INTRODUCTION:

In recent years, a considerable research activity in the field of colonic drug delivery has occurred. Several prolonged release dosage forms are under investigation for delivery of drugs to colon e.g. treatment of ulcerative colitis, Crohn's disease, colon carcinomas, for systemic absorption of protein and peptide drugs. It is due to less hostile environment with lesser diversity and intensity of enzymatic activities of colon as compared to stomach and small intestine (1). The anti-asthmatics targeted to colon for the treatment of nocturnal asthma are systemically absorbed. It is also useful for delivery of insulin susceptible for degradation by enzymes in upper gastrointestinal tract (GIT).

The enzymatic activities associated with microflora of colon can be used as a tool for colon specific drug delivery. In addition, colon has a longer retention time and appears to be highly responsive to agents that enhance the absorption of poorly absorbed drugs. A colonic delivery system could be of absolute value where delay in systemic absorption is therapeutically desirable, especially in the case of diseases, which are affected by circadian rythms (2).

A number of delivery systems based on polysaccharides which are degraded in the colon are being used. Being approved for use as pharmaceutical excipients is their major advantage. Most of them form gel and are hydrophilic and therefore methods are to be devised to ensure that drug does not prematurely diffuse from the dosage form before it reaches the colon.

A colon specific drug delivery system is required to protect the drug during its transit through the upper gastrointestinal tract and to allow its release in the colon. It is advantageous if drug release from a formulation can begin immediately after it enter the colon, even though drug release may subsequently be retarded.

Drug release from ideal formulation should begin in the ascending colon, or a specified leg time, at predetermined rate. Delivery of drug to the colon has implications in a number of therapeutic areas. It includes local treatment of colonic disease like ulcerative colitis, colon cancer, and inflammatory bowel disease. So to achieve these objectives guar gum and xanthan gum were used as polysaccharides for preparing matrix tablet. Guar gum as colon drug release retarding excipient in matrices does not achieve the desired retardation. Presence of xanthan gum in the tablets not only retards the initial drug release from the tablets, but due to high swelling, make them more vulnerable to digestion by the microbial enzymes in the colon. Hence, it was envisaged to develop colon specific tablets of ibuprofen as model drug.

MATERIALS:

Ibuprofen was gratis sample from Zim Laboratories, Nagpur. Sodium chloride, Guar gum, Xanthan gum, Microcrystalline cellulose were pbtained from Signet Chemical Corporation, Mumbai.

METHODS:

Assessment of biodegradability of polysaccharides by viscosity measurement

Biodegradability of guar gum and xanthan gum was assessed by conducting viscosity measurement on guar gum and xanthan gum dispersion prepared in Sorensen phosphate buffer pH 5.9 in presence of rat caecal contents and galactomannase enzyme.

Studies in presence of galactomannase enzyme

A 0.5% w/v dispersion was prepared by dispersing guar gum and xanthan gum powder in pH 5.9 Sorensen phosphate buffer with Galactomannase enzyme (0.1 mg/ml) previously bubbled with CO₂ and allowed to hydrate for 24 hours in stoppered conical flask maintaining CO₂ environment. After 24 hours viscosity was measured at 20 rpm ate 37 °C using spindle no. 2 with Brookfield viscometer. The dispersion was incubated at 37 °C for 2 hours and again viscosity was determined at 37 °C. The incubation was continued for 24 hours at 37 °C. After 24 hours viscosity was determined at 37 °C, 20 rpm, CO₂ environment was maintained all through the experiment, which were done in triplicate.

Studies in absence of rat caecal contents

A 0.5% w/v dispersion was prepared by dispersing guar gum and xanthan gum in pH 5.9 Sorensen phosphate buffer previously bubbled with CO₂. The dispersion was allowed to hydrate for 24 hours in stoppered conical flask maintaining CO₂ environment. After 24 hours viscosity was determined at 20 rpm at 37 °C with spindle no. 2 using Brookfield viscometer. Then dispersion was incubated at 37°C for 2 hours and again viscosity was determined at 37 °C. The incubation was continued for 24 hours at 37 °C. After 24 hours Viscosity was determined at 37 °C, 20 rpm and CO₂ environment was maintained through about the experiment. The viscosity measurements were done in triplicate.

