Colon Specific Drug Delivery System of Mesalamine for Eradication of Ulcerative Colitis

S. Sudarshan*¹, S. Sangeeta², NR Sheth³, P. Roshan⁴, YV Ushir⁵ and R. Gendle⁶

¹Dept. of Pharmaceutics, Shree H. N. Shukla Institute of Pharmaceutical Education and Research, Rajkot, (Gujarat.)

²Dept. of Pharmaceutical chemistry, C.P.S. Mahuda college of Pharmaceutical sciences, Bhermpur, (Orissa),

³Dept. of Pharmaceutical sciences, Saurasrta University, Rajkot, (Gujarat.), India

⁴Department of Pharmacognosy, Shree Leuva Patel Trust Pharmacy Mahila College, Amreli, (Gujarat.), India

⁵Dept. of Pharmacognosy, Shree H. N. Shukla Institute of Pharmaceutical Education and Research, Rajkot, (Gujarat)

⁶Dept. of Pharmaceutics, Institute of Pharmacy, RITEE, Raipur (Chhattisgarh) India.

Corresponding Author-E-mail: sudarshansingh83@gmail.com

ABSTRACT

Ulcerative colitis is a disease of the intestine, explicitly the large intestine or colon that includes characteristic ulcers, or open sores, in the colon. For eradication of Ulcerative colitis, there are various methods among that delivery of drug to colon is one of them. Colon specific delivery can achieve by using polymer, which will release the drug at specific pH, or by enzyme depended system, which will break the bond between drugs and polymer. Present study was slanting to explore the utility of coating technology for colonic targeting of single unit tablet systems. Mesalamine USP Tablets were prepared using synthetic polymer as binders and methoxy polymer as release retardant. Different polymer such as Eudragit E100 and S100 used to get desired release of drug to colon for specific time. Core tablet were coated in singular percentage as 5%, 7.5% and 10%. Similarly core tablet were coated using triple coating using release retardant. The coated tablets were tested in-vitro for their suitability as colon specific drug delivery systems in different pH 1.2, 6.0 and 7.2. Drug release was delayed as on going on increasing the concentration of coating polymer. Triplicate coating gave 0.61% at pH 1.2, 0.49% at pH6.0 and 87.28% at pH7.2 from 75 mg tablet. Drug content was determined by UPLC and it was found 98.33% of drug was present in a tablet. The statistical analysis of the parameters of dissolution data obtained before and after storage for 3 month at 25ºC/60%RH and 40ºC/75%RH as per ICH guidelines showed no significant changes indicating the two dissolution profile were similar.

KEYWORDS: Ulcerative colitis, Mesalamine, Eudragit E100, Eudragit S100.

INTRODUCTION:

Colon Specific drug delivery is a reasonably 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 interactions¹.

The functional requirement of an oral colonic drug delivery system is twofold a robustness of form to prevent drug release in the upper gastrointestinal regions and sensitivity to the trigger mechanism to ensure prompt drug release in the colon².

The pH dependent approach for colonic drug delivery is based on the pH differential along the gastrointestinal tract with values increasing from about 1 to 2.5 in the stomach through 6.6 in the proximal small bowel to a peak of about 7.5 in the terminal ileum followed by a fall in pH to 6.4 in the colon³. This concept utilizes polymeric carriers that are insoluble in the low pH media of the upper gastrointestinal tract, but dissolve at the higher, near neutral pH of the distal gut. The current perspective of this study is to prolong the release of the anti-inflammatory drug mesalamine to the colon using one such pH dependent polymeric systems, this new system will stay intact and enable the drug to be delivered in a delayed manner in order to provide effective treatment for IBS. The intent of the present cram was to develop a single unit oral colon targeted drug delivery system for mesalamine using various pH dependent polymeric systems in order to ensure the release of the drug in a prolonged manner.

