Formulation and optimization of a single-layer coat for targeting budesonide pellets to the descending Colon

Abstract

The current budesonide formulations are inadequate for addressing left-sided colitis, and patients might hesitate to use an enema for a prolonged time. This study focuses on developing a single-layer coating for budesonide pellets targeting the descending colon. Pellets containing budesonide (1.5%w/w), PVP K30 (5%w/w), lactose monohydrate (25%w/w) and Avicel pH 102 (68.5%w/w) were prepared using extrusion spheronization technique. Coating formulations were designed using response surface methodology with pH and time-dependent Eudragits. Dissolution tests were conducted at different pH levels (1.2, 6.5, 6.8, and 7.2). Optimal coating formulation, considering coating level and the Eudragit (S + L) ratio to the total coating weight, was determined. Budesonide pellets were coated with the optimized composition and subjected to continuous dissolution testing simulating the gastrointestinal tract. The coating, with 48% S, 12% L, and 40% RS at a 10% coating level, demonstrated superior budesonide delivery to the descending colon. Coated pellets had a spherical shape with a uniform 30 µm thickness coating, exhibiting pH and time-dependent release. Notably, zero-order release kinetics was observed for the last 9 h in colonic conditions. The study suggests that an optimized single-layer coating, incorporating pH and time-dependent polymers, holds promise for consistently delivering budesonide to the descending colon.

Keywords:

• Budesonide pellets
• targeted delivery
• descending colon
• pH-dependent
• time-dependent

1. Introduction

Inflammatory bowel disease (IBD) is a chronic and idiopathic inflammation condition in the gastrointestinal tract (GIT) (Chao et al. 2017; Chen et al. 2021). Ulcerative colitis (UC) is one of the most prevalent types of IBD (Hassan and Hassan 2018; Ruban et al. 2022), that affects the rectum and colon (Yan et al. 2019; Sardou et al. 2021). Different types of ulcerative colitis are often classified according to the location of inflammation (Gros and Kaplan 2023) and this location is important in making a decision and the selection of the most effective treatment (by the physician) for each type of disease (Segal et al. 2021). Left-sided colitis is the most common subtype of ulcerative colitis that affects the left side of the colon from the rectum up to the splenic flexure (Kayal and Shah 2019). This kind of inflammatory bowel disease is currently treated with enemas (Harbord et al. 2017; Cohen and Weisshof 2020) but patients are usually reluctant to enema use. Therefore oral administration of anti-inflammatory drugs is more suitable for long-term therapy (Cohen 2006; Denesh et al. 2021).

Budesonide is a potent anti-inflammatory corticosteroid with high topical activity (Bruscoli et al. 2021) and its oral formulations are currently approved as the second-line treatment of UC (Gherardi et al. 2018; Rojo et al. 2020). Although many oral formulations of budesonide are commercially available on the market, none of them is suitable for the treatment of inflammation of the descending colon (Gareb et al. 2019). Therefore appropriate targeting delivery of the drug to the left side of the colon with the orally administered formulation is still one of the major challenges (Bokemeyer et al. 2012).

New approaches including nanosystems (Ali et al. 2016; Brusini et al. 2020; Ganguly et al. 2023) and osmotic-based (Nie et al. 2020; Vani et al. 2023) formulations have been applied for colon targeting. Also, personalized colonic drug delivery systems were investigated using 3D printing technology (Sangnim et al. 2021; Asadi et al. 2023). However, these formulations are less noticed from the pharmaceutical industry’s point of view due to the complicated scale-up processes and the high costs (Soltani et al. 2022). Among oral formulations multi-particulate dosage forms especially pellets offer many advantages in comparison with other classical formulations. These include more rapid distribution and predictable movement in the GI tract and less variations in gastric emptying (Ghebre-Sellassie 1989; Wang et al. 2012; Hussain et al. 2021). Since GI motility disorder is a complicated symptom in IBD patients (Bassotti et al. 2020) (which could affect the therapeutic effects of oral medications), the formulation of budesonide in pellets dosage form could present an opportunity for addressing this challenge (Desai and Momin 2020; Bhagwat et al. 2021; Singh et al. 2021).

