FORMULATION AND EVALUATION OF metformin hydrochloride microspherEs using

IONotropIC GELATION TECHNIQUE

DISSERTATION PROTOCOL

Submitted to the

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCE,KARNATAKA

BANGALORE

BY

ABHIJITH G. DESHPANDE

M.PHARM, PART- I DEPARTMENT OF PHARMACEUTICS

UNDER THE GUIDANCE OF

Dr. RAVADA RAMESH, M.Pharm, Ph.D.

PROFESSOR

DEPARTMENT OF PHARMACEUTICS

Dr.H.L.T College of Pharmacy,

Kengal, Channapatna-562 161

2011-2012

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1. / Name of the candidate andaddress /

mr. abhijitH g. deshpande

DEPARTMENT OF pharmaceutics, Dr. H.L.T. COLLEGE OF PHARMACY, KENGAL, CHANNAPATNA- 562 161, RAMANAGARA (Dist), KARNATAKA
2. /

Name of the institution

/ Dr. H.L.T. COLLEGE OF PHARMACY, KENGAL, CHANNAPATNA- 5621 161, Ramanagara (Dist), KARNATAKA.
3. /

Course of study & subject

/ Master of Pharmacy in Pharmaceutics.
4. /

Date of admission to course

/ 17/12/2011
5. /

Title of the topic

FORMULATION AND EVALUATION OF metformin hydrochloride microspherEs using
IONotropIC GELATION TECHNIQUE

6. Brief resume of the intended work :

6.1 Need for the study:

Despite tremendous advancement in the drug delivery system, oral route remains the preferred route for the administration of therapeutic agents and because of low cost therapy and ease of administration leads to higher levels of patient compliance. Conventional oral dosage forms such as tablets and capsules provide specific drug concentration in systemic circulation without offering any control over drug delivery and also cause great fluctuations in plasma drug levels. The design of oral controlled drug delivery system should be primarily aimed to achieve more predictable and increased bioavailability. An incomplete release of the drug and shorter residence time of the dosage forms in the upper GIT, which is a prominent site for the absorption of many drugs, leads to decreased bioavailability1.

Numerous approaches have been investigated for formulation of controlled release dosage forms of different therapeutic agents. Microencapsulation has become a common technique in the production of controlled release dosage forms. Microcapsules can provide sustained release properties and a more uniform distribution of drugs, including within the gastrointestinal tract. Furthermore bioavailability of drugs formulated in microcapsules can be enhanced.

Ionotropic gelation is based on the ability of polyelectrolytes to cross link in the presence of counter ions to form hydrogel. Since the use of alginates,HPMC K15M, sodium alginate, chitosan, calcium choloride, potassium chloride, acetone etc., for the encapsulation of drug and even cells, Ionotropic gelation technique has been widely used for this purpose2.

Most of oral antidiabetics have biological half life ranging from 1.5 to 6.5 and require frequent administration i,e twice to thrice a day and there is a fluctuation in plasma concentration during medication3.

Metformin Hydrochloride(anti diabetic drug) is a water soluble drug with a short biological half life of 1.5 to 4.9 hours and suitable dosage regimens of the drug include unit doses of 500 mg two to three times daily and can even be built up to five times daily or 850 mg once or twice daily. These are good candidates for controlled release formulations.

The present work is aimed at the development and evaluation of controlled release microcapsules for Metformin hydrochloride using HPMC K15M, sodium alginate, chitosan, calcium choloride, potassium chloride, acetone etc.

Advantages of Microencapsulation: -

  1. Taste and odour masking of drug.
  2. Protection of drug against the environment (moisture, light, heat and oxidation).
  3. To increase the patient compliance.
  4. To reduce the dose frequency.
  5. To have better therapeutic efficacy.
  6. To reduce the fluctuation in plasma drug concentration.
  7. To decrease the side effects.

