RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE
M. PHARM SYNOPSIS
YEAR OF 15/05/2010
TITLE OF THE SYNOPSIS
FORMULATION AND EVALUATION OF MUCOADHESIVE
MICROSPHERES OF ANTI-CANCER DRUG
BY
VANDANA YADAV
M.PHARM, PART- I
DEPARTMENT OF PHARMACEUTICS,
UNDER THE GUIDANCE OF
Dr. SANJAY P.UMACHIGI, M.PHARM,Ph.D
Professor & HOD
DEPARTMENT OF PHARMACEUTICS
INSTITUTION
GAUTHAM COLLEGE OF PHARMACY
R. T. NAGAR, BANGALORE-32, KARNATAKA
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1
Name of the candidate and address
VANDANA YADAV
PERMANENT ADDRESS
C/O Rama Reddy ,#368 ,1ST Floor ,
Wind Tunnel Road,
MURUGESHPALYA,
BANGALORE-560017.
2
Name of the institution
GAUTHAM COLLEGE OF PHARMACY,
Bhuvnaeswari Nagar,
Sultanpalya,
R.T.NAGAR POST,
BANGALORE – 560032.
3
Course of study and subjectMASTER OF PHARMACY IN
PHARMACEUTICS
4
Date of the admission
15/05/2010
5
Title of the topic:
“FORMULATION AND EVALUATION OF MUCOADHESIVE MICROSPHERES OF
ANTI-CANCER DRUG ”
2
Brief resume of the intended work:
6.1 Need for the study:
Oral controlled release (CR) dosage forms (DFs) have been
developed over the past three decades due to their considerable
therapeutic advantages such as ease of administration, patient
compliance and flexibility in formulation. However, this approach
is bedilled with several physiological difficulties such as
inability to restrain and locate the controlled drug delivery
system within the desired region of the gastrointestinal tract
(GIT) due to variable gastric emptying and motility. Furthermore,
the relatively brief gastric emptying time (GET) in humans which
normally averages 2-3 h through the major absorption zone, i.e.,
stomach and upper part of the intestine can result in incomplete
drug release from the drug delivery system leading to reduced
efficacy of the administered dose.1
The word new or novel in the relation to drug delivery system is
a search for something out of necessity. An appropriately designed
sustained or controlled release drug delivery system can be major
advance toward solving the problem associated with the existing
drug delivery system.2-3
Various attempt have been made to increase the bioavailability
as well as prolong the gastric residence time of dosage form in the
stomach resulted in development of bio adhesive drug delivery
system.
Microsphere carrier systems made from the naturally occurring
biodegradable polymers have attracted considerable attention for
several years in sustained drug delivery. Recently, dosage forms
that can precisely control the release rates and target drugs to a
specific body site have made an enormous impact in the formulation
and development of novel drug delivery Systems. Microspheres form
an important part of such novel drug delivery systems.4-6
They have varied applications and are prepared using assorted
polymers.7 However; the success of these microspheres is limited
owing to their short residence time at the site of absorption. It
would, therefore, be advantageous to have means for providing an
intimate contact of the drug delivery system with the absorbing
membranes.8-11 this can be achieved by coupling bioadhesion
characteristics to microspheres and developing bioadhesive
microspheres. Bioadhesive microspheres have advantages such as
efficient absorption and enhanced bioavailability of drugs owing to
a high surface-to-volume ratio, a much more intimate contact with
the mucus layer, and specific targeting of drugs to the absorption
site 12-15
Chitosan obtained by deacetylation of chitin, is a cationic
polymer that has been proposed for use in microsphere systems by
various authors.16-20 Chitosan was selected as a polymer in the
preparation of mucoadhesive microspheres due to its good
mucoadhesive and biodegradable properties.
