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FORMULATION AND IN VITRO EVALUATION OF MATRIX
TABLETS CONTAINING REPAGLINIDE.
Synopsis for M.Pharm dissertation
Submitted to
Rajiv Gandhi University of Health Sciences, Bangalore,
Karnataka
BY
Mr. J. VENKATESH
Dept. of Pharmaceutics
BLDEA’s College of Pharmacy,
BLDE University campus, Bijapur-586 103
Formulation and in vitro Evaluation of Matrix Tablets Containing
Repaglinide Drug .
M.Pharm Dissertation Protocol Submitted
To
Rajiv Gandhi University of Health Sciences,
Karnataka, Bangalore.
By
Mr.J.Venkatesh B.Pharm
Under the guidance of
Dr. C.C. Patil
M.Pharm., Ph.D.
Professor and Head
Department of Pharmaceutics
B.L.D.E.A’s College of Pharmacy, Bijapur-586103.
2012-2013.
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Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1.
Name of the Candidate and
Address
(In block letters)
Mr. J.VENKATESH,
PERMANENT ADDRESS :
5#17 REPELLAWADA (V), ENKOOR (M),
KHAMMAM ( DIST ),
ANDHRA PRADESH - 507168 .
.
2.
Name of the Institution
B.L.D.E A’s COLLEGE OF PHARMACY,
SOLAPUR ROAD , UNIVERSITY CAMPUS,
BIJAPUR , KARANATAKA – 586 103.
3.
Course of study and subject
M.Pharm in Pharmaceutics
4.
Date of admission to Course
15-06-2011.
5.
Title of the Topic
Formulation and In-Vitro Evaluation of Matrix
Tablets Containing Repaglinide
6.
7.
Brief resume of the intended work :
6.1 Need for the study
Enclosure-I
6.2 Review of literature
Enclosure-II
6.3 Objectives of the study
Enclosure-III
Material and Methods :
7.1 Source of data
: Enclosure-IV
7.2 Method of collection of data (including sampling procedure, if any)
: Enclosure-IV
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.
: Enclosure-V
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7.4
Has ethical clearance been obtained from your institution in case of 7.3
: No
8.
List of References (about 4-6)
9.
Signature of candidate
10.
Remarks of the guide
11.
Name & Designation of
(in block letters)
12.
11.1
Guide
11.2
Signature
11.3
Co-Guide (if any)
11.4
Signature
11.5
Head of Department
11.6
Signature
: Enclosure-VI
: Enclosure-VII
Dr. C.C .PATIL
Professor & Head
Department of Pharmaceutics
B.L.D.E.A’s College of Pharmacy, BIJAPUR-586
103
Dr. C. C. PATIL
Professor & Head
Department of Pharmaceutics
B.L.D.E.A’s College of Pharmacy, BIJAPUR-586
103
12.1 Remarks of the chairman & principal: This study can be carried out in our
laboratory
12.2
Signature
4
ENCLOSURE-I
6) Brief resume of the intended work:
6.1. Need for the study:
Among various dosage forms, matrix tablets are widely accepted for oral sustained release
(SR) as they are simple and easy to formulate. Matrix system is the release system, which
prolongs and controls the release of drug that is dissolved or dispersed. Sustained release
formulations are preferred for such therapy because they maintain uniform drug levels,
reduce dose and side effects, better patient compliance, and increase safety margin for high
potency drugs. Oral administration of drugs has been the most common and preferred route
for delivery of most therapeutic agents. It remains the preferred route of administration
investigated in the discovery and development of new drug candidates and formulations.1
Repaglinide is an oral blood glucose-lowering drug of the meglitinide class used in the
diabetis mellitus. Repaglinide lowers blood glucose levels by stimulating the release of
insulin from the pancreas. This action is dependent upon functioning beta (ß) cells in the
pancreatic islets. Insulin release is glucose-dependent and it diminishes at low glucose
concentrations.The mean absolute bioavailability is 56%.2,10 It has a short plasma half-life of
2 to 4 hours, but this drug is likely to be absorbed or degraded in the stomach and small
intestine Therefore it is preferred to use in the matrix dosage form.
