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FORMULATION AND EVALUATION OF SUSTAINED RELEASE MATRIX
TABLETS OF THEOPHYLLINE
M. Pharm. Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore– 560 041
By
Mr. PATEL BHAUTIKKUMAR.V. B.Pharm
Under the Guidance of
Prof.A.M.GODBOLE M.Pharm.P.hD
Department of Pharmaceutics
S.E.T’s COLLEGE OF PHARMACY
S. R. Nagar, Dharwad–560 002
2011-2012
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE.
ANNEXURE –II
PROFORMA FOR REGISTRATION OF SUBJECT DISSERTATION
1.
NAME OF THE CANDIDATE
AND ADDRESS
Mr. PATEL BHAUTIKKUMAR V.
DEPT. OF PHARMACEUTICS
SET’s COLLEGE OF PHARMACY
S.R.NAGAR,
DHARWAD-580002.
2.
NAME OF THE INSTITUTION
SET’s COLLEGE OF PHARMACY
S. R. NAGAR,
DHARWAD-580002.
3.
COURSE OF STUDY AND
SUBJECT
MASTER OF PHARMACY IN
PHARMACEUTICS
4.
DATE OF ADMISSION TO THE
COURSE
JUNE-2011
5.
TITLE OF THE PROJECT:
FORMULATION AND EVALUATION OF SUSTAINED RELEASE MATRIX
TABLETS OF THEOPHYLLINE
1
6.
BRIEF RESUME OF THE INTENDED WORK:
6.1 Need for study:
Asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis are
commonly encountered respiratory diseases. Each of these conditions may be associated
with troublesome cough, which may be the patient’s only presenting complaint.1
Chronic obstructive pulmonary diseases (COPD) include bronchial asthma, chronic
bronchitis, and emphysema. These three disorders different in their etiology but have one
common characteristic. i.e. airway obstruction which blocks effective pulmonary
ventilation.2
Sustained release dosage forms are designed to complement the pharmaceutical
activity of the medicament in order to achieve quick onset and longer duration of action.2
The usual goal of a sustained release product is to maintain therapeutic blood levels
over an extended period of time. Therapeutic compounds with short half lives are considered
to be excellent candidates for sustained release preparations, since this can reduce dosing
frequency. Sustained release systems usually tend to mimic zero order release by providing
drug release in a slow manner.3
Sustained release products have become popular for the oral administration of such
drugs because they exhibit more consistant blood levels.4 Oral sustained release dosage
forms have been used to improve therapeutic efficacy and achieve greater patient
compliance.
6.2 Review of literature:
Dandagi PM et al., studied the Development and Evaluation of Theophylline and
Salbutamol Sulphate Sustained Release Matrix Tablets. The matrix tablets were prepared by
wet granulation method using hydroxypropylmethylcellulose K4M and K15M in various
percentages. The results of formulation containing 20% hydroxypropylmethylcellulose of
grade K15M and K4M in 1:2 ratios gave extended release of Theophylline and Salbutamol
sulphate up to 12 hrs. and was found to be comparable with marketed sustained release
tablets.2
Panther SI. et al., Formulated Sustained release theophylline tablets by direct
compression Part 1: formulation and in vitro testing. They were prepared theophylline
2
tablets by direct compression. Principally, of the drug (theophylline) and ethylcellulose was
investigated. Ethylcellulose compact well and also retards drug release. In addition, matrices
of this polymer display slow surface erosion which can be enhanced by the incorporation of
a swelling agent. The theophylline to ethylcellulose ratio and tablet hardness was found to
influence the rate of drug release. It was possible to sustain the release of a therapeutic dose
of theophylline over a 12-hrs period.4
Ferrero C et al., studied the Effect of polymer moisture content on drug release
behavior from Methyl methacrylate-Starch matrix tablets. Both water content of the
copolymer and the type of drug influenced the compaction characteristics of the mixtures.