Up to now, many budesonide pellet formulations based on different colon targeting approaches have been developed (Patel 2011; Varshosaz et al. 2011; 2012; Raval et al. 2013; Patel et al. 2023; Soltani et al. 2023). Among these formulations, those based on a single approach for colon delivery have been accompanied by some drawbacks including failure in in vivo studies (Raval et al. 2013). This failure has been due to the inter- and intra-variations in gastrointestinal pH, motility and transit times in IBD patients (Maroni et al. 2017; Lee et al. 2020). Many researchers have tried to fix this limitation by applying different colon targeting approaches as separate multi-layer coating systems (Patel et al. 2011; Varshosaz et al. 2012). However, it is noticeable that applying different coating layers is a time-consuming and costly process. Some studies have demonstrated that the combination of different colon targeting strategies in a single-layer coat not only reduces the production cost but also decreases the dependency of the drug delivery system on the variations in GI conditions (Nguyen et al. 2019; Sardou et al. 2022). A combination of pH and time-dependent polymers is the most used approach for colonic drug delivery (Park et al. 2017; Foppoli et al. 2019; Sardou et al. 2022). These delivery systems could create a bimodal release profile, with an initial lag time (due to the presence of pH-dependent polymers) followed by a controlled release phase (due to the presence of time-dependent polymers) (González-Rodríguez et al. 2003; Sardou et al. 2022; Vemula et al. 2023). Researchers demonstrated that with a constant drug release through the colonic region, the opportunity for the delivery of drugs to the entire colon would be increased and such a system could be suitable to treat left-sided colitis (Gareb et al. 2019).

Since the drug release profiles in such combined systems could be manipulated with varying coating compositions and coating levels (Crowe et al. 2019), the application of a full factorial design could be helpful for the optimization of the coating system to enhance the site specificity and therapeutic effects of the drug.

In this study, an attempt was made to address a critical gap in the current therapeutic approaches for left-sided colitis, a subtype of ulcerative colitis affecting the descending colon. This deficiency has prompted our investigation into the development of a novel, optimized single-layer coating for budesonide pellets, employing a strategic combination of pH and time-dependent polymers (Eudragit S, L, and RS). Furthermore, the application of a full factorial design in manipulating coating compositions and levels, guided by our study, promises to optimize the coating system. This optimization is anticipated to enhance the site specificity and overall therapeutic efficacy of budesonide delivery to the left side of the colon.

2. Materials and methods

2.1. Materials

Budesonide was obtained from Jaber Ebne Hayyan Pharmaceutical Company (Tehran, Iran). Lactose monohydrate (Merk, Germany), Avicel pH 102 (Merck, Germany), Polyvinylpyrrolidone (PVP K30) (Rahavard Tamin, Iran), Eudragit S100 PO, (Evonik Industries AG, Hanau, Germany), Eudragit L100 PO, (Evonik Industries AG, Hanau, Germany), Eudragit RS 30D, (Evonik Industries AG, Hanau, Germany), Talc, (Merck, Germany), Triethyl citrate (TEC) (Merck, Germany), Isopropyl alcohol (2-propanol) (Dr. Mojallaly, Iran) and Sodium lauryl sulfate (SLS) (Scharlau, Spain) were used. All other reagents and solvents were of analytical grades.

2.2. Preparation of budesonide pellets

The extrusion-spheronization technique was used to prepare pellets containing 1.5% w/w budesonide. Pellets were prepared according to a method established in our previous study (Soltani et al. 2022). In brief, a powder blend consisting of budesonide (1.5% w/w), PVP K30 (5% w/w), lactose monohydrate (25% w/w) and Avicel pH 102 (68.5% w/w), were blended with a mixer (FUMA, Fu-1877 Hand Mixer, Japan) for 20 min. Then the proper amount of water (10 ml per 25 g of formulation), as granulating agent was added to this mixture to form a wet mass. The wet mass was extruded using an axial screw extruder (Dorsa Tech, EX-01, Iran) through a flat sieve of 1 mm at room temperature, and then spheronized for 5 min at 1200 rpm using a spheronizer (Dorsa Tech, EX-01, Iran) with a cross-hatched friction plate. The prepared pellets were placed in an oven (40 °C) for 24 h, and then those with a size range of 850–1180 µm were collected for further studies. Due to the hydrophobic nature of budesonide, its integration into the matrix pellets may hinder the release process, resulting in inadequate drug concentrations at the target site. Thus, in our previous study, for preparation of the budesonide pellets, the focus was made to ensure both sufficient release kinetics and favourable mechanical properties conducive to the coating process (Soltani et al. 2022).

