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Background/Objectives: For several decades, protein drugs (biologics) made in cell cultures have been delivered as sterile injections, decreasing their affordability and patient preference. Angiotensin Converting Enzyme 2 (ACE2) gum is the first engineered human blood protein expressed in plant cells approved by the FDA without the need for purification and is a cold-chain and noninvasive drug delivery. This biologic is currently being evaluated in human clinical studies to debulk SARS-CoV-2 in the oral cavity to reduce coronavirus infection/transmission (NCT 0543318). Methods: Chemistry, manufacturing, and control (CMC) studies for the ACE2/Ang(1–7) drug substances (DSs) and ACE2 gum drug product (DP) were conducted following USP guidelines. GLP-compliant toxicology studies were conducted on Sprague Dawley rats (n = 120; 15/sex/group) in four groups—placebo, low (1.6/1.0 mg), medium (3.2/2.0 mg), and high (8.3/5.0 mg) doses IP/kg/day. Oral gavage was performed twice daily for 14 days (the dosing phase) followed by the recovery phase (35 days). Plasma samples (n = 216) were analyzed for the product Ang(1–7) by ELISA. Results: The ACE2 protein was stable in the gum for at least up to 78 weeks. The toxicology study revealed the dose-related drug delivery to the plasma and increases in the AUC (56.6%) and Cmax (52.9%) after 28 high-dose gavages (95% C.I.), although this quantitation excludes exogenously delivered membrane-associated ACE2/Ang(1–7). Vital biomarkers and organs were not adversely affected despite the 10-fold higher absorption in the tissues, demonstrating the safety for the first in-human clinical trials of ACE2/Ang(1–7). The NOAEL observed in the rats was 2.5–7.5-fold higher than that of the anticipated efficacious therapeutic dose in humans for the treatment of cardiopulmonary disorders, and it was 314-fold higher than the NOAEL for topical delivery via chewing gum. Conclusions: This report lays the foundation for the regulatory process approval for noninvasive and affordable human biologic drugs bioencapsulated in plant cells. [ABSTRACT FROM AUTHOR]

[Display omitted] To evaluate the impact of the surface decoration of cannabidiol (CBD) loaded self-emulsifying drug delivery systems (SEDDS) on the efficacy of the formulations to cross the various barriers faced by orally administered drugs. Polyethylene glycol (PEG)-free polyglycerol (PG)-based SEDDS, mixed zwitterionic phosphatidyl choline (PC)/PEG-containing SEDDS and PEG-based SEDDS were compared regarding stability against lipid degrading enzymes, surface properties, permeation across porcine mucus, cellular uptake and cytocompatibility. SEDDS with a size of about 200 nm with narrow size distributions were developed and loaded with 20–21 % of CBD. For PG containing PEG-free SEDDS increased degradation by lipid degrading enzymes was observed compared to PEG-containing formulations. The surface hydrophobicity of placebo SEDDS increased in the order of PG-based to mixed PC/PEG-based to PEG-based SEDDS. The influence of this surface hydrophobicity was also observed on the ability of the SEDDS to cross the mucus gel layer where highest mucus permeation was achieved for most hydrophobic PEG-based SEDDS. Highest cellular internalization was observed for PEG-based Lumogen Yellow (LY) loaded SEDDS with 92 % in Caco-2 cells compared to only 30 % for mixed PC/PEG-based SEDDS and 1 % for PG-based SEDDS, leading to a 100-fold improvement in cellular uptake for SEDDS having highest surface hydrophobicity. For cytocompatibility all developed placebo SEDDS showed similar results with a cell survival of above 75 % for concentrations below 0.05 % on Caco-2 cells. Higher surface hydrophobicity of SEDDS to orally deliver lipophilic drugs as CBD seems to be a promising approach to increase the intracellular drug concentration by an enhanced permeation through the mucus layer and cellular internalization. [ABSTRACT FROM AUTHOR]

AbstractImplementing therapeutic deep eutectic systems (THDESs) in various drug delivery systems (DDSs) has expanded enormously. THDESs offer eco-friendly alternatives to conventional organic solvents, featuring adaptable and simple preparation methods with high-yield products. Previously, the solubility of risperidone (RISP) was immensely enhanced by forming a hydrophobic THDES of RISP with capric acid (CA). To build upon the previous findings and utilize the hydrophobic properties of THDES, a self-emulsifying drug delivery system (SEDDS) was developed. A stable SEDDS formulation was successfully developed using the THDES as the nonpolar phase, a nonionic surfactant, Tween 20, and a co-surfactant, PEG 400. By employing a pseudo-ternary phase diagram, the ideal ratio of Tween 20 to PEG 400 was determined to be 3:1. The developed SEDDS demonstrated robust stability in thermal stability tests, dispersity evaluations, and dilution tests, exhibiting no instances of phase separation or precipitation. Gratifyingly, the in vitro dissolution of RISP through the developed SEDDS showed a higher release by 3-fold after 5 min and achieved 90% release within 2 hours. More interestingly, the plasma profile of RISP and the SEDDS were compared in rats, which revealed an improved drug bioavailability, as indicated by the attained higher AUC0–∞ (3907.06 versus 3426.28 h µg/ml) and a significantly higher Cmax (68.97 versus 50.35 µg/ml) with the SEDDS formulation when compared to RISP. [ABSTRACT FROM AUTHOR]

A casein-methyl cellulose nanocomplex, loaded with curcumin and coated with dextran (DX-CasCur-MC), is designed to enhance curcumin's oral delivery and inhibit cancer growth. Its physicochemical properties reveal chemical bonding between protein and polysaccharides, transforming curcumin from crystalline into amorphous state to improve water solubility. The encapsulation efficiency of curcumin reaches 92%, and its release profile in physiological and tumor microenvironments exhibits controlled and sustained release. In vitro studies confirm the significant therapeutic efficacy of DX-CasCur-MC in inducing cancer cell death and DNA damage compared to free curcumin. The effectiveness of DX-CasCur-MC for oral drug delivery is validated in simulated gastrointestinal fluids, with 23 and 69% release in gastric and intestinal fluids, respectively. In vivo studies demonstrate a significant reduction in tumor volume in mice treated with DX-CasCur-MC compared to those treated with free curcumin or untreated, confirming DX-CasCur-MC's ability to improve curcumin's pharmacological properties and inhibit tumor growth via repeated oral administration. The conjugation of the two polysaccharides with the hydrocolloidal casein nanomicelles improves the nanocomplexes stability, making DX-CasCur-MC a promising natural candidate for oral curcumin delivery with a significant cancer therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Giredestrant (GDC-9545) is a selective estrogen receptor degrader (SERD) that was developed for treatment of ER+/HER2− metastatic breast cancer. An anhydrous crystalline tartrate salt was identified as the solid form suitable for clinical development. An early clinical batch of the active pharmaceutical ingredient (API)/drug substance failed to pass the GMP purity specifications owing to the presence of a substantial amount of high molecular weight impurities (oligomers), as determined by size exclusion chromatography. Several trial rework batches were manufactured using various re-slurry and recrystallization conditions to purge impurities in the drug substance to adhere to purity specifications. Based on the melting point depression of the API in presence of oligomers in these rework batches, a differential scanning calorimetry method was developed to quantify impurity content as a function of melting point onset of the API. This thermal analysis method was used as a surrogate for chromatography as a rapid, effective in-process check method for impurity quantitation to enable the timely release of the final reworked clinical batch. Post release, the % w/w oligomer value determined by calorimetry was in excellent agreement to that obtained by size exclusion chromatography. [ABSTRACT FROM AUTHOR]