Studies in presence of rat caecal contents

Preparation of rat caecal content medium

Albino rats weighing 150-200 g maintained on normal animal feed, (Gold Mohar rat feed, Hindustan Lever Ltd.) were used for the preparation of rat caecal content medium, without enzyme induction. Thirty minutes before commencement of studies, three rats were sacrificed. The abdomen was opened and the caecum isolated, legated at both ends, cut loose and immediately transferred to pH 5.9 Sorensen phosphate buffer previously bubble with CO₂. The caecal bags were opened, the contents were individually weighed, mixed and suspended in pH 5.9 Sorensen phosphate buffer to give required caecal dilution of 2% w/v. As the caecum is naturally anaerobic, all these operations were carried out in CO₂environment_. Similarly six rats were used for preparing a caecal dilution of 4% w/v.

The biodegradation study was carried out in the same way as in the absence of rat caecal contents except that, before incubation at 37 °C, 5 ml Sorensen phosphate buffer containing 2 % w/v and 4 % w/v rat caecal contents was added separately to the respective dispersed guar and xanthan gum. CO₂ environment was maintained during the biodegradation studies. The study was performed in triplicate.

Viscosity studies of combination of guar and xanthan gum

The ratio of combination of guar gum and xanthan gum for preparing matrix tablets were based on synergistically enhanced gel properties by viscosity measurement and ratio that were highest viscosity were chosen were preparing tablets. As shown in table 1, the viscosity measurement were done using spindle 2 at 200 rpm. The ratio 4:6 for guar gum and xanthan gum respectively was chosen for matrix tablet preparation having concentration ranging form 10 to 60% (w/w) of tablet weight.

Table 1 Ratios of guar and xanthan gum for viscosity measurements

Ratio No.	Guar gum	Xanthan gum	Viscosity (Cps)
	0.5% w/v
1	10 Parts	0 Parts	280
2	9	1	1080
3	8	2	840
4	7	3	880
5	6	4	920
6	5	5	1020
7	4	6	1180
8	3	7	900
9	2	8	800
10	1	9	760
11	0	10	600

Drug − excipient interaction studies

Differential scanning calorimetry (DSC)

Thermal analysis of ibuprofen, guar gum and xanthan gum and granules of ibuprofen with guar gum and xanthan gum were assessed by DSC Q10V9 instrument.

Fourier transform Infrared spectroscopy (FT-IR)

FT-IR spectra of ibuprofen, guar gum and xanthan gum and granules of ibuprofen with guar gum and xanthan gum were recorded with FT-IR spectrophotometer (FTIR−8001, Shimadzu, Japan), operated with omnic software on sample prepared by KBR pellet method.

Preparation of granules

Guar gum and xanthan gum powder was sieved separately and mixed with ibuprofen and MCC and sieved together to ensure complete mixing. The blend was granulated using 10% w/v polyvinylpyrrolidone (PVP) in isopropyl alcohol as binder. The wet mass was passed through and dried at 40 °C for 6 hours.

Preparation of tablet

Six tablet formulations were prepared (table 2). The amount of ibuprofen in each case was 100 mg. The dried granules were passed through a sieved and mixed with magnesium stearate and talc. The lubricated granules were compressed using 8 mm round, standard biconcave punches on a pilot press tablet machine (Chamunda Pharma Machinery Pvt. Ltd.). The average weight of tablet was kept between 198−209 mg.

