Oral Bioavailability Of Peptide Drugs Research Articles

Barriers to the Intestinal Absorption of Four Insulin-Loaded Arginine-Rich Nanoparticles in Human and Rat.

Peptide drugs and biologics provide opportunities for treatments of many diseases. However, due to their poor stability and permeability in the gastrointestinal tract, the oral bioavailability of peptide drugs is negligible. Nanoparticle formulations have been proposed to circumvent these hurdles, but systemic exposure of orally administered peptide drugs has remained elusive. In this study, we investigated the absorption mechanisms of four insulin-loaded arginine-rich nanoparticles displaying differing composition and surface characteristics, developed within the pan-European consortium TRANS-INT. The transport mechanisms and major barriers to nanoparticle permeability were investigated in freshly isolated human jejunal tissue. Cytokine release profiles and standard toxicity markers indicated that the nanoparticles were nontoxic. Three out of four nanoparticles displayed pronounced binding to the mucus layer and did not reach the epithelium. One nanoparticle composed of a mucus inert shell and cell-penetrating octarginine (ENCP), showed significant uptake by the intestinal epithelium corresponding to 28 ± 9% of the administered nanoparticle dose, as determined by super-resolution microscopy. Only a small fraction of nanoparticles taken up by epithelia went on to be transcytosed via a dynamin-dependent process. In situ studies in intact rat jejunal loops confirmed the results from human tissue regarding mucus binding, epithelial uptake, and negligible insulin bioavailability. In conclusion, while none of the four arginine-rich nanoparticles supported systemic insulin delivery, ENCP displayed a consistently high uptake along the intestinal villi. It is proposed that ENCP should be further investigated for local delivery of therapeutics to the intestinal mucosa.

Molecular targeting of FATP4 transporter for oral delivery of therapeutic peptide.

Low oral bioavailability of peptide drugs has limited their application to parenteral administration, which suffers from poor patient compliance. Here, we show that molecular targeting of the FATP4 transporter is an effective approach to specifically transport long-chain fatty acid (LCFA)-conjugated peptides across the enterocytic membrane and, thus, enables oral delivery of drug peptides. We packaged LCFA-conjugated exendin-4 (LCFA-Ex4) into liposomes and coated with chitosan nanoparticles to form an orally deliverable Ex4 (OraEx4). OraEx4 protected LCFA-Ex4 from damage by the gastric fluid and released LCFA-Ex4 in the intestinal cavity, where LCFA-Ex4 was transported across the enterocyte membrane by the FAPT4 transporter. OraEx4 had a high bioavailability of 24.8% with respect to subcutaneous injection and exhibited a substantial hypoglycemic effect in murine models of diabetes mellitus. Thus, molecular targeting of the FATP4 transporter enhances oral absorption of therapeutic peptides and provides a platform for oral peptide drug development.

Semi-elastic core-shell nanoparticles enhanced the oral bioavailability of peptide drugs

The rigidity of nanoparticles was newly reported to influence their oral delivery. Semi-elastic nanoparticles can enhance the penetration in mucus and uptake by epithelial cells. However, it is still challenging and unclear that the semi-elastic core-shell nanoparticles can enhance the oral bioavailability of peptide drugs. This study was for the first time to validate the semi-elastic core-shell poly(lactic-co-glycolic acid) (PLGA)-lipid nanoparticles (LNPs) as the carrier of the oral peptide drug. The antihypertensive peptide Val-Leu-Pro-Val-Pro (VP5) loaded LNPs (VP5-LNPs) were prepared by a modified thin-film ultrasonic dispersion method. Uptake experiment was performed in Caco-2 and HT-29 cells and monitored by high content screening (HCS) and flow cytometric (FCM). Pharmacokinetics of VP5-LNPs was carried out in Sprague-Dawley (SD) rats and analyzed by DAS 2.0. The optimal VP5-LNPs had an average particle size of 247.3±3.8nm, zeta potential of −6.57±0.45mV and excellent entrapment efficiency (EE) of 89.88%±1.23%. Transmission electron microscope (TEM) and Differential scanning calorimeter (DSC) further confirmed the core-shell structure. VP5-LNPs could increase the cellular uptake in vitro and have a 2.55-fold increase in AUC0-72h, indicating a great promotion of the oral bioavailability. The semi-elastic LNPs remarkably improved the oral availability of peptide and could be a promising oral peptide delivery system for peptide drugs in the future.

