Design and Evaluation of a new Capsule-type Dosage form for Colon-Targeted Delivery of Etoricoxib

Transcription

1 International Journal of Pharma Sciences Vol. 3, No. 1 (2013): Research Article Open Access ISSN: Design and Evaluation of a new Capsule-type Dosage form for Colon-Targeted Delivery of Etoricoxib Kiran Kumar GB*, Naresh Yadav S, Mohammed Gulzar Ahamed and Abdul Nasir K Department of Pharmaceutics, S.A.C. College of Pharmacy, B.G. Nagara, Nagamangala Taluk Mandya Dist , India. * Corresponding author; gbkk330@gmail.com Received: 24 December 2012 Accepted: 01 January 2013 Online: 10 January 2013 ABSTRACT A new capsule-type dosage form was investigated to approximate the chronobiology of rheumatoid arthritis for colonic targeting. 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 Succinic acid together with physical mixture of Etoricoxib (1:6ratio) in a capsule coated with a three-layered film consisting of an acid-soluble polymer, a watersoluble 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. The ability of colon targeted drug capsule to provide colon specific drug delivery was assessed by in vitro drug release studies in buffer solution at ph 1.2 for 2 h, and at ph 6.8(Simulated colonic fluid) for remaining hour. The results indicated that all the formulations shown no drug release in the stomach but the major portion of the drug was released in the colon and the drug release pattern was found to be F4>F3>F2>F1. From the analysis, it was found that, a predictable timed-release mechanism of a drug can be attained by adjusting the loading amount of Succinic acid. The outer enteric coating with cellulose acetate phthalate provided acceptable acid-resistibility. All these results suggested that this approach can provide a useful and practical means for colon-targeted delivery of drugs. Keywords: Colon-targeted delivery, hard gelatin capsule, Succinic acid, Eudragit E, Cellouse acetate phthalate INTRODUCTION The principal goal of site specific delivery is to deliver the drug in the specific organ of body. The therapeutic advantages of targeting the drug to the diseased organ include reduced incidence of adverse side effects, lower conventional dose and delivery of drug as close as possible to the target site [1]. Orally administered dosage forms normally dissolves in the stomach fluid or intestinal fluid and absorb from these regions of the gastro intestinal tract (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 GIT [2, 3]. Delivery of drugs via the colon offers numerous therapeutic advantages. Various diseases of colon such as ulcerative colitis, Chron s disease, carcinoma and infections require local therapy. So, the development of locally acting colon targeted drug delivery systems may revolutionize the treatment of colonic diseases. Colon specific system could also be used in conditions in which a diurnal rhythm is evident e.g. asthma, rheumatic disease, ulcer diseases and ischemic heart disease [4]. Rheumatoid arthritis is a chronic illness, patients may experience long periods without symptoms. Typically, however rheumatoid arthritis is a progressive illness that has a potential to cause joint destruction and functional disability. The cause of it is unknown; it is suspected that certain infections or factors in the environment might trigger the immune systems to attack the body s own tissue, resulting in inflammation. Two classes of medication are used, fast acting drugs such as Aspirin, Naproxen, Ibuprofen, Celecoxib, Rofecoxib, Etoricoxib etc and slow acting drugs such as Gold, Methotrexate and Hydroxychloroquine [5]. Etoricoxib is a nonsteroidal anti-inflammatory agent (5- chloro-6-methyl-3-[4-(methylsulfonyl) phenyl]-2,3 - bipyridine) for oral administration. It is a selective 147

