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A multifaceted peer reviewed journal in the field of Pharm Analysis and Pharmaceutics Formulation Development and in-vitro Evaluation of Sulfasalazine and Dexamethasone Combination Tablets Containing Natural and Semi Synthetic Polymer for Colon

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The present research was to develop oral sustained release tablets for colon targeting. Two drugs in combination form were used in this research to prepared tablets. Combination of sulfasalazine and dexamethasone used with natural and semi synthetic
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  Pharm Methods, 2016; 7(2): 112-120. A multifaceted peer reviewed journal in the field of Pharm Analysis and Pharmaceuticswww.phmethods.net | www.journalonweb.com/phm Original Article Pharmaceutical Methods, Vol 7, Issue 2, Jul-Dec, 2016   112 Formulation Development and in-vitro  Evaluation of Sulfasalazine and Dexamethasone Combination Tablets Containing Natural and Semi Synthetic Polymer for Colon Targeting ABSTRACT The present research was to develop oral sustained release tablets for co-lon targeting. Two drugs in combination form were used in this research to prepared tablets. Combination of sulfasalazine and dexamethasone used with natural and semi synthetic polymers (tragacanth and HPMC K15). Sustained release matrix tablets of sulfasalazine and dexamethasone were prepared by using different ratios of drug, HPMC K15 and tragacanth. Microcrystalline cellulose (MCC) and lactose were used as diluents. Both polymers were mixed with other ingredients and formed a matrix system using direct compression technique. All the ingredients of formulation were compressed using concave punches in ZP 19 compression machine. Compressed tablets were evaluated for assay, diameter, hardness, thick-ness, friability, weight variation and in vitro dissolution using USP dissolu-tion apparatus type II. Different formulations were prepared and evaluated with respect to dissolution profile in 900 mL 0.1 N Hcl and phosphate buffer pH 6.8 and pH7.4 including microbial flora for 12 h at 37˚C. Rising the amount of polymer (HPMC K15) in the formulation led to slow release of drug and decreasing the amount of polymer gave enhanced release of sulfasalazine and dexamethasone. Different mathematical mod-els used to evaluate the matrix system (Zero order, First order, Higuchi and Hixson-Crowell). T5, T7, T8 solid matrix formulations followed zero order and Higuchi. The results showed that the formulation T7 containing 17% HPMC K15 and 17% gum tragacanth gives better results in microbial flora with phosphate buffer. Key words:  HPMC K15, Tragacanth gum, Sulfasalazine, Dexamethasone, Sustained release. Correspondence: Yasir Mehmood, Faculaty of Pharmacy, University of Central Punjab. Ameer and Adnan Pharmaceutical ,Lahore, PAKISTAN E-mail: yasirmehmoodamjad@gmail.com DOI :  10.5530/phm.2016.7.17 Yasir Mehmood Faculty of Pharmacy, University of Central Punjab.Ameer and Adnan Pharmaceutical, Lahore, PAKISTAN. INTRODUCTION Sustained release dosage orms are the ormulations which release the therapeutically active agents or longer period o time at expected rate afer its single dose administration. 1  When highly water soluble drugs are produce or oral sustained release dosage orm cause problems like they may be released more rapidly and produce toxicity i not prepared in appropriate procedure. 2  several methods are there to prepared colon targeted sustained release dosage orm. 3  Among which matrix system is most appropriate due to efficiency, consistency, validation, scale up and cost effective. Microcrystalline cellulose and lactose were used as diluents. 4  Colon targeted drug delivery systems present a variety o ben-efits above conventional dosage orms that include decrease in dosage rate, minimum toxic effect and improved patient compliance. 5  On the other hand, more constant level o drug in the blood constant flow with minimum peak-valley is reached, achieve greater efficacy. 6  A process or manuacturing colon targeting extended release dosage orm is expen-sive which makes these products expensive than the conventional dos-age orms. 7,8  Other actors that we have considered are motility o the GI, difference in pH and absorption . Development o colon targeted sustained release tablet or highly water-soluble drugs has always been a difficult job because water soluble drugs, i not prepared properly and administered orally, are released at a high rate and cause problems due to toxic concentrations. 