For the delivery of the drug, the oral route is the most preferable due to ease of administration. However, the effective delivery of poorly aqueous soluble drugs is very challenging for the pharmaceutical scientist which leads to a low drug permeation profile across the biological membrane, poor drug bioavailability, and ultimately low therapeutic profile with less patient comfort. The inclusion of a therapeutic agent into the nanostructured-based lipid carrier can improve the limitation associated with the poorly soluble drug and it includes better drug therapeutic, pharmacokinetic profile, and controlled drug release up to a longer duration of time which causes patient compliance. Nanostructure lipid carriers (NLCs) are nanosized-based carrier systems which comprise solid lipid matrix combined with liquid lipids and surfactants. The aim of the paper is to explore the various advantages of formulation technology along with the characterization parameter of the NLCs and also report the clinical finding of the investigated NLCs for oral drug delivery system. This paper also highlighted the various patents on the NLCs. [ABSTRACT FROM AUTHOR]

The oral delivery of most atypical antipsychotics is severely challenged by their low oral bioavailability and significant food effects that necessitate patient compliance. Lipid formulations are an attractive delivery system for overcoming the dosing challenges of antipsychotics, but their negative impact on the gut microbiota can interfere with the pharmacodynamic response through disruption of the gut‐brain axis. Here, novel gut microbiota‐targeting microcapsules are engineered to provide a multifunctional approach for improving both the pharmacokinetic and pharmacodynamic properties of the antipsychotic, lurasidone. The microcapsules are comprised of a lipid core that facilitates the solubilization and oral absorption of the lipophilic drug and an outer carbohydrate polymer (inulin) shell that positively modulates the gut microbiota by facilitating microbial fermentation. Fed‐fasted variability in lurasidone solubilization is mitigated through microencapsulation with inulin‐lipid microcapsules (ILM), while microbiota enrichment is coupled with enhanced serotonin levels in the small intestine, faeces, and plasma. The realization of multifunctional ILM confirms the pharmacokinetics and efficacy of mental health therapies, such as antipsychotics, can be optimized through strategic encapsulation within functional formulations that target the gut microbiota for effective modulation of the gut‐brain axis. [ABSTRACT FROM AUTHOR]

This study focuses on the preparation and evaluation of famotidine-loaded solid lipid nanoparticles (SLNs) for enhancing oral drug delivery. Famotidine, a commonly used H2 receptor antagonist for treating gastric acid-related conditions, faces challenges in oral administration due to its poor aqueous solubility and low bioavailability. To address these limitations, SLNs were formulated using a solvent emulsification-evaporation method, employing biocompatible lipids to encapsulate the drug and improve its absorption. The prepared SLNs were characterized for particle size, zeta potential, drug loading efficiency, and encapsulation efficiency. Results showed that the SLNs had an average particle size of 150 nm, a zeta potential of -25 mV, and a high drug encapsulation efficiency of 90%, ensuring stability and effective drug loading. Morphological analysis confirmed spherical nanoparticles with a smooth surface, supporting the uniformity of the formulation. In vitro release studies demonstrated a sustained drug release profile, with 60% of famotidine being released over a prolonged period, highlighting the potential of SLNs in maintaining therapeutic drug levels. Furthermore, pharmacokinetic evaluations indicated that the bioavailability of famotidine was significantly enhanced when delivered via SLNs compared to the free drug. These findings suggest that famotidine-loaded SLNs could be a promising approach for overcoming the limitations of oral famotidine delivery, offering improved bioavailability, stability, and controlled release, which could lead to better therapeutic outcomes in clinical settings. [ABSTRACT FROM AUTHOR]

The oral route stands out as the most commonly used method for drug administration, prized for its non-invasive nature, patient compliance, and easy administration. Several elements influence the absorption of oral medications, including their solubility, permeability across mucosal membranes, and stability within the gastrointestinal (GI) environment. Research has delved into comprehending physicochemical, biochemical, metabolic, and biological obstacles that impact the bioavailability of a drug. To improve oral drug absorption, several pharmaceutical technologies and delivery methods have been studied, including cyclodextrins, micelles, nanocarriers, and lipid-based carriers. This review examines both traditional and innovative drug delivery methods, as well as the physiological and pharmacological barriers influencing medication bioavailability when taken orally. Additionally, it describes the challenges and advancements in developing formulations suitable for oral use. This graphical abstract summarizes the key elements of oral drug delivery systems. It depicts the human digestive system, highlighting the journey of orally administered drugs. The illustration focuses on different drug molecules, including nucleic acids, proteins, peptides, and small molecular drugs, and their delivery through platforms such as liposomes, hydrogels, bacteria, algae, and microneedles. It also identifies target regions in the gastrointestinal tract—stomach, small intestine, and colon—while emphasizing the physiological barriers that affect drug absorption, such as cellular permeability, digestive enzymes, and luminal pH variations. [ABSTRACT FROM AUTHOR]

Introduction and purpose: Despite the attractive properties of hyaluronic acid (HA), The preparation of HA beads is still challenging. This article reports the preparation of pH-sensitive gel HA beads. The ionic gelation method was used to prepare the HA gel beads using ferric ions. This cross-linking type is based on forming coordination bonds, which enhance the mechanical properties of the prepared beads. Methods: The developed beads were characterized using Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). Scanning electron microscopy (SEM) examined the bead's morphology. Furthermore, the potential of HA gel beads as an oral drug delivery system was investigated using metformin as a hydrophilic model drug. The entrapment efficiency and in vitro, release, and release kinetics were evaluated. The crosslinking density and HA concentration effect on drug release and bead swelling capacity under pH 1.2 and 7.4 were also investigated. Results: The entrapment efficiency of metformin in HA beads was found to be 79.56 ± 3.89%. FTIR analysis indicated the ionic interaction between ferric ions and the carboxylic groups on the HA molecule. At the same time, there was no substantial interaction between metformin and the polymeric bead. Morphological evaluation and DSC analysis suggested the successful incorporation of metformin within the beads. The in vitro drug release evaluation showed pH-dependent extended release where the release kinetics followed the first-order mathematical model. Conclusions: This study provides a value-added formulation with the potential for drug delivery use, which can be further investigated for biomedical applications. [ABSTRACT FROM AUTHOR]

