Design and Evaluation of Melt-In-Mouth Tablet of Rizatriptan Benzoate

DESIGN AND EVALUATION OF MELT-IN-MOUTH TABLET OF RIZATRIPTAN BENZOATE

M.PHARM DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA.

PANDIT KENDRE

UNDER THE GUIDANCE OF

M A SALEEM

PG Dept. of Pharmaceutics

DEPARTMENT OF PHARMACEUTICS

LUQMAN COLLEGE OF PHARMACY,

GULBARGA – 585102

2013-2014

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,KARNATAKABANGLORE

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR M.PHARMA DISSERTATION

1. / NAME OF THE CANDIDATEAND
ADDRESS (IN BLOCK LETTERS) / PANDIT ANKUSHRAO KENDRE
AT.POST NANDI BIJALGAON
TQ. AURAD (B) DIST. BIDAR
2. / NAME OF THE INSTITUTION / LUQMAN COLLEGE OF PHARMACY, GULBARGA, KARNATAKA
3. /

COURSE OF STUDY AND SUBJECT

/ MASTER OF PHARMACY
(PHARMACEUTICS)
4. / DATE OF ADMISSION OF COURSE / 08/08/2013
5. /

TITLE OF TOPIC

/ DESIGN AND EVALUATION OF MELT-IN-MOUTH TABLET OF RIZATRIPTAN BENZOATE
6. / BRIEF RESUME OF THE
INTENDED WORK
6.1 Need for the study
6.2 Review of the literature
6.3 Objectives of the study / ENCLOSURE-I
ENCLOSURE-II
ENCLOSURE-III
7. /