Table 2 Composition of ibuprofen matrix tablets

Ingredient	Quantity per each matrix tablet (mg)
Ingredient	F₁	F₂	F₃	F₄	F₅	F₆
Ibuprofen	75	75	75	75	75	75
Guar gum	8	16	24	32	40	48
Xanthan gum	12	24	36	48	60	72
Microcrystalline cellulose	101	81	61	41	21	1
magnesium stearate	2	2	2	2	2	2
Talc	2	2	2	2	2	2
Total (mg)	200	200	200	200	200	200

Evaluation of Physical properties of matrix tablets

Weight variation

Twenty tablets from each composition were weighed individually and average weight was calculated. Then the individual tablet weights were compared to the average tablet weight⁵⁴.

Thickness testing

The thickness of the matrix tablets was determined using screw gauge, and the results are expressed as mean values of 10 determinations.

Friability

Ten tablets were weighed and placed in the rotating disc of Roche friabilator. The apparatus was operated for four minutes at 25 rpm, dedusted and weighed again. The per cent of friability was calculated based on weight loss after the test.

Hardness

The tablet was placed between the two anvils of Monsanto hardness tester and increasing amount of force was applied. The reading was directly read on the marked scale till a pressure required to break tablet was recorded.

In vitro drug release

Drug release studies were carried out in 0.1M HCl, pH 6.8 Sorensen phosphate buffer and pH 5.9 phosphate buffer saline without rat caecal content.

The matrix ibuprofen tablets were evaluated for their integrity in the physiological environmental of stomach and the small intestine under condition mimicking mouth to colon transit. The studies were carried out using a USP dissolution test apparatus I at 100 rpm and 37 °C. Each tablet was placed in baskets of apparatus and tested for 2 hours in 900 ml 0.1M HCl as the average gastric emptying time is about 2 hours. The dissolution medium was replaced with 900 ml pH 6.8 Sorensen phosphate buffer for 3 hours as the average small intestinal transit time is about 3 hours. At the end of the time periods i.e. 2 h and 3 h, samples each of 1 ml were taken separately, suitable diluted and analyzed for ibuprofen at 221 nm.

The studies simulating the drug release in colon were carried out in USP dissolution test apparatus I at 100 rpm and 37 °C with slight modification. A beaker of capacity 500 ml containing 200 ml of pH 5.9 phosphate buffer saline as dissolution medium was kept in water bath of dissolution test apparatus. The experiment was carried out with the continuous CO₂ supply into beakers. The drug release studies were carried out for 21 hours since the usual colonic transit time is 20−30 hours. Samples, 1ml, were taken at different time intervals and volume was made up to 10 ml with Sorensen phosphate buffer, filtered and absorbance was measured at 221 nm.

Drug release studies in presence of galactomannase enzyme

Drug release studies were carried out using USP dissolution test apparatus I at 100 rpm and 37 °C. The tablets were placed in baskets of the apparatus and tested for 2 hours in 0.1M HCl (900 ml) as the average gastric emptying time is about 2 hours. The dissolution medium was replaced with pH 6.8 Sorensen phosphate buffer (900 ml) and tablets were tested for 3 hours as the average small intestinal transit time 3 hours. At the end of the time period i.e. 2 and 3 hours. samples each of 1 ml were taken separately, suitably diluted and analyzed for ibuprofen content at 221 nm. Experiments were carried out similarly as previous section (i) and a beaker of capacity 500 ml containing 200 ml dissolution medium as pH 5.9 phosphate buffer saline with galactomannase enzyme (0.1 mg/ml), was kept in water bath of dissolution test apparatus. The experiment was carried out with continuous CO₂ supply into beakers. The drug release study was carried out for 21 hours since the colonic transit time is 20−30 hours and 1 ml sample was withdrawn at different time intervals. The volume was made up to 10 ml with Sorensen phosphate buffer, filtered and absorbance was measured at 221 nm.

Drug release studies in presence rat caecal contents

Due to similarity of human intestinal microflora with the rat caecal contents, the drug release studies were carried out in presence of rat caecal contents to assess the susceptibility of polysaccharides guar and xanthan gum to colonic bacteria.

