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Formulation of Ketorolac Tromethamine for Controlled Release in Gastrointestinal and Colonic Delivery System

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Formulation of Ketorolac Tromethamine for Controlled Release in Gastrointestinal and Colonic Delivery System Indonesian J. Pharm. Vol. 29 No. 2 : 49 – 59 Research Article ISSN-p : 2338-9427 DOI: 10.14499/indonesianjpharm29iss2pp49 Formulation of Ketorolac Tromethamine for Controlled Release in Gastrointestinal and Colonic Delivery System Md. Amzad Hossain1, Swapon Kumar Shill2, Shakhawat Hasan Khan2, S. M. Moazzem Hossen3 and Mohammad Nasir Uddin2* 1Department of Pharmacy, ABSTRACT University Science and A suitable matrix system of ketorolac tromethamine (KTR) Technology Chittagong, formulation has been developed with the aim of increasing the Bangladesh. contact time, achieving controlled release, reducing the 2 Department of Chemistry, frequency of administration, improving patient compliance. In University of Chittagong, this concern an enteric-coated KTR matrix tablet intended for Chittagong-4331, specific delivery of drugs to the colon by combining the use of a Bangladesh. time dependent core with a pH-sensitive film coating. Eudragit 3Department of Pharmacy, L100, with a threshold pH 7, was selected as coating material. University of Chittagong, New formulation is proved to be noble as to KTR delivery through Chittagong-4331, both gastrointestinal and colonic system. New formulation is Bangladesh. considered to reduce gastrointestinal side effects and achieve Submitted: 08-02-2018 high local drug concentration at the afflicted site in the gastro- Revised: 20-03-2018 intestine and colon. Accepted: 16-04-2018 Key words: Drug Formulation, Ketorolactromethamine, gastrointestinal and colonic delivery system, HPLC analysis *Corresponding author M. Nasir Uddin *Corresponding author Email: [email protected] INTRODUCTION postoperative cancer pain and in the treatment The magnitude of these fluctuations due of migraine pain (Andrade et al., 1994). As the to the administration of drugs in conventional biological half-life of KTR is 4–6 h frequent dosage forms depends on the rates of dosing is necessary to sustain the action of drug absorption, distribution and elimination and to alleviate pain in postoperative patients. It dosing intervals. Again though intravenous causes gastro intestinal complications including administration of drug provides the advantages irritation, ulcer, bleeding and perforation when like direct entry of drug into the systemic administered as the conventional formulation circulation, and control of circulating drug (Shankar and Mishra, 2003; Shyamala and levels but this drug delivery has certain Sanmathi, 2001). Although oral bioavailability disadvantages, which would require of KTR was reported to be 90% with a very hospitalization of the patients and close medical low first pass metabolism, its short biological supervision of the medication (Joseph et half-life and many adverse effects, such as al.1987). The novel drug delivery system upper abdominal pain and gastrointestinal includes transdermal drug delivery system, ulceration, restrict its oral use. mucoadhesive drug delivery system, nasal drug delivery system, gastrointestinal, colonic drug delivery system etc. Ketorolac tromethamine (KTR) (Figure 1), a potent nonnarcotic analgesic with moderate anti-inflammatory activity, has been investigated extensively for use in post- operative analgesia and has an excellent Figure 1. Structural formulae for ketorolac applicability in the emergency treatment of tromethamine Volume 29 Issue 2 (2018) 49 Formulation of Ketorolac Tromethamine Oral administration of different dosage colon specific matrix tablets. Ethyl cellulose can forms has high patient acceptance due to be applied to prepare sustained release tablets greater flexibility in design of dosage form but by direct compression. Lower viscous grades of the gastrointestinal tract presents several ethyl cellulose or a higher percentage of ethyl formidable barriers to drug delivery (Girish et cellulose in the formulation can slow down the al., 2006). Colon has a large amount of drug release rate. Furthermore, it has been seen lymphoma tissue negligible brush boarder that lower viscous grades produce harder membrane activity and much less pancreatic tablets and a smaller particle size leads to a enzymatic activity as compared with the small slower release rate. Membranes made of only intestine. Therefore, in oral colon-specific drug Ethyl cellulose are water insoluble with good delivery system facilitates direct absorption in mechanical properties, but poor water to the blood (Chourasia, Jain, 2003) and this permeability. These properties strongly delivery by oral route has gained increased decrease the release of an active substance. importance from last two decades to treat local Sodium alginate, a hydrophilic biopolymer