MATERIALS AND METHODS

7.1 Source of data
7.2 Method of collection of data
7.3 Does study require any Investigations or interventions to be conducted on patients or Other human or animal? If so, Please describe briefly.
7.4 Has ethical clearance been obtained from your institution in case of 7.3 / ENCLOSURE-IV
ENCLOSURE-V
ENCLOSURE-VI
ENCLOSURE-VII
8. / LIST OF REFERENCES / ENCLOSURE-VIII
9. / SIGNATURE OF CANDIDATE / (PANDIT ANKUSHRAO KENDRE)
10. / REMARKS OF GUIDE / This tablet will be formulated for regulated market which might prove to be beneficial to the pediatric, geriatric and bedridden patients and for active patients who are busy and traveling and may not have access to water. Hence recommended for registration.
11. / NAME AND DESIGNATION OF
11.1 Guide
11.2 Signature
11.3 Co guide (if any)
11.4 Signature
11.5 Head of department
11.6 Signature / M. A. SALEEM
H.O.D
DEPARTMENT OF PHARMACEUTICS,
LUQMAN COLLEGE OF PHARMACY, GULBARGA, KARNATAKA
--
--
M. A. SALEEM
H.O.D
DEPARTMENT OF PHARMACEUTICS,
LUQMAN COLLEGE OF PHARMACY, GULBARGA, KARNATAKA
12. / 12.1 Remarks of theprincipal
12.2 Signature of the principal
6 / BRIEF RESUME OF THE INTENDED WORK
ENCLOSURE-I
6.1 Need for the study
A solid dosage form that dissolves or disintegrates rapidly in oral cavity, resulting in solution or suspension without the need of water is known as oral/oro dispersible tablet, mouth dissolving tablet. The concept of oral dispersible tablet emerged from the desire to provide patient with more conventional means of taking their medication. It is difficult for many patients to swallow tablets and hard gelatin capsules. Hence, they do not comply with prescription, which results in high incidence of non-compliance and ineffective therapy. EP has used the term oral dispersible tablets that disperse rapidly and within 3 min in mouth before swallowing.1
Migraine is a chronic neurological disorder characterized by recurrent moderate to severe headaches often in association with a number of ANS symptoms. Typically the headache is unilateral and pulsating in nature, lasting from 2 to 72 hrs. Associated symptoms may include nausea, vomiting, phonophobia and the pain is generally aggravated by physical activity. Up to one-third of people with migraine headaches perceive an aura: atransient visual, sensory, language, or motor disturbance which signals that the headache will soon occur. Migraines are believed to be due to a mixture of environmental and genetic factors.2
Rizatriptan belongs to a group of drugs called triptans. Rizatriptan benzoate, a selective 5-hydroxytryptaminereceptor agonist. It affects a certain natural chemical (serotonin) that constricts blood vessels in the brain. It may also block other pain pathways in the brain. Rizatriptan is used to treat migraines. It helps to relieve headaches, pain and other symptoms of migraines, including sensitivity to light/sound, nausea, and vomiting. Its empirical formula is C15H19N5•C7H6O2 representing a molecular weight of the free base of 269.4. Rizatriptan benzoate is a white to off-white, crystalline solid that is soluble in water at about 42 mg per ml at 25°C.3
The aim of the proposed work is to optimizeoral dispersible tabletof Rizatriptan benzoate for rapid dissolution and absorption of drug, which may produce rapid onset of action in the management of acute migraine attacks.
ENCLOSURE II
6.2Review of literature
1Swamy PV,et al designed orodispersible tablets of pheniramine maleate by effervescentmethod containing mixture of sodium bicarbonate and tartaric acid (each of 12% w/w) along with superdisintegrants, i.e., pregelatinized starch, sodium starch glycolate, croscarmellose sodium and crospovidone. The prepared batches of tablets were evaluated. Based on in vitro dispersion time (approximately 60 s), three formulations were tested for in vitro drug release pattern (in pH 6.8 phosphate buffer). Among three promising formulations formulation containing 4% w/w crospovidone and mixture of sodium bicarbonate and tartaric acid (each of 12% w/w) emerged as the overall bestformulation (t70%= 1.65 min) based on the in-vitro drug release characteristicscompared to commercial conventional tablet formulation.4
2Swamy PV,et alpreparedorodispersible tablets of carbamazepine by direct compressionmethod using 3² full factorial design. Crospovidone (2-10 % w/w) was used as superdisintegrant and microcrystallinecellulose (0-30 %w/w) was used as diluent, along with directly compressible mannitol to enhance mouth feel. Based on in vitro dispersion time (approximately 10 s); the formulation containing 2% w/w crospovidone and 30%w/w microcrystallinecellulose was found to be promising and tested for in vitro drug release pattern (in pH 6.8 phosphate buffer). This formulation showed four-fold faster drug release compared to the conventional commercial tablet formulation.5
3Singh J,et aloptimized orodispersible formulation of indomethacin using a combined approach of subliming agent and superdisintegrant. A 23factorial design was used to investigate the effects amount of subliming agentsnamely camphor and ammonium bicarbonate and taste masking andsmoothening hydrophilic agent mannitol as independent variables anddisintegration time and crushing strength as dependent responses. Resultsshow that higher levels of camphor and mannitol and a lower level ofammonium bicarbonate is desirable for orodispersion.6
4Jadon RS, et al.preparedbitter less oral disintegrating tablet of Lornoxicam. Taste masking was done by complexing Lornoxicam with Eudragit EPO in different ratios. Three superdisintegrants, sodium starch glycolate, crospovidone and crosscarmellose sodium were used. Formulation F6 containing 7 mg of crosscarmellose sodium show least disintegration time i.e. 38 s. In-vitro release profile of F6 at pH 6.2 indicates that perceivable amount of drug was not release in saliva while, high percentage release (more than 80 % in 30 mins.) at acidic pH 1.2 of the stomach.7
5Jain CP,et al prepared fast dissolving tablets of valsartan using different superdisintegrants by direct compression method. Fast dissolving tablets were evaluated for physicochemical properties and in vitro dissolution. The drug release from Fast dissolving tablets increased with increasing concentration of superdisintegrants. The release of valsartan from Fast dissolving tablets was found to follow non-Fickian diffusion kinetics.8
