Poor Oral Absorption Research Articles

Hansen parameters and GastroPlus assisted optimized topical elastic liposomes to treat breast cancer using a novel isatin derivative

Breast cancer treatment is a global health challenge using conventional toxic chemotherapeutic agents. A novel isatin could be a promising alternative. An isatin derivative (TM-19) was synthesized and characterized using NMR (nuclear magnetic resonance), mass spectrometry, Fourier transform infrared (FTIR), and differential scanning calorimetry (DSC). HSPiP and GastroPlus predictive software were used to predict suitable solvents for solubility and in vivo oral pharmacokinetics in humans (fasted condition), respectively. Based on predictive findings, topical elastic liposomes (phosphatidylcholine as PC and span 80 by film hydration method) was prepared, characterized, and optimized using QbD (quality by design). QbD identified the impact of composition on response variables (Y1 for size, Y2 for polydispersity index, Y3 for zeta potential, and Y4 for %EE). In vitro cytotoxicity study was carried out against MCF-7 cell lines. Low molecular weight and lipophilic TM-19 was crystalline in nature (255 g/mol). GastroPlus program predicted limited in vivo dissolution and poor oral absorption (10.4 %). Results confirmed the highest TM-19 solubility in DMSO (dimethyl sulfoxide) ˃ chloroform ˃ PEG 400 (polyethylene glycol 400). Considering experimental and predicted data, topical delivery of TM-19 using optimized (desirability parameter value = 0.97) elastic liposomes (TF1) was quite promising due to optimal size (344 nm), high %EE (61.7 %), low PDI (0.45), and optimal zeta potential (− 12.34 mV). TM-19 loaded TF1 elicited concentration dependent cytotoxic effect (˃ 90 % at 10 µM) against MCF-7 as compared to TM-19 suspension.

Bioavailability enhancement of atazanavir sulphate using mixed micelles: in vitro characterization and in vivo pharmacokinetic study.

This study aims to enhance the oral bioavailability of atazanavir sulphate, a human immunodeficiency virus-1 protease inhibitor known for its poor oral absorption, by formulating mixed micelles using Soluplus® and Kolliphor HS 15. Mixed micelles were prepared through the thin film hydration technique. The micelles were characterized for particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, drug loading, and confirmed for atazanavir sulphate encapsulation via FTIR studies. In vitro release studies were conducted, and the morphology of the micelles was examined using TEM. Atazanavir sulphate mixed micelles exhibited a particle size of 62.92nm, PDI of 0.221, zeta potential of - 17.8mV, high entrapment efficiency (99.76 ± 1.06), and drug loading (14 ± 0.82). In vitro release studies demonstrated sustained release up to 12h, with maximum solubility observed at 2h under pH 1.2 conditions. TEM analysis revealed spherical micelle morphology. Oral administration of atazanavir sulphate mixed micelles showed a 1.23-fold increase in relative bioavailability compared to pure drug suspension. The formulation of mixed micelles using Soluplus® and Kolliphor HS 15 offers a promising strategy to improve the oral bioavailability of atazanavir sulphate. These findings suggest the potential utility of mixed micelles as an effective delivery system for atazanavir sulphate, offering enhanced therapeutic outcomes for patients.

PK-PD relationship of poorly absorbable active ingredients from traditional Chinese medicines explaining by metabolic enzyme of gut microbiota: A case study of Dehydrocorydaline