Additive manufacturing of pharmaceutical formulations offers advanced micro-structure control of oral solid dose (OSD) forms targeting not only customised dosing of an active pharmaceutical ingredient (API) but also custom-made drug release profiles. Traditionally, material extrusion 3D printing manufacturing was performed in a two-step manufacturing process via an intermediate feedstock filament. This process was often limited in the material space due to unsuitable (brittle) material properties, which required additional time to develop complex formulations to overcome. The objective of this study was to develop an additive manufacturing MicroFactory process to produce an immediate release (IR) OSD form containing 250 mg of mefenamic acid (MFA) with consistent drug release. In this study, we present a single-step additive manufacturing process employing a novel, filament-free melt extrusion 3D printer, the MicroFactory, to successfully print a previously 'non-printable' brittle Soluplus®-based formulation of MFA, resulting in targeted IR dissolution profiles. The physico-chemical properties of 3D printed MFA-Soluplus®-D-sorbitol formulation was characterised by thermal analysis, Fourier Transform Infrared spectroscopy (FTIR), and X-ray Diffraction Powder (XRPD) analysis, confirming the crystalline state of mefenamic acid as polymorphic form I. Oscillatory temperature and frequency rheology sweeps were related to the processability of the formulation in the MicroFactory. 3D printed, micro-structure controlled, OSDs showed good uniformity of mass and content and exhibited an IR profile with good consistency. Fitting a mathematical model to the dissolution data correlated rate parameters and release exponents with tablet porosity. This study illustrates how additive manufacturing via melt extrusion using this MicroFactory not only streamlines the manufacturing process (one-step vs. two-step) but also enables the processing of (brittle) pharmaceutical immediate-release polymers/polymer formulations, improving and facilitating targeted in vitro drug dissolution profiles. [ABSTRACT FROM AUTHOR]

The antiparasitic drug ivermectin is approved for persons > 15 kg in the US and EU. A pharmacometric (PMX) population model with clinical PK data was developed (i) to characterize the effect of the patient-friendly ivermectin formulation CHILD-IVITAB on the absorption process and (ii) to evaluate dosing for studies in children < 15 kg. Simulations were performed to identify dosing with CHILD-IVITAB associated with similar exposure coverage in children ≥ 15 kg and < 15 kg as observed in adults receiving the reference formulation STROMECTOL®. A total of 448 ivermectin concentrations were available from 16 healthy adults. The absorption rate constant was 2.41 h−1 (CV 19%) for CHILD-IVITAB vs. 1.56 h−1 (CV 43%) for STROMECTOL®. Simulations indicated that 250 µg/kg of CHILD-IVITAB is associated with exposure coverage in children < 15 kg consistent with that observed in children ≥ 15 kg and adults receiving 200 µg/kg of STROMECTOL®. Performed analysis confirmed that CHILD-IVITAB is associated with faster and more controlled absorption than STROMECTOL®. Simulations indicate that 250 µg/kg of CHILD-IVITAB achieves equivalent ivermectin exposure coverage in children < 15 kg as seen in children ≥ 15 kg and adults. [ABSTRACT FROM AUTHOR]

Sleep disorders, particularly insomnia, are a prevalent issue, often requiring pharmacological intervention. Zaleplon (ZLN), a Biopharmaceutical Class System (BCS) Class II drug with low solubility, is a notable candidate for such treatment. The challenges in drug solubility and bioavailability prompted the exploration of nanocarrier-based delivery systems, such as mesoporous silica nanoparticles (MSNs) and, specifically, mobil crystalline materials (MCM)-41 MSNs. This study investigated the in vivo bioavailability enhancement of the hypnotic drug, zaleplon, through MSNs. Mobil crystalline material (MCM)-41 MSNs were formulated. MCM-41 MSN in vitro and in vivo characterization studies were performed. The ZLN-loaded MCM-41 MSNs were fabricated using a modified sol–gel method at room temperature. Various techniques were employed for drug loading, including a solvent removal method, with MSNs. The resulting zaleplon-loaded MCM-41 MSNs were characterized using the powder X-ray diffraction study, particle size analysis along with zeta potential, scanning electron microscopy, BET surface area analysis, in vitro drug release study, and transmission electron microscopy. In vivo studies were conducted to assess their drug bioavailability and therapeutic efficacy. The results indicated that ZLN-loaded MCM-41 MSNs effectively enhanced the solubility and bioavailability of ZLN. The zaleplon-loaded MCM-41 MSNs exhibited a particle size of 459 nm and a PDI of 0.24. In vitro studies demonstrated the impact of the drug loading method on drug release, with the solvent removal method exhibiting the highest percentage of cumulative drug release (%CDR). The in vivo experiments provided evidence supporting the twice enhancement of bioavailability of ZLN-loaded MCM-41 MSNs in comparison to the pure drug. The findings of this study highlight the potential of MCM-41 MSNs as a promising platform for oral drug delivery, particularly for drugs with solubility and bioavailability challenges. Furthermore, the study underscored the safety and efficacy of MCM-41 mesoporous silica nanoparticles (MSNs), emphasizing their significance in advancing drug administration and enhancement of patient well-being. This research contributes to addressing the unmet needs in the treatment of sleep disorders and provides insights into novel drug delivery strategies. [ABSTRACT FROM AUTHOR]

In this study, a novel oral formulation of berberine hydrochloride (BBH) hydrogel was successfully synthesized through physical cross-linking using chitosan (CS) and carboxymethyl-β-cyclodextrin (CMCD). The characterization results confirmed the successful synthesis of the CS/CMCD hydrogel and the subsequent loading of BBH into this composite (CS/CMCD/BBH) was effectively accomplished. The BBH was used as a model drug and the resulting hydrogel demonstrated a sustained drug release profile. In addition to its improved solubility and sustained release characteristics, the hydrogel exhibited excellent antibacterial activity against common pathogens such as Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Candida albicans (C. albicans). Additionally, in vitro studies indicated that the hydrogel was not cytotoxic to NIH3T3 and HaCaT cells, suggesting its safety for biomedical applications. This lack of cytotoxic effects, combined with the mechanical strength, solubility improvements, and antibacterial properties of the hydrogel, positions the CS/CMCD/BBH hydrogel as a promising candidate for the effective oral delivery of BBH. By addressing the solubility and delivery challenges of BBH, this hydrogel offers a viable solution for the oral administration of BBH, with potential applications in various biomedical fields. [ABSTRACT FROM AUTHOR]