6Kakade SM,et alformulated mouth dissolving tablets of losartan potassium to achieve a better dissolution rate and further improving the bioavailability of the drug. Mouth dissolving tablets prepared by direct compression and using super disintegrants like Polyplasdone XL 10, Croscarmellose sodium and Explotab in different concentration and evaluated for the pre-compression parameters. Among all, the formulation containing 5%w/w superdisintegrant Polyplasdone XL 10 was considered to be best formulation, which release up to 99.26% in 12 minutes.9
7Bhardwaj V,et alprepared mouth dissolving tablet of Amlodipine using different superdisintegrants by sublimation method. Different concentrations (2%, 4% and 6%) of superdisintegrants such as Ac-Di-Sol, sodium starch glycolate, Kollidon-CL were used respectively. Camphor was used as an sublimating agent. Tablets are prepared by direct compression and mannitol is used as bulking agent. The result revealed that the dissolution rate and disintegration time can be improved by using camphor as the sublimating agent and with the addition of superdisintegrants.10
8Kulkarni U, et alprepared fast dissolving tablets of Aceclofenac by employing sublimation method to study the effect of different subliming agents and fillers. Drug compatibility with excipients was checked by FT-IR studies. The results revealed that quantity of camphor, menthol, urea and type of filler significantly affect the response variables.11
9Gudas GK, et alpreparedfast dissolving tablets of Chlorpromazine HCl to enhanced dissolution rate. The tablets were prepared with five superdisintegrants eg: Sod. starch glycolate, Crospovidone, Croscarmellose, L- HPC, Pregelatinised starch. It was concluded that fast disintegrating tablets of chlorpromazine hydrochloride can be successfully prepared by selecting suitable superdisintegrants in order to improve disintegrants/dissolution of the drug in oral cavity & hence better patient’s compliance & effective therapy.12
10Zade PS,et alprepared bitterless fast dissolving tablet of Tizanidine HCl using Eudragit E 100 as a taste masking agent. Mass extrusion was the technique used for preparing taste masked granules. The tablet were prepared with 3 super disintegrants e.g. sod. starch glycolate, crosscarmellose sodium & crospovidone. The result, showed that tabletsprepared by addition of superdisintegrant has less disintegration time than thoseprepared by sublimation method.13
11Kalia A,et alprepared mouth dissolving tablets of oxcarbazepine using two different technologies, direct compression method and solid dispersion technology. Tablets produced by direct compression method contain crospovidone as a superdisintegrant and aspartame as a sweetener. Solid dispersions of oxcarbazepine with polyvinylpyrrolidone K-30 and polyethylene glycol 6000 in different weight ratios were prepared with a view to increase its water solubility. The results compared for both the technologies showed that the oxcarbazepine tablets prepared using solid dispersion technology was found to have good technological properties and satisfying reproducible drug dissolution profiles.14
12Kumar DN,et aldesigned fast dissolving tablets of granisetron hydrochloride by direct compression method using disintegrant blend with a view to enhance patient compliance. A combination of super-disintegrants ie.sodium starch glycolate-crospovidone,sodium starch glycolate-croscarmellose sodium and sodium starch glycolate-L-hydroxy propyl cellulose were used along with directly compressible mannitol to enhance mouth feel. The result declears that the formulation prepared by direct compression method using 4.0% w/w sodium starch glycolate and 2.0% w/w of crospovidone was found to be promising formulation based on the in vitro drug release characteristics compared to control tablet formulation.15
13Chhandira RM,et al formulated mouth dissolving tablets by direct compression method using various superdisintegrants such as kollidone, Ac-Di-sol, primogel, L-Hydroxy propyl cellulose, L- Hydroxypropyl methyl cellulose in different concentration like 4% and 8%. The result revealed that the formulation containing (8% L-Hydroxy propyl cellulose) showed minimum disintegration time, wetting time as compared to other formulation. Dissolution studies concluded that 97% of the drug was released at the end of 20 minutes and disintegration time was increased in the manner of L- Hydroxy propyl cellulose < Kollidone < Ac- Di-sol < Primogel < L- Hydroxypropyl methyl cellulose.16
6.3 Objectives of the study
The present project involves the development of a NON-INFRINGING formula for an orally administrable Orodispersible tablet of Anti-Migraine drug with reproducible and robust process.
Under these consideration, objective of the work is,
To carry out Preformulation study of Rizatriptan Benzoate (i.e. API)
To choose excipients which are stable & compatible with Rizatriptan Benzoate, by carrying out drug-excipients compatibility study.
To formulate convenient dosage form.
To match the formulation with specification given in official compendia.
To study the effect of different processing parameters on final formulation & to optimize the best condition for formulation. (i.e. Worst case study)
To evaluate the all parameters of formulation in detail including stability study.
MATERIALS AND METHODS:
Materials:
Drug : Rizatriptan benzoate.
Super disintegrant : Ac-Di-Sol, Crospovidone, Sodium Starch Glycolate, Kollidone,
L-Hydroxy propyl methyl cellulose,croscarmellose sodiumetc.
Methods:
Rizatriptan benzoatemelt in mouth tablets will be prepared byDirect compression
method.
ENCLOSURE-IV
7.1. Source of Data
1) Review of literature from :
a. Journals : such as
- Indian journal of pharmaceutical sciences.
- International journal of comprehensive pharmacy.
- International journal of pharmaceutical research.
- European journal of pharmaceutical sciences.
- International journal of pharmaceutical sciences and Nanotechnology.
- DhakaUniversity Journal of Pharmaceutical Sciences.
- AAPS Pharmaceutical Science & Technology.
- International journal of pharmaceutical & Technical Research.
- England Journal of Medicine.
b. Internet browsing.
2) Library: Luqman College of Pharmacy.
3) Laboratory based studies.
ENCLOSURE-V
7.2. Method of Collection of Data
Data on drugs will be collected through literature survey and from physiochemical
database. Extensive preformulation trials would provide the basis for selection of
the suitable excipients and system for final formulation development.
1. Preformulation studies
a) Drug excipient compatibility studies
b) Pharmaceutical evaluation :

