Oral Delivery Of Peptide Drugs Research Articles

The Synthesis of SNAC Phenolate Salts and the Effect on Oral Bioavailability of Semaglutide.

Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) is a well-known penetration enhancer widely used in commercial applications. This study aims to broaden its properties through a novel strategy of converting it into its phenolate salts. The objective is to investigate the synthesis of SNAC phenolate salts, specifically SNAC-choline (SNAC-CH), SNAC-sodium (SNAC-Na), and SNAC-phosphatidylcholine (SNAC-PC), and to explore their potential application in improving the oral absorption of semaglutide. The synthesis of SNAC phenolate salts was confirmed through 1H-NMR, FTIR, and an elemental analysis of C, H, N, and O. In vivo testing was conducted to assess the oral delivery of semaglutide using these synthesized SNAC phenolate salts. Pharmacokinetic (PK) values were measured to evaluate the impact on drug absorption. The synthesis of SNAC phenolate salts (SNAC-CH, SNAC-Na, and SNAC-PC) was successfully achieved under appropriate conditions, and their structures were confirmed using analytical techniques such as IR, NMR, and CHN elemental analysis. The paradigm of their use was evaluated through an oral pharmacokinetic (PK) in vivo study using SNAC phenolate salts, which did not impair the original SNAC PK values. This suggests that this strategy holds promise as a potential new effective enhancer for oral absorption. The utilization of SNAC phenolate salts presents a novel and promising strategy for extending the verity of penetration enhancers' molecules and properties. Synthesizing phenolate salts represents a new chemical strategy that may open new avenues in molecular development. This approach holds future potential to enhance the oral delivery of peptide drugs like semaglutide without compromising therapeutic efficacy. Overall, it offers significant advancements in the field by providing a potential alternative to injectable peptides through oral delivery systems.

Nanotechnology Enabled Advances in Oral Delivery of Therapeutic Peptides: Mechanistic Insights for Translation to Clinic

Abstract: Peptides represent a rapidly expanding class of novel treatments with distinct pharmacokinetic properties when compared to macromolecular proteins or small-molecule medications. Peptides are polymers with a molecular mass of less than 10 kDa. Protein-protein interactions have been the primary goal of oral delivery of peptide drugs for the last two decades. Recent trends suggest the possibility of mechanistically targeting challenging binding interfaces with the right binding affinity and specificity for molecules like peptides that bring conformational flexibility. Over 80 peptide medications have received regulatory approval to treat a range of conditions, from human immunodeficiency infection caused by viruses to fatal diseases like cancer. This review covers the need for peptide delivery via the oral route and offers insights to overcome the challenges. For successful translation to the clinic, oral delivery of therapeutic peptides coupled with nano formulation strategies has gained increased attention in recent years. The role of permeation boosters, and digestive enzyme inhibitors to overcome major hurdles such as degradation in the gastrointestinal tract and low intestinal permeability are presented here. Alteration of physicochemical characteristics of peptide molecules, the addition of functional excipients to specifically designed drug delivery systems, nanoformulation approaches, amongst other recent methodologies, to increase the oral bioavailability of peptide medications, are also presented herein. Numerous peptide candidates, both approved and under clinical trials, are included in this review.

Self-Emulsifying Drug Delivery Systems (SEDDS) Containing Reverse Micelles: Advanced Oral Formulations for Therapeutic Peptides.

