Development and In‑Vitro Evaluation of Colon Specific Indomethacin Matrix Tablet for the Treatment of Inflammatory Bowel Disease

 

Rohitas Deshmukh

Institute of Pharmaceutical Research, GLA University, Mathura - 281406, India.

*Corresponding Author E-mail: rohitas.deshmukh@gla.ac.in

 

ABSTRACT:

IBD is a chronic inflammatory disease of the gastrointestinal tract, particularly small and large intestine consisting of ulcerative colitis (UC) and Crohn’s disease (CD). Oral route of drug delivery is considered as the most appropriate route of drug delivery of drugs. But this route has certain limitations of poor bioavailability due to gastric degradation and increase in dose size and frequency. Therefore, the present aim of the study is to prepare and evaluate Indomethacin loaded matrix tablet using guar gum, HPMC (release controlling polymer) and citric acid to facilitate the drug solubility in the colon. A total 8 different formulations were prepared by wet granulation method and coated with Eudragit S 100 polymer a pH dependent enteric coating polymer which dissolve at colonic pH (7.4) and specifically release the drug in the colon region in sustain release fashion. The granules evaluated for its micrometrics properties and tablets were evaluated for its hardness, thickness, friability, weight variation, drug content, and in‑vitro drug release studies. The % cumulative drug release profile of all tablets was little and insignificant at pH 1.2 and 6.8. In colonic pH the coating dissolves tablets starts to release drugs. Among all the formulation the formulation F3 having guar gum and HPMC ratio 3:1 shows a maximum release of drug of 80.41±6.5%. At 24 h. The study demonstrated that the prepared tablets can release the Indomethacin in sustained release manner and helps in management of IBD with reduced side effect of the therapy. The results of this study show that oral administration of aspartame (250mg/kg body weight) was correlated to a significant increase in the lipid profile, fasting blood glucose and some marker enzymes and this increase is time related.

 

KEYWORDS: Indomethacin, Tablets, Crohn’s disease, Ulcerative colitis, inflammatory bowel disease.

 

 


INTRODUCTION:

IBD is a chronic inflammatory disease of the gastrointestinal tract, particularly small and large intestine consisting of ulcerative colitis (UC) and Crohn’s disease (CD)1. It may be either progressive or chronic with unknown Etiology effecting millions of people worldwide2,3.   Inflammation of the GIT reduces its capability to work accurately in IBD. Both Crohn’s disease and ulcerative colitis are the most common form of inflammatory bowel disease and affected the inflammation and remission of patients. These diseases are mostly affecting the quality of life of people4

 

The intestinal clinical symptoms associated with UC and CD are abdominal pain, bloody diarrhea, weight loss and vomiting whereas extra-intestinally are mostly affected with eyes, joints, skin and bile duct. IBD have been associated with numerous factors like environment, immune system, microorganism, GIT microflora and genes. IBD pathogenesis and development is also linked with irregular protein glycosylation5. If these problems is not early diagnosed and treated, severe intestinal complications can be arisen in the form of fistulae, extreme abdominal pain, colon cancer, bowel function impairment, and disability6-8. Till date a permanent treatment of IBD is not established therefore the treatment of disease is symptomatic and sometime lifelong9.

 

Oral route of drug delivery is considered as the most appropriate route of drug delivery of drugs. The advantages associated with oral routes are ease of administration, patient’s compliance, no sterility checks, cost effective and high flexibility in their manufacturing 10,11.  In the last few decades, a continuous quest has been raised towards colonic delivery of drugs to enhance their therapeutic efficacy at target sites and minimize related side effects. Although, merely a few approaches like colon targeted drug delivery system that has the ability to work in a complex environment of the gastrointestinal tract (GIT) of the human. An effective level of drug absorption is depended on the physico-chemical properties of GI fluids12. But this route has certain limitations of poor bioavailability due to gastric degradation at acidic (pH ~1.5) surrounding of the stomach. Hence, to get a therapeutic response required dose of the drug is increased. Dose frequency and related side effects also persists13,14. Therefore, the targeted oral drug delivery approaches have been popularized with biodegradable and biocompatible polymers. The presence of polysaccharidase microflora and enzymes (pectinase, xylanase, D-sylosidase, amylase, dextranase etc) in colon region make the polysaccharide-based polymers a suitable candidate for employing them as a drug carrier15-17. Several natural origin biodegradable polysaccharides like chitosan, pectin, and guar gum has been reported to be used as carriers for targeting to the drugs to colon region.18-21

