FORMULATION AND EVALUATION OF HYDROGEL MICROBEADS OF SELECTEDANTI-HYRERTENSIVE DRUGS

Synopsis forM.Pharm dissertation

Submitted to

Rajiv Gandhi University of Health Sciences, Bangalore,

Karnataka

By

Ramesh R Halli

Dept. of Pharmaceutics

BLDEA’s College of Pharmacy,

BLDE University campus, Bijapur-586 103

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1 /

Name of the candidate and address

/ RAMESH R HALLI
C/o Prof.H Venkatesh,Aksobhy Nilaya, Ashwini Colony, Behind Kundargi Hospital, Bldea’s Road.
Bijapur-586 103.

PERMANENT ADDRESS
Ramesh R Halli
S/O Rewappa H Halli
At/po:Hattalli, Tq: Indi
Dist: Bijapur- 586 205
2 /

Name of the institution

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BLDEA’S COLLEGE OF PHARMACY

University campus, Bijapur-586 103.
3 /

Course of study and subject

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MASTER OF PHARMACY IN PHARMACEUTICS

4 /

Date of the admission

/ 28-07-2011
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Title of the topic:

FORMULATION AND INVITRO EVALUATION OF HYDROGEL MICROBEADS OF SELECTEDANTI-HYRERTENSIVE DRUGS

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6. / Brief resume of the intended work:
6.1 Need for the study:
  • The main objective of any drug therapy is to achieve a desire concentration of drug in blood or tissue, which is therapeutically effective and non toxic for an extended period of time. This can be achieved by proper design of sustained release drug regimen. Variousapproaches have been developed for sustain release; microbeads are the potential candidatefor oral sustained release of drug.1
Hydrogel Microbeads have been widely accepted as a oral sustain release dosage form. In the present study, spherical microbeads are able to prolong the release of drug and usually prepared by ionotropic gelation method, using sodium alginate and other polymers such as guar gum, chitosan and pectin hydrogels as drug release modifiers in various proportions to overcome the drug related adverse effects and to improve the drug bioavailability in different GI tract conditions.2
Metoprolol is the FDA-approved drug for clinical use for the treatment of Hypertension, arrhythmia and other antihypertensive agents. Metoprolol is typically administered orally as a tablet.Thedrug has a short half life 3-4 hrs and Bioavailability is 38%. Hence, the drug in a suitable candidate to formulate in the sustained release dosage form.3
No work on metoprolol microbeads has reported. And, hence, main aim of thepresent study is to develop a sustained drug delivery system of Metoprolol using natural polymers such as sodium alginate,gellan gum and chitosan in order to increase its biological half life and to determined the influence of formulation and preparation variables onmicroparticals characteristics.4
6.2 Review of the literature:
  1. Patil J S et al., have reviewed on ionotropic gelation and polyelectrolyte complexation: the novel techniques to design hydrogel particulate sustained, modulated drug delivery system. The utilization of natural and chemically modified polysaccharides as a part of drug development has increased in the past two decades. Great attention has also been focused on biopolymer based hydrogels for use as potential carriers in controlled drug delivery. In this present review, an attempt was made to narrate the different natural polyanions and their mechanism to form cross-linked hydrogel beads. This review was also focused on various methods of preparation of beads.5
