Development and Evaluation of Controlled Release Microspheres Containing Fluvastatin
M. Pharm Dissertation Protocol Submitted to the
Rajiv Gandhi University of Health Sciences,
Karnataka, Bangalore.
By
Mr. Vishal D. Heralgi B.Pharm
Under the Guidance of
Dr. Raghavendra V. Kulkarni M.Pharm., Ph.D.
Professor Head
Department of Pharmaceutical Technology
BLDEA’s College of Pharmacy, Bijapur 586103
2012-2013
Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the Candidate andAddress
(In block letters) / MR. VISHAL D. HERALGI
2. / Name of the Institution / B.L.D.E.A’s College of Pharmacy, Bijapur-586 103
3. / Course of study and subject / M.Pharm in Pharmaceutical Technology
4. / Date of admission to Course / 10/12/2011
5. / Title of the Topic / Development and Evaluation of Controlled Release Microspheres Containing Fluvastatin
6. / Brief resume of the intended work :
6.1 Need for the study
6.2 Review of literature
6.3 Objectives of the study / Enclosure-I
Enclosure-II
Enclosure-III
7. / 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.
: YES, Enclosure-V
7.4 Has ethical clearance been obtained from your institution in case of 7.3
: YES,
8. / List of References (about 4-6) : Enclosure-V
9. / Signature of candidate
10. / Remarks of the guide / : Enclosure-VII
11. / Name & Designation of
(in block letters)
11.1 Guide
11.2 Signature
11.3 Co-Guide (if any)
11.4 Signature
11.5 Head of Department
11.6 Signature / Dr. RAGHAVENDRA V. KULKARNI
Professor & Head
Department of Pharmaceutical Technology
B.L.D.E.A’s College of Pharmacy, BIJAPUR-586 103
---
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Dr. RAGHAVENDRA V. KULKARNI
Professor & Head
Department of Pharmaceutical Technology
B.L.D.E.A’s College of Pharmacy, BIJAPUR-586 103
12. / 12.1 Remarks of the principal : This study can be carried out in our
laboratory
12.2 Signature
ENCLOSURE-I
6) Brief resume of the intended work
6.1. Need for the study
Oral conventional drug administration does not usually provide rate-controlled release or target specificity. In many cases, conventional drug delivery provides sharp increase in drug concentration often achieving toxic level and following a relatively short period at the therapeutic level of the drug concentration eventually drops off until re-administration. In order to obtain maximum therapeutic efficacy, it becomes necessary to deliver drugs to the target tissue in the right quantity for the required period of time, thereby causing little toxicity and minimal side effects1. Microparticulate drug delivery systems are considered and accepted as a reliable to deliver the drugs to the target site with specificity, to maintain the desired drug concentration at the site of interest without untoward effects2. Microencapsulation is a useful method which prolongs the duration of drug effect significantly and improves patient compliance. Eventually the total dose and few adverse reactions may be reduced since a steady plasma concentration is maintained3.
Fluvastatin is a clinically used 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor to reduce cholesterol biosynthesis, exerts additional beneficial pleiotropic effects independent of its lipid-lowering action, such as scavenging of free radicals, anti-inflammatory, antithrombotic and antioxidant actions. Fluvastatin is rapidly absorbed after oral administration, with time to reach peak concentrations (tmax) within 0.5–1 h but possess poor oral bioavailability (20%). It also has shorter biological half life of 2.5 hours. Poor bioavailability has necessitated the administration of repeated and higher doses which often leads to risk of toxicity. Therefore, it is needed to develop a controlled release formulation for fluvastatin.4
Therefore present work is aimed at the development and evaluation of controlled release microspheres containing fluvastatin using natural/synthetic polymers.
ENCLOSURE-II
6.2. Review of literature
1. Lakshmana Prabu et al., have reported the preparation of microspheres containing aceclofenac using rosin by o/w emulsion solvent evaporation technique. The effect of three formulation variables including the drug:polymer ratio, emulsifier (polyvinyl alcohol) concentration and organic solvent (dichloromethane) volume were examined. The prepared batches were characterized for microspheres particle size distribution, encapsulation efficiency and in vitro release behavior. The study reveals that drug:polymer ratio had a considerable effect on the entrapment efficiency; however particle size distribution of microspheres was more dependent on the volume of dichloromethane and polyvinyl alcohol concentration rather than on the drug: polymer ratio. Drug, polymer concentrations were varied to obtain optimum release profile for sustaining the action of the drug.5
2. Deepa et al., have developed floating microspheres of cefpodoxime proxetil (CP) in order to achieve an extended retention in the upper GIT to protect the prodrug from enzymatic attack which may enhance the absorption and improve the bioavailability. The microspheres were prepared by non aqueous solvent evaporation method using different ratios of Cefpodoxime Proxetil, hydroxyl propyl methyl cellulose (HPMC K4M) and ethyl cellulose (1:1:1, 1:1:2,1:1:3,1:1:4,1:1:5 and 1:1:6), in the mixture dichloromethane and ethanol at ratio of (1:1), with tween80 as the surfactant. The floating microspheres were characterized by and results obtained are Particle size analysis (75-600 μm), buoyancy percentage (68.2-88.45), drug entrapment efficiency (27.5%-48.5%), % yield (50.5-70.1) and in vitro drug release was studied for 12 h. The floating microspheres showed better result and it may be use full for prolong the drug release in stomach and improve the bioavailability.6
3. Roy et al., developed the mefenamic acid loaded chitosan microspheres by thermal and glutaraldehyde crosslinking methods. The high level of entrapment of mefenamic acid was obtained in glutaraldehyde crosslinking method. The microspheres exhibited good swelling properties. Thermal analysis confirmed that the mefenamic acid was in solid dispersion in glutaraldehyde crosslinked microspheres. These microspheres exhibited faster release at low loading in comparison with high loading. As the polymer content increased, the drug release was approached nearly zero order kinetics.7
4. Yamada et al., have prepared ketoprofen microspheres (MS) by the dry-in-oil method using ethylcellulose (EC) as a matrix polymer. Further, the microspheres modified by addition of polyethylene glycol (PEG) (MS-P) and hydroxypropyl cellulose (HPC) (MS-H), respectively. Chitosan-coated ketoprofen microparticles (Chi-MP) were prepared by the precipitation of droplets of chitosan solution containing MS, and their adhesion to the rat small intestinal mucosa was tested. The plasma concentrations after duodenal administration were investigated for ketoprofen powder suspension, MS and Chi-MP. The particle size was raised with the increase in amount of ketoprofen added. The drug content and addition of PEG or HPC affected the drug release rate. Chi-MP showed a good mucoadhesion. The maximum plasma concentration of ketoprofen for Chi-MP was less than one-third of that for ketoprofen powder suspension. Chi-MP tended to show the higher and steadier plasma levels than MS.8
ENCLOSURE-III
6.3. Objectives of the study
The present work is planned with the following objectives.