2.3. Design of coating formulation

A 3² full factorial design was applied for the design of coating formulation using design expert software (Design-Expert software, Version 11, Stat-Ease, USA). The decision to employ a full factorial design was driven by the need to systematically explore the influence of different factors on the response variables. A full factorial design allows for the examination of all possible combinations of the chosen factors, providing a comprehensive understanding of their individual and interactive effects on the outcomes (Antony 2014). The independent variables were the ratio of Eudragit S and L to the total weight of coating polymers (Eudragit S, L and RS) (X₁), and coating level (X₂). These variables were identified as crucial parameters influencing the dissolution behavior of coated formulations based on preliminary investigations and existing literature (Sardou et al. 2022). By limiting the number of independent variables to two, we aimed to maintain experimental tractability and ensure a manageable number of experimental runs, thus optimizing the efficiency of our study. The independent variables were the ratio of Eudragit S and L to the total weight of coating polymers (Eudragit S, L and RS) (X₁), and coating level (X₂). Due to the hydrophobic nature of budesonide, its integration into the matrix pellets may hinder the release process, resulting in inadequate drug concentrations at the target site. Thus, in our previous study, for the preparation of the budesonide pellets, the research was focused on ensuring both sufficient release kinetics and favourable mechanical properties conducive to the coating process (Soltani et al. 2022). Based on the previous studies, in all of the experiments, the ratio of Eudragit S to L was fixed at a ratio of 4 to 1 (Akhgari et al. 2005). The percentage of drug release during 2 h at pH 6.8 (Y₁), The percentage of drug release within 10 h at pH 6.8 (Y₂) as well as the lag time (the time before 2% drug release) in pH 7.2 (Y₃), were considered as responses (dependent variables) in this study. Tables 1 and 2 show the independent variables and levels as well as suggested formulations by Design-Expert software respectively.

Table 1. Independent variables and their levels in design experiment.

Independent variables	Levels used
	−1	0	+1
X1 = ratio of (S + L) to (S + L + RS)	20	60	100
X2 = coating level (%)	5	10	15

Table 2. The runs and composition of experimental formulations.

Run	Variable factors
	X1 (ratio of (S + L) to (S + L + RS))	X2 coating level (%)
1	100	5
2	100	10
3	100	15
4	60	5
5	60	10
6	60	15
7	20	5
8	20	10
9	20	15

2.4. Coating of pellets

2.4.1. Preparation of coating formulations

Proper amounts of Eudragit S, L and RS were dissolved in a solvent consisting of 90% isopropanol and 10% distilled water under continuous stirring to make a 10% (w/v) solution. Triethyl citrate (TEC) was then added to this solution as a plasticizer (10% w/w based on polymers weight) and stirred for 1 h. Talc at 5% w/w (based on polymers weight) was finally added to this solution as an anti-adherent agent. The resulting solution was stirred for 20 min before use in the coating process.

2.4.2. Coating procedures and conditions

50 grams of budesonide pellets were coated using a fluidized bed coater (Wurster insert, Werner Glatt, Germany) by different coating formulations. Coating conditions are listed in Table 3. Samples of coated pellets were removed from the apparatus when the coating amount reached the designed level mentioned in Table 2. All pellets were dried in an oven (45 °C) for 24 h.

Table 3. The conditions used for coating.

