RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE

M. PHARM SYNOPSIS
YEAR OF ADMISSION 2011
TITLE OF THE SYNOPSIS
FORMULATION AND EVALUATION OF FLOATING MICROSPHERES OF CAPTOPRIL
BY
SUMAN RAWAT
M. PHARM, PART- I
DEPARTMENT OF PHARMACEUTICS
UNDER THE GUIDANCE OF
Dr. PRASANTH V.V., (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,

1

KARNATAKA, BANGALORE.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR
DISSERTATION

Name of the candidate and address

SUMAN RAWAT
PERMANENT ADDRES
S/O Mr.K.S. RAWAT
VILLAGE:JAKHAND
POST OFFICE:JAKHAND
PIN CODE:249161
DISTRICT:TEHRI GARHWAL
STATE:UTTARAKHAND

Name of the institution

GAUTHAM COLLEGE OF PHARMACY,

Bhuvnaeswari Nagar,
Sultanpalya,
R.T.NAGAR POST,
BANGALORE 560032.

Course of study and subject

MASTER OF PHARMACY IN
PHARMACEUTICS

Date of the admission

29/06/2011

TITLE OF THE TOPIC :FORMULATION AND EVALUATION OF FLOATING

MICROSPHERES OF ANTI-HYPERTENSIVE DRUG

6. BRIEF RESUME OF THE INTENDED WORK

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6.1 Need for the study

The oral route is considered as the most promising route of drug delivery due to
the ease of administration, patient compliance and flexibility in formulation 1. However, this
approach has 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 time and motility. Furthermore, the relatively brief gastric
emptying time (GET) in humans which normally averages 2-3 hrs 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 dose2.
It is evident from the recent scientific and patent literature that an increased interest in novel
dosage forms that are retained in the stomach for a prolonged and predictable period of time
exists. One of the most feasible approaches for achieving a prolonged and predictable drug
delivery profile in the GIT is to control the gastric residence time3-4.
A prolonged residence time in the stomach is desirable for controlled release
device delivering drugs, which are
Locally active in stomach, e.g. Misoprostol, antacid and antibiotics against
Helicobacter pylori
Absorption window in the stomach or in the upper small intestine, e.g L-dopa
, p-aminobezoic acid and Furesemide
Unstable in the intestine or colonic environment, e.g. Captopril
Exhibit low solubility at high pH values, e.g. Diazepam

and

Chlordiazepoxide and Verapamil HCL5.

After oral administration, such a dosage form would be retained in the stomach
and release the drug there in a controlled and prolonged manner, so that the drug could be
supplied continuously to its absorption sites in the upper GIT. Dosage forms that can be
retained in the stomach are called gastro retentive drug delivery systems (GRDDS)6.
Gastro retentive dosage form can remain in the gastric region for several hours
and hence significantly prolong the gastric residence time of drugs. Prolonged gastric
retention improves bioavailability, reduces drug waste, and improves solubility of drugs that
are less soluble in a high pH environment. It is also suitable for local drug delivery to the

stomach and proximal small intestine7. Gastro retention helps to provide better availability of
new products with suitable therapeutic activity and substantial benefits for patients.
The need for gastro retentive dosage forms has led to extensive efforts in both
academia and industry towards the development of such drug delivery systems. These efforts
resulted in GRDFs that were designed, in large part, based on the following approaches

Low density dosage form that causes buoyancy in gastric fluid8

High density dosage form that is retained in the bottom of the stomach9
Bioadhesion to stomach mucosa10
Slowed motility of the gastrointestinal tract by concomitant

