Formulation and Comparitive Characterization Ofglimepiride Mucoadhesive Microspheres With

“FORMULATION AND COMPARITIVE CHARACTERIZATION OFGLIMEPIRIDE MUCOADHESIVE MICROSPHERES WITH VARIOUS POLYMERS”

MASTER OF PHARMACY DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE.

By

Miss. AYSHA HASSAINAR T

M.PHARM – I

Under The Guidance of

Mr. VIRESH K.CHANDUR,M. Pharm

ASST. PROFESSOR

DEPARTMENT OF PHARMACEUTICS.

SRINIVAS COLLEGE OF PHARMACY, VALACHIL, MANGALORE – 574143

2012-2014

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1. / Name of the Candidate and Address: / MISS. AYSHA HASSAINAR T
1stYEAR M.PHARM,
DEPT. OF PHARMACEUTICS,
SRINIVAS COLLEGE OF PHARMACY,
VALACHIL, MANGALORE-574143.
2. / Name of the Institution: / SRINIVAS COLLEGE OF PHARMACY,
VALACHIL, FARANGIPETE POST, MANGALORE-574143.
3. / Course of Study and Subject: / MASTER OF PHARMACY
PHARMACEUTICS
4. / Date of Admission: / 25-06-2012
5. / Title of the Project:
“FORMULATION AND COMPARITIVE CHARACTERIZATION OF GLIMEPIRIDE MUCOADHESIVE MICROSPHERES WITH VARIOUS POLYMERS”
6.
7.
8. / Brief Resume of the intended work:
6.1 Need of the study:
Oral administration is the most convenient and preferred means of any drug delivery to the systemic circulation1. Oral administration of most of the drugs in conventional dosage forms has short-term limitations due to their inability to restrain and localize at gastro-intestinal tract.2 The drug has to be delivered for a prolonged period of time and many medicines have to be taken simultaneously in case of chronic patients,frequent administrationis necessary when those have shorter half-life. All these leads to decrease in patient compliance. In order to overcome these problems various types of controlled release formulations have been formulated.3
Microparticulate drug delivery systems are considered as a reliable one to deliver the drug to the target site with specificity, to maintain the desired concentration, without untoward effects. It is one of the methods to provide controlled and sustained delivery of drug for long period of time.Desired drug release can be provided by rate-controlling membranes or by implanting biodegradable polymers containing dispersed medication.4
Microspheres are one of the novel drug delivery system which possess several applications and are made up of assorted polymers.5 They constitute an important part of these particulate drug delivery systems by virtue of their small size and efficient carrier capacity. Microspheres are the carrier linked drug delivery system in which particle size ranges from (1-1000 µm) in diameter having a core of drug and entirely outer layers of polymers as coating material. Microspheres can encapsulate many types of drugs including small molecules,proteins, and nucleic acids and are easily administered.Theyare generally biocompatible, can provide high bioavailability, and are capable of sustained release for long period of time.6However the success of these microspheres is limited due to their short residence time at site of absorption.It would therefore be advantageous to have means for providing an intimate contact of the drug delivery system with absorbing gastric mucosal membranes. It can be achieved by coupling mucoadhesion characteristics to microsphere and developing bioadhesivemicrospheres.7
Mucoadhesive microsphere drug delivery systems are delivery system which utilises the property of bioadhesion of certain polymers which become adhesive on hydration and can be used for targeting a drug to particular region of the body for extended period of time.Bioadhesive microspheres can be tailored to adhere to any mucosal tissue including those found in eye, nasal cavity, urogenital tract, the airways, ears etc. Hence mucoadhesive drug delivery systems can be formulated for ocular, nasal, vaginal, rectal,buccal route of administration.7
Advantages of mucoadhesive drug delivery system :-
.

• Provides constant and longer therapeutic effect.
• Reduces the frequency of daily administration and therebyimproves the patient compliance.

• Improves the absorption of drug hence improve the bioavailability of drug and reduce the chances of adverse effects.
• The morphology of microspheres permits a controllable variability in degradation and drug release.
• Cost reductions may be achieved and dose-related side effects may be reduced due to active pharmaceutical ingredient localization at the disease site.8