 

Guar gum (GG) is natural gum obtained from the seeds of Cyamopsis tetragonolobus. GG is a reverse type polysaccharide containing mannose [(1→4)-β-D-mannopyranosyl] and galactose [α-D-galactopyranosyl] unit linked by (1→6) linkage. GG has been well explored as a polymer for colon targeting due to its extraordinary gelling efficiency, mucoadhesiveness, biodegradability and sustained release property22. GG is a pH responsive polymer act by chemical modifications of functional groups like -CH3, -COOH, SO3H, -CONH2 which makes it more suitable for delivery of bioactive molecules to the colon23,24.

 

Indomethacin is a potent an inflammatory drug is indole acetic acid derivative   categories as nonselective COX inhibitors (traditional NSAIDs). It is primilarly used in the management of pain and inflammation caused due to rheumatic arthritis. In addition, it shows anticolorectal cancer activity via cyclooxygenase- (COX-) independent mechanisms.  It is believed that Indomethacin inhibits the   prostaglandin synthesis and suppresses neutrophil motility. Inspite of have excellent anti-inflammatory activity, gastric irritation and associated side effect are the main drawback observed in the conventional dosage form.25-28. Therefore, enteric coated tablets of this drug which specific release the content can be a good approach for the management of IBD.

 

Therefore, the present aim of the study was to prepare and evaluate Indomethacin loaded matrix tablet using GG and hydroxyl propyl methyl cellulose (HPMC) polymer. Among the various ingredients the GG was used as matrix former, HPMC provides control, release of drug and citric acid enable the drug solubility in the colon. The tablet was coated with a pH dependent enteric coating polymer, Eudragit S 100 which dissolve specifically at colonic pH (7.4) and allow the tablet to release the drug in the colon region in sustain release fashion. Thus, after oral administration, enteric coated tablets will be intact in upper part of GIT but release the drug in colon lumen which is prerequisite for the effective treatment of IBD.

 

MATERIAL AND METHOD:

Indomethacin drug was purchased from yarrow chem, Mumbai, India.  Guar gum, HPMC K4M and Eudragit S-100 was purchased from CDH, New Delhi, India.  Citric acid was procured from Merck, Mumbai, India. All other chemicals and reagents used during the experiments were of analytical grade and purchased from Loba Chemicals, Mumbai. Distilled water was used throughout the experiment.

 

Formulation of tablet by wet granulation:

Wet granulation technique was used to prepare the matrix tablet of Indomethacin. The various ingredients and quantity require to make different matrix tablets (F1-F8) is given in table 1. Here guar gum used in the formulation acts as a matrix former, HPMC acts as a release controlling polymer and citric acid enhanced the solubility of the drug in colon region. Before the granulation process all the pectin and HPMC was passed through the sieve no 60 and the drug was passed through sieve no 100. All the ingredients of the tablets were uniformly blended and starch paste (10% w/v) was used for granulation. Thereafter the wet mass was granulated by passing it through sieve no 18and then subjected to drying at 45°C for 2h.  The obtained granules were subjected to sieving (No. 24) to get uniform granules and further lubricated with talc and magnesium stearate. The lubricated granules were compressed using 12mm flat punch on rotary compression machine.

 

Tablet coating with Eudragit S 100:

The  various batches of matrix tablets  were coated with Eudragit S 100 polymer solution for protection of tablets to release its content in upper part of GIT as described by Deshmukh et al. with slight modification20. Briefly 500 mg of Eudragit S 100 was dissolved in isopropyl alcohol: (2:1) mixture to get a uniform solution of 10%. PEG 4000 (1% w/v) was use as a plasticizer. These tablets were coated by Eudragit S 100 solution by dip coating method to increase the weight of tablet by 10%.