Many active ingredients in traditional Chinese medicines generally have the characteristic of poor oral absorption but definite efficacy. It is necessary to establish a comprehensive technical system to explain the “PK-PD relationship” of them. Dehydrocorydaline (DHC), the quality control component in the Chinese patent drug “Kedaling Tablets”, has poor oral absorption but clear efficacy for coronary heart disease. Using DHC as a model drug, the changes in absorption and pharmacological effects of DHC in rats before and after inhibiting nitroreductase (NR) from gut microbiota were studied. The results showed that after inhibiting of NR activity, the plasma concentration of DHC in rats was decreased, the serum level of total cholesterol, triglyceride and low-density lipoprotein cholesterol were significantly increased. The levels of tumor necrosis factor-α, interleukin-1β, hypersensitive C-reactive protein, intercellular cell adhesion molecule-1 and Monocyte chemoattractant protein-1 were significantly increased, and pathological sections also showed that the efficacy of DHC decreased after inhibiting the activity of NR. We further investigated the drug metabolism of DHC under NR and found that DHC was metabolized into a hydrogenated metabolite, which may have stronger membrane permeability. In summary, NR may mediate the absorption degree and efficacy of DHC in vivo by metabolizing DHC into absorbable metabolite.

Myristic Acid Solid Lipid Nanoparticles Enhance the Oral Bioavailability and Therapeutic Efficacy of Rifaximin against MRSA Pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is one of the leading causes of death and an immense financial burden on healthcare systems. Rifaximin (RFX) has good antibacterial activity against MRSA, but its clinical application is limited due to its poor oral absorption. Solid lipid nanoparticles have good biocompatibility, high drug loading, sustained release performance, and the inertia of lipids in gastric acid, which facilitates oral drug delivery. In order to improve the oral bioavailability of rifaximin and expand the clinical application of RFX for MRSA pneumonia, this study developed RFX-loaded myristic acid solid lipid nanoparticles (RFX-SLNs). This study first prepared RFX-SLNs through hot melt emulsification and ultrasonic methods and selected the optimal formula of RFX-SLNs through single-factor screening. Afterward, the particle size, zeta potential, and polydispersity index (PDI) of the RFX-SLNs were measured, the morphology of RFX-SLNs was observed by transmission electron microscopy, and the encapsulation efficiency (EE) and drug loading capacity (LC) of RFX-SLNs were detected by high-performance liquid chromatography. Then, the sustained release ability and oral bioavailability of RFX-SLNs were studied through in vitro release and pharmacokinetics. Finally, the therapeutic effect of RFX-SLNs on MRSA pneumonia infection was studied by using a mouse MRSA pneumonia infection model. The optimal formulation of RFX-SLNs was 1% RFX with water (3% PVA) and oil (myristic acid) ratio of 1:19. RFX-SLNs were spherical in shape with a smooth surface and uniform size. The EE and LC of three different batches of RFX-SLNs were 89.35±2.47%, 90.45±3.69%, 88.72±1.18%, and 9.50 ± 0.01%, 10.09±0.01%, and 9.68±0.00%, respectively. In vitro release and pharmacokinetic studies showed that the myristic acid solid lipid nanoparticles showed excellent sustained release as expected and increased the oral bioavailability of RFX by 2.18 times. This indicates that RFX-SLNs can be used for the oral treatment of bacterial infections. Compared to RFX, RFX-SLNs showed good therapeutic effects in a mouse MRSA pneumonia infection model. This study indicates that the myristic acid solid lipid nanoparticles might be an effective way to enhance the oral absorption and therapy effects of RFX and other insoluble drugs. This not only opens up avenues for the clinical application of RFX but also provides a way for the development of new dosage forms of water-soluble drugs and the expansion of their clinical application scope.

Tumor-Specific Nano-Herb Delivery System with High L-Arginine Loading for Synergistic Chemo and Gas Therapy against Cervical Cancer.