3  Hence, it is a difficult task to ormulate a suit-able colon targeted tablet or sustaining action o highly water- soluble drugs. 8  Hydrophilic polymers are widely used in the ormulation o co-lon targeted sustained release oral dosage orms. 8  Different natural ma-terials (tragacanth gum, trxanthan gum, guar gum, and chitosan) have been used by various researchers and these materials are biodegradable. 9  It has been shown that in hydrophilic matrices, swelling as well as ero-sion o the polymer occurs simultaneously, and both processes contrib-ute to the overall drug release rate. 10  HPMC k15 offers potential utility as a drug carrier because o its in-ertness and biocompatibility. 11  Hpmc k15 not only retards in vitro drug release and provides time independent release kinetics, but also works effectively in vivo and establishes constant drug plasma levels. 12 Sulfasalazine is used in treatment o a certain type o bowel disease(BD) called ulcerative colitis. 13 Tis drug does not cure this condition, but de-crease the symptoms such as inflammation, ever, stomach pain, diar-rhea, and rectal bleeding. 14  Te mechanism o action o Sulasalazine (SSZ) or its metabolites, 5-aminosalicylic acid (5-ASA) and sulapyri-dine (SP), is not clear, but its anti-inflammatory and immunomodula-tory properties have been observed in animal and in vitro models, to its affinity or connective tissue, and in high concentration it reaches in serous fluids, in the liver and intestinal walls, as established in autoradio-graphic studies in animals. 15  Clinical studies afer rectal administration o SSZ, SP, and 5-ASA have show that this major therapeutic action in ulcerative colitis. 16 In vivo  studies show that the absolute bioavailability o orally administered sulasalazine is less than 15% or parent drug. 17,18  In the intestine, sulasalazine metabolized by several intestinal bacteria to SP and 5-ASA. 19  Sula pyridine is relatively well absorbed rom the intes-tine and highly metabolized, while 5-ASA is much less well absorbed. 15 Corticosteroids are extensively used in the cureo inflammatory bowel disease (IBD). 20  argeted o drugs to the colon is helpul in the treatment and cure o different colonic diseases  Pharmaceutical Methods, Vol 7, Issue 2, Jul-Dec, 2016   113 Mehmood et al  .: Formulation and in vitro evaluation o matrix tablet in combination(ulcerative colitis and crohn’s disease). 21  Corticosteroids are traditionally use or treating inflammatory bowel disease. 22  However chronic treat-ment o inflammatory bowel disease with corticosteroids, while ofen efficient, but this has serious side-effects (e.g. acne, moonace, hyper-tension, peptic ulcer and mood disturbances). 23  Steroids would have the potential o being perect therapeutic treatments o inflammatory bowel disease. 24 ragacanth is a naturally occurring gum produce rom Astragalus gum-mier Labillardiere and other species o Astragalus. 25  Te tragacanth gum consists o a mixture o water-insoluble and water-soluble poly sac-charides. 9  Bassorin, which constitutes 60% to 70% o the gum, 9  is the main water-insoluble portion, while the remainder o the gum consists o the water-soluble material, tragacanth. 26  ragacanth gum is used as an emulsiying and suspending agent in a variety o pharmaceutical ormu-lations. 27  It is used in creams, gels, and emulsions at various concentra-tions according to the application o the ormulation and the grade o gum used. 28 Te aim o this research work was to assess drug release rom gum traga-canth and HPMC K15 based matrix tablet ormulations o sulasalazine and dexamethasone and the ability o these polymers in the ormation o colon targeted sustained release tablets. MATERIALS AND METHODSMaterials Sulasalazine and dexamethasone (AA Pharmaceuticals, Pakistan), HPMC K15 and tragacanth (Colorcon, pakistan), microcrystalline cel-lulose (PH 101), lactose monohydrate, Aerosil and magnesium stearate (Merck, Germany). Preparation of matrix tablet Preparation o matrix tablets using different proportions o HPMC K15 and tragacanth gum. Solid matrix tablets o sulasalazine and dexameth-asone were prepared using direct compression method. Sulasalazine and dexamethasone, different proportion o HPMC K15 and tragacanth gum, Aerosil (colloidal silicon dioxide), lactose, microcrystalline cellu-lose (MCC) and magnesium stearate were used in preparing these ma-trix tablets. Developed ormulations are presented in able 1. All active and inactive ingredients were weighed individually and sieved through mesh size no. 60 and were blended or 10 min in a blender, at the end o mixing or blending