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ENCLOSURE-II
6.2. Review of literature
Praveen S. Hiremath et al., have developed controlled release (C.R.) matrix tablet
formulations of rifampicin and isoniazid combination, to study the design parameters and to
evaluate in vitro release characteristics. In the present study, a series of formulations were
developed with different release rates and duration using hydrophilic polymers
hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC). The duration of
rifampicin and isoniazid release could be tailored by varying the polymer type, polymer ratio
and processing techniques. Further, Eudragit L100-55 was incorporated in the matrix tablets
to compensate for the pH-dependent release of rifampicin. Rifampicin was found to follow
linear release profile with time from HPMC formulations. In case of formulations with HPC,
there was an initial higher release in simulated gastric fluid (SGF) followed by zero order
release profiles in simulated intestinal fluid (SIFsp) for rifampicin. The release of isoniazid
was found to be predominantly by diffusion mechanism in case of HPMC formulations, and
with HPC formulations release was due to combination of diffusion and erosion. The initial
release was sufficiently higher for rifampicin from HPC thus ruling out the need to
incorporate a separate loading dose. The initial release was sufficiently higher for isoniazid in
all formulations. Thus, with the use of suitable polymer or polymer combinations and with
the proper optimization of the processing techniques it was possible to design the C.R.
formulations of rifampicin and isoniazid combination that could provide the sufficient initial
release and release extension up to 24 h for both the drugs despite of the wide variations in
their physicochemical properties.3
Anna Viriden et al., have developed the release of a model drug substance, methylparaben,
was studied in matrix tablets composed of hydroxypropyl methylcellulose (HPMC) batches
of the USP 2208 grade that had different chemical compositions. It was found that chemically
heterogeneousHPMCbatches with longer sections of low substituted regions and lower
hydroxypropoxy content facilitated the formation of reversible gel structures at a temperature
as low as 37 ◦C. Most importantly, these structures were shown to affect the release of the
drug from matrix tablets, where the drug release decreased with increased heterogeneity and a
difference in T80 values of 7 h was observed between the compositions. This could be
explained by the much lower erosion rate of the heterogeneous HPMC batches, which
decreased the drug release rate and also released the drug with a more diffusion based release
mechanism compared to the less heterogeneous batches. It can therefore be concluded that
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the drug release from matrix tablets is very sensitive to variations in the chemical
heterogeneity of HPMC.4
Mina Ibrahim Tadros has developed a gastroretentive controlledrelease of drug delivery
system with swelling, floating, and adhesive properties. Ten tablet formulations were
designed using hydroxypropylmethylcellulose (HPMC K15M) and/or sodium alginate (Na
alginate) as release-retarding polymer(s) and sodium bicarbonate (NaHCO3) or calcium
carbonate (CaCO3) as a gas former. Swelling ability, floating behaviour, adhesion period and
drug release studies were conducted in 0.1 N HCl (pH 1.2) at 37 ± 0.5 _C. The tablets
showed acceptable physicochemical properties. Drug release profiles of all formulae
followed non-Fickian diffusion. Statistical analyses of data revealed that tablets containing
HPMC K15M (21.42%, w/w), Na alginate (7.14%, w/w) and NaHCO3 (20%, w/w) (formula
F7) or CaCO3 (20%, w/w) (formula F10) were promising systems exhibiting excellent
floating properties, extended adhesion periods and sustained drug release characteristics.
Both formulae were stored at 40 _C/75% RH for 3 months according to ICH guidelines.