1. To prepare fluvastatin loaded microspheres using natural polymers like chitosan, gum ghatti, loacust bean gum, xanthan gum rosin etc., and synthetic polymer like ethyl cellulose, Eudragits, polymethymethacrylate, etc., by solvent evaporation/emulsification method.
2. To evaluate the prepared microspheres for drug encapsulation efficiency, drug-polymer interactions, nature of drug in the formulations, and surface morphology.
3. To study the effect of formulation variables on the drug release.
4. To study the in vitro drug release from the prepared microspheres using dissolution tester.
5. To study the pharmacodynamic activity in rat model.
6. 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 fluvastatin loaded microspheres will be prepared by solvent evaporation/emulsification method using natural polymers like chitosan, gum ghatti, loacust bean gum, xanthan gum rosin etc., and synthetic polymer like ethyl cellulose, Eudragits, polymethymethacrylate, etc.
2) The microspheres 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 on the drug release will be studied by conducting dissolution experiments and data will be collected.
4) The pharmacodynamic activity of the prepared microspheres will be carried out in the rat model and data will be collected.
5) The stability studies of the microspheres will be carried out as per ICH guidelines and data will be collected.
ENCLOSURE-V
7.3. This study is aimed to carry out the following animal studies.
Anti-hyperlipidemic activity: The prepared microspheres will be subjected for Anti-hyperlipidemic activity in Albino rats. (No of rats required: 24, Sex: Either, Weight: 150-200 gm).
7.4. Has animal ethical clearance been obtained to carry out the above said animal
Experiments?.
Applied for IAEC permission and meeting expected to be held in the month of
August 2012.
ENCLOSURE-VI
8) List of References
1. Fu X., Ping Q., Gao Y. 2005 “Effects of formulation factors on encapsulation efficiency and release behavior in vitro of huperzine A-PLGA microspheres”. J. Microencap. 22: 705-714.
2. Jalil R., Nixon J.R. 1990 “Biodegradable poly(lactic acid) and poly(lactide-co-glycocide) microcapsules: problems associated with preparative techniques and release properties”. J. Microencap., 7: 297–325.
3. Mueller R.H., Jacobs C., Kayser O. 2001 “Nanosuspensions as particulate drug formulations in therapy rationale for development and what we can expect for the future”. Adv. Drug Deliv. Review, 47: 3-19.
4. Yamamoto A., Hoshi K., Ichihara K. 1998 “Fluvastatin, an inhibitor of 3-hydroxy-3- methylglutaryl-CoA reductase, scavenges free radicals and inhibits lipid peroxidation in rat liver microsomes. Eur J Pharmacol., 361: 143–149
5. Lakshmana P.S., Shirwaikar A, A., Shirwaikar A., Kumar A. 2009 “Formulation and evaluation of sustained release microspheres of rosin containing aceclofenac”. Ars Pharm., 50: 51-62.
6. Deepa K., Karthikeyan M., Ramasamy C. 2010 “Development of floating microspheres to improve oral bioavailability of cefpodoxime proxetil”. Acta Pharmaceutica Sciencia, 52: 101-104.
7. Roy S., Panpalia S.G., Nandy B.C., Rai V.K., Tyagi L.K., Dey S., Meena K.C. 2009 “ Effect of method of preparation on chitosan microspheres of mefenamic acid”. Int. J. Pharm. Sci. Drug Res., 1: 36-42
8. Yamada T., Onishi H., Machida Y. 2001 “In vitro and in vivo evaluation of sustained Release chitosan-coated ketoprofen microparticles”. Yakugaku Zasshi, 121: 239-245.
ENCLOSURE-VII
10) Remarks of the Guide
The present work is aimed to develop and evaluate the controlled release microspheres containing fluvastatin. Fluvastatin is used to reduce cholesterol biosynthesis, it exerts additional beneficial pleiotropic effects independent of its lipid-lowering action, such as scavenging of free radicals, anti-inflammatory, antithrombotic and antioxidant actions. Fluvastatin is rapidly absorbed after oral administration, with time to reach peak concentrations (tmax) within 0.5–1 h but possess poor oral bioavailability (20%). It also has shorter biological half life of 2.5 hours. The poor bioavailability has necessitated the administration of repeated and higher doses which often leads to risk of toxicity. Therefore, it is needed to develop a controlled release formulation for fluvastatin.4
Hence, to overcome this limitation, development of controlled release system for fluvastatin is necessary.
The proposed study can be carried out in the laboratory.
Dr. R. V. Kulkarni
Research Guide
11