Methacrylic Acid Co-Polymers:

Crucial agents for the Colon Targeted Oral Drug Delivery System

 

Jaymin Patel1,2, Kaushika Patel1, Shreeraj Shah1*

1L. J. Institute of Pharmacy, LJ University, Ahmedabad - 382210, India.

2Research Scholar, Gujarat Technological University, Ahmedabad.

*Corresponding Author E-mail: shreeraj.shah@ljinstitutes.edu.in

 

ABSTRACT:

The objective of this research was to formulate an Ornidazole tablet capable of delivering the drug intact to the colon for the treatment of IBD, ulcerative colitis, and Crohn's disease. In the current investigation, pH-independent and pH-dependent polymers were used to target the Ornidazole tablet to the colon. This study evaluated two time-dependent (sustained release) polymers (Eudragit RS and Eudragit RL) and one pH-dependent polymer (Eudragit S100). The influence of the two formulation variables of the colon drug delivery system on the two response variables were examined simultaneously using a statistical 32-Full factorial design. X1 Ratio of Eudragit RS 100 to Eudragit RL 100 and X2 % weight gain with Eudragit S 100 were treated as independent variables in a factorial design, while Y5 and Y12 were treated as dependent variables. Through this procedure, a total of nine F9 samples were produced. Y5 in-vitro release should not exceed 10%, whereas Y12 should surpass 85%. Based on these results, batch B8 is considered the finest of all cohorts. According to the results, the enhanced formulation provides optimal intact drug delivery to the targeted region.

 

KEYWORDS: Ornidazole, Eudragit RS 100, Eudragit RL 100, Eudragit S 100, Colon targeted drug delivery system, pH-dependent Polymer, pH independent Polymers.

 

 


1. INTRODUCTION: 

It is advantageous to use colon-targeted drug delivery systems to deliver intact medications to the colon. In order to treat inflammatory bowel diseases (IBD) like ulcerative colitis and Crohn's disease (CD), the substance must be administered locally and selectively to the colon.1,2,3 The small or large intestine wall becomes irritable, inflamed, and distended in Crohn's disease. Crohn's disease affects the terminal portion of the small intestine and the commencement of the large intestine most frequently. In this instance, the numerous pharmacological techniques for drug delivery to the colon are predominately based on a pH-dependent, time-dependent, bacteria-dependent, and pressure-dependent delivery mechanism, as well as patented technologies such as Phloral® Technology, Codes ® Technology, etc.4,5

 

 

The majority of IBD-treating pharmaceuticals are absorbed systemically or degraded in the upper GIT, preventing their delivery to the colon in conventional dosage forms.6,7

 

Earlier research employed a pH-dependent system to restrict drug release at stomach pH while permitting the majority of drug release in the small intestine.8,9

 

Thus, in the current work, a combination of techniques was used in which an inner Time-dependent (sustained release) matrix was utilized to limit drug release in the small intestine by providing appropriate lag time, which was then covered with a pH-dependent polymer. The study evaluated two time-dependent (sustained release) polymers (Eudragit RS and Eudragit RL) and one pH-dependent polymer (Eudragit S100)10,11. Eudragit RL was more hydrophilic than Eudragit RS 100, and the release of drug was significantly faster from a single Eudragit RL 100 matrix tablet compared to a single Eudragit RS100 matrix tablet; consequently, different combinations of Eudragit RL and RS to provide varying degrees of sustained-release of the drug were used as the time-dependent system in the present study.8,9,10,11,12

This study aimed to determine the optimal ratio of polymers for delivering the most substance to the colon. As a model drug, ornidazole is effective in treating mild to moderate cases of perianal fistulae in Crohn's Disease and is also employed as an anti-amoebic agent.14,15,16

 

In this research, two formulation variables examined were the Ratio of Eudragit RS 100 to Eudragit RL100 and the Eudragit S100 coating level.17

 

The two response variable experiments investigated the amount of drug release in five and twelve hours, respectively. Due to the low water content in the colonic region, the expected in vitro release pattern for colon targeting was below 10 percent drug release up to the end of the small intestine (5hours) for targeting and to deliver the maximum quantity to the colon, and more than 85% drug release up to 12hours. Consequently, the release across the colon would be deficient if less than 85 percent were released.