Considering the predominantly milk-based diet of neonates and infants and their immature gastrointestinal digestion, milk proteins may affect drug behaviour and absorption in this population. Using in vitro models, this study investigated the impact of the representative milk proteins, whey and casein, on the solubility and permeation of the lipophilic model drugs spironolactone, clopidogrel and ritonavir. Drug solubility experiments revealed that the presence of milk proteins increased drug solubility. Next, permeation studies demonstrated that the same milk proteins reduced drug permeation across an artificial membrane. These results highlight the importance of the solubility-permeability interplay and indicate the effect of these proteins may be considered during (paediatric) drug development. Lastly, the findings underscore the importance of considering milk protein-drug interactions to optimize drug delivery strategies during (paediatric) drug development and especially for the youngest and most vulnerable part of this population.

Background: Losartan potassium, an antihypertensive medication, has high solubility and a short half-life that result in potential adverse effects and rapid drug clearance. Multiparticulate drug delivery systems enhance the drug’s bioavailability, decrease patient-to-patient variability, and optimize drug distribution. Herein, losartan potassium pellets for sustained drug release were developed and characterized. Methods: The formulation process involved varying the concentrations of Eudragit RSPO (200 mg, 400 mg, or 600 mg) and Eudragit L100 (200 mg, 400 mg, or 600 mg) across nine pellet batches, and adjusting the triethyl citrate concentrations accordingly. The pellets’ bulk density, tapped density, flow properties (Carr’s index, Hausner’s ratio, and angle of repose), drug content, particle size distribution, and in vitro drug release were evaluated. Interactions between losartan potassium and the excipients were analyzed with FTIR and DSC. Results: FTIR spectra indicated physical interactions without major chemical alterations, whereas DSC thermograms revealed changes in thermal behavior due to excipient interactions. In vitro drug release studies indicated that formulations with higher concentrations of Eudragit RSPO and triethyl citrate achieved controlled, prolonged drug release. The optimized batch (F7) demonstrated balanced characteristics including favorable bulk and tapped density, good flow properties, and a sustained release profile. Varying the polymer and plasticizer concentrations significantly influenced pellet performance, and F7 was found to be the most promising formulation for sustained-release applications. Conclusion: This study underscores the importance of polymer selection and formulation optimization in developing effective sustained-release drug delivery systems, and has potential implications for enhancing therapeutic outcomes in clinical practice.

Joshua T Myers, Jacques Van Dam, Mir Imran, Mir Hashim, Arvinder K Dhalla Rani Therapeutics, San Jose, CA, USACorrespondence: Joshua T Myers, Rani Therapeutics, 2051 Ringwood Ave, San Jose, CA, 95131, USA, Tel +1 408-457-3700, Email joshua.myers@ranitherapeutics.comBackground: Rani Therapeutics is developing a robotic pill (RP), an oral drug delivery platform called RaniPill™ that can deliver a number of biotherapeutics with high bioavailability; eliminating the need for injections. While patients in general prefer oral to injectable therapies, preference for a more frequent oral regimen compared to a less frequent injectable regimen is unknown. Two marketing surveys were conducted to gather data on preference for oral versus injectable therapies. A clinical study gathered data on participant preference for oral pills vs injections before and after swallowing a Mock-RP capsule.Methods: A total of 1689 adults taking injections (mean duration 3– 7 years) to treat endocrine or inflammatory conditions were anonymously surveyed online for their preference to administer/prescribe medications orally via the RP. In the clinical study, 150 participants currently taking injections for chronic conditions evaluated the swallowability of a Mock-RP and completed a questionnaire regarding their preferences.Results: Majority of respondents surveyed stated they would be willing to convert to an oral alternative over their current parenteral therapy regardless of drug or disease. In the clinical study, all participants were able to swallow the Mock-RP and 91% indicated their preference for the oral route versus their current parenteral route of drug administration. Survey respondents and those in the clinical study using frequent injections were more willing to select a once-daily capsule compared to those injecting infrequently. Even study participants who inject infrequently (≥monthly: 80%) would prefer a once-daily pill over their injection regimen.Conclusion: Patients taking injections and prescribing physicians strongly prefer oral dosing to parenteral administration of biologics even if dosing frequency with the oral option, such as the RP, is increased.Keywords: oral drug delivery, biotherapeutic, robotic pill, once-daily pill, swallowability

Abstract Background Type I interferons (IFN-I)—a group of cytokines with immunomodulatory, antiproliferative, and antiviral properties—are widely used as therapeutics for various cancers and viral diseases. Since IFNs are proteins, they are highly susceptible to degradation by proteases and by hydrolysis in the strong acid environment of the stomach, and they are therefore administered parenterally. In this study, we examined whether the intestinal bacterium, enteropathogenic Escherichia coli (EPEC), can be exploited for oral delivery of IFN-Is. EPEC survives the harsh conditions of the stomach and, upon reaching the small intestine, expresses a type III secretion system (T3SS) that is used to translocate effector proteins across the bacterial envelope into the eukaryotic host cells. Results In this study, we developed an attenuated EPEC strain that cannot colonize the host but can secrete functional human IFNα2 variant through the T3SS. We found that this bacteria-secreted IFN exhibited antiproliferative and antiviral activities similar to commercially available IFN. Conclusion These findings present a potential novel approach for the oral delivery of IFN via secreting bacteria.

