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Interferon α (IFNα) and interferon γ (IFNγ) play pivotal roles in mediating crucial biological functions, including antiviral activity and immune regulation. However, the efficacy of monomeric IFN is limited, and its administration relies solely on injection. To address this issue, we successfully expressed and purified a recombinant porcine IFNα and IFNγ fusion protein (rPoIFNα/γ). Furthermore, we developed a pH-triggered humic acid hydrogel delivery system that effectively protects rPoIFNα/γ from gastric acid degradation, enhancing its oral bioavailability. Neither the humic acid hydrogel nor rPoIFNα/γ exhibited cytotoxic effects on porcine kidney-15 (PK-15) cells in vitro. The replication of vesicular stomatitis virus and pseudorabies virus (PRV) was effectively inhibited by rPoIFNα/γ, resulting in an antiviral activity of approximately 104 U/mL. Scanning electron microscopy revealed that the humic acid hydrogel had a loose and porous honeycomb structure. The IFNα/γ@PAMgel hydrogel effectively adsorbed rPoIFNα/γ, as confirmed by Fourier transform infrared spectroscopy analysis, demonstrating a favourable IFN-loading capacity. In vitro experiments revealed that IFNα/γ@PAMgel swelled and released IFNα/γ rapidly at pH 7.4 but not at pH 1.2. The oral administration of IFNα/γ@PAMgel in mice enhanced the proliferation and differentiation of CD4+ and CD8+ cells. Additionally, mice infected with PRV and treated with IFNα/γ@PAMgel presented increased transcription levels of interferon-stimulated genes in the serum, reduced mortality rates, lower viral loads in various tissues, and decreased levels of organ damage. In conclusion, this study demonstrates that orally administered IFNα/γ@PAMgel has antiviral and immunomodulatory effects, highlighting its potential as a therapeutic agent against PRV infection. [ABSTRACT FROM AUTHOR]

Abstract Interferon α (IFNα) and interferon γ (IFNγ) play pivotal roles in mediating crucial biological functions, including antiviral activity and immune regulation. However, the efficacy of monomeric IFN is limited, and its administration relies solely on injection. To address this issue, we successfully expressed and purified a recombinant porcine IFNα and IFNγ fusion protein (rPoIFNα/γ). Furthermore, we developed a pH-triggered humic acid hydrogel delivery system that effectively protects rPoIFNα/γ from gastric acid degradation, enhancing its oral bioavailability. Neither the humic acid hydrogel nor rPoIFNα/γ exhibited cytotoxic effects on porcine kidney-15 (PK-15) cells in vitro. The replication of vesicular stomatitis virus and pseudorabies virus (PRV) was effectively inhibited by rPoIFNα/γ, resulting in an antiviral activity of approximately 104 U/mL. Scanning electron microscopy revealed that the humic acid hydrogel had a loose and porous honeycomb structure. The IFNα/γ@PAMgel hydrogel effectively adsorbed rPoIFNα/γ, as confirmed by Fourier transform infrared spectroscopy analysis, demonstrating a favourable IFN-loading capacity. In vitro experiments revealed that IFNα/γ@PAMgel swelled and released IFNα/γ rapidly at pH 7.4 but not at pH 1.2. The oral administration of IFNα/γ@PAMgel in mice enhanced the proliferation and differentiation of CD4+ and CD8+ cells. Additionally, mice infected with PRV and treated with IFNα/γ@PAMgel presented increased transcription levels of interferon-stimulated genes in the serum, reduced mortality rates, lower viral loads in various tissues, and decreased levels of organ damage. In conclusion, this study demonstrates that orally administered IFNα/γ@PAMgel has antiviral and immunomodulatory effects, highlighting its potential as a therapeutic agent against PRV infection.

With the growing prevalence of diabetes, there is an urgent demand for a user‐friendly treatment option that minimizes side effects related to the use of subcutaneous injections. Scientists have dedicated over a century to developing an oral dosage form of insulin that can be administrated orally. The oral route of administration is the most desirable route for regularly dosed drugs in terms of safety and patient compliance. However, oral delivery of insulin remains a formidable challenge due to its intrinsically limited ability to cross the intestinal epithelium membrane and susceptibility to enzymatic degradation. This article reviews oral insulin research over the past decade, with a particular focus on surface modifications of nanoparticles (NPs). Various strategies involving controlling surface charges, utilizing protective proteins, and targeting specific receptors with ligands have been explored. Notably, surface modifications of the NPs for targeting specific intestinal receptors have shown promise in enhancing insulin oral absorption and bioavailability. Advanced technologies such as oral microneedles and gene therapy have also been developed, but their safety requires further assessment. Despite encouraging preclinical results across numerous strategies, the current clinical evidence is less optimistic. In summary, the present findings highlight the substantial journey that still lies ahead before achieving successful oral delivery of insulin. Practical Applications: This review provides a summary of recent progress in oral insulin delivery, particularly highlighting surface‐modified functional nanoparticles serving as an effective drug delivery system, which offers valuable information to the researchers. Due to the limited effectiveness of oral protein drugs caused by biological barriers, innovative technologies and drug delivery systems have been developed to overcome these obstacles and achieve therapeutic goals. This review concluded that surface modifications to nanoparticles can improve insulin stability and permeability, thereby enhancing oral bioavailability. It could assist researchers in developing more effective and patient‐friendly oral drug delivery systems. [ABSTRACT FROM AUTHOR]

Food‐derived extracellular vesicles (FEVs) are nanoscale membrane vesicles obtained from dietary materials such as breast milk, plants and probiotics. Distinct from other EVs, FEVs can survive the harsh degrading conditions in the gastrointestinal tract and reach the intestines. This unique feature allows FEVs to be promising prebiotics in health and oral nanomedicine for gut disorders, such as inflammatory bowel disease. Interestingly, therapeutic effects of FEVs have recently also been observed in non‐gastrointestinal diseases. However, the mechanisms remain unclear or even mysterious. It is speculated that orally administered FEVs could enter the bloodstream, reach remote organs, and thus exert therapeutic effects therein. However, emerging evidence suggests that the amount of FEVs reaching organs beyond the gastrointestinal tract is marginal and may be insufficient to account for the significant therapeutic effects achieved regarding diseases involving remote organs such as the liver. Thus, we herein propose that FEVs primarily act locally in the intestine by modulating intestinal microenvironments such as barrier integrity and microbiota, thereby eliciting therapeutic impact remotely on the liver in non‐gastrointestinal diseases via the gut‐liver axis. Likewise, drugs delivered to the gastrointestinal system through FEVs may act via the gut‐liver axis. As the liver is the main metabolic hub, the intestinal microenvironment may be implicated in other metabolic diseases. In fact, many patients with non‐alcoholic fatty liver disease, obesity, diabetes and cardiovascular disease suffer from a leaky gut and dysbiosis. In this review, we provide an overview of the recent progress in FEVs and discuss their biomedical applications as therapeutic agents and drug delivery systems, highlighting the pivotal role of the gut‐liver axis in the mechanisms of action of FEVs for the treatment of gut disorders and metabolic diseases. [ABSTRACT FROM AUTHOR]

