Formulation and Evaluation of Hydrogel Based Microcapsules Loaded with Simvastatin

M.Pharm Dissertation Protocol Submitted to the

Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore.

By Miss. Vineeta V. NagathanB.Pharm

Under the guidance of Dr. Raghavendra V. Kulkarni Professor Department of Pharmaceutics

M.Pharm., Ph.D.

B.L.D.E.As College of Pharmacy, Bijapur-586103

2010-2011

Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1. 2. 3. 4. 5. 6. Name of the Candidate and Address (In block letters) Name of the Institution Course of study and subject Date of admission to Course Title of the Topic Brief resume of the intended work : 6.1 Need for the study 6.2 Review of literature 6.3 Objectives of the study 7. Material and Methods : 7.1 Source of data : Enclosure-IV Enclosure-I Enclosure-II Enclosure-III

MISS. VINEETA V. NAGATHAN B.L.D.E.As College of Pharmacy, Bijapur586 103 M.Pharm in Pharmaceutics 19-06-2009 Formulation and Evaluation of Hydrogel Based Microcapsules Loaded with Simvastatin

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. : No

7.4

Has ethical clearance been obtained from your institution in case of 7.3 : No : Enclosure-V

8. 9.

List of References (about 4-6) Signature of candidate

10. 11.

Remarks of the guide Name & Designation of (in block letters) 11.1 Guide

: Enclosure-VI

Dr. Raghavendra V. Kulkarni Professor Department of Pharmaceutics B.L.D.E.As College of Pharmacy, BIJAPUR586 103

11.2

Signature

11.3 11.4

Co-Guide (if any) Signature

-----

11.5

Head of Department

Dr. C. C. Patil Professor &Head Department of Pharmaceutics B.L.D.E.As College of Pharmacy, BIJAPUR586 103

12.

11.6 12.1

Signature Remarks of the chairman & principal: This study can be carried out in our laboratory Signature

12.2

ENCLOSURE-I 6) Brief resume of the intended work 6.1. Need for the study Sustained release (SR) drug delivery system significantly improve therapeutic efficacy of a drug. Drug release retarding polymers are the key performers in such systems. Much of the development in SR drug delivery systems is focusing on the preparation and use of polymers with specificity designed macroscopic and microscopic structural and chemical features1. The controlled release systems have made significant progress in terms of clinical efficacy and patient compliance.2 Of the several drug delivery systems used, multiparticulate drug delivery systems gained significant importance. 3 The use of multi-particulate based therapy allows drug release to be carefully tailored to the specific site through the choice of appropriate formulations variables. Oral controlled release particulate systems like microbeads, pellets, microparticles etc. are becoming more popular than the single unit dosage forms, as these systems tend to spread uniformly over the GIT and high local drug concentration as well as risk of toxicity can be avoided. Multi-particulate systems also avoid the vagaries of gastric emptying and different transit rates; thereby release the drugs more uniformly.4 Simvastatin is a powerful lipid-lowering drug that can decrease cholesterol levels by 50%. It is an inhibitor of HMG-CoA reductase, the enzyme that inhibits the biosynthesis of cholesterol. Hence, it is used in the treatment of hypercholesterolemia. After oral administration at a dose of 10-20 mg, it readily absorbs from the gastro-intestinal tract (GIT) and is having a bioavailability of less than 5% and plasma half life of about 1.9 hours.5 These characteristics make simvastatin, a suitable candidate for development of controlled release multi-unit dosage forms, which avoids the need of repeated administration. The present work is aimed at the development of hydrogel based controlled release microcapsules for simvastatin using natural polymers.

ENCLOSURE-II 6.2. Review of literature 1. Rashmi et al., have prepared the novel interpenetrating network (IPN) hydrogel beads of sodium carboxymethylcellulose and egg albumin loaded with simvastatin by ionotropic gelation and covalent cross-linking method. The IPN beads were characterized by DSC analysis, XRD to understand the crystalline nature of drug after entrapment into IPN matrix. FTIR was used to find the chemical stability of drug in the polymer matrix and SEM was performed to study the surface morphology. The ionically cross-linked beads were capable of releasing drug up to 7 h, whereas the drug release was extended up to 12 h in case of dual cross-linked beads. The beads which were prepared with higher concentration of glutaraldehyde released the drug more slowly. The formulations exhibited non-Fickian trend for drug transport.5 2. Rashmi et al., have reported the carboxymethylcellulose based hydrogel microbeads loaded with simvastatin prepared by ionotropic gelation method. The beads were characterized by DSC analysis, and SEM. DSC studies confirmed the amorphous dispersion of the drug in the hydrogel matrix. The effect of crosslinking agent and polymer concentration on drug release was also studied. Increase in concentration of crosslinking agent and polymers decreased the drug release rate. Drug release followed anomalous/non-Fickian transport mechanism.6 3. Yesmin et al., have developed aceclofenac loaded agarose beads by ionotropic gelation method. The entrapment efficiency was 1005 %. The swelling index was found to be highest (18.22 % in 4 hours) for beads containing aceclofenac-agar (1:2) in 4 % electrolyte solutions and the swelling property was decreased with increasing electrolyte concentration. The dissolution data were treated with zero order, first order and Higuchi model. Half of the formulations were fitted to Higuchi model and rest half to first order model. With increasing polymer (agar) concentration, the release rate of aceclofenac was decreased and swelling index was increased and while increasing electrolyte concentration, the release rate was increased and swelling index was decreased.7 4. Khazaeli et al., have prepared the ibuprofen loaded Ca-alginate beads using different crosslinking agents. Results showed that only Ca ion is suitable for the formation of ibuprofen beads. In addition, formulation of Na-alginate (2%) and Ca-chloride (2%) beads resulted in an encapsulation efficacy of around 90%. The drug release studies showed a rapid and complete ibuprofen release from the beads.8

