Study on Preparation of Colon-Released Mesalamine Pellets

4.1.3. Research on preparation of colon-release coated mesalamine pellets

4.1.3.1. Mesalamine pellet coating method

Fluidized bed coating machine is the most suitable equipment for controlled release coating of pellets at the colon. In this thesis, the fluidized bed coating machine with bottom spray is used, which is one of the common spraying types used in fluidized bed coating machine.

The preparation process is carried out by spraying the coating solution into the coating chamber containing the core pellet. After the coating solution adheres to the core pellet, under the effect of the air flow in the coating chamber, the solvent will evaporate and the solid will gradually adhere to the surface of the core pellet. The film coating efficiency depends on the density of the pellet appearing in the spray area, the adhesion of the liquid to the core surface, the solid content in the solution, the spray speed and the volume of hot air blown in [7].

Factors affecting the pellet coating process:

Maybe you are interested!

Coating solution: The coating solution uses the polymers zein, Eudragit S100 and EC. Of which, zein is soluble in ethanol, insoluble in water; EC is soluble in ethanol, insoluble in water and Eudragit S100 is soluble in ethanol and water at pH > 7. Therefore, ethanol can be chosen as the solvent to dissolve the above polymers in the coating solution. However, the concentration of ethanol must be used at an appropriate ratio. If absolute ethanol is used, the pellet coating process is difficult to control safely, fires are likely to occur during the preparation process and the solvent evaporates too quickly during the preparation and film coating process. On the contrary, low ethanol concentration in the solution may not dissolve the above 3 controlled release polymers. Based on the experiment, the thesis chose 80o ethanol as the solvent in the controlled release coating solution. At a polymer concentration of 6% in the coating solution, the coating process was carried out conveniently, without pellet sticking during coating or the formation of daughter nuclei due to the liquid droplets drying before meeting the core pellet.

Injection speed: The injection speed must be controlled and adjusted appropriately. If the injection speed is too low, the coating fluid may dry out before it adheres to the pellet, causing product loss and reduced coating efficiency. If the injection speed is too high, the coating fluid will be too wet, causing pellet sticking. To overcome this phenomenon, the study selected the injection speed as presented in section 2.2.2.2.

Air pressure: Low air pressure for spraying the coating fluid will form larger droplets and tend to increase agglomeration. On the contrary, high air pressure for spraying the fluid can make the fluid spray too fine and strong outside the high density pellet area, reducing the film coating efficiency or causing the fluid to dry too quickly before it adheres to the pellet. Therefore, the air pressure for spraying the fluid during the process is adjusted at 1 bar. Experiments show that this air pressure level is suitable for the formulation process.

Air flow in the coating chamber: If the air flow is too low, there will not be enough force to push the pellets evenly in the coating chamber. On the contrary, if the amount of foul air is too high, the pellets will fly too high and stick to the filter bag wall. Therefore, when coating film with Qui Long fluidized bed coating equipment, the research adjusted the suction fan speed to 28 - 30 Hz. At this speed, the pellets are blown with air suitable for the coating process.

Inlet air temperature: The coating process is carried out smoothly when the inlet air temperature is set at 30 o C. At this temperature, the film formation process occurs uniformly on the surface of the pellet. The SEM image shows that when the inlet air temperature is raised to 60 o C, there are gaps between the coating layer and the rough pellet surface due to the 80% ethanol solvent evaporating too quickly. On the other hand, when the film coating temperature is 30 o C, the coating film is even, uniform, and forms a block in the coating layer and the coating film surface is quite smooth and continuous.

4.1.3.2. Film coating formula

Mesalamine-coated pellets were prepared by fluidized bed coating equipment using a solution consisting of: controlled release polymers (zein, Eudragit S100 and EC), plasticizers (dibutyl phthalate), anti-adhesion agent (talc) and 80 o ethanol as a solvent .

Controlled release polymers

In recent years, zein is an excipient widely used in research on controlled-release coatings in the colon. In the thesis, the in vitro research results demonstrated that zein alone cannot be used for controlled-release coatings in the colon because zein is degraded quite quickly by pepsin and pancreatin enzymes in the stomach, so the latency time of the pellet is very low, not meeting the requirements of 4 - 6 hours. This research result is consistent with the research of Minh NU Nguyen et al. (2019)

When zein alone was used in a pellet-coated formulation of prednisolone, it was released in the colon. After 3 hours, about 30% of the drug was released [65].