Background: Isoformononetin (IFN) is a methoxyl derivative of daidzein and has been stated as a potent osteogenic isoflavone. However, IFN has low oral bioavailability. Advancement in the technology has led to the development of newer drug carrier systems, featuring the delivery of drugs with low oral bioavailability to advance their clinical application. Methods: The IFN nanoemulsion (IFN-NE) was developed and optimized using the design of the experiment tool and technique approaches. Results: The optimized IFN-NE has a particle size of 174.65 ± 1.63 nm, PDI of 0.244 ± 0.004, and zeta potential of − 30.69 ± 4.99 mV, respectively. The TEM images of optimized IFN-NE showed the spherical globular size of the nanoemulsion. The entrapment efficiency showed higher entrapment of IFN in the NE (96.04 ± 1.28%). The compatibility of IFN with excipients was confirmed by physical state characterization such as FTIR and DSC, illustrating no interaction. Optimized IFN-NE formulation was stable at different temperature conditions. In comparison to a free drug suspension, IFN-NE showed sustained drug release over a 24-h period of time. Additionally, in situ, single-pass intestinal perfusion (SPIP) results displayed significant enhancement of IFN permeability through the intestine of rats from IFN-NE when compared to free IFN. Conclusions: Pharmacokinetics results revealed the enhanced relative oral bioavailability of IFN-NE compared to IFN suspension using female Sprague–Dawley (SD) rats as animal models. The developed IFN-NE can be a promising candidate to overcome the low oral bioavailability of IFN. [ABSTRACT FROM AUTHOR]

Glipizide; an insulin secretagogue belonging to the sulfonylurea class, is a widely used antidiabetic drug for managing type 2 diabetes. However, the need for life-long administration and repeated doses poses challenges in maintaining optimal blood glucose levels. In this regard, orally active sustained-release nano-formulations can be a better alternative to traditional antidiabetic formulations. The present study explored an innovative approach by formulating orally active sustained-release nano-micelles using the amphiphilic lauric acid-conjugated-F127 (LAF127) block copolymer. LAF127 block copolymer was synthesized through esterification and thoroughly characterized before being employed to develop glipizide-loaded nano-micelles (GNM) via the thin-film hydration technique. The optimized formulation exhibited mean particle size of 341.40 ± 3.21 nm and depicted homogeneous particle size distribution with a polydispersity index (PDI)

[Display omitted] Soybean phospholipid was used as an amphiphilic material to form reverse micelles (RMs) in medium glycerol monolinoleate (Maisine) with Exenatide (EXT.) encapsulated in the polar core formed by the hydrophilic part of phospholipid. Cremopher RH40 and caprylocaproyl macrogol-8 glycerides EP/caprylocaproyl polyoxyl-8 glycerides NF (Labrasol) were added as surfactants to prepare reverse micelles-self emulsifying drug delivery system (RMs-SEDDS). On this basis, oil in water (O/W) emulsion was further prepared. By adding DOTAP, the surface of the emulsion was positively charged. Finally, hyaluronic acid wrapping in the outermost layer by electrostatic adsorption and reverse micelles-O/W-sodium hyaluronate (RMs-O/W-HA) nanoparticles containing Exenatide were prepared. RMs-SEDDS was spherical with an average particle size of 213.6 nm and RMs-O/W-HA was double-layered spherical nanoparticle with an average particle size of 309.2 nm. HA coating enhanced the adhesion of nanoparticles (NPs), and RMs-O/W-HA increased cellular uptake through CD44-mediated endocytosis. Pharmacodynamics results showed that RMs-SEDDS and RMs-O/W-HA could reduce blood glucose in type 2 diabetic rats, protect pancreatic β cells to a certain extent, and relieve insulin resistance and hyperlipemia complications with good safety. [ABSTRACT FROM AUTHOR]

Temozolomide (TMZ) is an oral DNA-alkylating drug used in colorectal cancer (CRC) chemotherapy. In this work, we proposed a safe and biomimetic platform for macrophages-targeted delivery of TMZ and O6-benzylguanine (O6-BG). TMZ was loaded in poly (D, l -lactide-coglycolide) (PLGA) nanoparticles, followed by sequential coating with O6-BG-grafted chitosan (BG-CS) layers and yeast shell walls (YSW) via layer-by-layer assembly (LBL) process, forming TMZ@P-BG/YSW biohybrids. Due to the yeast cell membrane-camouflage, TMZ@P-BG/YSW particles exhibited significantly enhanced colloidal stability as well as low premature drug leakage in simulated gastrointestinal conditions. In vitro drug release profiles of TMZ@P-BG/YSW particles revealed noticeable higher TMZ release in simulated tumor acidic environment within 72 h. Meanwhile, O6-BG could down-regulate MGMT expression in CT26 colon carcinoma cells, ultimately facilitating TMZ-induced tumor cell death. After oral delivery of yeast cell membrane-camouflaged particles containing fluorescent tracer (Cy5), TMZ@P-BG/YSW and bare YSW displayed high retention time of 12 h in the colon and small intestine (ileum). Correspondingly, oral gavage administration of TMZ@P-BG/YSW particles afforded favorable tumor-specific retention and superior tumor growth inhibition. Overall, TMZ@P-BG/YSW is validated to be a safe, targetable and effective formulation, paving a new avenue towards highly effective and precise treatment of malignancies. PLGA-based bioinspired platform for tumor-specific retention and enhanced colorectal cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Orally administered peptides or proteins are garnering increasing preference owing to their superiority in terms of patient compliance and convenience. However, the development of oral protein formulations has stalled due to the low bioavailability of macromolecules that encounter the aggressive gastrointestinal environment and harsh mucus villi barrier. Herein, we propose an ideal reverse micelle/self-emulsifying drug delivery system (RM/SEDDS) nanoplatform that is capable of improving the oral bioavailability of hydrophilic peptides by preventing enzymatic degradation and enhancing mucosal permeability. Upon the passage through the mucus, the self-emulsifying drug delivery system with optimal surface properties effectively penetrates the viscoelastic mucosal barrier, followed by the exposure of the inner reverse micelle amphipathic vectors, which autonomously form continua with the lipidic cell membrane and facilitate the internalization of drugs. This membrane-fusion mechanism inaugurates a new way for hydrophilic peptide delivery in the free form, circumventing the traditional impediments of the cellular internalization of nanocarriers and subsequent poor release of drugs. And more importantly, reverse micelles are not spatially specific to the laden drugs, which enables their delivery for a myriad of peptide clinical drugs. In conclusion, as an exquisitely designed nanoplatform, RM/SEDDS overcomes multiple physiological barriers and opens a new path for drug cellular entry, providing new prospects for the development of oral drug delivery systems. [ABSTRACT FROM AUTHOR]

Tablet is most popular among all dosage forms today because of its convenience, ease of administration, greater flexibility in dosage form design, ease of production, and low cost and non-invasive therapy. Formulation of tablets requires API along with excipients. Excipients include lubricants, diluents, binders, glidants, disintegrants, sweetening agents, flavoring agents, etc. Recent trends indicate that multi-particulate drug delivery systems are suitable for achieving extended-release oral formulation with a low risk of dose dumping, mixing flexibility to attain difference release patterns, and reproducible and short gastric residence time. Modern technology in immediate-release tablets, such as novel granulation techniques and electrostatic dry powder coating techniques, are prevalent nowadays. Recently, the immediate-release formulation has been similar to various sustained-release formulations that are currently readily attainable.