6.2. Review of Literature:

  1. MD Sarfaraz et al., were formulated and evaluated Rifampicin biodegradable microcapsules by feasible emulsification-ionic gelation method for a novel controlled release product. Sodium alginate, carbopol974p were used as a coating polymers in different ratios1:1, 1:2, 1:3 and 1:4 to obtain elegant microcapsules. The formulations were characterized for encapsulation efficiency, drug loading, sieve analysis, scanning electron microscopy and In –vitrorelease.The microcapsules were discrete,large,almost spherical and free flowing with the encapsulation efficiency with the range of 75% to 89% extended over longer periods of time, drug loding 75% to 86% and size 440µm to 500µm. Refampicin release from these microcapsules was slow and extenended over longer period of time depending on polymer coat.Drug release was diffusion controlled and followed first order kinetics.The formulation MC with a coating ratio of1:1 was found to be suitable for controlled release4.
  1. KalyRashmi Boppana et al., were formulated and evaluated Carboxymethylcellulose based hydrogel micro beads loaded with Simvastatin using ionotropic gelation method. The beads were characterized by differential scanning calorimetric (DSC) analysis, and scanning electron microscopy (SEM). DSC studies confirmed the amorphous dispersion of the drug in the hydrogel matrix. The effect of cross linking agent and polymer concentration on drug release was studied. Increase in concentration of crosslinking agent and polymers decreased release rate of simvastatin.The release data were fitted to an empirical equation to determine the transport mechanism. Drug release followed anomalous/non-fickian transport mechanism5.
  1. P. S.Goudanavar et al., were formulated and evaluated sustained release oral product namely microbeads for Diclofenac sodium by Ionotropic gelation technique using Sodium alginate alone and combination with Hydroxypropyl methyl cellulose,Chitosan, Pectin as release rate modifiers, and investigated for flow behavior, particle size, swellingproperties, surface study by SEM, and In -vitro drug release potential.While increase in the concentration of sodium alginate and other polymer dispersions increased sphericity,size distribution, mean partical size. Drug entrapment approached nearly 95%.The mechanism of drug release from micro beads was found to be followed super case-II transport6.
  1. A.V Yadav et al.,were formulated and evaluated Aceclofenac as novel enteric microcapsules for improved delivery to the intestine using the polymer ethyl cellulose as the retardant material. Aceclofenac was used as core and microcapsules were prepared by anemulsion solvent evaporation method. The prepared microcapsules were evaluated for size analysis, drug content,encapsulation efficiency, wall thickness, optical microscopy and drug release characteristics7.
  1. Farhana SA et al.,were formulated and evaluated sustained release micro capsules of Verpamil hydrochloride (VH) using biodegradable polymers. For this purpose microcapsulses embedded Verpamil hydrochloride were prepared using sodium alginate alone and also by incorporating some co polymers like methyl cellulose, sodium corboxy methyl cellulose,polyvinyl pyrollidone and xanthan gum by employing complex emulsion method microencapsulation.Microcapsulse were prepared in various core:coat ratios to know the effect of polymer and co polymer on drug release. Over all ten formulations were prepared evaluated for flow property,sieve analysis,drug entrapment efficiency,In-vitro dissolution studies,stability studies,including scanning electron microscopy and DSC.The resulting microcapsulses were discrete,large,spherical and also free flowing.Fom the study it was concluded that,sustained release verpamil hydro chloride microcapsulses could be achived with successes using sodium alginate alone and also combination with other biodegradable polymers8.
