Formulation and Evaluationof Oral Novel ColonTargeted Drug Delivery SystemUsing Natural Polymers.
M.Pharm. dissertation protocol
Submitted to the
RajivGandhiUniversity of Health Sciences,
Bangalore,Karnataka.
By
PADGAONKAR GURUNATH SUBHASH
Under the esteemed guidance of
Dr. C.C. Patil
M. Pharm., Ph.D.
Prof. and Head,
Departmentof Pharmaceutics,
B.L.D.E.A.’sCOLLEGE OF PHARMACY, BIJAPUR,
KARNATAKA.
(2008-2009)
RajivGandhiUniversity of Health Sciences,
Bangalore,Karnataka.
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION.
1
/Name and address of the candidate(In block letters)
/Mr. PADGAONKAR GURUNATH SUBHASH
2
/Name of the Institution
/B.L.D.E.A.’sCOLLEGE OF PHARMACY,
BIJAPUR, KARNATAKA.
3
/Course of the study and subject
/M.PHARM. (PHARMACEUTICS)
4
/Date of Admission to the Course
/15th JULY, 2008.
5
/ Title of the Topic:Formulation and evaluation of oral novel colon targeted drugdelivery system using natural polymers.
6
/Brief Resume of the intended work:
6.1 Need for the study.
6.2 Review of literature.
6.3 Objective of the study.
7
/Materials and Methods
7.1 Source of the Data.
7.2 Method of collection of data (including sampling procedure, if any).
7.3Does the study require any investigations or interventions to be conducted on patient of other humans or animals? If so, please describe in brief
YES7.4 Has ethical clearance been obtained from your institution in case of 7.3?
YES
8
/List of references
9
/Signature of candidate
/ Padgaonkar Gurunath Subhash10
/Remarks of the guide
/The proposed work is recommended and can be carried out in laboratory.
11
/Name & Designation of
(In block letters)
11.1 Guide
11.2 Signature
/Dr. C.C.Patil. M.Pharm., Ph.D.
Prof. and Head, Department of Pharmaceutics,
B.L.D.E.A.’sCollege of Pharmacy,
Bijapur, Karnataka.
11.3 Co-Guide (if any)
11.4 Signature
/-----
-----
11.5 Head of Department
11.6Signature
/Dr. C.C. Patil. M.Pharm., Ph.D.
Department of Pharmaceutics,B.L.D.E.A.’sCollege of Pharmacy
BIJAPUR , KARNATAKA.
12
/12.1 Remarks of the
Principal
12.2 Signature
/ Dr. Navnath V. Kalyane M. Pharm., Ph.D.6. BriEf resume of the intended work
6.1 NEED FOR THE STUDY
During the last decade, there has been interest in developing site specific formulations for targeting drugs to the colon. Colon is a site where both local and systemic drug deliveries can take place.1
The present work has been aimed at for the development of some site-specific drugdelivery systems for colon region mainly concentrating on designing of oral tablet dosage form for the treatment of colon inflammations (Ulcerative colitis and Crohn’s disease). Management of colon diseases is poor as the drug is absorbed largely in the stomach and small intestine region before reaching the colon. Although there are several formulations available in the market for the treatment of colon diseases through the rectal route, this route is less acceptable in routine administration. Colon diseases require the drug to be present in sufficient concentrations in the colon region. The present work of investigation will be an attempt to design tablet dosage form for “colon inflammatory” diseases.