  1. Piyakulawat P et al., have developed preparation and evaluation of chitosan/carrageenan beads for controlled release of sodium diclofenac. The polyelectrolyte complex (PEC) hydrogel beads based on chitosan (CS) and carrageenan (CR) have been studied as a controlled release device to deliver sodium diclofenac (DFNa) in the simulated gastrointestinal condition. Various factors potentially influencing the drug release (i.e., CS/CR proportion, DFNa content, types and amount of cross-linking agents) were also investigated. The optimal formulation was obtained with CS/CR proportion of 2/1 and 5 %( wt/vol) DFNa. The release of drug was controlled by the mechanism of the dissolution of DFNa in the dissolution medium and the diffusion of DFNa through the hydrogel beads.6
  1. Zhang Z-Q et al., have developed tannic acid cross-linked gelatin–gum Arabic coacervate microspheres for sustained release of allyl isothiocyanate:Characterization and in vitro release study. Tannic acid cross-linked gelatin–gum Arabic coacervate microspheres, capable of sustained release of allyl isothiocyanate (AITC) with high encapsulation efficiency, were developed for safe and efficient oral delivery of AITC. Release studies showed that the sustained release performance of
the optimized microspheres was greatly enhanced by using more tannic acid without loss in the encapsulation efficiency.7
  1. Mark Det al., have developed manufacture of chitosan microbeads using centrifugally driven flow of gel-forming solutions through a polymeric micronozzle. The shrinkage of chitosan drops during gelation was estimated from the observations and the theoretical model.8
  1. Maiti Set al., have developedAl+3 ion cross-linked and acetalated gellan hydrogel network beads for prolonged release of glipizide. Considering relatively fast drug release rate of Ca+2/gellan beads in phosphate buffer solution, a novel glipizide-loaded bead system was developed through ionotropic gelation of gellan with trivalent Al+3 ions and covalent cross-linking with glutaraldehyde (GA). The drug release did correlate well with their swelling behaviours. The anomalous drug transport mechanism shifted to super case II transport for GA-treated beads, where the polymer relaxation phenomenon was dominant. The drug was relatively stable, amorphous in the beads. Thus both GA-treated and -untreated Al+3/gellan beads could be useful carriers for the controlled oral delivery of glipizide.9
  1. Kim W-T et al., have developed characterization of calcium alginate and chitosan-treatedcalcium alginate gel beads entrapping allyl isothiocyanate. Swelling studies showed that all the gel beads suddenly shrunk in simulated gastric fluid (pH 1.2). In simulated intestinal fluid (pH 7.4), CA and CCA-I gel beads rapidly disintegrated, whereas CCA-II gel beads highly swelled without degradation probably due to the strong chitosan–alginate complexation. Release studies revealed that most entrapped AITC was released during the shrinkage, degradation, or swelling of the gel beads, and the chitosan treatments, especially the chitosan–alginate complexation, were effective in suppressing the release. CCA-II gel beads showed the highest bead stability and AITC retention under simulated gastrointestinal pH conditions.10
  1. Costa Eet al., have developed tailoring thermoresponsive microbeads in supercritical carbon dioxide for biomedical applications.Herein we report the successful optimization of poly (Nisopropylacrylamide) (PNIPAAm) synthesis strategy to obtain cell-sized hydrogel microbeads with defined and systematically varied mechanical properties. Cytotoxicity assays showed that the obtained cross linked PNIPAAm microbeads do not present any toxic effect on fibroblast cell cultures. Microbeads biocompatibility and adequate mechanical compliance enable their potential application on biomedical settings.11