The rat caecal content 4% w/v was prepared as described in the previous section. The drug release studies were carried out using USP dissolution test apparatus I at 100 rpm and 37 °C. The experiments were carried out initially in the same manner in 0.1M HCl and pH 6.8 Sorensen phosphate buffer. After this testing the dissolution medium was replaced with 500 ml beaker containing 200 ml of 4% w/v rat caecal contents in pH 5.9 SPB which is kept in water batch of dissolution test apparatus. The experiment was carried with continuous CO₂ supply into beakers to simulate anaerobic environment of caecum. At different time intervals, 1 ml of the sample was withdrawn and replaced with 1 ml of fresh pH 5.9 Sorensen phosphate buffer bubbled with CO₂ and the experiment or drug release studies were carried out for 21 hours since the usual colonic transit time is 20−30 hours. The volume of samples were finally made up to 10 ml with pH 5.9 SPB and centrifuged. The supernatant was filtered through a bacteria proof filter and the filtrate was analyzed for ibuprofen content at 221 nm.

At the end of 21 hours, the tablet remnants were suspended in ethanol and the remaining drug content was estimated to make sure that the amount of drug remained, when added to the cumulative amount of the drug released up to 21 hours equals to the average drug content of the tablets estimated prior to the drug release studies.

RESULT AND DISCUSSION:

Assessment of biodegradability of polysaccharides

The enzyme galactomannase induced in rat caecal fluid hydrolyze polymeric linkages in guar and xanthan gum. As shown in table 3 and figure 1, the degradation of polysaccharides is more in presence of 4% w/v rat caecal content (RCC) in presence of galactomannase enzyme as compared to 2 % rat caecal content as evidenced by decreased viscosity in 4% w/v rat caecal content than 2 % rat caecal content. The control samples have not shown any drastic changes in the viscosity values.

Table 3 Viscosity measurement studies in presence and absence of rat caecal content and in presence of galactomannase enzyme

Viscosity	Sample without RCC (Control)	Sample with RCC (2% w/v)	Sample with RCC (4% w/v)	Sample with galactomanse enzyme (0.1 mg/ml)
At 37 °C initial hydrated	1180	1160	1120	1160
At 37 °C after 2h incubation	1180	1100	1040	1060
At 37 °C after 24 h incubation	1160	940	660	820

Figure 1 Viscosity changes of polysaccharides with and without rat caecal contents and in presence of galactomannase enzyme.

Drug-excipients interaction compatibility studies

Fourier transform infrared spectroscopy (FT-IR)

The FT-IR spectra of ibuprofen, guar gum, xanthan gum, and granules of guar gum and xanthan gum with ibuprofen have been shown in figure 2,3,4,5 respectively.

The FT-IR spectra of drug, guar gum and xanthan gum were compared with FT-IR spectra of granules. FT-IR peaks (in cm^-1) and its functional groups are shown in table 4.

Table 4 FT-IR peaks and functional groups

Material

Peaks

(cm^-1)

Characteristics functional groups

Ibuprofen

1715

3000-2500

3000-2900

3100-3000

CO stretching (normal dimeric carboxylic acid)

Broad OH stretching

Aliphatic (CH₃, CH₂, CH) stretching

Aromatic CH stretching

Guar gum

3600-3300

3000-2900

OH stretching

Aliphatic CH stretching

Xanthan gum

3600-3300

3000-2900

OH stretching

Aliphatic CH stretching

Granules of ibuprofen with guar gum and xanthan gum.

1715

3000-2500

3000-2900 3100-3000

3600-3300

CO stretching (normal dimeric carboxylic acid)

Broad OH stretching carboxylic

Aliphatic (CH₃, CH₂CH) stretching

Aromatic CH stretching

OH stretching (alcoholic)

From the above table it was concluded that there were no change in the peak shape and no shift of peaks. So the drug was compatible with the polymers guar and xanthan gum

Figure 2 FT-IR spectra of ibuprofen

Figure 3 FT-IR spectra of guar gum

Figure 4 FT-IR spectra of xanthan gum

Figure 5 FT-IR spectra of granules of ibuprofen with guar gum and xanthan gum

Differential scanning calorimetry (DSC)

The DSC thermograms of ibuprofen, guar gum, xanthan gum and granules of ibuprofen with guar and xanthan gum are shown in figure 6,7,8,9 respectively.