Cancer is basically a disease of cells characterized by shift in
the control mechanism that governs cell proliferation and
differentiation.21
Since from 1950s, Alkylating agents such as Methotrexate, is
used as first chemotherapeutic agent in treatment of cancer which
is also known as “AMETHOPTERIN”.It is found to be curative
treatment for choriocarcinoma a solid tumour unlike leukemia,(which
is the cancer of blood).22
The drug was then investigated as a treatment for many other
cancers alone or combination with other drugs and was studied for
other cancer indication in 1970s. In 1988s, it was approved by the
USFDA to treat the rheumatoid arthritis. In 2002, the FDA approves
Methotrexate to treat Crohn’s disease.22
Methotrexate competively inhibit dihydrofolate reductase enzyme
, which will involve in conversion of dihydrofolate to active
tetrahydrofolate results in inhibition of purin base synthesis,
therefore inhibition of synthesis of DNA,RNA and protein take
place.22
Methotrexate is a weak dicarboxylic acid with pKa of 4.8 to 5.5,
thus it is mostly ionized at physiological pH and oral absorption
is saturated & dose dependent. A mean oral bioavailability of
about 33% and mean intra muscular bioavailability is 76%.22
Methotrexate is metabolized by intestinal bacteria to the
inactive metabolite 4-amino-4 deoxy-N-methylpteroic acid (DAMPA)
and account for less than 5% loss of oral dose. Factor that
decrease absorption include food, oral non-absorbable antibiotics
(such as vancomycin, neomycin, bacitracin etc.), more rapid
gastrointestinal transit through the GI tract such as diarrhoea,
while slower transit in the GI tract due to constipation.22
Mucoadhesive microspheres of Methotrexate prepared by using
polymer like chitosan, which is obtained by dealkylation of chitin.
It is a cationic polymer that has been proposed for use in
microsphere system by various authors. Chitosan is selected due to
its good mucoadhesive and biodegradable properties.
6.2 Main objectives of the study:
A new oral drug delivery system was developed utilizing both the
concepts of controlled release and Mucoadhesiveness, in order to
obtain a unique drug delivery system which could remain in stomach
and control the drug release for longer period of time by improving
its permeability and solubility.
6.3 Review of the literature:
CHOWDARY K.P.R.et al 15 ., Prepared ethyl cellulose microspheres
of Glipizide. In this study glipizide was incorporated into ethyl
cellulose and were investigated by in vivo and in vitro
methods.
M.NAZMUDDIN.et al 23 ., Prepared floating microspheres of
ketoprofen by solvent evaporation methods using HPMC and Different
grades of Ethyl cellulose as polymer. Results of evaluation shows
that as the concentration of polymer increases it affects the
particle size, percentage yield, In vitro buoyancy and Drug release
of microspheres. Microspheres prepared by using this polymer will
show 98.88% of drug release for a period of 12 hrs. And it will
reduce the dosing frequency.
BHASKAR MAZUMDER.et al 24 ., Carried out study on preparation
and in vitro evaluation of Chlorpheniramine maleate loaded
microspheres by using combination of ethyl cellulose and cellulose
acetate polymer by using oil in oil emulsion solvent evaporation
method. The obtained microsphere was spherical, non-aggregated and
porous in nature and drug- polymer is compatible.
JAYVADEN K.PATEL.et al 25 ., Prepared mucoadhesive microspheres
of glipizide by simple emulsification phase separation techniques
using a chitosan as polymer and glutaraldehyde as a cross linking
agent .Microspheres obtained was discrete, spherical, and free
flowing. The microspheres exhibited good mucoadhesive property in
the in vitro WASH-OFF test and also showed high percentage drug
entrapment efficiency.
SK.SINGH.et al 26., Formulated and evaluated mucoadhesive
microsphere of Amoxicillin trihydrate in management of H.Pylori
infections. The microsphere was prepared by solvent evaporation
method by using Eudragit RS 100, HPMC K4 M as mucoadhesive
polymers. The drug content determination showed that even if the
polymer composition was changed, the solvent evaporation process
was highly efficient to give microspheres having maximum drug
loading and prolonged gastrointestinal residence time.
P.M.DANDAGI.et al 27 ., Formulated mucoadhesive microspheres of
Propanolol HCL for nasal delivery with the aim to avoid first pass
metabolism and to improve patient compliance. The microspheres was
prepared by using chitosan, gelatin as a polymer and Glutaraldehyde
as a cross linking agent by using emulsion cross linking method.
Increases in the drug: polymer concentration in the formulation
showed good bioadhesive properties, swelling index and good
sustained release of drug.