In vivo evaluation of an oral self-microemulsifying drug delivery system (SMEDDS) for leuprorelin

The objective of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) for the model peptide drug leuprorelin to prove a protective effect against luminal enzymatic metabolism. In order to incorporate leuprorelin into microemulsion droplets (o/w), the commercially available hydrophilic leuprolide acetate was modified by hydrophobic ion paring with sodium oleate. The obtained hydrophobic leuprolide oleate was dissolved in the SMEDDS formulation (30% (m/m) Cremophor EL, 30% (m/m) Capmul MCM, 10% (m/m) propylene glycol and 30% (m/m) Captex 355) in a concentration of 4mg/g showing a mean droplet size of 50.1nm when dispersed in a concentration of 1% (m/v) in phosphate buffer pH 6.8. The microemulsion was able to shield leuprolide oleate from enzymatic degradation by trypsin and α-chymotrypsin, so that after 120min 52.9% and 58.4%, respectively, of leuprolide oleate were still intact. Leuprolide acetate dissolved in an aqueous control solution was completely metabolized by trypsin within 60min and by α-chymotrypsin within 5min. Moreover, an in vivo study in rats showed a 17.2-fold improved oral bioavailability of leuprolide oleate SMEDDS compared to a leuprolide acetate control solution. This is the first time, to our knowledge, that hydrophobic ion pairing is utilized in order to incorporate a peptide drug in SMEDDS and evidence of a protective effect of oil-in-water (o/w) microemulsion droplets against enzymatic degradation of a peptide drug was provided. According to these results, the system could be likely a novel platform technology to improve the oral bioavailability of peptide drugs.

Enhancing the Oral Bioavailability of Peptide Drugs by using Chemical Modification and Other Approaches

In regards to patient compliance for drug delivery, oral drug delivery is generally the preferred route of administration. However, parental injection of peptide drugs has always been the primary method of peptide drug administration. This is a result of the poor oral bioavailability of peptide drugs, which are typically under 1%. The degradation of peptides in the gastrointestinal (GI) tract by peptidase enzymes and harsh pH, combined with the poor intestinal mucosal penetration properties of the non-drug-like peptide drugs have been identified as the major barriers towards improving the oral bioavailability. Nevertheless, oral delivery of peptide drug presents a significant challenge due to the enzymatic degradation by enzymes in the GI tract and the poor penetration of the peptides across gastro-intestinal epithelium membranes, particularly for adults. Therefore, a novel peptide drug analogue or pro-drug that both protect peptide drugs from degradation by the enzymes in the GI tract that also improves its penetration across the intestinal epithelium membrane would greatly advance the development of peptide drugs as effective candidates for the treatment of various diseases. So far several approaches are being investigated to improve the oral bioavailability of peptide drugs by different researchers. Indications suggest that chemical modification such as incorporation of unnatural amino acids, unnatural peptide bonds, cyclisation and pro-drug approaches as well as nanoparticulates systems such as nanoparticles and microemulsions offer great potential for improvement and likelihood of enabling peptide drug to be administered orally. This review will focus on the chemical modification methods and other approaches (such as using variable nanoparticular delivery systems), that could be used to overcome the barriers involved in low oral bioavailability of peptide drugs.