Table 1: Composition of tablet formulation:

 

Ingredients

Quantity (mg) present in each tablet

F1

F2

F3

F4

F5

F6

F7

F8

Indomethacin

100

100

100

100

100

100

100

100

Guar gum

112.5

150

168.75

180

75

56.25

45

225

HPMC

112.5

75

56.25

45

150

168.75

180

----

Citric acid

75

75

75

75

75

75

75

75

MCC

60

60

60

60

60

60

60

60

Lactose

25

25

25

25

25

25

25

25

Starch

250

250

250

250

250

250

250

250

Talc

7.5

7.5

7.5

7.5

7.5

7.5

7.5

7.5

Magnesium stearate

7.5

7.5

7.5

7.5

7.5

7.5

7.5

7.5

HPMC = hydroxyl propyl methyl cellulose, MCC= Microcrystalline cellulose

 


Evaluation of granules:

Bulk density and tapped density:

Accurately weighed quantity (W) of prepared granules was poured in the flat bottom graduated cylinder to note down the bulk volume (V0). Further the graduated cylinder was transferred to the density determination apparatus keeping the mouth of lid closed. The apparatus was operated for 100 taps and the volume is measured (Vf). This procedure was repeated thrice. The formulae used for calculating bulk density and tapped density was as follows

 

                                  weight of granules

Bulk density = ------------------------------

                                   bulk volume

 

                              weight of tapped granules

Tap density = ----------------------------------

                                  tapped volume

 

Compressibility index:

It is also known as Carr’s index. It generally measures the % compressibility of the granules which help in compaction of granules into tablet. It is generally expressed in %. It is generally calculated by the formula:

 

                          Tap density – bulk density

Carr’s index = ------------------------------------- X 100

                                      Tap density

 

Hausner’s ratio:

It is defined as tapped density divided by bulk density. It is unit less. It was calculated by the formula

 

                                                    Tap density

Hausner’s ratio =  ----------------------

                                  Bulk density

Angle of repose:

It generally measures the angle between the pile of powder surface and its horizontal plane. It determines the ease with which the powder flow in die cavity. It is calculated by the formula

 

                  h

Tan ϴ = -------

                  R

 

ϴ = angle of repose, h = height of the powder pile and r = radius of the pile.

 

Evaluation of tablets:

Hardness:

Hardness of tablet is the load requite for the crushing or fracture placed on its edges. It is the measure of resistance to capping, abrasion or breakage under transportation and handling. Hardness of the tablet was performed by Monsanto hardness tester which measures the force required to break the tablet when kept at the anvils. The tables were kept between the anvils and force was applied to break the tablet and reading was recorded when tablet breaks. A total 6 tablets were taken from each formulation batch randomly for measurement and average value was calculated.

 

Friability:

Tablets were tested for it friability in order to access their durability during packing and transit. The friability of each batch formulation was tested with the help of Roche friabilator. 20 tablets from each formulation were weighed and kept in the chamber of friabilator and operated at 25 RPM for 4min resulting in abrasion and shock to tablets. The tablets were dusted and inspected for broken tablets and reweight to calculate the loss of tablet mass by following formula:

 

          Tablet weight before friability – tablet weight after friability

% Friability = ------------------------------------------------------------- X100

                                     Tablet weight before friability

 

Weight variation test:

Weight variation test was performed to ascertain that every tablet contains the proper amount of drug.  20 tablets were individually weighed in analytical balance and then average weight was calculated. The individual weight was compared with average weight of tablet and percentage weight variation was calculated by using the following formula.

 

                    individual tablet weight – average weight of tablets

% weight variation = -------------------------------------------------- X 100

                  Average weight of tablets

 

Drug content:

A 10 tablet from each batch were triturated in a mortar pestle to get a finely powdered. Power equivalent to 25 mg of Indomethacin was taken and transferred to 100mL volumetric flask and the drug was dissolved with 10ml of methanol. Further the volume was made up to the mark (100mL) with phosphate buffer pH 7.4. The resultant solution was filtered with Whattman filter paper (# 41) and again diluted to get a final concentration of 10μg/ml.  The absorbance was then measured by using UV-Visible spectrophotometer at absorbance maxima of 318nm29.

 

In vitro drug release studies:

Drug release studies of all coated tablets (F1-8) were made according to the method stated by Pawar et al30. A multiple dissolution rate apparatus (six paddles) was employed for drug release study. A 900mL of simulated GI fluid (SGF) was used as the dissolution medium. Tablets from each batch were placed in each beaker and the dissolution content was rotated at 100rpm at 37 ± 0.5 ˚C and exact equilibrium (sink) condition was maintained during the study period. The different pH of SGF and GI transit conditions were obtained by changing the dissolution medium at different periods. In the initial study period, pH 1.2 of SGF was maintained for 2 h with the help of 0.1N HCl. Further the pH of the SGF was changed to 6.8 by adding potassium di-hydrogen phosphate (1.7g) and di-sodium-hydrogen-phosphate-dihydrate (2.2g) and adjusting the pH using 1.0 M NaOH. The release study was continued for next 2 h. After 4 h, the pH of SGF medium was adjusted to 7.4 with 0.1N NaOH and maintained up to 24 h. A sample (5 mL) was withdrawn from the dissolution medium at predetermined time intervals and an equivalent volume of fresh SGF was replaced to preserve the sink conditions. Samples were filtered through the syringe filter (0.45μm, NYL) and were analyzed by using UV-vis spectrophotometer at 318 nm. Indomethacin concentrations in the samples were calculated based on standard drug calibration curve. All experiments were performed in triplicate (n = 3).