 

2. MATERIALS AND METHODS:

2.1 MATERIALS:

Ornidazole is received as gift sample from Endoc Pharma in Rajkot. Tablettose 100 and Flowlac 100, as well as Plasdone K 90, are all sourced from Anshul Agencies, Mumbai. The Eudragit series, comprising Eudragit S 100, Eudragit RS 100, and Eudragit RL 100, is obtained from Degussa Rohm Pharma, Mumbai. Polyvinyl pyrrolidone (PVP- K30) and Sodium starch glycolate (SSG) are part of the formulation. Additionally, the formulation includes Titanium dioxide and Tartrazine, which are sourced from Loba Chemie Pvt. Ltd., situated in Mumbai. Tri Ethyl citrate is procured from Himedia Laboratory, Mumbai.

 

2.2 Preparation of Ornidazole tablets:

Ornidazole matrix tablets were prepared by direct compression using different proportions of Eudragit RS/RL 100; Flowlac 100 as diluents, PVP K30 as a binder, and SSG as super disintegrants. All of the ingredients were sieved through a 100# mesh. In a glass mortar, all ingredients besides Talc and Magnesium Stearate were thoroughly mixed. After adequate combining of the drug and other ingredients, Talc and Magnesium Stearate were added and mixed for an additional 2 to 3 minutes. The tablets were compressed using a single-stroke crushing machine with a 12mm concave-faced hammer with a concave face.

Composition of formulations of Ornidazole Matrix Tablet were summarized in table 1

 

Table 1: Composition of formulations of Ornidazole Matrix Tablet A1- A5 batches

Ingredients

A1

A2

A3

A4

A5

Ornidazole

500

500

500

500

500

Eudragit RS 100

110

-

27.5

55

82.5

Eudragit RL 100

-

110

82.5

55

27.5

Flowlac

69

69

69

69

69

Talc

14

14

14

14

14

Magnesium Stearate

7

7

7

7

7

Total

700

700

700

700

700

2.3 Drug content:

The tablets of Ornidazole were analyzed for their drug content. Ten tablets were finely pulverized, and 50 mg of Ornidazole-equivalent powder was accurately weighed and transferred to a 100ml volumetric flask. The flask was filled with phosphate buffer solution with a pH of 6.8 and thoroughly mixed. The solution was diluted and then filtered. From this, 10ml of solution was taken out and diluted to a volume of 250ml using phosphate buffer with a pH of 6.8. The absorbance of the resulting solution was measured using a UV/Visible double beam spectrometer at 319.6nm against a pH 6.8 phosphate buffer as a reference.18,19

 

2.4 Swelling Studies and Erosion Studies:

2.4.1 Swelling index:

The degree of swelling is expressed as a percentage of the tablet's weight gain.

Using a formula, the swelling index was calculated.20

% swelling = S/R*100

Where,   S = Weight of matrix after swelling

R = Weight of eroded matrix.

 

2.4.2 Erosion Studies:

In this method, tablets were initially weighed and placed in a dissolution apparatus with a paddle rotating at 50 revolutions per minute. After one hour, the tablets were removed and dry in an oven at 500 degrees Celsius. After relaxing in the desiccator, these were accurately weighed, and % weight loss (% attrition) was calculated using the appropriate formula.21

 

% Erosion = (T- R)/T * 100

Where,   T = Initial weight of the matrix

R = Weight of eroded matrix

 

2.5 In-vitro drug release studies:

The in-vitro drug release of a colon-specific tablet was performed in a USP Type II (Paddle) apparatus at 50 rpm and 37±0.50C. Initially, the test was conducted in 0.1 N HCl for two hours to simulate the gastrointestinal environment. The test was then conducted for three hours in phosphate buffer pH 7.4, which simulates the small intestine's environment. The small intestine is actually divided into three sections: the duodenum (pH 5 to 6), the jejunum (pH 6.63±0.53), and the ileum (pH 7.49±0.45)22. As the longest section of the small intestine, the ileum has a mean pH of 7.3±0.34. The remainder of the study was carried out in a dissolution medium with a pH of 6.8, which is comparable to the mean pH of the large intestine (6.63±0.03)23. At regular intervals, 1 ml of the samples were taken out and filtered through 0.45 micron-pored Whatman filter paper. Each 1 milliliter was further diluted with an appropriate dissolution medium up to 10ml and spectrophotometrically analyzed for drug content at a wavelength of 319.6nm.