DSC thermograms of ibuprofen shows sharp endothermic peak at 77.9 °C, indicating the melting point o stable crystalline drug. However, the DSC thermograms of granules of ibuprofen with guar gum and xanthan gum show sharp endothermic peak at 76.9 °C. These thermograms indicted that no significant change in peak shape, area and no shift or peaks were found. Therefore this study revealed that there were no interaction between the drug and polymers or may be little interaction because guar gum and xanthan gum are hydrocolloids and they do not melt and not give the sharp peak.

Figure 6 DSC thermogram of ibuprofen

Figure 7 DSC thermogram of guar gum

Figure 8 DSC thermogram of xanthan gum

Figure 9 DSC thermogram of granule of ibuprofen with guar and xanthan gum

Evaluation of physical properties of granules

The physical properties of granules are shown in table 5. Angle of repose is an indication of interparticle frictional force of a sample which in turn may affect its flowability. It has been reported that material having angle of repose £30° have good flowability.⁵³

Table 5 Physical properties of granules

Carrier Concentration (%w/w)	Angle of repose (q°)	Bulk density p_b (g/cm³)	Tapped density p_T(g/cm³)	% compressibility
10	20.0	0.911	0.961	5.2
20	23.8	0.819	0.882	7.14
30	23.8	0.820	0.892	8.07
40	22.1	0.877	0.956	8.26
50	21.0	0.872	0.969	10.01
60	21.3	0.812	0.915	11.25

Table depicts that the angle of repose is less than 30° suggesting that granules have good flowability. This is a very critical parameter, as flow property may affect the die filling; tablet weight and drug content present in the tablet, and is important for compaction.

Bulk density is an indication of packing properties of material. Variations in the bulk density can cause change in fill volume. The bulk density of the powder depends primarily on particle size distribution, particle shape and frequency of particles to adhere together. The particles may pack in such a way so as to leave large gaps between their surfaces resulting in a light powder of low bulk density. On the other hand, the smaller particles may pack between the larger ones to form a heavy powder or one of high bulk density.

It has been reported that bulk density⁵⁸ less than 1.25 g/cm³indicate good flowability.⁵⁹ It is evident from table 4.3 that granules do not have significant variation in bulk density, with all the batches in the range of 0.8-0.9 g/cm³. All granules shown good compression properties.

Evaluation of physical properties of tablets

As shown in table 6, the compressed tablets were tested for weight variation, thickness hardness, friability and drug content. All the weights were within ±7.5% deviation range and passed the weight variation test according to IP 1996. The hardness of the tablets was found to be about 3.0 kg/cm². Friability index is a measure of integrity of the material, which is a function of cohesiveness.

It is an indication of endurance of material during various operations like packaging, transportation and handling. The generally agreed upper limit for friability is 1%. The friability of the tablets was found within the desirable range 0.4-1% and hence the tablets passed the friability test. The tablets were assayed and the drug content was found to be in the range 95.0 - 105%. Hence the tablets complied with IP standards.

Drug release studies

Studies in absence of rat caecal contents

The ability of guar and xanthan gum polysaccharides to retain integrity of the tablets in the physiological environment of stomach and small intestine, and prevent complete drug release was assessed by conducting drug release studies in 0.1M HCl and 6.8 Sorensen phosphate buffer for 2 and 3 hours respectively, according to conditions mimicking mouth to colon transit (table 7).