VEENA BELGAMWAR.et al 28., Developed Mucoadhesive
Multiparticulate System Of Metoprolol Tartarte For Oral drug
Delivery using ionic gelation techniques. In this techniques cross
linking of sodium alginate with calcium chloride was done which
retarded the release of drug from the mucoadhesive polymers like
HPMC of various grades like K4M,K15M,K100M,E50LV,Carbopol of grades
971P,974P and polycarbophil.The obtained microspheres were
discrete, bulky, free flowing and showed an average encapsulation
efficiency ranging from 50-60% .The prepared microspheres
formulation also exhibited a good mucoadhesive strength which was
determined in in-vitro conditions through falling film technique
and was compared with ex-vitro studies. The metoprolol microspheres
released from the multiparticulate system was regulated and
extended until 12h and exhibited a non-fickian drug release
kinetics approching to zero order.
RAJESHWAR KAMAL KANT ARYA.et al 29.,Developed mucoadhesive
microspheres with famotidine by the w/o emulsification solvent
evaporation method using mucoadhesive polymers sodium CMC and a
release controlling polymer sodium alginate for prolongation of
gastric residence time .Effects of the stirring rate and polymer
concentration on size of microspheres and drug release were
observed. The prepared microspheres exhibited prolonged drug
release (M 8h) .The mean particle size increased as the
concentration of sodium alginate increased , as the sodium CMC
polymer concentration increases the mucoadhesion increased and drug
release rate decreased at the higher concentration of sodium
alginate .In-vitro studies demonstrated diffusion controlled drug
release from the microspheres.
DHAKAR R.C.et al 30., Sustained release mucoadhesive
microspheres of metformin HCL were designed and evaluated to reduce
the dosing frequency and to improve patient compliance for
effective control of diabetes type-2 . Microspheres were prepared
by emulsification solvent evaporation method using sodium carboxy
methyl cellulose (SCMC) ,carbopol 934P(CP) , and hydroxyl propyl
methyl cellulose K4M(HPMC) , as a mucoadhesive polymers. The
microspheres prepared were found discrete; spherical and free
flowing .The microspheres exhibits good mucoadhesive properties and
showed high drug entrapment efficiency. Metformin HCL released from
these microspheres was slow and extended and dependent on the type
of polymer used .Among all formulation, the formulation containing
SCMC and CP showed the best reproducible results and mucoadhesive
profile with good surface morphology. The obtained mucoadhesive
microspheres can successfully design for sustained delivery of
metformin HCL and to improve patient compliance.
MALAY K.DAS.et al 31., Developed Diltiazem HCL loaded
mucoadhesive microspheres prepared by emulsification –internal
Gelation technique due to the problems of frequent administration
and variable low bioavailability (40-60%) after oral administration
of conventional dosage forms of Diltiazem can be attenuated by
designing it in the form of mucoadhesive microspheres which would
prolong the residence time at the absorption site to facilitate
intimate contact with the absorption surface and thereby improve
and enhance the bioavailability .The obtained microspheres were
spherical in shape and the drug remained dispersed in the polymer
matrix at amorphous state. The in-vitro drug release mechanism was
non-fickian type controlled by swelling and relaxation of
polymer.
7.0 Materials and methods:
DRUG: Anti- Cancer Drug (BCS CLASS –IV).
POLYMERS: Chitosan
OTHER CHEMICAL: Acetic acid,
Sodium Acetate,
Dioctyl Sodium Sulfo succinate,
Petrolium Ether,
Liquid Paraffin,
METHOD: Simple Emulsification Phase Separation Method .
7.1 Source of data:
Data will be obtained from Drug Invention Today, Pub med,
Science Direct, Medline, US patent office website and other
Internet facilities, literature search, and related articles from
library of Gautham College of Pharmacy.
7.2 EVALUATION PARAMETERS:
1. Preformulation study.
2. Drug entrapment efficiency.
3. Particle size determination.
4. Swelling index of microspheres.
5. In vitro WASH-OFF test for microspheres.(Rat Mucosa)
6. Drug release study.
7. Scanning Electron Microscopy.
8. Accelerated stability studies.
7.3 Does the study require any investigation or interventions to
be
Conducted on patients or other humans or animals?