Inlet temperature (°C)	40-43
Outlet temperature (°C)	36-39
Nozzle diameter (mm)	1
Atomization pressure (bar)	2

2.5. Dissolution studies

The release profiles of coated pellets (630, 660 and 690 mg of coated pellets for formulations with 5%, 10% and 15% coating level respectively) of budesonide (n = 6) equivalent to 9 mg of budesonide were studied using USP dissolution apparatus I (Pharmatest, PTWS 3E, Germany) in 250 ml of HCl 0.1 N (pH 1.2 simulating gastric medium) and phosphate buffers at pH 6.5, 6.8, and 7.2 (simulating different parts of small and large intestinal medium). To provide sink condition, SLS (0.25% w/v) was added to all media in order to prevent the saturation of the dissolution medium with the drug substance. The duration of the dissolution test was 2 h for gastric medium and 10 h for other media. Dissolution tests were performed at 37 ± 0.5 °C at the basket rotation speed of 75 rpm. At pre-determined times, samples (5 ml) were withdrawn from the medium and replaced with 5 ml of fresh medium. Samples were filtered through a 0.22 μm syringe filter. The amount of budesonide in 1 ml of filtrate was quantified using high-performance liquid chromatography (HPLC, Shimadzu, Japan) at 240 nm. HPLC was performed using a Teknokroma column (BRISA LC2 C18 250 mm × 4.6 mm, 5 μm) and the isocratic mobile phase was a mixture of acetate buffer (pH 3.9) and acetonitrile (35:65) delivered at a flow rate of 1.5 ml/min.

The drug release profile of the pellets coated with the optimum coating formulation was evaluated in the continuous mode of the dissolution test. To simulate GIT conditions, dissolution tests were performed for 2, 1, 2, 1, and 10 h at pH levels of 1.2, 6.5, 6.8, 7.2, and 6.8 respectively. At the end of the incubation time in each medium, baskets containing pellets were transferred to the next dissolution medium. At each sampling time, samples (5 ml) were withdrawn manually and replaced with 5 ml of fresh medium. Samples were analysed by HPLC as explained before.

2.6. Morphology of pellets

The surface morphology of the optimized coated pellets as well as their cross-section were characterized using a scanning electron microscope (SEM) (Leo, VP1450, Germany). The morphology of coated pellets after the dissolution test was also studied. The pellets were fixed on an aluminium stub and sputter-coated with a thin layer of gold for 180 s using a sputter coating machine (Polaron, SC7620 sputter coater, England) under an argon atmosphere, and then analyzed using SEM. The voltage of 5 kV was selected for accelerating the electrons from the electron gun onto the specimen. The cross-sectional samples were prepared using a razor.

2.7. Statistical analysis

Graph Pad Prism software (Graph Pad Prism, version 7, San Diego, CA) was used for statistical analysis, and one & two-way analyses of variance (ANOVA) followed by Tukey–Kramer test were used to compare the differences between means. P values below 0.05 were considered statistically significant.

3. Results

3.1. Dissolution study

According to the obtained results, the drug release from all coated pellets during 2 h in simulated gastric fluid (pH 1.2) was below 5% (data not shown). With increasing the pH values of the dissolution medium (from 6.5 to 7.2), the amount of drug release increased in all formulations (Figure 1A–C). As it can be seen, by increasing the proportion of pH-dependent polymers (S + L) in the coating composition, the rate of drug release increased. So, the highest drug release in all dissolution media belongs to the formulations with no Eudragit RS in their coating compositions. Such formulations (S80 + L20) in any coating level, released almost 40% and 30% of their drug content in simulated jejunum condition (pH 6.8 during 2 h resistance time) as well as simulated ileum condition (pH 7.2 during 1 h resistance time) respectively. Thus the remaining amount of drug that could be delivered to the colon through these formulations would be little (almost 30%). In contrast, as can be seen in Figure 1 increasing the level of coating (from 5% to 15%) in formulations with Eudragit RS in their coating compositions resulted in a remarkable decrease in drug release. The results also indicated that an increase in RS amount in coating composition resulted in the long lag time before drug release at pH 7.2 (Figure 1C). So the formulations with 80% Eudragit RS even at the lowest coating level (5%), released less than 5% of its drug content during the first 2 h of the dissolution test.