  1. P.Venkatesan et al., were formulated and evaluated and highlight the potential of microencapsulation technique as a vital technique in novel drug delivery9.
  1. D.Worthen et al.,were formulated and evaluated microcapsules using Methyl salicylate as a model flavoring agent, a primary flavor emulsion was prepared in a 1.25 % w/v solutioncontaining one of a series of hydrophilic polymers, including PVA, HPMC and PEG.The rate of methyl salycilate from calcium alginate beads was approximately 25% of the control.Methyl salicylate release was also 6 fold slower from the aluminium alginate beads as compared to control10.
  1. Sing-Muk Nga,C,Det al., were formulated and evaluated Microencapsulation of drugs into solid biodegradable polymeric microspheres via solvent evaporationtechnique remains challenging with those having low molecular weight and high hydrophilicitynature.They presents an efficient encapsulation protocol for this group of drugs,demonstrated using hydrogen peroxide as a model compound that is encapsulated in to poly microspheres. Hydrogen peroxide can be employed as antiseptic agent. The new encapsulation technique was developed based on the modification of conventional double emulsion and solvent evaporation protocol with a backward concentration gradient of hydrogen peroxide.Evaluation on the encapsulation efficiency and release profile has been indirectly by monitoring dissolved oxygen level of the solution where the microspheres were incubated11.
  1. Abhishek Pandey et.al.,were studied formulation and evaluation of pioglitazone hydrochloride microsphers using ionotropic gelation technique The objective of the present study is to prepare sustained-release Pioglitazone Hydrochloride microspheresin different ratios by calcium chloride cross-linking method using iontropic gelation method. The prepared Microsphers were evaluated for Compatibility study, Drug Entrapment Efficiency, In-vitroDissolution, Scanning Electron Microscopy, DSC method. Among the six formulations prepared andevaluated F5 are found to show satisfactory results. The Prepared Microsphers shows entrapment efficiencyof 69.62% to 91.25% and % yield value from 72% to 90%. Infrared spectroscopy confirmed the absence ofany Drug-Polymer interaction. In-vitro release of Optimize batch (F5) was carried out in 7.4 pH phosphatebuffer solution shows 92 % release up to 12 hour12.
  1. Garud Navneet et.al.,.were studied Formulation design and in-vitro evaluation of metformin microspheres using ionotropic gelation technique Metformin hydrochloride microspheres were prepared by ionotropic gelation method using non-ionic (ethylcellulose and HPMC), anionic (Carbopol 934P) and cationic (chitosan) polymers,The prepared microspheres were studied for their morphology, average particle size, % drug content, % drug entrapment, % yield and micromeritic properties. Ethylcellulose microspheres showed least swelling andmucoadhesion property in both simulated gastric pH and simulated intestinal pH medium depicting its non-mucoadhesive nature. The microspheres prepared at 10% calcium chloride concentration and 1:3 drug:polymer ratio showed the most sustained effect13.
  1. Ashok kumar A et.al., were studied Formulation and evaluation of mucoadhesivemicrocapsules of metformin hydrochloride with gum karaya using ionotropic gelation techniquewith a coat consisting of alginate and Gum Karaya by employingIonotropic Gelation process and Emulsification Ionotropic Gelationprocess. The microcapsules wereevaluated for flow properties, Carr’s index, hausner ratio, micro‐encapsulation efficiency, drug release characteristics, surface characteristics; compatibility studies and mucoadhesive properties. Among the two methods Emulsification Ionotropic Gelation method was found to be more suitable for Controlled release of Metformin HCl over a long period of time. These microcapsuleswere subjected to in‐vitro wash‐off test and exhibited good mucoadhesive property14.

