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FORMULATION AND EVALUATION OF SUSTAINED RELEASE
TABLETS OF METFORMIN HYDROCHLORIDE
Synopsis for M. Pharm Dissertation submitted to the
Rajiv Gandhi University of Health Sciences Bengaluru, Karnataka.
Submitted By
Ms. VIJAYALAKSHMI E
1st year M.Pharm
Under the guidance of
Dr. B. A. VISHWANATH M. Pharm, Ph.D.,
HOD, DEPT. OF PHARMACEUTICS.
ADITYA BENGALURU INSTITUTE OF PHARMACY EDUCATION & RESEARCH
BENGALURU-64.
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BENGALURU.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1.
NAME OF THE CANDIDATE
Ms. VIJAYALAKSHMI E
AND ADDRESS
PRESENT ADDRESS:
ADITYA BENGALURU INSTITUTE FOR
PHARMACY EDUCATION & RESEARCH
#12, KOGILU MAIN ROAD,
YELAHANKA , BENGALURU-64
PERMANENT ADDRESS:
NARAVA(VILLAGE), GIDDALUR(MD),
PRAKASHAM (DT), A.P.
ADITYA BENGALURU INSTITUTE OF
PHARMACY EDUCATION & RESEARCH,
#12, KOGILU MAIN ROAD,
BENGALURU-64.
2.
NAME OF THE INSTITUTION
3.
COURSE OF STUDY AND
SUBJECT
MASTER OF PHARMACY IN PHARMACEUTICS.
4.
DATE OF ADMISSION OF
COURSE
27th july 2011.
5.
TITLE OF TOPIC
FORMULATION AND EVALUATION OF SUSTAINED RELEASE TABLETS OF
METFORMIN HYDROCHLORIDE
6.0
BRIEF RESUME OF THE INTENDED WORK
6.1
Need for the study
In pharmaceutical practice, several approaches exist for administration of drugs to the patient. If
the drug is given in conventional dosage form, it has to be administered several times a day, to
produce the desired therapeutic effect. Because of frequent dosing, fluctuations in plasma drug
level occur. The pronounced fluctuations resulting from the conventional drug administration are
likely to yield periods of therapeutic effects, when the drug concentration falls below the
minimum therapeutic level. Drug concentration can be controlled within a narrow therapeutic
range by the use of sustained release (SR) systems, which will furthermore minimize the severity
of side effects. Sustained release formulations may also be economical, because the average cost
of treatment over an extended time may work out less.1
Metformin Hcl is a biguanide derivative used in the treatment of type -2 diabetes mellitus. The
recommended adult oral dosage of Metformin HCl is 250mg three times a daily, gradually
increased to 1000mg-2500mg per day.2
Metformin is having a short biological halflife of 1.5 - 4.5 h and has only 50% bioavailability.
Sustained Release formulation is needed for metformin to avoid fluctuations in blood levels due
to short biological half life and repeated administration and to produce better hypoglycemic
effect. The bioavailability also enhances due to slow release and absorption over longer
periods.Thus Sustained release formulation of Metformin enhance patient compliance. A few SR
formulations of Metformin are available commercially.3
Metformin is slowly and incompletely absorbed from the GI tract, mainly from the small
intestine; absorption is complete with in 6 hours. The absolute bioavailability of the drug
under fasting conditions is reported to be approximately 50-60% with Metformin
hydrochloride doses of 0.5-1.5g.4
Studies using single oral doses of Metformin
tablets of 500mg, 850mg, 1500mg, and
2500mg indicate the there is a lack of dose proportionality with increasing doses , which
is due to decreased absorption rather than an alteration in elimination.5
Food decreases the extent and slightly delays the absorption of Metformin hydrochloride as
shown by approximately 40% lower peak plasma concentration and 25% lower AUC in
plasma and a 35 min prolongation of time to peak plasma concentration following
administration of a single 850mg tablet of Metformin with food.6
Distribution:
The apparent volume of distribution of Metformin following single oral doses of 850mg