The important bacteria present in the colon such as Bacteroides, Bifidobacterium, Eubacterium, Peptococcus, Lactobacillus, Clostridium secrete a wide range of reductive and hydrolytic enzymes such as β-glucuronidase, β-xylosidase, β-galactosidase, α-arabinosidase, nitroreductase, azoreductase, deaminase and urea hydroxylase.2 These enzymes are responsible for degradation of di-, tri- and polysaccharides. Pectin is a polysaccharide obtained from plant cell walls. Inulin is a polysaccharide which is obtained from plants such as onion, garlic, chicory and artichoke. Being soluble in water, pectin is not able to shield its drug load effectively during its passage through the stomach and small intestine. Hence a coat of a considerable thickness is required to protect the drug core in simulated in vivo conditions. The aim of the present study is to develop pectin based matrix tablet with sufficient mechanical strength and promising in vitro mouth-to-colon release profile. The matrix tablets will be coated with inulin and shellac to target the tablets to colon. The coated tablets will be evaluated for weight gain, coat thickness and in vitro dissolution studies.7
6.2 REVIEW OF LITERATURE
1)Fast release enteric coated tablets were formulated for drug delivery to the colon. Two different approaches were used for the preparation of these tablets. The first one was by using super disintegrant (SD) in the tablet. The second approach consisted of development of osmogen based tablets for drug delivery into the tracts of the colon. Celecoxib was used as the model drug. In vitro drug release studies showed that super disintegrants were more effective in showing burst effect in the tablets and therefore showed a rapid drug release as compared to osmogens which would show a sustained drug release all through the colon.4
2)‘Azo-polysaccharide’ gels were designed, more specifically azo-inulin and azo-dextran gels for colon drug delivery. Breakdown of the inulin and dextran chains in the azo-polysaccharide gels by inulinase and dextranase respectively, was observed. The degradation of azo- dextran gels by dextranase seemed more pronounced than the degradation of azo- inulin by inulinase. In rat caecal content medium, reduction of ‘azo’ function in azo- inulin gels was not observed. This may be attributed t a low partitioning of nicotinamide adenine dinucleotide phosphate (NADP+) in the gels.5
3)Matrix tablets containing various proportions of guar gum were prepared by wet granulation using starch paste as a binder. Guar gum matrix tablets released 8-15 % of the mebendazole in the physiological environment of the stomach and small intestine depending upon the proportion of guar gum used in the formulation. The results of the study showed that matrix tablets containing either 20% or 30% of guar gum are most likely to provide targeting of mebendazole for local action in the colon. Matrix tablets containing either 20% or 30% of guar gum showed no change in physical appearance, drug content and dissolution pattern after storage at
45C/75% humidity for 3 months. Differential scanning calorimetry
indicated no possibility of interaction between mebendazole and guar
gum.6
4)A novel colon targeted tablet formulation was developed using pectin as carrier and diltiazem HCl and indomethacin as model drugs. The tablets were coated with inulin followed by shellac and were evaluated for average weight, hardness and coat thickness. In vitro release studies for prepared tablets were carried out for 2 h in pH 1.2 HCl buffer, 3 h in pH 7.4 phosphate buffer and 6 h in simulated colonic fluid. The drug release from the coated systems was monitored using UV/Vis spectroscopy. In vitro studies revealed that the tablets coated with inulin and shellac have limited the drug release in stomach and small intestinal environment and released maximum amount of drug in the colonic environment. The study revealed that polysaccharides as carriers and inulin and shellac as a coating material can be used effectively for colon targeting of both water soluble and insoluble drugs.7
5) Colon specific drug delivery system was developed for sennosides and Triphala. These drugs are reputed Ayurvedic medicines for constipation in India. The proposed device explored the application of pectin and ethyl cellulose as a mixed film for colon specific delivery. This mixed film was prepared using non-aqueous solvents like acetone and isopropyl alcohol. A 32 factorial design was adopted to optimize the formulation variables like, ratio of ethyl cellulose to pectin (X1) and coat weight (X2). The rate and extent of drug release were found to be related to the thickness and the ratio of pectin to ethyl cellulose within the film. Statistical treatments to the drug release data revealed that the X1 variable was more important than X2. Under simulated colonic conditions, drug release was more pronounced from coating formulations containing higher proportions of pectin. The surface of the device was coated with Eudragit S100 to ensure that the device was more pH dependent and triggered drug release only at higher pH. The final product was expected to have the advantage of being biodegradable and pH dependant. The film effectively released the drug while maintaining its integrity.8
6) Copolymers like N-(2- Hydroxypropyl) methacrylamide (HPMA) were evaluated as colon specific drug carriers. Their design was based on the concept of site specific binding of carbohydrate moieties complementary to colon mucosal lectins and on the concept of site specific drug [5- aminosalicylic acid (5-ASA)] release by the microbial azoreductase activity present in the colon. The incorporation of 5-ASA containing aromatic side chains into HPMA polymers further increased their adherence probably by combination of non-specific hydrophobic binding with specific recognition.9
6.3 OBJECTIVES OF THE STUDY
The main objective of study is to design and evaluate oral colon targeted tablets using pectin as a carrier and 5- aminosalicylic acid (5-ASA, mesalamine) or any of its derivatives like olsalazine, sulfasalazine, balsalazine, etc. as the model drug.5-ASA is an anti-inflammatory drug used in the treatment of Inflammatory Bowel Disease and Ulcerative Colitis. Mesalamine is a derivative of salicylic acid. Mesalamine works as an anti-inflammatory agent in treating inflammatory diseases of the intestines.3 Its derivatives(olsalazine, sulfasalazine, balsalazine, etc.) are converted by the colonic bacteria to mesalamine on reaching the colon.
