colon specific drug delivery system

FORMULATION DESIGN AND DEVELOPMENT OF COLON SPECIFIC MATRIX TABLETS OF 5-

AMINO SALICYLIC ACIDProject seminar presentation

ForPartial Fulfillment of the requirements for the award of

“Degree of Bachelor of Pharmacy”By

Mainak DasB.Pharm. (7th Semester)Regd. No.: 1003254038

Under the guidance of

Dr. Prasanta Kumar Choudhury M.Pharm., Ph.D.

Assistant ProfessorRoyal College of Pharmacy & Health Sciences, Berhampur , Affiliated to Biju patnaik University of Technology, Rourkela,

Odisha2013-14

CONTENTS

Introduction

Literature review

Aim and objectives

Plan of work

References

INTRODUCTIONTargeted drug delivery systems: The major goal of any drug delivery system is to supply a therapeutic

amount of drug to a target site in a body. Targeted drug delivery implies selective and effective localization of

drug into the target at therapeutic concentrations with limited access to non target sites.

A targeted drug delivery system is preferred in drugs having instability, low solubility and short half life,

WHY COLON TARGETED DRUG DELIVERY IS NEEDED?

Rational for the Development of Oral Colon Targeted Drug Delivery:

• Treatment of local pathologies

• Greater responsiveness to the absorption enhancers

• Site for delivery delicate drugs (Proteins and Peptides)

ADVANTAGES:

Targeted drug delivery to the colon. Decrease in dose administration. Decrease side effects. Improved drug utilization.

DISADVANTAGES:

There are variations among individuals with respect to the pH level in the small intestine and colon which may allow drug release at undesired site.

The pH level in the small intestine and caecum are similar which reduces site specificity of formulation.

Diet and diseases can affect drug targeting to colon

ANATOMY OF COLON:

Ascending colon Transverse colon Descending colon Sigmoid colon

•Serosa

•Muscularis externa

•Submucosa

•Mucosa

Layers:

COLON ABSORPTION :

Factors affecting colon absorption : pH level Colonic residence time. Degradation by bacterial enzymes. Local physiological actions of drug. Disease state. Use of chemical absorption enhancers.

(eg:ethylacetoacetate.)

HUMAN DIGESTIVE TRACT PH RANGE

LOCATION pH

1.STOMACH:

Fasted

Fed

1.5-2.0

3.0-5.0

5.0-6.5

2.SMALL

INTESTINE:

Jejunum

Ileum

6.0-7.5

6.4

6.7-7.3

3.LARGE

INTESTINE:

Right colon

Mid colon

Left colon

6.5-7.0

6.6-7.0

6.6

7.0

DISORDERS OF COLON INFLAMMATORY BOWEL

DISEASE Crohn’s disease:

•Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract

•It is characterized by a granulomatous inflammation affecting any part of the tract, normally form fistulae.

Ulcerative colitis:-

•It is a chronic inflammatory disorder of colon limited to the large intestine as against the case with Crohn's Disease where any part of the alimentary tract may be involved.

The various pharmaceutical approaches which have been used for targeting drugs to the colon are mainly based on:

pH dependent

Time-dependent

Bacteria-dependent

Pressure dependent delivery system

DIFFERENT APPROACHES

PH DEPENDENT POLYMERS:

MECHANISM OF ACTION:

pH sensitive polymer

TIME DEPENDENT:

Organ Transit time

Stomach <1(Fasting) , >3(Fed)

Small intestine 3-4

Large Intestine 20-30

BACTERIA DEPENDENT:Major metabolic processes occurring in the colon are hydrolysis and reduction

Enzymes in Colon:

Reducing enzymes Hydrolytic enzymesNitroreductase EsterasesAzoreductase AmidasesN-oxide reductase GlycosidasesSulphoxide reductase GlucuronidaseHydrogenase Sulfatase

Azoreductases, which reduces azo-bonds selectively and

Polysaccharidases which degrades the polysaccharides

.

AZO BOND CONJUGATES:

SAS on colon in presence of diazoreductase cleaves the azo bond to form 5 ASA and Sulfapyridine.

Hydrolysis of sulphasalazine: (i) 5-aminosalicylic acid .(ii) And sulfapyridine.

