Inclusion Scenarios and Conformational Flexibility of the SSRI Paroxetine as Perceived from Polymorphism of β-Cyclodextrin–Paroxetine Complex

Depression, a global mental health problem, is prevalent during the coronavirus disease 2019 (COVID-19) pandemic and can be efficiently treated by selective serotonin reuptake inhibitors (SSRIs). Our study series aims at forwarding insights on the β-cyclodextrin (β-CD)–SSRI inclusion complexes by X-ray crystallography combined with density functional theory (DFT) calculation. Here, we report a new crystal form (II) of the 1:1 β-CD–paroxetine (PXT) complex, which is inspired by the reported 2:1 β-CD–PXT complex (crystal form I), reflecting an elusive phenomenon of the polymorphism in CD inclusion complexes. The β-CD–PXT polymorphism stems from the PXT conformational flexibility, which is defined by torsion angles κ, ε around the -CH2–O- group bridging the A- and C–D-rings, of which those of PXT in I and II are totally different. While PXT (II) in an open V-shaped conformation that has the B-ring shallowly inserted in the β-CD cavity, PXT (I) in a closed U-shaped structure is mostly entirely embedded in the β-CD dimeric cavity, of which the A-ring is deeply inserted in the main β-CD cavity. However, PXT molecules in both crystal forms are similarly maintained in the CD cavity via host–guest N–H···O5/O6 H-bonds and C/O–H···π(B/C) interactions and β-CDs have similar 3D arrangements, channel (II) vs. screw-channel (I). Further theoretical explorations on the β-CD–PXT thermodynamic stabilities and the PXT conformational stabilities based on their potential energy surfaces (PESs) have been completed by DFT calculations. The 2:1 β-CD–PXT complex with the greater presence of dispersion interactions is more energetically favorable than the unimolar complex. Conversely, whereas free PXT, PXT (II) and PXT in complex with serotonin transporter are more energetically stable, PXT (I) is least stable and stabilized in the β-CD cavity. As SSRIs could lessen the COVID-19 severity, the CD inclusion complexation not only helps to improve the drug bioavailability, but also promotes the use of antidepressants and COVID-19 medicines concurrently.

Effects of Prebiotic Supplement on Gut Microbiota, Drug Bioavailability and Adverse Effects in Patients with Colorectal Cancer at Different Primary Tumor Locations Receiving Chemotherapy: Study Protocol for a Randomized Clinical Trial

Background: The prevalence of colorectal cancer (CRC) worldwide is a huge challenge to human health. Primary tumor locations found to impact prognosisand response to therapy. The important role of gut microbiota in the progression and treatment of CRC has led to many attempts of alleviating chemotherapy-induced adverse effects using microecologics. However, the underlying mechanism of the difference in the prognosis of different primary tumor locations and the synergistic effect of prebiotics on chemotherapy need to be further elucidated. This study aims to explore the differences in tumor microbiota and examine the effectiveness of xylooligosaccharides (XOS) on gut microbiota, adverse effects, and bioavailability of chemotherapy drugs in CRC patients at different primary tumor locations.Methods: This is a double-blinded, randomized, parallel controlled clinical trial. Participants with left-sided CRC (LSCRC, n = 50) and right-sided CC (RSCC, n = 50) will randomly allocated to prebiotic group (n = 25) or control group (n = 25) and will receive either a daily XOS (3 g/d) or placebo, respectively, for 12 weeks. The primary outcomes will be the differences in the mucosa microbiota composition at different tumor locations, and differences in gut microbiota composition, adverse effects, and blood concentration of capecitabine posttreatment. The secondary outcomes will include other blood indicators, short-chain fatty acids (SCFAs) concentration, quality of life, and mental health.Discussion: This study will reveal the potential benefits of prebiotic for improving the gut microbiota composition, alleviating the adverse effects, and improving the efficacy of chemotherapy in patients with CRC. In addition, this study will provide data on the different distribution of tumor microbiota and the different changes of gut microbiota during treatment in LSCRC and RSCC, which may provide novel insights into personalized cancer treatment strategies based on primary tumor locations and gut microbiota in the future.Trial registration: Chinese Clinical Trial Registry(www.chictr.org.cn): ChiCTR2100046237. Registered on 12 May 2021.

