INTRODUCTION:

Numerous drug entities based on oral delivery have been successfully commercialized, but many others are not readily available by oral administration, which are incompatible with the physical and/or chemical environments of the upper gastrointestinal tract (GIT) and/or demonstrate poor uptake in the upper GI tract. Due to the lack of digestive enzymes, colon is considered as suitable site for the absorption of various drugs. Over the past two decades the major challenge for scientist is to target the drugs specifically to the colonic region of GIT. Previously colon was considered as an innocuous organ solely responsible for absorption of water, electrolytes & temporary storage of stools. But now it is accepted as important site for drug delivery [1-3].

Retardation of drug release in the diverse and hostile conditions of the stomach and small intestine is not easily achieved, since the dosage form will be subjected to a physical and chemical assault that is designed to break down ingested materials. While in the colon, the low fluid environment and viscous nature of luminal contents may hinder the dissolution and release of the drug from the formulation. Moreover, the resident colonic microflora may impact on the stability of the released drug via metabolic degradation. In spite of these potential difficulties, a variety of approaches have been used and systems have been developed for the purpose of achieving colonic targeting. Targeted drug delivery is reliant on the identification and exploitation of a characteristic that is specific to the target organ. In the context of colonic targeting, the exploitable gastrointestinal features include pH, transit time, pressure, bacteria and prodrug approach[4-6].

· Anatomy and physiology of colon[7-8]:-

The GI tract is divided into stomach, small intestine and large intestine. The large intestine extending from the ileocaecal junction to the anus is divided into three main parts. These are the colon, the rectum and the anal canal. The location of the parts of the colon is either in the abdominal cavity or behind it in the retroperitoneum. The colon itself is made up of the caecum, the ascending colon, the hepatic flexure, the transverse colon, the splenic flexure, the descending colon and the sigmoid colon. It is about 1.5 m long, the transverse colon being the longest and most mobile part³ and has a average diameter of about 6.5 cm. The colon from the cecum to the splenic flexure (the junction between the transverse and descending colon) is also known as the right colon. The remainder is known as the left colon.

Fig.1.anatomy of colon.

METHODOLOGY:

Preparation of standard graph of tinidazole[9,10]:-

Accurately weighed amount of 100 mg of tinidazole was transferred into a 100 mL volumetric flask. Distilled water was added to dissolve the drug and the primary stock solution was made by adding 100 mL of distilled water. This gives a solution having concentration of 1 mg/mL, of tinidazole stock solution. From this primary stock 10 mL was transferred in to another volumetric flask and made up to 100 mL with simulated gastric fluid (SGF, pH 1.2), from this secondary stock 0.5, 1.0, 1.5, 2.0, 2.5 and 3.0 mL, was taken separately and made up to 10 ml with SGF (pH 1.2) solution, to produce 5, 10, 15, 20, 25 and 30 µg/ mL respectively. The absorbance was measured at 320nm using a UV spectrophotometer (Systronic, Ahmedabad, India)

Similarly tinidazole standard graphs were plotted in simulated intestinal fluid (SIF, pH 6.8) by following the above procedure and their calibration curves.

Preparation of tinidazole matrix tablets [11]

Each matrix tablet (average weight 800 mg) for in vitro drug release studies consisted of tinidazole, microcrystalline cellulose (MCC), guar gum, HPMC K4M, HPMC K15M, talc and magnesium stearate. The materials were weighed, mixed and passed through a mesh no 60 to ensure complete mixing. The thoroughly mixed materials were then directly compressed into tablets using 12 mm round, flat and plain punches on a multiple station tablet machine (Cadmach, Ahmedabad). Tablet quality control tests such as weight variation, hardness, friability, thickness, and dissolution in different media were performed on the matrix tablets.

Tablet quality control tests such as weight variation, hardness, friability, thickness, and drug release studies in different media were performed on the compression coated tablets.