6.3 Objectives of the Study:

The present work is planned with the following objectives.

  1. To prepare metformin hydrochloeride entrapped microcapsules using polymers like HPMC K15M, sodium alginate, chitosan, calcium choloride, potassium chloride, acetone by ionotropic gelation technique
  2. To evaluate the formulation for drug entrapment efficiency,drug polymer interaction,nature of drug in the formulation, and surface morphology.
  3. To study the In-vitro drug release from the prepared microcapsules using dissolution test apparatus.
  4. The stability studies of optimized formulations will be carried out as per ICH guidelines and data will be collected.

7. Materials and Methods:

Materials:-

1)Drug: Metformin Hydrochloride.

2)Polymers:HPMC K15M, sodium alginate,chitosan, calcium choloride, potassium chloride, acetone etc.

Method:-

  • Preparation of microcapsules by Ionic Gelation Technique.
  • Evaluation: percentage yield, Drug loading and encapsulation efficiency, In-vitrodrug release studies, Comparison of dissolution profiles, Stability studies of the optimized formulation.

7.1 Source of Data:

The preliminary data required for the experimental study was obtained from:

  1. CD-Rom search available at National Center for Scientific Information (NCSI). Indian Institute of Sciences, Bangalore; Dr.H.L.T. college of pharmacy library; Scientific abstracts; Journals; Internet sources; Relevant books.
  2. The data will be collected by laboratory investigationat Pharmaceutics Department Laboratory of Dr. H.L.T.College of pharmacy and recording observation. Microcapsules shall prepare by using suitable methods.

7.2Method of collection of data : (Including sampling procedure, if any)

  1. The Metformin Hydrochloride entrapprd microcapsules will be prepared by ionotropic gelation method using polymers like HPMC K15M, sodium alginate, chitosan, calcium choloride, potassium chloride, acetone etc.
  2. The formulation will be charractrized by Differential scanningcalorimetery(DSC), Infrared Sprectroscopy(FTIR), 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.

7.3 Does the study require any investigation or intervention to be conducted on patients or

other humans or animals? If so, please mention briefly.

Not applicable.

7.4 Has ethical clearance been obtained from your institution in case of 7.3?

- Not applicable -

  1. List of References :
  1. Poonam Salunke, Bhushan Rane, Sunil Bakliwal, Sunil Pawar.Journal of Pharmaceutical Science and Technology,2010; Vol. 2 (6): 230-240.
  2. J.S.Patil, M.V.Kamalapur, S.C.Marapur, D.V.Kadam.Digest Journal of Nanomaterials and Biostructures, 2010 ; Vol. 5(1): 241 – 248.
  3. Sundram, C.R.Ananda Moses, S.hango,V.Seshiah.INT. j.Diab.Dev. countries 1998;18:40-43.
  4. M.D.Sarfaraz,D.Hiemath and K.P.R.Chowdary. formulation and evaluation of rifampicin biodegradable microcapsules by feasible emulsification ionc gelation method. Indian journal of pharmaceutical science, 2010; 72(1):101-105.
  5. KalyRashmi,Boppana, Raghavendra, and Navanath ane. Formulation and evaluation of carboxy methyl cellulose based on hydro gel microbeads loaded with simvastatin using ionotropic gelation method.Acta Pharmaceutica Sciencia, 2010;52: 137-143.
  6. P.S.Goudanavar, R.S.Bagali, Chandrashekhara.S and S.M.patil. formulation and evaluation ofsustained release of micro beads for Diclofenac sodium by ionotropic gelation technique.Internatioal journal of pharma and Bio Sciences, 2010;1(2):1-10.
  7. A.V Yadav , A.S.Shete, A.P.Dabke and V.R. Shinde. Formulation and evaluation of aceclofenac as novel enteric microcapsules.InternationalJournal of PharmTech researchcoden, 2009; 1(2): 135-138.
  8. Farhana S.A,SanthakumarS.M,Shylaes,Shalam M,Narasu L. formulation and evaluation of sustained release microcapsules of verpamil hydrochloride.curr Drug Delive,2010 ;7(2):98-110.
  9. P.Venkatesan, R.Manavalan and K.Valliappan.Venkatesan P ..J. Pharm. Sci. & Res, 2009; 1(4): 26-35.
  10. D.Worthen, D.Johnson, P.DeLuca. formulation and evaluation of microcapsules using methyl salicylate as a model flavouring agent. Lexington, KY 40536 USA.,Swedish Match NorthAmerica, Inc., Owensboro, KY 42302 USA.
  11. Sing-Muk Nga,C,D, Jeong-Yeon Choia,d, Hyung-Soo Hanb,d, Jeung-Soo Huhc,, Jeong Ok Lima Novel. Formulation and evaluation of microencapsulation of drug into solid biodegradable polymeric microspheres. International Journal of Pharmaceutics, 2010;384:120–127.
  12. Abishek pandey, vivek singh Bhadoria formulation and evaluation of pioglitazone hydrochloride microsphers using ionotropic gelation technique. Pharmacia, 2011; 1(2): 67-75.
  13. Garud Navneet,Garud Akanksha,Jain Neetesh.Formulation design and in-vitro evaluation of metformin microspheres using ionotropic gelation technique.Journal of Pharmacy Reseach,2011;4(7): 2103-2106.
  14. Ashok kumar.A, Balakrishna.T, Rajiv jash, K.Murthy, Anil kumar.A.Sudheer..Formulation and evaluation of mucoadhesive microcapsules of metformin hydrochloride using gum karaya. International Journal of Pharmacy and Pharmaceutical Sciences,2011;3(3): 150-155.
  15. Sundram, C.R.Ananda Moses, S.Hango,V.Seshiah.International Journal of Pharmaceutics,2010; 382: 140–146
  16. Silvina A,Bravo, R,Claudio J.Indian journal of Pharmaceutic.sci2002;513-519.
  17. M. A. Altaf, et al, Sreedharan and N. Charyulu.Indian Journal of Pharmaceutiical Sciences, 2008;70(5): 655-658.
  18. Payam Khazaeli, Abbas Pardakhty and Fereshteh Hassanzadeh.Iranian Journal of Pharmaceutical Research, 2008;7(3): 163-170.
  19. V.R.Sinhaet al, A.K Singla, S.Wadhawan, R. Kaushik, R.Kumria, K Bansal, S. Dhawan. International Journal of Pharmaceutics,2004;274:1–33.
  20. Ilic, R.Dreu,, M.Burjak, M.Homar, J.Kerc, S.Srcic. International Journal of Pharmaceutics,2009;381:176–180.
  21. P.M.Dandagi, F.V.Manvi, A.P.Gadad, V.S.Masthiholimath, M.B.Patil, V. Balamuralidhara. Indian Journal of Pharmaceutiical Sciences, 2004; 66 (5): 631-635