Cancer metastasis poses significant challenges in current clinical therapy. Osthole (OST) has demonstrated efficacy in treating cervical cancer and inhibiting metastasis. Despite these positive results, its limited solubility, poor oral absorption, low bioavailability, and photosensitivity hinder its clinical application. To address this limitation, a glutathione (GSH)-responded nano-herb delivery system (HA/MOS@OST&L-Arg nanoparticles,HMOA NPs) is devised for the targeted delivery of OST with cascade-activatable nitric oxide (NO) release. The HMOA NPs system is engineered utilizing enhanced permeability and retention (EPR) effects and active targeting mediated by hyaluronic acid (HA) binding to glycoprotein CD44. The cargoes, including OST and L-Arginine (L-Arg), are released rapidly due to the degradation of GSH-responsive mesoporous organic silica (MOS). Then abundant reactive oxygen species (ROS) are produced from OST in the presence of high concentrations of NAD(P)H quinone oxidoreductase 1 (NQO1), resulting in the generation of NO and subsequently highly toxic peroxynitrite (ONOO-) by catalyzing guanidine groups of L-Arg. These ROS, NO, and ONOO- molecules have a direct impact on mitochondrial function by reducing mitochondrial membrane potential and inhibiting adenosine triphosphate (ATP) production, thereby promoting increased apoptosis and inhibiting metastasis. Overall, the results indicated that HMOA NPs has great potential as a promising alternative for the clinical treatment of cervical cancer.

Benefits of combining supersaturating and solubilizing formulations – Is two better than one?

A variety of enabling formulations has been developed to address poor oral drug absorption caused by insufficient dissolution in the gastrointestinal tract. As the in vivo performance of these formulations is a result of a complex interplay between dissolution, digestion and permeation, development of suitable in vitro assays that captures these phenomena are called for. The enabling-absorption (ENA) device, consisting of a donor and receiver chamber separated by a semipermeable membrane, has successfully been used to study the performance of lipid-based formulations. In this work, the ENA device was prepared with two different setups (a Caco-2 cell monolayer and an artificial lipid membrane) to study the performance of a lipid-based formulation (LBF), an amorphous solid dispersion (ASD) and the potential benefit of combining the two formulation strategies. An in vivo pharmacokinetic study in rats was performed to evaluate the in vitro-in vivo correlation. In the ENA, high drug concentrations in the donor chamber did not translate to a high mass transfer, which was particularly evident for the ASD as compared to the LBF. The solubility of the polymer used in the ASD was strongly affected by pH-shifts in vitro, and the ph_dependence resulted in poor in vivo performance of the formulation. The dissolution was however increased in vitro when the ASD was combined with a blank lipid-based formulation. This beneficial effect was also observed in vivo, where the drug exposure of the ASD increased significantly when the ASD was co-administered with the blank LBF. To conclude, the in vitro model managed to capture solubility limitations and strategies to overcome these for one of the formulations studied. The correlation between the in vivo exposure of the drug exposure and AUC in the ENA was good for the non pH-sensitive formulations. The deconvoluted pharmacokinetic data indicated that the receiver chamber was a better predictor for the in vivo performance of the drug, however both chambers provided valuable insights to the observed outcome in vivo. This shows that the advanced in vitro setting used herein successfully could explain absorption differences of highly complex formulations.

Preclinical pharmacokinetics, pharmacodynamics, and toxicity of novel small-molecule GPR119 agonists to treat type-2 diabetes and obesity

The escalating global prevalence of type-2 diabetes (T2D) and obesity necessitates the development of novel oral medications. Agonism at G-protein coupled receptor-119 (GPR119) has been recognized for modulation of metabolic homeostasis in T2D, obesity, and fatty liver disease. However, off-target effects have impeded the advancement of synthetic GPR119 agonist drug candidates. Non-systemic, gut-restricted GPR119 agonism is suggested as an alternative strategy that may locally stimulate intestinal enteroendocrine cells (EEC) for incretin secretion, without the need for systemic drug availability, consequently alleviating conventional class-related side effects. Herein, we report the preclinical acute safety, efficacy, and pharmacokinetics (PK) of novel GPR119 agonist compounds ps297 and ps318 that potentially target gut EEC for incretin secretion. In a proof-of-efficacy study, both compounds demonstrated glucagon-like peptide-1 (GLP-1) secretion capability during glucose and mixed-meal tolerance tests in healthy mice. Furthermore, co-administration of sitagliptin with investigational compounds in diabetic db/db mice resulted in synergism, with GLP-1 concentrations rising by three-fold. Both ps297 and ps318 exhibited low gut permeability assessed in the in-vitro Caco-2 cell model. A single oral dose PK study conducted on healthy mice demonstrated poor systemic bioavailability of both agents. PK measures (mean ± SD) for compound ps297 (Cmax 23 ± 19 ng/mL, Tmax range 0.5 – 1 h, AUC0–24 h 19.6 ± 21 h*ng/mL) and ps318 (Cmax 75 ± 22 ng/mL, Tmax range 0.25 – 0.5 h, AUC0–24 h 35 ± 23 h*ng/mL) suggest poor oral absorption. Additionally, examinations of drug excretion patterns in mice revealed that around 25 % (ps297) and 4 % (ps318) of the drugs were excreted through faeces as an unchanged form, while negligible drug concentrations (<0.005 %) were excreted in the urine. These acute PK/PD assessments suggest the gut is a primary site of action for both agents. Toxicity assessments conducted in the zebrafish and healthy mice models confirmed the safety and tolerability of both compounds. Future chronic in-vivo studies in relevant disease models will be essential to confirm the long-term safety and efficacy of these novel compounds.