Figure 1. The drug release profile from the coated pellets at various pH conditions. CL: coating level.

3.2. Determination of optimum coating composition and level

Based on the analysis of variance (ANOVA) of dissolution data, the Quadratic model was selected for analysing all three responses. Equations 1–3 shows the best-fitted mathematical relationship between the independent variables (Xs) and responses (Ys) in terms of coded factors: (Equation 1) $${\mathrm{Y}}_1=+\text{5}.920+\text{14}.940{\text{X}}_1-\text{3}.580{\text{X}}_2-0.{\text{315 X}}_1{\mathrm{X}}_2+\text{8}.730{\text{X}}_1{}^2+\text{3}.820{\text{X}}_2{}^2$$(Equation 1) (Equation 2) $${\mathrm{Y}}_2=+\text{62}.630+\text{24}.400{\text{X}}_1-\text{16}.010{\text{X}}_2+\text{1}0.260{\text{X}}_1{\mathrm{X}}_2+\text{3}.820{\text{X}}_1{}^2-\text{8}.110{\text{X}}_2{}^2$$(Equation 2) (Equation 3) $${\mathrm{Y}}_3=+\text{27}.930-\text{35}.000{\text{X}}_1+\text{15}.000{\text{X}}_2-\text{15}.000{\text{X}}_1{\mathrm{X}}_2+\text{22}.240{\text{X}}_1{}^2+\text{22}.240{\text{X}}_2{}^2$$(Equation 3)

To better illustrate the effects of independent variables on each response the three-dimensional surface plots are presented (Figure 2(A–C)).

Figure 2. The response surface plots for the responses predicted at different independent variables.

The model predicted a coating composition of 48% S, 12% L and 40% RS at a coating level of 10% as the optimized coating formulation for the fulfilment of the requirements for colonic delivery of budesonide pellets. The optimized formulation was prepared and subjected to morphological analysis and dissolution tests.

3.3. Morphological characteristics

Figure 3. A Illustrates the SEM images of the optimized coated pellets. As it could be seen these pellets had a spherical shape. The cross-sectional image showed a uniform coat with almost 30 µm thickness (Figure 3B). Many pores could be observed in the SEM images of the surface of these pellets after the dissolution test (Figure 3C).

Figure 3. Scanning electron microscopy of the optimized coated pellets (a), the cross-sectional image of optimized coated pellets (B) and optimized coated pellets after dissolution test (C).

3.4. Dissolution studies of budesonide pellets coated with optimized coating formulation

To check the validity of the optimization process, the values ​​of the measured responses were compared with the values ​​predicted by the software. According to the results presented in Table 4, close agreement between these two values ​​showed the validity of the optimization method.

Table 4. Observed and predicted values for the responses of optimum formulation.

Responses	Observed	Predicted	Residual
Y1 (%)	5.03	5.29	0.89
Y2 (%)	64.88	62.62	2.26
Y3 (min)	30	27	3

Figure 4 shows the release profile of the optimized formulation in a continuous mode of the dissolution test. Accordingly, coated pellets released all their drug content during the test period and the premature drug release was prevented before reaching the simulated colonic condition. So, only 20% of drug content was released slowly during the first 6 h. Although the drug release was started in simulated jejunum fluid (pH 6.8), the amount of drug release was negligible (5%). As it could be seen, only 15% of drug content was released in the simulated ileum condition during transition time (1h), and the rest of the drug was released in the simulated colonic condition in a sustained manner (80% release during 10 h).

Figure 4. The release profile of budesonide from the optimized coated pellets in the continuous dissolution test.

Although in the simulated colonic condition, 30% of the drug was immediately released during the first hour, sustained release of the rest of the drug (50%) was observed during the next 9 h. Drug release kinetic in simulated colonic conditions during this period (from the 7th to the 16th hour of the dissolution study) was characterized by fitting the release data into various kinetic models. Table 5 shows the regression coefficient and release parameters for the fit of dissolution data to the Korsmeyer–Peppas, zero-order, Higuchi and first-order kinetic models. The higher R² value indicated that the zero-order model was the best fit for the dissolution data after 1 h in simulated colonic conditions (Navarro-Ruíz et al. 2022), and the release rate was 6.744%/h during this period.

