Indian Journal of Pharmaceutical and Biological Research (IJPBR)

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1 Indian J.Pharm.Biol.Res. 2013; 1(4):64-70 Original Research Article Development and evaluation of nifidipine loaded tablet formulation for colon drug delivery Renu Dinkar 1, Govind Mohan 2, Kumud Upadhyaya 3* CODEN (USA): IJPB07 ISSN: Indian Journal of Pharmaceutical and Biological Research (IJPBR) 1 Department of Pharmacy,GIS Institute of Professional Studies, Dehradun. (Uttarakhand), India. 2 Department of Pharmacy,NIMS University, Jaipur. (Rajasthan), India. Journal homepage: 3 Department of Pharmaceutical Sciences, Kumaun Univesity, Nainital. (Uttarakhand), India. ARTICLE INFO: Article history: Received: 3August 2013 Received in revised form: 14 September 2013 Accepted: 25 September 2013 Available online: 7 December 2013 Keywords: Pulsatile system, Enteric polymer, Entrapment, Lag time. ABSTRACT Pulsatile release profile is characterized by a lag time followed by rapid and complete drug release. Pulsatile drug delivery systems are classified into time-controlled and site-specific delivery systems. The lag time is taken as the time of less than 10% drug release. The objective of present study was to develop a pulsatile compression coated tablet. The system was developed into two steps i.e. firstly core tablet was prepared containing Nifidipine; secondly core tablet was coated with polymer blend of ethyl cellulose (water insoluble polymer) and Eudragit L 100 (Enteric polymer). From the study it was concluded that the formulation having a coating level of 50% w/w of core and weight ratio of ethyl cellulose to Eudragit L 100 (20%) showed lesser release profile as compared to other formulation i.e % in 12hrs. As we increase the weight ratio of ethyl cellulose to Eudragit L 100 better entrapment of drug leading to controlled release of drug. 1. Introduction Conventional controlled release drug delivery systems were based on single- or multiple-unit reservoir or matrix systems, which were designed so that constant or nearly constant drug levels over an extended period of time can be achieved [1]. However, pulsatile delivery is desirable for drugs acting locally or having an absorption window in the gastro-intestinal tract or for drugs with an extensive first pass metabolism, e.g. β-blockers or for drugs, which develop biological tolerance, where the constant presence of the drug at the site of action diminishes the therapeutic effect, or for drugs with special pharmacokinetic features designed according to the circadian rhythm of human. A pulsatile release profile is characterized by a lag time followed by rapid and complete drug release [2]. Pulsatile drug delivery systems are generally classified into time-controlled and sitespecific delivery systems. The release from the first group is primarily controlled by the system, while the release from the second group is primarily controlled by the biological environment in the gastro-intestinal tract such as ph or enzymes. Most pulsatile drug delivery systems are reservoir devices covered with a barrier coating. The barrier can dissolve, erode or rupture during/after a certain lag time, after which the drug is released rapidly from the inner reservoir core [3-6]. The rupturing of the barriers is induced by an expanding core upon water penetration through the barrier coating. The expansion can be caused by effervescent excipients or swelling agents [7]. The objective of present study is to develop a pulsatile, compression coated tablet. The system was developed into two steps: first, core tablet was prepared containing Nifedipine; second, core tablet were coated with polymer blend of ethyl cellulose (water insoluble polymer) and eudragit L 100 (enteric polymer). *Corresponding Author: Dr. Kumud Upadhyaya, Department of Pharmaceutical Sciences, Kumaun University, Nainital, India. E- Mail: upkuupku@gmail.com 64

