Development And In-Vitro Evaluation Of Gastro-Retentive Cefpodoxime Proxitle Floating Microspheres

FORMULATION AND EVALUATION OF MUCOADHESIVE BUCCAL TABLETS OF REPAGLINIDE

M.Pharm. Dissertation Protocol Submitted to the

Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka.

Miss. MEGHNABAHEN C. PATEL B.Pharm

Under the esteemed guidance of

Dr. Chandrashekar C. Patil M.Pharm, Ph.D Professor Department of Pharmaceutical Technology B.L.D.E.A’S COLLEGE OF PHARMACY, BIJAPUR-586103. 2012-2013 Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka.

ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. Name of the Candidate and Address Miss. MEGHNABAHEN C. PATEL (In block letters) B.L.D.E.A’s College Of Pharmacy, Bijapur-586 103 2. Name of the Institution B.L.D.E.A’S College Of Pharmacy, B.L.D.E.A’s University Campus, 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 FORMULATION AND EVALUATION OF MUCOADHESIVE BUCCAL TABLETS OF REPAGLINIDE 6. Brief resume of the intended work : ENCLOSURE-I 6.1 Need for the study

ENCLOSURE-II 6.2 Review of literature

ENCLOSURE-III 6.3 Objectives of the study

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.

7.4 Has ethical clearance been obtained from your institution in case of 7.3 : NO 8. List of References (about 4-6) : ENCLOSURE-V

9. Signature of candidate

10. Remarks of the guide ENCLOSURE-VI 11. Name & Designation of (in block letters)

11.1 Guide Dr. Chandrashekar C. Patil M.Pharm, Ph.D Professor Department Of Pharmaceutical Technology B.L.D.E.A’s College Of Pharmacy, Bijapur-586 103

11.2 Signature _ 11.3 Co-Guide (if any) _ 11.4 Signature Dr. Raghvendra V. Kulkarni M.Pharm, Ph.D 11.5 Head of Department Professor & Head Department Of Pharmaceutical Technology B.L.D.E.A’s College Of Pharmacy, Bijapur-586 103

11.6 Signature

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

In common, the delivery of a drug requires some type of dosage form, present in the oral cavity, to release a drug, which then diffuses through the mucosa into the local blood flow and is then taken added to the systemic blood circulation1. Within the oral mucosal cavity, the buccal region offers an attractive route of administration for controlled systemic drug delivery. Buccal delivery is the administration of drugs through the mucosal membrane lining the cheeks2. The buccal route has been advocated as a possible route of administration for drugs which undergo extensive hepatic first pass metabolism or which are susceptible to degradation in the gastrointestinal tract3. Buccal drug delivery is a highly effective way to improve bioavailability. This is because the buccal mucosa has a rich blood supply which facilitates direct entry of drug molecules into the systemic circulation. Buccal drug delivery is well accepted by patients as the buccal cavity is easily accessible for self-medication. In addition, buccal dosage forms allow drug absorption to be rapidly terminated in case of an adverse reaction4. Repaglinide is an oral antidiabetic drug, administered in patients with type 2 diabetes mellitus, it is having very low water solubility (34 μg/mL at 37°C) and high lipophilicity (logP = 3.97)5. It has an extremely short biological half life of 1 h6. In addition, the oral bioavailability of Repaglinide is low (56 %) due to extensive hepatic first-pass effect. It has melting point of 130-131°C and mol. wt. is 452.587. It is poorly soluble in water and belongs to biopharmaceutical classification system (BCS) class II, having low solubility and high permeability8-9. Poor solubility in gastrointestinal fluids causes variations in its dissolution rate which leads to incomplete bioavailability10. Hence to improve the bioavailability and drug instability in the GIT, an attempt will be made to present the drug in the form of mucoadhesive buccal tablets.