Alternative methods to hydrophobic ion pairing for the formation of lipophilic complexes of peptide drugs to incorporate them in lipid-based nanocarriers such as self-emulsifying drug delivery systems (SEDDS) for oral administration are highly on demand. Such an alternative might be reverse micelles. Within this study, SEDDS containing dry reverse micelles (dRMsPMB ) formed with an anionic (sodium docusate; AOT), cationic (dimethyl-dioctadecyl-ammonium bromide; DODAB), amphoteric (soy lecithin; SL), or non-ionic (polysorbate 85; P85) surfactant loaded with the model peptide drug polymyxin B (PMB) are developed. They are characterized regarding size, payload, release kinetics, cellular uptake, and peptide activity. SEDDS exhibit sizes from 22.2±1.7 (AOT-SEDDS-dRMsPMB ) to 61.7±3.2nm (P85-SEDDS-dRMsPMB ) with payloads up to 2% that are approximately sevenfold higher than those obtained via hydrophobic ion pairing. Within 6h P85-SEDDS-dRMsPMB and AOT-SEDDS-dRMsPMB show no release of PMB in aqueous medium, whereas DODAB-SEDDS-dRMsPMB and SL-SEDDS-dRMsPMB show a sustained release. DODAB-SEDDS-dRMsPMB improves uptake by Caco-2 cells most efficiently reaching even ≈100% within 4h followed by AOT-SEDDS-dRMsPMB with ≈20% and P85-/SL-SEDDS-dRMsPMB with ≈5%. The peptide drug maintains its antimicrobial activity in all SEDDS-dRMsPMB . According to these results, SEDDS containing dRMs might be a game changing strategy for oral peptide drug delivery.

Herbal Bioenhancers with Nanocarriers: A Promising Approach for Oral Peptide Delivery

The oral delivery of protein and peptide drugs faces immense challenges due to the harsh gastrointestinal (GI) environment, large molecular size, and low stability. Even though different approaches are employed to deliver peptide drugs efficiently, they have limited success. Recently, the use of nanoparticles as carriers for peptides as a means of surmounting the gastrointestinal barrier and as an effective alternative to parenteral administration has gained much attention. It is often necessary to supplement this mode of delivery by using strategies such as permeation enhancers. Bio-enhancers play a significant role in reducing the dose, drug resistance, toxicity, and treatment expenses. The potential of herbal bio-enhancers as a safe and effective substitute to non-herbal permeation enhancers in improving oral absorption of peptides from nanoparticulate systems has been explored recently. Piperine is counted first in the list of bio-enhancers and can improve the bioavailability of peptides and other drugs. Other molecules like naringin, glycyrrhizin, quercetin have great significance either alone or in combination in improving the oral bioavailability of drug molecules. Bioenhancers are beneficial for drugs with poor lipid solubility and large molecular size, causing poor absorption and low bioavailability. Herbal bioenhancers can decrease the dose, drug resistance, toxicity, adverse effects, and overall treatment cost as they are inert, easily procured and economical. This review article focuses on the significance of nanoparticles in the oral delivery of peptide drugs and the vital role played by herbal bioenhancers in their absorption from the GI tract.

Dietary-Polysaccharide-Modified Fish-Oil-Based Double Emulsion as a Functional Colloidal Formulation for Oral Drug Delivery.

Oral delivery is the most convenient drug administration route. However, oral delivery of peptides is extremely challenging due to the physical and chemical barriers within the gastrointestinal tract. Polysaccharides are often utilized as polymeric biomaterials in drug delivery. Among these, dietary polysaccharides extracted from okra, yam, and spirulina have been reported to stimulate innate immunity with well-known nutritional benefits. In this study, we developed a dietary-polysaccharide-modified fish-oil-based emulsion for oral co-delivery of a hydrophilic PD-L1 blocking peptide and the hydrophobic small molecule simvastatin. The optimal emulsion was nano-sized and exhibited a negative surface charge, high drug encapsulation efficiency of over 97%, low viscosity, and sustained drug release manner. The formulation could significantly increase the uptake of peptides by intestinal Caco-2 cells, which demonstrated the great potential of the formulation for promoting the oral absorption of peptides. Additionally, these dietary polysaccharides could promote dendritic cell maturation and cytokine expression in macrophages, demonstrating that these nutraceutical polysaccharides had dual roles of functioning as promising colloidal delivery systems and as potential immune modulators or adjuvants. Thus, this food-based colloidal delivery system shows promise for the oral delivery of peptide drugs and lays a great platform for future applications in immunotherapy.

Physical and barrier changes in gastrointestinal mucus induced by the permeation enhancer sodium 8-[(2-hydroxybenzoyl)amino]octanoate (SNAC).