QbD-guided phospholipid-tagged nanonized boswellic acid naturosomal delivery for effective rheumatoid arthritis treatment

Studies have reported the potential role of Boswellic acids (BAs), bioactive pentacyclic triterpenes from Boswellia serrata (BS), in treating rheumatoid arthritis (RA). However, poor water solubility and limited oral absorption are restricting factors for its better therapeutic efficacy. Based on these assumptions, the current study aimed to develop naturosomal delivery of BAs to boost their extremely low bioavailability, colloidal stability, and water solubility. Nanonized naturosomes were developed and subsequently analyzed to show their physicochemical and functional features employing the quality-by-design approach. The solubility analysis of Boswellic acid naturosomes revealed a 16 times improvement in aqueous solubility compared to BS extract (BSE). The zeta potential and dynamic light scattering findings of BSE naturosomes (BSENs) have demonstrated their colloidal stability with regulated nano-size particles. Additionally, compared to BSE (⁓31%), in-vitro dissolution experiments showed that >99% of pentacyclic triterpenes were released from BSENs. Studies on ex-vivo permeation showed that BSENs' permeation (>79%) significantly improved over BSE's (⁓20%). In-vivo efficacy studies using CFA-prompted arthritis in rodents showed a critical expansion in body wt and an undeniable reduction in paw thickness, paw volume, and TNF-α treated with BSEN compared to the arthritis control and BSE-treated group. These findings suggest that BSENs can help treat RA drugs by demonstrating their efficacy in further clinical research to validate the significant improvements.

Nanostructured Lipid Carriers for oral treatment of leishmaniasis: Design and preclinical evaluation

Pentavalent antimonials are the primary treatment for leishmaniasis due to their proven efficacy and cost-effectiveness. However, they present poor oral absorption, parenteral administration, and serious adverse effects due to prolonged use. Nanostructured Lipid Carriers (NLC) offer a promising solution, providing prolonged release, enhanced intestinal permeability, and oral bioavailability. This study aimed to address these issues by developing Nanostructured Lipid Carrier loaded with meglumine antimoniate (NLC-MA) for oral leishmaniasis treatment. We used design of experiments (DoE) for optimization. The chosen NLC-MA was characterized assessing size, polydispersity index (PdI), zeta potential (ZP), entrapment efficiency (EE), pH, and by analytical techniques such as DSC, FTIR, XRD, and TEM. Stability under simulated gastrointestinal conditions, in vitro release kinetics, cytotoxicity in RAW 264.7 macrophages, and leishmanicidal activity were assessed. NLC-MA presented 41.13 nm, PdI 0.227, ZP −27.9 mV, EE of 62.43%, and pH 5.23. Characterization techniques confirmed drug incorporation and nanoparticles with reduced crystallinity. TEM images showed spherical morphology. NLC remained stable in gastrointestinal pH and under refrigeration storage, while lyophilized formulations retained their initial properties. MA release from NLC followed the Peppas-Sahlin model, an anomalous transport mechanism. Importantly, MA showed no cytotoxicity in macrophages, but the NLCs exhibited cytotoxicity beyond 50 µg/mL. NLC-MA displayed improved efficacy against Leishmania infantum. Overall, these results highlight the potential of utilizing a lipid nanocarrier incorporating meglumine antimoniate as an innovative drug delivery platform for oral treatment against leishmaniasis.