Table 7 Cumulative mean per cent drug release (Mean± SD; n=3) After 2 hours in 0.1M HCl and 3 hours in pH 6.8 Sorensen phosphate buffer from matrix tablets

Sr. No.	Formulation Code	Concentration of carriers (% w/w of tablet weight)	Mean per cent drug release (Mean±SD; n=3)		Cumulative mean per cent drug release (Mean ±SD; n=3) (After 5 hours)
Sr. No.	Formulation Code	Concentration of carriers (% w/w of tablet weight)	0.1M HCl (2 hours)	pH 6.8 SPB (3 hours)
1.	F₁	10	9.52±0.577	32.6±0.254	42.±0.415
2.	F₂	20	9.55±0.517	23.88±0.463	33.43±0.490
3.	F₃	30	7.39±0.151	16.07±0.340	23.46±0.245
4.	F₄	40	6.57±0.00	9.62±0.340	16.19±0.170
5.	F₅	50	3.50±0.08	7.84±0.112	11.34±0.096
6.	F₆	60	3.44±0.08	5.74±0.228	9.18±0.154

Table 8 Cumulative mean per cent drug release (Mean±SD; n=3) in pH 5.9 Sorensen phosphate buffer for 19h from matrix tablets prepared using carrier concentration ranging from 10-60% w/w of tablets

Sr. No.	Time (Hours)	Cumulative mean per cent drug released (Mean±SD; n=3)
Sr. No.	Time (Hours)	F₁	F₂	F₃	F₄	F₅	F₆
1.	3	23.19±0.24	20.20±6.28	18.30±0.28	16.73±0.26	15.16±0.17	14.71±0.01
2.	6	28.15±0.03	26.15±6.18	24.15±0.18	21.59±0.01	19.38±0.20	18.62±0.04
3.	9	40.32±0.15	39.31±0.08	33.76±0.04	26.55±0.15	23.70±0.03	22.43±0.02
4.	14	46.56±0.28	42.21±0.09	38.31±0.09	31.30±0.04	27.76±0.01	26.27±0.62
5.	19	55.82±0.41	46.31±0.18	42.72±0.00	35.85±0.06	35.51±0.21	30.22±0.02

Results of the drug release studies in 0.1M HCl for 2h and pH 6.8 SPB for 3 hours from ibuprofen matrix tablets indicate that guar gum and xanthan gum polysaccharide is capable of protecting the drug at higher concentration (40%, 50% and 60 %w/w) as the cumulative per cent drug release after 5 hours were 16.19±0.170, 11.34±0.096 and 9.18±0.154 respectively. The drug release was relatively higher at lower concentration i.e. (10, 20 and 30%). As the carrier concentration increases from 10 − 60% w/w, there was progressive decrease in drug release. The per cent drug release in pH 6.8 SPB was more than 0.1M HCl.

Figure 10 Per cent drug release (Mean ± SD; n=3) of 10 to 60% carrier concentration from matrix tablets.

The results of drug release studies in pH 5.9 SPB after 19 hours of testing are shown table 8 and figure 10 respectively. The results indicate that the cumulative mean per cent drug release decrease with increased carrier concentration. Tablets retained its shape at the end of 24 hours, indicating the drug release by matrix diffusion and not by erosion of the carrier.

Considering drug release in pH 5.9 Sorensen phosphate buffer and protection provided by the carrier in simulated upper GI fluids and 40,50 and 60% w/w carrier concentration were selected for further studies in rate caecal contents and in galactomannase enzyme, as at these concentration the drug release was less, indicating higher resistance to drug release.

Drug release studies in the presence of rat caecal contents

The drug release in presence of rat caecal contents are shown in table 9 and 10 respectively. Rat caecal microflora was used because of the similarity with human intestinal microflora.