To increase the ability to control release, zein was studied in combination with another polymer such as pectin, stearic acid or Eudragit S100. The combination of zein and pectin in the composition of the colonic controlled-release coating was studied by Wai-Wa Tang et al. in 2006. The coating was prepared by dipping vitamin C tablets in 20% zein solution and drying to form a thin zein coating on the surface of the tablet. The tablet was then dipped in 2% pectin solution and immediately dipped in zein solution. Because the zein layer was dried before dipping in pectin solution and zein is insoluble in water, the zein coating was not miscible with the 2% pectin solution. After dipping in pectin solution, the tablet was immediately dipped in zein solution and dried. Scanning electron microscopy (SEM) images show that a smooth, hard, non-porous layer is formed between the two layers of the pectin and zein coating. This interlayer was shown to be resistant to degradation in in vitro dissolution tests in a dissolution medium containing gastric juice and gastric enzymes. The T lag of the coated tablet was more than 5 hours and more than 80% was released after 24 hours [107].

The research results in the thesis show that when zein and pectin are dissolved into a solution and coated on the surface of the pellet with a thickness of 20%, the coating containing the zein-pectin mixture releases quickly after the first 2 hours. This result is also consistent with the research of Wai-Wa Tang et al. [107]. Similarly, the coating containing the mixture of zein and stearic acid also releases quickly after 2 hours in a pH 1.2 environment.

However, the combination of zein and Eudragit S100 gave better release control , T lag reached 4 - 5 hours and showed signs of rapid release in the following hours. The combination of positively charged zein and a negatively charged polymer soluble at pH > 5.5, Kollicoat MAE 100P, was studied by Minh NU Nguyen and colleagues (2019) on film-coated prednisolone pellets released in the colon. In vitro dissolution studies were conducted by the author in a pH 1.2 environment for 2 hours; a pH 4.6 environment for the next 2 hours; a pH 6.8 environment for the next 1 hour and a pH 7.4 environment for the last 2 hours. The research results showed that at the ratio of zein: Kollicoat MAE 100P = 4

: 6 then T lag reaches 5 hours and releases most of the drug after 7 hours [65]. Kollicoat MAE

100P is a polymer that dissolves at pH > 5.5, so when tested for dissolution in the first 4 hours at pH < 5.5, the coating was almost not corroded, the release control ability of the coating was very good, but when the pH increased to 6.8 in the next 2 hours, the coating was quickly corroded, the drug was released very quickly. Thereby, it can be seen that the in vitro test model greatly affects the T lag results when using pH-dependent soluble polymers in the controlled release coating. There is still no consensus on the in vitro dissolution test model, so to determine the release control effectiveness of the coating, in vivo tests on animal models and volunteers are needed to evaluate, compare and find the correlation in vitro - in vivo .

The study in the thesis shows that the zein-Eudragit S100 mixture controls release well at pH 1.2 for 2 hours and pH 6.8 for the following hours (dissolution test condition 1). However, when changing the test conditions to a harsher pH 1.2 environment for 2 hours, then pH 7.4 phosphate buffer for the next 3 hours and finally pH 6.8 phosphate buffer for the remaining times, the delayed release ability of the pellet coated with the zein-Eudragit S100 mixture is not achieved, the drug is released quickly when transferred to pH 7.4 environment because Eudragit S100 dissolves at pH > 7. Therefore, to increase the delayed release ability of the drug to 4 - 6 hours, the study incorporated EC in the controlled release coating formula. EC is a water-insoluble polymer, when combined with zein and Eudragit S100 in the coating membrane, it increases the ability to control drug release, prolongs the T lag time of the mesalamine-coated pellet, so the coated pellet and hard capsule containing the coated pellet release little mesalamine in the first hours at pH 7.4 environment, but at the following times, the pellet coating membrane gradually wears away and breaks down, helping to release more at the following times at pH 6.8 environment. The research results of the thesis show that at the appropriate ratio of zein, Eudragit S100 and EC in the coating membrane, the T lag time of the mesalamine-coated pellet reaches more than 4 hours and the drug is released about 80% after 9 hours, meeting the requirements for drug release in the colon.