2 2. Materials and Methods Nifidipine supplied by High media, Polyvinylpyrrrolidone was supplied by ISP, Sodium carboxymethylstarch was obtained from the Linghu Food Co Ltd.., Eudragit L 100 (Supplied by Rohm), Ethyl cellulose (Supplied by Rohm). 2.1Preparation of Pulsatile Release Tablet I. Preparation of core tablet Nifedipine tablet core were prepared by wet granulation. The mixture for compression of core tablets was obtained by manually granulating Nifedipine (30 mg), cross-linked polyvinyl pyrrrolidone (40 mg) or sodium carboxy methyl starch (40mg) with 10% corn starch paste. Following drying and sieving, magnesium stearate (1% w/w) and talc (2% w/w) were added and blended for 10 minute. Core tablets (diameter, 6 mm; average tablet weight, 120mg) were compressed within 6 mm of punches on Cadmach 16 station compression machine under a common compression force of 3-4 Kg/cm 2. II. Preparation of compression coated tablet Six mm diameter drug cores were compression-coated into coated tablets with coating level (25% and 50%) based on the experimental design. The weight ratios of Eudragit L 100 to ethyl cellulose were (100:0%, 90:10% and 80:20% w/w) based on the experimental design. Compression coated tablet were prepared by first filling half of the polymer blend in the die cavity, then centrally positioning the tablet core on the powder bed followed by filling the remaining half of the polymer blend on top. Then compressed Cadmach 16 station compression machine with a compression force adjusted to obtain tablets with hardness in the range of at 6-7 Kg/cm 2. III. Drug Excipients Compatibility Study FT-IR spectra of drug and physical mixture of excipients and drug (1:1) were recorded with a FT-IR spectrophotometer (Shimadzu Corporation, Japan, 8400s) using KBr disc method. Each sample was gently triturated with KBr powder in a weight ratio of 1: 100 and pressed using a hydrostatic press (Kimaya Engineers, Mumbai, India) at a pressure of 10 tons for 5min. The disc was placed in the sample holder and scanned from 4000 to 500 cm-1 at a resolution of 1 cm - 1. IV. Pre-Compression Characterization of Coating Powder Blend and Core Tablet Powder Blend The quality of tablet, once formulated by rule, was generally dictated by the quality of physicochemical properties of blends. There were many formulations and process variables involved in mixing steps and all these can affect the characteristics of blend produced. a) Bulk Density Apparent bulk density (ρb) was determined by pouring the blend into a graduated cylinder. The bulk volume (Vb) and weight of powder (M) was determined. The bulk density was calculated using the formula Where M=Mass; Vb= Bulk Volume b) Tapped Density The measuring cylinder containing a known mass of blend was tapped 100 times using density apparatus. The constant minimum volume (Vt) occupied in the cylinder after tapping s and the weight (M) of the blend was measured. The tapped density (ρt) was calculated using the formula Where M=Mass; Vt= True Volume c) Compressibility Index The simplest way for measurement of flow of the powder was its compressibility, an indication of the ease with which a material can be induced to flow. It is expressed as compressibility index (I) which can be calculated as follows Where, ρt = Tapped density; ρb = Bulk density. d) Hausner s Ratio Hausner s ratio (HR) is an indirect index of ease of powder flow. It was calculated by the following formula Where, ρt is tapped density and ρb is bulk density. Lower Hausner s ratio (<1.25) indicates better flow properties than higher ones. e) Angle of Repose Angle of Repose was determined using funnel method. The blend was poured through a funnel that can be raised vertically until a specified cone height (h) was obtained. Radius of the heap (r) was measured and angle of repose (θ) was calculated using the formula. ; Therefore; Where, θ is angle of repose; h is height of cone; r is radius of cone. V. Post-Compression Characterization After compression of powder blends, the prepared tablets were evaluated for weight variation, tensile strength, thickness, friability and drug content. a) Weight Variation The weight variation test would be satisfactory method of determining the drug content uniformity. As per Original Research Article 65