Formula F10 showed better physical stability. Abdominal X-ray imaging of formula F10,
loaded with barium sulfate, in six healthy volunteers revealed a mean gastric retention period
of 5.50 ± 0.77 h.5
Harikrishna Boyapally et al., have developed theophylline buccal adhesive tablets using
direct compression. Buccal adhesive formulations were developed using a water soluble resin
with various combinations of mucoadhesive polymers. The prepared theophylline tablets
were evaluated for tensile strength, swelling capacity and ex vivo mucoadhesion
performance. Ex vivo mucoadhesion was assessed using porcine gingival tissue and the peak
detachment forces were found to be suitable for a buccal adhesive tablet with a maximum of
1.5N approximately. The effect of formulation composition on the release pattern was also
investigated. Most formulations showed theophylline controlled release profiles depended on
the grade and polymer ratio. The release mechanisms were found to fit Peppas’ kinetic model
over a period of 5 h. In general the majority of the developed formulations presented suitable
adhesion and controlled drug release.6
J.C.O. Villanova et al., have developed design of new excipients that extend the release of
drugs from tablets over prolonged periods is essential in reaching enhanced therapeutic
performances. In this sense, the objective of this study was to develop new excipients, based
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on acrylic monomers (ethyl acrylate, methyl methacrylate, and butyl methacrylate) for use in
direct compression (DC). The polymeric excipients were prepared by suspension and
emulsion polymerization reactions and were characterized by FTIR to confirm the
polymerization reaction. For the success of direct compression, excipients must present good
flow and compactability properties. Therefore, excipients were submitted to analysis of
morphology (SEM), particle size and size distribution by laser diffraction, and powder
density (bulk density and tapped density). The Carr index, Hausner ratio, flow ratio, and
cotangent of the angle a were determined. Thereafter, the polymeric excipients were used to
prepare inert matrices by DC using propranolol hydrochloride (PHCl) as a model drug. The
tablets were evaluated for average weight, breaking force, and friability tests. The release
profiles were determined, and the dissolution kinetics was studied. The results indicated that
matrices prepared from excipients obtained by suspension polymerization (NWCB and
PECB) presented a release of PHCl for a period exceeding 12 h, most likely due to the higher
micromeritic properties. The results suggested that the increase in the percentage of
polymers, as well as in the compression time, resulted in a higher hardness of the matrix with
a reduced rate release of the PHCl. Finally, in vitro preliminary tests showed that the
polymeric excipients produced were non-toxic for the gingival fibroblasts.7
M.A. Holgado et al., have developed
a new pharmaceutical formulation for the
administration of morphine. This system is based on a polymeric complex previously
characterized. After the studies performed, it has been selected the following formulation:
62.5% of morphine complex, 15% of free morphine and 22.5% of Eudragit_ RS. The
morphine formulation proposed has been characterized by means of the study of the influence
of several parameters such as pH, ionic strength, mean particle diameter of the components
and total morphine dose by means of the tablet dimensions. This assayed formulation is able
to provide a specific in vitro release profile that will be no influenced by possible variations
in the GIT conditions. Moreover, this formulation can reproduce the same biopharmaceutical
behaviour in an independent manner of the mean diameter particle of the components and the
dimension of the tablet produced with several doses inside a wide interval of doses.8
Matej Pavli et al., have developed matrix tablet by using polymeric polyelectrolytes as
matrix-forming agents is far from optimally or fully understood. Polyelectrolyte carrageenan
(CARR) matrices loaded with oppositely charged active substance doxazosin mesylate (DM)
were investigated according to their water-uptake/erosion properties, in situ complexation
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ability of CARR with DM, and the possibility to achieve dual drug release control.
Interactions between different CARR types (_-, _-, and _-) and DM were confirmed by
differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and zeta
potential measurements. Combination of water-uptake/erosion with in situ complexation
prolonged DM release from CARR matrices for more than 24 h. The rate order of drug
release was in accordance with the number of ester sulfate moieties per disaccharide unit of
CARRs (_ (1) > _ (2) >_ (3)). The higher the charge on the CARR backbone, the higher the
number of interactions with DM and the slower the drug release. Low pH, more vigorous
hydrodynamics, and higher ionic strength resulted in faster drug release. Based on zeta
potential measurements of DM and CARRs, proposed influence of counterion condensation
and its effect on screening polyelectrolyte–drug interactions was confirmed to lower in situ
DM–CARR complexation. Dual drug release control from polyelectrolyte matrices by wateruptake/erosion and in situ complexation offers many new approaches for designing
controlled-release systems.9
ENCLOSURE-III
6.3. Objectives of the study :
The present work is planned with the following objectives.
1. To prepare matrix tablets by wet granulation technique using hydrophilic polymers
such as methyl cellulose, hydroxypropylmethylcellulose , hydroxyethyl cellulose and
sodium carboxy methyl cellulose.
2. To examine the granules for angle of repose, compressibility index, bulk density etc.
3. To evaluate the tablets for hardness, weight variation, uniformity in drug content,
drug-polymer interactions, nature of drug in the formulations and surface
morphology.