The oral route is the most preferred route for systemic and local drug delivery. However, the oral drug delivery system faces the harsh physiological and physicochemical environment of the gastrointestinal tract, which limits the bioavailability and targeted design of oral drug delivery system. Innovative pharmaceutical approaches including nanoparticulate formulations, biomimetic drug formulations, and microfabricated devices have been explored to optimize drug targeting and bioavailability. In this review, the anatomical factors, biochemical factors, and physiology factors that influence delivering drug via oral route are discussed and recent advance in conventional and novel oral drug delivery approaches for improving drug bioavailability and targeting ability are highlighted. We also address the challenges and opportunities of oral drug delivery systems in future. [ABSTRACT FROM AUTHOR]

As endogenous courier vesicles, exosomes play crucial roles in macromolecule transmission and intercellular communication. Therefore, exosomes have drawn increasing attention as biomimetic drug-delivery vehicles over the past few years. However, few studies have investigated the encapsulation of peptide/protein drugs into exosomes for oral administration. Additionally, the mechanisms underlying their biomimetic properties as oral delivery vehicles remain unknown. Herein, insulin-loaded milk-derived exosomes (EXO@INS) were fabricated and the in vivo hypoglycemic effect was investigated on type I diabetic rats. Surprisingly, EXO@INS (50 and 30 IU/kg) elicited a more superior and more sustained hypoglycemic effect compared with that obtained with subcutaneously injected insulin. Further mechanism studies indicated that the origin of excellent oral-performance of milk-derived exosomes combined active multi-targeting uptake, pH adaptation during gastrointestinal transit, nutrient assimilation related ERK1/2 and p38 MAPK signal pathway activation and intestinal mucus penetration. This study provides the first demonstration that multifunctional milk-derived exosomes offer solutions to many of the challenges arising from oral drug delivery and thus provide new insights into developing naturally-equipped nanovehicles for oral drug administration.

Extracellular vesicles (EVs) are biological nanoparticles with phospholipid bilayers that regulate cell communication through molecular cargo transport and surface signaling. EVs are found in almost all body fluids, including milk. In addition to the advantages of traditional EVs, such as low immunogenicity and high biocompatibility, milk EVs also have the characteristics of high yield, partially digestive resistance, oral administration and targeting the intestinal tract to regulate intestinal growth and development. Based on the above characteristics of milk EVs, we believe that milk EVs are very suitable for oral treatment of intestinal diseases. In this review, we introduced the physical and biochemical characteristics of milk EVs, the advantages of oral treatment for intestinal diseases, the potential application of milk EVs in treating such conditions. And we also discussed the problems encountered in the study of milk EVs. It provides a new direction for the treatment of intestinal diseases mediated by nanoparticles. We expect that the ongoing advancements in therapeutic and delivery nanoplatforms based on milk EVs will further support their clinical applications in the treatment of intestinal diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

This study was designed to improve oral bioavailability of the methotrexate (MTX) by sustaining its release profile and integration into core-shell polymeric nanoparticles. The self-micellization and ionotropic gelation technique was employed which resulted into spherical shaped nanoparticles (181-417 nm) with encapsulation efficiency of 80.14% to 85.54%. Furthermore, Fourier Transform Infrared Spectroscopy and Differential Scanning Calorimetry analyses were carried out to investigate physicochemical and thermal stability of the produced engineered core shell nanoparticles of the methotrexate.. Entrapment of drug in polymeric core was confirmed by X-ray diffraction analysis. In-vitro sustained release behavior of nanoparticles was observed at pH 6.8 for 48 h while low drug release was observed at pH 1.2 due to pH-responsive nature of Pluronic F127. Acute toxicity study confirmed safety and biocompatible profile of nanoparticles. MTX loaded polymeric nanoparticles ameliorated the pharmacokinetic profile (8 folds greater half-life, 6.26 folds higher AUC 0−t and 3.48 folds higher mean residence time). In vivo study conducted in rat model depicted the improved therapeutic efficacy and healing of arthritis through MTX loaded polymeric nanoparticles , preferentially attributable to high accretion of MTX in the inflamed site. In conclusion, MTX loaded polymeric nanoparticles is an attractive drug delivery strategy for an effective management and treatment of rheumatoid arthritis. [Display omitted] [ABSTRACT FROM AUTHOR]

β-Caryophyllene (BCP), a common constituent of many spice and food plants, is gaining increased attention due to recent research identifying numerous potential health benefits. Due to limited oral bioavailability observed in preclinical models, the described benefits of BCP may be maximized by using a suitable delivery system. Additionally, human pharmacokinetics (PK) remain unknown. This study evaluates the relative oral bioavailability of BCP formulated in a self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology (BCP-SEDDS) compared to BCP neat oil. Hence, a randomized, double-blind, cross-over design, single oral dose study (100 mg BCP) in 24 healthy subjects (12 men/12 women) was performed under fasting conditions. Pharmacokinetic parameters were analyzed from individual concentration-time curves. The data show that BCP-SEDDS resulted in a 2.2/2.0-fold increase in AUC0–12h/AUC0–24h and a 3.6-fold increase in Cmax compared to BCP neat oil. Moreover, BCP was absorbed faster from BCP-SEDDS (Tmax: 1.43 h) compared to BCP neat oil (Tmax: 3.07 h). Gender analysis revealed that there is no significant difference between men and women for both the investigated formulations and all investigated PK endpoints. In conclusion, BCP-SEDDS offers a well-tolerated and effective oral delivery system to significantly enhance the oral bioavailability of BCP in humans. [ABSTRACT FROM AUTHOR]

The present study was aimed towards the development of controlled release formulations of Losartan Potassium based on designed to enhance the bioavailability by prolonging its duration in the stomach via the floating dosage forms with controlled release. This study was intended to evaluate the influence of formulation variables like levels of polymer, amount of mannitol concentrations, and coating solution ratios of semi permeable membrane on the drug release from the developed formulations. Thus, there is a strong clinical need and market potential for a dosage form that will deliver Losartan Potassium in a controlled manner to a patient needing this therapy, thereby resulting in a better patient compliance. This study was designed to enhance the bioavailability of drug by prolonging its duration in the stomach via the floating dosage forms with controlled release. Floating matrix tablets of Losartan Potassium were prepared by the direct compression method, using locust bean gum and HPMC K 15M as polymers and Sodium bicarbonate as floating agent. The effect of the nature of polymers was studied by preparing various formulations of tablets. In all these formulations, a constant amount of drug (100 mg) was maintained. The blend was initially characterized for precompression and post-compression parameters. Pre-compression characterization was done for angle of repose, bulk density, tapped density, Carr's index, and Hausner's ratio. The results of precompression characterization were indicated good to excellent flow characteristics. Post-compression characterization includes thickness, hardness, friability, weight variation, drug content, buoyancy lag time, floating time and in-vitro drug release. All the results were satisfactory as per the guideline of pharmacopoeia. The in vitro drug release studies found that formulations LPFT4 showed best sustained release profile in 24 hrs. Among the nine formulations (LPFT1 to LPFT9) prepared formulations LPFT4 was found to be the best formulations in terms of sustained drug release. Drug release kinetics was performed by using various kinetic models such as Zero order, First order, Korsmeyer-Peppas and Higuchi's equation and followed supercase II transport diffusion kinetic models. [ABSTRACT FROM AUTHOR]