averaged 654 ± 358 liters. Metformin is negligibly bound to plasma proteins in contrast to
sulfonylureas
which
are
more
than
90%
protein
bound. Metformin partitions
into
erythrocytes most likely as a function of time .7
At usual clinical doses and dosing schedules of Metformin , steady state plasma
concentrations of Metformin are reached with in 24-48 hours, and are generally < 1ug/ml.
During controlled clinical trials maximum Metformin plasma levels did not exceed 5 ug/ml
even at maximum doses.8
TYPES OF SUSTAINED RELEASE SYSTEMS
Based on The Route Of Administration
1) Oral
2) Parenteral
3) Transdermal
Oral: The oral route of administration is the most important route of administration for
sustained release systems
6.2
Review of the literature
Colocon asia lab.(2004) reported on development of Metformin hydrochloride (500mg) slow
release formulation using methocel hydrophilic matrices.1
Fujioka, et al.,(2003) reported on glycemic controlled in patient with type 2 diabetes
mellitus switched from twice daily immediate release Metformin to once daily extend
release formulation. The extend release formulation of Metformin prolongs drug absorption
in the upper gastrointestinal tract and permits once daily dosing in patient with type 2
diabetes mellitus.2
Santosh J, et al.,(2003) reported
on
Thiazolidinedione
derivaties
derivaties. Both
insulin
sensitizing
agents: Metformin
improve insulin
resistance , a
and
major
pathogenesis of type 2 diabetes and decrease blood glucose level without stimulating
insulin secretion. Metformin inhibits glucose output from the liver while TZDS increase
glucose utilization in the peripheral tissue.3
Rajdziuk J, et al.,(2003) reported on Metformin and its lie targets in the treatment of type
2 diabetes and glucose production in particular(EGP).4
Barbieri RL.(2003) reported on Metformin for the treatment of polycystic ovary syndrome.9
Chang et al. (2002) reported that Metformin associated lactic acidosis.10
Jones KL. et al. (2002) reported on effect of Metformin in pediatric patient with type 2
diabetes by randomized controlled trial. The result showed safe and effective for treatment
of type 2 diabetes in pediatric patients.11
Dicola, et al., (2002) reported on in vitro evaluation of a system for PH controlled per oral
delivery of Metformin. Oral absorption of Metformin hydrochloride is confined to the
upper part of the intestine, there fore controlled release oral formulation of this drugs
should ensure a complete release during transit from stomach to jejunum.5
Arno E.A., et al. (2002) reported on the formulation Metformin/Glizipide extended release
tablets, formulated with Eudragit NE30D by wet granulation method. The data obtained
from in vitro release studied were fitted with various kinetic models and was found follow
Higuchi kinetics.6
Gusler, et al.,(2001) reported on pharmacokinetic of Metformin gastric retentive tablets in
healthy volunteers by an open levels, single dose randomized three way cross over study
in healthy volunteers. The result showed gastric retentive tablets showed extended release
plasma concentration of Metformin and increased bioavailability of controlled dosage forms
and extend of glucose lowering affects.7
Abdullah, et al., (1988) reported on preparation and evaluation of Metformin
controlled
release tablets by using cellulose polymers and acrylic resins, dissolution characteristic and
tablet properties favoured the use of methyl cellulose in a wet granulation method.
Kartium, et al., (1983) reported on pharmacokinetic of Metformin.12
Wulffelr MG. et al. (2002) reported on combination of Metformin and insulin in the
treatment of type 2 diabetes. The result showed in superior glycemic controlled compared
with insulin therapy alone.8
6.3
MEHODOLOGY:
Preformulation studies