Although the plasticising effect of water improved the binding properties at 25–50% relative
humidities conditions, the surfacial contaminant effect of multilayer adsorbed water makes
difficult the union formation at 75% relative humidities, being necessary to apply higher
maximum upper punch pressures to obtain the desired crushing force (70–80 N). Concerning
the drug, the incorporation of Salbutamol sulphate led to worse compression and friction
properties than the addition of anhydrous Theophylline in the formulations. The drug
dissolution rate and drug release mechanism from the matrices evaluated were clearly
conditioned by the type of drug, so that lower dissolution rates and a Fickian diffusion
mechanism were identified for anhydrous Theophylline formulations while faster dissolution
rates and an anomalous transport were postulated for matrices containing Salbutamol
sulphate.5
Bhupendra G. Prajapti. et al., prepared and studied matrix tablet of Nicorandil. It was
evident from the results that a matrix tablet prepared with hydrophilic polymer and
hydrophobic polymer is a better system for once-daily sustained release of a highly water
soluble drug like Nicorandil. All formulations exhibited diffusion-dominated drug release.6
Raghavendra Rao NG. et al., studied the Formulation and Evaluation of sustained
release matrix tablets of Tramadol hydrochloride. They prepared formulations with drug:
polymer ratio 1:1 showed 100% drug release in 6 to 8 hrs and formulations prepared with
drug: polymer ratio 1:2 could retard the drug release up to desired time period. The tablets
containing polymer blend of hydroxypropylmethylcellulose K15M and Karaya gum (KG)
retard the drug release because both are swellable polymer. The tablets containing polymer
blend of hydroxypropylmethylcellulose K15M and Carrageenan (CG) retard the drug
release. From the release study it was observed that as we increase the concentration of
3
hydroxypropylmethylcellulose, the release of drug is decreased. This is possibly due to
slower erosion of hydroxypropylmethylcellulose and may be due to the increased viscosity
of Carrageenan (CG) which might have helped to keep the hydrated gel intact thus releasing
the drug for 12 hrs.7
Pandey VP. et al., carried out Formulation and Release Charecteristics of
Sustained Release Tablets of Diltiazem Hydrochloride . They prepared sustained release
tablets using hydroxyl propyl methyl cellulose (methocel), ethyl cellulose and Eudragit as
sustaining materials in various proportions. Release profile at 15,30 and 45 d of drug from
fabricated DSR 3 kept at 40+_ 1.in various physiological buffer pH. Thus the present study
warrants further in vivo study of DSR 3.From the present study it may be concluded that
diltiazem hydrochloride may be formulated as sustain release tablets drug delivery system
with HPMC(drug:polymer ratio;1:0.6)for maintaing hardness of tablets of 7.5 kg/cm2. 8
Reza MS. et al., studied that Development of Theophylline Sustained Release
dosage froms based on kollidon SR. containing (Polyvinyl acetate and povidone based
matrix retarding polymer ) were developed in this study in an attempt to design a dosage
form that manifests desirable release profile and thorough adherence to official monographs.
Four matrix tablet formulation were prepared by dry blending and direct compression of
Kollidon SR and HPMC-15 cps (hydroxyl propylmethylcellulose)in varing proportion with
fixed percentage of theophylline. Tables containing only Kollidon SR with the active
ingredient demonstrated a rapid rate of drug release with an initial brust effect. Incorporation
of HPMC-15cps in the matrix tablet prolonged the release of drug with subsequent
minimization of burst effect as confirmed by mean dissolution time, T50 and Higuchi release
rate data.9
Yadav AS. et al., carried out Design and Evaluation of Guar gum based controlled
release matrix tablets of zidovudine. The tables were prepared by wet granulation metod.