Opportunities and Challenges of Nanoparticles in Digestive Tumours as Anti-Angiogenic Therapies

Digestive tumours, a common kind of malignancy worldwide, have recently led to the most tumour-related deaths. Angiogenesis, the process of forming novel blood vessels from pre-existing vessels, is involved in various physiological and pathological processes in the body. Many studies suggest that abnormal angiogenesis plays an important role in the growth, progression, and metastasis of digestive tumours. Therefore, anti-angiogenic therapy is considered a promising target for improving therapeutic efficacy. Traditional strategies such as bevacizumab and regorafenib can target and block the activity of proangiogenic factors to treat digestive tumours. However, due to resistance and some limitations, such as poor pharmacokinetics, their efficacy is not always satisfactory. In recent years, nanotechnology-based anti-angiogenic therapies have emerged as a new way to treat digestive tumours. Compared with commonly used drugs, nanoparticles show great potential in tumour targeted delivery, controlled drug release, prolonged cycle time, and increased drug bioavailability. Therefore, anti-angiogenic nanoparticles may be an effective complementary therapy to treat digestive tumours. In this review, we outline the different mechanisms of angiogenesis, the effects of nanoparticles on angiogenesis, and their biomedical applications in various kinds of digestive tumours. In addition, the opportunities and challenges are briefly discussed.

Evaluation of Excipient Risk in BCS Class I and III Biowaivers

The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here.

Biosynthesised Drug-Loaded Silver Nanoparticles: A Vivid Agent for Drug Delivery for Human Breast Carcinoma

The use of nanoparticles as drug carriers has been investigated, and it offers various benefits, including the controlled and targeted release of loaded or associated drugs, as well as enhanced drug bioavailability. They do, however, have certain disadvantages, such as in vivo toxicity, which affects all organs, including healthy ones, and overall disease treatment improvement, which might be undetectable or limited. Silver nanoparticles are being studied more and more due to their unique physical, chemical, and optical properties, which allow them to be used in a variety of applications, including drug delivery to specific targets in the body. Given the constraints of traditional cancer treatment, such as low bioavailability and the resulting usage of high doses that produce side effects, attempts to address these challenges are essential. In this work, Biocompatible Silver nanoparticles (AgNps) loaded with tamoxifen have been prepared using the gelation process. Tamoxifen-loaded green synthesized AgNps are reported to be amorphous. The phytochemicals present in the extract of Hemionitis arifolia leaf were responsible for the reduction of silver nitrate to AgNPs. The functional groups existing in the particles were identified with FT-IR analysis. XRD analysis state that the particles were crystalline in nature and arranged in quartzite crystal. Particle size and shape were illustrated from SEM analysis and revealed that the particles were amorphous in nature. UV-visible spectrophotometer showed the band around 440nm which was identified as “surface Plasmon resonance band”. The synthesized AgNps loaded with tamoxifen were significantly effective against Human breast cancer cells. The silver nanoparticle loaded with tamoxifen was found to be inducing apoptotic signals in the selected cells. It inhibits the breast cancer cells even at the lower concentration of AgNPs and TAM-AgNPs. Further apoptotic studies (AO/EtBr and DAPI) reveal that cell death is due to the fragmentation of nuclear material of the treated cells.

3D Printed Buccal Films for Prolonged-Release of Propranolol Hydrochloride: Development, Characterization and Bioavailability Prediction

Gelatin-polyvinylpyrrolidone (PVP) and gelatin-poly(vinyl alcohol) (PVA) mucoadhesive buccal films loaded with propranolol hydrochloride (PRH) were prepared by semi-solid extrusion 3D printing. The aim of this study was to evaluate the effects of the synthetic polymers PVP and PVA on thermal and mechanical properties and drug release profiles of gelatin-based films. The Fourier-transform infrared spectroscopy showed that hydrogen bonding between gelatin and PVP formed during printing. In the other blend, neither the esterification of PVA nor gelatin occurred. Differential scanning calorimetry revealed the presence of partial helical structures. In line with these results, the mechanical properties and drug release profiles were different for each blend. Formulation with gelatin-PVP and PRH showed higher tensile strength, hardness, and adhesive strength but slower drug release than formulation with gelatin-PVA and PRH. The in silico population simulations indicated increased drug bioavailability and decreased inter-individual variations in the resulting pharmacokinetic profiles compared to immediate-release tablets. Moreover, the simulation results suggested that reduced PRH daily dosing can be achieved with prolonged-release buccal films, which improves patient compliance.

