Formulation and Evaluation of Hydrogel Based Multi-Particulate Drug Delivery Systems Entrapped

Development, Characterization and Evaluation of Microparticlesfor Controlled Release of Nateglinide

M.Pharm Dissertation Protocol Submitted to the

RajivGandhiUniversity of Health Sciences,

Karnataka, Bangalore.

By

Miss. K. NiharikaB.Pharm

Under the Guidance of

Dr. Raghavendra V. Kulkarni M.Pharm., Ph.D.

Professor

Department of Pharmaceutics

BLDEA’s College of Pharmacy, Bijapur 586103

2012-2013

RajivGandhiUniversity of Health Sciences, Karnataka, Bangalore

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

ENCLOSURE-I

6) Brief resume of the intended work

6.1. Need for the study

Development of microspheres is a common technique used in the production of sustained release dosage forms. Microspheresbased drug delivery systems have received considerable attention in recent years. Numbers of methods have been reported to prepare microspheres of desired size, shape and surface properties.1The sustained release systems have made significant progress in terms of clinical efficacy and patient compliance.2Of the several drug delivery systems used, microparticles havegained significant importance.3 The use of microparticlesbased therapy allows drug release to be carefully tailored to the specific site through the choice of appropriate formulations variables. These systems tend to spread uniformly over the GIT and high local drug concentration as well as risk of toxicity can be avoided; thereby release the drugs more uniformly.4

Nateglinide [N(trans-4-isopropylcyclohexylcarbonyl)-dphenylalanine] is a novel oral mealtime glucose regulator, and was approved for the treatment of type II diabetes mellitus recently. Nateglinide can increase the insulin release from pancreatic β-cells through inhibition of potassium-ATP channels after oral administration. It can be rapidly absorbed and peak plasma concentrations are reached after 0.5–1.0 h. The elimination of the substance is also fast, with a biological half-life of approximately 1.4 h.5This is a major drawback associatedwith conventional dosage forms of Nateglinide.

Therefore present work is aimed at the development and evaluation of controlled release microparticles for Nateglinideusing natural and/or synthetic polymers.

ENCLOSURE-II

6.2. Review of literature

1. Pani et al., have carried out the selection of superdisintegrants among sodium starch glycolate, cross povidone, starch-1500 and cross carmellose sodium (CCS) for development of immediate release nateglinide tablets. A 32 full factorial design was used to investigate the influence of two independent variables, i.e., amount of selected superdisintegrants and hardness of the tablets, on two dependent variables, i.e., disintegration time and percentage of drug release at 30 min. The results revealed that CCS was the best superdisintegrant for the development of immediate release tablets of NTG. Stability studies of optimized formulations indicated that there was no significant change in the physical parameters, disintegration time, and percentage of drug release of tablets. The systematic formulation approach helped to understand the effect of formulation processing variables.6

2. 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.7

3. Venkatesh et al., have reported the preparation and evaluation of sustained release dosage form of ambroxol embedded in alginate microbeadsby ionotropic gelation technique. The beads were characterized for particle size, drug content and in vitro release studies. The results revealed that the surface adhering drug was found to release immediately and a steady state of release was obtainedup to 12 hours from all the batches. The results indicated there was an inverse relationship between the concentration of alginate and drug release. The drug release was found to follow non-fickian diffusion.8

ENCLOSURE-III

6.3. Objectives of the study

The present work is planned with the following objectives.

1. To prepare nateglinide loaded microparticles using natural polymers likerosin, chitosan, guar gum, xanthan gum etc., and synthetic polymer like polymethylmethacrylate, ethyl cellulose, Eudragits etc., by emulsification/solvent evaporation method.
2. To evaluate the microparticles 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 microparticles using dissolution tester.
5. To carry out the in vivo studies in Wistar rats.
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 standard 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 nateglinide loaded microparticles will be prepared by emulsification/solvent evaporation method using natural polymers like rosin, chitosan, guar gum, xanthan gum etc., and synthetic polymers like polymethylmethacrylate, ethyl cellulose, Eudragits etc.

2)The microparticles 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 in vivostudies of the selected formulations will be conducted in Wistar rats and data will be collected.

5)The stability studies of the microparticles will be carried out as per ICH guidelines and data will be collected.

ENCLOSURE-V

7.3. Thisstudy is aimed to carry out the following animal studies.

Pharmacodynamic study: The selected microparticles will be subjected for Pharmacodynamic study i.e., anti-diabetic activity in Wistar rats. (No of rats required: 25, Sex: Male, Weight: 150-200 gm).

7.4. Animal ethical clearance has been obtained to carry out the above said animal

experiments.

ENCLOSURE-VI

8) List of References

1. Yadav A.V., Shete A.S., Dabke A.P., Shinde V.R. 2009 “Formulation and in-vitro evaluation of aceclofenac microcapsules”. Int. J. Pharm. Tech. Res. 1: 135-138.
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. Hu S., Wang S., Fanelli B., Bell P.A.,Dunning B.E., Geisse S., Schmitz R., Boettcher B.R. 2000 “Pancreatic beta-cell K(ATP) channel activity and membranebindingstudies with nateglinide: Acomparison with sulfonylureas andrepaglinide”. J. Pharmacol. Exp. Ther.293:444-452.
6. Pani N.R., Nath L.K., Bhunia B.2010 “Formulation, development, and optimization of immediaterelease nateglinide tablets by factorial design”. Drug Disc. Therapeut.4:453-458.
7. 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.
8. Venkatesh N.D., Ramesh N., Karthick1 S., Fakrudeen1 K.M., Uthayakumar B., Valliappan R.M., Deepak S.V., Debnath B., Samanta M.K., Suresh B. 2008 “Design and in vitro evaluation of alginate beads of ambroxol hydrochloride”. J. Phar. Res. 1:139-142

ENCLOSURE-VII

10) Remarks of the Guide

The present work is aimed to formulate the controlled release microparticles for nateglinide. Nateglinide is approved for the treatment of type II diabetes mellitus recently. It can be rapidly absorbed and peak plasma concentrations are reached after 0.5-1.0 h. The elimination of the substance is also fast, with a biological half-life of approximately 1.4 h.This is a major drawback associatedwith conventional dosage forms of Nateglinide andit needs to be administered frequently in order to achieve constant plasma levels. Hence, to overcome this drawback, development of controlled release system for nateglinide is essential.

The proposed study can be carried out in the laboratory.

Dr. R. V. Kulkarni

Professor

Research Guide

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