Table 9Mean per cent drug released (Mean±SD, n=3) 0.1M HCl and pH 6.8 Sorensen phosphate buffer and cumulative mean % drug release after 5 hours from matrix tablets

Sr. No.	Formulation code	Mean per cent drug release		Cumulative mean per cent drug release (Mean±SD; n=3) (After 5 hours)
Sr. No.	Formulation code	0.1M HCl (2 hours)	pH 6.8 SPB (3 hours)
1.	F₄	6.23±0.088	9.52±0.35	15.75±0.194
2.	F₅	3.50±0.120	7.84±0.112	11.34±0.116
3.	F₆	3.45±0.08	5.63±0.20	9.08±0.14

Table 10 Cumulative mean per cent drug release (Mean±SD; n=3) in pH 5.9 Sorensen phosphate buffer with 4% w/v rat caecal contents for 19h from matrix tablets

Sr. No.	Time (Hours)	F₄	F₅	F₆
1.	3	0.10	33.81±0.14	29.94±0.07
2.	6	0.10	37.74±0.16	35.55±0.095
3.	9	0.10	47.96±0.26	54.59±0.12
4.	14	0.10	62.39±0.19	62.95±0.13
5.	19	0.10	78.55±0.16	75.34±0.14

In vitro drug release with rat caecal contents

The dissolution study was carried out without rat caecal contents (control study) to ensure that drug release is not due to the mechanical erosion likely to occur because of the bowel movement in humans. On exposure to the dissolution fluids, the guar and xanthan gum gets hydrated and form a viscous gel layer that slow down, further seeping in of dissolution fluid towards the core tablets.

The main aim of the drug delivery system targeted to the colon is not only to protect the drug from being released in the physiological environment of stomach and small intestine, but also to release the drug in the colon after enzymatic degradation of colonic bacteria.

Hence, the in vitro drug release studies were carried out in pH 5.9 SPB containing 4% w/v of rat caecal content (simulated colonic fluid).

Figure 11 Release profile of matrix tablets containing 40% w/w carrier

Per cent of ibuprofen released from matrix tablets containing 40% w/w of polymer in dissolution study with and without rat caecal contents.

The per cent of ibuprofen released from the matrix tablets containing 40% guar and xanthan gum (F₄) is shown in figure 11.

The per cent of ibuprofen released from F4 at the end of 24 h was found to be 96.27%. Whereas the control studies, it was found to be 52.04%. Significant difference was observed in the amount of ibuprofen released at the end of 24h of the dissolution study with rat caecal content medium when compared with the dissolution study without RCC. The Results shows that F4 formulation might be acted upon by colonic bacteria within 5-6h of entering the colon and release most of the drug in the colon.

The per cent drug release from matrix tablet containing 50% w/w carrier (F₅) is shown in figure 10.

Figure 12 Release profile of matrix table containing 50% carrier

The per cent of ibuprofen released from matrix tablets containing 50% carrier is dissolution study with and without rate caecal contents is shown in figure 12.

Drug release from the F₅ at the end of 24 h was found to be 89.89% whereas the control study (without RCC) it was only 46.82% significant difference was observed in the amount of ibuprofen released at the end of 24 h of the dissolution study with RCC medium when compared to dissolution study without RCC. The result shows that the release of ibuprofen in the physiological environment of colon is due to the microbial degradation of matrix tablets in presence of RCC.

On increasing the amount of carrier in the matrix tablets, the release of drug decreased at the end of 24 h of dissolution study. The 60% of carried (F₆) concentration released 84.42% of drug in presence of RCC, where as in the control study, the formulation released only 39.40% of ibuprofen.

Figure 13 Release profile of matrix tablet containing 60% carrier

Per cent of ibuprofen released from matrix tablets (mean ± SD; n= 3) containing 60% W/w carrier in dissolution study with and without RCC is shown in figure 13.

The result showed that, the matrix formulation F₄ released almost the entire quantity of the drug at the end of 24 h dissolution study. It appears from these results that F₄ could target ibuprofen to colon. The F₅ and F₆ considered as potential formulations for targeting of drug to colon because of the fact that the human caecal contents would be far more than what was used in the present study.

Studies in presence of galactomannase enzyme

The per cent of ibuprofen released from matrix tablets contain 40% w/w carrier (F₄) is shown in table 11 and 12 and figure 14. Galactomannase was used as a degrading enzyme which is induced from intestinal microflora.