Bulk density
Tapped density
True density
Porosity
Angle of repose
Haunser ratio
Carr’s index
Moisture content

2. Preparation of tablets:

Direct compression method.
Evaluation parameters: weight variation, hardness, friability, disintegration, wetting time & water absorption ratio, content uniformity,in-vitrodissolution study etc.

ENCLOSURE-VI
7.3. Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly.
-NO-
ENCLOSURE-VII
7.4. Has ethical clearance been obtained from your institution in case of 7.3?
-NOT APPLICABLE-
ENCLOSURE-VIII
8. LIST OF REFERENCES
1Tripathi KD, Essentials of Medical Pharmacology, 5thedition, 2003, 145-155
2Mohire NC, Yadav AV, Gaikwad. Novel Approaches in Development of Metronidazole Orodispersible Tablet. Research J pharma and tech 2009;2:283286.
3 Khemariya P, SinghR, ShuklaA. Preparation and evaluation of mouth dissolving tablets of meloxicam. Int J Drug Delivery 2010; 2: 76-80.
))
4Swamy PV, Divate SP, Shirsand SB, Rajendra P. Preparation and evaluation of
orodispersible tablet of pheniramine maleate by effervescent method. Indian J.
Pharm. Sci. 2009; 71(2): 151-54.
5Swamy PV, Shahidulla SM, Shirsand SB, Hiremath SN, Ali MY. Orodispersible
tablets of carbamazepine prepared by direct compression using 32 full factorial
design. Dhaka Univ J Pharm Sci 2008; 7(1): 1-5.
6Singh J, Philip AK, Pathak K. Optimization studies on design and evaluation of
orodispeersible pediatric formulation of indomethacin. AAPS PharmSciTech 2008 Mar; 9(1): 60-66.
7Jadon RS, Nayak S, Amlan S, Vaidya VD, Khemariya P, Sumbhate S et al. Taste masking of lornoxicam by polymer carrier system and formulation of oral
disintegrating system. Int J Drug Delivery 2009; 1: 27-31.
8Jain CP, Naruk PS. Formulation and evaluation of fast dissolving tablets of
valsartan. Int J. of Pharm. & pharmaceutical sci. July-Sep. 2009;1(1): 219-226.
9Kakade SM, Mannur VS, Ramani KB, Dhada AA, Naval CV, Bhagwat A.
Formulation and evaluation of mouth dissolving tablets of losartan potassium by direct compression techniques. Int. J. Res. Pharm. Sci. 2010; 1(3): 290-295.
10Bhardwaj V, Bansal M, Sharma PK. Formulation and Evaluation of Fast Dissolving Tablets of Amlodipine Besylate Using Different Super Disintegrants and Camphor as Sublimating Agent. Am-Euras. J. Sci. Res. 2010; 5(4): 264-269.
11Kulkarni U, Raghavendra NG, Hariprasanna RC, Rabbani G, Patil BS. Formulation and development of aceclofenac fast dissolving tablets: Effect of functionality of subliming agents. J App Pharm. 2011; 02(03): 179-190.
12Gudas GK, Manasa B, Rajesham VV, Kumar SK, Kumari JP. Formulation and
evaluation of fast dissolving tablets of Chlorpromazine HCl. J. of Pharma. Sci.and Tech. 2010; 2(1): 99-102.
13Zade PS, Kawtikwar PS, Sakarkar DM. Formulation, Evaluation of Fast dissolving tablet containing Tizanidine HCl. Int.J. PharmTech Res. 2009; 1(1): 34-42.
14Kalia A, Khurana S, Bedi N. Formulation and evaluation of mouth dissolving tablet of oxcarbazepine. Int J. of Pharm. & pharmaceutical sci. Nov.-Dec. 2009; 1(1): 12-23.
15Kumar DN, Raju SA, Shirsand SB, Para MS. Formulation design of novel fast
dissolving tablets of granisetron hydrochloride using disintegrant blends for improved efficacy. Int. J. of Res. in Ayur. and Pharm. 2010; 1(2): 468-474.
16Chhandira RM, Venkataeswarlu BS, Kumudhavalli MV, Bhwmik D, Jayakar B.
Formulation and evaluation of mouth dissolving tablets of the etoricoxib. Pak.
J. Pharm. Sci. April 2010; 23(2): 178-181.