Qiyuan Zhong,1,&ast; Jingqi Zeng,1,&ast; Xiaobin Jia1,2 1School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, People’s Republic of China; 2State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaobin Jia, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing, Jiangsu, 211198, People’s Republic of China, Email jiaxiaobin2015@163.comAbstract: The self-assembling aggregated structures of natural products have gained significant interest due to their simple synthesis, lack of carrier-related toxicity, and excellent biological efficacy. However, the mechanisms of their assembly and their ability to traverse the gastrointestinal (GI) barrier remain unclear. This review summarizes various intermolecular non-covalent interactions and aggregated structures, drawing on research indexed in Web of Science from 2010 to 2024. Cheminformatics analysis of the self-assembly behaviors of natural small molecules and their supramolecular aggregates reveals assembly-favorable conditions, aiding drug formulation. Additionally, the review explores the self-assembly properties of macromolecules like polysaccharides, proteins, and exosomes, highlighting their role in drug delivery. Strategies to overcome gastrointestinal barriers and enhance drug bioavailability are also discussed. This work underscores the potential of natural products in oral drug delivery and offers insights for designing more effective drug delivery systems. Keywords: natural products, self-assembly, aggregated structures, supramolecules, oral drug delivery, gastrointestinal barrier

Archaeosomes were manufactured from natural archaeal lipids by a microfluidics-assisted single-step production method utilizing a mixture of di- and tetraether lipids extracted from Sulfolobus acidocaldarius. The primary aim of this study was to investigate the exceptional stability of archaeosomes as potential carriers for oral drug delivery, with a focus on powdered formulations. The archaeosomes were negatively charged with a size of approximately 100 nm and a low polydispersity index. To assess their suitability for oral delivery, the archaeosomes were loaded with two model drugs: calcein, a fluorescent compound, and insulin, a peptide hormone. The archaeosomes demonstrated high stability in simulated intestinal fluids, with only 5% of the encapsulated compounds being released after 24 h, regardless of the presence of degrading enzymes or extremely acidic pH values such as those found in the stomach. In a co-culture cell model system mimicking the intestinal barrier, the archaeosomes showed strong adhesion to the cell membranes, facilitating a slow release of contents. The archaeosomes were loaded with insulin in a single-step procedure achieving an encapsulation efficiency of approximately 35%. These particles have been exposed to extreme manufacturing temperatures during freeze-drying and spray-drying processes, demonstrating remarkable resilience under these harsh conditions. The fabrication of stable dry powder formulations of archaeosomes represents a promising advancement toward the development of solid dosage forms for oral delivery of biological drugs. [ABSTRACT FROM AUTHOR]

Upadacitinib, classified as a highly soluble drug, is commercially marketed as RINVOQ®, a modified-release formulation incorporating hydroxypropyl methylcellulose as a matrix system to target extended release throughout the gastrointestinal (GI) tract. Our study aimed to explore how drug release will occur throughout the GI tract using a plethora of in vitro and in silico tools. We built a Physiologically-Based Pharmacokinetic (PBPK) model in GastroPlus™ to predict the systemic concentrations of the drug when administered using in vitro dissolution profiles as input to drive luminal dissolution. A series of in vitro dissolution experiments were gathered using the USP Apparatus I, III and IV in presence of biorelevant media, simulating both fasted and fed state conditions. A key outcome from the current study was to establish an in vitro-in vivo correlation (IVIVC) between (i) the dissolution profiles obtained from the USP I, III and IV methods and (ii) the fraction absorbed of drug as deconvoluted from the plasma concentration-time profile of the drug. When linking the fraction dissolved as measured in the USP IV model, a Level A IVIVC was established. Moreover, when using the different dissolution profiles as input for PBPK modeling, it was also observed that predictions for plasma C max and AUC were most accurate for USP IV compared to the other models (based on predicted versus observed ratios). Furthermore, the PBPK model has the utility to extract the predicted concentrations at the level of the colon which can be of utmost interest when working with specific in vitro assays. Graphical abstract was created with Biorender.com [Display omitted] • New IVIVC protocol evaluated the predictive capability of various USP apparatuses. • USP IV provided the best dissolution profiles for the HPMC formulation. • Biopredictive dissolution was input into PBPK to understand upadacitinib GI absorption. • USP IV data and PBPK model were used to predict drug levels in the colon. [ABSTRACT FROM AUTHOR]

Background: Type I interferons (IFN-I)—a group of cytokines with immunomodulatory, antiproliferative, and antiviral properties—are widely used as therapeutics for various cancers and viral diseases. Since IFNs are proteins, they are highly susceptible to degradation by proteases and by hydrolysis in the strong acid environment of the stomach, and they are therefore administered parenterally. In this study, we examined whether the intestinal bacterium, enteropathogenic Escherichia coli (EPEC), can be exploited for oral delivery of IFN-Is. EPEC survives the harsh conditions of the stomach and, upon reaching the small intestine, expresses a type III secretion system (T3SS) that is used to translocate effector proteins across the bacterial envelope into the eukaryotic host cells. Results: In this study, we developed an attenuated EPEC strain that cannot colonize the host but can secrete functional human IFNα2 variant through the T3SS. We found that this bacteria-secreted IFN exhibited antiproliferative and antiviral activities similar to commercially available IFN. Conclusion: These findings present a potential novel approach for the oral delivery of IFN via secreting bacteria. [ABSTRACT FROM AUTHOR]

Rapidly dissolving polymer thin films, or oral thin films (OTFs), have recently emerged as an improved oral drug delivery vehicle with its ability to bypass liver first pass metabolism, longer shelf-life, and simpler transport and distribution requirements, compared to traditional tablets and liquid formulations. Loratadine (LOR), an antihistamine commonly used to treat allergic rhinitis, undergoes liver first pass metabolism and is a prime candidate for incorporation within an OTF. However, loratadine is a BCS II drug with low aqueous solubility. Herein, the solubility of loratadine was improved by complexation with methyl β-cyclodextrin (MBCD) by co-evaporation of 2:1, 1:1, and 1:2 LOR:MBCD ratios and incorporation into a pullulan-based OTF at 4 wt% by solvent casting at 50 °C for 30 – 35 min. A therapeutically relevant 10 mg LOR dose could be prepared in a 3 cm by 3 cm OTF. The feasibility of complexation was observed with a B s -type phase solubility diagram, and complexation itself was confirmed via differential scanning calorimetry (DSC) by disappearance of the LOR melting peak, Fourier-transform infrared spectroscopy (FTIR) by shifting of the C=O peak, via 1H NMR spectroscopy by downfield shifting and change in peak multiplicity of the LOR aromatic protons, and via diffusion-ordered spectroscopy by a decrease in the diffusion coefficient of LOR:MBCD complex. LOR:MBCD could be incorporated homogeneously throughout an OTF, and LOR:MBCD OTFs exhibited reasonable mechanical strength and endured 12 ± 3 folds before breaking. LOR:MBCD OTFs disintegrated within 38 ± 10 s. The cumulative in vitro release of LOR:MBCD OTFs peaked at 80 % within 3–4 min of dissolution, and LOR in LOR:MBCD OTFs exhibited permeability across a 0.22 μm nitrocellulose membrane, demonstrating its applicability as a rapid drug delivery vehicle. [Display omitted] [ABSTRACT FROM AUTHOR]