Drug delivery systems (DDS) for oral delivery of peptide drugs contain excipients that facilitate and enhance absorption. However, little knowledge exists on how DDS excipients such as permeation enhancers interact with the gastrointestinal mucus barrier. This study aimed to investigate interactions of the permeation enhancer sodium 8-[(2-hydroxybenzoyl)amino]octanoate (SNAC) with ex vivo porcine intestinal mucus (PIM), ex vivo porcine gastric mucus (PGM), as well as with in vitro biosimilar mucus (BM) by profiling their physical and barrier properties upon exposure to SNAC. Bulk mucus permeability studies using the peptides cyclosporine A and vancomycin, ovalbumin as a model protein, as well as fluorescein-isothiocyanate dextrans (FDs) of different molecular weights and different surface charges were conducted in parallel to mucus retention force studies using a texture analyzer, rheological studies, cryo-scanning electron microscopy (cryo-SEM), and single particle tracking of fluorescence-labelled nanoparticles to investigate the effects of the SNAC-mucus interaction. The exposure of SNAC to PIM increased the mucus retention force, storage modulus, viscosity, increased nanoparticle confinement within PIM as well as decreased the permeation of cyclosporine A and ovalbumin through PIM. Surprisingly, the viscosity of PGM and the permeation of cyclosporine A and ovalbumin through PGM was unaffected by the presence of SNAC, thus the effect of SNAC depended on the regional site that mucus was collected from. In the absence of SNAC, the permeation of different molecular weight and differently charged FDs through PIM was comparable to that through BM. However, while bulk permeation of neither of the FDs through PIM was affected by SNAC, the presence of SNAC decreased the permeation of FD4 and increased the permeation of FD150 kDa through BM. Additionally, and in contrast to observations in PIM, nanoparticle confinement within BM remained unaffected by the presence of SNAC. In conclusion, the present study showed that SNAC altered the physical and barrier properties of PIM, but not of PGM. The effects of SNAC in PIM were not observed in the BM in vitro model. Altogether, the study highlights the need for further understanding how permeation enhancers influence the mucus barrier and illustrates that the selected mucus model for such studies should be chosen with care.

Mucus- and pH-mediated controlled release of core-shell chitosan nanoparticles in the gastrointestinal tract for diabetes treatment

For the successful oral delivery of peptide drugs, considerable barriers created by the harsh environment of the gastrointestinal tract, mucus, and epithelial cells must be overcome. This study was to establish a core-shell structure with chitosan (CS) nanoparticles (NP) as the core and poly-N-(2-hydroxypropyl) methacrylamide (pHPMA) as the intelligent escape shell to overcome pH and mucus barriers and improve the delivery efficiency of peptide drugs. A core-shell system (COS) composed of pHPMA-AT-1002-cys-chitosan (LRA-PA-CNPs) was prepared and used for the treatment of type 2 diabetes mellitus with the large-molecule peptide drug liraglutide (LRA). The complete COS system was observed through electron microscopy; the particle size of the LRA-PA-CNPs was approximately 160 nm; the encapsulation efficiency was approximately 69% ± 5%; the zeta potential was close to neutral; the mucus and epithelial penetration of the COS system were increased; and animal experiments showed that the COS system enhanced the oral hypoglycaemic effect of LRA. HIGHLIGHTS Intelligent escape material of poly-N-(2-hydroxypropyl) methacrylamide as the shell. Core-shell nanoparticles penetrate the mucus layer and exposing the chitosan core. Overcome pH and mucus barriers to improve the delivery efficiency of peptide drugs.

Thermo-Sensitive mPEG-PA-PLL Hydrogel for Drug Release of Calcitonin.