MATERIALS AND METHODS:

Mesalamine was procured as a gift sample form Sarex overseas Chennai, Micro crystalline cellulose USP, Lactose, Citric acid, PVP K30, Magnesium stearte, Aerosil-Kawarlal and Co., Chennai., Isopropyl alcohol, Methlene chloride-Vijay Scientific and Co. Chennai., Sodium starch glycolate IP-Jain Impex., Eudragit S100: Drug coat S100 & Eudragit E100: Drug coat E100 was obtained as a gift sample form Vikram Thermo India Ltd., All other ingredients used were of analytical grade.

METHODS

Preparation of mesalamine colon specific tablet

Core tablets of mesalamine USP were prepared by wet granulation technique using PVP as a binder. Lactose was used as diluents and was granulated by passing through #10 mesh and prior to granulation by passing all the materials were passed through #10 mesh. The dried granules were passed through #20 mesh and these granules were lubricated with the mixture of aerosil and magnesium stearate. Finally granules were compressed into tablets using rotary tablet press (M/S RIMEK). The prepared tablets of each batch were subjected for evaluation of hardness test, friability, drug content and in vitro drug release studies. Eight different batches were formulated according to the direct compression and wet granulation techniques. The other batch was varied only in the addition of citric acid 10% as a retardant material. Other ingredients were the same. Ingredient required per tablet is presented in Table 1. Coatings of core tablet were done using polymer such as Eudragit E100 and Eudragit S100 in three concentration 5%, 7.5%, 10% and finally triplicate coating was done using Eudragit E100, HPMC and Eudragit S100.

Evaluation of powder blend

The formulated powder blends were evaluated for compatibility, particle size analysis using Malvern particlesizer (MS 2000), angle repose, hausner’s ratio, compressibility index, bulk density, true density^4-7.

Evaluation of core and triplicate coated tablet

The compressed tablets were tested for hardness, percentage friability, percentage weight variation, disintegration time and the percentage drug content^8-9.

In vitro Release Studies

The in-vitro release profiles of mesalamine triplicate coated tablet examined in pH 1.2, 6.0 and 7.2 using rotating basket method specified in the USP XXIII Tablet Dissolution Tester (TDT06P, Electro lab). The temperature of the bath was maintained at 37 ± 0.5°C and the stirring speed at 100 rpm. Samples of the dissolution Medium (5 ml) were withdrawn at various time intervals. The same volume of fresh fluid was added to the test medium to maintain the volume. The dissolution medium is 0.1 N HCl for 2 hrs and phosphate buffer solution of pH 6.0 for one hour and then 50ml of sodium hydroxide solution was added to adjust the pH to 7.2 and continued the in-vitro test for 90min and at the end an aliquot of sample was withdrawn and analyzed by using UPLC at 230nm. Study was carried out in triplicate and the mean values were plotted versus time with standard deviation less than 3 indicating the reproducibility of the result. In order to characterize release of mesalamine from triplicate coated tablet, the in-vitro release data for all formulation was subjected to kinetic data treatment using mathematical models like zero order, first order, Higuchi model & Erosion model¹⁰. Exposing the core formulations as per ICH guidelines carried out stability studies.

RESULTS AND DISCUSSION:

Colon targeted drug delivery of mesalamine were formulated, by using various polymer and it was coated with three different polymers in three different concentrations. Mesalamine which is preferably used for the eradication of ulcerative colitis. Mesalamine colon specific tablet were prepared by wet granulation techniques. Mesalamine meets all the ideal characteristics to formulate in the form of oral drug delivery system.

The FTIR spectral analysis showed that there was no appearance or disappearance of any characteristic peaks of pure drug mesalamine in the physical mixture of drug and polymer (Figure 3,4,5), which confirms the absence of chemical interaction between drug and polymers.

Mesalamine raw material were subjected to all quality control test which showed (Table 2.) that they were within the official pharmacopoeial limits except the flow properties of the drug.