Yes
7.4 Has ethical clearance been obtained from your institution in
case of
7.3?
Yes
8. List of References:
1. RougeN,Buri P,Doelker E. Drug absorption sites in the
gastrointestinal tract and
Dosage forms for site specific delivery. Int .J. Pharm. 1996;
136:117-139.
2. D.M.Brahmankar, Sunil B. Jaiswal., “Biopharmaceutics and
Pharmacokinetics A Treatise”, First edition, Vallabh Prakashan
Pitampura, Delhi- 2001; 337-341.
3. Baumgastners, Kristal J, Vreer F, Vodopivec P, Zorko
B.Optimisation of Floating matrix tablet and evaluation of their
gastric residence time. Int .J. Pharm. 2000; 195: 125 – 130.
4. Woo BH, Jiang G, Jo YW, DeLuca PP. Preparation and
characterization of a composite PLGA and poly (acryloyl
hydroxymethyl starch) microsphere system for protein delivery.
Pharm Res. 2001; 18:1600-1606.
5. Capan Y, Jiang G, Giovagnoli S, DeLuca PP. Preparation and
characterization of poly
D, L-lactide-co-glycolide) microsphere for controlled release of
human growth hormone. AAPS PharmSciTech. 2003; 4:E28.
6. Gohel MC, Amin AF. Formulation optimization of controlled
release diclofenac sodium Microspheres using factorial design. J
.Control Release. 1998; 51:115-122.
7. Vasr JK, Tambwekar K, Garg S. Bioadhesive microspheres as a
controlled dug delivery Drug delivery system. Int. J. Pharm. 2003;
255:13-32.
8. Ikeda K, Murata K, Kobayashi M, Noda K. Enhancement of
bioavailabity of dopamine Via nasal route in beagle dogs. Chem
Pharm Bull (Tokyo). 1992; 40:2155-2158.
9. Nagai T, Nishimoto Y, Nambu N, Suzuki Y, Sekine K. Powder
dosage form of insulin For nasal administration. J. Control
Release. 1984; 1:15-22.
10. Ilium L, Farraj NF, Critechley H, Davis SS. Nasal
administration of gentamicin using a novel microsphere delivery
system. Int. J. Pharm. 1988; 46:261-265.
11. Schaefer MJ, Singh J. Effect of isopropyl myristic acid
ester on the physical characteristics and in vitro release of
etoposide from PLGA microspheres. AAPS PharmSciTech. 2000;
1:E32.
12. Rao SB, Sharma CP. Use of chitosan as biomaterial: studies
on its safety and hemostatic potential. J. Biomed Mater Res. 1997;
34:21-28.
13. Lehr CM, Bouwstra JA, Schacht EH, Junginger HE. In vitro
evaluation of mucoadhesive properties of chitosan and some other
natural polymer. Int .J. Pharm. 1992; 78:43-48.
14. Henriksen I, Green KL, Smart JD, Smistad G, Karlsen J.
Bioadhesion of hydrated
Chitosans: an in vitro and in vivo study. Int .J. Pharm. 1996;
145:231-240.
15. Chowdary KPR, Rao YS. Design and in vitro and in vivo
evaluation of mucoadhesive
Microcapsules of glipizide for oral controlled release: a
technical note. AAPSPharmSciTech. 2003; 4:E39.
16. Thanoo BC, Sunny MC, Jayakrishnan A. Cross-linked chitosan
microspheres: Preparation and evaluation as a matrix for the
controlled release of pharmaceuticals.
J .Pharm Pharmacol. 1992; 44:283-286.
17. Hari PC, Chandy T, Sharma CP Chitosan/calcium alginate
microcapsules for intestinal delivery of nitrofurantoin. J.
Microencapsul.1996; 13: 319-329.
18. Liu LS, Liu SQ, Ng SY, Froix M, Heller J. Controlled release
of interleukin 2 for tumour immunotherapy using alginate/chitosan
porous microspheres. J. Control.
Release. 1997; 43: 65-74.
19. Patel JK, Bodar MS, Amin AF, Patel MM. Formulation and
optimization of mucoadhesive microspheres of metoclopramide. Ind.