Glimepiride is a very potent, first III generation sulphonyl urea derivative, used for treating noninsulin dependent type 2 diabetes mellitus. It is used with diet to lower blood glucose level by increasing the secretion of insulin from pancreas and increasing the sensitivity of peripheral tissues to insulin. The mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells, and increasing sensitivity of peripheral tissues to insulin. It likely binds to ATP-sensitive potassium channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Membrane depolarization stimulates calcium ion influx through voltage-sensitive calcium channels. This increase in intracellular calcium ion concentration induces the secretion of insulin. It is having a half -life of about 5 hrs and over 99.5% bound to plasma protein. It is insoluble in water. Different brands of glimepiride tablets available in the market are amaryl, glimpid, glimy.9
Diabetes mellitus type 2 (noninsulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes) is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Type 2 diabetes is due to insufficient insulin production from beta cells in the setting of insulin resistance. Insulin resistance, which is the inability of cells to respond adequately to normal levels of insulin, occurs primarily within the muscles, liver, and fat tissue. It is initially managed by increasing exercise and dietary modification. If blood glucose levels are not adequately lowered by these measures, anti-diabetic medications such as metformin, sulfonylureas, nonsulfonylureasecretagogues, alphaglucosidaseinhibitors, thiazolidinediones, glucagon-like peptide-1 analog, and dipeptidylpeptidase-4inhibitors can be given.10
In the present study, attempt is made to develop mucoadhesive microsphere delivery system of glimepiride using natural and synthetic polymer as a carrier and to improve the therapeutic efficiency.
6.2 – Review of literature:
Kaza R, Pravallika P, Reddy TVR, Naga KRP, Bai B J, JyothiPA , have formulated and evaluated controlled release microspheres of acyclovir sodium. Microspheres were prepared by ionotropicgelation method using different polymers like sodium alginate, HPMC, sodium carboxy methyl cellulose. They concluded that retention time of microspheres at its absorption site was increased.11
Nallasamy V, Perumal S, haveformulated and evaluated stomach specific amoxicillin loaded mucoadhesive microspheres. Microspheres were prepared by solvent evaporation method by using polymers like eudragit, HPMC, carbopol. From the study it has been concluded that bioadhesive property of the microsphere increases with increase in the concentration of the polymer.12
Hardenia SS, Jain A, Patel R, Kaushal A, have formulated and evaluated mucoadhesive microspheres of ciprofloxacin. Microspheres were prepared using ethyl cellulose as polymer by solvent evaporation method. It was concluded from the study that drug release from the formulation depends upon the polymer concentration, RPM and temperature.13
Kalyankar TM, Rangari NT, Khan M, Hosmani A, Sonwane A, have formulated and evaluated mucoadhesive microspheres of pioglitazone HCL. Orifice ionic gelation method was used for the preparation and the prepared microspheres exhibited good mucoadhesive property and the drug release was sustained for more than 12 hours.14
Senthil A, Thakkar HKR, Dave MV, Tejas BL, BattuBL, have formulated and evaluated mucoadhesive microspheres of venlafaxine HCL by simple emulsification phase separation method using glutaraldehyde as across linking agent. It has been concluded from the study that polymer to drug ratio and stirring speed affected the mucoadhession and drug entrapment efficiency of the microsphere. Increasing concentration of cross linking agent had a negative effect on mucoadhesiveness and time had no significant effect.15
Yadav A, Jain DK, haveformulated and evaluatedmucoadhesive microspheres of propranolol hydrochloride byemulsification solvent evaporation method, using HPMC, carbopol, sodium carboxy methyl cellulose as polymers. Study showed that prepared microspheres had good mucoadhesive properties, moreover higher stirring speed of emulsion decreased the particle size and increased the drug release rate of the formulation .16
Bansode DS, Kasture VS, Pawar SS, Kasture SB,have formulated and evaluated telmisartan microspheres by emulsion solvent evaporation technique using ethyl cellulose as polymer.From the study it has been found thatpolymer concentration influences drug loading and drug release from microsphere. Drug entrapment increased with increase in the concentration of the polymers.17
Deshmukh T, Deshmukh V, Jadhav P, Kasat K, Patil R,have formulated and evaluated the mucoadhesive polymers of ziprasidone hydrochloride by ionic cross linking using sodium alginate and HPMC. It has been concluded that the prepared microspheres delivered the drug for a longer period of time and had good mucoadhesive property.18
Ramachandran S, Nandhakumar S, Dhanaraju MD,have formulated and characterized biodegradable microspheres of famotidine cross linked with glutaraldehyde by simple emulsification technique. Study showed controlled delivery of famotidine.19
Gangadhar CB, Sunder SR, VarmaVK, Raju S, Kiran S, have formulated and evaluated indomethacin microspheres using natural and synthetic polymers by solvent evaporation method. It has been found from the study that the drug to polymer ratio and particle size influenced the release of indomethacin from the formulation and were diffusion and dissolution controlled.20
Dhakar RC, Prajapati SK, Maurya SD, Gupta AK, Yadav GK, Dangi G, have formulated and evaluated microspheres of rosiglitazone by emulsification solvent evaporation techniques. Spherical and free flowing microspheres were obtained with good mucoadhesive property and drug release depended on the type of the polymer and size of the microspheres.21
Pachuau L, Sarkar S, Mazumder B,have formulated and evaluated matrix microspheres of salbutamol sulphate and theophylline for simultaneous delivery by emulsion solvent evaporation method using ethyl cellulose as polymerand the formed microspheres had potential for prolonged and simultaneous delivery of the drugs with good entrapment efficiency.22
Reichal RC, Lakshmi JB, Ravi TKhave formulated and evaluated floating tablets of glimepiride by direct compression method using rate controlling polymer carbopol. From the study of physicochemical properties and invitro release characteristics it has been concluded that release of glimepiride prolonged for about 8hrs.23
Hadi MA, Babu VL, Pal Nhave formulated and evaluated sustained release matrix tablet of glimepiride by wet granulation method using a combination of hydrophilic and hydrophobic polymers. From the study it has been concluded that polymers sustained the release of the drug from the formulation for about 12 hrs. and they followed first order release kinetics.24
6.3 – Objectives of the study:
The objective of the study is