2 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 [6, 7]. Etoricoxib (EXB) is practically insoluble in water. The rate of dissolution can be increased by increasing the surface area of available drug by various methods like micronization, complexation and slid dispersion (SD). Hence, an attempt was made to improve the dissolution characteristics using the solid dispersion technique. Among various approaches to improve the dissolution rate of poorly soluble drugs, the preparation of solid dispersions has often proved to be successful [8]. 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. Among the more practical technologies, a conventional enteric coating approach is not sufficient because all the drugs loaded will be released immediately after the gastric emptying, resulting in a poor site-specificity. Even though the use of various enteric polymers with higher dissolution ph or combination thereof have been tried to delay the timing of drug release, this approach does not seem relevant because the release behavior of such a system is reported to be greatly affected by a small change in ph or other ionic conditions. The sustainedrelease or timed-release approach, in which drugs are released on the basis of time-controlled principle is also insufficient because the large variation of gastric emptying time in humans makes it difficult to achieve sufficient and reliable colonic availability of a drug by those methods. Although the above-mentioned controlled- release approaches are thought quite practical in terms of producibility, the site-selectivity of drug delivery should be further improved [8]. With this in mind, we recently developed a new colon-targeted delivery system in capsule form, which was designed to possess a ph-sensing function and a timed-release function. In this paper, the concept for the design of this new device and the principle of drug release are introduced, and the potential for colonic delivery of drugs will be demonstrated through a series of in- vitro studies. MATERIALS AND METHODS Etoricoxib was used as a model drug. PEG 6000 was used as a carrier, Eudragit E100 was used as a cationic polymer which is soluble in low ph aqueous medium up to ph 5. Cellulose acetate phthalate was used as an enteric polymer. Hydroxypropylmethylcellulose was used as a neutral water-soluble polymer. Succinic acid was used as the ph adjusting agent. All other chemicals and solvents were of reagent grade. Preparation and evaluation of physical mixture of Etoricoxib with PEG-6000 Physical mixtures were prepared by simple blending of accurately weighed quantities of drug and carrier in different ratios 1:1, 1:3 and 1:6 and sifted through sieve # 100 in a closed glass bottle. The powder was then stored in a desiccator. A quantity of solid dispersion equivalent to 100 mg of Etoricoxib was accurately weighed and dissolved in 0.1 N HCl in100 ml. An ultraviolet (UV) Spectrophotometric method based on the measurement of absorbance at 234 nm in 0.1 N HCl was developed and used for the estimation of Etoricoxib. The method obeyed Beer s law in the concentration range of 0-10 mcg/ml. The dissolution rate of Etoricoxib as such and from its solid dispersions was studied using Lab India DS-8000 dissolution rate test apparatus with a basket type by filling in capsules. The dissolution rate was studied in 900ml of 0.1 N HCl containing 1 % SLS. Sodium lauryl sulphate was added to the dissolution fluid to maintain sink condition. Etoricoxib (50 mg) or its solid dispersion equivalent to 50 mg of Etoricoxib, with speed of 50 rpm and temperature of 37±1 0 c were used in each test samples of dissolution medium (5 ml) were withdrawn through a filter (0.45 μ) at different time intervals, suitably diluted and assayed for Etoricoxib by measuring absorbance at 234 nm and compared the dissolution profiles of mixtures. The results are shown in the Fig. 1. Preparation of CTDC Hard gelatin capsules were filled with the physical mixture (1:6) of Etoricoxib and organic acid with different amount of Succinic acid as shown in Table 2, after being sealed with 5% (w/w) Ethyl cellulose in ethanolic solution, the core capsules obtained were coated with three polymeric films successively in the order of Eudragit E100, HPMC, and CAP, by dipping method. The formula for the polymeric coating solution for each layer is described in Table 1. The amount of organic acid loaded in a capsule, and the amount of each coating film were varied depending on the research purpose. In dipping method the core capsules obtained were pre-weighed in an analytical balance and the weight is noted. Each capsule was slightly pierced with a 21G hypodermic needle; this served to provide a firm support in order to avoid direct contact with the hand. The capsule was then dipped into the Eudrgit E-100 coating solution for 3-5 sec and removed. It was dried under a fan (28 0 C) and allowed to equilibrate for 24hrs and same procedure was repeated for the 2 nd (HPMC) and 3 rd (CAP) coatings. After drying the needle was removed and the piercing spot sealed off with a little drop of Eudrgit E-100 coating solution followed by HPMC and CAP and again allowed to dry for another 24hrs and the design of CTDC was shown in Fig. 2. Table 1. Composition of coating solution Formula (w/ V %) Coating solution Eudragit E coating HPMC Coating CAP Coating Eudragit E 5.0 Ethanol 95.0 HPMC 5.0 Water 95.0 CAP 15.0 Acetone

3 Table 2. Formulation of Etoricoxib CTDC Three layered coating Name of ingredient Empty gelatin Capsule bodies Etoricoxib physical mixture(1:6) F1 F2 F F Succinic acid Eudrgit 100 film HPMC film CAP film Wt of capsule without coating Wt of capsule after coating ± ± ±7.4 Evaluation of Colon Targeted Drug Capsule The capsules were subjected to the following tests ±5.8 Thickness of three layered coating: The thickness of the CAP coating was measured using Vernier calipers, expressed in mm. In- vitro release profile Prepared colon targeted drug capsule formulations were subjected to preliminary in -vitro release studies. Dissolution was carried in two media, namely simulated gastric fluid (acidic buffer, ph 1.2) for the first two hours, and simulated colonic fluid (phosphate buffer ph 6.8) for the subsequent hours. After ingestion of the capsule, there was no drug release in the stomach due to the acid resistibility of the outer polymeric layer with all the formulation, indicating the efficiency of cellulose acetate phthalate as enteric coating polymer. This polymer proved that the drug was not released in the stomach. After gastric emptying, the outer layer and the intermediate layer quickly dissolved, but the inner polymeric layer still remains and effectively prevented the drug release in the intestine. However, when the micro-environmental ph inside the capsule gradually decreased according to the dissolution of organic acid and when the inner polymeric layer was finally dissolved by the acidic fluid the drug content was quickly released. The onset of the drug release, therefore, can be controlled by the thickness of the inner polymeric layer. When sufficient acid-resistibility and the suitable thickness of the inner layer are given to adjust the onset time of drug release to 3±1 hrs, a site-specific drug release to the proximal colon will be realized and the in- vitro release profile is shown in Fig. 4. A. Weight variation: 10 capsules were selected randomly from each batch and weighted individually to check for weight variation. The test requirements are met if none of the individual weights are less than 90% or more than 110% of the average. B. Effect of the loading amount of Succinic acid The coated capsules containing various amounts of Succinic acid were prepared and tested for Etoricoxib release. C. In- vitro release study The capsules were placed in a vessel with 900 ml of the 1 st fluid (phosphate buffer ph 1.2) and 2 nd fluid (phosphate buffer ph 6.8) at 37±0.5 C rotating at 100 rpm. The released amount was periodically determined by the Spectrophotometric method. All the experiments were carried out in more than triplicate. The morphological change of capsules during dissolution testing in the 2 nd fluid was observed. Assumed mechanism of drug release from CTDC in the gastrointestinal tract shown in Fig. 3. RESULTS AND DISCUSSION The thickness of the three layered coating was measured using Vernier calipers. The values ranged from mm. Figure 1. Comparison of dissolution profile of physical mixtures of Etoricoxib Figure 2. Basic structure and pharmaceutical composition of the Colon-Targeted Delivery Capsule 149