ENCLOSURE-II 6.2 REVIEW OF LITERATURE

1) Ìkinci G et al., have developed Buccal bioadhesive tablet of nicotine into the oral cavity. The tablets were prepared by using Carbomer (Carbopol®974P NF) (CP) and alginic acid sodium salt (NaAlg) were used as bioadhesive polymers in combination with hydroxypropyl methylcellulose (HPMC) at different ratios. Magnesium carbonate was incorporated into the formulations as a pH increasing agent. In-vitro release and bioadhesion studies were performed on the developed tablets. In the formulations containing CP:HPMC, the NHT released increased with the increasing HPMC concentration whereas a decrease was observed with increasing HPMC concentration in formulations containing NaAlg:HPMC. The bioadhesive properties of the tablets containing NaAlg:HPMC was not affected by the concentration of the NaAlg (P > 0.05) but increased significantly with the increasing CP concentration (P < 0.05). A decrease in pH of the dissolution medium to acidic values was avoided by incorporation of magnesium hydroxide into the formulations. The developed formulations released NHT for 8 h period, and remained intact except for the formulation containing CP:HPMC at 20:80 ratio11.

2) Kumar G et al., have developed Muccoadhesive buccal tablet of caffeine. In this study, a bioadhesive dosage form of caffeine anhydrous was designed using a combination of bioadhesive polymers (sodium carboxymethyl cellulose Carbopol 934P and Hydroxypropyl methyl cellulose) in different ratios. The bioadhesive strength was evaluated by measuring the force required to detach the tablets from sheep buccal mucosal membrane. Carbopol 934P showed maximum bioadhesion and required maximum force for detachment of the force required for detachment was directly proportional to its content. The formulation were tested for their swelling behavior using the agar gel plate method in which formulations containing sodium carboxymethyl cellulose and Carbopol 934P and was found to swell to a greater extent than those containing sodium carboxymethyl cellulose and Hydroxypropylmethyl cellulose. In-vitro release studies showed that the formulation consisting of 3:1 ratio of sodium carboxymethyl cellulose and Carbopol 934P/sodium released Caffeine over 8 h. The dissolution profiles before and after storage were similar; suggesting good stability of mucoadhesive buccal tablets prepared using a combination of Carbopol 934P and sodiumcarboxymethyl cellulose12.

3) Giunchedi P et al., have developed buccal tablets of chlorhexidine diacetate using drug loaded chitosan microsphere. The microparticles were prepared by a spray- drying technique, their morphological characteristics were studied by scanning electron microscopy and the in-vitro release behaviour was investigated in pH 7.0 USP buffer. Chlorhexidine in the chitosan microspheres dissolves more quickly in- vitro than does chlorhexidine powder. The anti-microbial activity of the microparticles was investigated as minimum inhibitory concentration, minimum bacterial concentration and killing time. The loading of chlorhexidine into chitosan is able to maintain or improve the anti-microbial activity of the drug. The improvement is particularly high against Candida albicans. This is important for a formulation whose potential use is against buccal infections. Drug-empty microparticles have an anti- microbial activity due to the polymer itself. Buccal tablets were prepared by direct compression of the microparticles with Mannitol alone or with sodium alginate. After their in-vivo administration the determination of chlorhexidine in saliva showed the capacity of these formulations to give a prolonged release of the drug in the buccal cavity13.

4) Tsutsumi K et al., have developed Buccal tablets of ergotamine tartrate (ET) combined with polyvinyl alcohol (PVA) gel brought about higher plasma concentration of ET compared with that of oral administration of capsules in guinea- pigs. Tmax of ET in plasma of buccal administration was significantly smaller than that of oral administration. For the buccal dosage form of ET, the bioadhesive tablet system (BTS) was newly developed. It consisted of a reservoir of drug and an adhesive region. BTS showed better absorption of ET compared with PVA gel in guinea pigs. Among several pharmaceutical bases in the reservoir of BTS, Witepsol W-35 was most effective. It is likely that the high lipophilic property of Witepsol W- 35 in which ET was dissolved facilitated the drug release by its relatively low melting point (around 35 °C), consequently a rapid absorption. In addition, the enhancing activity of the cod-liver oil extract (CLOE) in hydrophilic ointment on the in-vivo buccal ET absorption was clarified to be comparable to that in the in-vitro study utilizing the keratinized epithelial-free membrane (KEF-membrane) of the hamster cheek pouch14.