As endogenous courier vesicles, exosomes play crucial roles in macromolecule transmission and intercellular communication. Therefore, exosomes have drawn increasing attention as biomimetic drug-delivery vehicles over the past few years. However, few studies have investigated the encapsulation of peptide/protein drugs into exosomes for oral administration. Additionally, the mechanisms underlying their biomimetic properties as oral delivery vehicles remain unknown. Herein, insulin-loaded milk-derived exosomes (EXO@INS) were fabricated and the in vivo hypoglycemic effect was investigated on type I diabetic rats. Surprisingly, EXO@INS (50 and 30 IU/kg) elicited a more superior and more sustained hypoglycemic effect compared with that obtained with subcutaneously injected insulin. Further mechanism studies indicated that the origin of excellent oral-performance of milk-derived exosomes combined active multi-targeting uptake, pH adaptation during gastrointestinal transit, nutrient assimilation related ERK1/2 and p38 MAPK signal pathway activation and intestinal mucus penetration. This study provides the first demonstration that multifunctional milk-derived exosomes offer solutions to many of the challenges arising from oral drug delivery and thus provide new insights into developing naturally-equipped nanovehicles for oral drug administration. Insulin-loaded milk-derived exosomes overcame multiple oral drug delivery barriers in the meanwhile by different mechanisms, exerting excellent hypoglycemic effect on type I diabetic rats. [Display omitted] [ABSTRACT FROM AUTHOR]

Microsponges are at the forefront of the field of new drug delivery technology, which is rapidly evolving. Microsponge drug delivery technology holds a lot of potential in terms of reaching the aim of controlled and site-specific drug delivery, thus it’s gotten a great deal of interest from scientists. Microsponges are porous microsphere and biologically inert. Particle size of microsponges was 10- 25μm. The Quasi emulsion solvent diffusion method was used to construct microsponges. It is a unique technique for controlled release formulation.This page gives an overview of the Microsponges delivery system, including the principles and methods of preparation. Particle size and distribution, surface morphology, porosity, and density are all considered as appropriate analytical methods for characterization of Microsponges. The advantages, drawbacks, and possible responses of microsponge drug delivery are also examined. The advantages, drawbacks, and alternative solutions of microsponge drug delivery are also explored. These microsponges are included in sunscreens, balms, ointments, and over-the-counter skin care products that are designed for external use. Microsponge drug delivery can provide increased efficacy for topically active agents with enhanced safety, extended product stability and improved aesthetic properties in an efficient and novel manner. They are mostly used for topical use and have recently been used for oral administration. [ABSTRACT FROM AUTHOR]

Ze-Liang Wu,1 Jun Zhao,2 Rong Xu1,3 1Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; 2Department of Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; 3The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, People’s Republic of ChinaCorrespondence: Rong XuDepartment of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of ChinaTel/Fax +86-27-83691785Email rongxu@hust.edu.cnAbstract: Bacterial infections are the main infectious diseases and cause of death worldwide. Antibiotics are used to treat various infections ranging from minor to life-threatening ones. The dominant route to administer antibiotics is through oral delivery and subsequent gastrointestinal tract (GIT) absorption. However, the delivery efficiency is limited by many factors such as low drug solubility and/or permeability, gastrointestinal instability, and low antibacterial activity. Nanotechnology has emerged as a novel and efficient tool for targeting drug delivery, and a number of promising nanotherapeutic strategies have been widely explored to overcome these obstacles. In this review, we explore published studies to provide a comprehensive understanding of the recent progress in the area of orally deliverable nano-antibiotic formulations. The first part of this article discusses the functions and underlying mechanisms by which nanomedicines increase the oral absorption of antibiotics. The second part focuses on the classification of oral nano-antibiotics and summarizes the advantages, disadvantages and applications of nanoformulations including lipid, polymer, nanosuspension, carbon nanotubes and mesoporous silica nanoparticles in oral delivery of antibiotics. Lastly, the challenges and future perspective of oral nano-antibiotics for infection disease therapy are discussed. Overall, nanomedicines designed for oral drug delivery system have demonstrated the potential for the improvement and optimization of currently available antibiotic therapies.Keywords: bacterial infection, nanomedicine, antibiotic, oral drug delivery system

Glipizide; an insulin secretagogue belonging to the sulfonylurea class, is a widely used antidiabetic drug for managing type 2 diabetes. However, the need for life-long administration and repeated doses poses challenges in maintaining optimal blood glucose levels. In this regard, orally active sustained-release nano-formulations can be a better alternative to traditional antidiabetic formulations. The present study explored an innovative approach by formulating orally active sustained-release nano-micelles using the amphiphilic lauric acid-conjugated-F127 (LAF127) block copolymer. LAF127 block copolymer was synthesized through esterification and thoroughly characterized before being employed to develop glipizide-loaded nano-micelles (GNM) via the thin-film hydration technique. The optimized formulation exhibited mean particle size of 341.40 ± 3.21 nm and depicted homogeneous particle size distribution with a polydispersity index (PDI) < 0.2. The formulation revealed a surface charge of −17.11 ± 6.23 mV. The in vitro release studies of glipizide from developed formulation depicted a sustained release profile. Drug loaded micelles exhibited a substantial reduction in blood glucose levels in diabetic rats for a duration of up to 24 h. Notably, neither the blank nano-micelles of LAF127 nor the drug loaded micelles manifested any indications of toxicity in healthy rats. This study provides an insight on suitability of synthesized LAF127 block copolymer for development of effective oral drug delivery systems for anti-diabetic activity without any significant adverse effects. [ABSTRACT FROM AUTHOR]