is diseases associated with colon (Vincent, 2002). used to increase the permeability of films. The traditional approaches for colon targeting Combination of both swells and drug are prodrug formulation, pH-sensitive drug molecules begin to move out of the system by delivery, time-dependent systems and microbial diffusion. degradation methods to formulate different In fact the polymers used to achieve dosage forms (Vemula, 2009). With colon targeting should be able to withstand, conventional tabletting facilities and less unchanged, the lower pH values of stomach processing variables, formulation of matrix and small intestine and dissolve at the neutral tablets is inexpensive method and easy to or slightly alkaline pH of the terminal ileum manufacture (Demiroz et al., 2004). (Chourasia, 2003). Keterolac tromethamine (KTR), a non-steroidal anti-inflammatory drug was efficient to treat inflammation and pain related to colon. The frequent intake of NSAIDS like KTR leads to gastric ulceration, bleeding and other gastric complications (Chopra et al., 2008). Hence the objective is to R=H or CH2 CH3 develop new KTR formulation for the delivery through both gastrointestinal and colonic Figure 2. Ethyl cellulose, a synthetic retardant system. That is to reduce gastrointestinal side widely used as a release agent effects and achieve high local drug Preparation of matrix tablets is simple concentration at the afflicted site in the gastro- method compared to other methods like tablets intestine and colon, optimal therapeutic coated with different polymers and chemical effectiveness and good patient compliance. conjugation of drug. Ethyl cellulose (Figure 2), a synthetic retardant, is widely used as an MATERIAL AND METHODS extended release agent in the pharmaceutical KTR was gift sample from industry. Ethyl cellulose is an inert, Glaxosmithkline Labs, Chittagong, Bangladesh. hydrophobic polymer and is essentially Na alginate, Mg stearate, Xanthine gum, Guar tasteless, odorless, colorless, non-caloric, and gum etc. of analytical grade (purity > 95%) physiologically inert. As solvent-based tablet were supplied by local agents of Aldrich Co. and pellet coating, tablet binder, to prepare Ethyl cellulose (EC), actual viscosity 9.9 microcapsules and microspheres Ethyl cellulose centipoises, was obtained from ICN has long been used. It is also used both as film- Biomedicals, Inc. (Ohio, USA). Eudragit L 100 and matrix- forming material for sustained- (purity > 95%) was gift samples from Opsonin release dosage forms. It shows good swelling Pharmaceutical Ltd. Bangladesh. All other and gel-forming properties and its controlled chemicals and solvents used were also of release mechanism is applied to formulate pharmaceutical grade. 50 Volume 29 Issue 2 (2018) Md. Amzad Hossain Table I. The compositions of the matrix tablets of proposed formulation Ingredient F1 F2 F3 F4 F5 F6 Ketorolac tormethamine 10mg 10mg 10mg 10mg 10mg 10mg Xanthine gum 10mg 0 0 0 10mg 5mg Guar gum 0 10mg 0 0 10mg 5mg Ethyl cellulose 0 0 10mg 0 10mg 5mg Na alginate 0 0 0 10mg 10mg 5mg DCP 178mg 178 mg 178mg 178mg 148mg 168mg Mg stearate 2mg 2mg 2mg 2mg 2mg 2mg Total weight 200mg 200mg 200mg 200mg 200mg 200mg Table II. Composition of coating solution Sr. No Name of reagent Amount used 1 Eudragit L 100 5% 2 Talc 2% 3 PEG 400 1% 4 Ethanol QS Powder characterization ethyl cellulose and excipients other than glidant Before preparation of tablets, the and lubricant were passed through 60-mesh powder mixtures of different formulations were sieve and mixed in a poly bag for 5-10min, then evaluated for angle of repose, bulk density granules were prepared with the addition of tapped density and compressibility index. The sufficient amount of 5% poly vinyl pyrrolidine angle of repose (θ) was measured using fixed in alcohol as binding agent, dried and sieved to funnel method and it was calculated using the obtain uniform size granules. The obtained following formula: granules were lubricated with talc and magnesium stearate for another 5 min blending θ = …………………………………….... (1) and the resultant mixture was compressed into Where, h is height of the cone and r is radius of tablets with 8 mm round flat punches using 16- the cone base. Angle of repose less than 30 station rotary tabletting machine. The final shows the free flowing of the material. weight of the tablet was adjusted to 200mg. The compressibility index or Carr‟s Batch size was limited to 100g. The Index is a measure of the propensity of a compositions of the matrix tablets (Table I). powder to be compressed. Carr‟s Index is determined from the bulk and tapped densities. Composition and preparation of coating It is calculated using the following formula: solution The compositions of coating solution are given in following table. Eudragit L100 was Carr‟s Index =[ ×100] …….…(2) dissolved in organic solvent 5 % w/v (ethanol), and then it was stirred
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