Magnesium stearate 1.0% w/w was added and blend-ed or additional 5 min. ablets were compressed by direct compaction using multi punch machine ZP 19. Te weight o tablets was adjusted to 360 mg and compressed. Physical tests of tablets 29 In order to determine the uniormity in weight o tablets, 20 tablets o each ormulation were randomly collected and weighed using Sartorius weight balance. We find weight variation o all tablets within specifica-tion o BP 2015, result show that the filling o die cavity or tablets was uniorm. All the prepared ormulations were checked and the deviation was not greater than limit. Te result o tablets weight variation is shown in able 3. Hardness o tablets was also determined using curio Hardness ester. en tablets o each ormulation were used and the average hard-ness value was observed. Friability o each prepared ormulation were also determined and also shown in table. Diameter and thickness o each prepared tablet also determined by using vernier calliper. Fourier transforms infrared spectroscopy (FTIR) 30 Te ‘Bruker’ FIR was used to obtain the transmittance spectrums o different polymers to check any incompatibility between the polymers used to obtain the co-processed excipients In vitro  dissolution study of sulfasalazine 31 In vitro  dissolution studies o solid matrix system In vitro  dissolution o all the tablets was determined using the USP apparatus II, Pharma est, China. Te apparatus was validated by counting the revolutions o the paddle per minute. Te test was perormed in 900 mL o phosphate.buffer (pH 6.8) with the temperature maintained at 37.0 ± 0.5˚C, while the stirring speed was maintained at 50 rpm. Samples o about 10 mL each were collected at, 1, 2, 3, 4, 5, 6, 8, 10 and 12 hours with the help o pipette. Sulasalazine was analyzed at 358nm using spectrophotometer. Dissolution study was perormed in 0.1 Hcl media or 2 hours and in phosphate buffer 7.4 pH or 3 hours, at the end tablet was checked in microbial flora with phosphate buffer o pH 6.8. In vitro  dissolution study of dexamethasone In vitro dissolution studies o solid matrix system In vitro dissolution o all the tablets was determined using the USP apparatus II, Pharma est, China. Te apparatus was validated by counting the revolutions o the paddle per minute. Te test was perormed in 900 mL o phosphate bu-er (pH 6.8) with the temperature maintained at 37.0 ± 0.50, while the stirring speed was maintained at 50 rpm. Samples o about 10 mL each were collected at, 1, 2, 3, 4, 5, 6, 8, 10 and 12 hours with the help o pi-pette. Dexamethasone was analyzed at 241nm using spectrophotometer. Dissolution study was perormed in 0.1 Hcl media or 2 hrs and in phos-phate buffer 7.4 pH or 3 hrs, at the end tablet was checked in microbial flora with phosphate buffer o pH 6.8. All the tests were run in triplicate and the average o three values were taken. Figure 1 shows dissolution behavior o sulasalazine in phosphate buffer (pH 7.4), 0.1 N HCl and microbial flora media (pH 6.8) or 10 h. Figure 2 indicate release profile o dexamethasone in same medium. Kinetic modeling of drug release Drug release shows the process o change drug in an appropriate orm which could undergo the pharmacokinetic parameters (i.e. drug ab-sorption, drug distribution, drug metabolism & excretion) & ultimately become available to produce pharmacological effect. Te outcome o in vitro  dissolution studies was applied in different mathematical models to determine the kinetics o drug release by the Sulasalazine sustained re-lease matrix tablets. Value o correlation co-efficient (i.e. r), derived rom different mathematical models, was used to determine the model which describes the drug release rom the matrix tablet system most appropri-ately. Te zero-order kinetic model indicates the system in which inde-pendent drug release rate. In first order kinetic model, the drug release rate depends on concentration. Higuchi describes the release o the drug rom an insoluble matrix as square root o time dependent process. Te Hixson-Crowell cube root law indicates the drug release rom a system in which there is change in the surace area and diameter o the particles present in dosage orm. Korsmeyer-Peppas Equations (Diffusion/Relax-ation Model) Mt/M0 = k5t.First order Kinetics Log Qt = (Kt/2.303) + Log Q0. Zero order Kinetics Qt = K0 t + Q0.Higuchi’s release model (Diffusion model) f = KHt1/2.Equation or Korsmeyer – peppas release model Mt/M∞ = Ktn.  114   Pharmaceutical Methods, Vol 7, Issue 2, Jul-Dec, 2016 Mehmood et al  .: Formulation and in vitro evaluation o matrix tablet in combination Table 1: absorbance of sulfasalazine and dexamethasone at different concentration Sr noconcentration(mcg)Absorbance Sulasalazine1100.6962141.0463201.500dexamethasone1100.3942200.8043301.290 Table 2: Formulations with varying %age concentration of polymer and excipients Sr.