Analysis of gut microbiota metabolites of platycodin D and activity verification

As the main saponin component of Platycodon grandiflorum A.DC, Platycodin D has been reported to have an anti-obesity effect. Due to poor oral absorption, the intestinal microflora usually transforms saponins into potential bioactive substances. In this study, we profiled the metabolic changes of platycodin D by incubating it with intestinal microflora extracted from mice feces subjected to either a standard control diet or a high-fat diet. A UPLC-LTQ-Orbitrap-MS method was used for rapid analysis of the metabolic profile of platycodin D. A total of 10 compounds were identified 9 of which were assessed to be metabolized by intestinal microflora. Dehydroxylation and deglycosylation were the major metabolic process of platycodin D. The metabolic profile of platycodin D biotransformed by intestinal microflora was elucidated based on the metabolite information. Platycodin D and its metabolites had anti-inflammatory effects in LPS-stimulated RAW 264.7 cells. Only platycodin D could alleviate lipid accumulation in FFA-treated HepG2 cells.

Nano-encapsulation of EGCG in dextran 70-stabilized chitosan/SDS nanoparticles: Characterization, permeability behavior and oral bioavailability

Epigallocatechin gallate (EGCG) declares massive health benefits, while poor oral absorption and susceptibility to oxidation and degradation constrained clinical applications. EGCG-encapsulated chitosan/SDS nanoparticles coated with dextran 70（EDCSNs）were here prepared by ionic interaction. The nano-formulations stabilized by dextran 70 presented sizes less than <200 nm, > 30 mV zeta potential, excellent dispersion action and higher encapsulation efficiency, which outdistanced pluronic F-68 as stabilizer. Interaction mechanism of EGCG, chitosan, dextran 70 and SDS in EDCSNs were through hydrogen bond, ion–dipole and electrostatic of opposite charge. Compared with EGCG, EDCSNs demonstrated a superior stability and retention ability with the pH-responsive protection EGCG against degradation under the simulated gastrointestinal fluids. Furthermore, EDCSNs emanated remarkably antioxidant activity and permeability through the intestinal epithelial barrier. Oral administration of nano-formulations in rats evidently increased the plasma Cmax and area under-the-curve 1.95-fold than naked EGCG. Results evidenced that EDCSNs, as a new delivery system, has great potential improvement the stability of EGCG and enhancement the oral absorption and bioavailability.

Effects of Wuzhi Capsule on Whole-Blood Tacrolimus Concentration Levels: A Systematic Review and Meta-Analysis.

Wuzhi Capsule (WZC) is a traditional Chinese medicinal herb widely used to treat drug-induced hepatitis or liver dysfunction and is usually prescribed in China to increase tacrolimus concentration. Several studies with small sample sizes have shown that WZC can increase tacrolimus concentration levels in clinical practice. This study aimed to evaluate the effect of WZC on whole-blood tacrolimus concentration levels and safety. We searched 7 databases for randomized clinical trials (RCTs) and observational studies (OSs) comparing whole-blood tacrolimus concentration levels between WZC and non-WZC treatments. Data analysis was performed using Review Manager version 5.3. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. Eleven studies involving 6 RCTs and 5 OSs were included. The meta-analysis indicated that whole-blood tacrolimus concentration levels in the WZC group was significantly higher than that of the non-WZC group [weighted mean difference = 1.38, 95% CI (confidence interval), 1.21-1.56, P < 0.001], and similar results were shown in all the subgroups of follow-up time, different primary disease, and different WZC doses. In the self-control OSs, the whole-blood tacrolimus concentration levels in the WZC group was significantly higher than the non-WZC group (weighted mean difference = 1.17, 95% CI, 0.71-1.64, P < 0.001). WZC was generally well tolerated and there was no significant difference in the incidence of adverse reactions between the 2 groups. WZC can increase whole-blood tacrolimus concentration levels. This may be an economical and practical treatment choice for patients, especially those with poor oral tacrolimus absorption capabilities. Nevertheless, RCTs and OSs with large sample sizes and high quality are needed in the future to confirm these positive results.