Delivery and formulation of oral peptide and protein therapeutics have always been a challenge for the pharmaceutical industry. The oral bioavailability of peptide and protein therapeutics mainly relies on their gastrointestinal solubility and permeability which are affected by their poor membrane penetration, high molecular weight and proteolytic (chemical and enzymatic) degradation resulting in limited delivery and therapeutic efficacy. The present review article highlights the challenges and limitations of oral delivery of peptide and protein therapeutics focusing on the application, potential and importance of solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) as lipid-based drug delivery systems (LBDDSs) and their advantages and drawbacks. LBDDSs, due to their lipid-based matrix can encapsulate both lipophilic and hydrophilic drugs, and by reducing the first-pass effect and avoiding proteolytic degradation offer improved drug stability, dissolution rate, absorption, bioavailability and controlled drug release. Furthermore, their small size, high surface area and surface modification increase their mucosal adhesion, tissue-targeted distribution, physiological function and half-life. Properties such as simple preparation, high-scale manufacturing, biodegradability, biocompatibility, prolonged half-life, lower toxicity, lower adverse effects, lipid-based structure, higher drug encapsulation rate and various drug release profile compared to other similar carrier systems makes LBDDSs a promising drug delivery system (DDS). Nevertheless, undesired physicochemical features of peptide and protein drug development and discovery such as plasma stability, membrane permeability and circulation half-life remain a serious challenge which should be addressed in future.

Water-in-oil-in-water (w/o/w) double emulsions have shown excellent capability in augmenting the enteral bioavailability of BCS class III drugs, besides being effective controlled-release formulations. However, the problem of thermodynamic instability has restrained their industrial applicability. The self-double emulsifying drug delivery system (SDEDDS) is one of several approaches used to improve the stability of double emulsions. SDEDDS is a mixture of primary emulsion and secondary surfactant that can spontaneously emulsify into double emulsions in an external aqueous environment with mild agitation. Here, we prepared SDEDDS of gentamicin sulfate by response surface methodology. Selected optimized formulations (ODS1 and ODS2) were evaluated for zeta potential (Y1), optical clarity (Y2), release at 420 min (Y3), emulsion stability index (Y4) and self-emulsification time (Y5). For ODS1, Y1=−35.45 (±1.06)mV, Y2=53.19 (±0.35)%, Y3=75.79 (±0.60)%, Y4=93.97(±0.15)% and Y5=0.631 (±0.014)min, whereas for ODS2, Y1=−35.70 (±0.56)mV, Y2=48.09 (±0.64)%, Y3=76.61 (±0.99)%, Y4=93.00(±0.94)% and Y5=0.687(±0.02)min. Furthermore, ex-vivo studies on intestinal permeability revealed that SDEDDS improved membrane permeability compared to drug solution. Histopathology investigations revealed that SDEDDS promoted permeation without causing significant local membrane distortion. In addition, in - vivo studies revealed a 2.84 -fold increase in AUC 0-∞ of optimized SDEDD compared to pure drug oral solution. [ABSTRACT FROM AUTHOR]

Drug administration by oral delivery is the preferred route, regardless of some remaining challenges, such as short resident time and toxicity issues. One strategy to overcome these barriers is utilizing mucoadhesive vectors that can increase intestinal resident time and systemic uptake. In this study, biomimetic nanoparticles (NPs) were produced from 14 types of edible algae and evaluated for usage as oral DDSs by measuring their size, surface charge, morphology, encapsulation efficiency, mucoadhesion force, and cellular uptake into Caco-2 cells. The NPs composed of algal materials (aNPs) exhibited a spherical morphology with a size range of 126–606 nm and a surface charge of −9 to −38 mV. The mucoadhesive forces tested ex vivo against mice, pigs, and sheep intestines revealed significant variation between algae and animal models. Notably, Arthospira platensis (i.e., Spirulina) NPs (126 ± 2 nm, −38 ± 3 mV) consistently exhibited the highest mucoadhesive forces (up to 3127 ± 272 µN/mm²). Moreover, a correlation was found between high mucoadhesive force and high cellular uptake into Caco-2 cells, further supporting the potential of aNPs by indicating their ability to facilitate drug absorption into the human intestinal epithelium. The results presented herein serve as a proof of concept for the possibility of aNPs as oral drug delivery vehicles. [ABSTRACT FROM AUTHOR]

Zileuton is a leukotriene inhibitor used to treat asthma. As a BCS class II drug it exhibits challenges with solubility which likely impact its absorption. As patient gender significantly impacts the pharmacokinetics of many drugs, this study aimed to investigate potential gender-based pharmacokinetic differences after oral zileuton administration in rats. Male and female Sprague Dawley rats received single oral gavage doses of pure zileuton as an active pharmaceutical ingredient (30 mg/kg body weight (bw)), physical mixture (PM; at 30 mg/kg bw of the formulation contains zileuton, kollidon VA64 fine, dowfax2A1 and trehalose), and nanocrystalline formulation of zileuton (NfZ; at 30 mg/kg bw of the formulation). Plasma, tissue, and urine concentrations were quantified using high performance liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis showed higher zileuton levels in the plasma of female versus male rats across all evaluated forms of zileuton (API, PM, and NfZ). Female rats demonstrated higher peak plasma concentrations (Cmax) and increased area under the plasma concentration-time curve (AUC) relative to males, regardless of formulation. These findings reveal substantial gender disparities in the pharmacokinetics of zileuton in the rat model. This study emphasizes the critical need to evaluate gender differences during preclinical drug development to enable gender-based precision dosing strategies for equivalent efficacy/safety outcomes in male and female patients. Additional studies are warranted to investigate underlying mechanisms of such pharmacokinetic gender divergences.

Recent advances in the use of nano- and microparticles in drug delivery, cell therapy, and tissue engineering have led to increasing attention towards nanostructured microparticulate formulations for maximum benefit from both nano- and micron sized features. Scalable manufacturing of monodisperse nanostructured microparticles with tunable size, shape, content, and release rate remains a big challenge. Current technology, mainly comprises complex multi-step chemical procedures with limited control over these aspects. Here, we demonstrate a novel technique for high-yield fabrication of monodisperse monolayer and multilayer nanofibrous microparticles (MoNami and MuNaMi respectively). The fabrication procedure includes sequential electrospinning followed by micro-cutting at room temperature and transfer of particles for collection. The big advantage of the introduced technique is the potential to apply several polymer-drug combinations forming multilayer microparticles enjoying extracellular matrix (ECM)-mimicking architecture with tunable release profile. We demonstrate the fabrication and study the factors affecting the final three-dimensional structure. A model drug is encapsulated into a three-layer sheet (PLGA-pullulan-PLGA), and we demonstrate how the release profile changes from burst to sustain by simply cutting particles out of the electrospun sheet. We believe our fabrication method offers a unique and facile platform for realizing advanced microparticles for oral drug delivery applications.

