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DEVELOPMENT AND EVALUATION OF TRIMETAZIDINE
HYDROCHLORIDE MICROSPHERES USING NATURAL POLYMERS
DISSERTATION PROTOCOL
SUBMITTED TO THE
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA
BY
CH. PAVAN VEENA
M.PHARM, PART-I
DEPARTMENT OF PHARMACEUTICS
UNDER THE GUIDENCE OF
Mr. GANESH. N.S.
ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACEUTICS
BHARATHI COLLEGE OF PHARMACY
BHARATHI NAGARA, MANDYA
KARNATAKA–571422
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1.
2.
AND ADDRESS (IN BLOCK
LETTERS)
CH.PAVAN VEENA,
M.PHARM, PART-I,
DEPARTMENT OF PHARMACEUTICS,
BHARATHI COLLEGE OF PHARMACY,
BHARATHI NAGARA, MANDYA
KARNATAKA-571422
NAME OF THE INSTITUTION
BHARATHI COLLEGE OF PHARMACY,
NAME OF THE CANDIDATE
BHARATHI NAGARA.
3.
COURSE OF STUDY AND SUBJECT
MASTER OF PHARMACY IN
PHARMACEUTICS.
4.
DATE OF ADMISSION OF COURSE
16-05-2008.
5.
TITLE OF TOPIC
DEVELOPMENT AND EVELUATION OF
TRIMETAZIDINE HYDROCHLORIDE
MICROSPHERES USING NATURAL
POLYMERS.
6.
BRIEF RESUME OF THE
INTENDED WORK
7
6.1 Need for the study
ENCLOSURE-I
6.2 Review of the literature
ENCLOSURE-II
6.3 Objectives of the study
ENCLOSURE-III
MATERIALS AND METHODS
7.1 Source of data
ENCLOSURE-IV
7.2 Method of collection of data
ENCLOSURE-V
7.3 Does study require any
ENCLOSURE-VI
investigations or interventions
to conduct on patients or
Other human or animal? If so,
please describe briefly
8
7.4 Has ethical clearance been
obtained from your institution in case of
7.3
ENCLOSURE-VI
LIST OF REFERENCES
ENCLOSURE-VII
9
SIGNATURE OF CANDIDATE
10
REMARKS OF GUIDE
11
NAME AND DESIGNATION OF
11.1 Guide
Recommended
Mr. GANESH. N.S
ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACEUTICS
BHARATHI COLLEGE OF PHARMACY
BHARATHI NAGARA, MANDYA
KARNATAKA-571422
11.2 Signature
11.3 Co guide (if any)
Not applicable.
11.4 Signature
Not applicable.
11.5 Head of department
11.6 Signature
12
12.1 Remarks of the
chairman and principal
12.2 Signature
Dr. T. SIVAKUMAR
PROFESSOR & HEAD
DEPARTMENT OF PHARMACEUTICS
BHARATHI COLLEGE OF PHARMACY
BHARATHI NAGARA, MANDYA
KARNATAKA-571422
6.0
BRIEF RESUME OF THE INTENDED WORK
ENCLOSURE-I
6.1 need for the study
Controlled drug delivery system received tremendous attention and the significant
research interest in the long term maintenance of drug levels coincides with the increased
medical and public acceptance of such systems1. Oral ingestion has long been the most
convenient and commonly employed route of drug delivery due to its ease of administration,
high patient compliance, least sterility constraints and flexibility in the design of the dosage
forms.
Most per oral sustained products have been formulated as encapsulations or tablets.
Formulations based on modification of the physicochemical properties of the dosage forms can
be classified in to three product types:
1. Encapsulated slow release beads (or granules).
2. Tableted mixed or slow release granulations.
3. Slow release (core) tablets.
Encapsulated slow release beads (or granules) can be prepared by the process of
microencapsulation. In case of microspheres as drug delivery system, various biodegradable
polymers and manufacturing methods using a variety of active pharmaceutical ingredients is
available (2-3).
The applications of microencapsulation might well include sustained- release or
prolonged action medication,taste-masked chewable tablets,powders and suspensions,single
layer tablets containing chemically incompatible ingredients and new formulation concepts for
creams,ointments,aerosols,dressings,plasters,suppositories and injectables.
The present study reports a novel attempt to prepare microspheres of the anti-anginal
drug trimetazidine hydrochloride by using natural polymer as carrier.
Trimetazidine hydrochloride, 1-[(2,3,4-trimethoxyphenyl)methyl] piperazine, used in
angina pectoris and in ischemia of neuro-sensorial tissues as in menieres disease was chosen as
a model drug having high solubility. In placebo -controlled studies in patients with coronary
heart disease and exertional anginal, trimetazidine hydrochlorode enhanced exercised tolerance
and delayed ischemia onset without significantly modifying heart rate, blood pressure or
both4.Because of its high solubility, short half life(6±1.4 hrs)5 and therapeutic use in chronic
disease it is considered as an ideal drug candidate for the design of oral controlled release
dosage form. The use of a controlled release dosage form assists physicians in obtaining
optimal treatment through better patient compliance and safer systems with low peak/through
ratios.
Natural polysaccharides as polymers offer certain advantages over synthetic one in
respect to toxicity, availability and cost. Chitosan has been considered for pharmaceutical
formulation and drug delivery application in which attention has been focused on its
absorption-enhancing, controlled release and bio-adhesive properties. Chitoson lacks irritation