Determination of drug content [13-15]

Both the matrix tablets of tinidazole were tested for their drug content. Ten tablets were finely powdered; quantities of the powder equivalent to 50 mg of tinidazole were accurately weighed, transferred to a 100 mL volumetric flask containing 50 mL of distilled water and allowed to stand for 5 h with intermittent sonication to ensure complete solubility of the drug. The mixture was made up to volume with distilled water. The solution was suitably diluted and the absorption was determined by UV-Visible spectrophotometer at 320nm. The drug concentration was calculated from the calibration curve.

Table 1.Different Formulations Of Tinidazole[12]:

	Quantity (mg) present in each formulation
Ingredients	F1	F2	F3	F4	F5	F6	F7	F8
Tinidazole	500	500	500	500	500	500	500	500
K4M	125	150	175	-	-	-	175	-
K15M	-	-	-	125	150	175	-	175
Guargum	150	125	100	-	-	-	75	75
Eudragit	-	-	-	150	125	100	75	75
Talk	12.5	12.5	12.5	12.5	12.5	12.5	12.5	12.5
Mg stearate	12.5	12.5	12.5	12.5	12.5	12.5	12.5	12.5
TOTAL WEIGHT	800	800	800	800	800	800	800	800

In vitro drug release studies[16] :-

Drug release studies of tinidazole matrix tablets

The matrix tablets containing 500 mg of tinidazole were tested in SGF (pH 1.2),and SIF (pH 6.8) solutions for their dissolution rates. Dissolution studies were performed using USP dissolution test apparatus (Apparatus 1 50 rpm, 37±0.5 °C). At various time intervals, a sample of 5 ml was withdrawn and replaced with equal volume of fresh medium. The samples were analyzed spectrophotometrically at 320 nm. The release of tinidazole from matrix tablets was carried out using USP basket-type dissolution apparatus at a rotation speed of 100 rpm, and a temperature of 37±0.5 °C. For tablets, simulation of gastrointestinal transit conditions was achieved by using different dissolution media. Thus, drug release studies were conducted in simulated gastric fluid without pepsin (SGF, pH 1.2) for the first 2 h as the average gastric emptying time is about 2 h. Then, the dissolution medium was replaced with enzyme-free simulated intestinal fluid (SIF, pH 6.8) and tested for drug release to mimic colonic conditions. Drug release was measured from tinidazole matrix tablets, added to 900 mL of dissolution medium. Samples withdrawn at various time intervals were analyzed spectrophotometrically at 320 nm. All dissolution runs were performed in triplicate.

FT-IR spectroscopy[17]

The infrared spectra of tinidazole, physical mixture of drug (tinidazole) and excipients and placebo were recorded between 400 to 4000 cm^-1on FTIR to detect the drug-excipients interactions. The IR spectra for the test samples were obtained using KBr disk method using an FTIR spectrometer (PERKIN ELMER BX-I SYSTEM). The resultant spectra were compared for any possible changes in the peaks of the spectra.

RESULTS AND DISCUSSION

The present study was aimed to developing matrix tinidazole formulations for colon targeting using natural gum (guar gum) and hydroxy propyl methyl cellulose (HPMC K4M). It was reported earlier that guar gum/HPMC could be used as a carrier for colon-specific drug delivery in the form of either a matrix tablet or as a compression coat over a matrix tablet.

The present study discloses an active pharmaceutical agent formulated as a tablet, which is matrix by non-interacting materials. The terms "compression-coated solid dosage form" as used herein refer to a solid matrix comprising the active ingredient, which solid matrix is substantially covered with a compression coating.

Compression coating allows the formulated dosage to be used as an oral dosage form, and provides the following advantages

1. Elimination of the bitter taste and unpleasant smell of the active pharmaceutical ingredient

2. Elimination of water or other solvent in the coating procedure and thereby decreasing the possible degradation of the active pharmaceutical ingredient; and

3. Easier and more economical manufacturing processes.

Hence, attempts were made to minimize the drug release in the physiological environment of stomach and small intestine and to ensure maximum drug release in the physiological environment of colon by applying guar gum/HPMC K4M as a compression coat over the tinidazole matrix tablets. So compression-coated tablets were developed for targeting of tinidazole for local action in the treatment of colonic inflammation.