Development and In Vitro Evaluation of Nanoparticles of Silymarin Using Central Composite Design

Silymarin is a phytoconstituent derived from the plant Silybum marianum with poor oral absorption and bioavailability but possesses hepatoprotective activity, anticancer activity, cardioprotective, neuroprotective, stabilizing, anti-inflammatory, and antioxidant activity. Therefore, the current work aims to develop a nanoformulation of silymarin to increase bioavailability, reduce dosing frequency, minimize toxicity, and improve patient compliance. Silymarin nanoparticles were created via the ionic gelation technique, employing chitosan and TPP as the primary polymers. A central composite design was employed for formulation optimization. Chitosan and TPP were employed as independent variables, while particle size and encapsulation efficiency were considered as dependent variables. The prepared nanoparticles were evaluated through entrapment efficiency, in vitro drug release, and drug-excipient interaction studies. Thirteen experiments were conducted using the experimental runs created by the central composite design. The average particle size was between 149nm and 294nm. The encapsulation efficiency percentage was between 65.4% and 87.3%. The polydispersity index had a value of 0.437. The zeta potential of the optimized formulation was determined to be 38.1 mV. The compatibility studies between the drug and excipients were confirmed using Fourier Transform Infrared Spectroscopy and Differential Scanning Calorimetry. The successful encapsulation of silymarin within the polymer core was verified through scanning electron microscopy analysis. The silymarin-loaded nanoparticles were observed to have a significant drug release of 98,942.43% over 24 hours. The outcomes of the study of Silymarin nanoparticles showed a substantial increase in the dissolution rate, which can be ascribed to the changed solubility properties of the drug. This result is consistent with the stated aim of improving drug absorption. Keywords: Silymarin, nanoformulation, central composite design.

Research Progress on Quercetin's Biological Activity and Structural Modification Based on Its Antitumor Effects

AbstractQuercetin is a naturally existing flavonoid with numerous physiological effects, including antitumor activity. It functions as an antitumor agent by inducing apoptosis and inhibiting tumor cell development, preventing tumor cell invasion and metastasis, and reversing tumor multidrug resistance. Quercetin has limited therapeutic usefulness due to its low water solubility, poor oral absorption, and low bioavailability. New quercetin derivatives are being developed and manufactured via a variety of methods to address inadequacies and for utilization in disease prevention and therapy. The synthesis and anticancer effects of quercetin derivatives, as well as the structure‐activity relationship of quercetin derivatives, were explored, and the unique dosage forms of these derivatives were summarized to serve as a reference for future quercetin research and development.

Tea saponins as novel stabilizers for the development of diosmin nanosuspensions: Optimization and in vitro evaluation

Diosmin (DSN) is a plant-origin polyphenolic component that has attracted considerable interest for various physiological applications. Nevertheless, DSN shows high intersubject variation and poor oral absorption because of its poor solubility and permeability. This study examined the use of phytosaponins, specifically, tea saponins (TS), as novel stabilizers for optimizing and preparing diosmin nanosuspensions using top-down methods. The main formulation and process variables in particle size and polydispersity index were investigated by single-factor experiment optimization. The DSN nanocrystals were prepared and then characterized by electron microscopy, Fourier transform infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD). Compared with conventional stabilizers, TS exhibited better stabilizing performance at low concentrations. The lyophilized powder, which had a particle size 478.4 ± 9.4 nm after redispersion, coupled with mannitol as lyoprotectant showed good redispersibility. Electron microscopy revealed that the nanocrystals had an irregular and lamellar morphology. PXRD and FT-IR spectroscopy indicated that the crystallinity of DSN was reduced during the production process. DSN nanosuspensions significantly enhanced the accelerated dissolution rate due to the amorphous status and decreasing particle size. Overall, this study presents an advantageous solution to poor solubility and offers a reasonable strategy for expanding the application range of DSN.