Table 11 Mean per cent drug released (Mean±SD; n=3) in 0.1M HCl and pH 6.8 Sorensen phosphate buffer and cumulative mean per cent drug release after 5 hours from matrix tablet

Formulation code	Mean % drug released		Cumulative mean % drug released (Mean±SD; n=3) (After 5 hours)
Formulation code	0.1M HCl (2h)	pH 6.8 SPB (3 hours)
F₄	6.52± 0.082	9.62± 0.46	16.14± 0.271
F₅	3.65 ±0.120	7.62 ±0.112	11.27± 0.116
F₆	3.48 ±0.10	5.23± 0.20	8.71± 0.15

Table 12 Cumulative mean per cent drug released (Mean±SD; n=3) in pH 5.9 SPB with galactomannase enzyme (0.1mg/ml)

Time (Hours)	Cumulative mean per cent drug released (Mean±SD; n=3) in pH 5.9 SPB with enzyme
Time (Hours)	F4	F5	F6
3	46.83± 0.53	31.23± 0.143	28.91± 0.06
6	50.15 ±0.15	34.28± 0.17	33.55± 0.06
9	57.23± 0.10	42.92 ±0.26	51.59± 0.13
14	68.27 ±0.43	58.78 ±0.13	58.23 ±0.25
19	73.52 ±0. 06	72.55± 0.92	69.38± 0.14

The per cent of drug released from F4 at the end of 24 h was found to be 89.69%. Whereas the control study, it was found to be 52.04% significant difference was observed in the amount of drug released at the end of 24 h dissolution study with galactomannase enzyme, when compare with control study. The result shows that F4 formulation might be acted upon by enzyme within 5 hours of entering the colon and releases most of drug locally in the colon.

Figure 14 Release profile of matrix tablet containing 40% carrier

Per cent of ibuprofen released from matrix tablet (mean ±SD; n=3) containing 40% carrier in dissolution study with galactomannase enzyme and control study.

The per cent of ibuprofen released from matrix tablets contain 50% w/w carrier (F5) is shown in figure 13.

The per cent of drug released from F5 at the end of 24 h was found to be 83.82%. Whereas the control study, it was found to be 46.85% significant difference was observed in the amount of drug released at the end of 24 h dissolution study with galactomannase enzyme, when compare with control study.

Figure 15 Release profile of matrix tablet containing 50% carrier

Per cent of ibuprofen released from matrix tablets (mean ±SD; n=3) containing 50% carrier in dissolution study with galactomannase enzyme and control study is shown in figure 15.

The per cent of ibuprofen released from matrix tablets contain 60% w/w carrier (F6) is shown in figure 14..

The per cent of drug released from F6 at the end of 24 h was found to be 77.79%. Where as the control study, it was found to be 39.40%. Significant difference was observed in the amount of drug released at the end of 24 h dissolution study with galactomannase enzyme, when compared with control study.

Per cent of ibuprofen released from matrix tablet (mean ±SD; n=3) containing 60% carrier in dissolution study with galactomannase enzyme and control study is shown in figure 16.

Figure 16 Release profile of matrix tablet containing 60% carrier

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Received on 25.09.2011 Accepted on 01.10.2011

Asian J. Pharm. Res. 1(4): Oct. - Dec. 2011; Page 91-101

Sr. No.	Formulation code	Hardness (kg/cm²)	Thickness (mm)	Weight variation (mg)	Friability (%)	Content uniformity (%)
1.	F₁	3.0±0.04	2.75±0.04	198.34±7.23	0.79	96.5
2.	F₂	2.9±0.09	2.75±0.06	198.38±8.56	0.91	95.75
3.	F₃	3.0±0.00	2.70±0.06	197.25±6.23	0.82	99.10
4.	F₄	2.8±0.00	2.80±0.02	202.63±9.56	0.65	101.40
5.	F₅	2.9±0.06	2.80±0.00	202.42±8.25	0.55	100.2
6.	F₆	3.0±0.00	2.74±0.08	197.15±9.56	0.43	98.50