or allergic effects. It has been used extensively as a biomaterial, owing to its
immunostimulatory activities, anticoagulating properties, antibacterial and antifungal action
and for its action as a promoter of wound healing in the field of surgery
(6-7).
Gelatin is a
biocompatible and biodegradable protein and has a unique characteristic of temperaturedependent sol-gel change. Alginate promising strategy for cell microencapsulation and used as
a coating polymer.
ENCLOSURE-II
6.2 Review of Literature
1. Krishnaiah YSR et al., studied on Three-layer guar gum matrix tablet formulation for
oral controlled delivery of highly soluble timetazidine hydrochloride, to design oral
controlled drug delivery system for highly water-soluble drugs and provided the
required release rate on par with the theoretical release rate for guar gum formulations
meant for twice daily administration4.
2. Shu XZ et al., developed Chitosan/Gelatin microspheres prepared by modified
emulsification and ionotropic gelation. The key point of the modified process is the
introduction of gelatin and allowing the ionic cross-linking process of chitosan/gelatin
w/o emulsion to take place under coagulation conditions at a low temperature7.
3. Limor Baruch et al., formulated Alginate-chitosan complex coacervation for cell
encapsulation : Effect on mechanical properties and an long-term variability. An
alginate-chitosan cell encapsulation system was devised to achieve high cell viability
levels as well as to improve mechanical properties, thus holding great potential for
future clinical application9.
4. Murali Mohan Babu GV et al., formulated Controlled release diclofenac sodium by
gum karaya-chitosan complex coacervate : Invivo evaluation. In this study
microcapsules prepared by using principle of complex coacervation. The formulation
displayed a sustained In vivo blood level pattern that is comparable to that of a
commercial controlled release formulation10.
5. Shu XZ et al., developed A novel approach to prepare tripolyphosphate/chitosan
complex beads for controlled release drug delivery. A novel approach was developed
to improve the mechanical strength of tripolyphosphate(TPP)/chitosan beads prepared
under coagulation condition at 4˚C in the presence of gelatin. Cross-linking TPP
solution pH and other preparation factors had an effect on the drug release performance
of beads. It seems that TPP/chitosan bead prepared by the novel method is a promising
formulation for drug delivery11.
6. Carmen Remunan-Lopez et al., studied on the Effect of formulation and process
variables on the formulation of chitosan-gelatin coacervates. The formulation of
complex coacervates between the oppositely charged polyions, chitosan and type B
gelatin was investigated. The complex formulation was rapid and only observed at very
diluted chitosan concentration over a narrow pH range12.
7. Dandagi PM et al., developed Microencapsulation of verapamil hydrochloride by
ionotropic gelation technique. The release of the drug from the micropellets was found
to be following non-fickian diffusion : drug diffusion coefficient and correlation
coefficient were also assessed using various mathematical models. From the study it
was concluded that prolonged release verapamil hydrochloride pellets could be
achieved with success using ionotropic gelation technique14.
8. Tapia C et al., studied the influence dissolution medium pH, degree of polymerization
and degree of swelling of the polymers on the mechanism of release of diltiazem from
matrices based on mixtures of chitosan/alginate. The drug release from the matrix is
controlled by the inter polymeric complex. In all formulations the order of release,
according to peppas’s model in the range of fast kinetic drug release was between 0.5
and 1.0. The mechanism of release was non-fickian diffusion, which corresponds to a
coupling mechanism of diffusion and relaxation of the polymer16.
ENCLOSURE-III
6.3 objectives of the study
In this present investigation, we propose
1. To formulate microspheres using polymers like chitosan, sodium alginate, gelatin, etc
for controlled delivery of anti-anginal drug such as trimetazidine hydrochloride.
2. To evaluate the polymer characteristic and microsphere characteristics.
3. To evaluate physico-chemical characteristics like drug interaction study (TLC/FTIR),
surface morphology (SEM), mean particle size, and size distribution etc.
4. To evaluate the drug loading capacity of the formulation.
5. To perform in vitro dissolution studies.
6. To evaluate the release kinetics.
7. To confirm the physical state of drug in the prepared microspheres (DSC and XRD)
7.0
MATERIALS AND METHODS
Materials:
Drug:
Anti-anginal drug such as Trimetazidine hydrochloride.
Polymers:
Chitosan,
Sodium alginate,
Gelatin, other chemicals and solvents etc.
Methods:
The following methods can be used for the formulation of trimetazidine hydrochloride
microspheres,