25 Years Full of Chemical Discovery

25 Years Full of Chemical Discovery

Oral Delivery of Peptide Drugs

A wide variety of peptide drugs are now produced on a commercial scale as a result of advances in the biotechnology field. Most of these therapeutic peptides are still administered by the parenteral route because of insufficient absorption from the gastrointestinal tract. Peptide drugs are usually indicated for chronic conditions, and the use of injections on a daily basis during long-term treatment has obvious drawbacks. In contrast to this inconvenient and potentially problematic method of drug administration, the oral route offers the advantages of self-administration with a high degree of patient acceptability and compliance. The main reasons for the low oral bioavailability of peptide drugs are pre-systemic enzymatic degradation and poor penetration of the intestinal mucosa. A considerable amount of research has focused on overcoming the challenges presented by these intestinal absorption barriers to provide effective oral delivery of peptide and protein drugs. Attempts to improve the oral bioavailability of peptide drugs have ranged from changing the physicochemical properties of peptide molecules to the inclusion of functional excipients in specially adapted drug delivery systems. However, the progress in developing an effective peptide delivery system has been hampered by factors such as the inherent toxicities of absorption-enhancing excipients, variation in absorption between individuals, and potentially high manufacturing costs. This review focuses on the intestinal barriers that compromise the systemic absorption of intact peptide and protein molecules and on the advanced technologies that have been developed to overcome the barriers to peptide drug absorption.

Administração oral de peptídeos e proteínas: II. Aplicação de métodos de microencapsulação

A escolha de um método de Microencapsulação adequado para promover o aumento da biodisponibilidade oral de fármacos peptídicos depende das características físico-químicas do fármaco a encapsular, das condições operacionais e dos polímeros utilizados. Nesta abordagem é feita uma avaliação dos diversos métodos de Microencapsulação e sua aplicação na administração oral de peptídeos e proteínas. As técnicas de Microencapsulação que utilizam polímeros de origem natural, não recorrendo a condições drásticas de preparação, são consideradas opções privilegiadas.

Regional differences in intestinal spreading and pH recovery and the impact on salmon calcitonin absorption in dogs.

To investigate the regional influence of intestinal spreading and pH recovery on the performance of drug and excipient delivery systems and their impact on the oral absorption of a model peptide drug, salmon calcitonin (sCT), in conscious beagle dogs. Male beagle dogs were surgically prepared with subdermal Intestinal Access Ports (IAP). The catheter from one port was placed in the duodenum and the other in the ileum. Fluoroscopy and Heidelberg pH capsule studies were performed to characterize intestinal spreading and pH recovery, respectively. Three treatments were performed: (1) a radiopaque dye and citric acid (CA) were infused into the intestinal segments, (2) a radiopaque powder capsule containing CA was given orally, and (3) capsules containing CA and sCT were given orally. Regular blood samples were collected and analyzed by radioimmunoassay (RIA) to determine the absorption characteristics of sCT. Since sCT is an excellent substrate for the pancreatic serine protease trypsin, the rate of degradation of sCT in the GI lumen is dependent upon the regional pH, activity of digestive enzymes and the concentration of sCT at the site of absorption. Fluoroscopy results clearly showed that when the radiopaque dye was infused into the duodenum and capsule disintegration occurred early, there was significant dilution and spreading of the excipients throughout a large section of the upper small intestine (USI). However, when the radiopaque dye was infused into the ileum and capsule disintegration occurred in the lower small intestine (LSI), the excipients moved along as a bolus (i.e., plug). The pH monitoring results were consistent with the fluoroscopy results. The pH dropped only momentarily and rose quickly in the USI consistent with well-stirred mixing kinetics. In the LSI, dilution and spreading were minimal and the drop in pH was greater and persisted for a longer period of time. Plasma levels of sCT were maximal when disintegration occurred in the LSI. Since significantly less dilution and spreading occurred in the LSI, the exposure of the intestine to pharmaceutical excipients and sCT was more concentrated resulting in a higher fraction of sCT absorbed. The results of this study demonstrate that intestinal mixing kinetics have a dramatic impact on the ability of pharmaceutical excipients to modulate the oral bioavailability of peptide drugs like sCT.