3 USP42, twenty tablets were taken and weighted individually, calculating the average weight, and comparing the individual tablet weights to the average. The average weight of one tablet was calculated. b) Tablet Thickness Ten tablets were taken and their thickness was recorded using micrometres (Mityato, Japan). c) Friability Friability of the tablets was determined using Roche Friabilator. This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inch in each revolution. Preweighed sample of tablets was placed in the Friabilator and were subjected to 100 revolutions. Tablets were dedusted using a soft muslin cloth and reweighed. The friability (F %) was determined by the formula Where, W 0 is initial weight of the tablets before the test and W is the weight of the tablets after test. d) Tensile Strength The tensile strength of tablets was determined using a Ubique tensile tester by keeping tablet between upper and lower platen (60001; Ubique Enterprises, Pune, India). The test was performed by applying a diametrical load, measuring the maximum load F at the tablet fracture and calculating the radial tensile strength T using the following equation Where D is the tablet diameter and H is the tablet thickness. e) Drug Content Tablets, equivalent to about 420 mg of Nifedipine were taken. The tablets were finely powdered and transferred to a 250-mL volumetric flask containing 130 ml of water, homogenized until a uniform suspension was achieved (about 2 minutes), and transferd the suspension with the aid of a mixture of acetonitrile and methanol (1:1) to a 250 ml volumetric flask. Add a mixture of acetonitrile and methanol (1:1) to volume, and stir for 30 minute. The resulting solution was centrifuged to obtain a clear supernatant stock solution. Transferred 3.0 ml of the stock solution to a 50-mL volumetric flask and diluted with acetonitrile and methanol (1:1) to volume, mixed and the drug content was analysed spectrophotometrically (Shimadzu, UV- 1601) at 350nm. VI. In Vitro drug release study To study how composition of the coat and core to coat ratio interfere drug release profile of tablet in vitro drug release study was undertaken. The dissolution test was carried out using the USP XXXIII type II apparatus (Paddle apparatus TDL 08 L; Electro lab India Pvt. Ltd., Mumbai, India) with a rotation speed of 100 rpm and 900 ml medium at 37±0.5 0 C. With the medium change method, the release was performed in ph 1.2 for 2 h followed by ph 6.8 for 10 hr. Five ml sample was withdrawn at pre-determined time interval (1, 2, 3,4,5,6,8,10 and 12 hr) and replaced by the fresh dissolution medium. All the samples were filtered and analysed by UV spectrophotometer (to volume, mix and the drug content was analysed spectrophotometrically (Shimadzu, UV-1601) at wavelengths of 350 nm. The lag time was taken as the time of <10% drug released [8]. VII. Kinetics of drug release from coated tablet The release from the different formulations was determined by curve fitting method. Data obtained from in vitro release studies were fitted to various kinetic equations. The kinetic models used were: Q t = k o t (zero-order equation), ln Q t = ln Q 0 - k 1.t (first-order equation), Q t = K.S. t = k H. t (Higuchi eqn based on Fickian diffusion) Where, Q is the amount of drug release in time t, Q 0 is the initial amount of drug in the microsphere, S is the surface area of the microcapsule and k o,k 1,and k H are rate constant of zero order, first order and Higuchi rate equations respectively [9]. In addition to these basic release models, there are several other models as well. One of them is Peppas and Korsmeyer equation (power law). Mt / M = k t n Where Mt is the amount of drug release at time t and M is the amount release at time t =, thus Mt / M is the fraction of drug released at time t, k is the kinetic constant, and n is the diffusion exponent. 3. Results 3.1Drug excipients compatibility study Fourier Transformed Infrared Spectroscopy: FT-IR spectra of, drug and physical mixture of excipients and drug (1: 1) shown in Figure 1 and Figure 2. The characteristic absorption peaks of Nifedipine were also found in FT-IR spectra of physical mixture. 3.2 Pre-compression characterization of coating powder blend and core tablet powder blend Pre compression characteristic of the compression coated tablet were evaluated by determining bulk density, tapped density, Hausner s ratio, compressibility index and angle of repose. The bulk density of powder blend varied between 0.371± ±0.034 gm/cc. The tapped density was found in the range of 0.395± ±0.014 gm/cc. The results indicated good packaging capacity of powder blend. By using these two density data, Hausner s ratio and compressibility index was calculated. If the bed particle was more compressible then the powder will be less flowable and vice versa. The value of compressibility index was found between 4.556± ±1.012 %. The powder blend had Hausner s ratio less than 1.25 indicates good flow characteristics. The compressibility flowability correlation data indicates a good flowability of the powder blend. The flowability Original Research Article 66

