals, HELINET, internet facilities, related articles, and standard books from library of the college.
7.2 Methods of collection of data
(Including sampling procedure, if any)
a. To develop the spectrophotometric method for the estimation of ranitidine HCl in water as a solvent.
b. Preformulation studies including solubility (Shakers flask method), compatibility with the excipients (using IR and DSC methods) etc.
c. To evaluate the physical properties of powder blend of tablet batches such as particle size distribution, angle of repose, bulk density, compressibility index, etc.
d. Preparation of ranitidine hydrochloride chewable tablets by observing the following
i) Application of factorial design.
ii) Masking bitter taste.
iii) Use of suitable organoleptic additives.
iv) Use of antacids.
v) Preparation of dummy tablets for comparision.
vi) Use of different tabletting methods.
e. Evaluation of ranitidine hydrochloride chewable tablets for the parameters such as hardness, friability, dimensions, drug content, drug release, uniformity of weight, bitterness and sweet taste intensity etc.
f. In vitro release characteristics of ranitidine hydrochloride from the chewable tablets.
g. Short term stability studies of prepared formulations as per ICH guidelines.
i) Normal storage: 25°C ± 2°C/60% RH ± 5% RH
ii) Accelerated conditions: 40°C ± 2°C/75% RH ± 5% RH
iii) Stress testing is conducted on a single batch of the tablets. The study includes testing the effect of temperature at 50°C, 60°C, etc. and humidity at 75% RH or greater as the drug is heat sensitive.
iv) Packing system ; The stability studies will be conducted on the drug substance packaged in a container.
v) Testing Frequency : Samples (n = 3) will be drawn every week and will be studied.
h. Statistical analysis and 6 sigma analysis of data obtained from the results.
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.
Bitter and sweet taste intensities will be determined by the sensation tests using healthy volunteers. Before measurement, informed consent will be completed to each volunteer. Quinine aqueous solution with a series of concentration will be prepared as standard solutions of bitter taste intensities, and the intensities were defined from 0 to 10. Similarly, sucrose aqueous solutions with a series of concentrations were used as standard solutions for measurement of sweet taste intensities. The bitter or sweet taste intensities of chewable tablets will be evaluated as follows: 1 ml of each standard solution will be dropped on the centre of the tongue, the solution will be retained in the mouth for 10 sec, then the mouth will be rinsed thoroughly with de-ionized water so that recognition of the taste intensities of the standards will be recovered. At 10 min after remembering the taste intensities of each standard solution, the mouth will be rinsed fully again, one tablet will be put in the mouth, chewed 10 times and retained on the centre of the tongue in the mouth for 10 sec. At that time, the subject decides the taste intensity of the chewed tablet by compression with that of each standard solution. For examination of the taste intensities of bitterness and sweetness, the number of the subjects in each group will be three.12
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
Will be submitted to the university after obtaining the permission from the IAEC.
LIST OF REFERENCES
1. Darshsana DH, Mangal SN, Sudhakar DG. Design and evaluation of an extended release tablet of prochlorperazine maleate. Ind drugs 2001;38:69-74.
2. Liversidge GG, Cundy KC. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs. Int J Pharn 1995;125:91-7.
3. Herbert AL, Leon L, Joseph LK. The theory and practice of industrial pharmacy. 3rd ed. Bombay: Varghese Publishing House; 1991. p.134-48.
4. Herbert A, Libermann, Leon L. Pharmaceutical dosage forms tablets. New York: Marcel Dekker Inc; 1980. p. 298-337.
5. Howard CA, Nicholas GP, Loyd VA. Pharmaceutical dosage form and drug delivery system. 6th ed. New Delhi: B.I.Waverty Pvt Ltd; 1995. p. 230,655-8.
6. Somade S, Singh K. Comparative evaluation of wet granulation and direct compression methods for preparation of controlled release ranitidine HCl tablets. Indian J Pharm Sci 2002;64:285.
7. Lauritsen K. Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases. Clin Pharmacokinet 1990;19:94-125.
8. Grant S. Ranitidine an updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in peptic ulcer and other allied diseases. Drugs 1989;37:801-70.
9. Swati J, Mahesh G, Dhaval B, Bhanudas K, Aniruddha C. Formulation and evaluation of chewable tablet of levamisole. Int J Res Pharm Sci 2010;1(3):282-9.
10. Kanaka DDN, Prameela RA, Radha MB, Sai MB. Formulation and evaluation of montelukast sodium chewable tablets. Int J Pharm sci Bio 2010;1(1):20-4.
11. Kathiresan K, Vijin P, Moorthi C, Manavalan R. formulation and evaluation of loratadine chewable tablets. Res J Pharm Bio Che Sci 2010;1(4):763-74.
12. Hiroyuki S, Hiraku O, Yuri T, Masanori I, Yoshiharu M. Development of oral acetaminophen chewable tablets with inhibited bitter taste.Int J Pharma 2003;251(1-2):123-32.
13. Maddi SS, Tandon S, Aithal KS. Clinical evaluation of sodium fluoride chewable tablets in dental caries. Indian J Dent Res 1999;10(4):146-9.
14. http://www.druglib.com/druginfo/ranitidine/description_pharmacology/ 4/12/2010.
9. /
Signature of the Candidate
10. / Remarks of the Guide:11. / Name and Designation of
(In block letters)
11.1 Guide
11.2 Signature
11.3 Co guide (If any)
11.4 Signature
11.5 Head of the Department
11.6 Signature / Mr. J. THIMMASETTY M. Pharm.
SG Lecturer,
Bapuji Pharmacy College, Davangere.
Mr. J. THIMMASETTY M. Pharm.
Head of the Department of Industrial Pharmacy
Bapuji Pharmacy College, Davangere.
12. / 12.1 Remarks of the Principal
12.2 Signature