5) Park CR et al., have developed Bilayer mucoadhesive tablets of nicotine were prepared and evaluated to determine the suitability of the formulation as a nicotine replacement product to aid in smoking cessation. A range of formulations containing 0–50% w/w Carbopol 934® and 0–50% w/w hydroxypropylcellulose (HPC) were prepared and tested for adhesive properties and drug release. Mucoadhesion was assessed using bovine buccal mucosa. Peak detachment force of the tablets was found to reach a maximum at 20% w/w Carbopol 934®, whilst work of adhesion continued to increase with Carbopol 934® concentration. HPC concentrations of 20–30% w/w were found to provide nicotine hydrogen tartrate (NHT) release approaching zero order kinetics over a 4 h test period. A combination of 20% w/w Carbopol 934® and 20% w/w HPC was thus found to provide suitable adhesion and controlled drug release. The formulation of a bilayer tablet containing the adhesive controlled release layer (CRL) and a fast releasing layer provided an initial burst release of NHT followed by the controlled release for a period of up to 4 h. The same biphasic type of release was identified during an in-vivo assessment using human volunteers This biphasic drug release could represent an improvement over current methods of nicotine replacement15.

6) Balamurugan M et al., have developed Mucoadhesive buccal tablet of Domperidone. The tablets were prepared by using mucoadhesive polymers like Carbopol 934P, Methocel K4M, MethocelE15LV and Chitosan. Tablets were prepared by direct compression method using polymer in different ratios. The formulations were characterized for swelling index, in-vitro bioadhesion strength and in-vitro release studies. The best mucoadhesive performance and in- vitro drug release profile were exhibited by the tablet containing chitosan and Methocel K4M in ratio of 1:1. It was observed that the optimized formulation follows Hixson Crowel release kinetics16. ENCLOSURE-III

6.3 OBJECTIVES OF THE STUDY

The present work is planned with the following objectives.

The aim and objectives of the study are

 Preparation of standard calibration curve of Repaglinide.

 To prepare mucoadhesive buccal tablets by wet granulation method using polymers

like chitosan, guar gum, HEC, carbopol, etc.

 Drug-excipients compatibility study by FTIR spectrophotometer.

 To characterize the formulation for thermal behavior (DSC) and scanning electron

microscopy (SEM) of the optimized formulation.

 To perform evaluation parameters like

1. Appearance, thickness, hardness, weight variation and friability test.

2. Drug content uniformity.

3. Bioadhesion.

4. In vitro drug release study using USP XXIII model (Electro Lab, TDT

06P) of different formulation and analyzed them using UV-Visible

spectrophotometer at 284 nm.

5. Swelling index.

6. In vitro residence time.

7. In vitro permeation studies of the optimized formulation.

8. Accelerated stability studies of the optimized formulation. ENCLOSURE-IV

7. MATERIALS AND METHODS

7.1 Source of data

Studies on design of repaglinide buccal tablets are laboratory based. The data will be collected by performing various laboratory experiments, referring journals, text books and other literatures.

7.2 Method of collection of data

The whole data is planned to collect from laboratory experiments which includes the following,

1) Preparation of repaglinide mucoadhesive tablets by using different polymers by wet

granulation method.

2) Compatibility study of drug with various polymers will be carried out by using

Fourier transform infrared spectrophotometer (FTIR-8400 S Shimadzu, Japan)

3) Evaluation parameters such as, appearance, thickness, hardness, weight variation test,

friability test, drug content uniformity, bioadhesion, in-vitro dissolution studies,

swelling index, in-vitro residence time.

4) In-vitro permeation studies will be carried out for the optimized formulation.

5) The stability studies of the formulations will be carried out as per ICH guidelines and

data will be collected. 7.3 Dose the study requires any investigation or intervention to be conducted on patient or other human or animal? If so please describe briefly.

----Not under the plan of work----

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

------Not applicable------ENCLOSURE-V

8) List of References

1. Patel A.R., Patel D.A., Chaudhry S.V., 2011 “Muccoadhesive buccal drug delivery system”. Int. J. Pharm. Life Sci. vol.2, 848-856.

2. Venkatalakshmi R., Sudhakar Y., Chetty C.M., Sasikala C., Varma M.M., 2012 “Buccal drug delivery using adhesive polymeric patches”. Int. J. Pharm. Sci. Res. Vol. 3, 35-41.