The combination of three polymers zein, Eudragit S100 and EC has not been reported in previous studies. Initial results show that this combination is quite convenient for the process.

preparation process, which can be applied on an industrial scale if further testing is conducted in the next stage.

Plasticizer

Plasticizers are substances that increase the flexibility of polymers. Polymers are often brittle, and the coating is prone to cracking because the glass transition temperature of polymers is much higher than normal temperature. Plasticizers can reduce the glass transition temperature of polymers by reducing the intermolecular interactions between polymer chains, increasing the flexibility of the coating, reducing cracking and improving the adhesion of the coating to the pellet core. The type of plasticizer and the ratio used in the coating film formulation affect the coating film properties, thereby affecting the release control ability of the coating. The choice of plasticizer is based on many factors such as miscibility with the polymer, slow diffusion in the polymer layer. On the other hand, the viscosity of the plasticizer also affects the permeability of the coating layer, adhesion, and durability of the coating layer [5], [ 78]. In this thesis, the plasticizers DBP, glycerin and TEC were studied. DBP is a colorless liquid, soluble in common organic solvents but insoluble in water, while glycerin and TEC are water-soluble plasticizers. The results showed that DBP plasticizer had a longer T lag time than the coating using glycerin or TEC. The reason may be that DBP is hydrophilic, so it can coordinate better with polymers to control release, creating a uniform coating film compared to glycerin and TEC. On the other hand, the ratio of plasticizer used in the formula affects the ability to control the drug of the coated pellet. If too little plasticizer is used, the polymer coating film will be brittle and easily broken, affecting the ability to control the release of the coating film. On the contrary, too much plasticizer will affect the bonding of polymer molecules in the coating film composition and can lead to slowing down the release process of the coating film [ 14]. On the other hand, the pellets stick together during the preparation process when the amount of plasticizer is too much, reducing the coating efficiency or making it impossible to coat. Therefore, it is necessary to investigate the appropriate plasticizer ratio in the formula. Research shows that a plasticizer ratio of 20% compared to the total amount of polymer used is suitable for the studied coating film.

Non-stick

Talc acts as an anti-adhesive excipient, reducing pellet adhesion during the coating process and during storage. Although anti-adhesive excipients are very common in coating formulations, they can affect the properties of the coating and the release of drug substances from the drug core. Talc can make the coating film more brittle and stiff, reducing the toughness of the coating film due to the solid particles of talc intercalating into the coating layer, reducing the flexibility of the polymer chain in the coating film. On the other hand, talc is an insoluble but hydrophilic excipient, so when used in excess, it will reduce the permeability of the coating film or can cause the spray gun to clog due to talc aggregation at the spray gun position during the coating process [46]. Studies in the thesis show that when using talc at a ratio of 20% compared to the total amount of polymer used, the spray gun does not stop during the formulation process.

Coating thickness

The thickness of the coating layer plays a decisive role in the ability to control the release of the coating layer. The research results show that when the coating layer thickness increases compared to the core mass, the T lag of the mesalamine coated pellet also tends to increase gradually. The reason is that when the coating layer thickness increases, the coating layer corrosion occurs longer, water takes longer to penetrate the drug core to dissolve the drug and causes the super-disintegrating excipient DST to swell, increasing the internal pressure to break the outer coating membrane, so the T lag time is also longer when the coating layer thickness increases. The study shows that a coating layer thickness of 34% helps the coated pellet to control the release according to the drug release model in the colon. Similar results in the study of Jaleh Varshosaz et al. (2012) when increasing the ratio of the coating layer to the core pellet, the T lag of the coated pellet tends to increase gradually [49]. Thus, depending on the preparation goal, the coating layer thickness can be changed to achieve coated pellets with suitable T lag .

4.1.3.3. Study on optimization of coating membrane

Experimental design and optimization of the coating film of mesalamine pellets released in the colon using MODDE 12.0 software. Through research and survey, 3 factors affecting the drug release process in pellets were selected: the percentage of Eudragit S100 compared to the total amount of polymer used, the coating film thickness compared to the core pellet and the incubation temperature. Experimental formula design according to the zygote surface model at the center obtained 17 formulas including 14 experimental formulas and 3 test formulas. Conduct preparation and evaluate the solubility of the research formulas. Experimental results found the formula

The optimal formula was then prepared 3 times to confirm the optimal formula results, as a basis for upgrading the scale, and positive results were obtained. The tablets prepared according to the optimal formula had the % of mesalamine released within the expected standard range, proving that the optimization results were highly reliable.

