Current Drug Therapy - Volume 9, Issue 1, 2014

The intestine seems to have solved a rather complex problem in immune surveillance, being able to capture luminal pathogens and trigger protective immunity yet tolerating the abundant array of ingested food antigens and commensal bacteria. Moreover, uptake mechanisms, while providing a surveillance method, also risk revealing a convenient gateway for the entry of live infectious pathogens. In this review, we look at the main elements of the immune surveillance of the intestinal lumen, focusing on the variety of solutions to selectively detect pathogens while maintaining an effectively sealed epithelial barrier. Among the innovative solutions described, we also address the relative impact of each mechanism on the induction of mucosal immunity. While some mechanisms may be effective in uptake, M cells present the most sophisticated array of mechanisms for selective and efficient capture of microbial particles. Though the contents of the gut are freely moving in the lumen, once M cells uptake matter, well-coordinated distribution of contained antigen and particles to distinct antigen presenting cells commences. M cells are a valuable tool for the maintenance and protection of the intestine and need to be further studied so their transcytotic potential can be employed for the advancement of vaccine therapeutics.

Mucosal vaccination is one of the most effective methods to prevent infectious diseases because most pathogens enter the body at mucosal surfaces. Mucosal vaccination induces not only systemic immune responses but also mucosal responses compared to parenteral vaccination that induces poor mucosal immunity. Another advantages of using mucosal vaccines are high patient compliance, low cost and easy other administration. Despite these advantages, very few mucosal vaccines are commercially available today. This is because mucosal vaccines are prone to degradation in the harsh conditions of the gastrointestinal (GI) tract lowering the bioavailability of antigens to induce immune responses. Therefore, protective and effective formulations are required for successful mucosal vaccination. Accordingly, the use of nano- and micro-polymeric particles has received much attention as delivery vehicles of antigens because they can protect the antigens from degradation in the GI tract and they also enhance the antigen uptake in mucosal-associated lymphoid tissue. Particularly, mucoadhesive polymeric carriers are the most promising vehicles for mucosal vaccine delivery because these carriers retain the vaccines on the mucosal tissues for longer period thus improving the bioavailability of the antigens. Most importantly, M cells on the follicle-associated epithelium of the Peyer’s patch play a key role in mucosal infection and immunity because they uptake and deliver antigens across mucosal epithelia to the lymphoid tissues via transcytosis. In this review, we dig the role and characteristics of M cells on mucosal immunization and explore the molecules of M cells for targeted delivery of antigens by polymeric particle system.

The oral delivery of therapeutics is of paramount importance to medical application and advancement. There has been remarkable advancement in the field of polymeric formulations for oral delivery of therapeutics. Novel polymeric formulation like polymeric nanoparticles, micelles and dendrimers are exploited and researched to further improve the bioavailability, stability, permeability and therapeutic efficacy. Over the last years, there have been number of approaches used for the effective delivery of bioactive(s). These include chemical modification, use of enzyme inhibitors and permeation enhancers, and novel drug delivery systems. Numerous polymeric nanoarchitectures based strategies are able to overcome restrictions and show the promising approach for efficient [P/P] drugs oral delivery. The aim of present review focuses on the need for the development of polymeric nanocarrier for oral-peptide and protein delivery with emphases on insulin delivery via various polymeric nanocarriers.

Oral drug delivery has always been considered the preferred route of drug administration. Nano-formulations are now constantly being researched for better absorption, higher bioavailability and greater therapeutic efficacy. Lipid based nanoformulations have found much favour with the formulation scientist due to their relatively higher safety profile and enhancement of bioavailability. These delivery systems are also able to protect the bioactives or drugs from the vagaries of the gastrointestinal tract. They also aid in the absorption of hydrophobic drugs which are entrapped in lipid matrices. Lipid excipients have been known to reduce efflux which is P-glycoprotein mediated and also to increase the bioavailability of bioactives which are given through the oral route. In the last 20 years, about a thousand articles and reviews about oral lipid carriers have been reported. Many dosage forms have been made by modifying liposome, sometimes to overcome a disadvantage and at other times to modify the dosage form in such a manner so as to suit the requirement of the drug molecules. Various other lipidic drug delivery systems also exist which are not vesicular but being made of lipids, are equally useful for delivering lipophilic drugs. Although a Lipid Formulation Classification System exists, but there is no exhaustive review which discusses the entire lipid based, oral nanoformulations. The present review envisages discussing the various types of oral, lipid, nanosized, delivery systems available, so that an insight is gained into all these carriers, and the formulation scientist can make a judicious decision regarding choice of a lipid based carrier.

Drug molecule has to overcome numerous encounters after oral administration and before it reaches to the site of action. The topmost hindrances to drug after oral administration comprise of degradation by enzymes, corporal fence of the intestinal epithelial membrane, biliary excretion and active efflux back into the lumen of the gastrointestinal tract. Nowadays with hurried advances in drug design technologies, druggable compounds have dramatically been introduced. However, several of these molecules have suffered from low bioavailability upon oral administration due to poor permeation across the gastrointestinal epithelia although they exhibit potential therapeutic effects. This issue of poor membrane permeability is mainly due to the transporter proteins present in the membrane. ATP binding cassette [ABC] super family acts as a carrier mediated active efflux transporter. In this family P-glycoprotein [P- gp], MRP1 and ABCG2 are most known multidrug efflux pumps. Amongst all the three efflux transporters, P-gp is extensively distributed in the human body and has enormous variety of substrates specificity for many drugs. Many therapeutically potential drugs have low bioavailability due to P-gp efflux. Therefore, to overcome multidrug resistance and deprived bioavailability of P-gp substrates, P-gp inhibitors have been discovered. The main aim of this review is to underline challenges in oral drug delivery, specifically focusing on P-gp efflux and contemporary strategies used for P-gp inhibition in drug discovery and formulation development.

Dramatic advancement in the field of oral delivery of biomacromolecules occurred within the last decades. Recently, a novel class of multifunctional polymers has risen in the pharmaceutical literature. These thiolated polymers designated thiomers are based on a variety of well-known polymers such as alginate, poly(acrylic acid) or chitosan. They are synthesized via covalent attachment of sulfhydryl group bearing ligands to the polymeric backbone. Forming disulfide bonds with mucus substructures, these thiomers offer the advantage of more pronounced mucoadhesive features in comparison with their unmodified polymers. This review enhances a comprehensive insight on thiomers history, mucoadhesion process as a complex phenomenon and oral drug delivery of biomacromolecules.

Drug delivery through mouth is still the most acceptable route to administer bioactives for the patient. The colon targeted drug delivery has gained increasing attention towards the treatment of colorectal cancer and other colon related disorders i.e., Crohn's disease, ulcerative colitis, irritable bowel syndrome, and spastic colon. The drugs such as cardiovascular and antiasthmatic agents have also been delivered via colon to avoid first pass metabolism or acidic environment of stomach. Colon targeting has also been demonstrated as a potential tool for systemic delivery of protein/peptide drugs due to relatively low proteolytic activities in the colonic environment. The GIT is dwelt by over 500 bacterial species, each having a specific place in the tract and developing variety of enzymes which are being utilized for development of colon-targeted drug delivery systems. There are various strategies presently followed for colontargeted delivery i.e., prodrugs that become active at the colonic site, drug-eluting system reacting to the pH, microfloraactivated drug delivery systems, hydrogels and matrices, and multicoating time-dependent drug delivery systems. The future steering towards colon targeted bioactives delivery would involve the application of specific binding with colonic mucosa.