Standard graph of tinidazole

Fig 2. Standard graph of tinidazole in SGF pH 1.2 and SIF pH 6.8

SGF = simulated gastric fluid; SIF = simulated intestinal fluid

Table 2. Characterization of powder mixture

Formulation code	Angle of Repose	Bulk density	Tapped Bulk density	% Carr’s Index
Matrix	26.12±1.13	0.311	0.362	14.088
F1	29.12±1.24	0.321	0.402	20.149
F2	31.23±1.32	0.332	0.412	19.417
F3	30.35±1.35	0.312	0.386	19.170
F4	29.56±1.46	0.323	0.398	18.844
F5	27.12±1.13	0.325	0.405	19.753
F6	30.35±1.35	0.365	0.469	22.174
F7	32.12±1.84	0.344	0.436	21.100
F8	30.65±1.35	0.332	0.412	19.417

Evaluation of tablets:

Table 3.Physical properties of tinidazole matrix tablets

Formulation Code	%Content of active ingredient	Hardness (Kg/cm²)	Average Weight (gm)	Friability (%)	Drug Content (%)
F1	102.00(±1.11)	3.9±0.4	0.809±0.012	0.570	102.03
F2	98.06(±2.10)	3.9±0.5	0.808±0.16	0.206	103.04
F3	102.46(±1.30)	4.3±0.75	0.806±0.008	0.258	104.04
F4	101.46(±2.10)	4.2±0.6	0.807±0.034	0.256	102.51
F5	100.87(±1.24)	4.5±0.5	0.808±0.35	0.253	103.25
F6	102.65(±3.05)	4.5±0.76	0.805±0.02	0.256	101.09
F7	95.76(±4.99)	4.3±0.28	0.805±0.021	-	100.06
F8	96.56(±5.04)	10.66±0.27	0.905±0.019	-	99.90

Fig3.percentage content of active ingredients

Fig 4.Hardness Of Different Formulations

Fig 5. Friability percentage of different formulations

Fig 6. Drug content percentage of different formulations

Table 4.Cumulative percent drug release of F1-F8 formulations of tinidazole matrix tablets

TIME(hr)	F1	F2	F3	F4	F5	F6	F7	F8
1	17.62	16.3	19.99	15.2	17.19	17.56	12.25	14.06
2	27.55	28.82	25.05	28.86	26.45	27.49	27.85	25.31
3	40.86	41.88	42.8	49.84	44.34	35.56	38.3	39.51
4	47.45	45.05	54.57	55.56	46.99	42.98	44.84	44.65
5	52.83	50.45	58.37	59.3	50.53	50.61	55.14	49.83
6	62.64	54.5	54.7	59.31	55.53	55.35	61.86	57.25
7	58.86	58.58	64.73	61.31	58.67	60.76	68.96	61.08
8	66.33	68.97	69.79	63.33	60.14	68.76	70.98	66.15
9	69.47	71.56	72.49	65.89	65.48	71.89	72.45	70.78
10	73.84	74.48	73.8	72.8	69.45	75.15	75.98	74.19

Fig 7. Cumulative percent drug release of F1-F8 formulations.

Analytical method [18]

The standard graph of tinidazole in SGF (pH 1.2) showed good linearity with r² value of 0.9992, which suggest that it obeys the “Beer–Lambert” law. The standard graphs in SIF (pH 6.8) had r² values of 0.9995.

CONCLUSION:

From the data of dissolution study, the prepared colon matrix tablets of Tinidazole (800 mg) could be used in place of 3-4 doses of 800 mg Tinidazole conventional tablet with better control of drug release for targeted drug delivery which might improves patient compliance and reduces gastric side effects. In summary, the optimized formulae was found to be F7 which were having the combination of Guar Gum and Eudragit (RF) along with matrix polymer of HPMC K4m which showed a slow controlled release about 10hrs specifically in the colon.

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Received on 17.04.2016 Modified on 24.04.2016

Res. J. Pharm. Dosage Form. & Tech. 2016; 8(3): 167-172.

DOI: 10.5958/0975-4377.2016.00022.7