 

RESULTS AND DISCUSSION:          

The aim of the current study was to develop a indomethacin tablet using guargum and HPMC coated with Eudragit S 100 which can specifically release the drug to the colon. The tablets were formulated by wet granulation technology and various the granules and tablets (7 different formulation batch) were subjected to various evaluation parameters.

 

Micrometric study:

The granules of various batches were subjected for various micrometric parameters and the resulted were reported in table 2. The value of tap and bulk density ranges from 0.51±0.001 to 0.62±0.007and 0.45±0.001 to 0.55±0.005 respectively. The carr’s index, hausner’s ratio and angle of repose were found to be in range of 11.76±0.01 to 16.61±0.05, 1.13±0.01 to1.2±0.02 and 23.0±0.3 to 26.0±0.64 respectively.  It has been well established that the optimum value of Carr’s index (%) and Hausner’s ratio should be upto 15% and 1.20 respectively and angle of repose less than or equal to 25 represents a good flow property. Comparison of the results of formulation batches with standard value reveals that they possess a good flow property. The uniform flow of granules helps in uniformity of dose in tablets. The granules were punched to form tablets and were evaluated for various pharmacopoeial parameters and in vitro drug release study.

 


 

Table 2: Micrometric properties of Indomethacin granules

Formulation Code

Angle of response

Bulk Density

Tapped Density

Carr’s index

Hausner’s ratio

F1

26.0 ± 0.5

0.53 ± 0.005

0.61 ± 0.006

13.11 ± 0.05

1.15 ± 0.02

F2

25.0 ± 0.8

0.5 ± 0.006

0.58 ± 0.003

13.79 ± 0.04

1.16 ± 0.01

F3

22.0 ± 0.5

0.51 ± 0.007

0.59 ± 0.004

13.55 ± 0.06

1.16 ± 0.02

F4

23.0 ± 0.3

0.52 ± 0.004

0.62 ± 0.007

16.61 ± 0.05

1.2 ± 0.02

F5

24.0 ± 0.5

0.55 ± 0.005

0.65 ± 0.002

15.38 ± 0.02

1.18 ± 0.01

F6

25.0 ± 0.8

0.45 ± 0.001

0.51 ± 0.001

11.76 ± 0.01

1.13 ± 0.001

F7

26.0 ± 0.5

0.49 ± 0.002

0.56 ± 0.005

12.5 ± 0.05

1.14 ± 0.01

F8

26.0 ± 0.64

0.49 ± 0.003

0.57± 0.003

14.03 ± 0.03

1.16 ± 0.01

Data were represented as mean ± SD (n = 3)

 


Pharmacopoeial test for matrix tablet of Indomethacin coated with Eudragit S100:

The prepared granules were compressed with tablet punching machine to form tablets. The various batches F1-8 were then subjected to coating with Eudragit S100 polymer. They were evaluated for hardness, thickness, friability, weight variation and drug content as per pharmacopoeial specification. The results were shown in table 3. The hardness of various batches was tested with Monsanto hardness tester and was found in range of 6.2 ±0.68 to 7.2±0.86 (kg/cm3). The results show that all the batches have a good mechanical strength. The various batches of tablet show the thickness in range of 5.4± 0.08 to 5.7±0.20mm. All batches of tablets showed less than 1% loss which was considered as acceptable. The tablets had an average weight of 750gm with weight variation of 5%, falling within limit.  The drug content was found in the range 99.11±0.75 to 99.55±0.37%. All the batches of tablets fulfil the standards mentioned in Indian Pharmacopoeia (IP).


