DESIGN AND EVALUATION OF A NEW CAPSULE-TYPE DOSAGE FORM FOR COLON-TARGETED DELIVERY OF ETORICOXIB
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BY
S. NARESHYADAV
B. Pharm,
UNDER THE GUIDANCE OF
G.B.KIRAN KUMAR
M.Pharm,
DEPARTMENT OF PHARMACEUTICS
SRI ADICHUNCHANAGIRI COLLEGE OF PHARMACY
B.G.NAGARA-571448
.
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERATION
1 / NAME OF THE CANDIDATE & ADDRESS / Mr. S. NARESHYADAV,Department of pharmaceutics
S.A.C. COLLEGE OF PHARMACY
B. G. NAGARA-571448, NAGMANGLA(TALUK)
MANDYA (DIST), KARNATAKA
PERMANENT ADDRESS:
S/O Anjaneyulu, H.NO. 36-60, VALLBNAGAR, WANAPARTHY (509103), MAHABUBNAGAR (DIST), ANDHRA PRADESH-517172.
2 / NAME OF THE INSTITUTE / S.A.C. COLLEGE OF PHARMACY,
B.G. NAGARA, NAGAMANGALA TALUK,
MANDYA DISTRICT,
KARNATAKA -571448.
3 / COURSE OF THE STUDY / MASTER OF PHARMACY (PHARMACEUTICS).
4 / DATE OF ADMISSION / 30-6-2010.
5 / TITLE OF THE TOPIC / DESIGN AND EVALUATION OF A NEW CAPSULE-TYPE DOSAGE FORM FOR COLON-TARGETED DELIVERY OF ETORICOXIB
6.
7. / 6.
BRIEF RESUME OF INTENDED WORK:
6.1 NEED FOR STUDY:
Oral route is considered to be most convenient route of drug administration. Orally administered dosage forms normally dissolves in the stomach fluid or intestinal fluid and absorb from these regions of the GIT depends upon the physicochemical properties of the drug. It is a serious drawback in conditions where localized delivery of the drugs in the colon is required or in the hostile environment of upper GIT1.
Oral controlled release formulations for small intestine and colon have received considerable attention in the past 20-25 years for variety of reasons including pharmaceutical superiority and clinical benefits derived from the drug release pattern that are not achieved with traditional immediate or sustained release formulation2.
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided (largely bacteria) fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a major role in absorption of foods and nutrients. However, the colon does absorb water, potassium and some fat soluble vitamins3.
Colonic drug delivery is not only restricted to treatment of local disorders but also for systemic drug delivery. This part of GIT is also being considered as a site for administration of protein and peptide drugs. This is because colon provides a less hostile environment for drugs due to low diversity and intensity of digestive enzymatic activities, and a near neutral pH less hostile environment prevailing in the colon compared to stomach and small intestine4.
Inflammatory bowel disease (IBD) is a localized inflammation of the small and large intestine. Since intestinal inflammation is confined to specific mucosal or transmural locations, it is possible to deliver drugs specifically to the site(s) of inflammation. In
site-specific (targeted) drug delivery it is possible to reduce the total amount of drug administered thus reducing side effects5.
Etoricoxib is a nonsteroidal anti-inflammatory agent (dipyridinyl derivative) for oral administration. It is a selective inhibitor of cyclooxygenase-2 (COX-2). The COX-1 isoenzyme is constitutively expressed in most tissues, and is particularly involved in prostaglandin synthesis in kidneys, platelets, and gastric mucosa; products of COX-1 appear cytoprotective, and inhibition of this isoform has been associated with antiplatelet and gastrointestinal toxicity. The inducible COX-2 isoform is expressed at sites of inflammation, and its inhibition is considered responsible for analgesic and anti-inflammatory properties of nonsteroidal anti-inflammatory agents. The COX-1-sparing effects of selective COX-2 inhibitors suggest they may be as effective as nonselective inhibitors of both COX-1 and COX-2 (i.e., naproxen, ibuprofen, ketorolac) in treating pain and inflammation with a reduced propensity for hematologic and gastrointestinal toxicity.Mean peak plasma concentrations of 201, 411, 788, and 2186 ng/mL were reported after single oral doses of 10, 20, 40, and 120 mg, respectively, in healthy subjects. Plasma levels fell to less than 400ng/mL within 48 hours of all doses. Results of this study suggested linearity of etoricoxi0b pharmacokinetics over the range of 5 to 120 mg. Bioavailability: ORAL, TABLET: 80% to 100%. Volume of Distribution: 119 L at steady state following 24- milligram single intravenous dose.Metabolism Sites and Kinetics: LIVER, at least 90% (Kassahun et al, 2001; Chauret et al, 2001). a) The major metabolic pathway is 6'-methyl hydroxylation, primarily via cytochrome P450 (CYP)-3A4. Other metabolites include the 1'-N-oxide, 6'-carboxylic acid, and 6'-hydroxylated glucuronide. To a lesser extent, CYP-2D6, CYP-2C9, CYP-1A2, and CYP-2C19 are also involved in metabolism. No metabolites are considered to contribute significantly to COX-2 (or COX-1) inhibition.Excretion: Kidney, Etoricoxib is excreted in the urine, primarily as metabolites; quantitative data are unavailable. Etoricoxib is used in the treating of ankylosing spondylitis, dentalpain, osteoarthritis and rheumatoid arthritis6.
