Gastric Degradation Research Articles

Advanced Technologies in Rectal Drug Delivery Systems: A Comprehensive Review of Recent Innovations and Future Prospects

Abstract: Rectal Drug Delivery System (RDDS) emerges as an alternative administration route due to the rectum's small surface area and limited enzyme activity, which contribute to efficient drug absorption. RDDS offers various advantages, such as reduced first-pass metabolism, rapid absorption of low molecular weight drugs, and the ability to accommodate large retention volumes and facilitate absorption via the lymphatic system. Moreover, RDDS is preferable for drugs with low stability, solubility, and permeability via oral administration, as well as effectively addressing concerns related to gastric irritation or degradation. This review delves into the factors influencing drug absorption in RDDS, including drug properties, formulation types, and physiological and pathology-associated considerations. It further explores conventional RDDS, including enemas, suppositories, tablets, gels, sprays, ointments, and creams, as well as novel approaches involving nanoparticles, liposomes, microspheres, and solid lipid nanoparticles (SLNs) in rectal dosage forms. Furthermore, the challenges and prospects of RDDS in treating rectal diseases are discussed. This review provides valuable insights into the potential of RDDS, highlighting the importance of continuous research and development in enhancing patient outcomes and advancing healthcare practices.

Engineering crystal network of supramolecular Oleogel via kinetical regulation for improved lutein bioaccessibility

This study presented an approach for controlling supramolecular oleogel crystal network by regulating kinetical factors - specifically, a combination of cooling temperature and aging period. Results indicated that only under long aging period, supramolecular oleogels prepared at different cooling temperature exhibited distinct crystal morphology compared to those under short aging period. The physicochemical properties of oleogels were affected by different crystal networks. Therefore, further research on oleogels under longed aging was explored. For lutein encapsulation, it was observed that supramolecular oleogels with denser crystal network exhibited higher lutein bioaccessibility. This was probably because the denser crystal network providing a solid physical barrier that effectively protected lutein unaffected by gastric acid degradation. Additionally, the micellar capacity was also enhanced to accommodate lutein due to release of long chain fatty acid from the gelator glycerol monostearate (GMS). Collectively, kinetical factors regulation facilitated rational design of oleogels for delivery of lipid-soluble bioactive compounds.

Inflammation-oriented montmorillonite adjuvant enhanced oral delivery of anti-TNF-α nanobody against inflammatory bowel disease

Oral delivery of proteins faces challenges due to the harsh conditions of the gastrointestinal (GI) tract, including gastric acid and intestinal enzyme degradation. Permeation enhancers are limited in their ability to deliver proteins with high molecular weight and can potentially cause toxicity by opening tight junctions. To overcome these challenges, we propose the use of montmorillonite (MMT) as an adjuvant that possesses both inflammation-oriented abilities and the ability to regulate gut microbiota. This adjuvant can be used as a universal protein oral delivery technology by fusing with advantageous binding amino acid sequences. We demonstrated that anti-TNF-α nanobody (VII) can be intercalated into the MMT interlayer space. The carboxylate groups (-COOH) of aspartic acid (D) and glutamic acid (E) interact with the MMT surface through electrostatic interactions with sodium ions (Na+). The amino groups (NH2) of asparagine (N) and glutamine (Q) are primarily attracted to the MMT layers through hydrogen bonding with oxygen atoms on the surface. This binding mechanism protects VII from degradation and ensures its release in the intestinal tract, as well as retaining biological activity, leading to significantly enhanced therapeutic effects on colitis. Furthermore, VII@MMT increases the abundance of short-chain fatty acids (SCFAs)-producing strains, including Clostridia, Prevotellaceae, Alloprevotella, Oscillospiraceae, Clostridia_vadinBB60_group, and Ruminococcaceae, therefore enhance the production of SCFAs and butyrate, inducing regulatory T cells (Tregs) production to modulate local and systemic immune homeostasis. Overall, the MMT adjuvant provides a promising universal strategy for protein oral delivery by rational designed protein.

Oral Microto-Nano Genome-Editing System Enabling Targeted Delivery and Conditional Activation of CRISPR-Cas9 for Gene Therapy of Inflammatory Bowel Disease.