MATRIX TABLETS: 

Introduction of matrix tablet excludes complex production procedures such as coating and pelletization

Drug release rate from the dosage form is controlled mainly by the type and proportion of polymer used in the preparations

Advantages offered by matrix tablets:

Reduction in toxicity by slowing drug absorption.

Minimize the local and systemic side effects.

Improved patient compliance.

ENTERIC-COATED POLYSACCHARIDE MATRIX

COMPRESSION COATED TABLETS :

NATURAL POLYSACCHARIDES AS POLYMER FOR COLON DRUG DELIVERY

Chitoson Pectin Guar gumChondroitin sulphateDextran Almond gum Locust bean gumCyclodextrins Inulin Boswellia gumKhaya gum

LITERATURE REVIEW

SL NO.

AUTHOR/YEAR

DRUG AND EXCIPIENT

METHOD/APPROACH

CONCLUSION

1. Cheng G.et al., (2004)

Diclofenac Sodium,5 Amino Salicylic Acid,Ethyl Cellulose,Eudragit L100,Eudragit S100

Time Dependent Approach

Eudragit® L100 and S100 pH- sensitive copolymersare able to achieve site-specific drug delivery targeting at colon following oral administration

2. Patil M.M. et al., (2009)

Mesalamine, Eudragit L100,Eudragit S100

Compression Coating,PH Dependent Approach

Compression coating layer was adopted to delay the drug release for about 2-3 hours and to allow the tablet to pass intact through the small intestine to the colon.

3. Aswar P.B. et al.,(2009)

Diclofenac sodium,Guar Gum,Ethyl Cellulose

Matrix tablets preparation

Matrix tablets containing guar gum as a carrier and ethyl cellulose as a binder was found to be suitable for targeting Diclofenac sodium for local action in the colon

SL NO.

AUTHOR/YEAR

DRUG AND EXCIPIENT

METHOD/APPROACH

CONCLUSION

4. Shendge R.S. et al.,(2010)

Aceclofenac,Ethyl Cellulose,sodium CMC,Sucrose

Wet Granulation Technique

The matrix tablet containing binder system of ethyl cellulose and dextrin as a carrier was found to be suitable for targeting the colon

5 Neekhra M. et al.,(2010)

Ketorolac tromethamine ,Guar Gum,CAP

Capsule Formation

That cellulose acetate phthalate coated capsules with 50% guar gum may be useful for drug targeted to the colon successfully.

6. Chickpetty S.M. et al., (2010)

Diclofenac Sodium guar gumlocust bean gumHPMC

Compression Coated Tablets

Ratio 6:4 released only 2.24% of drug in physiological environment of stomach and small intestine and released more than 90% of drug in colon.

SL NO. AUTHOR/YEAR

DRUG AND EXCIPIENT

METHOD/APPROACH

CONCLUSION

7. Naikwade S. et al., (2010)

Ornidazole, HPMC,Eudragit

Matrix Tablets Preparation

The formulation was found to be working as colon targeted drug delivery system.

8. Badmapriya D. et al.,(2011)

Guar Gum, Matrix Tablets Preparation

Guar Gum colon targeting coated with two different polymeric layers resulted in the drug release in range of 57.8 to 68.38%, due to the microbial enzymatic activity

3.0 DRUG PROFILE (Sulfasalazine)

Sulfasalazine was developed in the 1950s specifically to treat rheumatoid arthritis.

Sulfasalazine is a sulfa drug, (a derivative of mesalazine) It is formed by combining sulfapyridine and salicylate with an azo bond. It

may be abbreviated SSZ.

Structure:

Chemical name:

(2-hydroxy-5-[(E)-2-{4-[(pyridin-2-yl) sulfamoyl]

phenyl} diazen-1-yl] benzoic acid

Molecular formula:C18H14N4O5S 

Molecular weight:398.394 g/mol

Volume of distribution:7.5 ± 1.6 L

Half life:5-10 hours

Clearance:1 L/h [IV administration]

Mechanism of action: 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP), is still under

investigation. It may be related to the anti-inflammatory and/or immuno modulatory. Clinical studies utilizing rectal administration of Sulfasalazine, SP and

5-ASA have indicated that the major therapeutic action may reside in the 5-ASA moiety.