Selection of polymers and various excipients

Compatibility studies

Dose calculation for the formulation
Formulation of sustained release tablets

The tablets are formulated by using the different ratios of HPMC K4M, HPMC K100M,
Xanthangum by wet granulation method.
Evaluation parameters

Hardness

Friability

Drug content

In vitro drug release studies
Objectives of the study
 To develop, characterize, and optimize the sustained release tablets of metformin
hydrochloride.
 To study the physical parameters of the dosage form.
 To estimate the drug content in the formulation.
 To study the drug release pattern using suitable In - vitro method.
 To retard the release of drug over extended period of time.
 To develop the effective dosage form to avoid patient compliance, to decrease frequency
of dosing for better utilization of drug.
 To decrease local and systemic toxic effects.
7.0
MATERIALS AND METHODS
Drug
: Anti-diabetic drug such as metformin hydrochloride.
Polymers
: hydrophilic polymers like HPMC K4M, HPMC K100M, Xanthangum
Ingredients
: Lactose, microcrystalline cellulose, magnesium stearate, colorant, etc.
Solvent like ethanol, dichloromethane etc.
Method
: The Sustained release metformin hydrochloride tablets will be prepared by
direct compression method.
7.1
Source of data

The data will be obtained from the literature survey and internet source.

The data will be obtained from the experimental work, which includes formulation of self
micro emulsion, evaluation and stability studies.
7.2
Method of Collection of Data

Data on drug and excipients are collected from the drug information centre, patents,
reference books, text books, catalogs etc.

Data will be collected from the prepared formulations, in-vitro dissolution studies and
stability studies. In- vitro dissolution studies will be used as criteria for assessing the
enhancement of oral bioavailability of poorly aqueous soluble drug.
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.
-NOT APPLICABLE-
7.4
Has ethical clearance been obtained from your institution in case of 7.3?
-NOT APPLICABLE-
8.0
LIST OF REFERENCES
1. Colocon asia lab, “Metformin Hcl (500mg) slow release formulation using
methocell hydrophilic matrices” Pharm. Tech 2004;27(3):60-5.
2. Fujioka , K. Pans, M.Joyal,S. “Glycemic Contol in patient with diabetes mellitus
switch from twice daily immediate release Metformin once daily extended release
formulation .” Clinical Therapeutics 2003;2(1):529.
3. Satosh .J., Jonman J.H., Aliment pharmacol Ther,Dec,1996;6(3):913-18.
4. Rajdziuk, J “Metformin a review for the treatment of type-2 diabetics and glucose
production in particular, 2003;49(5):730-35.
5. Barbieri RL., “Metfromin Hcl for the treatment of polycystetic ovary syndrome”, J
nahrol. 2003;5(4):400 - 07.
6. Chang CT, Chen YC ,Fang JT, Haung CC. “Metformin associated lactic acidosis .”
Jnahrol.2002;15(4):398-402.
7. Jones, KL., “Effect of metformin Hcl in pediatric patients with type-2 diabetics by
randomized controlled trial” Pharm Res 2002;(10):1690-95.
8. Di colo, G. Falchi, S. Zambito,Y. “Invitro Evaluation Of A System Controlled Per
Oral Delivery Of Metformin .”Journal Of Controlled Release 2002;4(1):119-128.
9. Arno, EA.Anond ,P.Bhaskar,K,Sarvanan,M.Vinod,R.et al., “Eudragit 30 D based
Metformin /Glypezide extended release tablets; Formulation and characterization
of in vitro release studies .” Chemical & Pharmaceutical Bulletin 2002;6(3):145-9.
10. Gusler, “Aliment pharmacol. Ther 2001;6(1):914-20.
9.
Signature of the Candidate
(E.VIJAYALAKSHMI)
10.1
Guide
10.2
Remarks of Guide
10.3
Signature of Guide
DR. B A VISHWANATH
HOD, DEPT. OF PHARMACEUTICS
ADITYA BANGALORE INSTITUTE OF
PHARMACY EDUCATION AND RESEARCH
RECOMMENDED AND FORWARDED
s. OHI ( DR. B A VISHWANATH )
10.4
Co-Guide
NOT APPLICABLE
10.5
Signature of Co-Guide
NOT APPLICABLE
10.6
Head of the Department
DR. B A VISHWANATH
HOD, DEPT. OF PHARMACEUTICS
ADITYA BANGALORE INSTITUTE OF
PHARMACY EDUCATION AND RESEARCH
10.7
Signature of HOD
( DR. B A VISHWANATH )
11.0
Remark of the Principal
11.1
Principal
RECOMMENDED AND FORWARDED
DR. B A VISHWANATH
PRINCIPAL
ADITYA BANGALORE INSTITUTE OF
PHARMACY EDUCATION AND RESEARCH
BENGALURU-560064
11.2
Signature of the Principal
( DR. B A VISHWANATH )