The potent CRISPR-Cas9 technology can correct genes in human mutated cells to achieve the treatment of multiple diseases, but it lacks safe and effective delivery systems. Herein, we proposed an oral microto-nano genome-editing system aiming at the enteric excessive level of TNF-α for specific gene therapy of inflammatory bowel disease (IBD). This editing system facilitated the assembly of Cas9/sgRNA ribonucleoprotein (RNP) into nanoclusters (NCs) through the bridging of disulfide bonds. RNP-NCs were subsequently encapsulated within inflammatory cell-targeted lipopolysaccharide-deleted outer membrane vesicles (dOMVs) sourced from Escherichia coli Nissle 1917, which were further shielded by an outer layer of calcium alginate microspheres (CAMs). By leveraging the protection effect of CAMs, the oral administration system withstood gastric acid degradation upon entry into the stomach, achieving targeted delivery to the intestines with high efficiency. As the pH gradually rose, the microscale CAMs swelled and disintegrated, releasing nanoscale RNP-NCs encapsulated in dOMVs into the intestines. These RNP-NCs@dOMVs could traverse the mucosal barrier and target inflammatory macrophages where conditionally activated Cas9/sgRNA RNPs effectively perform genomic editing of TNF-α within the nucleus. Such oral microto-nano genome-editing systems represent a promising translational platform for the treatment of IBD.

Oral drug delivery vehicle for insulin and curcumin based on egg albumin-dextran conjugate: In vitro and in vivo studies

The increasing desire for oral delivery vehicle systems encouraged the development of micro and nano encapsulation technologies to protect drugs against gastric and enzymatic degradation. This study aimed to develop egg albumin-dextran conjugate as a delivery vehicle for oral administration. For this purpose, insulin was selected as a macromolecule drug and curcumin as a natural lipophilic polyphenol, both show negative absorption kinetics in gastrointestinal tract. Egg albumin-dextran conjugate was prepared by Maillard reaction under mild conditions and subsequently be used to encapsulate insulin and curcumin, respectively. The encapsulation efficiency reached to 97 % and 95.5 % at 300 mg/ml of insulin and curcumin, respectively. The profile of in vitro drug release for the insulin and curcumin indicates that approximately 60 % of the drugs were partially retained by the conjugate in gastric pH environment while a more extensive release was observed under intestinal pH conditions. Application of oral administration of insulin conjugate (IC) and/or curcumin conjugate (CC) to streptozotocin (STZ) induced diabetic rats was investigated for 6 weeks and compared with trade insulin drug. Fifty-four albino rats were separated into nine equivalent groups. Control, insulin conjugate (IC), curcumin conjugate (CC), and IC + CC. The remaining groups injected with STZ and subsequently received vehicle, IC, CC, IC + CC, and trade insulin drug; respectively.Interestingly, insulin conjugate and/or curcumin conjugate significantly reduced hyperglycemia, hyperlipidemia, decreased fructosamine level, decreased HOMA-IR, increased insulin level, increased HOMA-β, increased antioxidant defense molecules, along with modulating morphological pancreatic degeneration caused by STZ. In conclusion, oral insulin-conjugate is more effective than the trade insulin drug. Also, curcumin-conjugate has a promising role as antidiabetic agent as it may contribute in β-cells regeneration. Further, the combination between them may have synergetic antidiabetic effect. But, more detailed studies should be done to investigate the possible mechanisms of their antidiabetic effect.

Interaction of zein/HP-β-CD nanoparticles with digestive enzymes: Enhancing curcumin bioavailability

The low bioavailability of polyphenolic compounds due to poor solubility and stability is a major challenge. Encapsulation of polyphenols in zein-based composite nanoparticles can improve the water dispersion, stability, targeted delivery, and controlled release of polyphenols in the gastrointestinal tract. In this study, we investigated the fluorescence properties, bioactivity, and microstructural characteristics of polyphenols during digestion, revealing that zein nanoparticles protect polyphenols from gastric degradation and promote their sustained release in the small intestine. The effects of different ionic species and salt ion concentrations on the digestive properties of polyphenol complex delivery systems have also been explored. In addition, the formation of “protein corona” structures during digestion may affect bioavailability. These findings highlight the potential of nanoparticle formulations to improve polyphenol stability and absorption. The results of this study may provide new insights and references for the study of polyphenol bioavailability enhancement.