• To formulate mucoadhesiveglimepiridemicrospheres with or without cross linking agents of physical or chemical in nature by two formulation methods.

• To compare the efficiency of both natural and synthetic bioadhesive polymers.
• To check drug- excipient interaction.
• Evaluation and characterisation of the prepared glimepiride microspheres.
• Stability studies of the prepared formulations.

Materials and Methods:
Materials:
a)Drug : Glimepiride
b)Polymers:Natural polymers : Sodium alginate, chitosan, rosin, lecithin, etc
Synthetic polymers: poly acrylic acid, carbomer, poly vinyl pyrrolidone etc.
c)Methods: Emulsion solvent evaporation method, ionic gelation method, emulsion cross linking method, emulsion solvent diffusion method,
co-acervation method etc.
d)Equipments: FTIR Spectrometer,USP dissolution test apparatus, scanning electron microscopy,magnetic stirrer, UV etc.
7.1 Source of data:
Review of literature from
a)Journals such as
International Journal of Research in Pharmaceutical and Biomedical sciences.
International Journal of Innovative Pharmaceutical Research.
Iranian Journal of Pharmaceutical Sciences.
Journal of Advanced Pharmacy Education and Research.
International Journal of Pharma World Research.
International Research Journal of Pharmacy.
Asian journal of Pharmacy and Medical Science.
Journal of Applied Pharmaceutical Science.
Current Pharma Research.
Tropical Journal of Pharmaceutical Research.
International Journal of Drug Discovery.
International Journal of Pharma Research and Development
b)Internet Browsing.
c)Laboratory based studies.
7.2 – Method of Collection of Data:
a)An Overview of Microspheres.
b)Preformulation studies.

• Solubility
• λmax
• PH
• Melting point

• F.T.I.R Spectroscopy.

c)Formulation of microspheres.
d)Evaluation of formulated microspheres, as follows:

• Particle size determination.3,13,15,18
• Morphology of microspheres9,11,17 (SEM)
• Micromeritic properties.8,14
• Determination of loading efficiency.14,16,17
• Drug entrapment efficiency.12,14,16
• Swelling index.7,12
• In vitro wash-off test.7,10,15
• In vitro dissolution study.15
• Stability studies as per ICH guidelines.

7.3 Does the study require any investigations or interventions to beconducted on patients or other humans or animals? If so, please describe briefly.
-Not applicable.
7.4Has ethical clearance been obtained from your institution in case of 7.3?
-Not applicable
List of references:

1. Lohani A, Chaudhary GP. Mucoadhesive microspheres: A novel approach to increase gastroretention. Chronicles of young scientist Apr-Jun 2012;3(2):121-28.

1. Kaurav H, HariKumar SL, Kaur A. Mucoadhesive Microspheres as carriers in Drug Delivery: a Review. Int J Drug Dev & Res Apr-Jun 2012;4(2):21-34.

1. Prasanth VV, Chakraborthy A, Mathew ST, Mathapan R. Microspheres: An overview. Int J Res Pharm Biomed SciApr-Jun 2011;2(2):332-38.

1. Prabu S, Shirwaikar SS, Shirwaikar A, Kumar A. Formulation and evaluation of sustained release microspheres of rosin containing aceclofenac. ARS Pharm 2009;50(2):51-62.

1. Garg A, Upadhyay P. Mucoadhesive microspheres: a short review. Asian J PharmClinRes Apr-Jun 2012;5(3):24-27.

1. Kevin K, Pack DW. Microspheres for Drug Delivery. Bio & Biomed Nanotech 2006;1(22):19-50.

1. Parmar H, Bakliwal S, Gujarathi N, Rane B, Pawar S. Different methods of formulation and evaluation of mucoadhesive microsphere. Int J Appl BiolPharmTechnol Nov-Dec 2010;1(3):1157-67.

