Gastro resistant capsules why

Gastro-resistant soft gelatin capsules can prove their usefulness in oral administration of drugs of irritating or acid-labile nature, often displaying at the same time enhanced bioavailability in a liquid form, which can be considered an advantage to coated tablets [ 2 ].

The most obvious examples of the substances that need to be formulated in gastro-resistant dosage forms are non-steroidal anti-inflammatory drugs NSAIDs , which are irritating to gastric mucosa.

The products in the form of gastro-resistant capsules usually are designed as conventional hard capsule shells filled with the enteric-coated pellets or minitablets. Manufacturing of gastro-resistant soft capsules, however, is a challenge. Due to the liquid fill, modification of the drug release rate from soft capsules can be achieved only by modification of the capsule shell to make it resistant to acidic pH.

This issue can be approached by-coating of standard capsules with acid-resistant polymers such as methacrylic acid—methyl acrylate copolymers e. A less popular alternative is incorporation of gastro-resistant polymers in the shell material used to form the capsules [ 4 ].

Both approaches are technologically perplexing at some points, although modification of the shell material can be considered more beneficial from both economic and technological point of view.

However, it is not yet utilized in commercial products. It is substantial to take into consideration that any changes in the composition of the film-forming mixture can result in significant alteration of the overall physicochemical properties of the prepared films, that can lead to the loss of their potential to be formed into capsules in a conventional manufacturing process.

A very important issue associated with the development of a new capsule shell composition is to identify the physiochemical phenomena that can be utilized in designing and manufacturing of modified release gelatin-based films. In our previous work, selection of the most effective modification of the shell material composition was performed, and their microstructure and barrier properties were described [ 5 , 6 ].

However, there are still a few unexplained issues in the description of the phenomena that lead to formation of the films, as well as the changes that the films undergo when exposed to various conditions. Therefore, in the present work, a more detailed investigation of the events associated with the formation of the gastro-resistant film was performed and further, the structural changes upon submersion of such films in acidic dissolution fluid is performed.

For the purpose of better characterization of the films and film formation processes, several modern techniques may be employed. Additionally, the barrier properties of the films against oxygen were evaluated. In comparison to tablets or hard capsules, the transfer of a new technology for soft capsules from the lab to the production site is much more complicated, and a scale-up procedure may be complicated and time-consuming. One of the main issues when soft capsules are developed is a poor access to a lab-scale equipment that could allow to assess the utility of the modified films for capsule formation.

The most problematic is the fact that, at a commercial scale, specific rheological and mechanical properties of the film-forming material are required [ 7 , 8 , 9 ]. The fact that the shell-forming material has to be tested on a large scale, significantly increases the cost of technology development.

In our present work, the lab-scale production process of the soft capsules is presented, utilizing a simple mold for suppositories, what allowed to evaluate the shell compatibility with the filling material.

Disintegration and dissolution media 0. Schematic presentation of the capsule formation process is shown in Figure 1. The preparation method of the film-forming mixtures and films was described in detail in the previously published work [ 5 , 6 ].

The capsules were prepared using GAC composition Table 1 , by placing 2 pieces of the film immediately after casting in a steel form for suppositories. For a better visual identification of a disintegration test endpoint, the filling material was colored with small amount of a hydrophilic or lipophilic dye. The measured moisture content in the capsules was around 2. The imaging of samples was performed with use of a scanning electron microscopy SEM , confocal laser scanning microscopy CLSM , confocal Raman microscopy and optical microscopy.

The observation of film samples was performed before and after submersion in 0. The films after submersion in acid were frozen in a liquid nitrogen and freeze-dried for 24 h.

The investigated surface was 50 cm 2. The gelatin on the sensor was subjected to crosslinking by submersion in 1. Then the diluted 0. After stabilization of the system, the cells were once again pumped with deionized water to remove all the substances that were not bound to the film.

The images were analyzed using a Gwyddion software Version 2. The capsules were tested for min in 0. The study was performed using a vertical diffusion cell Enhancer cell, Erweka, Langen, Germany and a paddle dissolution apparatus DT Erweka, Langen, Germany equipped with a built-in autosampler.