The oral route of protein and peptide drugs has been a popular method of drug delivery in recent years, although it is often a challenge to achieve effective drug release and minimize the barrier functions of the gastrointestinal tract. Gastrointestinal mucosa can capture and remove harmful substances; similarly, it can limit the absorption of drugs. Many drugs are effectively captured by the mucus and rapidly removed, making it difficult to control the release of drugs in the gastrointestinal tract. The use of drug carrier systems can overcome the mucosal barrier and significantly improve bioavailability. Nanoparticle drug carriers can protect the drug from degradation, transporting it to a predetermined location in the gastrointestinal tract to achieve more efficient and sustained drug delivery. It is becoming clearer that the characteristics of nanoparticles, such as particle size, charge, and hydrophobicity, are related to permeability of the mucosal barrier. This review focuses on the latest research progress of nanoparticles to penetrate the mucosal barrier, including the delivery methods of nanoparticles on the surface of gastrointestinal mucosa, and aims to summarize how successful oral nanoparticle delivery systems can overcome this biological barrier in the human body. In addition, the in vitro model based on gastrointestinal mucus is an important tool for drug research and development. Here, we discuss different types of drug delivery systems and their advantages and disadvantages in design and potential applications. Similarly, we reviewed and summarized various methods for evaluating oral nanoparticles in in vitro and in vivo models. [ABSTRACT FROM AUTHOR]

To develop proliposome formulations to improve the oral bioavailability of l-glutathione (GSH), GSH-loaded proliposomes were prepared using the granule method. Mannitol was selected as an effective excipient to achieve the desired particle size, entrapment efficiency (EE), and solubility for oral delivery of the final formulation. To evaluate the effect of surface charge of proliposomes on the oral bioavailability of GSH, negative (F1–F4) and positive proliposomes (F5–F9) were prepared. Particle size of F1 and F5 was 167.8 ± 0.9 and 175.9 ± 2.0 nm, and zeta potential of F1 and F5 was –8.1 ± 0.7 and 21.1 ± 2.0 mV, respectively. Encapsulation efficiency of F1 and F5 was 58.6% and 54.7%, respectively. Considering their particle size, zeta potential, and EE, the proliposomes F1 and F5 were adopted as the optimal formulations for further experiments. Solid state characterization of the proliposomes confirmed lipid coating on the surface of mannitol. The release of GSH from F1 and F5 formulations was prolonged until 24 h and pH independent. The total antioxidant capacity of GSH was concentration-dependent and maintained after formulation of GSH proliposomes. Circular dichroism spectroscopy confirmed that the molecular structure of GSH was maintained in the proliposome formulations. GSH proliposomes exhibited no significant changes in particle size and zeta potential for 4 weeks. An oral bioavailability study in rats revealed that F5 exhibited 1.05-, 1.08-, and 1.11-fold higher bioavailability than F1, commercial capsule formulation, and pure GSH, respectively. In conclusion, the prepared GSH proliposomes enhanced the poor bioavailability of GSH and prolonged its duration of action.

Jiao Liu,1,* Jie Cao,1,* Jianhua Cao,2 Shangcong Han,1 Yan Liang,1 Mingfeng Bai,3 Yong Sun1 1Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, China; 2Department of Pharmacy, Qingdao No 3 Hospital, Qingdao, China; 3Department of Radiology and Radiological Sciences, Institute of Imaging Sciences, Vanderbilt University Medical Center, Nashville, TN, USA *These authors contributed equally to this work Introduction: Nanoparticles are increasingly used as drug carriers for oral administration. The delivery of drug molecules is largely dependent on the interaction of nanocarriers and gastrointestinal (GI) mucus, a critical barrier that regulates drug absorption. It is therefore important to understand the effects of physical and chemical properties of nanocarriers on the interaction with GI mucus. Unfortunately, most of the nanoparticles are unable to be prepared with satisfactory structural monodispersity to comprehensively investigate the interaction. With controlled size, shape, and surface chemistry, copolymers are ideal candidates for such purpose. Materials and methods: We synthesized a series of diblock copolymers via the atom transfer radical polymerization method and investigated the GI mucus permeability in vitro and in vivo. Results: Our results indicated that uncharged and hydrophobic copolymers exhibited enhanced GI absorption. Conclusion: These results provide insights into developing optimal nanocarriers for oral administration. Keywords: absorption barriers, oral drug delivery system, ATRP, nanoparticles

Compared with vein injection, oral administration is a preferred non-invasive and self-help treatment option for doctors and patients for cancer therapy. However, this convenient method has been severely limited by the harsh gastrointestinal tract (GI) and various biological barriers, such as the intestinal mucus/epithelial barrier and tumor matrix barrier. Those phenomena bring a huge challenge to the stability and efficiency of the oral drug delivery system that aims to improve the therapeutic effect of chemotherapy drugs. Liposomes owning good biocompatibility are able to maintain relative stability and reduce the toxic side effects of drugs. Nevertheless, liposomes still suffer from inaccurate drug release and low drug accumulation at the focus. To overcome the above problems and obtain a more efficient drug delivery platform, we screened the length of the carbon chain and introduced the disulfide bond (-S-S-) into Cerasome to prepare Cyssome. Results of our experiments prove that Cyssome owns the siliceous bodies (-Si-O-Si-) to keep them stable in the harsh environment of the gastrointestinal tract and the appropriate Young's modulus to help them penetrate the intestinal mucus/epithelial layer, as well as the thick pancreatic cancer matrix. Meanwhile, the glutathione responsive structure in Cyssome will accelerate drug release in tumor tissues which significantly improves the bioavailability of gemcitabine and reduces the related side effects. The anticancer experiments on the pancreatic cancer model in vitro and in vivo prove that Cyssome takes great potential in comprehensively improving the efficacy of oral medication for pancreatic cancer. [Display omitted] • The screened carbon chain, siliceous bodies, and disulfide network make Cyssome a promising carrier candidate. [ABSTRACT FROM AUTHOR]

Ding Qu,1,2 Mingjian Liu,1 Mengmeng Huang,1,2 Lixiang Wang,1 Yan Chen,1,2 Congyan Liu,1,2 Yuping Liu1,2 1Research Center for Multicomponent Traditional Medicine and Microecology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 2Research Center for Multicomponent Traditional Medicine and Microecology, Jiangsu Provincial Academy of Traditional Chinese Medicine, Nanjing, People’s Republic of China Abstract: A nanosized drug delivery platform with a combination of rational components and tumor targeting is significant for enhancement of anticancer therapy and reduction of side effects. In this study, we developed a octanoyl galactose ester-modified microemulsion system self-assembled by coix seed components (Gal(oct)-C-MEs), which improved the tumor accumulation through asialoglycoprotein receptor-mediated endocytosis and promoted the antitumor efficacy through multicomponent-mediated synergistic effect. Octanoyl galactose ester (Gal(oct)) with a yield of 82.3% was synthesized through a green enzymatic reaction and multidimensional characterization. Gal(oct)-C-MEs with a spherical shape had a small and uniform particle size (58.49±1.03 nm), narrow polydispersity index (0.09±0.01) and neutral surface charge (-5.82±0.57 mV). In the cellular uptake studies, the internalized Gal(oct)-C-ME was 2.28-fold higher relative to that of coix seed component-based microemulsions (C-MEs). The half-maximal inhibitory concentration of Gal(oct)-C-MEs against HepG2 cells was 46.5±2.4 µg/mL, which was notably higher than that of C-MEs. Importantly, the intratumor fluorescence of HepG2 xenograft-bearing nude mice treated with Cy5/Gal(oct)-C-MEs was 1.9-fold higher relative to treatment with Cy5/C-MEs. In the study of antitumor efficacy in vivo, HepG2 xenograft-bearing nude mice intragastrically administered Gal(oct)-C-MEs for 14 days exhibited the strongest inhibition of tumor growth and the lowest toxicity against liver and kidney among all the treatments. In summary, Gal(oct)-C-ME, as a highly effective and safe anticancer drug delivery system, showed promising potential for hepatoma therapy. Keywords: coix seed oil, coixan, multicomponent-based microemulsion, hepatic targeting, antihepatoma, oral drug delivery system