9. /

Signature of candidate

10. /

Remark of the guides

/

The above given information is true and this work will be done under my guidance.

11. / Name & Designation of ( in block letters)
11.1. Guide / Dr. RAVADA RAMESH M.Pharm, Ph.D.
PROFESSOR DEPARTMENT OF PHARMACEUTICS Dr.H.L.T. COLLEGE OF PHARMACY KENGAL, CHANNAPATNA- 562 161RAMANAGARA.KARNATAKA
11.2 Signature
11.3 Co-guide (if any) / ------
11.4 Signature / ------
11.5 Head of the Department / Dr. RAVADA RAMESH,M.Pharm, Ph.D.PROFESSOR DEPARTMENT OF PHARMACEUTICSDr.H.L.T. COLLEGE OF PHARMACYKENGAL, CHANNAPATNA-562 161 RAMANAGARA (Dist)KARNATAKA.
11.6 Signature
12. / 12.1Remarks of the Chairman and Principal / The above-mentioned information is correct and I recommend the same for approval.
12.2 Signature

From

Abhijith G. Deshpande

M.Pharm, Part I

Department of Pharmaceutics ,

Dr.H.L.T.College of Pharmacy,

Kengal, Channapatna,-562 161.

Ramanagara (Dist)

To

The Registrar (Evaluation),

Rajiv Gandhi University of Health Sciences,

4th ‘‘T’’ Block, Jaynagar,

Bangalore-560 041

(Through Proper Channel)

Sub: Submission of Synopsis of Dissertation

Respected Sir,

Herewith, I am submitting synopsis of dissertation work FORMULATION AND EVALUATION OF metformin hydrochloridemicrospherEs using IONotropIC GELATION TECHNIQUEfor registration in M.Pharm (Pharmaceutics) of RajivGandhi University of Health Sciences, Bangalore, Karnataka.

Kindly accept the same and acknowledge.

Thanking you,

Yours Faithfully,

(ABHIJITH G. DESHPANDE)

Place: Channapatna

Date:

Guide:

Dr. RAVADA RAMESH M.Pharm,Ph.D. PROFESSOR PRINCIPAL. Dr.HL.T.College of Pharmacy Dr.H.L.T.College of pharmacy Kengal-Channapatna-562 161 Kengal-Channapatna-562 161 Ramanagar(Dist), Karnataka Ramanagar(Dist), Karnataka

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