Table 5. The various release models and their release parameters.

Korsmeyer-Peppas		Zero-order		Higuchi		First-order
n	R^2	K0	R^2	KH	R^2	KF	R^2
0.838	0.937	6.774	0.981	23.884	0.816	0.139	0.743

R² regression line value; n: Release exponent in Korsmeyer-Peppas K₀: zero-order release rate constant; K_H: Higuchi release rate constant; K_F: first-order release rate constant.

4. Discussions

According to dissolution studies, all coated pellets demonstrated a pH-dependent release profile which was due to the presence of pH-dependent polymers in the coating compositions (Naeem et al. 2015). The pH value of descending colon (pH 6.6 to 6.9) is higher than ascending (pH 5.4 to 5.9) and transverse (pH 6.2) colon (Ilhan et al. 2017). Therefore, the higher dissolution susceptibility of coating polymers to pH 6.8 could result in more drug delivery to the descending colon by preventing drug release in the upper parts of the colon. As it is clear, Eudragit S does not dissolve at pH values less than 7 (Franco and De Marco 2020), and hence drug release at pH 6.8 could be due to the presence of the proper amount of Eudragit L in the coating composition (the ratio of Eudragit S to the L was fixed at a ratio of 4 to 1 in all formulations). Drug release from formulations with no Eudragit RS in their coating compositions was neither sustained nor dependent on the coating level. These results confirm that a sudden release of the drug could happen if the pH of the dissolution medium is similar to the pH of the dissolution of polymers used in a pH-dependent drug delivery system (Lin et al. 2015; Lee et al. 2020). In contrast, the drug release from formulations with Eudragit RS in their coating compositions was sustained showing both time and pH dependency. In these formulations, the drug release decreased, and the lag time increased in response to the increase in the coating level. Considering diffusion as one of the main mechanisms involved in drug release from time-dependent systems (Ozturk et al. 1990), such behaviours could be related to the long pass for diffusion (Gupta et al. 2001) as the coating level increases. It is interesting to note that colonic pH in some IBD patients might be about 5.3 which is far less than healthy ones (pH 6.8) (Nugent et al. 2001). Since Eudragit S and L cannot dissolve at this pH, the designed coating systems could act as an insoluble barrier in these patients providing a hurdle for drug release. Considering the time required for these types of films to become permeable to the dissolution medium (Kao et al. 1997) and the transition time in the ileum (1 h) (Sardou et al. 2022), having too long lag time (more than 1 h) may lead to insufficient and non-uniform drug delivery to the colon in some IBD patients (Nerella et al. 1993; Kao et al. 1997). This indicates the importance of adjusting the coating composition and level for proper colonic delivery.

Considering the importance of coating composition and level in the drug release profile, a full factorial design was applied for optimization of the coating system in order to enhance the site specificity for drug release. The ratio of pH-dependent polymers to the total weight of coating polymers (X₁) as well as the coating level (X₂) were considered as independent variables, and the percentage of drug release during 2 h at pH 6.8 (Y₁), The percentage of drug release within 10 h in pH 6.8 (Y₂) as well as the lag time (the time before 2% drug release) in pH 7.2 (Y₃), were selected as responses. The quadratic model showed high predictability in this study due to the Low standard deviations, high coefficient of determinations (R²) and lower predicted residual error sum of square values as well as enough high F-values (Jain et al. 2015). Furthermore, a low amount of p-values (less than 0.05) indicated that the assumed model was significant and valid for each response (Akhgari et al. 2005). According to the ANOVA, both independent variables affected the responses significantly. Based on the mathematical equations in the case of responses Y₁ and Y₂, the positive coefficient of X₁ indicates the increase of drug release with an increase in pH-dependent polymers ratio in the coating formulation, and the negative coefficient of X₂ indicates a decrease in drug release with an increase in coating level. For response Y₃, the negative coefficient of X₁ and positive coefficient of X₂ demonstrate that a decrease in the ratio of pH-dependent polymers in a coating formulation as well as an increase in coating level result in a longer lag time. These results were in agreement with three-dimensional surface plots.

