INTRODUCTION:

During the last decade many investigations have been carried out with the aim of discovering an ideal formulation for colon-specific drug delivery. Many approaches have been demonstrated [1]. The colon is a site where both local and systemic drug delivery can take place. Treatment might be more effective, if the drug substances were targeted directly on the site of action in the colon. Lower doses might be adequate and, if so, systemic side effects might be reduced [2,3]. The gastrointestinal tract presents several formidable barriers to the drug delivery. Colonic drug delivery has gained increased importance not just for the delivery of drugs for the treatment of local diseases of colon but also for its potential for the delivery of proteins and peptides.

The colon presents less hostile conditions for drug delivery because of less diversity and intensity of enzymatic activities and a near neutral pH [4,5]. In addition, colon may be the best site for drug delivery because of the long residence time and the low digestive enzymatic activities this may be useful for prolonged drug delivery [6,7]. Colon drug delivery is a relatively recent approach to the treatment of diseases and irritable bowel syndrome, recommended treatments include the administration of anti-inflammatory drugs, chemotherapy and antibiotics, which must be released in colon. Such local treatment has the advantages of requiring small drug quantities, possibly leading to reduce the incidence of side effects and drug interactions [8]. The usual treatment of anti-inflammatory bowel disease consists of frequent intake of anti-inflammatory drugs at high doses in order to induce remission of active diseases leads to side effects like dizziness, GI disturbances, head ache and skin rash [9]. In this study the active drug Mesalamine used as an anti-inflammatory drug used to treat inflammation of the digestive tract and Ulcerative Colitis. Mesalamine undergoes extensive and highly variable hepatic first-pass metabolism following oral administration, with a reported systemic oral bioavailability between 20% and 30%. Mesalamine has half-life of 5 hours so patients are routinely asked to take Mesalamine for several times in a day if taken by oral route. [10-12] Ease of controlled drug therapy improvespatient compliance. The objective of the present study was to develop sustained release formulations of Mesalamine and to examine the effects of both hydrophilic and hydrophobic polymers on in-vitro drug release. [13] In the present study, Mesalamine formulations were prepared by using hydrophilic polymer, hydroxyl propyl methyl cellulose (HPMC) and hydrophobic polymer, ethyl cellulose (EC) alone and in combination to study the release kinetics and find out the effects of both the polymers and their combinations. [14-16]

MATERIALS AND METHODS:

Materials:

Mesalamine was procured as a gift sample from Wockhardt Pharma Pvt Ltd., Aurangabad., Microcrystalline Cellulose, Magnesium Stearate, Talc, Sodium Starch Glycolate, Croscarmellose sodium, Polyvinyl pyrolidone K30 USP, Polyvinyl pyrolidone K30 USP, Colloidal Silicon dioxideNf, Sodium Starch Glycolate, Methacrylic acid copolymer type B NF, Acetyl Tributyl Citrate NF, Dibutyl Sebacate NF, Titanium dioxide NF, and Feric oxide Yellow NF used were of analytical grade. In vitro analysis of the prepared tablets was carried out as per the requirements of tablets as specified in official Pharmacopeia.

Preparation of tablets:

Tablet of mesalamine with other excipients were prepared by direct compression. The weight of mesalamine was kept constant in all the prepared tablets at 800mg/tablet. Micro crystalline cellulose (MCC) was selected as tablet diluents for increasing the compressibility and flow ability of the ingredients. Magnesium stearate was used as a lubricant. To make powder mixtures, the drug, polymer and MCC were thoroughly mixed for 30 min by means of pestle and mortar. This powder mixture was then lubricated with magnesium stearate and Talc then compressed into tablets in 6 mm rotary tablet punching machine. The force of compression was adjusted so that hardness of all the prepared tablets ranges from 5.5-6.5kg/cm. The detailed compositions of the prepared tablet formulations are given in (Table 1). The optimized formulation of tablet was coated using a combination of Eudragit S100 and Acetyl Tributyl Citrate by using a fluidized bed coating apparatus. The prepared tablets of each batch were subjected for evaluation of hardness test, friability, drug content and in vitro drug release studies.