The stirring rates of 50, and rpm were used. The enhancer cell with the mounted modified gelatin film is shown in Figure 2. The diffusion cell was filled with 2. Then the investigated film cut to a circle of 3 cm in diameter was carefully placed on the top of the solution and secured with a sealing ring and a screw cap; the active surface was 4.

The test was performed in mL of 0. Sampling of the acceptor fluid was performed every 15 min in the acid phase, and every 5 min in the buffer phase. Quantification of diclofenac was performed spectrophotometrically at nm wavelength.

The study was performed in triplicates. Macroscopically it was visible that the samples after the acid treatment became opaque and swollen. Under the microscope, the untreated samples had a smooth surface with no structures visible [ 6 ]. As presented in Figure 3 , the films after submersion in acid revealed a network-like structures, resembling scaffolds.

There are clear differences between the images of a top and a middle layer of the sample Figure 4. It appears that, after 2 h in acid, noticeably less solid material is left on the top of the film, than in the deeper part. However, it is suspected that the outer layer consists mostly of CAP, while in the inner layer a swollen and undissolved gelatin can be present as well.

Raman microscopy investigation was performed on GAC films before and after immersion in 0. Several points have been scanned to obtain Raman spectra, which have been overlaid and compared. The spectra are shown in Figure 5 and Figure 6. The Raman spectra of several points examined on the surface of GAC film: a before immersion in acid; b after immersion for 2 h in 0.

Multiple overlaid spectra are presented on each graph. Multiple spectra of each composition are presented. As it can be seen from the spectra in Figure 5 , the surface of the GAC sample is chemically uniform, without any phase separation visible. The spectra of the non-modified film GEL are not presented in the figure, but they were not different from the spectra of GAC.

In Figure 6 , different sets of spectra are overlaid. It appears that, in the untreated samples, the gelatin signals are overlapping with the peaks of CAP. After the acid-treatment, the signals from gelatin are weaker, but the signals from CAP are yet undetectable.

This outcome can be explained by presence of a small amount of gelatin-rich phase residue undissolved in acid and covering the CAP scaffold. Due to the fact that reliable results regarding particle deposition depend on the morphology of the used substrate, the films obtained in situ on the QCM sensors were investigated with AFM.

It was confirmed that the films had uniform thickness and smooth surface, as shown in the Figure 7. The surface morphology of the gelatin film on the quartz crystal microbalance with dissipation QCM-D sensor. Although a large deposition of CAP particles on the gelatin film was detected, the very high extent of the frequency change around Hz of all investigated overtones creates a risk of an error when calculating the mass deposition.

Therefore, the obtained results were used only for the qualitative, and not for the quantitative analysis. A QCM-D graph obtained at 5th overtone.

The approx. The deposition of particles proceeded, until the full coverage of the QCM sensor occurred after approximately 12, s, which on the graph in Figure 8 is visible as a plateau in the frequency shift. Afterwards, the system was flushed with deionized water for 50 min, what did not cause any significant decrease in the amount of latex particles adsorbed on the gelatin. Oxygen was a gas used for permeability test. The test was performed twice for all the samples, and the same results were obtained.

The results of disintegration time measurements are shown in Table 2. The current pharmacopeial standards European Pharmacopeia 10th for disintegration time of gastro-resistant capsules state that the investigated sample should not disintegrate in 0. In the investigated capsules, at the acid stage, no disruption of the capsule shell material was observed. However, the rupture of the capsule sealing was observed in several capsules.

Disintegration time of GAC capsules with various fill. Three capsules from each batch were subjected to the test. The results of disintegration time measurements are not significantly different in regard to the method applied. Surprisingly, the capsules filled with cetearyl alcohol disintegrated in acidic conditions within a relatively short time.

A careful observation in acid phase indicated that the shell did not disrupt in any other way but only through the sealing, while the walls of the capsules always retained their integrity. This indicates that the shell material itself is resistant to acid and the filling material does not change this property.

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Active ingredients Esomeprazole. Ingredients Active ingredient: Each capsule contains 20 mg esomeprazole as magnesium dihydrate Also contains: Sucrose and Parahydroxybenzoates.