3. Martin L., Wilson C.G., Koosha F., Uchegbu I.F., 2003 “Sustained buccal delivery of the hydrophobic drug denbufylline using physically cross-linked palmitoyl glycol chitosan hydrogels”. Eur. J. Pharm. Biopharm.55, 35-45.

4. Pendekal M.S., Tgginamat P.K., 2012 “Formulation evaluation of a bioadhesive patch for buccal delivery of Tizanidine”. Acta Pharm. Sinica B 2, 318-324.

5. Nicolescu C., Aramă C., Nedelcu A., Monciu C.M., 2010 “Phase solubility studies of the

Inclusion complexes of Repaglinide With β-cyclodextrin and Β-cyclodextrin derivatives,

Farmacia”. FARMACIA, Vol.58, 5.

6. Satyabrata B., Ellaiah P., Kumar S.M., Pravind S., Bhusan P.B., Debajyoti D., 2010

“Design and in-vitro evaluation of mucoadhesive buccal Tablets of Repaglinide”. Int. J.

Pharma. Sci. Tech., Vol-4, 42-53.

7. Prajapati S.T., Patel C.G., Patel C.N., 2011 “Formulation and Evaluation of Transdermal

Patch of Repaglinide”. ISRN Pharm., 9.

8. Ramanjireddy T., Dhachinamoorthi D., Chandrasekhar K.B., 2012 “Pharmacokinetic study of Repaglinide floating drug delivery system in rabbits by RP HPLC method”. J. Chinese

Pharm. Sci.21, 162-168.

9. Ramanjireddy T., Dhachinamoorthi D., Chandrasekhar K.B., 2011 “Study on enhancement of mean residence time of Repaglinide floating drug Delivery system by rabbit model”. Med.

Data, vol.3, 335-340. 10. Shams T., Sayeed M.S.B., Kadir M.F., Khan R.I., Jalil Reza-ul, Md. Islam S., 2011

“Thermal, infrared characterization and in-vitro evaluation of Repaglinide solid dispersion”.

Sch. Res. Lib., Der. Pharm. Lettre, 3, 142-150.

11. Ìkinci G., Senel S., Wilson C.G., Sumnu M., 2004 “Development of a buccal bioadhesive nicotine tablet formulation for smoking cessation”. Int. J. Pharm. 277, 173-178.

12. Kumar G., Gauri S., Hooda A., Saini S., Garg A., 2011 “Fabrication and evaluation of flavoured mucoadhesive buccal Tablet of caffeine as cns stimulant”. Int. J. Uni. Pharm. life sci. Vol.1, 85-97.

13. Giunchedi P., Juliano C., Gavini E., Cossu M., Sorrenti M., 2002 “Formulation and in- vivo evaluation of chlorhexidine buccal tablets prepared using drug-loaded chitosan microspheres”. Eur. J. Pharm. Biopharm.53, 233-239.

14. Tsutsumi K., Obata Y., Nagi T., Loftsson T., Takayama K., 2002 “Buccal absorption of ergotamine tartrate using the bioadhesive tablet system in guinea-pigs”. Int. J. Pharm. 238,

161-170.

15. Park C.R., Munday D.L., 2002 “Development and evaluation of a biphasic buccal adhesive tablet for Nicotine replacement therapy”. Int. J. Pharm. 237, 215-226.

16. Balamurugan M., Saravanan V.S., Ganesh P., Senthil S.P., Hemalatha P.V., Pandya S.,

2008 “Development and In-vitro Evaluation of Mucoadhesive Buccal Tablets of

Domperidone”. Res. J. Pharm. Tech. 1, 377-380. ENCLOSURE-VI

10) Remarks of the Guide

The present work is aimed to develop and in-vitro evaluation of mucoadhesive buccal tablets of Repaglinide. It is a widely used as an anti diabetic drug used in the treatment of type 2 diabetes mellitus. The drug has a shorter biological half-life of about 1 hour and it undergoes first pass metabolism. Therefore, it needs to be administered frequently in order to achieve constant plasma levels, but the frequent administration may leads to dose accumulation and toxicity. Hence, to improve the bioavailability mucoadhesive drug delivery system for Repaglinide is necessary.

The proposed study can be carried out in the laboratory.

Dr. C. C. Patil

Research Guide