Abstract The biological barriers have seriously restricted the efficacious responses of oral delivery system in diseases treatment. Utilizing a carrier based on the single construction means is hard to overcome these obstacles simultaneously because the complex gastrointestinal tract environment requires carrier to have different or even contradictory properties. Interestingly, spore capsid (SC) integrates many unique biological characteristics, such as high resistance, good stability etc. This fact offers a boundless source of inspiration for the construction of multi-functional oral nanoplatform based on SC without further modification. Herein, we develop a type of biomimetic spore nanoplatform (SC@DS NPs) to successively overcome oral biological barriers. Firstly, doxorubicin (DOX) and sorafenib (SOR) are self-assembled to form carrier-free nanoparticles (DS NPs). Subsequently, SC is effectively separated from probiotic spores and served as a functional vehicle for delivering DS NPs. As expect, SC@DS NPs can efficaciously pass through the rugged stomach environment after oral administration and further be transported to the intestine. Surprisingly, we find that SC@DS NPs exhibit a significant improvement in the aspects of mucus penetration and transepithelial transport, which is related to the protein species of SC. This study demonstrates that SC@DS NPs can efficiently overcome multiple biological barriers and improve the therapeutic effect.

Pectin hydrogels have emerged as a highly promising medium for the controlled release of pharmaceuticals in the dynamic field of drug delivery. The present review sheds light on the broad range of applications and potential of pectin-based hydrogels in pharmaceutical formulations. Pectin, as a biopolymer, is a versatile candidate for various drug delivery systems because of its wide range of properties and characteristics. The information provided on formulation strategies and crosslinking techniques provides researchers with tools to improve drug entrapment and controlled release. Furthermore, this review provides a more in-depth understanding of the complex factors influencing drug release from pectin hydrogels, such as the impact of environmental conditions and drug-specific characteristics. Pectin hydrogels demonstrate adaptability across diverse domains, ranging from applications in oral and transdermal drug delivery to contributions in wound healing, tissue engineering, and ongoing clinical trials. While standardization and regulatory compliance remain significant challenges, the future of pectin hydrogels appears to be bright, opening up new possibilities for advanced drug delivery systems.

Nanoscale liposomes are widely recognized as promising drug delivery materials; yet, their utilization in oral drug delivery has been hindered by their limited ability to efficiently penetrate the intestinal mucus layer. Herein, we present an approach to enhance oral drug delivery and improve the mucus penetration capability of liposomes by conjugating bromelain, a mucolytic enzyme derived from pineapple stems, to the liposome membrane (Bro-Lip). With an optimized bromelain payload of 11.1 nmol/mg, we achieved an impressive 47.8% conjugation efficiency while retaining 77.5% of the proteolytic activity post conjugation. Physicochemical analysis revealed that Bro-Lip measured 152.8 nm in size with a ζ potential of −2.3 mV. Notably, Bro-Lip exhibited a significantly enhanced capacity to penetrate the porcine mucus layer, demonstrating a 2.87-fold improvement compared with bare liposomes. Furthermore, we assessed the transcellular permeability of Bro-Lips using Caco-2 and Caco-2/HT29 coculture models, revealing substantial enhancements in permeability compared to unmodified liposomes. Specifically, in Caco-2 cell monolayers, mucus permeability increased by 3.80-fold, while in Caco-2/HT29 cocultures, it rose by 2.25-fold. Additionally, Bro-Lip demonstrated an improved cellular uptake in Caco-2 cells. These findings highlight the potential of Bro-Lip as an effective oral delivery system by enhancing mucus permeation and cell membrane permeation. [ABSTRACT FROM AUTHOR]

Ingestible self-configurable proximity-enabling devices have been developed as a non-invasive platform to improve the bioavailability of drug compounds via swellable or self-unfolding devices. Self-unfolding foils support unidirectional drug release in close proximity to the intestinal epithelium, the main drug absorption site following oral administration. The foils are loaded with a solid-state formulation containing the active pharmaceutical ingredient and then coated and rolled into enteric capsules. The coated lid must remain intact to ensure drug protection in the rolled state until targeted release in the small intestine after capsule disintegration. Despite promising results in previous studies, the deposition of an enteric top coating that remains intact after rolling is still challenging. In this study, we compare different mixtures of enteric polymers and a plasticizer, PEG 6000, as potential coating materials. We evaluate mechanical properties as well as drug protection and targeted release in gastric and intestinal media, respectively. Commercially available Eudragit® FL30D-55 appears to be the most suitable material due to its high strain at failure and integrity after capsule fitting. In vitro studies of coated foils in gastric and intestinal media confirm successful pH-triggered drug release. This indicates the potential advantage of the selected material in the development of self-unfolding foils for oral drug delivery. [ABSTRACT FROM AUTHOR]

Delivery and formulation of oral peptide and protein therapeutics have always been a challenge for the pharmaceutical industry. The oral bioavailability of peptide and protein therapeutics mainly relies on their gastrointestinal solubility and permeability which are affected by their poor membrane penetration, high molecular weight and proteolytic (chemical and enzymatic) degradation resulting in limited delivery and therapeutic efficacy. The present review article highlights the challenges and limitations of oral delivery of peptide and protein therapeutics focusing on the application, potential and importance of solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) as lipid-based drug delivery systems (LBDDSs) and their advantages and drawbacks. LBDDSs, due to their lipid-based matrix can encapsulate both lipophilic and hydrophilic drugs, and by reducing the first-pass effect and avoiding proteolytic degradation offer improved drug stability, dissolution rate, absorption, bioavailability and controlled drug release. Furthermore, their small size, high surface area and surface modification increase their mucosal adhesion, tissue-targeted distribution, physiological function and half-life. Properties such as simple preparation, high-scale manufacturing, biodegradability, biocompatibility, prolonged half-life, lower toxicity, lower adverse effects, lipid-based structure, higher drug encapsulation rate and various drug release profile compared to other similar carrier systems makes LBDDSs a promising drug delivery system (DDS). Nevertheless, undesired physicochemical features of peptide and protein drug development and discovery such as plasma stability, membrane permeability and circulation half-life remain a serious challenge which should be addressed in future. [ABSTRACT FROM AUTHOR]

