pH-responsive microencapsulation systems for oral delivery of biopharmaceuticals

Bahman Homayun
Oral delivery is the most attractive drug administration route due to many specific advantages. Ease of administration, large and diverse absorption surface area, applicability for solid formulations, patients' compliance, and intensified immune response due to mucosal effects are usually regarded as the main advantages of this route. On the other hand, gastric instability, mucus layer and tight junctions of the small intestine are principal biological barriers against this route. Additionally,
more » ... technical challenges such as drug denaturation through the microencapsulation process, insufficient loading capacity, unsatisfactory preservation efficiency, and limited fabrication throughput of the systems are considerable challenges against the commercialization of oral delivery systems. Previously in this group, pored microencapsulation was developed to specifically address two principle issues with available oral delivery systems: 1) drug denaturation through the microencapsulation process due to contact with organic solvents, and 2) drug instability in harsh gastric environment. In fact, pored microencapsulation system completely excluded the drug molecules from the fabrication process of the microparticles (MPs). As a consequence, the drugs could be loaded into the MPs through their surface pores in favorable environmental conditions, eliminating any concerns about technical drug denaturation. The surface pores of the MPs were subsequently closed through freeze drying to properly isolate the loaded drugs from the surrounding environment. Accordingly, the drugs were properly protected in stomach, and once the MPs reached the absorption target in small intestine, the surface pores would open due to their pH-responsive nature and release the drug. The remaining activity of vulnerable biomolecules released from pored MPs in simulated digestive conditions was reported to be ~50%. Although pored microencapsulation systems have successfully resolved the concerns associated with drug denaturation during the fabrication process and preserved the drug to iii acceptable levels, they still suffer from the other problems mentioned before, including insufficient loading capacity and low throughput. Additionally, this system could not properly deal with biological barriers such as mucus, which can dramatically reduce the absorption efficiency of the drug at the target. With all these in mind, this project was focused on the development novel architectures of oral pored microparticles, which can address the remaining problems as well. New protocols based on swelling/solvent evaporation and emulsion/solvent evaporation methods were developed for scalable fabrication of the oral microparticles with acceptable narrow polydispersity. In the first step, a new swelling/solvent evaporation protocol was developed as a facile fabrication process of MPs with pH-responsive surface pores. The MPs fabricated through this process showed up to 65% preservation efficiency of the loaded ingredients against simulated gastric environment and capability for the encapsulation of ingredients with a range of various sizes (100 nm simulating the size of viruses and protein therapeutics, 1 µm representing the size of bacteria, and 4 µm representing the size of cells). Although this part of the project led to improvements in both the fabrication throughput of the system as well as its preservation efficiency, the new MPs were still suffering from insufficient loading efficiency and lack of features for dealing with biological barriers at the absorption site. In the next step of the project, emulsion solvent evaporation protocol for the fabrication of the MPs, as this method provides a better control over the internal morphology of the MPs for increasing the interior void spaces of the particles. Also, new features were included in the system for co-delivery applications. As a consequence, mucolytic enzymes could be simultaneously delivered to dilute the mucus layer at the absorption site of the drug, make the epithelial layer beneath the mucus easily accessible and consequently improve the absorption efficiency of the drug at the target. The average diameter of the MPs prepared through this process was successfully iv increased up to 15x to increase the loading capacity of the system. Indeed, since the main drug in this system is loaded into the interior void space of the MPs, increasing the average diameter of the MPs would be the most effective key to address the issues with loading capacity. As a results, the loading efficiency of the system was improved up to 50x for different sizes of the drug molecules. Additionally, the new fabrication protocol showed promising potentials for scaling up and commercialization. Also, ex-vivo analyses confirmed that the new feature of the system can effectively remove the mucus barrier against the absorption of the drugs. The drug molecules released form the MPs also showed 60% remaining activity, confirming the potentials of the system for further investigations as a new and effective oral delivery architecture. In the final step, the MPs needed to be coated for further protection in mouth cavity, saliva and esophagus. Indeed, the MPs investigated in this study were all made of anionic hydrogels soluble in neutral and basic environments (pK 5.5); hence, the MPs were coated with cationic copolymers on the outer surface to be stable upper digestive system, before reaching the stomach. The results conformed the success of the coating for protecting the MPs up to the stomach. In summary, the present work presents a new comprehensive oral administration system for preserving vulnerable drug molecules against microencapsulation process and harsh biological media and safely delivering them to the absorption site in the small intestine. v
doi:10.7939/r3-d530-t080 fatcat:pd2eras77nbjvo33iglwvacgd4