The core tablets were prepared by wet granulation method and evaluated for weight variation, thickness, content uniformity, disintegration time, hardness, friability which showed (Table 2.) that they were within the official pharmacopoeial limits. Exploratory batches of mesalamine formulations ML01 to ML04 were prepared by wet granulation and evaluated for its physical properties of granules except ML01, which was formulated for direct compression. The result shows formulated granules ML01 to ML03 had poor flow behavior, which were not satisfactory for the formulation of tablets. ML04 showed an optimal angle of repose, Hausner’s ratio and compressibility index. So ML04 was taken as a base for the core formulation of mesalamine. F01, F02 batches were prepared by obtained knowledge form the exploratory batches, which basically differed only in the amount of organic acid, added. F02 had a 10% of citric acid, where as F01 didn’t have any organic acid added into the formulation. F01 batch had a content uniformity of 95.89% where as F02 showed a 97.73% of drug content. The result of content uniformity of the F01, F02 batches showed both the batches were found to be within the USP limits of 90-110%. Coating formula over core tablets were optimized by coating three batches of cores using three coating formulas. Among them Coat no:1 was very sticky and the surface of the coated tablet looked un-uniform and Coat no:3 was highly viscous and which was not able to coat. Coat no: 2 had a uniform smooth coating over the cores.

Table 1: Composition of tablet formulation

Contents	Ml 01 DIRECT Compression (mg)	Ml 02 WET Granulation (mg)	Ml 03 WET Granulation (mg)	Ml 04 WET Granulation (mg)	F01 WET Granulation (mg)	F02 WET Granulation (mg)
Mesalamine	50	50	50	75	75	75
MCC	15	13	13	19.5	19.5	12.5
Lactose	10	10	10	15	15	10
Citric acid	----	----	----	----	----	12
PVP	-----	2	2	3	3	3
Isopropyl alcohol	-----	q.s	q.s	q.s	q.s	q.s
Sodium starch glycolate	3.0	3	3	4.5	4.5	4.5
Magnesium state	0.5	0.5	0.5	0.5	0.5	0.5
Aerosil	1.5	1.5	1.5	2.5	2.5	2.5
Total	80	80	80	120	120	120

Table 2: Technological characterization of formulated Mesalamine powder blend and compressed tablet formulation*

Parameters	Mesalamine	ML01	ML02	ML03	ML04	F01	F02
Angle of repose	31°18’	38°9’	31°1’	34°2’	27°4’	24°6’	22°5’
Flow Property	Poor	Poor	Poor	Poor	Passable	Excellent	Excellent
Hausner’s ratio	1.8875	1.35	1.44	1.4	1.37	1.12	1.11
Compressibility index (%)	47.01	26	30	30	25	11	9
Bulk density (gm/ml)	0.226 ± 0.10	0.224 ± 0.18	0.224 ± 0.12	0.221 ± 0.10	0.228±0.15	0.211±0.14	0.211±0.11
Specific surface area	0.644	-	-	-	-	0.145	187.599
Diameter (0.5)mm	15.499	-	-	-	-	0.161	164.857
Hardness (kg/cm²)	-	4.5 ± 0.57	4.5 ± 0.51	4.5 ± 0.52	4.5 ± 0.55	4.5 ± 0.35	4.5 ± 0.52
Friability (%)	-	-	0.31	0.36	0.37	0.32	0.35
Disintegration (mint)	-	-	-	-	-	11	15
Weight variation (%)	-	81 ± 0.1	82 ± 0.3	79 ± 0.1	122 ± 0.3	121 ± 0.2	120 ± 0.1
Assay (%)	-	-	-	-	95.74	95.89	97.73

*All values are mean ± S.D. for n=3

Table 3: In-vitro Release Profile on Mesalamine coated core 1 and core 2 tablets

Sr. No	pH	Time (Min)	% Cumulative Drug release
			Coating with 5%		Coating with 7.5%		Coating with 10%		Triplicate coating
			Core 1.	Core 2.	Core 1.	Core 2.	Core 1.	Core 2.	Core 1.	Core 2.
1	1.2	120	1.81	1.69	1.52	1.49	0.61	0.73	0.61	0.73
2	6	60	0.89	0.76	0.73	0.53	0.99	0.51	0.53	0.49
3	7.2	90	86.13	89.94	90.24	95.49	91.73	82.65	99.03	87.28