Ionotropic Gelation technique.

Coacervation phase separation technique, etc.
ENCLOSURE-IV
7.1. Source Of Data
a. Library: Bharathi College of Pharmacy.
b. e-library: Bharathi College of Pharmacy.
ENCLOSURE-V
7.2 Method Of Collection Of Data
Data on drug will be collected through literature survey and from physiochemical data
base such as solubility in various solvents, pH of the drug solution and compatibility of the
drug with various polymers.
Microspheres containing trimetazidine hydrochloride are formulated with various types
of polymers like chitosan, sodium alginate, gelatin, etc.
The evaluation of formulated microspheres for various parameters like drug interaction study
(TLC/FTIR), surface morphology (SEM), mean particle size ,size distribution, drug loading
capacity, In vitro dissolution studies, Kinetics of drug release and physical state (DSC and
XRD).
I. Preformulation studies
a. Solubility
b. Melting point
c. pH
d. UV analysis
II. Preparation studies
Preparation of trimetazidine hydrochloride microspheres by using the polymers like
chitosan, sodium alginate, gelatin, etc. for controlled delivery of drug.
III. Evaluation studies

Drug interaction study (TLC/FTIR).

Surface morphology (SEM).

Particle size distribution of prepared microspheres.

Drug loading capacity.

In vitro dissolution studies.

Kinetics of dug release.

Physical state (DSC and XRD).
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.
Not applicable.
7.4. Has ethical clearance been obtained from your institution in case of 7.3?
Not applicable.
ENCLOSURE-VII
8.0
LIST OF REFERENCES
1. Gohel MC, Kaul, MM, Kawl JS, Patel RB, Patel SR, Jani TR. Investigation of the
synthesis of poly(D,L-Lactic acid) and preparation of
microspheres containing
indomethacin. Drug Dev Ind Pharm 1996;22(7):637-642.
2. Tilak RB, Meenakshi K, Roshan L, Anubha G. Natural gums and modified natural
gums as sustained-release carriers. Drug Dev Ind Pharm 2000;26(10):1025-1038.
3. Suheyla Kas H. Chitoson: Properties, Preparations and applications to microparticulate
systems. J Microencapsulation 1997;14(6):689-711.
4. Krishnaiah YSR, Karthikeyan RS, Gouri Sankar V, Satyanarayana V. Three-layer guar
gum matrix tablet formulations for oral controlled delivery of highly soluble
trimetazidine hydrochloride. J Contro Rel 2002;81:45-56.
5. http://www.ferrpatentsonline.com/search.html,
Sustained
release
trimetazidine
pharmaceutical composition and a method of their preparation.
6. Jameela SR, Misra A, Jayakrishnan A. Cross-linked chitosan microsphere as carrier for
prolonged delivery of macromolecular drugs. J Biomaterials and Sci polymer Edn
1994;6(7):621-632.
7. Shu XZ, Zhu KJ. Chitosan/Gelation microspheres prepared modified emulsification
and ionotropic gelation. J Microencapsulation 2001;18(2):237-245.
8. Krishnaiah YSR, Karthikeyan RS, Bhaskar P, Satyanarayana V. Bioavailability studies
on guar gum-based three layer matrix tablets of trimetazidine hydrochloride in human
volunteers. J Contro Rel 2002;83:231-239.
9. Limor Baruch, Marcelle Machluf. Alginate-chitosan complex coacervation for cell
encapsulation: effect on mechanical properties and on long-term viability. J
Biopolymers 2006;82:570-579.
10. Murali Mohan Babu GV, Himasankar K, Churuvu PSN, Ramana Murthy KV.
Controlled release of diclofenac sodium by gum karaya-chitosan complex
coacervate:In vivo evaluation. Ind J Pharm Sci 2001;63(5):408-412.
11. Shu XZ, Zhu KJ. A novel approach to prepare tripolyphosphate/ chitosan complex
beads for controlled release drug delivery. Int J Pharm 2000;201:51-58.
12. Carmen Remunan-Lopez, Roland Bodmeier. Effect of formulations and process
variables on the formulations of chitosan-gelatin coacervates. Int J Pharm 1996;135:6372.
13. Gohel MC, Sheth MN, Patel MM, Jani GK, Hetal Patel. Design of chitosan
microspheres containing diclofenac sodium. Indian J Pharm Sci 1994;56(6):210-214.
14. Dandagi PM, Manvi FV, Gadad AP, Mastiholimath VS, Patil MB, Balamuralidhara V.
Microencapsulation of verapamil hydrochloride by ionotropic gelation technique.
Indian J Pharm Sci 2004;66(5):631-635.
15. Olivia Felt, Pierre Buri, Robert Gurny. Chitosan: A unique polysaccharide for drug
delivery. Drug Dev Ind Pharm 1998;24(11):979-993.
16. Tapia C, Costa E, Moris M, Sapag-hagar J, Valenzuela F, Basualto C. Study on the
influence of the pH media dissolution , degree of polymerization and degree of
swelling of the polymers on the mechanism of release of diltiazem from matrices based
on mixtures of chitosan/alginate. Drug Dev Ind Pharm 2002;28(2):217-224.