4 Figure 3. In vivo behavior of CTDC in the gastrointestinal tract constant and n is release exponent which characterizes the drug transport mechanism. The values n were in the range of to The formulations F2, F3, and F4 are indicating non-fickian release mechanism ( n values between ) and F1 is following super II release ( n values are more than 0.89). Table 3. Release Exponent Values and Release Rate Constant Values for Different Formulation Figure 4. Comparison of dissolution profile CTDC with different loading amount Formulation Code Zero order First order Higuchi equation Koresmeyer- Peppas model R 2 R 2 R 2 N R 2 Effect of the loading amount of Succinic acid The colon targeted drug capsules containing various amounts of Succinic acid were prepared and tested for Etoricoxib release. As expected, acid content affected the drug release behavior of the capsules. The lag time was gradually delayed with decrease in the acid content. Without Succinic acid the lag time was considerably delayed, on the other hand, when the acid content was increased the lag time attained was almost constant at around 3 hrs, and drug release after the lag time was sharp as shown in the Fig. 1. These results suggest that the lag time of capsules might be controlled by the loading amount of Succinic acid to some extent, and the adequate amount of Succinic acid for CTDCs was estimated at more than 20 mg to obtain a constant lag time and a quick release. Drug Release Kinetics The examination of the correlation coefficient r indicated that the drug release followed dissolution controlled mechanism from the CTDC (Table.3), as the values of r for first order (ranged from to 0.986) found to be more in comparison to zero order (ranged from to 0.886) and Higuchi's square root of time (ranged from to 0.975). It was understood to be predominant first order release pattern. Further, to understand the drug release mechanism, the data were fitted into Peppas exponential model M t /M =Kt n, where M t /M is the fraction of drug released after time t and K is kinetic F F F F CONCLUSION The aim of this project was to optimize the therapy of rheumatoid arthritis by applying a chrono therapeutic approach. An oral, time dependent onset of delayed release formulation of Etoricoxib, intended to approximate the chronobiology of rheumatoid pain and proposed for colonic targeting was successfully formulated. From the above Study and physical observation it can be concluded that there is no significant drug- excipient interaction. So we can conclude that drug and other excipients are compatible with each other. From the in-vitro release studies of device, it was observed that with all formulation, there was absolutely no drug release in simulated gastric fluid (acidic ph 1.2) for 2 hours. Accelerated stability studies, proved that the formulation is stable. The present in vitro study revealed that the CTDC can be a useful means for the colon targeted delivery of drugs. 150

5 ACKNOWLEDGEMENTS The authors are sincerely thankful to Sri Adichunchanagiri College of Pharmacy, B.G.Nagara for providing us infrastructure facilities and moral support to carry out this research work. REFERENCES 1. Sinha V.R and Bhinge. (2007). J.R. Platform Technologies in colon Delivery. Pharma Buzz. 1 (5): Chourasia MK, Jain NK. (2003). Pharmaceutical approaches to colon targeted drug delivery systems. J Pharmaceutical Sci. 6(1): Naikwade sonali R, Kulakarni P, Jathar shripad R et al. (2008). Development of time and p H dependent delivery of tinidazole.daru. 16(3): Kinget R, Kalala W, Vervoort L, Mooter.(1998). G.V. Colonic drug targeting. J. Drug Targeting. 6: Marc CH. (2002).New directions in symptomatic therapy for patients with osteoarthritis and rheumatoid arthritis. Seminars in Arthritis and Rheumatism. 32(3): [Micromedex]. Version 2.1. September-December Arcoxia profile [cited 2008 Aug 25]; Available From: URL: 10:49:52 GMT. 8. Muralidhar S,.Devala RG,.Krishna Murthy M, Kiran Kumar K,Kranthi Teja K,Syed KN Narayana TV.( 2011). Enhancement of dissolution rate of etoricoxib through solid dispersion technique. Journal of Applied Pharmaceutical Science. 1(5): Takashi I, Harumi H, Masao K. (1998). Design and evaluation of new capsule dosage form for colon-targeted delivery of drugs. Int J Pharm. 168: ; AIZEON Publishers This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 151