The oral route is the most popular way of drug administration because of good patient compliance and ease of use. However, the oral delivery of peptides and proteins is difficult, mainly due to poor oral bioavailability. In past decades, researchers have developed several strategies to improve oral bioavailability by avoiding losing activity in the gastrointestinal (GI) tract and enhancing the intestinal permeability of these drugs. Methoxy poly(ethylene glycol)-poly(l-alanine) (mPEG-PA) is a thermo-sensitive hydrogel exhibiting a sol-to-gel phase transition property. This characteristic is appropriate for encapsulating peptide or protein drugs. To enhance the adhesion ability to intestinal mucus, a thermo-sensitive polymer, mPEG-PA, modified with charged amino acid lysine was developed. This positively charged material would help to bind the negatively charged mucin in mucus. The synthesis was conducted by individually synthesizing mPEG-PA and poly(l-lysine) (PLL) of different lengths via ring-opening polymerization. Then, mPEG-PA and PLL were combined using an NHS ester reaction to synthesize the triblock copolymer (mPEG-PA-PLL). Biocompatibility and the release of calcitonin from the synthesized hydrogel particles under different pH were examined. The initial data showed that the newly design material had a promising potential for the oral delivery of peptide drugs.

Advances in oral peptide drug nanoparticles for diabetes mellitus treatment.

Peptide drugs play an important role in diabetes mellitus treatment. Oral administration of peptide drugs is a promising strategy for diabetes mellitus because of its convenience and high patient compliance compared to parenteral administration routes. However, there are a series of formidable unfavorable conditions present in the gastrointestinal (GI) tract after oral administration, which result in the low oral bioavailability of these peptide drugs. To overcome these challenges, various nanoparticles (NPs) have been developed to improve the oral absorption of peptide drugs due to their unique in vivo properties and high design flexibility. This review discusses the unfavorable conditions present in the GI tract and provides the corresponding strategies to overcome these challenges. The review provides a comprehensive overview on the NPs that have been constructed for oral peptide drug delivery in diabetes mellitus treatment. Finally, we will discuss the rational application and give some suggestions that can be utilized for the development of oral peptide drug NPs. Our aim is to provide a systemic and comprehensive review of oral peptide drug NPs that can overcome the challenges in GI tract for efficient treatment of diabetes mellitus.

Nanostructured Lipid Carriers (NLCs) for Oral Peptide Drug Delivery: About the Impact of Surface Decoration.

This study was aimed to evaluate the impact of surfactants used for nanostructured lipid carriers (NLCs) to provide enzymatic protection for incorporated peptides. Insulin as a model peptide was ion paired with sodium dodecyl sulfate to improve its lipophilicity. Three NLC formulations containing polyethylene glycol ester (PEG-ester), polyethylene glycol ether (PEG-ether), and polyglycerol ester (PG-ester) surfactants were prepared by solvent diffusion method. NLCs were characterized regarding particle size, polydispersity index, and zeta potential. Biocompatibility of NLCs was assessed on Caco-2 cells via resazurin assay. In vitro lipolysis study was performed using a standard lipid digestion method. Proteolytic studies were performed in simulated gastric fluid containing pepsin and simulated intestinal fluid containing pancreatin. Lipophilicity of insulin in terms of log Poctanol/water was improved from −1.8 to 2.1. NLCs were in the size range of 64–217 nm with a polydispersity index of 0.2–0.5 and exhibited a negative surface charge. PG-ester NLCs were non-cytotoxic up to a concentration of 0.5%, PEG-ester NLCs up to a concentration of 0.25% and PEG-ether NLC up to a concentration of 0.125% (w/v). The lipolysis study showed the release of >90%, 70%, and 10% of free fatty acids from PEG-ester, PG-ester, and PEG-ether NLCs, respectively. Proteolysis results revealed the highest protective effect of PEG-ether NLCs followed by PG-ester and PEG-ester NLCs for incorporated insulin complex. Findings suggest that NLCs bearing substructures less susceptible to degrading enzymes on their surface can provide higher protection for incorporated peptides toward gastrointestinal proteases.