2.6 Preparation of coating solutions and coating of tablets:

In this investigation, the focus was on developing a tablet coating approach to achieve drug release in the colonic region for targeted delivery. For the coating process, an enteric polymer, Eudragit S 100, was selected due to its ability to remain stable in the acidic environment of the upper GI tract (pH below 7) and then dissolve in the colonic region where the pH is higher (pH above 7). The use of polymers based on methacrylic acid for colonic drug delivery is supported by an extensive record of research.17

 

The tablet coating procedure began with weighing the required quantity of Eudragit S 100, which was then dissolved in Acetone. To ensure good solubility, the mixture was placed on a magnetic stirrer at 50rpm. Complete solubilization of Eudragit S 100 was critical to obtaining a uniform coating solution. Tri-ethyl citrate, the most suitable plasticizer for Eudragit S 100, was applied at a concentration of 10% of the polymers' dried weight to improve the coating's flexibility and efficacy17.

 

In order to optimize the coating solution's characteristics, specific additives were introduced. Talc was used as an anti-adherent agent to prevent the tablets from sticking together during the coating process. For coloring purposes, Tartrazine, a yellow pigment, was incorporated into the solution, and Titanium dioxide served as an opacifier, enhancing the tablet's appearance.

 

Before application, the coating solution underwent filtration to remove any impurities or particles that could affect the coating quality. In the tablet coating procedure, the required quantities of tablets, along with some extra tablets, were carefully loaded into the coating pan. The pan was set to rotate at a speed of 50 revolutions per minute for five minutes, ensuring proper mixing and de-dusting of the tablets. Following this initial step, a specific quantity of tablets was selected for the coating process. Subsequently, the rotation speed of the coating pan was adjusted to 40 revolutions per minute, and the temperature was set to 50°C to create the optimal coating environment. To control the coating process precisely, a peristaltic pump was used to adjust the previously optimized discharge rate of of 0.4 ml/min, ensuring the appropriate amount of coating solution was applied to the tablets

 

The nozzle-to-bed distance was set at 7 inches to ensure precise and even coating distribution on the tablets. Additionally, the drying temperature was carefully controlled at 50°C to promote solvent evaporation while preventing any degradation of the active pharmaceutical ingredient. The tablet coating process continued until the desired weight gain percentage was achieved, indicating that the tablets had received the necessary amount of enteric polymer coating for targeted drug release in the colonic region. This methodological approach, along with the use of Eudragit S 100 as the enteric polymer, holds significant potential for enhancing drug delivery in colonic-specific treatments, leading to improved therapeutic outcomes.

 

2.7 Experimental design:

The formulations were developed utilizing a 32-factorial design. Independent variables included the ratio of Eudragit RS100 to Eudragit RL100 (X1) and the level of coating on Eudragit S100 (X2)24. The dependent variables (responses) were drug release rate up to five hours (Y5) and drug release rate up to twelve hours (Y12). Summary of the Independent variables, Dependent variables, and their levels for factorial design shown in table 2 and batches prepared according to table 3

 

Table 2: The levels of the independent variables and Dependent variables for factorial design

Variables

(Independent)

Levels

Variables

(Dependent)

Lower (-1)

Middle (0)

Upper (+1)

Y5= amount of drug release up to 5 hrs.

Y12= Amount of drug release up to 12 hrs.

X1- Ratio of Eudragit RS 100 to the Eudragit RL 100

25%

50%

75%

X2- Coating level of Eudragit S 100

0%

5%

10%

 

Table No. 3: Batches of Coded value and actual value of variables in factorial design

Batch No.

Coded values

Actual values

X1

X2

X1

X2

B1

-1

-1

25%

0%

B2

0

-1

50%

0%

B3

1

-1

75%

0%

B4

-1

0

25%

5%

B5

0

0

50%

5%

B6

1

0

75%

5%

B7

-1

1

25%

10%

B8

0

1

50%

10%

B9

1

1

75%

10%

 

2.8 Statistical analysis of data:

The data of drug released at the end of each dissolution test were analyzed. Statistical model of the effects of X1 and X2 variables upon the dependent variables Y5 & Y12 was based on following second order polynomial equation24

Y = b0+b1X1 + b2 X2 + b11 X12 +b22 X22 +b12 X1X2 --------- (2)

A second-order polynomial model was individually fitted to both the response variables using Microsoft Excel 2013.