administration of drugs or pharmaceutical excipients11-12

Expansion by swelling or unfolding to a large size which limits
emptying of the dosage form through the pyloric sphincter13
GRFDDS have a bulk density lower than that of gastric fluids and thus remains
buoyant in the stomach without affecting gastric emptying rate for a prolonged period of
time14. While the system is floating on gastric contents, the drug is released slowly at a
desired rate from the system. Gastro retentive floating microspheres have emerged as an
efficient means of enhancing the bioavailability and controlled delivery of many drugs.
Microsphere are characteristically free flowing powders consisting of protein or synthetic
polymers, which are biodegradable and biocompatible in nature and ideally having a particle
size less than 200m15. Microspheres are multiparticulate drug delivery systems which are
prepared to obtain prolonged or controlled drug delivery to improve bioavailability, stability
and to target the drug to specific site at a predetermined rate 16. They are made from polymeric
waxy or other protective materials such as natural, semi synthetic and synthetic polymers.
Hypertension or high blood pressure is a cardiac chronic medical condition in
which the systemic arterial blood pressure is elevated. Means is that the heart is having to
work harder than it should to pump the blood around the body. Blood pressure involves two
measurements, systolic and diastolic. Normal blood pressure is at or below 120/80 mmHg17.
High blood pressure is anything above 140/90 mmHg. Hypertension is the opposite
of hypotension. Hypertension is classified as either primary (essential) hypertension or
secondary hypertension; about 9095% of cases are categorized as "primary hypertension,"
which means high blood pressure with no obvious medical cause18.The remaining 5-10% of

cases (Secondary hypertension) are caused by other conditions that affect the kidneys,
arteries, heart or endocrine system19.
The antihypertensives are a class of drugs that are used to treat hypertension (high
blood pressure). Evidence suggests that reduction of the blood pressure by 5 mmHg can
decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the
likelihood of dementia, heart failure, and mortality from cardiovascular disease20. There are
many classes of antihypertensive, which lower blood pressure by different means; among the
most important and most widely used are the thiazide diuretics, the ACE inhibitors,
the calcium channel blockers, the beta blockers, and the angiotensin II receptor antagonists.
This type of medication to use initially for hypertension has been the subject of several large
studies and resulting national guidelines. The fundamental goal of treatment should be the
prevention of the important endpoints of hypertension, such as heart attack, stroke and heart
failure. Patient age, associated clinical conditions and end-organ damage also play a part in
determining dosage and type of medication administered21.

Captopril is an orally active inhibitor of angiotensin converting enzyme and it is

widely used in the treatment of hypertension and congestive cardiac failure. The
bioavailabilities of captopril is approximately 65 % and have relatively short half-life of 3
hours and requires frequent administration of dose 25 50 mg, 2 to 3times daily. Captopril is
freely water soluble drug and has site specific absorption from GIT and on other hand, the
drug is unstable in the alkaline pH of the intestine, where as stable in acidic pH and
specifically absorbed from stomach22. Based on the above reasons there is a clear need to
localize the developed formulation at the target area of the GIT by preparing a floating
microspheres.

6.2 Objectives of the study

To formulate and evaluate a dosage form containing an anti-hypertensive drug for
the purpose Gastro retention by floating microsphere
The individual objective to be achieved includes:
Selection of appropriate active pharmaceutical ingredient (API) and excipients to
develop the gastro retentive dosage form
Preformulation studies and development of proposed dosage form using the
screened formulation components
Characterization and evaluation of the formulation
Optimization of the formulation to meet official &/or pharmacokinetic
specifications.
Stability study of the optimized formulation as per ICH guidelines

6.3 Review of literature

1. Streubel et al; developed a multiparticulate gastroretentive drug delivery system composed
of polypropylene foam, eudragit RS, EC and poly methyl methacrylate (PMMA) and were
prepared by solvent evaporation technique. High encapsulation efficiencies were observed
and were independent of the theoretical drug loading. Good floating behavior was observed
as more than 83% of microparticles were floating for at least 8 hrs. At similar drug loading
the release rates increased in the following order PMMA < EC < eudragit RS. This could be
attributed to the different permeability of the drug in these polymers and the drug distribution
within the system 23.
2. Kamel et al; developed sustained release for ketoprofen floating microparticles by the
emulsion solvent diffusion method. Four different ratio of eudragit S100 and eudragit RL
were used to form the floating microparticles. All floating microparticle formulations showed
food flow properties, % drug retained, % yield, SEM and particle size analysis. Floating
ability in 0.1N HCl containing 0.02% tween 80 and simulated gastric fluid without pepsin
was also tested24.
3. Alaa et al; designed a new extended release gastroretentive multiparticulate delivery system
for verapamil by incorporation into hydrogel beads made of chitosan. The beads were formed
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by dropping solutions of verapamil and chitosan in a solution of tripolyphosphate using a