Characterization of bilayered matrix-type mucoadhesive buccal films containing tizanidine hydrochloride and piroxicam

Purpose: To formulate and characterize tizanidine hydrochloride (TZN) and piroxicam (PRX)-loaded bilayer mucoadhesive buccal films with an intention to improve the bioavailability and patient compliance in pain management.Methods: Bilayer buccal films were prepared by solvent evaporation technique using hydroxypropyl methylcellulose (HPMC) 15cps and polyvinylpyrrolidone (PVP K30 as immediate release (IR) layer forming polymers and HPMC K15 M, PVP K 90 along with various muco adhesive polymers (Carbopol P934, sodium alginate, etc), as sustained release (SR) layer forming polymers. The prepared films werecharacterized for thickness, weight variation, folding endurance, surface pH, swelling index,mucoadhesive strength, in vitro residence time, in vitro drug release, ex vivo permeation and drug release kinetics.Results: The prepared films were of largely uniform thickness, weight and drug content. Moisture loss (%) and folding endurance were satisfactory. Surface pH was compatible with salivary fluid. Disintegration time was 85 s for F1 and 115 s for F2 of IR films. In vitro dissolution studies showed 99.12 ± 1.2 % (F1) and 90.36 ± 1.8 % (F2) were released in 45 min. Based on the above results, F1 was chosen as the optimum formulation to be combined with SR layer of TZN. Amongst the SR layers of TZN in vitro drug release. The findings show that of F2 was 98.38 ± 0.82 % and correlated with ex vivo release. Drug release followed zero order release kinetics and mechanism of drug release was non-Fickian type diffusion. In vitro residence time was greater than 5 h.Conclusion: The findings show that the bilayer buccal films demonstrate the dual impact of deliveringPRX instantly from the IR layer, with good controlled release and permeation of TZN from the SR layer, thus providing enhanced therapeutic efficacy, drug bioavailability and patient compliance.

Development and characterization of effervescent floating tablet of famotidine for treatment of peptic ulcer

Floating drug delivery systems (FDDS) are utilized to target drug discharge in the stomach or to the upper parts of intestine. Famotidine has been the most extensively used drug for the management of peptic ulcer for various decades. The current study concerns the development and evaluation of floating tablets of famotidine which, after oral administration, are planned to extend the gastric residence time, enhance drug bioavailability and aim the gastric ulcer. A FDDS was expanded using gas-forming agents, like sodium bicarbonate, citric acid and hydrocolloids, like hydroxypropyl methylcellulose (HPMC) and carbopol 934P. The prepared tablets were evaluated in terms of their pre-compression parameters, physical characteristics, buoyancy, buoyancy lag-time, in vitro release, and swelling index. The formulations were optimized for the different viscosity grades of HPMC, carbopol 934P and its concentrations and combinations. The consequences of the in vitro release studies demonstrated that the optimized formulation (F6) could sustain drug release (98%) for 24 h and remain buoyant for 24 hr. Optimized formulation (F6) showed no considerable change in physical appearance, drug content, total buoyancy time or in vitro dissolution study after storage at 40°C/75% RH for 3 months. Lastly the tablet formulations establish to be economical and may conquer the draw backs associated with the drug during its absorption. Keywords: Famotidine, Floating drug delivery system, Hydrocolloids, Gastric residence time.

Drug Delivery Challenges in Brain Disorders across the Blood–Brain Barrier: Novel Methods and Future Considerations for Improved Therapy

Due to the physiological and structural properties of the blood–brain barrier (BBB), the delivery of drugs to the brain poses a unique challenge in patients with central nervous system (CNS) disorders. Several strategies have been investigated to circumvent the barrier for CNS therapeutics such as in epilepsy, stroke, brain cancer and traumatic brain injury. In this review, we summarize current and novel routes of drug interventions, discuss pharmacokinetics and pharmacodynamics at the neurovascular interface, and propose additional factors that may influence drug delivery. At present, both technological and mechanistic tools are devised to assist in overcoming the BBB for more efficient and improved drug bioavailability in the treatment of clinically devastating brain disorders.

Current Research on Pro-Drug Therapies for Parkinson's and Alzheimer's Disease

: Background: alzheimer's disease (ad) and parkinson's (pd) disease are common neurodegenerative conditions of the central nervous system (cns). Thus, these diseases have only been treated symptomatically since no approved drug is available that provides a complete cure. Objectives: through reading relevant literature published at home and abroad, the method and significance of prodrug strategy to increase the efficacy of ad and pd drugs were discussed. Methods: the biological mechanisms and currently approved drugs for both diseases have been discussed, revealing that most of these treatments utilized existing prodrug design strategies, including increased lipophilicity, and the use of transporters mediation and bio-oxidation to improve oral bioavailability and brain permeability. Results: the purpose of this paper is to review the research progress in the treatment of neurodegenerative diseases (ndds), especially ad and pd, using the prodrug strategy. The research of drug bioavailability and the prodrug strategy of cns targeted drug delivery lay the foundation for drug development to treat these diseases. Conclusion: the use of prodrug strategies provides important opportunities for the development of novel therapies for ad and pd.