Several approaches utilizing the GI-transit time of various formulation and the change in pH, bacterial concentration, and pressure in the GI-tract have been reported to achieve colon-specific drug delivery. The pH-sensitive delivery systems have used enteric coating materials such as EudragitL100. Some new synthetic polymers containing an aromatic azo group, which are degraded by intestinal flora, are used as coating materials7.
When the physical and physiological conditions of the human gastrointestinal tract are considered, a site-specific oral drug delivery seems to be achieved by appropriately integrating a combination of pH-sensing functions and time-controlled Release functions into a single pharmaceutical. These two functions of the CTDC could improve the above-mentioned drawbacks of pH-triggered system and time-controlled system. That is, since the gastric emptying time greatly varies depending on various factors, the drug release in the stomach must be minimized. Imparting a pH-sensing function to the pharmaceutical should be effective for this purpose. Meanwhile, the passage of pharmaceuticals in the small intestine is known to be less variable, after gastric emptying, therefore, the time-controlled release function must be effective to deliver the drug to the target site in the intestine8.
Hence the present study was taken to develop a formulation design and to evaluate the invitro properties of the colon targeted drug capsule (CTDC).
6.2 REVIEW OF THE LITERATURE:
Ø Takashi Ishibashi et al., 8 conducted a study on Design and evaluation of a new capsule-type dosage form for colon-targeted delivery of drugs.The system was designed by imparting a timed-release function and a pH-sensing function to a hard gelatin capsule. The technical characteristics of the system are to contain an organic acid together with an active ingredient in a capsule coated with a three-layered film consisting of an acid-soluble polymer, a water-soluble polymer, and
an enteric polymer. In order to find the suitable formulation, various formulation factors were investigated through a series of in vitro dissolution studies. As a result, it was found that: (1) various organic acids can be used for this system; (2) a predictable timed-release mechanism of a drug can be attained by adjusting the thickness of the Eudragit®E layer; and (3) the outer enteric coating with HPMC®-AS provided acceptable acid-resistibility. All these results suggested that this approach can provide a useful and practical means for colon-targeted delivery of drugs.
V.R. Sinha et al., 9 developed a Colon-specific drug delivery.it is designed to target drug molecules specifically to this area. Development of site-specific delivery systems may exploit a specific property of the target site for drug activation release. The gastrointestinal tract is inhabited by over 400 bacterial species; each having a specific niche in the tract.This flora produces a vast number of enzymes which are being exploited for formulation of colon-specific drug delivery systems. A number of microbially activated systems for colon-specific drug delivery are being evaluated. These include prodrugs and synthetic or natural polymer-based delivery systems. This article aims at reviewing the various microbially activated drug delivery systems for colon-specific drug delivery with specific reference to the micro flora of the various segments of the gastrointestinal tract and their role in targeting drug delivery to the colon.
Ø V.R. Sinha et al., 10 studied to evaluate a formulation with a considerably reduced coat weight and gum concentration for colonic drug delivery in vivo using\ gamma scintigraphy. In vitro studies have found this formulation to be useful for delivery of 5-fluorouracil to the colon. Rapidly disintegrating core tablets containing 99mTc-DTPA were prepared and compression coating with 150 mg of granules containing a mixture of xanthan, guar gum and starch. The ratios of the two gums XG: GG in the coat was kept 10:20. In vitro dissolution studies on XG: GG: 10:20 tablets containing 99mTc-DTPA were carried out in simulated upper GIT conditions and also in presence of colonic contents.
Cumulative percent release of technetium in the upper GIT conditions and transit time amounted to 4%. The total amount of technetium released in the 24 h of the
Dissolution study was 53±3.23%. Upon introduction of cecal content into the dissolution medium (4%), the release of technetium from the compression-coated tablet increased to 78.34±5.34%. Gamma scintigraphy studies carried out in six healthy human volunteers showed that the tablet remained intact during its transit through the upper GIT. The anatomical site of disintegration was found to be the ascending colon/hepatic flexure and the disintegration of the tablet started between 4 and 6 h post-dose in all the volunteers with a further spread of tracer into the ascending, transverse, descending and sigmoidal colon.
Ø M.K.chourasia et al.,1 developed a prodrug approach to colon targeted drug delivery system.That is based on the covalent linkage between drug and carrier.The type of linkage that is formed between drug and carrier would decide the triggering mechanism for the release of drug in the colon.The presence of azo reductase enzymes play pivotal role in the release of drugs from azo bonds prodrugs while glycosidase enzyme activity of the colonic microflora is responsible for liberation of drugs from glycosidic prodrugs1.