Route of elimination: The majority of 5-ASA stays within the colonic lumen and is excreted as

5-ASA and acetyl-5-ASA with the feces.

AIM AND OBJECTIVES

Present aim of the research work is based on Formulation Design and Development of Colon Specific Matrix Tablets of 5-Amino Salicylic Acid. Here the work is emphasized on formulation of matrix tablets intended for colonic delivery.

The results are to be compared with marketed formulation to see that whether any deviation occurred between the marketed formulation and the prepared formulation.

PLAN OF WORK:

Experimental protocol: Selection of model drug and analytical studies.

Characterization of the drug: Physical properties Solubility study UV spectral analysis FTIR analysis

Preparation calibration curve of model drug Preformulation Drug-Excipients compatibility study Formulation of matrix tablets for colonic delivery. Selection of final formulation and evaluation for potentiality to deliver the

drug to colonic region. Comparison of the drug release data and fitting to different kinetic models. Stability studies of the optimized formulations  

REFERENCES1) Chourasia M.K., Jain S.K.,Pharmaceutical approaches to colon specific drug delivery system,J

Pharm PharmaceutSci,2003; 6(1):33-66

2) Madhu E.N., Panaganti S., L. Prabakaran, and Jayveera K. N., Novel Colon Specific Drug Delivery System: A Review, , IJPSR, 2011; 2(10): 2545-2561

3) Tapaswi R.D., Verma P., Matrix Tablets: An Approach towards Oral Extended, Release Drug Delivery, International Journal of Pharma Research & Review, Feb 2013; 2(2):12-24

4) Kshirsagar S.J.,Bhalekar M.R,Umap R.R. In vitro in vivo comparison of two pH Sensitive Eudragit polymers for colon specific drug delivery. J. Pharm. Sci., 2009;1(4):61-70.

5) Shendge R.S., Fatima J., Sayyad, Kishor S., Salunkhe and Bhalke` R.D.,. Development of specific delivery of aceclofenac by using effective binder system of ethyl cellulose. Int. J. Pharm. Bio. Sci., 2010;1(3):1-5.

6) Patel B.P. and Avinash S. Dhake.,Multiparticulate approach: an emerging trend in colon specific drug delivery for Chronotherapy, Journal of Applied Pharmaceutical Science, 2011, 01 (05): 59-63

7) Gang C.F., An, Mei-Juan Zou, Jin Sun, Xiu-HuaHao, Yun-Xia He, Time- and pH-dependent colon-specific drug delivery for orallyadministereddiclofenac sodium and 5-aminosalicylic acid, World J Gastroenterol World, 2004, 10(12): 1769-1774

8) Badmapriya D, Rajalakshmi A.N,Guar Gum Based Colon Targeted Drug Delivery System: In-Vitro Release Investigation, 2011, RJPBCS, 2(3):899-907

9) Mei-Juan Z, Gang C., Hirokazu Okamoto, Xiu-HuaHao, Feng An, Fu-De Cui, Kazumi Danjo ,Colon-specific drug delivery systems based on cyclodextrin-prodrugs: In vivo evaluation of 5-aminosalicylic acid from its cyclodextrin conjugates, World JoranalGastroenterol, 2005, 11(47):7457-7460

10) Naikwade S., Kulkarni P., Jathar S R, Bajaj A N.,Development of new dissolution test and HPLC-RP method for anti-parasitic ornidazole coated tablets, International Journal of pharmaceutical Research,2010, 16(3): 478-481

11) Chauhan C.S., Singh P., Naruka, Rathore R.S., Badadwal V., Formulation and evaluation of prednisolone tablets for colon targeted drug delivery system. J. Chem. Pharm. Res., 2(4):993-98.

12) Patel M.M., Santnu L. Patel, Manish N. Bhadani, Tejal J. Shah and Avani F. Amin, A synchronous colon-specific drug delivery system for orally administered mesalamine,ActaPharmaceuticaSciencia, 2009,51: 251- 260

13) Jose S, Dhanya K, Cinu TA, Aleykutty NA. Multi particulate system for colon targeted Delivery of ondonsetrone. Ind. J. Pharm. Sci.,2010;72(1):58-64.