Nanoformulations of curcumin: An alliance for effective cancer therapeutics

Cancer is intimidating in its diversity, genetics, epigenetics, pathology, diagnosis, and response to therapy. The high rate of recurrence and development of resistance to therapies hinder the prognosis and the inadvertent side effects of contemporary medications can reduce the quality of life in patients. These observations emphasize the need for multi-targeted treatments that are not only relatively safe and economical, but also provide a more effective alternative to the conventional treatment modalities. Over the last few decades, scientific data has demonstrated that curcumin has a wide range of anti-cancer effects that are orchestrated via affecting diverse cancer signaling pathways. Nonetheless, the therapeutic applicability of curcumin is severely limited due to its low water solubility, poor oral absorption, and rapid clearance. These limitations prompted the development of various curcumin formulations including nanotechnology based delivery systems for the prevention and treatment of cancers. Therefore, we aimed to review the potential benefits of nanocurcumin in treating various cancer. We conducted a comprehensive search on the PubMed database to identify relevant publications concerning the use of nanocurcumin in cancer treatment, utilizing the search term 'nanocurcumin and cancer'. This review summarizes various preclinical and clinical studies that highlight the anticancer activities of curcumin nanoformulations including cyclodextrin complexes, dendrimers, exosomes, liposomes, gold nanoparticles (NPs), graphene nanocomposites, magnetic NPs, micelles, nanogels, polymeric NPs and solid-lipid NPs (SLNs). We further presented cellular mechanisms and clinical investigations, thus, emphasizing its potential in cancer prevention and treatment or even as an adjuvant therapy with conventional drugs to enhance therapeutic results in cancer patients.

Designing novel piperine-vanillin nano-crystals for bioavailability enhancement

Piperine (PIP) exhibits various pharmacological effects including anti-inflammatory, antipyretic, anti-convulsant, and neuroprotective activity, but its poor water solubility and oral absorption limit its therapeutic uses. In the present study, nano-crystal technology was employed to enhance the dissolution rate and bioavailability of PIP. Piperine-vanillin (PIP-VN) nano-crystals were formulated by top-down and bottom-up techniques and evaluated both in vitro and in vivo. The results revealed that the PIP-VN nano-crystal exhibited an average particle size of 34.03 ± 0.51 nm. In the release study, PIP-VN nano-crystal performed 2.63-fold enhancement than PIP coarse powder. Upon oral administration, in the brain AUC0–24 of PIP-VN nano-crystal was significantly higher than PIP suspension. The brain/blood ratio of the drug for PIP-VN nano-crystal was higher than PIP suspension; indicating that administration of PIP-VN nano-crystal was superior for the delivery drug to the brain. PIP-VN nano-crystal showed AUC0–24 of 5.654 ± 0.230 ngh/mL in the brain which was more than PIP suspension (AUC0–24 of 2.025 ± 0.009 ngh/mL in the brain). From AUC data it may be concluded that brain delivery efficiency was improved using the nano-crystal approach. Compared with PIP coarse powder PIP-VN nano-crystals exhibit excellent performance in both in vitro and in vivo studies.

Boosting systemic absorption of peptides with a bioinspired buccal-stretching patch.