PEGylated chitosan nanoparticles as oral delivery system for protein drugs were constructed by polyelectrolyte composite method. BSA-loaded nanoparticles were prepared by optimizing the conditions using bovine serum albumin (BSA) as protein drug model. The average particle size was 205.74±1.96 nm with PDI of 0.090 and the zeta potential was –36.76±9.4 mV, when the molar ratio was 0.20, the concentration was 0.6 mg/mL and polyethylene glycol grafting degree was 16%. The system showed high loading capacity and encapsulation efficiency for BSA which was up to 22.8±5.8% and 82.3±6.2% respectively. The cumulative release rate decreased with increasing initial amount and BSA was released slower in strong acid environment, such as simulated gastric pH 1.4, with cumulative release rate of 45% after 180 h, indicating that the nanoparticles can protect BSA from degradation. The Korsmeyer-Peppas and first-order kinetic models were used to fit well, dominated by the diffusion of BSA adsorbed on the surface, the dissolution of nanoparticles and the diffusion of BSA from the nanoparticles. The results suggested that PEGylated chitosan nanoparticles show excellent biocompatibility, with the potential as promising nanocarriers for oral delivery of protein drugs. [ABSTRACT FROM AUTHOR]

In this study, a polymer-stabilized nanoemulsion (PNE) was developed to improve the inflammatory and analgesic activities of diclofenac (DA). DA-PNEs were prepared from sesame oil and poloxamer 188 (P188), polysorbate 80, and span 80 as emulsifiers and optimized by a systematic multi-objective optimization method. The developed DA-PNEs exhibited thermodynamical stability with low viscosity. The mean diameter, PDI, surface charge, and entrapment efficiency of DA-PNEs were 122.49±3.42 nm, 0.226±0.08, −47.3 ± 3.6 mV, and 93.57±3.4 %, respectively. The cumulative in vitro release profile of DA-PNEs was significantly higher than the neat drug in simulated gastrointestinal fluids. The anti-inflammatory activities of DA-PNEs were evaluated in the λ-carrageenan-induced paw edema model. To investigate the effect of P188 on analgesic and anti-inflammatory activities, a formulation without P188 was also prepared and named DA-NEs. Following oral administration, DA-PNEs showed a significantly higher (p <0.05) effect in reducing pain and inflammation symptoms as compared to free diclofenac and DA-NEs. Moreover, histopathological examination confirmed that DA-PNEs meaningfully reduced the extent of paw edema, comparable to that of DA. Taken together, the findings of the in vitro and in vivo studies suggest that diclofenac-loaded P188-stabilized nanoemulsion can be considered a potential drug delivery system for treating and controlling inflammatory disorders and alleviating pains. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Functionalized calcium carbonate (FCC), a novel pharmaceutical excipient, has shown promising properties in the field of oral drug delivery. The current study aimed at evaluating the feasibility of FCC as a carrier for the solidification of self-nanoemulsifying drug delivery systems (SNEDDS) containing the poorly water-soluble model drug carvedilol (CRV). Conventional, subsaturated SNEDDS (80 %-SNEDDS liquid) and supersaturated SNEDDS (200 %-SNEDDS liquid) were loaded onto FCC via physical adsorption at three ratios; 2.5:1, 3.0:1 and 3.5:1 (w/w) of FCC:SNEDDS liquid , respectively, generating free-flowing powders (SNEDDS FCC) with drug loading ranging from 0.8 % to 2.6 % (w/w) CRV. The emulsification of SNEDDS FCC in a USP II dissolution setup (in purified water) was characterized using dynamic light scattering, resulting in similar droplet sizes and PDIs as observed for their liquid counterparts. The morphology and physical state of the obtained SNEDDS FCC were characterized using scanning electron microscopy and differential scanning calorimetry. The physical stability and drug release upon dispersion were assessed as a function of storage time. The 200 %-SNEDDS liquid were physically stable for 6 days, however, solidification using FCC stabilized the supersaturated concentrations of CRV for a test period of up to 10 weeks (solidification ratios 3.0:1 and 3.5:1 (FCC:SNEDDS liquid)). SNEDDS FCC achieved an improved rate and extent of drug release upon dispersion compared to the crystalline CRV in tap water (pH 7.5), however, to a lesser extent than their liquid counterparts. After 8 weeks of storage (25 °C at dry conditions), FCC was still able to rapidly release the SNEDDS liquid and demonstrated the same rate and extent of drug release as freshly prepared samples. The solidification of 200 %-SNEDDS liquid in presence of FCC greatly improved the drug loading and showed an enhanced drug release profile compared to the conventional systems. In conclusion, FCC showed potential as a carrier for solidification of SNEDDS and for the development of novel supersaturated solid SNEDDS for the oral delivery of poorly water-soluble drugs. [ABSTRACT FROM AUTHOR]

Acyclovir has a 10-30 % oral bioavailability with a half-life of 2-3 h. Acyclovir mainly gets solubilized in acidic conditions, and its absorption is found in the upper GIT. The primary aim of this research work was to formulate gastroretentive dosage form of acyclovir that can float on gastric content. The polymer used was sodium alginate, while the floating agent was calcium carbonate. The dependent variables of drug release, floating lag time and viscosity were significantly impacted by sodium alginate and CaCO3 concentrations. To assess the desired release pattern, a dissolution was performed in 0.1 N HCl at 50 rpm. Shear-thinning behaviour, instant gelation, 99.2 % drug release at 12 h, and instant floating ability greater than 12 h in 0.1 N HCl were all observed in the suspension. consequently, a sustained-release floating dosage form for acyclovir, with a duration of 12 h, was successfully developed. [ABSTRACT FROM AUTHOR]

Oral dosage forms are the preferred solution for systemic treatment and prevention of disease conditions. However, traditional dosage forms face challenges regarding treatment adherence and delivery of biologics. Oral therapies that require frequent administrations face difficulties with patient compliance. In addition, only a few peptide- and protein-based drugs have been commercialized for oral administration so far, presenting a bioavailability that is generally low. Therefore, research and development on novel formulation strategies for oral drug delivery has bloomed massively in the last decade to overcome these challenges. On the one hand, approaches based on lumen-release of drugs such as 3D-printed capsules and prolonged gastric residence dosage forms have been explored to offer personalized medicine to the patient and reduce frequent dosing of small drug compounds that are currently in the market as powdered tablet or capsules. On the other hand, strategies based on mucus interfacing such as gastrointestinal patches, or even epithelium injections have been investigated in order to enhance the permeability of biologic macromolecules, which are mostly commercialized in the form of subcutaneous injections. Despite the fact that these methods are at an early development stage, promising results have been revealed in terms of personalized medicine and improved bioavailability. In this review, we offer a critical overview of novel ingestible millimeter-sized devices and technologies for oral drug delivery that are currently used in the clinic as well as those that could emerge on the market in a not too distant future. [Display omitted] [ABSTRACT FROM AUTHOR]