syringe pump with adjustable constant rate. The formed beads were then further crosslinked
using glutraldehyde and the excess glutaraldehyde were then washed. The physical properties
of the prepared beads such as sizes, shapes, frabilities and loading efficiencies were
determined. The floating characteristics and the release profiles were also studied. The
preparation of chitosan beads using the technique would provide a simple and commercially
viable method of preparation of chitosan beads for controlling the release of some drugs25.
4. Karthikeyan et al; developed floating microspheres of cefpodoxime proxetil were prepared
by non - aqueous solvent evaporation method using different grade of HPMC such as HPMC
K15M, HPMC K4M, HPMC 100LV and EC. The prepared microspheres were characterized
by polymer compatibility, percentage yield, buoyancy percentage. Drug entrapment
efficiency (DEE) and in vitro drug release was observed by USP apparatus type II26.

5. Srivastav et al; prepared and evaluated floating microspheres with cimetidine for
prolongation of gastric residence time. The microspheres were prepared by solvent
evaporation method using polymers HPMC and ethyl cellulose. The shape and surface
morphology of prepared microspheres were characterized by optical and scanning electron
microscopy. In vitro drug release studies were performed and drug release kinetics was
evaluated using the linear regression method. Effects of the stirring rate during preparation,
polymer concentration, solvent composition and dissolution medium on the size of
microspheres and dug release were also observed. The prepared microspheres exhibited
prolonged drug release 8 h. The mean particle size increased and the drug release rate
decreased at higher polymer concentration. In vitro studies demonstrated diffusion controlled
drug release from the microspheres27.
6. Ninen et al; developed biodegradable, somastatin acetate containing microspheres prepared
by various aqueous (O/W) and non aqueous (O/O) solvent evaporation method using polymer
of high molecular weight poly (D,L-lactide/glycolide) or low molecular weight poly (D,Llactide). Acceptable encapsulation efficiencies were obtained with all methods. The total
volume of organic solvent and co-solvent were found to be important preparation factors of
the O/W co-solvent method28.
7. Wakode et al; developed pramipexole loaded microspheres were prepared by solvent
evaporation method using polymers like EC and HPMC. The processes of parameters were
optimized using 23 factorial design. The size, shape and surface morphology of the
microspheres were characterized by image analyzer and SEM respectively. In vitro drug
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release studies were performed and drug release kinetics was evaluated using the liner
regression method. The prepared microspheres showed prolonged release of pramipexole for
a period of 24 h. The in vitro release kinetics showed that drug release from microspheres is
8.

diffusion controlled29.
Goyal et al; prepared and evaluated floating microspheres of amoxicillin ,consisting of
calcium silicate, hydroxypropyl methyl cellulose (HPMC) and ethyl cellulose as polymers.
The floating microspheres were evaluated for particle size , micromeritics properties ,
percentage drug content, invitro floating behavior, and invitro drug release. The result
suggested that calcium silicate is a useful carrier for the development of floating and

sustained release preparations30.