Alginate/silk fibroin/Zn2+ composite microspheres for site-specific delivery for enhanced ulcerative colitis therapy

The limited therapeutic efficacy of oral medications against ulcerative colitis (UC) is attributed to inadequate drug exposure to inflammation site in the colon. To address this challenge, we developed a pH-triggered oral hydrogel microsphere system composed of alginate/silk fibroin (Alg/SF) using zinc ions (Zn2+) as a crosslink agent for colon-targeted delivery. This system, with moderate gelation toughness, can protect the anti-inflammatory drug bornyl acetate (BA) from gastric degradation, ensuring its delivery to the colon. SF effectively shields the microspheres during passage through the small intestine and then facilitates rapid drug release upon reaching the colon. We evaluated the efficacy of this strategy in murine models of both acute and chronic colitis, demonstrating its significant capacity to attenuate pro-inflammatory cytokine secretion, enhance intestinal barrier restitution, and modulate immune cell responses for effective amelioration of colitis-associated symptoms. Upon oral administration of microspheres, their therapeutic efficacy against both acute and chronic UC is demonstrated to be superior to that of a widely used clinical drug, 5-aminosalicylic acid. Overall, the oral hydrogel microspheres offer a promising approach to enhance the therapeutic outcomes of small molecule drug against UC.

The Effect of Inflammatory Bowel Disease and Irritable Bowel Syndrome on Pravastatin Oral Bioavailability: In vivo and in silico evaluation using bottom-up wbPBPK modeling.

The common disorders irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) can modify the drugs' pharmacokinetics via their induced pathophysiological changes. This work aimed to investigate the impact of these two diseases on pravastatin oral bioavailability. Rat models for IBS and IBD were used to experimentally test the effects of IBS and IBD on pravastatin pharmacokinetics. Then, the observations made in rats were extrapolated to humans using a mechanistic whole-body physiologically-based pharmacokinetic (wbPBPK) model. The rat in vivo studies done herein showed that IBS and IBD decreased serum albumin (> 11% for both), decreased PRV binding in plasma, and increased pravastatin absolute oral bioavailability (0.17 and 0.53 compared to 0.01) which increased plasma, muscle, and liver exposure. However, the wbPBPK model predicted muscle concentration was much lower than the pravastatin toxicity thresholds for myotoxicity and rhabdomyolysis. Overall, IBS and IBD can significantly increase pravastatin oral bioavailability which can be due to a combination of increased pravastatin intestinal permeability and decreased pravastatin gastric degradation resulting in higher exposure. This is the first study in the literature investigating the effects of IBS and IBD on pravastatin pharmacokinetics. The high interpatient variability in pravastatin concentrations as induced by IBD and IBS can be reduced by oral administration of pravastatin using enteric-coated tablets. Such disease (IBS and IBD)-drug interaction can have more drastic consequences for narrow therapeutic index drugs prone to gastric degradation, especially for drugs with low intestinal permeability.

Quality by design (QbD) approach-based development of optimized nanocarrier to achieve quality target product profile (QTPP)-targeted lymphatic delivery

Background. Insulin, commonly used for diabetes treatment, needs better ways to improve its effectiveness and safety due to its challenges with poor permeability and stability. Various system has been developed for oral peptide delivery. The non-targeted system can prevent gastric and enzymatic degradation of peptides but cannot increase the bulk transport of peptides across the membrane. However, the non-selectivity is the limitation of the existing system. Numerous carbohydrate-binding receptors overexpressed on intestinal macrophage cells (M-cells) of gut-associated lymphoid tissue. It is the most desirable site for receptor-mediated endocytosis and lymphatic drug delivery of peptides. Objective. The prime objective of the study was to fabricate mannose ligand conjugated nanoparticles (MNPs) employing a quality-by-design approach to address permeability challenges after oral administration. Herein, the study’s secondary objective of this study is to identify the influencing factor for producing quality products. Considering this objective, the Lymphatic uptake of NPs was selected as a quality target product profile (QTPP), and a systematic study was conducted to identify the critical formulation attributes (CFAs) and critical process parameters (CPP) influencing critical quality attributes (CQAs). Mannosylated Chitosan concentrations (MCs) and TPP concentrations were identified as CFAs, and stirring speed was identified as CPP. Methods. MNPs were prepared by the inotropic gelation method and filled into the enteric-coated capsule to protect from acidic environments. The effect of CFAs and CPP on responses like particle size (X) and entrapment (Y) was observed by Box-Behnken design (BBD). ANOVA statistically evaluated the result to confirm a significant level (p < 0.05). The optimal conditions of NPs were obtained by constructing an overlay plot and determining the desirability value. HPLC and zeta-seizer analysis characterized the lyophilized NPs. Cell-line studies were performed to confirm the safety and M-cell targeting of NPs to enhance Insulin oral bioavailability. Results. The morphology of NPs was revealed by SEM. The developed NPs showed a nearly oval shape with the average size, surface potential, and % drug entrapment were 245.52 ± 3.37 nm, 22.12 ± 2.13 mV, and 76.15 ± 1.3%, respectively. MTT assay result exhibited that MNPs safe and Confocal imaging inference that NPs selectively uptake by the M-cell. Conclusion. BBD experimental design enables the effective formulation of optimized NPs. The statistical analysis estimated a clear assessment of the significance of the process and formulation variable. Cell line study confirms that NPs are safe and effectively uptake by the cell.