By designing a suitable study, the formula of mesalamine pellets released in the colon was basically established and the effects of input factors on output factors (T 10 and T 80 ) were determined. This approach is more effective than the traditional experimental design because the synergistic effects of input variables on output variables were seen. The statistically significant effects of these variables on T 10 and T 80 were also shown through analysis of variance. Also through response surface analysis, the optimal coating formula for 240 g of mesalamine pellets included: zein (33.72 g), Eudragit S100 (28.9 g), EC (33.72 g), DBP (19.27 g), talc (19.27 g) and 80% ethanol (sufficient for 1609 ml). Successful development of film-coated pellet form is not only significant for the drug mesalamine but also has potential applications for drugs used in the treatment of colon diseases.

The thesis has evaluated in vitro dissolution under two conditions as in section 2.2.4.4, however, there are still limitations in evaluating other in vitro test models because there are many in vitro dissolution evaluation models applied by researchers around the world to study controlled-release pellet dosage forms in the colon.

4.2. UPGRADE SCALE

When upgrading the pellet scale to 2.2 kg pellets/batch and 2 kg pellets/batch bag, the preparation process limits manual steps. All stages in the process use machines. Process parameters are strictly controlled to ensure consistent pellet quality between pellets in a batch and between batches.

Dry mixing stage: Mixing time and speed affect the dispersion of the powder content and uniformity of the powder mass. In the thesis, the mixing process of raw materials when upgrading the batch size was carried out on a high-speed mixer with a mixing time of 10 minutes and a mixing speed of 25 Hz.

Wet dough mixing stage: Mixing time and speed are also two main factors affecting the dispersion of content and uniformity of moisture in the dough. At this stage

In this thesis, the mixing time parameters were chosen as 10 minutes and the mixing speed was 25 Hz to help the powder after mixing to be uniform in content and moisture after mixing.

Sieving stage: Use a grain mill with a sieve hole size of 5 mm to break up the sticky wet lumps during the wet dough mixing process. In this stage, if a small sieve is used, the wet dough will form cylindrical fibers that stick together through the sieve, not loosening the wet dough. Therefore, this stage must choose the appropriate sieve size for the preparation purpose.

Dough incubation stage: As presented, the dough incubation time helps the moisture to be uniform in the dough and the dough is flexible enough to facilitate the pellet rolling process. However, for products that are easily decomposed in high humidity conditions such as mesalamine, the dough incubation time should be moderate, just enough for the dough to be flexible enough to facilitate the pellet rolling process. Based on the experiment, it is found that the dough incubation time of about 1 hour does not reduce the drug content. In addition, the humidity of the dough is a very important factor for the extrusion and rolling process to meet the requirements. If the humidity is low, the pellet after rolling is often cylindrical, round at both ends. On the contrary, if the humidity of the dough is too high, the pellet will stick together during the rolling process, reducing the efficiency of pellet preparation. The moisture content of the mesalamine pellet is around 30 - 35%, helping the pellet ball forming process to meet the preparation requirements. To control the humidity within the desired range, it is necessary to control the time of the previous steps, which are the wet dough mixing and sieving steps. The time to perform these two steps should not be too long, otherwise the solvent will evaporate and reduce the moisture content of the dough, affecting the quality of the pellets in the extrusion and rolling stages.

Extrusion stage: Extrusion speed affects the hardness of the pellet. If the extrusion speed is too high, the resulting hard pellet will affect the dissolution rate of the active ingredient from the core pellet. If the extrusion speed is low, the pellet will be softer, and the subsequent rolling process may form small, uneven pellets. Based on the experience of producing similar pellet products at the company, an extrusion speed of 80 rpm helps the pellet rolling process to be more uniform.

Rolling stage: The amount of dough each time, the speed and time of rolling greatly affect the shape of the pellet, the uniformity of the pellet each time and the different rolling times. Through experimentation, the amount of dough each time is determined to be 200 g of wet dough and the rolling time is 1.5 minutes/time.

Comment