  1. Belyaeva E et al., have developed new approach to the formulation of hydrogel beads by emulsi&cation/thermal gelation using a static mixer.A new approach in the formulation of hydrogel beads by emulsi&cation/in situ thermal gelation using static mixer technology isdescribed. The resulting beads had a Sauter mean diameter ranging from 350 to 200µm, which decreased with the increase of carrageenan injection temperature, total flow rate and/or the number of static mixer elements. Theoretical values of maximal bead diameter and Sauter mean diameter were calculated on the base of critical Weber number, which was demonstrated through good agreement with the experimental values. It was demonstrated that an existing model for the prediction of gel bead diameter in a SMX static mixer is applicable for the new procedure described in this study.12
  1. ChanE-Set al., have developedeffect of formulation of alginate beads on their mechanical behaviour and stiffness.The aim of this work was to determine the effect of formulation of alginate beads on their mechanical behaviour and stiffness when compressed at high speed. Increasing the concentration of alginate and gelling ions also generated a similar effect. At such a compression speed, the values of Young’s modulus of the beads were found to be in the range between 250 and 900 kPa depending on the bead formulation.13
  1. Almeida P Fet al., have developed cross-linked alginate–gelatine beads: a new matrix for controlled release of pindolol.This work is focused on the development of a new particulate drug delivery system using a sodium alginate matrix containing pindolol as a model drug molecule for intestinal drug prolonged release. Pindolol-loaded alginate–gelatine beads have been developed using a solvent-free technique that involves a cross-linking reaction. Several parameters, such as matrix gelling rate, encapsulation efficiency, drug release profile and matrix erosion rate, were investigated. Physicochemical characterisation indicates the formation of a new alginate–gelatine matrix and shows that pindolol does not interfere with the matrix formation process. The modifications introduced in the initial calcium alginate formulation by means of an appropriate method such as the use of a cross-linking agent successfully changed the matrix performance, allowing the controlled release of pindolol.14
  1. Bernardo M.V et al., have developed sustained release of bupivacaine from devices based on chitosan. Chitosan beads loaded with bupivacaine (169/3 mg of drug per milligram of beads) were prepared by cross-linking with glutaraldehyde. The in vitro results indicate a possible application of these bupivacaine loaded chitosan systems as drug release devices with an analgesic action. Thus, they could be used in the treatment of dental pain in the buccal cavity, where drug release would be made easier by lysozyme of the saliva.15
6.3 Main objectives of the study:
  • The main objective of study is to design and evaluate the Metoprolol microbeads for itsimproved biological half-life and release of drug over extended period of time form theformulation.
  1. To prepare microbeads of Metoprolol by using ionotropic-gelation method using gellan gum and chitosan as the rate controlling matrix materials and hydroxyprophylmethylcellulose phosphate as a coating material.
  2. To perform the percentage encapsulation efficiency of the microbeads with suitable methods.
  3. To perform in-vitro drug release study using USP of different formulations and analyzed them for drug release using UV-Visible spectroscopy.
  4. To evaluate the microbeads for particle size, micromeretic profiles.
  5. To detect the drug-polymer compatibility by performing Fourier Transform Infrared Spectroscopy (FTIR).
  6. To characterize the formulation for thermal behaviour (DSC), and surface morphology (SEM).
  7. To perform the study of swelling index of the prepared beads.
  8. To conduct the stability study of the prepared beads as per ICH guidelines.