Granules were prepared and evaluated for loose bulk density, tapped density, compressibility
index and angle of repose,show satisfactiory result.The in vitro dissolution studies was
carried out for 12 hours. F-2 show 95.97% of drug release end of 12 hours. F-2 was
subjected to stability study for 3 months.10
Vanessa Alves Pinheiro. et al., carried out Development and in vitro Evaluation
of extended-release theophylline matrix capsules. Polymers like cellulose (Methocel TM
K100MPRCR, K15MPRCR and E4MCR) at different proportion (15-35%) were used to
4
slow the release of theophylline (100 mg) from capsules. Volumetric method for powder
filling capsules was used to prepare the capsules. Drug release from capsule was performed
using apparatus 1, at 100 rpm and 900 mL of intestinal medium without enzymes (pH 7.5),
at 350 C, following the USP XXVII ed. (Test 8). Capsule compounded with 35% (w/w) of
Methocel
TM
E4MCR showed dissolution profile according to the official specifications of
the percentage of drug in solution.11
Shanmugam S. et al., Developed the Formulation and Evaluation of Sustained
Release Matrix Tablets of Losartan potassium. Sustained release tablets were prepared by
wet granulation and formulated using different drug polymer ratios, formulations such as F1
to F9. Hydrophilic polymer like Hydroxypropyl methylcellulose (HPMC), hydrophobic
polymer like Ethyl Cellulose (EC) and natural polymer like Xanthan Gum(XG) were used. A
decrease in release kinetics of drug was observed on increasing polymer ratios.12
Vendruscolo CW.et al., studied that directly compressed theophylline tablets,
containing commercial xanthan and a highly hydrophilic galactomannan from the seeds of
Minosa scabrella as release-controlling agents, were obtained. Gums were used at 4,8,12.5
and 25%(w/w), either alone or in mixture(xanthan:galactomannan 1:1). The in vitro drug
release was evaluated at different time intervals during 8hrs using apparatus 1(USP 26) at
100rpm. The drug release decreased with the increased with increase of polymer
concentration and all formulation at 25% w/w of gums showed excessive sustained release
effect.13
6.3 Objectives of study:
 To carry out compatibility studies between drug and polymers (HPMC of
various grades, Natural) using FT-IR.
 To formulate sustained release matrix tablets containing Theophylline using
various polymers with different ratios.
 To Evaluate Pre compression and Post compression parameters.
 Comparative studies with Marketed Product.
7.0
MATERIALS AND METHODS:
A. Materials:
Drug: Theophylline.
Polymer: HPMC of Various Grades, PVP, Natural, etc.
5
Other Excipients: Magnesium stearate, MCC, Isopropyl Alcohol, and other
Tablet excipients, etc.
B. Methods:
Preparation of matrix tablets: Matrix tablets will be prepared by suitable
method. Drug and polymers (Combinations of HPMC of Various Grade,
Natural) were passed through 60 # sieve and the dry blend of the drug was
granulated with PVP as a binder which was dissolved in isopropyl alcohol.
Finally the blend passed through the 22# sieve. And then compressed on the
rotary machine.
C. Evaluation Studies:
1. Compatibility study: Compatibility of drug with polymers will be
investigated using FT-IR spectroscopy.
2. Preparation of standard calibration curve of Theophylline drug.
3. Pre compression studies: The prepared blends will be subjected to
various parameters, viz bulk density, tapped density, Carr’s index, angle
of repose.
4. Post compression studies: The tablets will be evaluated for diameter,
thickness, hardness, friability and weight variation, Drug content
(Content Uniformity).
5. In vitro release study: The release studies will be carried out using USP
ΧΧΙV dissolution apparatus at the speed of 100 rpm using 900 ml of
acid buffer (pH 1.2) for the initial period of 2 hours, followed by
phosphate buffer (pH 6.8) until completion of dissolution. A (10ml) of
the solution was withdrawn from the dissolution apparatus at 1, 2, 4 and
8 hours. The samples were replaced with fresh dissolution medium of
same quantity. The dissolution medium is maintained at 37±oC, at
specific intervals sample will be withdrawn and examined for drug
content using UV spectrophotometer (Shimadzu) at 271nm.
6. Comparative studies with the Marketed Product.
6
7. 1 Sources and collection of data:
 www.sciencedirect.com
 www.informahealthcare.com
 www.google.com
 J-Gate@ Helinet etc
 Brazilian Journal Of Pharmaceutical Sciences
 AAPS Journal of Pharmaceutics
 Indian Journal of Pharmaceutics
7.2 Method of collection of data:
The data will be collected from various standard journals, prepared formulations,
in vitro evaluation and various standard reference books, & other sources like research
literature data bases such as Science Direct etc.
7.3 Does the study require any investigation or interventions to be conducted on
patients or other humans or animals? If so please describe briefly.
------------ NO ------------
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
------------- Not applicable.-----------
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8.0
LIST OF REFERENCES:
1. Harvey RA, Champe PC. Lippincott’s Illustrated Reviews: Pharmacology. 4thed.
New Delhi: Walter Kluwer(India)Pvt.Ltd;2009.p.319.
