Halloysite nanotube-embedded microparticles for intestine-targeted co-delivery of biopharmaceuticals.

Microparticles (MPs) with pH-responding macropores have recently proved their significance for the delivery of vulnerable biomolecules for oral drug administration. The previous MP systems were proven to provide enhanced protection against the gastric environment, however, their application is hindered due to insufficient loading efficiencies and deficient penetration capabilities of encapsulated drugs across the mucus barrier. Here, we report a new co-delivery approach based on amine-functionalized halloysite nanotube (HNT)-embedded MPs (amine-HNT-MPs) with pH-responding macropores specifically designed to deal with the mucus barrier at the absorption site. The mean diameter and polydispersity index of the pored MPs were measured by a particle size analyzer to be 37.6 ± 1.3 µm and 1.15, respectively. The drug loading capacity of the co-delivery system was shown to be 50-times higher than previously reported pored MPs. Fluorescence microscopy analysis of sulforhodamine B (into a hollow interior of HNTs)/ fluorescent nanoparticles (into a hollow interior of MPs)-encapsulated MPs confirmed biphasic release behavior due to pH-dependent pore closing/opening in the simulated gastrointestinal (GI) digestive conditions. To verify the protective effect of the co-delivery system, bromelain and lactase were loaded into HNTs and MPs, respectively, and found to exhibit 94.5 ± 3.3% (bromelain) and 70 ± 14.1% (lactase) functional activity in simulated GI tract conditions. The considerable improvement in the stability of the encapsulated enzymes against gastric conditions are attributed to the efficient pore sealing of the co-delivery system after the encapsulation of enzymes and maintenance of these closed pores in the gastric environment. Furthermore, the mucolytic enzyme (i.e. bromelain)-encapsulated co-delivery system was found to enhance mucopenetration of the encapsulated drug from histological analysis using ex vivo porcine intestine tissue. Therefore, the new microencapsulation design proposed in this study provides a promising solution to the major issues hampering the wide-spread application of MPs in the development of oral drug formulations for biopharmaceuticals and vaccines.

Challenges and Recent Progress in Oral Drug Delivery Systems for Biopharmaceuticals.

Routes of drug administration and the corresponding physicochemical characteristics of a given route play significant roles in therapeutic efficacy and short term/long term biological effects. Each delivery method has favorable aspects and limitations, each requiring a specific delivery vehicles design. Among various routes, oral delivery has been recognized as the most attractive method, mainly due to its potential for solid formulations with long shelf life, sustained delivery, ease of administration and intensified immune response. At the same time, a few challenges exist in oral delivery, which have been the main research focus in the field in the past few years. The present work concisely reviews different administration routes as well as the advantages and disadvantages of each method, highlighting why oral delivery is currently the most promising approach. Subsequently, the present work discusses the main obstacles for oral systems and explains the most recent solutions proposed to deal with each issue.

Macropored microparticles with a core-shell architecture for oral delivery of biopharmaceuticals.

Microparticles (MPs) have been extensively researched as a potential drug delivery vehicle. Here, we investigated the fabrication of MPs with pH-responsive macropores and evaluated their potential applicability in developing solid oral drug formulations. Our previous study showed that macropored MPs, made of Eudragit® L100-55, could encapsulate 100 nm, 1 µm, and 4 µm sized fluorescent beads-model drugs that are mimicking vaccines, bacteria, and cells. In the present study, closed-pored MPs after freeze-drying were coated with a gastric soluble Eudragit® EPO layer to protect MPs in the simulated pregastric environment. Subsequently, drug encapsulated MPs maintained their intact closed-pored structure in the simulated gastric environment and exhibited a rapid release in the simulated intestine environment. Our MP system was found to provide a significantly higher level of protection to the encapsulated lactase enzyme compared to the control sample (i.e. without using MPs). Real-time fluorescence microscopy analysis showed that macropored MPs released encapsulated drugs in a burst-release pattern and in a size-independent manner. This work shows that our proposed EPO-coated MPs with pH-responsive macropores can meet the challenges posed by the multiple physiological environments of the digestive tract and be used in developing highly effective solid oral drug/vaccine formulations.

Facile fabrication of microparticles with pH-responsive macropores for small intestine targeted drug formulation.

Oral drugs present the most convenient, economical, and painless route for self-administration. Despite commercialization of multiple technologies relying on micro- and nanocrystalline drugs, research on microparticles (MPs) based oral biopharmaceuticals delivery systems has still not culminated well enough in commercial products. This is largely due to the drugs being exposed to the destabilizing environment during MP synthesis process, and partly because of complicated process conditions. Hence, we developed a solvent swelling-evaporation method of producing pH-responsive MPs with micron-sized macropores using poly(methacrylic acid-co-ethyl acrylate) in 1:1 ratio (commercial name: Eudragit® L100-55 polymer). We investigated the effects of temperature and evaporation time on pore formation, freeze-drying induced pore closure, and the release profile of model drugs (fluorescent beads, lactase, and pravastatin sodium) encapsulated MPs in simulated gastrointestinal tract conditions. Encapsulated lactase/pravastatin maintained >60% of their activity due to the preservation of pore closure, which proved the potential of this proof-of-concept microencapsulation system. Importantly, the presence of macropores on MPs can be beneficial for easy drug loading, and solve the problem of bioactivity loss during the conventional MP fabrication-drug encapsulation steps. Therefore, pH-sensing MPs with macropores can contribute to the development of oral drug formulations for a wide variety of drugs and bio-macromolecules, having a various size ranging from genes to micron-sized ingredients with high therapeutic efficacy.