Metal-Organic Framework Based Mucoadhesive Nanodrugs for Multifunction Helicobacter Pylori Targeted Eradication, Inflammation Regulation and Gut Flora Protection.

The prevalence of drug-resistant bacteria presents a significant challenge to the antibiotic treatment of Helicobacter pylori (H. pylori), while traditional antimicrobial agents often suffer from shortcomings such as poor gastric retention, inadequate alleviation of inflammation, and significant adverse effects on the gut microbiota. Here, a selenized chitosan (CS-Se) modified bismuth-based metal-organic framework (Bi-MOF@CS-Se) nanodrug is reported that can target mucin through the charge interaction of the outer CS-Se layer to achieve mucosal adhesion and gastric retention. Additionally, the Bi-MOF@CS-Se can respond to gastric acid and pepsin degradation, and the exposed Bi-MOF exhibits excellent antibacterial properties against standard H. pylori as well as clinical antibiotic-resistant strains. Remarkably, the Bi-MOF@CS-Se effectively alleviates inflammation and excessive oxidative stress by regulating the expression of inflammatory factors and the production of reactive oxygen species (ROS), thereby exerting therapeutic effects against H. pylori infection. Importantly, this Bi-MOF@CS-Se nanodrug does not affect the homeostasis of gut microbiota, providing a promising strategy for efficient and safe treatment of H. pylori infection.

Polyelectrolyte composite hydrogels based on a derivative of functional dietary fiber for long-term gastric retention and drug delivery

Gastric retention drug delivery is experiencing significant demand for hydrogels that exhibit in situ controllable forming in the stomach, resistance against severe gastric degradation, and exceptional biocompatibility. However, current studies lack comprehensive investigations on these requirements. In this study, resistant starch is chosen as a kind of novel dietary fiber with remarkable gastric retention effects compared to conventional natural polymers. To address its limited solubility, resistant starch was modified by carboxymethyl groups. Moreover, a semi-dissolution acidification sol–gel transition method was employed to enable in situ gelation under gastric acid conditions and fabricate physically crosslinked polyelectrolyte composite hydrogels (CMRS/CTS) based on carboxymethylated resistant starch and chitosan. This method obviates the need for toxic chemical crosslinkers and initiators, ensuring favorable biocompatibility. The influence of carboxymethyl substitution degree and the anion-to-cation ratio of the composite hydrogels on the mechanical, rheological, and swelling properties was thoroughly investigated. Compared to conventional carboxymethyl starch-based hydrogels, CMRS/CTS maintained a relatively intact structure even after immersion in simulated gastric fluid for 30 days owing to the enzymatic stability of the hydrogel. Upon drug loading, CMRS/CTS exhibited sustained and controlled drug release, facilitating prolonged therapeutic effects. Simultaneously achieving in situ gastric drug release, biocompatibility, resistance to degradation, and sustained release, CMRS/CTS represents a promising avenue for the development of long-term gastric retention hydrogels.

Revolutionizing transdermal drug delivery: unveiling the potential of cubosomes and ethosomes.