Coating of PLA-nanoparticles with cyclic, arginine-rich cell penetrating peptides enables oral delivery of liraglutide

Until today, the oral delivery of peptide drugs is hampered due to their instability in the gastrointestinal tract and low mucosal penetration. To overcome these hurdles, PLA (polylactide acid)-nanoparticles were coated with a cyclic, polyarginine-rich, cell penetrating peptide (cyclic R9-CPP). These surface-modified nanoparticles showed a size and polydispersity index comparable to standard PLA-nanoparticles. The zeta potential showed a significant increase indicating successful CPP-coupling to the surface of the nanoparticles. Cryo-EM micrographs confirmed the appropriate size and morphology of the modified nanoparticles. A high encapsulation efficiency of liraglutide could be achieved. In vitro tests using Caco-2 cells showed high viability indicating the tolerability of this novel formulation. A strongly enhanced mucosal binding and penetration was demonstrated by a Caco-2 binding and uptake assay. In Wistar rats, the novel nanoparticles showed a substantial, 4.5-fold increase in the oral bioavailability of liraglutide revealing great potential for the oral delivery of peptide drugs.

Protamine nanocapsules as carriers for oral peptide delivery

Peptides represent a promising therapeutic class with the potential to alleviate many severe diseases. A key limitation of these active molecules relies on the difficulties for their efficient oral administration. The objective of this work has been the rational design of polymer nanocapsules (NCs) intended for the oral delivery of peptide drugs. For this purpose, we selected insulin glulisine as a model peptide. The polymer shell of the NCs was made of a single layer of protamine, a cationic polypeptide selected for its cell penetration properties, or a double protamine/polysialic acid (PSA) layer. Insulin glulisine-loaded protamine and protamine/PSA NCs, prepared by the solvent displacement method, exhibited a size that varied in the range of 200–400 nm and a neutral surface charge (from +8 mV to −6 mV), depending on the formulation. The stability of the encapsulated peptide was assessed using circular dichroism and an in vitro cell activity study. Colloidal stability studies were also performed in simulated intestinal media containing enzymes and the results indicated that protamine NCs were stable and able to protect insulin from the harsh intestinal environment, and that this capacity could be further enhanced with a double PSA-Protamine layer. These NCs were freeze-dried and stored at room temperature without alteration of the physicochemical properties. When the insulin-loaded protamine NCs were administered intra-intestinally to diabetic rats (12 h fasting) it resulted in a prolonged glucose reduction (60%) as compared to the control insulin solution. This work raises prospects that protamine NCs may have a potential as oral peptide delivery nanocarriers.

Oral delivery of vancomycin by tetraether lipid liposomes

Despite the outstanding progress in modern medicine, the oral delivery of peptide drugs is limited until today due to their instability in the gastrointestinal tract and low mucosa penetration. To overcome these hurdles, liposomes containing the specific tetraether lipid GCTE (glycerylcaldityltetraether lipid) were examined. For this purpose, the glycopeptide antibiotic vancomycin was used as model substance and liposomes were prepared by DAC (dual assymetric centrifugation). These liposomes showed a size and polydispersity index comparable to standard liposomes. A high encapsulation efficiency of 58.53±1.76% of the peptide drug vancomycin could be obtained as detected by HPLC. FCS analysis showed that in average each liposome contains 30 molecules of vancomycin. TEM and Cryo-EM micrographs verified the size and lamellarity of the liposomal formulations. Cytotoxicity tests in Caco-2 cells showed no significant cytotoxicity for all liposomal concentrations tested, indicating the good tolerability of these formulations. Furthermore, the use of sucrose as lyoprotector enabled the long term storage of the liposomal formulation for at least three months.The potency of this drug delivery system could be proven in an animal model using Wistar rats. One hour after oral application, 4.82±0.56% of the administered dose of vancomycin could be found in the blood as detected by immunoassay measurements. This transport did also not affect the integrity of the peptide as verified by immunoassay measurements. In combination with long term storage stability, this formulation appears to be a promising delivery system for oral application of peptide drugs.

