Hard capsules are one of the most common oral forms of solid dosage that are often used for delivering medicinal compounds [1]. Hard capsules are easier to use compared to tablets. These are typically easier to swallow, fast released, and absorbed in the stomach. They can be easily opened and the contents can be mixed with food or liquids for individuals who have difficulty swallowing whole capsules or tablets. This flexibility is particularly beneficial for children, elderly individuals, or those with swallowing difficulties. Some medications have an unpleasant taste, which can be masked more effectively in hard capsules compared to tablets. The capsule shell helps to prevent direct contact between the medication and taste buds, making it more palatable. Hard capsules can be customized with different colors, shapes, and markings to aid in identification. Also, the production and quality control of tablets require more time, formulation development, and quality control [2–4].
Capsules provide an easy delivery system for nutrients (especially powders) without the need for creating complex formulas. They have been used in developing a series of drugs that are tested in animal or clinical trials due to their simplicity and rapid formulation. Hard capsules can be produced in diverse sizes and with different materials depending on their main purpose and content. Most of the hard capsules are made of gelatin. Gelatin capsules are vital capsules in the capsule industry [5–7].
Gelatin is one of the most popular gelling agents and a natural polypeptide polymer that can be used for hydrogel formulations based on gelatin and in drug delivery [8, 9]. Gelatin exhibits the thermoreversible sol–gel transition, which is the furthermost popularly thermoreversible gelling agent for gel formulations at the typical temperature of the human body and thus enables the rapid release of the drug [10, 11]. In recent studies, some physical properties of gelatin, such as modifications within the structure of the gel during the gelation procedure, have been considered [12, 13].
Reviews show that the gelatin capsules themselves cannot control the drug release process at the pH level of stomach acid, and also, the gel networks produced by gelation do not show strong mechanical properties. Although the combination of some compounds such as alginate and pectin with gelatin creates stronger mechanical networks compared to gelatin, their gels do not demonstrate useful pH responsivity for drug-release profiles [14, 15].
Several studies have indicated that achieving controlled drug release within the gastrointestinal tract of the human body through the use of a single gelling agent, consisting mainly of biocompatible and biodegradable polymers, is not a straightforward process. Therefore, the application of additional polymers, in combination with gelatin, can ensure the control of drug release conforming to thermal and pH responsiveness [16, 17]. Nevertheless, limited studies have been done about what happens when gelatin and other polymers react to alterations in pH or temperature [18].
In the technology of enteric hard capsules, one way is to add an additional coating step to the capsules with acid-sensitive polymers through a delayed-release mechanism. These methods do not show a pH-generated release but are a replacement for relying on a time delay in the expectation of timely emptying from the stomach. For the preparation of coat enteric capsules, there are two processes. Firstly, the drug particles or pellets are coated with enteric-coated materials, and in a second way, the enteric coating solution is sprayed on the outer layer of the capsule and then filled with drugs. These methods have some problems such as coated drug capsules must be made by uniformly spraying the gastric solution through the coating process on the out of drug particles or capsules, the preparation process is complex, and there are a lot of organic solvents in the enteric coating solution which has great safety risks to operators and manufactures workspaces with possible effects on the manufacturing prices [19–21].
Consequently, altering of initial composition is one of the most recent techniques implemented in the development of enteric empty capsules. The present approach entails the inclusion of a polymer that exhibits resistance to stomach acid through changes in the formulation of the capsule. As a consequence, the enteric characteristics are developed in the capsules through the modification of additive ratios [19].
Eudragit (polymethacrylates) and HPMCPh (hydroxypropyl methylcellulose phthalate) are synthetic polymers that display pH sensitivity and act as enteric polymers owing to the presence of phthalyl and acrylic groups covalently linked to the hydrophobic polymer chains. The pH-dependent solubility property makes these polymers suitable for drug delivery applications in the context of targeted intestinal release [22].
The pH-sensitive polymers are polymers that contain functional groups that changes in the pH of the environment leading to acceptance or donation of these functional groups and changes in the polymer's structure, solubility, or other properties. The polymers containing carboxylic groups display pH-dependent solubility whereby the carboxylic groups become ionized under high pH (may deprotonate) thus their conformation has been changing and expanding due to the repulsion between the negative charges of the carboxylates, so facilitate polymer dissolution. while at low pH, the carboxylic groups are not ionized (may protonate) and their conformations are close causing insolubility and leading to shrinkage. Combinations of Eudragit with HPMC or talc stabilized loaded drugs provided a controlled release of them [23–25].
The present study aimed to develop a formulation for hard gelatin gastro-resistant capsules utilizing a widely used polymer in the pharmaceutical industry, specifically for acid-resistant pharmaceutical capsules. Uncoated enteric capsules based on Eudragit (an acrylic polymer) and gelatin have not been reported in the literature so far. Accordingly, the objective of this study is to improve the formulation of hard gastro-resistant capsules using one of the most common polymers used in the pharmaceutical industry for the product of acid-resistant pharmaceutical capsules. The effect of polymer and solvent was studied on capsule shells based on the capsule formation and enteric properties.