The area of drug delivery systems has witnessed significant advancements in recent years, with a particular focus on improving efficacy, stability, and patient compliance. Transdermal drug delivery offers numerous benefits compared to conventional methods of drug administration through the skin. It helps in avoiding gastric irritation, hepatic first-pass metabolism, and gastric degradation of the drug. It bypasses the gastrointestinal tract, eliminating the risk of first-pass metabolism and allowing drugs to be administered without being affected by pH, enzymes, or intestinal bacteria. Additionally, it allows for sustained release of the drug, is noninvasive, and enhances patient adherence to the treatment regimen. The transdermal drug delivery system (TDDS) can serve as an alternative route for drug administration in individuals who cannot tolerate oral medications, experience nausea, or are unconscious. When compared to intravenous, hypodermic, and other parenteral routes, TDDS stands out due to its ability to eliminate pain, reduce the risk of infection, and prevent disease transmission associated with needle reuse. Consequently, the overall patient compliance is significantly improved with the utilization of TDDS. Among the noteworthy developments are cubosomes and ethosomes, two distinct yet promising carriers that have garnered attention for their unique properties. In conclusion, this review synthesizes the current knowledge on cubosomes and ethosomes, shedding light on their individual strengths and potential synergies. The exploration of their application in various therapeutic areas underscores their versatility and establishes them as key players in the evolving landscape of drug delivery systems.

Chitosan-based intelligent polymeric networks for site-specific colon medication delivery: A comprehensive study on controlled release of diloxanide furoate and network formation dynamics

Oral medications are prone to gastric degradation and enzymatic inactivation, diminishing their efficacy. This study investigates a solution by developing intelligent polymeric networks, incorporating chitosan, methacrylic acid, N, N, methylene bisacrylamide, and montmorillonite clay, to enable the controlled release of Diloxanide Furoate (DF), an anti-protozoal drug. Employing a swelling-assisted diffusion technique, drug loading percentages varied from 63.96 % to 76.82 % among different formulations. Increased chitosan and methacrylic acid content enhanced drug loading, while N, N, methylene bisacrylamide and montmorillonite clay demonstrated an inverse relationship affecting diffusion and swelling.Equilibrium swelling studies unveiled formulation-dependent behaviors, with chitosan reducing swelling and methacrylic acid promoting it. Higher N, N, methylene bisacrylamide concentrations decreased swelling, indicating a denser cross-linked structure, while montmorillonite clay reduced hydrophilicity and swelling capacity. Further analyses confirmed successful gel formation, particularly in formulations with higher chitosan, methacrylic acid, and N, N, methylene bisacrylamide content, while montmorillonite clay limited gel fraction due to restricted polymer chain mobility. Techniques such as Fourier transform infrared spectroscopy, Differential scanning calorimetry, and thermal gravimetric analyses supported network development, enhancing thermal stability and cross-linking density. This research underscores the flexibility of polymeric networks for precise drug delivery, offering potential advancements in targeted therapies for various medical conditions.

Efficient Cytotoxicity of Recombinant Azurin in Escherichia coli Nissle 1917-Derived Minicells against Colon Cancer Cells.

Compared to chemical drugs, therapeutic proteins exhibit higher specificity and activity and are generally well-tolerated by the human body. However, the limitations, such as poor stability both in vivo and in vitro as well as difficulties in penetrating cell membranes, hinder their widespread application. To overcome the challenges, a highly efficient protocol was developed and implemented for the recombinant expression of the therapeutic protein azurin and secretion into minicells derived from probiotic Escherichia coli Nissle 1917. The novel coupled production with a delivery system of therapeutic proteins based on minicells was obtained through purification to enhance protein activity, circulation characteristics, and targeting specificity. This protein drug carrier integrates the production of carrier materials and the loading of expression proteins. The drug carrier also protects the encapsulated polypeptide drugs from enzymatic or gastric acid degradation until they are released. Escherichia coli Nissle 1917-derived minicells have natural targeting to colon cancer cells, low toxicity, and can accumulate for a long time after penetrating tumor tissue. This self-produced protein drug delivery system simplified the process of protein preparation, and its inhibitory effect on different types of colon cancer cells was verified by CCK-8 cytotoxicity assay, cancer cell invasion, and migration assay. This work provided a simple method to prepare minicell drug delivery systems for protein drug production and a novel approach for the transport of recombinant protein drugs.