ENCLOSURE-III 6.3. Objectives of the study The present work is planned with the following objectives.

1. To prepare novel simvastatin entrapped hydrogel based microcapsules using natural

polysaccharides like agar, chitosan, carrageenan carboxymethyl cellulose, xanthan gum etc by ionotropic gelation and covalent crosslinking method.

2. To evaluate the formulations for drug entrapment efficiency, drug-polymer

interactions, nature of drug in the formulations, and surface morphology. 3. To study the effect of cross-linking of polymers on the drug release.

4. To study the in vitro drug release from the prepared microcapsules using dissolution
tester.

5. To carry out the stability studies for the prepared formulations.

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 simvastatin entrapped hydrogel microcapsules will be prepared by ionotropic

gelation and covalent crosslinking method using natural polysaccharides like agar, chitosan, carboxymethyl cellulose, xanthan gum etc and different cross-linking agents. 2) 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. 3) The effects of formulation variables and cross-linking agents on the drug release will be studied by conducting dissolution experiments and data will be collected. 4) The stability studies of the formulations will be carried out as per ICH guidelines and data will be collected.

ENCLOSURE-V 8) List of References

1. Bhabani SN., Sunil KG., Tripati BP. 2009 Preparation and characterization of
famotidine microcapsule employing mucoadhesive polymers in combination to enhance gastro retention for oral delivery. Int. J. Pharm. Pharmaceut. Sci., 1: 112120.

2. Silvina A., Bravo R., Claudio J. 2002 In vitro studies of diclofenac sodium controlled
from bio-polymeric hydrophilic matrices. J. Pharm. Pharmaceut. Sci, 5: 213-19.

3. Ravikumar M.N.V. 2000 Nano and micro-particles as controlled drug delivery

devices. J. Pharm. Pharmaceut. Sci, 3: 234-58.

4. Davis S.S., Hardy J.G., Taylor M.J., Whalley D.R., Wilson C.G. 1984 Comparative
study of gastrointestinal transit of a pellet and tablet formulation. Int. J. Pharm, 21: 167-77.

5. Rashmi B., Kulkarni R.V., Mutalik S.S., Setty C.M., Sa B. 2009 Interpenetrating
network hydrogel beads of carboxymethylcellulose and egg albumin for controlled release of lipid lowering drug. J. Microencapsu, In Press.

6. Rashmi B., Kulkarni R.V., Setty C.M., Kalyane N.V. 2009 Carboxymethylcellulosealuminum hydrogel microbeads for prolonged Pharmaceut. Scienc, In press. release of simvastatin. Acta

7. Yesmin F., Uddin M., Talukder M., Islam S., Laila S., Haque T. 2008 Evaluation of
aceclofenac loaded agarose beads prepared by ionotropic gelation method. S. J. Pharm. Sci, 1:10-17.

8. Khazaeli P., Pardakhty A., Hassanzadeh F. 2008 Formulation of ibuprofen beads by

ionotropic gelation. Iran. J. Pharm. Res. 7:163-170.

ENCLOSURE-VI

10) Remarks of the Guide The present work is aimed to formulate and evaluate the hydrogel based microcapsules for controlled release of simvastatin. Simvastatin is a powerful lipid-lowering drug that can decrease cholesterol levels by 50%. The drug has a shorter biological half-life of about 1.9 hours and it undergoes first pass metabolism. Therefore, it needs to be administered frequently in order to achieve constant plasma levels, but the frequent administration may leads to dose accumulation and toxicity. Hence, to conquer this limitation, development of controlled release system for simvastatin is necessary. The proposed study can be carried out in the laboratory.

Dr. R. V. Kulkarni Professor Research Guide