#FORMULATION INGREDIENTSFormulation CodeT1T2T3T4T5T6T7T8T9 1Sulasalazine1001001001001001001001001002dexamethasone1010101010101010103Lactose Anhydrous101.4101.4101.484848466.566.566.54MCC5656565656565656565Magnesium Stearate5555555556ragacanth Gum43.82214.652.526.2517.561.2530.6320.427HPMC K1543.865.637352.578.7587.561.2591.9102.08OAL360 mg360 mg360 mg360 mg360 mg360 mg360 mg360 mg360 mg Table 3: various physical tests performed on the tablet formulations Trial No.Diameter (mm)Thickness (mm)Hardness Kg/cm 2 Friability (%)Weight Variation (%) 110.64 ± 0.01334.22 ± 0.11886.75 ± 0.9910.251.2210.65 ± 0.02334.43 ± 0.09117.52 ± 0.2210.612.3310.62 ± 0.00664.24 ± 0.09886.82 ± 0.9210.351.4410.63 ± 0.00334.26 ± 0.07886.94 ± 0.8010.470.71510.62 ± 0.00664.28 ± 0.05888.34 ± 0.5980.511.4610.61 ± 0.01664.50 ± 0.16117.24 ± 0.5010.570.25710.63 ± 0.00334.48 ± 0.14118.36 ± 0.6180.291.1810.620. ± 00664.26 ± 0.07889.5 ± 1.7580.611.7910.62 ± 0.00664.38 ± 0.04118.2 ± 0.4580.372.1 Table 4: Assay (percentage drug content in various formulations) Trial No.Assay of Dexamethasone Assay of Sulfasalazine 197.298.32102.4101.63103.197.14101.7103.25102.5101.56104.4102.2799.898.28103.5103.99104.2103.1  Pharmaceutical Methods, Vol 7, Issue 2, Jul-Dec, 2016   115 Mehmood et al  .: Formulation and in vitro evaluation o matrix tablet in combination Table 5: release profile (sulfasalazine) of various tablet formulation Time(hr)01234681012 1031.9949.2357.7997.87----2032.7448.8255.3150.2371.9580.7394.25-3035.0347.7351.2463.8687.1595.74--4036.7654.0561.9380.493.68---5025.7231.9538.6665.9474.6287.898.61-6024.8636.2838.1750.2365.0291.0295.371007029.4940.9142.8249.2469.6595.65--8021.1541.0449.0465.9475.0886.1898.961009011.1630.947.9959.2471.178.1185.0697.7 Table 6: Release profile (dexamethasone) of various tablet formulation Time(hr)01234681012 1022.039.2347.2997.87----2031.3239.2245.3150.2371.9580.73--3025.0337.2341.2463.8687.15---4026.7644.0564.4380.493.68---5015.7229.2548.3645.4484.62---6034.8646.2838.3746.2365.0283.43--7021.4930.9142.8349.2469.6585.65--8013.1521.0449.0465.9475.0886.18--9011.2620.937.4949.2461.3278.1185.06- Table 7: Blend flow properties of pre compressed powder Sr. no.Formulation trial no.Angle of repose(θ)Bulk density (gm/ml)Tapped density (gm/ml)Compressibility index (%)Hausner’s ratio 1128.720.6180.76118.751.232226.350.6490.76915.631.193327.120.6100.69712.501.144425.240.7210.7817.691.085529.360.6360.74915.151.186629.640.6680.7136.251.077728.740.6590.7279.381.108825.920.6250.70811.761.139926.580.6460.7119.091.10  116   Pharmaceutical Methods, Vol 7, Issue 2, Jul-Dec, 2016 Mehmood et al  .: Formulation and in vitro evaluation o matrix tablet in combination Table 8: Kinetic modeling of in vitro dissolution data all trial formulations (sulfasalazine) FormulationpHZero order release kineticsFirst order release kineticsHiguchi modelK  0 (h -1 )r 2 K  1 ( h -1 )r 2 K  2 (h -1 )r 2 51.29.9620.965-0.2590.9860.380.9636.89.9620.9650.0220.030.3640.997.410.860.990.0220.030.3920.99271.210.510.956-0.2590.9860.3800.9636.89.9620.965-0.4460.9860.3640.9907.410.8670.9900.0220.0300.3920.99281.212.9590.898-0.0140.0040.4730.9206.88.9330.753-0.9990.9920.3480.8797.410.0420.9080.0240.0090.3740.972 Table 9: Korsemeyer–peppas model of i n vitro  dissolution data of the trial (sulfasalazine) FormulationpHKorsemeyer –peppas modelMechanism of Drug transportRelease exponent ‘n’r 2 51.20.80.965Non- Fickian diffusion6.80.5430.991Non- Fickian diffusion7.40.6140.994Non- Fickian diffusion71.20.8000.966Non- Fickian diffusion6.80.5430.992Non- Fickian diffusion7.40.6140.995Non- Fickian diffusion81.20.8770.929Non- Fickian diffusion6.80.500.942Non- Fickian diffusion7.40.500.983Non- Fickian diffusion Table 10: Kinetic modeling of in vitro dissolution data dexamethasone FormulationpHZero order release kineticsFirst order release kineticsHiguchi modelK  0 (h -1 )r 2 K  1 ( h -1 )r 2 K  2 (h -1 )r 2 71.29.8060.96-0.2170.9790.350.9446.88.6890.998-0.2080.9720.3080.9677.48.9230.973-0.2150.9930.3230.983 Table 11: Korsemeyer–peppas model of in vitro dissolution data of dexamethasone FormulationpHKorsemeyer –peppas modelMechanism of Drug transportRelease exponent ‘n’r 2 71.20.800.964Non- Fickian diffusion6.80.5330.951Non- Fickian diffusion7.40.6340.944Non- Fickian diffusion
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