Efficient oral delivery of resveratrol-loaded cyclodextrin-metal organic framework for alleviation of ulcerative colitis

Developing innovative strategies for the oral administration of phytochemicals presents a promising approach to addressing intestinal diseases. However, numerous challenges persist, including limited therapeutic efficacy, poor bioavailability, and inadequate biocompatibility. In this study, we employed a cross-linked cyclodextrin-metal organic framework (CDF) to encapsulate resveratrol (Res), generating Res-CDF, which was subsequently incorporated into natural polysaccharide hydrogel microspheres (Res-CDF in MPs) for targeted oral delivery to alleviate ulcerative colitis (UC). The underlying adsorption mechanism of Res by γ-CD elucidated by molecular dynamics simulations. Importantly, the Res-CDF in MPs formulation protected against gastric acid degradation while preserving the bioactivity of Res. Moreover, the design enabled specific release of Res-CDF in response to the mildly alkaline environment of the intestinal tract, followed by sustained Res release. In UC mice model, Res-CDF in MPs demonstrated potent anti-inflammatory effects by attenuating pro-inflammatory cytokine production and exhibited antioxidant properties. Additionally, Res-CDF in MPs enhanced the expression of tight junction proteins ZO-1, Occludin, and mucin-2 (Muc-2), thereby maintaining normal intestinal barrier function. This innovative oral delivery strategy capitalizes on the advantageous properties of polysaccharide hydrogel and CDF to augment bioavailability of phytochemicals, laying the groundwork for developing novel oral interventions employing natural phytochemicals to address intestinal-related diseases.

Formulation of Chitosan-Zein Nano-in-Microparticles for Oral DNA Delivery.

Gene delivery via the oral route offers a promising strategy for improving DNA vaccination and gene-based therapy outcomes. The noninvasive nature of oral delivery lends to ease of dosing, which can facilitate convenience and patient compliance. Moreover, oral administration allows for both local and systemic production of therapeutic genes or, in the case of DNA vaccination, mucosal and systemic immunity. Here, we describe the methods to produce a dual biomaterial, oral DNA delivery system composed of chitosan (CS) and zein (ZN). In this system, CS serves to encapsulate and deliver DNA cargo to intestinal cells in the form of CS-DNA nanoparticles (CS-DNA NPs), while ZN is used to form a protective matrix around the CS-DNA NPs that prevent degradation during gastric transit but then degrades to release the CS-DNA NPs for transfection upon entry into the intestines. These particles have demonstrated the ability to effectively protect cargo DNA from simulated gastric degradation in vitro and mediate transgene production in vivo, making them an effective oral gene delivery system.

Chitosan Microparticles Enhance the Intestinal Release and Immune Response of an Immune Stimulant Peptide in Oncorhynchus mykiss.

The aquaculture industry is constantly increasing its fish production to provide enough products to maintain fish consumption worldwide. However, the increased production generates susceptibility to infectious diseases that cause losses of millions of dollars to the industry. Conventional treatments are based on antibiotics and antivirals to reduce the incidence of pathogens, but they have disadvantages, such as antibiotic resistance generation, antibiotic residues in fish, and environmental damage. Instead, functional foods with active compounds, especially antimicrobial peptides that allow the generation of prophylaxis against infections, provide an interesting alternative, but protection against gastric degradation is challenging. In this study, we evaluated a new immunomodulatory recombinant peptide, CATH-FLA, which is encapsulated in chitosan microparticles to avoid gastric degradation. The microparticles were prepared using a spray drying method. The peptide release from the microparticles was evaluated at gastric and intestinal pH, both in vitro and in vivo. Finally, the biological activity of the formulation was evaluated by measuring the expression of il-1β, il-8, ifn-γ, Ifn-α, and mx1 in the head kidney and intestinal tissues of rainbow trout (Oncorhynchus mykiss). The results showed that the chitosan microparticles protect the CATH-FLA recombinant peptide from gastric degradation, allowing its release in the intestinal portion of rainbow trout. The microparticle-protected CATH-FLA recombinant peptide increased the expression of il-1β, il-8, ifn-γ, ifn-α, and mx1 in the head kidney and intestine and improved the antiprotease activity in rainbow trout. These results suggest that the chitosan microparticle/CATH-FLA recombinant peptide could be a potential prophylactic alternative to conventional antibiotics for the treatment of infectious diseases in aquaculture.