Optimization of the coating composition and the level was carried out to find out the level of independent variables which could result in less than 10% drug release during the first 2 h at pH 6.8, at least 50-70% drug release at pH 6.8 during 10 h, as well as the lag time of less than 1 h at pH 7.2. As the authors intended to prevent premature drug release in the upper parts of the GIT, selected criteria for Y₁ were chosen to prevent drug release in the jejunum with a similar pH value of descending colon (pH 6.8) during transition time (2 h) (Sardou et al. 2022), so that much of the drug (50-70%) could be delivered to the descending colon (Y₂). Considering the fact that in IBD patients the pH value of the terminal ileum and colon might be below 7.0, the start of drug release at pH 6.8 is important for ensuring colonic drug delivery at these constraints (Akhgari et al. 2005). Furthermore, as mentioned above, too long lag time (more than 1 h) in pH 7.2 may lead to insufficient and non-uniform drug delivery to the colon in some IBD patients (Y₃) (Nerella et al. 1993; Kao et al. 1997).

As it could be seen, coated pellets released all of their drug content during the test period. This result indicates that the formulation of budesonide, which is a practically insoluble drug (Bhatt et al. 2014), as such a slow-release multi-particulate dosage form could avoid incomplete drug release. Therefore, the incomplete drug release, which is one of the drawbacks of some marketed brands of budesonide (Gareb et al. 2016), can be addressed based on these results. In the first 3 h of the dissolution test, the insolubility of coating polymers at pHs 1.2 and 6.5 was responsible for the prevention of dissolution medium entrance into the dosage form (Park et al. 2017), and premature drug release in these parts. During the next 2 h in simulated jejunum fluid (pH 6.8) the drug release was started due to the dissolution of pH-dependent polymers in the coating. A negligible amount of drug release in this period could be related to the presence of insoluble and low permeable Eudragit RS (Kaur and Kim 2009). In the simulated ileum, the condition increased the permeability of Eudragit RS resulting from long contact time with the dissolution medium and sufficient hydration (Kao et al. 1997), as well as increased porosity of the coating (as a result of the dissolution of more amount of Eudragit S and L) accelerated the drug release. Based on the obtained results, it seems that this formulation has met our requirements for colonic delivery of budesonide. SEM images of the pellets after the dissolution test confirmed the contribution of the pore formation mechanism in drug release.

The higher R² value of Zero order kinetic indicated that this model was the best fit for the dissolution data after 1 h in simulated colonic conditions (Navarro-Ruíz et al. 2022). This type of release is the ideal one for controlled drug delivery (Ofokansi and Kenechukwu 2013) and indicates the ability of formulation for delivery of the drug at a constant rate to the rest of the colon. Considering the release rate (6.7%/h) and transition time of 10 h in the colon, it seems that this formulation could also increase the opportunity for drug delivery to the left side of the colon and could be useful in the treatment of left-sided colitis (González-Rodríguez et al. 2003; Gareb et al. 2019).

5. Conclusions

It was shown that an optimized single-layer film coating system based on pH and time-dependent polymers could be used efficiently for targeted budesonide delivery to the colon. Based on the RSM technology, a coating formulation composed of 48% Eudragit S, 12% Eudragit L and 40% Eudragit RS at 10% w/w coating level was found to be the optimum formulation for delivery of budesonide pellets to the colonic region. In simulated colonic conditions, except for the first hour drug release rate from optimized formulation was constant throughout the rest of the test. In view of these results, it seems that the developed formulation could successfully deliver the drug to the descending colon and can be suitable for the treatment of left-sided colitis.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was a part of the Ph.D. thesis (Grant number: 981658) supported by the Vice Chancellor for Research and Technology of Mashhad University of Medical Sciences, Mashhad, Iran (MUMS).