1. Wise DL. Handbook of pharmaceutical controlled release technology. New York: Marcel Dekker, Inc; 2000:255-65.

1. Glimepiride. [Online] [Cited 2012 Nov 25]; [2 screen] Available from URL://

1. Diabetes mellitus type 2. [Online] [Cited 2012 Nov 23]; [1 Screen] Available from URL://en.wikipedia.org/wiki/diabetes_mellitus_type_2.

1. Kaza R, Pravallika P, Reddy TVR, Naga KRP, Bai BJ, Jyothi PA. Formulation and evaluation of controlled release microspheres of acyclovir sodium. Int JInnovPharm Res 2011;2(1):98-101.

1. Nallasamy V, Perumal S. Formulation and evaluation of stomach specific amoxicillin loaded mucoadhesive microspheres. Iran JPharmSci 2010;6(4):227-33.

1. Hardenia SS, Jain A, Patel R, Kaushal A. Formulation and evaluation of mucoadhesive microspheres of ciprofloxacin. J Adv PharmEduc & Res 2011;1(4)214-24.

1. Kalyankar TM, Rangari NT, Khan M, Hosmani A, Sonwane A. Formulation and evaluation of mucoadhesivepioglitazoneHCl microspheres. Int J Pharm World Res Jun-Sep 2010;1(3):01-14.

1. Senthil A, Thakkar HKR, Dave MV, Tejas BL, BattuBL. Formulation and evaluation of mucoadhesive microspheres of venlafaxineHCl. Int Res J Pharm 2011;2(4):194-99.

1. Yadav A, Jain DK. Formulation and evaluation of mucoadhesive microspheres of propranolol hydrochloride for sustained drug delivery. Asian J Pharm & Med Sci 2011;1(1):01-08.

1. Bansode DS, Kasture VS, Pawar SS, Kasture SB. Formulation and evaluation of telmisartan microspheres by emulsion solvent evaporation technique. JApplPharm Sci 2012;2(10):113-16.

1. Deshmukh T, Deshmukh V, Jadhav P, Kasat K, Patil R. Formulation and evaluation of mucoadhesive microspheres of ziprasidone hydrochloride for oral controlled release. CurrPharmRes 2012;2(2):497-502.

1. Ramachandran S, Nandhakumar S, Dhanaraju MD. Formulation and characterization of glutaraldehyde cross-linked chitosan biodegradable microspheres loaded with famotidine. Trop J Pharm Res 2011;10(3):309-16.

1. Gangadhar CB, Sunder SR, VarmaVK, Raju S, Kiran S. Formulation and evaluation of indomethacin microspheres using natural and synthetic polymers as controlled release dosage forms. Int J Drug Discov 2010;2(1):08-16.

1. Dhakar RC, Prajapati SK, Maurya SD, Gupta AK, YadavGK,Dangi G. Rosiglitazone maleate microspheres for extending drug release: formulation and evaluation. Int J Pharm Res & Dev 2010;2(10):56-65.

1. Pachuau L, Sarkar S, Mazumder B. Formulation and evaluation of matrix microspheres for simultaneous delivery of salbutamol sulphate and theophylline. Trop J Pharm Res 2008;7(2):995-1002.

1. Reichal RC, Lakshmi JB, Ravi TK. Studies on formulation and invitro evaluation of glimepiride floating tablets. J ChemPharm Res 2011;3(3):159-64.

1. Hadi MA, Babu VL, Pal N.Formulation and evaluation of sustained release matrix tablets of glimepiride based on combination of hydrophilic and hydrophobic polymers. J ApplPharmSci 2012;2(6):101-07.

9. / Signature of the candidate / (AYSHA HASSAINAR T)
10. / Remarks of the Guide / The work, which is assigned to
Miss. AYSHA HASSAINAR T is under my guidance.
11. / 11.1 Name and Designation of the
Guide / Mr.VIRESH K.CHANDUR,M.Pharm, Asst prof
Department of Pharmaceutics
Srinivas College of Pharmacy
Valachil, Mangalore- 574143
11.2 Signature / (Mr. VIRESH K.CHANDUR)
11.3 Name and Designation of the
Co-Guide / ------
11.4 Signature / ------
11.5 Head of the Department / Dr. A. R. SHABARAYA M.Pharm.,Ph.D.
HOD and Principal
Department of Pharmaceutics,
SrinivasCollege of Pharmacy,
Valachil, Mangalore- 574143
11.6 Signature / (Dr. A. R. SHABARAYA)
12. / 12.1 Remarks of the Principal / Recommended and forwarded for favourable consideration.
12.2 Signature / Dr. A.R. SHABARAYA