Table No: 1 Formulation of mesalamine tablet 800mg

Sr No	Ingredients	Quantity per tablets (mg)
		F1	F2	F3	F4	F5	F6
A	Roller Compaction
1	Mesalamine	800	800	800	800	800.00	800
2	Sodium Starch Glycolate	1.6	4	8	12	16.00	20
3	Croscarmellose sodium	3	3	3	3	3.00	3
4	Polyvinyl pyrolidone K30 USP	5	5	5	5	5.000	5
5	Magnesium stearate NF	4.5	3.5	3.5	3.5	3.500	3.5
	Weight of Compacted Material	813.10	815.50	819.50	823.50	827.50	831.50
B	RMG Granulation
6	Microcrystalline cellulose NF (Avicel PH-101)	34	38	42	46	50.00	54
7	Polyvinyl pyrolidone K30 USP	110	110	110	110	110.00	110
8	Polyvinyl pyrolidone K30 USP	--	--	--	--	21.00	--
9	Purified water USP	q.s	q.s	q.s.	q.s.	q.s.	q.s.
Weight of Dried Granules		957.10	963.50	971.50	979.50	1008.50	995.50
C	Blending and Lubrication
10	Colloidal Silicon dioxideNf (Aerosil 200)	--	--	2.15	4.60	4.60	4.60
11	Talc (Micronized) USP	5.20	6.00	6.80	6.00	5.20	6.80
12	Sodium Starch Glycolate NF (Type-A)	--	--	--	--	25.00	--
13	Magnesium Stearate NF	1.85	1.85	2.0	2.25	2.70	3.20
Weight of Core Tablet		964.15	971.35	982.45	992.35	1046.00	1010.10
D	Delayed Release Coating
14	Methacrylic acid copolymer type B NF (Eudragit S 100	24	24	28	28	46.00	48
15	Acetyl Tributyl Citrate NF	6.00	6.00	6.2	6.4	8.00	7.2
16	Dibutyl Sebacate NF	3.30	--	--	--	3.30	2.40
17	Talc (Micronized) USP	10.47	10.47	10.47	10.47	10.479	10.47
18	Titanium dioxide NF	2	2	2	--	2.00	--
19	Ferric oxide Red NF	0.48	0.52	0.50	0.50	0.525	0.53
20	Feric oxide Yellow NF	0.48	0.52	0.50	0.580	0.525	0.53
21	Isopropyl Alcohol (95 parts)	q.s	q.s	q.s	q.s	q.s	q.s
22	Purified water (5 parts)	q.s	q.s	q.s	q.s	q.s	q.s
Weight of DR coated Tablet		1010.88	1014.86	1030.12	1038.22	1116.829	1079.23

Evaluation:

Precompression:

The micromeritic properties of Granules like bulk density, tapped density, Carr’s index, Hausner’s ratio and angle of repose were evaluated to check the flow properties of granules

Post Compression:

The quality control tests for the tablets, such as hardness, friability, weight variation etc. were determined using reported procedure.

Thickness:

Prepared matrix tablets were evaluated for thickness by using vernier caliper.

Hardness:

The resistance of the tablets to chipping, abrasion or breakage under the condition of storage, transportation and handling before usage depends on its hardness. Several devices are used to test tablet hardness such as Monsanto tester, Strong-cob tester, Pfizer tester, Erweka tester and the Schlleuniger tester. Hardness of the tablets was evaluated using Monsanto hardness tester, which is expressed in kg/cm2

Friability:

Friability of tablets was determined using Roche friabilator. Twenty tablets were weighed and placed in a chamber. The friabilator was operated at 25rpm for four minutes (per 100 revolutions) and the tablets were subjected for combined effect of abrasion and shock because the plastic chamber carrying the tablets drops them at a distance of six inches with every revolution.

Weight variation:

Weight variation test was performed according to USP 2004. Twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The percentage deviation was calculated and checked for weight variation.

Drug Content:

The mesalamine tablets were tested for their drug content following crushing and powdering five tablets from each batch separately. The amount of powder equivalent to 500mg of the drug was weighed and dissolved in 100mL of distilled water. After 10 minutes of centrifugation, aliquots of 1mL were taken from this solution and diluted to 100mL with water (10μg/mL). The absorbance of resulting solutions was measured in a UV spectrophotometer at 299nm. Simultaneously, a 10μg/mL of mesalamine standard solution was prepared in the same medium and the absorbance was recorded and drug content was calculated.

In- vitro drug release studies:

The release studies of all the matrix tablets were performed using a USP type I dissolution test apparatus (paddle apparatus, 100rpm, 37±0.5ºC) in 900mL of dissolution medium (SGF). 5ml samples were withdrawn with pipetting syringe at appropriate time intervals and filtered through Whatmann filter paper. Samples were estimated for drug using UV spectrophotometer (Simadzu, 1800) at suitable wave length 299nm. Sink conditions were adjusted with the addition of an equal volume of fresh dissolution medium at the same temperature throughout the test. The pH of the dissolution medium was kept 1.2 for 2h then, pH of the dissolution medium was adjusted to 7.4 (SIF- simulated intestinal fluid) and maintained up to 24h.