J. Pharm. Sci. 2004; 66(3):300-305.
20. Dubey RR, Parikh RH. Two-Stage Optimization Process for
Formulation of Chitosan
Microspheres. AAPS PharmSciTech. 2004; 5(1): article 5.
21. Bertram G.Katzung. “ Basic and Clinical Pharmacology”
,Edition Ninth 2004,Cancer
Chemotherapy: PP898.
22. Meyer LM, Miller FR, Rowen MJ, Bock G, Rutzky J (1950).
"Treatment of acute
Leukemia with amethopterin (4-amino, 10-methyl pteroyl glutamic
acid)" ActaHaematologica. ;4 (3): 157–167.
23. M.najamuddin, Aejaz Ahmed, Sachin shelar, V.patel, T.khan.
Floating Microspheres of Ketoprofen: Formulation and Evaluation.Int
.J. Pharm. Sci. 2010; 2(2):164-168.
24. Bhasker mazumder,sanjib bhattacharya.Bibhash Mohanta,Sanjay
dey.Preparation
And In vitro evaluation of chlorpheniramine maleate loaded
Microspheres. Int.J.PharmTech Res.2009; 1(3):905-913.
25. Jayvaden K.patel, Rakesh P.Patel, Avani F. Amin. Madhabhai
M. Patel. “Formulation and evaluation of mucoadhesive glipizide
microspheres.AAPS PharmSci Tech. 2004.
26. S.K.Singh, V.R.Chaidrawar, Y.U.Ushir, K.R. Vadalia,
N.R.Sheth, S.Singh. “Pharmaceutical characterization of amoxicillin
trihydrates as mucoadhesive microspheres in management of
h.pylori”.Int .J. PharmTech Res.2010; 2(1):349-358.
27. P.M.Dandagi,VS Mastiholimath,AP Gaded,SR Iliger.Mucoadhesive
Microspheres of
Propranolol HCL For nasal delivery.Ind.J.pharmSci. 2007;
69(3):402-407.
28. Veena Belgamwar, Viral Shah and S.J.Surena. “Formulation and
Evaluation of oral Mucoadhesive Multiparticulate system containing
Metoprolol Tartarate: An In vitro-Ex vivo characterization”.
Current Drug Delivery. 2009; 6:113-121.
29. Rajeshwar Kamal Kant Arya, Ripudam Singh, Vijay Jujal.
“Mucoadhesive Microspheres of Famotidine: Preparation
Characterization and In vitro Evaluation”.Int.J.of Engineering
Science and Technology. 2010; 2(6):1575-1580.
30. Ramchand Dhakar, Sheo Dutta Maurya, Shweta Aggarwal, Girish
Kumar, Vijay Kumar Tilak. “Design and Evaluation of SRM
Microspheres of Metformin Hydrochloride”.Pharmacie Globale (IJCP).
2010; 1(01):1-5.
31. Malay K.Das and Divya P.Maurya. “Evaluation of Diltiazem
Hydrochloride loaded
Mucoadhesive Microspheres Prepared by Emulsification Internal
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Technique”.Actapoloniae Pharmaceutica-Drug Research. 2008;
65(2):249-259.
9.
Signature of the Candidate
VANDANA YADAV
((R
VV
10.
Remarks of the Guide:
11.
Name & Designation (in BLOCK LETTERS)
11.1 Guide
Dr. SANJAY P. UMACHIGI.
Prof & HOD
Department of Pharmaceutics,
Gautham College of Pharmacy,
Bangalore – 560032.
11.2 Signature of Guide
(Mrs. ROHINI R. M.)
11.3 Head of the Department
Dr. SANJAY P. UMACHIGI.
Prof & HOD
Department of Pharmaceutics,
Gautham College of Pharmacy,
Bangalore – 560032.
11.4 Signature of HOD:
12.
12.1 Remarks of the Principal:
The program and the resea
rch work that Mr. Rajesh
12.2 Signature of the Principal
Mrs.ARCHANA.P.SWAMY
PRINCIPAL
Gautham College of Pharmacy,
Bhuvnaeswari Nagar,
Sultanpalya,
R.T.NAGAR POST,
BANGALORE – 560032.