Capsulated Cellular Nanosponges for the Treatment of Experimental Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal tract disorder characterized by uncontrolled inflammatory responses to the disrupted intestinal epithelial barrier and gut microbiome dysbiosis. Currently available small-molecule immunosuppressive agents and anticytokine biologics show limited potency, mainly due to the complexity of the inflammatory network involved in IBD. Here, we develop an oral formulation of macrophage membrane-coated nanoparticles capsulated in enteric polymer-coated gelatin capsules (denoted "cp-MΦ-NPs") for IBD treatment. The capsules protect the nanoparticles from gastric degradation and allow for targeted delivery to the colon. At the inflamed colon, cp-MΦ-NPs act as macrophage decoys that bind and neutralize pro-inflammatory cytokines. The in vivo treatment efficacy of cp-MΦ-NPs is tested in a mouse model of dextran sulfate sodium-induced colitis. In both prophylactic and delayed treatment regimens, the oral delivery of cp-MΦ-NPs significantly alleviates IBD severity, reflected by reduced intestinal inflammation and intestinal barrier restoration. Overall, cp-MΦ-NPs provide a biomimetic nanomedicine strategy for the treatment of IBD.

Formulation Development and Characterization of Vancomycin Hydrochloride Colon-Targeted Tablets Using In-Situ Polyelectrolyte Complexation Technique

Introduction: Vancomycin hydrochloride (VH) is an amphoteric glycopeptide antibiotic used to manage enterocolitis and pseudomembranous colitis. However, VH is prone to proteolytic degradation in the stomach, thus obscuring the drug entry into the colon. Colon-targeted drug delivery can prevent gastric degradation and localise the drug in the colon. &#x0D; Methodology: The applicability of in situ polyelectrolyte complexation technique using the polymers Chitosan, Karaya gum, and Hupu gum at various concentrations along with enteric coating using Eudragit S100 was studied for the preparation of colon-targeted tablets of VH.&#x0D; Colon-targeted tablets of VH are developed by incorporating natural polymers like chitosan, karaya gum, and hupu gum at different concentrations such that in-situ polyelectrolyte complex is formed and the formulations were then coated with Eudragit S100(6%, 8%, and 10% weight gain) to release the drug in a controlled manner in the colon. &#x0D; Results: Prepared formulations were subjected to in vitro, ex vivo, and in vivo evaluation studies. Out of all the prepared formulations, the formulation H2C10 prepared with 10:2 PEC and 10% Eudragit S100 coating has shown a sufficient lag time of 2 hours in 0.1N HCl, 3 hours of lag time in pH 6.8 phosphate buffer and has shown a 100.02% drug release at 22 hours in pH 7.4 phosphate buffer. &#x0D; Conclusion: The research results suggested that a colon-targeted drug delivery system of VH can decrease drug degradation and achieve higher concentrations in the colon to provide more therapeutic benefits.

Metabolism characterization and chemical and plasma stability of casearin B and caseargrewiin F.

Oral preparations of Casearia sylvestris (guacatonga) are used as antacid, analgesic, anti-inflammatory and antiulcerogenic activities. The clerodane diterpenes casearin B (cas B) and caseargrewiin F (casg F) are major active compounds in vitro and in vivo. The oral bioavailability and metabolism of cas B and casg F were not previously investigated. We aimed to assess the stability of cas B and casg F in physiological conditions and their metabolism in human liver microsomes (HLM). The compounds were identified by UHPLC-QTOF-MS/MS and quantified by validated LC-MS methods. The stability of cas B and casg F in physiological conditions was assessed in vitro. Both diterpenes showed a fast degradation (p < 0.05) in simulated gastric fluid. Their metabolism is not mediated by cytochrome P-450 enzymes, but the depletion was inhibited by the esterase inhibitor NaF. Both diterpenes and their dialdehydes showed log P in the range of 3.6 to 4.0, suggesting high permeability. Metabolism kinetic data were fitted to the Michaelis-Menten profile with KM values of 61.4 μM and 66.4 μM and Vmax values of 327 and 648 nmol/min/mg of protein for cas B and casg F, respectively. Metabolism parameters in HLM were extrapolated to predict human hepatic clearance and suggest that casg F and cas B have a high hepatic extraction ratio. In conclusion, our data suggest that casg F and cas B present low oral bioavailability due to extensive gastric degradation and high hepatic extraction.