Comparison of the protective effect of self-emulsifying peptide drug delivery systems towards intestinal proteases and glutathione

AimThe aim of this study was to evaluate the protective effect of self-emulsifying drug delivery systems (SEDDS) for therapeutic peptides towards intestinal proteases and reduced glutathione (GSH). MethodsSodium docusate was applied as anionic surfactant for hydrophobic ion pairing with leuprorelin (LEU), insulin (INS) and desmopressin (DES). The complexes were loaded into SEDDS that were characterized regarding droplet size distribution and zeta potential. The release profile of the peptides was examined by dialysis membrane method. Enzymatic digestion studies were performed by applying α-chymotrypsin, trypsin and elastase. Furthermore, the protective effect of SEDDS towards degradation through thiol-disulfide exchange reactions was examined by addition of GSH. ResultsSEDDS showed a mean droplet size of 0.27–3.9μm and a zeta potential of –25 to –33mV. All formulations provided a sustained release of the peptides over 6h. Degradation of the model peptides by intestinal proteases and GSH could only be observed in the release medium. In the oily phase of SEDDS neither any of the proteases nor GSH was soluble (≤0.1%). Furthermore, no degradation of the model peptides by proteases and GSH took place in the oily phase of SEDDS. ConclusionSEDDS can provide a 100% protective effect towards protease degradation and deactivation by GSH. According to this, SEDDS might be promising tools for oral delivery of peptide drugs.

Microfluidic Assembly of a Multifunctional Tailorable Composite System Designed for Site Specific Combined Oral Delivery of Peptide Drugs.

Multifunctional tailorable composite systems, specifically designed for oral dual-delivery of a peptide (glucagon-like peptide-1) and an enzymatic inhibitor (dipeptidyl peptidase 4 (DPP4)), were assembled through the microfluidics technique. Both drugs were coloaded into these systems for a synergistic therapeutic effect. The systems were composed of chitosan and cell-penetrating peptide modified poly(lactide-co-glycolide) and porous silicon nanoparticles as nanomatrices, further encapsulated in an enteric hydroxypropylmethylcellulose acetylsuccinate polymer. The developed multifunctional systems were pH-sensitive, inherited by the enteric polymer, enabling the release of the nanoparticles only in the simulated intestinal conditions. Moreover, the encapsulation into this polymer prevented the degradation of the nanoparticles' modifications. These nanoparticles showed strong and higher interactions with the intestinal cells in comparison with the nonmodified ones. The presence of DPP4 inhibitor enhanced the peptide permeability across intestinal cell monolayers. Overall, this is a promising platform for simultaneously delivering two drugs from a single formulation. Through this approach peptides are expected to increase their bioavailability and efficiency in vivo both by their specific release at the intestinal level and also by the reduced enzymatic activity. The use of this platform, specifically in combination of the two antidiabetic drugs, has clinical potential for the therapy of type 2 diabetes mellitus.

Editorial (Thematic Issue: Oral Delivery of Biotechnology based Drugs: Dream or Reality?)

Biotechnology has provided a wide array of therapeutic agents such as peptide, protein, vaccine and gene products that are currently mainly administered by means of injections. Therapeutic agents produced by biotechnological processes such as recombinant DNA technology, fermentation, tissue and cell culture technology as well as genetic engineering are usually large, hydrophilic molecules facing delivery challenges, for example, these drugs are susceptible to degradation and are generally poorly membrane permeable. Since successful delivery of any drug is a pre-requisite to achieve the therapeutic goal, novel strategies have emerged in the late 20th century to overcome challenges associated with the oral route of drug administration. These strategies include, but are not restricted to micro- and nanotechnology including self-emulsifying lipid based formulations, dendrimers and devices, permeability enhancing technology, targeting of active transporters and membrane receptors, use of cell penetrating peptides, chemical modifications of peptides such as inclusion complex formation and peptide conjugates, site-specific delivery systems, muco-adhesive systems and polymeric hydrogels. Despite the initial excitement regarding the potential of these technologies to provide effective oral delivery, few have advanced from the pre-clinical stage into clinical trials and very few, if any, resulted so far in registered medicinal products. Moreover, most literature provides information on effectiveness and mechanisms based on in vitro investigations without revealing the viability of these technologies in clinical practice. Although this topic of oral peptide delivery has gone through different phases in terms of attracting attention from the scientific community, it remains a timely research subject. The therapeutic benefits to patients and potential economic benefits to the producer serve as the driving forces behind finding an effective oral delivery system for biotechnology derived drugs. This special issue aims at assessing some of the latest developments in the field of oral delivery of biotechnological therapeutic agents. The reader will not only gain an understanding of the challenges associated with oral delivery of protein and peptide based drugs, but certain strategies that emerged to overcome these drawbacks are also discussed. From the discussions it is clear that scientific research has contributed to a deeper understanding of older drug delivery strategies, while new discoveries keep the vision of producing an effective oral peptide drug delivery system alive.