9. Najmuddin et al., prepared floating microspheres of ketoprofen by solvent evaporation
method using HPMC and two different grades of ethylcellulose as polymer. The floating
microsphere was evaluated such as micromeritic properties, particle size,percentage yield, in
vitro buoyancy, incorporation efficiency, drug polymer compatibility (IR study ), scanning
electron microscopy and drug releaseof microsphere. Results show that as the concentration
of polymer increases it affects the particle size, percentage yield, in vitro buoyancy and
drugrelease of microsphere. The micromeritic properties were found to be good and scanning
electron microscopy confirmed their hollow structure with smooth surface. Formulation F5
prepared with HPMC 5 cps and ethylcellulose 710 cps which exhibited excellent
micromeritic properties, percentage yield, in vitro buoyancy, incorporation efficiency and
percentage drug release 98.88% for a period of 12 hrs. Results of our present study suggest
that floating microsphere of ketoprofen can be successfully designed to develop sustained
drug delivery which can reduce dosing frequency31.
10. Punitha et al., prepared floating microspheres of Ranitidine Hydrochloride with HPMC 15
cps and Eudragit E100 in various ratios of 1: 1, 1: 2, and 1: 3. Floating microspheres were
aimed to achieve an extended retention in the upper gastrointestinal tract, which may result in
enhanced absorption and thereby improved bioavailability. The formulations were evaluated
for FTIR, drug loading, % entrapment, particle size,SEM, buoyancy, dissolution study and
the drug release kinetics. The enhanced floatability of the formulation and its retention in GIT
may attribute for the increased bioavailability and decrease in frequency of administration.
Comparison of both the polymers revealed HPMC to be a suitable candidate for sustained
release32.
11. Josephine et al., developed the floating microspheres of Stavudine by emulsion solvent
diffusion method using eudragit RS 100 as a rate controlling polymer. The floating
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microspheres were evaluated for micromeritic properties, particle size, % yield, in vitro
buoyancy, incorporation efficiency and drug release. The size or average diameter of prepared
microspheres were recognized and characterized by scanning electron microscopic methods.
The prepared microspheres were found to be spherical and free flowing and remain buoyant
for more than 12 hrs. The drug-loaded microspheres showed encapsulation efficiencies up to
88% and also showed good micromeritic properties for their suitability as oral dosage forms.
The microspheres having lower densities exhibited good buoyancy effect and hence, these
could be retained in the gastric environment for more than12 hrs. Thus, the present
formulations would be capable of reducing the frequency of administration and the dosedependent side effects associated with the repeated administration of conventional stavudine
tablets33.

7.1 Materials and methods:

DRUG

POLYMERS

: Captopril

: Eudragit RS 100, L 100, E100, S100, L100

Ethyl cellulose, Methyl cellulose, HPMC, PVA,
Acrycoat S100 or any other suitable polymers.

EXCIPIENTS

: Dichloromethane, Ethanol, Methanol, Acetone,

n- hexane, Liquid paraffin, Petroleum ether, Chloroform
or any other suitable solvents.

METHOD

: Solvent evaporation method23 /

Emulsion solvent diffusion method33 /
Ionic orifice gelation technique 34

7.2 EVALUATION PARAMETERS

Preformulation studies33
Flow property33
Drug content determination33
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 In vitro buoyancy test33

In vitro drug release study33
Micromeritic properties33
Scanning Electronic Microscopy34
Mechanism of drug release35,36,37
Drug-polymer compatibility study and surface morphology study of formulation
using FTIR/DSC33,34
Stability studies according to ICH guidelines