4. To study the in vitro drug release from the prepared tablets.
5. To carry out the stability studies on the prepared formulations.
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ENCLOSURE-IV
7) MATERIALS AND METHODS :
7.1. Source of data
The data will be collected by performing various laboratory experiments, referring
journals, text books and other literature.
7.2. Method of collection of data:
The whole data is planned to collect from laboratory experiments which includes the
following,
1) The matrix tablets of Repaglinide will be prepared using the hydrophilic polymers
such as methyl cellulose, hydroxypropylmethylcellulose , hydroxyethyl cellulose and
sodium carboxy methyl cellulose etc.
2) The granules will be evaluated for angle of repose, compressibility index and bulk
density.
3) The formulations will be characterized by Differential scanning calorimetry (DSC),
Infrared Spectroscopy (FTIR), x-ray Diffraction Studies (XRD), Scanning Electron
Microscopy (SEM) and data will be collected.
4) The effects of formulation variables on the drug release will be studied by conducting
dissolution experiments .
5) The stability studies of the formulations will be carried out as per ICH guidelines and
data will be collected.
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ENCLOSURE-V
7.3 The in vivo studies in the animals will not be carried out in the laboratory .
ENCLOSURE-VI
8) List of references:
1) Nilesh V. 2011 “Ingle Preparation and Evaluation of Ambroxol hydrochloride matrix
tablet using different Combination of Polymers” ,31 309-313.
2) UK Drug Information Pharmacists Group May 1999 4/99/06.
3) Praveen S. Hiremath, Ranendra N. Saha 2008 “Oral matrix tablet formulations for
concomitant controlled release of anti-tubercular drugs: Design and in vitro evaluations” Int.
J. of Pharm. 362 118–125.
4) Anna Viriden Anette Larssona, Herje Schagerlöfb, Bengt Wittgrenc 29 September 2010
“Model drug release from matrix tablets composed of HPMC with different substituent
heterogeneity”, Inter J of Pharma 401 60–67.
5) Mina Ibrahim Tadros November 2009, “Controlled-release effervescent floating matrix
tablets of ciprofloxacin hydrochloride”, European Journal of Pharm and Biopharmaceutics 74
- 332–339.
6)J.C.O. Villanova a,, E. Ayres b, R.L. Oréfice, July 2011 “Design of prolonged release
tablets using new solid acrylic excipients for direct compression”, European Journal of
Pharmaceutics and Biopharmaceutics 79 - 664–673 29 .
7) M.A. Holgado A. Iruin, J. Alvarez-Fuentes, M Fernández-Arévalo June 2008
“Development and in vitro evaluation of a controlled release formulation to produce wide
dose interval morphine tablets”, European Journal of Pharmaceutics and Biopharmaceutics
70 544–549 6 .
8) Matej Pavli Franc Vreˇcer, Saˇsa Baumgartner August 2010 “Matrix tablets based on
carrageenans with dual controlled release of doxazosin mesylate”, International Journal of
Pharmaceutics 400 15–23.
9) Krishna Reddy K.V.S.R., MosesBabu J., Mathad V.T., Eswaraiah, S., Reddy
S. M., Dubey P.K. and Vyas K.,2003 “Impurity Profile Study of Repaglinide”,
J.Pharm.Biomed. Anal.,32, , 461-467.
10) Guay DRP 1998. Repaglinide, a novel, short-acting hypoglycaemic agent for Type 2
diabetes mellitus. Pharmacotherapy; 18: 1195-204
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ENCLOSURE-VII
9) Remarks of the Guide:
The present work is aimed to formulate the matrix tablets for anti diabetic drug, Repaglinide.
It is a metaglinide derivative which is used to treat type II diabetes mellitus. It is particularly
useful for patients who require control of post-prandial glucose levels.When administered
orally, 50% of bio availability is obtained with a half life of 1hr.It is short acting with rapid
onset of action. It has a short plasma half-life of 2 to 4 hours, but this drug is likely to be
absorbed or degraded in the stomach and small intestine Therefore it is preferred to use in the
matrix dosage form.
The proposed study can be carried out in the laboratory.
Dr. C .C. PATIL
Professor and HOD
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