1)To prepare pectin matrix tablets of 5- aminosalicylic acid (5-ASA, mesalamine) or any of its derivatives like olsalazine, sulfasalazine, balsalazine, etc. by wet granulation process and to coat them with inulin by solution coating. After drying, the inulin coated tablets will be further coated with shellac.
2)Physicochemical characterization of the prepared formulation including granular parameters and evaluation of coated formulations.
3)To perform in-vitro dissolution study of formulations using simulated colonic environment and analyzethem for drug release using UV-Visible spectroscopy.
4)To characterize the formula by FTIR and DSC analysis.
5)To perform stability studies at different temperatures and humidity.
7. MATERIALS AND METHODS
7.1 SOURCE OF DATA
Studies on 5-ASA (or any of its derivativeslike olsalazine, sulfasalazine, balsalazine, etc.) colon targeted tablets will be laboratory based. Data will be generated by performing laboratory experiments and by referringvarious journals, abstracts and textbooks, internet sources, etc.
7.2 METHOD OF COLLECTION OF DATA
The data is planned to be collected from laboratory experiments:
- Matrix tablets of 5-ASA (or any of its derivativeslike olsalazine, sulfasalazine, balsalazine, etc.) will be prepared by wet granulation method using pectin polymer. These tablets will be further coated using inulin and shellac.
- Granules will be characterized by their physicochemical parameters like bulk density, percentage compressibility (Carr’s index), angle of repose, flow rate, etc.
- Tablets will be evaluated for thickness, weight gain after coating, weight variation, friability test, drug content, drug release, etc.
- Simulated colonic fluid prepared by using rat caecal contents will be used for studying in vitrorelease of the drug.
7.3Does the study require any investigation or intervention to beconducted on patient or other humans or animals? If so please describe briefly.
YES. Caecal contents of rat will be isolated for preparing simulated colon environment. This simulated colonic fluid will be used for In-vitro dissolution studies. For this purpose, 10 experimental rats will be needed.
7.4Has ethical clearance been obtained from your institution in case of 7.3?
YES
8. LIST OF REFERENCES
- Bussemer T., OttoI., and Bodmeier R., Pulsatile drug- delivery systems, Crit. Rev., Ther. Drug carrier syst., 18, 2001; 433-458.
- S.P Vyas, Roop. K. Khar, “Controlled Drug Delivery- CONCEPTS AND ADVANCES”, Vallabh Prakashan, Delhi, First Edition- 2002, pg no. 222.
- “Drug Bank” Showing Drug Cards For 5- aminosalicylic acid and its derivatives (olsalazine, slufasalazine, balsalazine), DB00244, DB01250,DB00795.
- Sinha, Bhinge V., Kumria J., Rachna et. al., “Development of pulsatile systems for targeted drug delivery of celecoxib for prophylaxis of colorectal cancer”, Drug delivery May-June 2006, pp 221-225.
- Stubbe B., Maris B., Vanden Mooter G., De Smedt S.C. Demeester J. et. al. In vitro evaluation of azo containing polysaccharide gels for colon delivery, Journal of controlled release, 10th July 2001, pp 103-114 .
- Krishnaiah YSR, Veer Raju P., Dinesh Kumar B. et. al., “Development of colon targeted drug delivery system for mebendazole”, Journal of Controlled Release, 9th Nov., 2001, pp 87-95.
- V. Ravi, TM Pramod Kumar, Siddaramaiah, “Novel colon targeted drug delivery system using natural polymers”, Indian Journal of Pharmaceutical Sciences, 2008, volume 70, issue 1, pp 111-113.
- Munira Momin, K Pundarikakshudu, SA Nagori, “Design and development of mixed film of pectin: Ethyl cellulose for colon specific drug delivery of sennosides and Triphala”, Indian Journal of Pharm. Sci., 2008, volume 70, Issue 3, pp.338-343.
- Kopekovaa P., Rathia R., Takadaa S., et. al., ”Bioadhesive N-(2- hydroxypropyl) methacrylamide copolymers for colon specific drug delivery, Nov. 2002, Online 8.