7.3 Method of collection of data

Literature review including pub/med line and internet search
Lab experiment

7.4 Does the study require any investigation or interventions to be conducted on patients
or other humans or animals?
NA

7.5 Has ethical clearance been obtained from your institution in case of 7.4?
NA

8. List of References:
1. Singh B.N., Kim K. N. Floating Drug Delivery Systems: An Approach of Oral
Controlled Drug Delivery via Gastric Retention. Journal of Controlled Release.
2000; 63 : 235-259.
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2. Rouge N., Buri P., Doelker E. Drug absorption sites in the gastrointestinal tract
and Dosage forms for site specific delivery. Int .J. Pharm. 199; 136: 117-139.
3. Vyas S. P., and Khar. Targeted and Controlled Drug Delivery Novel Carrier
System. First Edition, CBS Publishers and Distributors, New Delhi, 2002: 417-54.
4. Babu V. B. M., Khar R. K. In-vitro and in-vivo studies of sustained release floating
dosage forms containing salbutamol sulphate. Pharmabiz 1995; 45: 268-270.
5. Matharu R. S., and Sanghavi N. M., Novel drug delivery system for Captopril.
Drug Development and Industrial Pharmacy: 1992: 18: 15671574.
6. Streubel A., Siepmann J., Bodmeier R., Gastroretentive drug delivery system.
Expert Opin Drug Deliv. 2006; 3 (2): 217-233.
7. Ali J., Arora S., Khar R. K. Floating drug delivery System. A Review. AAPS
Pharm Sci Tech. 2005; 06(03) : E372-E390.
8. Deshpande A. A., Shah N. H., Rhodes C .T., Malick W. Development of a novel
controlled-release system for gastric retention. Pharm Res. 1997; 14: 815-819.
9. Davis S. S, Stockwell A. F., Taylor M. J., The effect of density on the gastric
emptying of single and multiple unit dosage forms. Pharm Res. 1986; 3: 208-213.
10. Lehr C. M., Bioadhesion technologies for the delivery of peptide and protein drugs
to the gastrointestinal tract. Crit. Rev. Ther. Drug Carrier Syst. 1994; 11: 119-160.
11. Groning R., Heun G. Oral dosage forms with controlled gastrointestinal transit.
Drug Dev Ind Pharm. 1984; 10: 527-539.
12. Groning R., Heun G. Dosage forms with controlled gastrointestinal passage studies
on the absorption of nitrofurantion. Int J Pharm. 1989; 56: 111-116.
13. Klausner E. A., Lavy E., Friedman M., Hoffman A., Expandable gastro retentive
dosage forms. J. Control Release. 2003; 90: 143-162.
14. Singh B. N, Kim K. H. Floating drug delivery systems: an approach to oral
controlled drug

delivery via gastric retention. J. Control Release. 2000; 63: 235-

239.
15. Vyas S. P. and Khar. Targeted and Controlled Drug Delivery Novel Carrier System.
Ist Ed., CBS Publishersn and Distributors, New Delhi, 2002, pp. 417-54.
16. Gholap, S. B., Banarjee, S. K., Gaikwad, D. D., Jadhav, S. L., Thorat, R. M. Hollow
microsphere: a review. 2010; 1(1): 0-15.
17. Tripati. K. D. Essentials of medical pharmacology. Fifth edition, jaypee brothers
medical publishers. Delhi - 2003; 503.
18. Carretero O. A, Oparil S. "Essential hypertension. Part I: definition and
etiology" . Circulation. 2000; 101(3): 329335.

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19. Secondary hypertension, Mayo Foundation for Medical Education and Research
2008: 336.
20. Law M, Wald N, Morris J ."Lowering blood pressure to prevent myocardial
infarction and stroke: a new preventive strategy" . Health Technol Assess ; 2003:
7 (31): 1-94.
21. Nelson, Mark. "Drug treatment of elevated blood pressure" . Australian Prescriber.
2010; (33): 108112.
22. Oates J. A. Antihypertensive agents and the therapy of hypertension.In. Hardman
JG, Limbard LE, Molinoff PB, Ruddon RW Gilman AG, editors. Goodman and
Gilmans the pharmacological basis of therapeutics. 9th ed. New York: McGraw Hill;
1996: 781.
23. Streubel A, Siepmann J, Bodmier R. Floating microsphere based on low density
foam power. Ind J Pharm Sci. 2002; 241: 279-292.
24. Kamel A. H, Sokar MS, Salgamal S, Naggar VF. Preparation and evaluation of
ketoprofen floating oral delivery system. Ind J Pharm Sci. 2001; 220: 13-21.
25. Alaa E. B, Ibrahim A, Abdulah M, Al-Mohizea. Chitosan beads of new
gastroretentive system of verapamil. Sci Pharm. 2006; 74: 175-188.
26. Karthikeyan. D, Karthikeyan M, Ramasamy C. Effect of different grades of HPMC
on drug release profile. J Pharm Res. 2008; 1 (1): 23-28.
27. Srivastav. A, Ridhurkar D. N, Wadhwa R. Floating microspheres of cimetidine
formulation, characterization and in vitro evaluation. Acta Pharm Technol. 2005; 55:
277-285.
28. Ninen M, Luxy, Qifangwang, Xlangrong Z, Wenji Z. Development and evaluation
of new sustained release floating microspheres. Int J Pharm. 2008; 358 (1-2): 82-90.
29. Wakode. R. R, Baja A. N. Formulation and characterization of pramipexole loaded
microspheres.priory.com. 2008: 1-7.