2. Dandagi PM, Mastiholimath VS, Patil MB, Manvi FV, Gadad AP, Sharma R.
Development and evaluation of Theophylline and Salbutamol sulphate sustained
release matrix tablets. Ind J Pharm Sci 2005Sept-Oct;67(5):598-602.
3. Banker GS, Rhodes CT. Informa healthcare, Modern pharmaceutics, 4thed. Drug
Pharm Sci 2009;121.p.502-03.
4. Panther SI, Russell I, Syce JA, Neau SH. Sustained release theophylline tablets by
direct compression Part 1: formulation and in vitro testing. Int J Pharm 1998;164:110.
5. Bravo-Osuna, Ferrero C, Jimenez-Castellanos MR. Drug release behaviour from
Methyl methacrylate-starch matrix tablets: effect of polymer moisture content. Eur J
Pharm Biopharm 2008;69:285–93.
6. Prajapti BG, Patel KR. Design and in vitro evaluation of novel Nicorandil
sustained release matrix tablets on combination of hydrophilic and hydrophobic
Matrix system. Int J Pharm Pharm Sci 2010 Mar-Apr;1(1):33-38.
7. Raghavendra Rao NG, Gandhi S, Patel T. Formulation and evaluation of sustained
release matrix tablets of Tramadol hydrochloride. Int J Pharm Pharm Sci 2009 NovDec;1(1):60-70.
8. Pandey VP, Manavalan R, Rajan TS, Ganesh KS. Formulation and release
charecteristics of sustain release diltiazem hydrochloride tablets. Ind J Pharm Sci
2003;65(1):44-48.
9. Reza MS, Quadir MA, Haider SS. Development of theophylline sustained release
dosage form based on kollidon SR. Pakistan J Pharm Sci 2002;15(1):63-70.
10. Yadav AS, Kumar AP, Vinod R, Rao SB, Kulkarni SV. Design and evaluation of
Guar gum based controlled release matrix tablets of zidovudine. J Pharm Sci Tech
2010;2(3):156-62.
11. Vanessa Alves Pinheiro, Telma Mary Kaneko, Maria Valeria Robles Velasco,
Vladi Olga Consiglieri. Development and in vitro evaluation of extended-release
theophylline matrix capsules. Brazilian J Pharm Sci 2007;43(2)253-61.
8
12. Shanmugam S, Chakrahari R, Sundaramoorthy K, Ayyappan T. Formulation and
evaluation of sustain release matrix tablets of losartan potassium. Int J Pharm Tech
Res 2011;3(1):526-34.
13. Vendruscolo CW, Andreazza IF, Ganter JLMS, Ferrero C, Bresolin TMB. Xanthan
and galactomannam(from M.scabrella) matrix tablets for oral controlled delivery of
Theophylline. Int J Pharm 2005;296:1-11.
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9.
SIGNATURE OF THE STUDENT
10.
REMARK OF THE GUIDE
The above mentioned information and literature has been extensively investigated,
verified and was found to be correct. The present study will be carried out under my
supervision and guidance.
11.1 NAME AND DESIGNATION Prof. A.M.GODBOLE M. Pharm. PhD
OF THE GUIDE
PROFESSOR ,
DEPT. OF PHARMACEUTICS
SET’s COLLEGE OF PHARMACY,
S.R.NAGAR, DHARWAD- 580002.
11.
11.2 SIGNATURE
11.3 NAME AND DESIGNATION
OF CO-GUIDE
--------------------11.4 SIGNATURE
11.5 HEAD OF THE
DEPARTMENT
Prof. S.P. THAKKER M. Pharm.
PROFESSOR AND HEAD,
DEPT. OF PHARMACEUTICS
SET’s COLLEGE OF PHARMACY,
S.R.NAGAR, DHARWAD- 580002.
11.6 SIGNATURE
12.
12.1 REMARK OF THE
PRINCIPAL
The above mentioned information is correct and
I recommend the same for approval.
12.2 SIGNATURE
Dr. V. H. KULKARNI M. Pharm. Ph.D.
PROFESSOR & PRINCIPAL,
SET’s COLLEGE OF PHARMACY,
S.R.NAGAR, DHARWAD- 580002.
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