To develop proliposome formulations to improve the oral bioavailability of l-glutathione (GSH), GSH-loaded proliposomes were prepared using the granule method. Mannitol was selected as an effective excipient to achieve the desired particle size, entrapment efficiency (EE), and solubility for oral delivery of the final formulation. To evaluate the effect of surface charge of proliposomes on the oral bioavailability of GSH, negative (F1–F4) and positive proliposomes (F5–F9) were prepared. Particle size of F1 and F5 was 167.8 ± 0.9 and 175.9 ± 2.0 nm, and zeta potential of F1 and F5 was –8.1 ± 0.7 and 21.1 ± 2.0 mV, respectively. Encapsulation efficiency of F1 and F5 was 58.6% and 54.7%, respectively. Considering their particle size, zeta potential, and EE, the proliposomes F1 and F5 were adopted as the optimal formulations for further experiments. Solid state characterization of the proliposomes confirmed lipid coating on the surface of mannitol. The release of GSH from F1 and F5 formulations was prolonged until 24 h and pH independent. The total antioxidant capacity of GSH was concentration-dependent and maintained after formulation of GSH proliposomes. Circular dichroism spectroscopy confirmed that the molecular structure of GSH was maintained in the proliposome formulations. GSH proliposomes exhibited no significant changes in particle size and zeta potential for 4 weeks. An oral bioavailability study in rats revealed that F5 exhibited 1.05-, 1.08-, and 1.11-fold higher bioavailability than F1, commercial capsule formulation, and pure GSH, respectively. In conclusion, the prepared GSH proliposomes enhanced the poor bioavailability of GSH and prolonged its duration of action. [ABSTRACT FROM AUTHOR]

An appropriately designed sustained release dosage form is opted to be a major goal in solving the problems which arises regarding the targeting of a drug to a specific organ or tissue and for controlling its rate of delivery to the target site. The development of oral sustained release system has proven to be a major challenge to formulation scientist due to their inability to restrain as well as localize the system at targeted areas of the gastrointestinal tract. Therefore the development of matrix type drug delivery system is promising option regarding the development of an oral sustained release system. There is availability of wide variety of polymers which helps the formulation scientist to develop sustained/controlled release products. The attractiveness of these dosage forms is increasing because of their awareness towards toxicity and ineffectiveness when administered by oral route in the form of tablets and capsules. Numerous advantages are provided by sustained release products over conventional dosage forms through optimizing various bio-pharmaceutics, pharmacokinetic and pharmacodynamics properties of drugs and finally leads to reduction in dosing frequency to such an extent that only once daily dose is required for therapeutic management with maximum utility of drug with reduction in both local as well as systemic side effects. They can cure or control diseased condition in shortest possible time with smallest quantity of drug to assure greater patient compliance. Polymer swelling, drug dissolution and its diffusion are the known mechanisms for drug release through polymer network. [ABSTRACT FROM AUTHOR]

Each and every route of DDS has its own applications, merits and demerits depending on the characteristics of DDS and drug. The oral route of administration has wide acceptance and constitute about 50-60% of total drug formulations. Dosage forms that are administered orally, solid oral dosage forms i.e. tablets and capsules, represent the preferred class of products. Tablets being the most widely used dosage form, have number of advantages like low cost, dose adjustment, high stability, speed of manufacturing, ease of administration, patient compliance, acceptance and flexibility in formulation. While designing controlled release systems for better absorption and enhanced bioavailability, one of the difficulties is the inability to confine the dosage form to the desired area of the GIT. Recently, several technical advancements have been made. These have resulted in the development of new techniques in drug delivery. Hydrophilic matrix dosage forms essentially consist of a compressed blend of hydrophilic polymer and drug. According to the generally accepted mechanism, the drug release from hydrophilic matrix dosage forms starts when the tablet comes in contact with GI fluid. The surface of the tablet hydrates to release exposed drug and at the same time form a viscous polymer mucilage or gel. This gel fills the interstices within the tablet, retarding further ingress of liquid. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD), a phytocannabinoid compound of Cannabis sativa, shows limited oral bioavailability due to its lipophilicity and extensive first-pass metabolism. CBD is also known for its high intra- and inter-subject absorption variability in humans. To overcome these limitations a novel self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology incorporating CBD, as Hemp-Extract, was developed (SEDDS-CBD). The study objective was to evaluate the pharmacokinetic profile of SEDDS-CBD in a randomized, double-blind, cross-over design in 16 healthy volunteers under fasted conditions. As reference formulation, the same Hemp-Extract diluted with medium-chain triglycerides (MCT-CBD) was used. CBD dose was standardized to 25 mg. Pharmacokinetic parameters were analyzed from individual concentration-time curves. Single oral administration of SEDDS-CBD led to a 4.4-fold higher Cmax and a 2.85-/1.70-fold higher AUC0−8h/AUC0−24h compared to the reference formulation. Tmax was substantially shorter for SEDDS-CBD (1.0 h) compared to MCT-CBD (3.0 h). Subgroup analysis demonstrated a higher bioavailability in women compared to men. This difference was seen for MCT-CBD while SEDDS-CBD mitigated this gender effect. Overall, SEDDS-CBD showed a significant improvement for all determined pharmacokinetic parameters: increased CBD plasma values (Cmax), favorably enhanced bioavailability (AUC) and fast absorption (Tmax). No safety concerns were noted following either administration.

The primary goals in development of drug delivery systems are to protect an active therapeutic molecule from premature degradation, enhance drug efficacy and minimize side effects. Ideally, controlled release systems can meet the criteria by maintaining the drug concentration within a therapeutic window over an extended period of time, minimizing dosage and frequency of administration. The oral route for drug delivery is regarded as the optimal route for achieving therapeutic benefits & patient compliance. Despite phenomenal advances in injectable, transdermal, nasal and other routes of administration, the reality is that oral drug delivery remains preferred delivery route. This paper provide detail information about preparation and evaluation of Nanocomposite gel using biopolymer gel as drug carrier for delivery of therapeutic agents. Nanocomposite using biopolymer can overcome the major challenges associated with this route of administration: mainly poor solubility, stability and biocompatibility of drugs. Biopolymer-clay mineral hydrogel composites are expected to impart novel properties due to the plate-like shape which may also affect the mechanical properties and thermal stability. The excellent properties of the biopolymer-clay mineral composites such as easy degradation, biocompatibility and tunable mechanical properties are essential for controlled drug delivery. [ABSTRACT FROM AUTHOR]