14) Purushothaman M., VijayaRatna J., Formulation optimization and release kinetics of tinidazole matrix, compression and spray coated tablets: effect of organic acid on colon targeted drug delivery system. JITPS.,2010;2(1):18-32.

15) Kushwaha P., SheebaFareed and Sanju Nanda. Promising Approaches to target drug delivery to colon. Int. J. Ph. Sci., 2010:2(3):669-79.

REFERENCES

16) Thiruganesh R., Uma Devi SK, Suresh S. Preparation and characterization of pectin pellets of Aceclofenac for colon targeted drug delivery. J. Chem. Pharm. Res. 2010;2(1):361-74.

17) Neekhra M., Shrivastav S., Sharma S., Molvi K.I., Kumar V., Development and evaluation of oral colon targeted Ketorolac tromethamine capsule International Journal of PharmacueticalSciences and Research. 2010;1(5):61-7.

18) Aswar P.B., Khadabadi S.S., Kuchekar B.S., Wane T.P., Matake N., Development and in-vitro evaluation of colon-specific formulations for orally administered Diclofenac sodium. Arch Pharm Sci and Res. 2009;1(1):48-53.

19) Chickpetty S.M., Baswaraj R., Studies on design and in-vitro evaluation of compression coated delivery systems for colon targeting of Diclofenac sodium. International Journal of PharmaTech Research CODEN(USA):IJPRIF. 2010;2(3):1714-22.

20) Ghuleprashant J., Karle Ganesh D., Das S.,. Formulation and In-vitro evaluation of colon targeted drug delivery of Aceclofenac. Journal of Pharmacy Research,2010;3(5):1082-86.

21) Bhalke R.D., Raosaheb S., Shendge, Fatima J Sayyad, Kishore S Salunkhe. Development of colon specific drug delivery of Aceclofenac by using effective binder system of ethyl cellulose. International Journal of Pharma and Biosciences. 2010;1(3):1-5.

22) Davis S.S., Hardy J.G., Taylor M.J., Stockwell A., Whalley D.R., Willson C.G., The in vivo evaluation of an osmotic device (Osmet) using gamma scintigraphy. J Pharm Pharmacol 1984; 36: 740-42

REFERENCES

21) Tripathy K.D., Essentials of Medical Pharmacology,6th edition,2009;517-519

22) Drug Bank Encyclopedia,Open Data Drug and Data Target Database

23) Wikipedia The Free Encycloprdia,sulfasalazine

24) Marvola M., Aitoh, Ponto P., Kanniksoki A., Nykanen S., Kokkonen P., Gastrointestinal transit and Concomitant absorption of verapamil from a single unit sustained release tablet. Drug DevIndPhram 1987; 13: 1539-09.

25) Sinha V.R. and Kumaria R., Polysaccharides for colon specific drug delivery. Int J Pharm 2000; 224:19-38.

26) Jain S.K., Jain A., and Gupta Y., Perspectives of biodegradable natural polysaccharides for site Specific drug delivery to the colon. J Pharm PharmaceutSci 2007; 10 (1):86-128.

29) Remington, the science and practice of pharmacy, 20th edition, pp- 1043-1044

30) Sapkal N.P., Kilor V.A., Bhusari K.P., and Daud A.S., Trop J Pharm Res. 2007;6(4):833-840.

31) Shirse P., Rao K.S., and Mohammed M., Formulation and Evaluation of Cyclodextrin Inclusion Complex Tablets of Water Insoluble Drug-Glimipiride, IJRPC 2012, 2(1): 222-230

32) Pozzi F., Furlani P., GazzanigaA., Davis S. S. and Wilding I. R., The Time-Clock® system: a new oral dosage form for fast and complete release of drug after a predetermined lag time. J. Control. Release, 1994; 31: 99–108.

33) Lieon Lachman, Heart A. Lieberman, Joseph L. Kanig, The theory and practice of industrial pharmacy, 3rd Edition, Varghese publishing house, Bombay, 1990, pp 298-303.

REFERENCES

Thank You