Table 4: In-vitro Release Profile of 3 Month stability samples at 25ºC/60%RH & 40ºC/75%RH for Mesalamine triplicate coated core 1 and core 2

Sr. No	pH	Time (Min)	% Cumulative Drug release
			(0 months)		(3 months)
			Initial		25ºC/60%RH		40ºC/75%RH
			Core 1.	Core 2.	Core 1.	Core 2.	Core 1.	Core 2.
1	1.2	120	0.61	0.73	0.59	0.72	0.57	0.70
2	6	60	0.53	0.49	0.51	0.47	0.49	0.46
3	7.2	90	99.03	87.28	98.85	87.13	98.24	86.01

Coat no:2 was applied to both the formulations of F01, F02 with a percentage weight increase of 5%, 7.5%, 10% and triple coat was separately coated using Eudragit E100 as 8% coat over core and second layer comprising of coating layer

HPMC as 2% over Eudragit E100 and finally enteric layer using Eudragit S100 of 6% weight increase.

Disintegration study of the coated tablets were performed both in simulated gastric fluid for 1 hour and then in simulated intestinal fluid for 2 hours. 5% coat immediately disintegrated < 20min in simulated gastric fluid where as the 7.5% coating showed slight softening of coat but didn’t disintegrate in 0.1N HCl. The results showed that 7.5% coating had a 76mint disintegration time, 10% showed a 75mint disintegration time, triple coat (TC) showed a 100 min disintegration time in pH 7.2 phosphate buffers.

In-vitro release studies were carried out over the formulated F01, F02 batches to ensure the ability of the coated formulations to protect the content against the stomach and intestinal environments (pH-7.2) and to release the drug in the colon, with various pH of 1.2 (0.1N HCl), 6.0, 7.2 (phosphate buffer) the in vitro release study was carried out over the coated formulations of F01 and F02. The F01, F02 batch tablets coated with 7.5% of coating showed drug release of about 1.52%, 1.49% in 0.1N HCl for 2 hrs,

Which failed to comply with the USP standards of < 1% in 0.1N HCl. On the other hand 10% coating of F01, F02 batches showed 0.73%, 0.61% in pH 1.2 and 0.51%, 0.99% in pH 6.0 and 82.65%, 91.73% of drug release in pH 7.2. Triple coating of F01, F02 batches had a release of 99.03%, 87.28% of drug release in pH 7.2. The results showed that 7.5% failed to comply with the standards and 10%, triple coating of F01 and F02 batches were passed, hence the 10%, TC is proved to be of great interest. The plot of (1-Mt/M)^1/3 versus time was found to the linear for all the formulations that indicates the drug release occurs mainly by erosion. The linearity of the erosion plot was assessed by correlation co-efficient values.

Stability studies were carried out with the optimized formulation F01 and F02 for 3 month in two condition i.e.

25ºC/60%RH and 40ºC/75%RH. As per ICH guidelines, the formulations were subjected to drug assay and in-vitro dissolution studies. The statistical analysis of the parameters dissolution data (Table 4), after storage for 3 month showed no significant change indicating that the two dissolution profiles were similar.

CONCLUSION:

Colon targeted dosage forms have a distinct advantage over the existing conventional dosage forms. Mesalamine colon targeted dosage forms was prepared and coated by using Eudragit S100 and triple coat by Eudragit E100 and S100. Both formulations scarcely released mesalamine in pH 7.2 medium at 10% coating level, which indicate prepared formulations are suitable for the successful delivery of the drug into the colon and can be easily manufactured using conventional pharmaceutical coating technique and provided the promising candidate for specifically delivering drug to colon region, in particular for mesalamine 75mg in this study.

ACKNOWLEDGEMENT:

The authors are grateful to the Managing Director and Correspondent of Ordain Health care, Chennai, Tamil Nadu, India for providing necessary amenities and encouragement to carry out this work.

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Received on 13.06.2009 Modified on 17.08.2009

Research J. Pharm. and Tech.2 (4): Oct.-Dec. 2009; Page 819-823