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30. Goyal M. K, MehtaS. C. Preparation and Evaluation of calcium silicate based

floating microspheres of amoxicillin. Journal of applied pharmaceutical science.
2011; 1(5): 137-141.
31. Najmuddin M, Aejaz Ahmed, Sachin Shelar, V.Patel, T.Khan. Floating microspheres
of ketoprofen formulation and evaluation. International journal of pharmacy and
pharmaceutical sciences. 2010; 2(2): 164-168.
32. Pnitha k, khadhir.s, Ravichandiran. V, Umadevi.S. K, Vaijayanthi.V, Padmapriya,
Suresh kumar. S. Intragastric floating drug delivery system of ranitidine
hydrochloride formulation and evaluation. International journal of pharmacy and
pharmaceutical sciences. 2010; 2(2): 105-108.
33. Josephine J. L. J, Mehul. R. T, Wilson B, Shanaz B, Bincy R. Formulation and in
vitro evaluation of floating microspheres of anti-retro viral drug as a gastroretentive
dosage form. International journal of research in pharmacy. 2011; 1(3): 519-527.
34. Ramchand Dhakar, Sheo Dutta Maurya, Shweta Aggarwal, Girish Kumar, Vijay
Kumar Tilak. Design and evaluated of SRM Microspheres of Metformin
Hydrochloride. Pharmacie Globale. International journal of comprehensive
pharmacy . 2010; 1(01): 1-5.
35. Mathew S. T, G. D, V. V. Prasanth and B. Vinod,

Formulation and in vitro- in

vivo evaluation of ketoprofen-loaded albumin microspheres for intramuscular

administration.J. Microencapsul. 2009; 26: 456 469.
36. Higuchi T., Rate of release of medicaments from ointment bases containing drug
in suspension. J. Pharm. Sci. 1961: 874875.
37. Korsmeyer. R.W, Gurny R., Doelker E., Buri P. and Peppas N. A, Mechanism of
potassium chloride release from compressed, hydrophilic, polymeric matrices: Effect
of entrapped air. J. Pharm. Sci. 1983: 11891191.

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9.

Signature of the Candidate

SUMAN RAWAT
SSS((R
SSSASMSWDSKNFJJNNMD
VV

10.
Remarks of the Guide:
The above information is true to the best of my knowledge and the work will be done
under my guidance
11.
11.1 Name & Designation
Guide

Dr. Prasanth V.V, (M.Pharm., Ph.D)

Professor & HOD
Department of Pharmaceutics,
Gautham College of Pharmacy,
Sultanpalya, R.T Nagar (P.O)
Bangalore 560032.

11.2 Signature of Guide

(Mrs. ROHINI R. M.)
11.3 Head of the Department

Dr. Prasanth V.V, (M.Pharm., Ph.D)

Professor & HOD
Department of Pharmaceutics,
Gautham College of Pharmacy,
Sultanpalya, R.T Nagar (P.O)
Bangalore 560032.

11.4 Signature of HOD:

12.
12.1 Remarks of the Principal:
The above mentioned information is correct and I recommend the same for approval.
The program ch work that Mr. Rajesh
Mrs. ARCHANA P. SWAMY.,
12.2 Signature of the Principal
M. Pharm, (PhD)
Principal
Gautham College of Pharmacy
Sultanpalya, R.T Nagar (P.O)
Bangalore 32, Karnataka.

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