 

Response variable were significantly different or not that can be assessed by performing Dunnett test.

A value of P < 0.05 was considered statistically significant.

 

3. RESULTS:

The respective drug concentrations of samples A1 through A5 were 99.68±0.20, 99.73±0.24, 100.68±0.28, 98.77±0.28 and 99.31±0.14. Figure 1 illustrates the dissolution profiles of formulations A1 through A5 of Ornidazole matrix tablets without coating. Figure 2 (a and b) displays the results of% swelling index and% Erosion for batches A1 to A5.

 

 

Figure 1: dissolution profile of formulation A1 – A5 of Ornidazole matrix tablets

 

 

 

 

Figure 2: The results of (a) % swelling index and (b) % Erosion for A1- A5 batches

The expected in vitro release pattern for colon targeting was less than 10% drug release up to the end of the small intestine (5hours) and greater than 85% drug release up to 12 hours. Using a 32-Factorial design, formulation quantities B1-B9 were created, where X1 was the ratio of Eudragit RS 100 to RL 100 (25%, 50%, 75%) and X2 was the coating level of Eudragit S100 (0%, 5%, 10%). Figure 3 summarizes the dissolution profiles of Ornidazole-coated tablets B1 to B9 in 0.1 N HCl, 7.4 pH phosphate buffer, and 6.8 pH phosphate buffer.

 

 

Figure 3: Dissolution profiles of Ornidazole coated tablets from B1-B9 in 0.1 N HCl, 7.4 pH phosphate buffer & 6.8 pH phosphate buffer

 

Based on the results of this study, it was determined that the optimal formulation was a matrix tablet containing Eudragit RS: Eudragit RL (1:1) and super coated with 10% Eudragit S100.

 

Figure 3: Dissolution profiles of Ornidazole-coated tablet formulations B1-B9 in 0.1 N HCl, 7.4 pH phosphate buffer, and 6.8 pH phosphate buffer.

 

4. DISCUSSION:

In vitro drug release studies of batch A2 indicated complete drug release within 3 hours, as it solely consisted of the hydrophilic Eudragit RL 100. In contrast, batch A1, containing only the hydrophobic Eudragit RS 100, showed a drug release of only 72% within 12hours. Batches A3, A4, and A5 comprised various proportions of both hydrophilic and hydrophobic polymers, resulting in drug release durations of  7, 9, and 12hours, respectively.

 

The swelling studies demonstrated that the matrix swelling was influenced by the hydrophilic and hydrophobic nature of the polymers. Tablets from batch A2, containing Eudragit RL 100, exhibited an increased swelling index due to its high hydrophilicity. However, the high hydrophilicity also led to a rapid erosion rate, causing the tablets to rupture within 3 hours.

 


Table 4: Analysis of variance of dependent variables:

 

Source of variation

Sum of squares

Degree of freedom

Mean square

F-ratio

Significance F

Y5

Regression

5534.656

5

1106.931

98.81736

0.001583

Residual

33.60537

3

11.20179

-

-

Y12

Regression

918.1382

5

183.6276

29.10413

0.009571

Residual

18.928

3

6.309333

-

-

 


For batch A3, the swelling index increased compared to A2, but the increase was relatively less. This could be attributed to the presence of the hydrophobic Eudragit RS 100, which also reduced the erosion rate, leading to tablet rupture within 7hours.

 

In batch A4, the swelling index also increased, but the increase was less than that of A2 and A3. This was likely due to the reduced hydrophilicity of Eudragit RL 100 and an increase in the hydrophobic Eudragit RS 100. The tablets from batch A4 did not rupture up to 8 hours, as the increase in hydrophobicity of Eudragit RS 100 resulted in a decreased erosion rate.

 

Similarly, the swelling index of batch A5 increased compared to A4, but the increase was less. This was attributed to the reduced hydrophilicity of Eudragit RL 100 and increased hydrophobicity of Eudragit RS 100 compared to batch A4. The tablets from batch A5 also did not rupture up to 8 hours due to the reduced erosion rate resulting from the increased hydrophobicity of Eudragit RS 100.

 

Batches A3, A4, A5, and A1 showed lower swelling indices compared to A2, but the erosion rate of A2 was significantly higher. Batch A3 had a lower erosion rate than A2 but still eroded within 7 hours, making it unsuitable for further study. Batch A4 had lower swelling compared to A2 and A3, but its erosion rate was also less than that of A2 and A3. Despite this, Batch A4 did not rupture up to the target release time.