Ø Naikwade Sonali R et al.,4 developed a time and pH dependent controlled release colon specific delivery of tinidazole.From this study they revealed that the proposed single enteric coated tinidazole(500mg) tablet per day could be used in place of 3-4 doses of 500mg tinidazole conventional tablet with better controle of drug release for targeted drug release.
Ø R Margret handira et al., 11 formulated and evaluated mouth dissolving tablets by taking as a model drug.Etoricoxib is an effective and selective cox-inhibitor with anti-inflamatory and analgesic properties.The poor water solubility of etoricoxib gives rise to difficulties in the formulation of dosage form leading to variable dissolution rate.Hence etoricoxib was taken as a model drug for their study.
6.3 OBJECTIVES OF THE STUDY:
1. To carry out pre formulation studies of etoricoxib in order to improve the solubility and stability of etoricoxib in aqueous media
a. Stability studies of etoricoxib in distilled water and in different pH conditions.
b. To study the effect of acids on the stability of etoricoxib
c. To prepare and evaluate solid dispersion of etoricoxib by different methods.
2. To design and evaluate the colon targeted drug capsule
3. To perform in vitro studies for the colon targeted drug capsule.
MATERIALS AND METHODS:
7.1 MATERIALS:
Drug: Etoricoxib.
Capsule: Hard gelatin capsules.
Polymers: Eudragit®E100, Hydroxypropylmethylcellulose acetate succinate,
Hydroxypropylmethylcellulose, Ethylcellulose.
Organic acids: Succinic acid, tartaric acid, citric acid maleic acid, and fumaric
acid.
7.2 METHOD:
Primarily the preparation of the CTDC will be designed in the following steps as
follows:
1. Preparation of the drug etoricoxib solid dispersion.
2. Filling the formulated drug material in to the hard gelatin capsule.
3. Coating of the hard gelatin capsule.
4. Dissolution procedure by using different pH conditions.
7.3 SOURCE OF DATA:
1.The literature survey will be done by referring the abstracts of all the
2. National and International journals of pharmaceutical sciences.
3. The day to day development in this area will be updated by
literaturesurveythrough E-publishing and current periodicals in
library of SAC College of Pharmacy, B G Nagara.
7.4 METHOD OF COLLECTION OF DATA:
1. Preformulation studies such as:
· Solubility
· Compatibility drugs with excipients
· Calibration (melting point, pH etc.)
2. Laboratory investigations such as:
· By carrying out the in-vitro release pattern of this prepared colon targeted drug capsule by using Dissolution apparatus.
7.5 DOES THE STUDY REQUIRE ANY INVESTIGATION OR
INTERVENTIONS TO BE CONDUCTED ON ANIMALS/ PATIENTS?
Yes.
7.6 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR
INSTITUTION IN CASE OF ABOVE?
Yes.
7.7 DURATION OF THE STUDY:
The study will be conducted over a period of 9 months.
7.8 PLACE OF STUDY:
Sri Adichunchanagiri College of pharmacy, Dept of pharmaceutics, B.G.Nagara.
8
/ LIST OF REFERENCES:
1. M.K.chourasia, S.K.Jain.Pharmaceutical approaches to colon targeted drug deliverysystems. J Phamceut Sci 2003;6(1):33-66.
2. Prabhakara Prabhu, Nissara Ahmed, R.Narayanacharyulu, D Satyanarayana and EVS subrahmanayam. Invistigation and comparison of colon with guar gum. Pak J Pharm Sci 2010; 23(3):259-65.
3. Available from: URL: www.colonfunction.com as on 12/6/2010.
4. Naikwade sonali R, Kulakarni P, Jathar shripad R, Bajaj Amrita N. Development of time and pH dependent delivery of tinidazol.DARU 2008;16(3):119-27.
5. David R.Friend. New oral delivery systems for treatment of inflammatory bowel disease. Adv Drug Deliver Rev 2005;57:247-65.
6. [Micromedex]. Version 2.1. September-December 2010.
7. Masataka Katsuma, Shunsuke watanabe, Hitoshi Kawai, Shigea Takemura, Yoshinori Masude, Muneo Fakui. Studies on lactulose formulations for colon-specific drug delivery.Int J Pharm 2002;249:33-43.
8. Takashi Ishibashi, Harumi Hatano, Masao Kobayashi. Design and evaluation of new capsule dosage form for colon-targeted delivery of drugs.Int J Pharm 1998;168:31-40.
9. V.R Sinha, Rachna Kumria. Microbially triggered drug delivery to the colon.Eur J Pharm Sci 2003;18:3-18.
10. V.N.Sinha, B.R Mittal, Rachna Kumria. In-vivo evaluation of time and site of disintegration of polysaccharide tablet prepared for colon-specific drug delivery.Int J Pharm 2005;289:79-85.
11. R Margret Chandira, BS Venkataeswarlu, MV Kumudhavalli, Debjitbhowmik, B Jayakar. Formulation and evaluation of mouth dissolving tablets of the etoricoxib. Pak J pharm Sci 2010;23(2):178-81.