RESULTS AND DISCUSSION:

Precompression parameter:

Precompression parameter like bulk density, tapped density, Carr’s index Hausner’s ratio and angle of repose were evaluated to check the flow properties of tablets. The micromeritic properties of various formulations are given in table 2 The bulk density and tapped density ranged from 0.47gm/ml to 0.53gm/ml and 0.55gm/ml to 0.58gm/ml respectively. Carr’s index and Hausner’s ratio ranged from 12.17% to 15.19% and 1.13 to 1.17 respectively. The values obtained for angle of repose were 26.52º to 29.66º which indicates good flow properties of Tablets. All the formulation possessed good flow properties. Low value of angle of repose, Carr’s index and Hausner’s ratio revealed good micromeritic behavior of the granules. Since, the flow properties of the powder mixture are important for the uniformity of dose of the tablets.

Table No:2 Pre compression parameter of F1-F6

Formulation	Bulk density (gm/cm3) ± SD	Tapped density (gm/cm3) ± SD	Carr‘s index (%)± SD	Hausner‘s ratio ± SD	Angle of repose (°)± SD
F-1	0.51±0.011	0.56±0.009	12.17± 0.025	1.15±0.001	28.62 ±0.129
F-2	0.49±0.018	0.58±0.015	13.22± 0.020	1.13±0.004	29.32 ±0.124
F-3	0.48 ±0.008	0.56 ±0.008	15.19± 0.012	1.17 ±0.008	28.92 ±0.114
F-4	0.50±0.015	0.55±0.0219	13.32±1.231	1.13±0.001	29.66±1.527
F-5	0.53±0.0360	0.58±0.01	14.20±0.575	1.17±0.01	26.52±1.529
F-6	0.47±0.015	0.55±0.020	14.30±0.900	1.17±0.01	29.57±0.576

Table No:3 Post compression parameter of F1-F6.

Formulation	Weight variation ± SD	Hardnes kg/cm2± SD	Thickness (mm) ± SD	Friability (%)± SD	Drug Content (%)± SD
F-1	1113.23±0.01	4±0.408	6.44±0.01	0.90±0.020	97.52±0.49
F-2	1112.54±0.02	4.9±0.169	6.41±0.06	0.67±0.024	98.45±0.53
F-3	1117.02±0.03	4.6±0.402	6.50±0.01	0.70±0.049	98.27±0.82
F-4	1114.78±0.01	4.7±0.124	6.40±0.06	0.72±0.020	98.27±0.82
F-5	1115.72±0.02	5.5±0.249	6.59±0.03	0.67±0.032	98.88±0.85
F-6	1117.58±0.03	5.3±0.286	6.47±0.02	0.60±0.163	97.85±0.49

In vitro Drug Release:

Table No: 4 In vitro drug release of mesalamine tablet 800 mg.

Formulation	0h	1h	2h	3h	4h	5h	6h	7h	8h
F1	0	15.05	35.14	41.27	65.25	77.86	80.56	91.58	98.44
F2	0	16.84	45.12	44.16	58.69	70.86	72.98	92.35	100.14
F3	0	16.47	35.14	48.21	57.26	66.46	78.62	92.69	101.18
F4	0	12.14	30.86	39.56	42.98	69.84	75.98	95.85	99.88
F5	0	25.14	41.58	48.58	68.48	75.25	85.52	98.10	101.00
F6	0	10.03	25.73	43.49	63.03	73.84	88.32	90.66	100.55

Table no: 05: Kinetic model describing equation and R² value

Kinetic Model

Regression Co-efficient

value and Equation

Higuchi model

y = 10.34x – 13.72

R² = 0.913

Hixconcrowell

cube method

y = 0.435x + 1.813

R² = 0.676

Korysmeyer-

Peppas model

y = 1.439x + 0.857

R² = 0.620

The release kinetic data for all the formulations is shown in Table no 5. The kinetic data of all the formulation showed good fit in Higuchi model equation which indicated the combined effect of diffusion and erosion mechanism for controlled drug release from the swellable polymer. The R² values of Higuchi model is nearer to 1 hence test batch F5 produces desired release pattern which is responsible for maintaining concentration at colon. The release kinetic data of the optimum formulation was plotted.

Higuchi Model

Fig : 2 Percent drug release versus square root of time

Hixson Crowell cube Model

Fig: 3 cube root of percent drug remaining versus time (min)

Korsmeyer- Peppas Model

Fig: 4 log percent drug release versus log time

CONCLUSION:

Results of the present research work demonstrate that the combination of synthetic polymers successfully employed for formulating the colon release enteric coated tablets of mesalamine of 800mg by wet granulation method. It is observed that formulation F5 in both strengths shows targeted release of drug in 8 hours. The In vitro release was checked using different models of dissolution and found required results for targeted drug delivery.

The prepared tablet met the compendia limit in terms of physiochemical parameters and dissolution studies. HPMC and EC as sustained release polymers are suitable in colon targeted drug release of mesalamine to be absorbed in colon.

CONFLICT OF INTEREST:

No.

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Received on 08.08.2019 Modified on 19.09.2019

Research J. Pharm. and Tech 2020; 13(5):2241-2245.

DOI: 10.5958/0974-360X.2020.00403.5