Biopharmaceuticals, including proteins and peptides, have revolutionized the treatment of a wide range of diseases, from diabetes and cardiovascular disorders to virus infections and cancer. Despite their efficacy, most of these macromolecular drugs require parenteral administration because of their high molecular weight and relative instability. Over the past 40 years, only a few oral peptide drugs have entered clinical trials, even when formulated with substantial amounts of permeation enhancers. To overcome the epithelial barrier, devices that inject drugs directly into the gastrointestinal mucosa have been proposed recently. However, the robustness and safety of those complex systems are yet to be assessed. In this study, we introduced an innovative technology to boost drug absorption by synergistically combining noninvasive stretching of the buccal mucosa with permeation enhancers. Inspired by the unique structural features of octopus suckers, a self-applicable suction patch was engineered, enabling strong adhesion to and effective mechanical deformation of the mucosal tissue. In dogs, this suction patch achieved bioavailability up to two orders of magnitude higher than those of the commercial tablet formulation of desmopressin, a peptide drug known for its poor oral absorption. Moreover, systemic exposure comparable to that of the approved oral semaglutide tablet was achieved without further optimization. Last, a first-in-human study involving 40 healthy participants confirmed the dosage form's acceptability, thereby supporting the clinical translatability of this simple yet effective platform technology.

Fabrication of pH-dependent solid dispersion for oral colon-targeted delivery of notoginsenoside R1 and its protective effects on ulcerative colitis mice

Notoginsenoside R1 (R1), which originated from the rhizomes and roots of Panax notoginseng, is classified as a Biopharmaceutical Classification System class III drug with good solubility but poor oral absorption. Although R1 can alleviate the inflammation of dextran sulfate sodium (DSS)-induced colitis in mice, the problem of acid degradation and low bioavailability limit its application. The purpose of this study was aimed to design one kind of pH-dependent solid dispersion for oral colon-targeted delivery of R1. Using Eudragit S100 (ES 100) and PEG 4000 as the pH-dependent carriers, R1 solid dispersion (R1-SD) was fabricated by solvent evaporation method. Scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction analysis indicated that R1-SD was completely formed, the surface was smooth surface and the strip crystal structure of R1 disappeared. The in vitro release profile of R1-SD (R1-ES 100-PEG 4000, 1:7:1, weight ratio) exhibited that R1-SD was not released in media simulating the gastric condition (pH 1.2), but better release characteristics of the drug could be obtained in media simulating the intestinal condition (less than 30% in pH 6.8 phosphate-buffered saline and more than 90% in pH 7.6 condition). The in vitro colon absorption test showed that the absorption rate and cumulative release of R1-SD were higher than those of R1. R1-SD and R1 had apparent protective effect on colon shortening, inflammatory infiltrating tissue injury, weight loss, diarrhea, blood stool in mice with ulcerative colitis induced by DSS, and the protective effect of R1-SD was better than that of R1, which indicated R1-SD has good practical application prospects.

A comparative study on the dependence potential of thienorphine and buprenorphine

Background: As part of research to discover partial opioid agonists for new treatments of opioid abuse and dependency, thienorphine, a buprenorphine analogue, was synthesised and reported to be a potent, long-acting oripavine in multiple mammalian models. Thienorphine binds non-selectively to μ-, δ-, and κ-opioid receptors, and partially stimulates μ- and/or κ-opioid receptors in vitro. Compared with buprenorphine, thienorphine exhibits better analgesic effects and has higher oral bioavailability. Poor oral absorption and dependence have hindered the use of buprenorphine for detoxification therapy and relapse prevention in the clinic. The addiction potential of thienorphine is unknown, and is worthy of in-depth investigation. Methods: In the present study, we conducted a comparison of thienorphine and buprenorphine with respect to their physical and psychological dependence liabilities, using a naloxone-induced withdrawal test, a conditioned place preference test, and a self-administration experiment in rats. Results: In contrast to chronic buprenorphine administration, we failed to observe any severe abstinence syndromes in mice or rats treated with thienorphine after naloxone challenge in a physical dependence model. Compared with the dependence potentials of buprenorphine, rats treated with chronic thienorphine did not show a place conditioning response, self-administration, or psychological dependence. Conclusions: We demonstrated that thienorphine has a lower potential than buprenorphine for physical and psychological dependence. Our results indicate that thienorphine might be a good candidate to treat opioid addiction.