Orally Delivered Salmon Calcitonin-Loaded Solid Lipid Nanoparticles Prepared by Micelle–Double Emulsion Method Via The Combined Use of Different Solid Lipids

The purpose of this study was to develop a new orally delivered nanoparticulate system to improve the bioavailability of salmon calcitonin (sCT). Four sCT-loaded solid lipid nanoparticles (SLNs) were prepared successfully by micelle-double emulsion technique via either the sole use of stearic acid (SA) or the combined use of SA and triglycerides (including tripalmitin [TP], trimyristin or trilaurin). Compared with other SLNs, the combination of SA and TP could not only significantly improve the colloidal stability of SLNs and enhance the drug stability in the simulated intestinal fluids, but also intensively increase the intracellular uptake of drugs compared with the other SLNs (p < 0.05). The mechanism of internalization was an active transport involved in clathrin- and caveolae-dependent endocytosis. In vivo, the sCT SLNs prepared with SA and TP exhibited the highest reduction of plasma Ca(2+) level (17.44 ± 3.68%) with a bioavailability of 13.01 ± 3.24%. The SLNs formed by SA and TP as the solid lipids may be a promising carrier for oral delivery of peptide drugs.

Chiasma and Roche partner in oral peptide drug delivery

Chiasma and Roche partner in oral peptide drug delivery

Synthesis and Characterization of Luteinizing Hormone-Releasing Hormone (LHRH)-Functionalized Mini-Dendrimers

Luteinizing hormone-releasing hormone (LHRH) is the key regulator of the hypothalamic-pituitary-gonadal (HPG) axis, which is responsible for the development and functioning of the reproductive system. Delivery of a continuous supply of LHRH agonists causes down-regulation of the LHRH receptors, resulting in a marked decrease in androgens in males and estrogens in females. LHRH analogues are widely used in the treatment of various diseases, including prostate and breast cancer, and reproductive disorders, such as infertility and precocious puberty. However, they require parenteral administration, and no oral formulations are currently available. We synthesized two types of LHRH mini-dendrimers using thioether ligation, aiming to enhance the stability and bioavailability of the peptide drug while maintaining its biologically active conformation. These two compounds include a poly-lysine core conjugated to either the C-terminus of LHRH or a D-amino acid in position 6 of the LHRH sequence. The synthesized dendrimers were analysed using dynamic light scattering, and showed particle sizes of 155 and 115 nm, respectively. The nanometer size, well-defined structure and water solubility of these dendritic analogues make them excellent candidates for further exploration in oral peptide drug delivery.

The use of chitosan-6-mercaptonicotinic acid nanoparticles for oral peptide drug delivery

The aim of this study was to develop a novel nanoparticulate formulation and test its potential for oral peptide drug delivery. Chitosan-6-mercaptonicotinic acid is a novel thiolated chitosan with strong mucoadhesive properties. Nanoparticles were developed by an ionic gellation method. The obtained particles were characterized in terms of mucoadhesion, stability, toxicity, and in vitro release. Human insulin (HI) was chosen as a model peptide drug, incorporated in the particles and orally administered to rats. Human insulin was quantified in the blood by means of ELISA. The size of the obtained particles was in the range of 200–300 nm and the zeta potential was determined to be +8−+23 depending on the amount of thiol groups attached on the polymer. After 3 h of incubation up to 60% of the thiolated chitosan nanoparticles remained attached to the mucosa in contrast to 20% of unmodified chitosan particles. The AUC of HI after oral administration of thiolated chitosan nanoparticles was 4-fold improved compared to unmodified chitosan nanoparticles. Due to these improvements, chitosan-6-mercaptonicotinic acid nanoparticles are promising vehicles for oral delivery of peptide drugs.