 

Table 3: Pharmacopoeial test for matrix tablet of Indomethacin coated with Eudragit S100

Formulation Code

Hardness (kg/cm3)

Thickness (mm)

Friability (%)

Weight Variation (mg)

Drug Content (%)

F1

6.9±0.08

5.6 ± 0.05

0.54±0.75

0.39±0.01

99.19 ± 0.48

F2

7.1 ± 0.04

5.4 ± 0.08

0.67±0.75

0.38 ± 0.02

99.3 ± 0.63

F3

7.2 ± 0.12

5.6 ± 0.11

0.41 ± 0.02

0.35 ± 0.03

99.06 ± 0.91

F4

6.9 ± 0.22

5.7 ± 0.20

0.61 ± 0.03

0.33 ± 0.01

99.21 ± 0.71

F5

6.2 ± 0.68

5.3 ± 0.08

0.52± 0.60

0.39 ± 0.001

99.55 ± 0.37

F6

7.1 ± 0.64

5.5 ± 0.07

0.66 ± 0.79

0.31 ± 0.002

99.48 ± 0.21

F7

7.2 ± 0.86

5.4 ± 0.94

0.67 ± 0.03

0.29 ± 0.001

99.11 ± 0.75

F8

7.1 ± 0.58

5.4 ± 0.66

0.54± 0.32

0.30 ± 0.003

99.01 ± 0.52

Data were represented as mean ± SD (n = 3)

 


Drug release study:

The in vitro release study of the Indomethacin from different formulations (F1-8) was carried out in USP paddle type II dissolution apparatus using pH progression medium. The temperature of the buffer was maintained at 37°C and paddle was kept at 100rpm.  The % cumulative drug release profile of F1-8 was little and insignificant at pH 1.2 for first 2 h (figure 1 and 2).  The formulation shows the % cumulative drug release from 0.46±0.02% to 3.8±0.02%±0.09%. As the tablets were coated with pH sensitive coating material therefore no drug was released from formulation.  After 2h the pH of the dissolution media was changed to 6.8 in order to mimic the conditions of small intestine. The % cumulative drug release of formulations F1-8 was in range of 1.54±0.08% to 4.8±0.42%. The data shows that at this pH a very low amount of drug was released from the formulations. After 4 h the pH of the dissolution media was changed to 7.4. At this pH the coating start dissolving and the media start to swell the tablets. At the end of 8 h the % cumulative drug release of formulations F1-8 was in range of 13.34±3.23 % to 31.98±4.94%. At the end of 24 h the erosion of polymer takes place and the % cumulative release was found to be in the range of 65.92±5.9% to 80.41±6.5%. Among all the formulation the formulation F3 having guar gum and HPMC ratio 3:1 shows a maximum release of drug. Therefore, F3 was considered as the optimized formulation in the study. 

 

 

Figure 1:  In vitro drug release profile of Indomethacin loaded matrix tablets F1-4 at pH 1.2, 6.8 and 7.4. The values were mean ± SD (n = 3).

 

Figure 2:  In vitro drug release profile of indomethacin loaded matrix tablets F5-8 at pH 1.2, 6.8 and 7.4. The values were mean ± SD (n = 3).

 

CONCLUSION:

IBD is an inflammatory disorder occurred in GIT especially at colon region. Various anti-inflammatory drug were used by the physician for the management and remission of the IBD. But the current conventional drugs delivery system especially tablets have problem of high dose size and frequency with adverse effect. The objective of the current study was to develop and evaluate Indomethacin loaded matrix tablets for colon targeting.  The matrix tablet was formed using guar gum and HPMC as a polymer. The tablets were formed by wet granulation methods and the compress tablets were coated with Eudragit S 100 polymer which dissolve at colonic pH specific. A total 8 different batches were made and they fulfil the compendia limits in terms of micrometrics and physiochemical parameters. The formulation F3 having guar gum and HPMC in the ratio of (3:1) shows maximum drug release and was chosen as an optimized formulation. The HPMC and guargum can also offer a mucoadhesiveness which further helps in targeted release of Indomethacin in colon. Hence the prepared tablets can be a good alternative to traditional tablets which has drawback of high dose and more side effect.

 

CONFLICT OF INTEREST:

Authors have no conflict of interest.

 

ACKNOWLEDGEMENT:

Authors are grateful to the IPR, GLA University, Mathura, for providing necessary facility to carryout work.

 

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Received on 22.05.2020           Modified on 15.06.2020

Accepted on 30.06.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(5):2391-2396.

DOI: 10.52711/0974-360X.2021.00422