4 of the powder blend was also evidenced by the angle of repose. The angle of repose below 30 0 ranges indicates well to excellent flow properties of powder. The angle of repose was found to be in range 23.34± ± The results showed good flow property of the powder blend. (Table.2) I. Post-compression characterization Weight variation was found to be within USP limit. The tensile strength of core and compression coated tablets were found to be within the range 2.72 to 4.43 MPa. The friability was below 1% for all the formulations, which is an indication of good mechanical resistance of the tablet. Drug content was observed within the range %. (Table.3) II. In Vitro Drug release study The in-vitro release study of the compression coated tablet was carried out using USP rotating paddle method at 100 rpm at 37 ºC. Dissolution study was performed at ph 1.2 for 2 h followed by ph 6.8 for 10 hr. Table.4and Fig.3 shows the drug release profile of different compression coated tablet. Result indicated that addition of ethyl cellulose prolong the lag time because ethyl cellulose significantly retarded the erosion of the Eudragit L 100 coating and decrease in solvent uptake. III. Drug Release kinetic In order to know the mechanism of drug release from compression coated tablet, data was fitted in kinetic model like Zero order, Higuchi, First order& Korsmeyer-Peppas. Model fitting data of release profile for formulation CCT 1-CCT 6 was shown in table.5. Result indicated that compression coated tablet follows Higuchi s kinetic. By using Korsmeyer and Peppas Equation, the n values were obtained between (Table.5) for all compression coated tablet. These values are characteristic of super case II transport (n>0.89), possibly outstanding to polymer chain relaxation and swelling of polymer. Table 1: Formulation of press coated tablet Formulation code Coating level (%w/w of core) Weight ratio of ethyl cellulose to eudragit L 100 (%) CCT 1 25 % w/w 0 CCT 2 10 CCT 3 20 CCT 4 50 % w/w 0 CCT 5 10 CCT 6 20 Table 2: Pre compression characteristics Formulation code Bulk Density (gm/cc) Tapped Density (gm/cc) Hausner s Ratio Compressibility Index (%) Angle of Repose (θ) Core Tablet 0.396± ± ± ± ±1.363 CCT ± ± ± ± ±1.221 CCT ± ± ± ± ±1.007 CCT ± ± ± ± ±1.126 CCT ± ± ± ± ±1.096 CCT ± ± ± ± ±1.132 CCT ± ± ± ± ±1.165 Original Research Article 67

5 Table 3: Evaluation of core and compression coated tablet Formulation Thickness(mm) Friability (%) Tensile strength Drug Content code (MPa) Core 2.1± ± ±0.10 CCT ± ± ±0.81 CCT ± ± ±0.17 CCT ±0.01 0, ± ±0.21 CCT ± ± ±0.19 CCT ± ± ±0.72 CCT ± ± ±0.67 Table 4: In Vitro drug release of different compression coated tablet Time (hr) Formulation CCT 1 CCT 2 CCT 3 CCT 4 CCT 5 CCT Table 5: In vitro drug release kinetic data Formulation Zero Higuchi s First Korsmeyer Peppas Order order Regression Slope CCT CCT CCT CCT CCT CCT Original Research Article 68

6 Figure1: FT-IR spectra of Nifedipine Figure 2: FT-IR spectra of physical mixture Figure 3: In Vitro drug release of compression coated tablet Original Research Article 69

7 4. Conclusion From the study it was concluded that the formulation having a coating level of 50% w/w of core and weight ratio of ethyl cellulose to Eudragit L 100 (20%) showed lesser release profile as compared to other formulation i.e % in 12hrs. As we increase the weight ratio of ethyl cellulose to eudragit L 100 better entrapment of drug leading to lesser release of drug. Conflict of interest statement We declare that we have no conflict of interest. References 1. Sungthogjeen S., Puttipipatkhachorn S., Paeratakul O.,Dasheveky A.,Bodmeire R. J. Contr Rel., 2004;95: Kro I., Bodmeier R.Floating or pulsatile drug delivery systems based on coated effervescent cores, Int. J. Pharm. 1995;187: Poli, S., Busetti, C., Moro, L. (1993).Oral pharmaceutical compositions for specific colon delivery. EP , 8 December. 4. Phuapradit, W., Railkar, A., Shah, N.H. (1995).Pharmaceutical composition. EP , 27 September. 5. Ueda S., Hata T., Asakura S., Yamaguchi H., Kotani M., Ueda Y. Development of a novel drug release system, Time-Controlled Explosion System (TES). I. Concept and design. J. Drug Target. 1994;2: Minoru O., Kenji O., Shuichi K.., Akira I. (1995). Controlled release-initiation and controlled release-rate pharmaceutical composition. EP , 1 March. 7. Schultz, P., Kleinebudde, P. A new Multiparticulate delayed release system. I. Dissolution properties and release mechanism. J. Control. Release 1997; 47: Sangalli M., Maroni A., Zema L., Busett C., Giordano F., Gazzaniga F., In vitro and in vivo evaluation of an oral system for time and/ or site-specific drug delivery, J. Contr. Rel. 2001;73: McNeil,M.E., Rashid, A., Stevens, H.N.E. (1990) Dispensing device, WO Patent 90/ Cite this article as: Renu Dinkar, Govind Mohan, Kumud Upadhyaya. Development and evaluation of nifidipine loaded tablet formulation for colon drug delivery. Indian J. Pharm. Biol. Res.2013; 1(4): All 2013 are reserved by Indian Journal of Pharmaceutical and Biological Research Original Research Article 70