 

To design various formulations, a statistical full factorial design was employed. The independent variables were the ratio of Eudragit RS 100 to RL 100 (X1) and the coating level of Eudragit S100 (X2), with levels of 25%, 50%, and 75% for X1 and 0%, 5%, and 10% for X2. Formulations with higher proportions of Eudragit RS 100 and super coating (Eudragit S100) exhibited minimal drug release due to a synergistic effect. Possible ionic interactions between the cationic ammonia groups of Eudragit RS and the carboxylic groups of Eudragit S100 protected the anionic groups from rapid ionization, leading to a retardation of dissolution of pH-dependent polymers.

 

Optimization of formulation:

For the purpose of optimization, the expected in vitro release pattern for colon targeting was less than 10% drug release up to the end of the small intestine (5 hours) and greater than 85% drug release up to 12 hours. Actually, the transit time of the gastrointestinal tract is 15 to 30 hours, but a second dependent variable determined that more than 85 percent of the drug should be released within 12 hours because the primary function of the colon is to absorb water; therefore, the amount of water in the colon decreases with time, which may inhibit the drug's release from the dosage form. Therefore, a time value of 12 hours was deemed appropriate for 85-100% drug release from the delivery system in the colon.

 

The Excel-generated second-order polynomial equations for all of the responses are provided below.

Y5 = 40.10667 -10.5183X1 -28.2617X2 + 1.627 X12 -2.795 X22 +3.795 X1X2 --------- (2)

 

Y12 = 98.946 -9.315X1 -4.77X2 -7.696X12+0.85X22-5.95X1X2 -------- (3)

Analysis of variance (ANOVA) (Table 4) indicated that the selected regression models were significant and valid for each considered response.

 

The regression analysis equation reveals that Y5 experiences a negative impact due to both X1 and X2, implying that increased values of X1 and X2 lead to a decrease in the release of Ornidazole. Notably, X2 exhibits greater significance than X1, as its negative influence on Y5 is more pronounced. Consequently, the coating level of Eudragit S 100 significantly affects the release within 5 hours.

 

Similarly, Y12 is adversely affected by both X1 and X2, with X1 being more influential than X2 in this case. This indicates that the ratio of Eudragit RS100/RL100 plays a substantial role in influencing the dependent variable Y12. Eudragit RS and Eudragit RL 100, being sustained release polymers, can effectively regulate drug release after dissolution of pH-dependent polymers in different media.

 

5. CONCLUSION:

In conclusion, this research aimed to develop an effective Ornidazole tablet for the treatment of inflammatory bowel diseases (IBD), ulcerative colitis, and Crohn's disease. The study employed pH-independent and pH-dependent polymers to target drug delivery specifically to the colon. Three polymers, Eudragit RS, Eudragit RL, and Eudragit S100, were evaluated to achieve sustained and pH-dependent release. A statistical 32-complete factorial design was utilized to investigate the influence of two formulation variables on the drug delivery system simultaneously. Through this approach, Nine Factorial batches (F9) were evaluated based on two response variables: Y5 (in-vitro percentage release not exceeding 10%) and Y12 (in-vitro percentage release exceeding 85%). Among the batches, batch B8 was identified as the most promising formulation, meeting the desired release criteria.

 

Overall, the findings suggest that the optimized formulation using a combination of pH-independent and pH-dependent polymers facilitates efficient drug delivery intact to the targeted colon region. This innovative approach holds great potential for the effective treatment of IBD, ulcerative colitis, and Crohn's disease, providing a significant advancement in drug delivery technology.

 

6. CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

 

7. ACKNOWLEDGMENTS:

The authors, Jaymin Patel is thankful to Dr. Shreeraj Shah for valuable guidance and to the L. J. Institute of Pharmacy, LJ University, Ahmedabad for providing the research facilities which is a part of Doctor of Philosophy (Ph.D.) research work of Mr. Jaymin Patel, to be submitted to Gujarat Technological University, Ahmedabad

 

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Received on 01.01.2023            Modified on 19.05.2023

Accepted on 09.08.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2024; 17(4):1531-1536.

DOI: 10.52711/0974-360X.2024.00242