In the drug delivery area, versatile therapeutic systems intended to yield customized combinations of drugs, drug doses and release kinetics have drawn increasing attention, especially because of the advantages that personalized pharmaceutical treatments would offer. In this respect, a previously proposed capsular device able to control the release performance based on its design and composition, which could extemporaneously be filled, was improved to include multiple separate compartments so that differing active ingredients or formulations may be conveyed. The compartments, which may differ in thickness and composition, resulted from assembly of two hollow halves through a joint also acting as a partition. The systems were manufactured by fused deposition modeling (FDM) 3D printing, which holds special potential for product personalization, and injection molding (IM) that would enable production on a larger scale. Through combination of compartments having wall thickness of 600 or 1200 μm, composed of promptly soluble, swellable/erodible or enteric soluble polymers, devices showing two-pulse release patterns, consistent with the nature of the starting materials, were obtained. Systems fabricated using the two techniques exhibited comparable performance, thus proving the prototyping ability of FDM versus IM. [ABSTRACT FROM AUTHOR]

Background: The production of protein drugs has recently increased due to advances in biotechnology, but their clinical use is generally limited to parenteral administration due to low absorption in non-parenteral administration. Therefore, non-parenteral delivery systems allowing sufficient absorption draw much attention. Methods: Microparticles (MP) were prepared using chitosan-4-thio-butylamidine conjugate (Ch-TBA), trimethyl-chitosan (TMC), and chitosan (Ch). Using salmon calcitonin (sCT) as a model protein drug, Ch-TBA-, Ch-TBA/TMC (4/1)-, and Ch-based MP were produced, and their Eudragit L100 (Eud)-coated MP, named Ch-TBA-MP/Eud, Ch-TBA/TMC-MP/Eud, and Ch-MP/Eud, respectively, were prepared as oral delivery systems. These enteric-coated microparticles were examined in vitro and in vivo. Results: All microparticles before and after enteric coating had a submicron size (600-800 nm) and micrometer size (1300-1500 nm), respectively. In vitro release patterns were similar among all microparticles; release occurred gradually, and the release rate was slower at pH 1.2 than at pH 6.8. In oral ingestion, Ch-TBA-MP/Eud suppressed plasma Ca levels most effectively among the microparticles tested. The relative effectiveness of Ch-TBA-MP/Eud to the intramuscular injection was 8.6%, while the sCT solution showed no effectiveness. Conclusion: The results suggest that Eud-coated Ch-TBA-based microparticles should have potential as an oral delivery system of protein drugs. [ABSTRACT FROM AUTHOR]

Whey protein is a natural polymer recently used as an excipient in buccoadhesive tablets but its mucoadhesive properties were barely studied. In this work, we characterize mucoadhesion of whey protein in order to determine the mechanisms and optimal conditions for use as excipient in oral drug delivery. Thus, native and denatured whey protein (NWP and DWP) were investigated and the effect of concentration and pH were also studied. Many methods of characterization were selected to allow the study of chemical and physical interactions with mucin and then the results were bound with an ex vivo experiments. Turbidity of WP–mucin mixture increased at acidic pH 1.2 till 4.5 indicating interaction with mucin but not at pH 6.8. No interaction with mucin was also found by ITC method at pH 6.8 for native and denatured whey protein used at 1% (w/w). Forces of bioadhesion evaluated by viscosity measurements were the best for high concentrated (10.8%) DWP solutions at pH 6.8 and were low at pH 1.2 for NWP and DWP solutions. Addition of chemical blockers indicated that hydrogen bondings and disulfide bridges were the main mechanisms of interactions with mucin. Reticulation of DWP with calcium ions to obtain microparticles (MP) did not influence the ability of interaction with mucin as shown by FTIR analysis. These results correlated with ex vivo study on rat tissue demonstrating important adhesion (75%) of WP MP on the intestine and null on the stomach after 2 h of deposit. [ABSTRACT FROM AUTHOR]

Highlights: [•] Original starch-based microspheres were developed for controlled delivery of the antitumor drug curcumin. [•] The fraction released of curcumin is dependent on pH. [•] The release mechanism was found to be governed by anomalous transport. [•] Curcumin-loaded microspheres showed higher toxicity toward Caco-2 and HCT-116 tumor cell lines than free curcumin. [•] Starch-based microspheres have prospective to be efficient delivery device for curcumin in the treatment of colon cancer. [ABSTRACT FROM AUTHOR]

The oral route for delivery of pharmaceuticals is widely used and accepted. However, many biological therapeutics that have poor solubility, poor permeability, and/or poor stability in the gastrointestinal environment have poor oral bioavailability and are therefore rarely used for oral drug delivery. In recent years, nanocarriers are widely used, which can provide an alternative solution for oral administration of these drugs. In this article, several nanocarriers (nanoparticles, micelles, liposomes, nanocrystals, carbon nanotubes, nanoemulsions, dendrimers, and nanospheres) for drug delivery systems have been designed based on different nanomaterials for oral drug delivery. [ABSTRACT FROM AUTHOR]

Abstract: A novel liquefied gas based drug delivery system for the oral delivery of liquid and semi-solid drug formulations is presented. The capsule-shaped system is equipped with a capillary as an element controlling the release rate. The delivery mechanism is based on a constant vapor pressure produced by isopentane as a low-boiling liquefied gas. The liquid drug valproic acid (VA) was used as a model compound. The viscosity was increased by the addition of povidone (PVP). The VA–PVP gel exhibited pseudoplastic rheological properties, the shear rate was above 0.1s−1, similar to a Newtonian liquid. The gels tested in the gas based delivery system provided near-zero-order release kinetics. The longest delivery time was up to ca. 8h. The system is characterized by high flexibility of the delivery rate, which can be achieved by adjusting system parameters such as the diameter and length of the capillary, the vapor pressure of the propellant and the viscosity of the drug formulation. [Copyright &y& Elsevier]

The aim of this study was to prepare a biocompatible and biodegradable nanoparticulate drug delivery system to increase the efficiency and bioavailability of oral drugs. Chitosan nanoparticles containing salicylic acid (SA) were prepared by emulsion method. The morphology of nanoparticles was characterized by scanning electron microscopy (SEM). Particle size distribution was examined by laser light scattering. The drug released and drug content was examined by UVspectroscopy. The effects of different initial drug loading on the drug content and drug released were investigated. The nanoparticles were spherical and the average size of them was 300 nm, the drug content was in the range of 20-35%. All the nanoparticles had a burst release initially and the burst release behavior of them conformed best to higuchi model. The release of SA from chitosan nanoparticles was Fickian. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we demonstrated that the CSKSSDYQC-peptide ligand which was identified from a random phage-peptide library through an in vivo phage display technique with rats could prominently improve the transport efficiency of macromolecules, such as large filamentous phage particles (M13 bacteriophage), across the intestinal mucosal barrier. Synthetic CSKSSDYQC-peptide ligands significantly inhibited the binding of phage P1 encoding CSKSSDYQC-peptide ligands to the intestinal mucosal tissue and immunohistochemical analysis showed that the CSKSSDYQC-peptide ligands could be transported across the intestinal mucosal barrier via goblet cells as their specific gateway. Thus, we inferred that CSKSSDYQC-peptide ligand might have a specific receptor on the goblet cells and transported from intestinal lumen to systemic circulation by transcytosis mechanism. These results suggest that CSKSSDYQC-ligand could be a promising tool for development of an efficient oral delivery system for macromolecular therapeutics in the carrier-drug conjugate strategy. [Copyright &y& Elsevier]