Materials and methods:
7.1 Source of data:
Studies on design of Metoprolol microbeads are laboratory based. Data will be genarated by performing lab experiments and referring various journals, abstracts and textbook etc.
7.2Method of collection of data (including sampling procedures if any):
The data is planned to collect from laboratory experiments which includes.
  1. The microbeads will be prepared using ionotropic-gelation technique.
  2. Microbeads will be characterised by SEM, FTIR study using Fourier Transform Infrared Spectrophotometer (FTIR-8400 S Shimadzu, Japan), and DSE and data will be collected.
  3. The particle size, drug entrapment efficiency will be carried out and data will be collected.
  4. Microbeads will be subjected to in-vitro drug release study using dissolution apparatus and data will be collected.
7.3 Does the study require any investigation or interventions to be
Conducted on patients or other humans or animals?
- NO –
7.4 Has ethical clearance been obtained from your institution in case of
7.3?
- Not applicable -

LIST OF REFERENCES:

  1. Shabaraya A R, Narayanacharyulu R.2003 “Design and Evaluation of Chitosan Microsphere of Metoprolol Tartarate for Sustained release”. Indian. J. Pharm. Sci. 65(3):250-52.
  2. Manjanna K.M, Shivakumar.B , Pramod Kumar T M.2009 “Natural polysaccharide hydrogel dexibuprofen microbeads for oral sustained drug deliver”.J. Pharm. Res. Vol 2, No 7.
  3. K.Naga R, Velmurugan S, B.Deepika B, Vinushitha S. 2011 “Formulation and Invitro Evaluation of Buccal Tablets of MetoprololTartrate”. Int. J. Pharm. Pharm. Sci. Vol 3, Issue 2.
  4. Sahoo S K,Mallick A A, Barik B B, Senapat P C.2005“Formulation and in vitro Evaluation of Eudragit® Microspheres of Stavudine”.Topical. J. Pharm.Res. June; 4(1): 369-75.
  5. Patil J S, Kamalapur M V, Marapur S C, Kadam D V.2010 “Ionotropic Gelation and Polyelectrolyte Complexation:The Novel Techniques To Design Hydrogel Particulate Sustained, Modulated Drug Delivery System”.Digest. J. Nanomat. Biostruct. Vol. 5, No 1, p. 241 – 48.
  6. Piyakulawat P, Praphairaksit N, Chantarasiri N, Muangsin N. 2007 “Preparation and Evaluation of Chitosan/Carrageenan Beads for Controlled Release of Sodium Diclofenac”.AAPS. Pharm. Sci. Tech.8 (4) Article 97.
  7. Zhang Z-Q,Pan C-H,Chung D. 2011 “Tannic acid cross-linked gelatin–gum arabic coacervate microspheres for sustained release of allyl isothiocyanate: Characterization and in vitro release study”. Food. Res. Int. 44, 1000–7.
  8. MarkD,Haeberle S, Zengerle R, DucreeJ, Vladisavljevic G T. 2009 “Manufacture of chitosan microbeads using centrifugally driven flow of gel-forming solutions through a polymeric micronozzle”.J. Colloid. Interface. Sci. 336, 634–41.
  9. Maiti S, Ranjit S, Mondol R, Ray S, Biswanath S.2011 “Al+3 ion cross-linked and acetalated gellan hydrogel network beads for prolonged release of glipizide”.Carbohyd. Polym. 85,164–72.
  1. Kim W-T, Chung H , Shin I-S , Yam K L , Chung D. 2008 “Characterization of calcium alginate and chitosan-treated calcium alginate gel beads entrapping allyl isothiocyanate”.Carbohyd. Polym. 71, 566–73.
  2. Costa E, de-Carvalho J, Casimiro T, da Silva C L , Cidade M T, Aguiar-Ricardo A.2011 “Tailoring thermoresponsive microbeads in supercritical carbon dioxide for biomedical applications”.J. Supercrit. Fluids 56, 292–98.
  3. Belyaeva E, Valle D D, Neufeld R J, Ponceleta D. 2004 “New approach to the formulation of hydrogel beads by emulsi&cation/thermal gelation using a static mixer.Chem. Eng. Sci. 59, 2913 – 20.
  4. Chan E-S, Lim T-K, Voo W-P, Pogaku R, Tey B T, Zhang Z. 2011 “Effect of formulation of alginate beads on their mechanical behaviour and stiffness”.Particuol. 9, 228–234.
  5. Almeida P F, Almeida A J.2004 “cross-linked alginate–gelatine beads: a new matrix for controlled release of pindolol”. J. Control. Rel. 97, 431– 39.
  6. Bernardo M V,Blanco M D, Sastre R L, Teijo´n C, Teijo´n J M.2003 “sustained release of bupivacaine from devices based on chitosan”.Il Farmaco 58, 1187-91.

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10.
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Signature of the candidate:
(RAMESH.R.HALLI)
Remarks of the guide: Recommended.
Name And Designation of: MR.J.S.PATIL
11.1 Guide Assistant Professor,
Department of Pharmaceutics,
BLDEA’s College of Pharmacy,
BLDEA’s University campus,
Bijapur-586 103
11.2 Signature
11.3 Co-Guide
NOT APPLICABLE
11.4 Signature
11.5 Head of the department
11.6 Signature
12.1 Remarks of the Principal:
12.2 Signature
Remarks of the Guide:
The present work is aimed to formulate the hydrogel microbeads of the selected anti hypertensive drugs such as Metoprolol.The Metoprololis anti hypertensive drug. Metoprolol is reported to have a short biological mean half life of 3-4 hrs; Hence to conquer this limitation, development of sustained release system for such drugs is necessary. Hence we have selected Metoprolol as model drug for the development. The proposed study can be carried out in the laboratory.
.
Mr. J.S.PATIL
(Research Guide)

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