Therapeutic proteins and peptides (PPTs) have become one of the most important biological molecules for the management of many common and complex diseases due to their high specificity and high bioactivity. However, these biomolecules are mainly given by the hypodermic injection, which often leads to poor patient compliance due to the invasive nature of this route of administration. The oral route has been considered the most convenient and patient-friendly route for drug delivery relative to hypodermic injections. Despite the ease and simplicity conferred by oral administration, this drug delivery route suffers rapid peptide degradation in gastric fluid and low intestinal uptake. In order to circumvent these issues, several strategies, such as enzyme inhibitors, permeation enhancers, chemical modification, mucoadhesive and stimuli-responsive polymers, and specialised particulate formulation have been developed. Such strategies are designed with the aim of protecting PPTs from the harsh gastrointestinal environment as well as providing a strategy to enhance the uptake of the therapeutic across the gastrointestinal tract. This review aims to provide an overview of the current development in enteral drug delivery strategies for PPTs. The design of these drug delivery systems in overcoming physical and chemical barriers along the gastrointestinal tract while improving oral bioavailability will be highlighted and discussed.
Carvedilol, a β-blocker prescribed for chronic heart failure, suffers from poor bioavailability and rapid first pass metabolism when administered orally. Herein, we present the development of tip microarray patches (MAPs) composed of ternary cyclodextrin (CD) complexes of carvedilol for transdermal delivery. The ternary complex with hydroxypropyl γ-cyclodextrin (HPγCD) and poly(vinyl pyrrolidone) (PVP) reduced the crystallinity of carvedilol, as evidenced by DSC, XRD, NMR, and SEM analysis. MAPs were fabricated using a two-step process with the ternary complex as the needle layer. The resulting MAPs were capable of breaching ex vivo neonatal porcine skin to a depth ≈600 μm with minimal impact to needle height. Upon insertion, the needle dissolved within 2 h, leading to the transdermal delivery of carvedilol. The MAPs displayed minimal toxicity and acceptable biocompatibility in cell assays. In rats, MAPs achieved significantly higher AUC levels of carvedilol than oral administration, with a delayed Tmax and sustained plasma levels over several days. These findings suggest that the carvedilol-loaded dissolving MAPs have the potential to revolutionise the treatment of chronic heart failure.
Malaria is a global parasitic infection that leads to substantial illness and death. The most commonly-used drugs for treatment of malaria vivax are primaquine and chloroquine, but they have limitations, such as poor adherence due to frequent oral administration and gastrointestinal side effects. To overcome these limitations, we have developed nano-sized solid dispersion-based dissolving microarray patches (MAPs) for the intradermal delivery of these drugs. In vitro testing showed that these systems can deliver to skin and receiver compartment up to ≈60% of the payload for CQ-based dissolving MAPs and a total of ≈42% of drug loading for PQ-based dissolving MAPs. MAPs also displayed acceptable biocompatibility in cell tests. Pharmacokinetic studies in rats showed that dissolving MAPs could deliver sustained plasma levels of both PQ and CQ for over 7 days. Efficacy studies in a murine model for malaria showed that mice treated with PQ-MAPs and CQ-MAPs had reduced parasitaemia by up to 99.2%. This pharmaceutical approach may revolutionise malaria vivax treatment, especially in developing countries where the disease is endemic. The development of these dissolving MAPs may overcome issues associated with current pharmacotherapy and improve patient outcomes.