Peptides, although high efficacy and specificity in their physiological function, usually have low therapeutical activities due to their poor bioavailability when administrated orally. Nanoparticles have been regarded as a useful vector for targeted drug delivery system because they can protect drug from being degraded quickly and pass the gastrointestinal barriers. Here we described a novel oral N-trimethyl chitosan nanoparticles formulation containing thymopentin (Tp5-TMC-NP). N-trimethyl chitosan (TMC) was synthesized and then used to prepare Tp5-TMC-NP by ionotropic gelation. A three-factor, five-level CCD (Central Composite Design) design was used in the optimization procedure, with HPLC as the analyzing method. The resulting Tp5-TMC-NP had a regular spherical surface and a narrow particle size range with a mean diameter of 110.6 nm. The average entrapment efficiency was 78.8%. The lyophilized Tp5-TMC-NP formulation was stable in 4°C or −20°C after storage of 3 months without obvious changes in morphology, particle size, pH and entrapment ratio. The results of the flow cytometer determination showed that the ratio of CD4+/CD8+ of Wistar female rat given Tp5-TMC-NP (ig) was 2.59 time that of the group give Tp5 (ig). [ABSTRACT FROM AUTHOR]

Currently, delayed/pulsatile release and colon delivery represent topics of remarkable interest. The present paper deals with the study and development of an oral dosage form devised to release drugs following a programmed time period after administration or, when opportune design modifications are introduced, to target the colon. The system is composed of a drug-containing core and a hydrophilic swellable polymeric coating capable of delaying drug release through slow interaction with aqueous fluids. An optional external gastroresistant film is applied to overcome gastric emptying variability, thus allowing colon delivery to be pursued according to the time-dependent approach. The aim of this work was to evaluate different hydroxypropyl methylcellulose (HPMC) viscosity grades as possible materials for the attainment of the system retarding hydrophilic layer. Both the relevant suitability for application onto tablet cores by aqueous spray-coating in fluid bed and capability of delaying drug release for a programmable period were explored and compared. Methocel® E50 was found to afford the best balance among different important items, i.e. process time, retarding ability, dimensions of the coated units and possibility of finely tuning the delay duration. Further results pointed out the robustness of Methocel® E50-based systems, which have shown to be practically unaffected by the concentration of the employed coating solution and the pH of the release medium, as well as only poorly influenced by ionic strength, at least with regard to values encompassed in the physiological range for gastrointestinal fluids. [Copyright &y& Elsevier]

In order to develop a controlled-release oral drug delivery system (DDS) which sustains the plasma acetaminophen (AAP) concentration for a certain period of time, microporous membrane-coated tablets were prepared and evaluated in vitro. Firstly, highly water-soluble core tablets of AAP were prepared with various formulations by wet granulation and compression technique. Then the core tablets were coated with polyvinylchloride (PVC) in which micronized sucrose particles were dispersed. Effect of formula compositions of core tablets and coating suspensions on the pharmaceutical characteristics such as drug release kinetics and membrane stability of the coated tablets was investigated in vitro. AAP was released from the coated tablets at a zero-order rate in a pH-independent manner. This independency of AAP release to pH change from 1.2 to 7.2 is favorable for the controlled oral drug delivery, since it will produce a constant drug release in the stomach and intestine regardless of the pH change in the GI tract. Drug release could be extended upto 10 h according to the coating condition. The release rate could be controlled by changing the formula compositions of the core tablets and coating suspensions, coat weight per each tablet, and especially PVC/sucrose ratio and particle size of the sucrose in the coating suspension. The coated tablets prepared in this study had a fairly good pharmaceutical characteristics in vitro, however, overall evaluation of the coated tablets should await in vivo absorption study in man. [ABSTRACT FROM AUTHOR]

[Display omitted] • pH-/thermo-responsive hydrogels were prepared using PAA, CsNb, and bisTz-PNIPAM. • Porous structure formed by Tz-Nb reaction greatly increased the drug loading content. • Hydrogels released a much higher amount of drug at pH 7.4 than at pH 2.2. • The drug release from hydrogels was enhanced at 37 °C via "shrinkage" of PNIPAM. A dual pH-/thermo-responsive hydrogel was designed based on a polyelectrolyte complex of polyacrylic acid (PAA) and norbornene-functionalized chitosan (CsNb), which was synergized with chemical crosslinking using bistetrazine-poly(N-isopropyl acrylamide) (bisTz-PNIPAM). The thermo-responsive polymeric crosslinker, bisTz-PNIPAM, was synthesized via reversible addition–fragmentation transfer polymerization of NIPAM. FTIR, XRD, rheological and morphological analyses demonstrated the successful formation of the polyelectrolyte network. The highly porous structure generated through the in-situ "click" reaction between Tz and Nb resulted in a higher drug loading (29.35 %). The hydrogel (COOH/NH 2 mole ratio of 3:1) exhibited limited drug release (8.5 %) of 5-ASA at a pH of 2.2, but it provided an almost complete release (92 %) at pH 7.4 and 37 °C within 48 h due to the pH responsiveness of PAA, hydrogel porosity, and shrinkage behavior of PNIPAM. The hydrogels were biodegradable and non-toxic against human fibroblast cells, suggesting their considerable potential for a colon-targeted drug delivery system. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD), a phytocannabinoid compound of Cannabis sativa, shows limited oral bioavailability due to its lipophilicity and extensive first-pass metabolism. CBD is also known for its high intra- and inter-subject absorption variability in humans. To overcome these limitations a novel self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology incorporating CBD, as Hemp-Extract, was developed (SEDDS-CBD). The study objective was to evaluate the pharmacokinetic profile of SEDDS-CBD in a randomized, double-blind, cross-over design in 16 healthy volunteers under fasted conditions. As reference formulation, the same Hemp-Extract diluted with medium-chain triglycerides (MCT-CBD) was used. CBD dose was standardized to 25 mg. Pharmacokinetic parameters were analyzed from individual concentration-time curves. Single oral administration of SEDDS-CBD led to a 4.4-fold higher Cmax and a 2.85-/1.70-fold higher AUC0–8h/AUC0–24h compared to the reference formulation. Tmax was substantially shorter for SEDDS-CBD (1.0 h) compared to MCT-CBD (3.0 h). Subgroup analysis demonstrated a higher bioavailability in women compared to men. This difference was seen for MCT-CBD while SEDDS-CBD mitigated this gender effect. Overall, SEDDS-CBD showed a significant improvement for all determined pharmacokinetic parameters: increased CBD plasma values (Cmax), favorably enhanced bioavailability (AUC) and fast absorption (Tmax). No safety concerns were noted following either administration. [ABSTRACT FROM AUTHOR]