Nose to brain delivery of mirtazapine via lipid nanocapsules: Preparation, statistical optimization, radiolabeling, in vivo biodistribution and pharmacokinetic study.

Mirtazapine (MZPc) is an antidepressant drug which is approved by the FDA. It has low bioavailability, which is only 50%, in spite of its rapid absorption when orally administered owing to high first-pass metabolism. This study was oriented towards delivering intranasal (IN) mirtazapine by a direct route to the brain by means of preparing lipid nanocapsules (LNCs) as a targeted drug delivery system. MZP-LNCs were constructed by solvent-free phase inversion temperature technique applying D-Optimal mixture design to study the impact of 3 formulation variables on the characterization of the formulated nanocapsules. Independent variables were percentage of Labrafac oil, percentage of Solutol and percentage of water. Dependent variables were particle size, polydispersity index (PDI), Zeta potential and solubilization capacity. Nanocapsules of the optimized formula loaded with MZP were of spherical shape as confirmed by transmission electron microscopy with particle diameter of 20.59 nm, zeta potential of - 5.71, PDI of 0.223 and solubilization capacity of 7.21 mg/g. The in vivo pharmacokinetic behavior of intranasal MZP-LNCs in brain and blood was correlated to MZP solution after intravenous (IV) and intranasal administration in mice. In vivo biodistribution of the drug in mice was assessed by a radiolabeling technique using radioiodinated mirtazapine (131I-MZP). Results showed that intranasal MZP-LNCs were able to deliver higher amount of MZP to the brain with less drug levels in blood when compared to the MZP solution after IV and IN administration. Moreover, the percentage of drug targeting efficiency (%DTE) of the optimized MZP-LNCs was 332.2 which indicated more effective brain targeting by the intranasal route. It also had a direct transport percentage (%DTP) of 90.68 that revealed a paramount contribution of the nose to brain pathway in the drug delivery to the brain.

Differential Signaling Pathways in Medulloblastoma: Nano-biomedicine Targeting Non-coding Epigenetics to Improve Current and Future Therapeutics.

BACKGROUND: Medulloblastomas (MDB) are malignant, aggressive brain tumors that primarily affect children. The survival rate for children under 14 is approximately 72%, while for ages 15 to 39, it is around 78%. A growing body of evidence suggests that dysregulation of signaling mechanisms and noncoding RNA epigenetics play a pivotal role in this disease. METHODOLOGY: This study conducted an electronic search of articles on websites like PubMed and Google. The current review also used an in silico databases search and bioinformatics analysis and an extensive comprehensive literature search for original research articles and review articles as well as retrieval of current and future medications in clinical trials. RESULTS: This study indicates that several signaling pathways, such as sonic hedgehog, WNT/ß-catenin, unfolded protein response mediated ER stress, notch, neurotrophins and TGF-ß and ERK, MAPK, and ERK play a crucial role in the pathogenesis of MDB. Gene and ncRNA/protein are also involved as an axis long ncRNA to sponge micro-RNAs that affect downstream signal proteins expression and translation affection disease pathophysiology, prognosis and present potential target hit for drug repurposing. Current treatment options include surgery, radiation, and chemotherapy; unfortunately, the disease often relapses, and the survival rate is less than 5%. Therefore, there is a need to develop more effective treatments to combat recurrence and improve survival rates. CONCLUSION: This review describes various MDB disease hallmarks, including the signaling mechanisms involved in pathophysiology, related-causal genes, epigenetics, downstream genes/epigenes, and possibly the causal disease genes/non-protein coding (nc)RNA/protein axis. Additionally, the challenges associated with MDB treatment are discussed, along with how they are being addressed using nano-technology and nano-biomedicine, with a listing of possible treatment options and future potential treatment modalities.

Acetaminophen-traces bioremediation with novel phenotypically and genotypically characterized 2 Streptomyces strains using chemo-informatics, in vivo, and in vitro experiments for cytotoxicity and biological activity.

We isolated two novel bacterial strains, active against the environmental pollutant acetaminophen/Paracetamol®. Streptomyces chrestomyceticus (symbol RS2) and Flavofuscus (symbol M33) collected from El-Natrun Valley, Egypt-water, sediment, and sand samples, taxonomically characterized using a transmission electron microscope (TEM). Genotypic identification, based on 16S rRNA gene sequence analysis followed by BLAST alignment, were deposited on the NCBI as 2 novel strains https://www.ncbi.nlm.nih.gov/nuccore/OM665324  and https://www.ncbi.nlm.nih.gov/nuccore/OM665325 . The phylogenetic tree was constructed. Acetaminophen secondary or intermediate product's chemical structure was identified by GC/LC MS. Some selected acetaminophen secondary-product extracts and derived compounds were examined against a panel of test micro-organisms and fortunately showed a good anti-microbial effect. In silico chemo-informatics Swiss ADMET evaluation was used in the selected bio-degradation extracts for absorption (gastric), distribution (to CNS), metabolism (hepatic), excretion (renal), and finally not toxic, being non-mutagenic/teratogenic or genotoxic, virtually. Moreover, in vitro cytotoxic activity of these selected bio-degradation secondary products was examined against HepG2 and MCF7 cancer cell lines, where M33 and RS2 extract effects on acetaminophen/paracetamol bio-degradation products were safe, with higher IC50 on HepG2 and MCF7 than the acetaminophen/paracetamol IC50 of 108.5 µg/ml. Moreover, an in vivo oral acute single-dose toxicity experiment was conducted, to confirm these in vitro and in silico lower toxicity (better safety) than acetaminophen/paracetamol.

The potential immuno-stimulating effect of curcumin, piperine, and taurine combination in hepatocellular carcinoma; a pilot study.

BACKGROUND: This is a phase II clinical trial to investigate the immunotherapeutic effect of Curcumin, Piperine, and Taurine (CPT) combination in hepatocellular carcinoma (HCC). METHODS: Twenty-six HCC patients aged (50-80 years) were recruited for administration of a daily dose of 5 g of curcumin, 50 mg of piperine, and 500 mg of taurine divided into three doses for successive 3 months. The three components (CPT) were prepared in one capsule. Patients were assessed after each month (cycle) for the plasma levels of CD4, CD8, CD25, Interleukins-2 (IL-2), IL-6, IL-12, Interferon-gamma (IFN- γ), Lactate dehydrogenase (LDH), and Vascular endothelial growth factor (VEGF), FOXP3 mRNA, and miRNA 21. RESULTS: There was a significant increase in the plasma levels of CD4 and CD8, while a significant decrease in the CD25 level after the second and third cycles compared to the baseline level [P < 0.001 for both]. Also, there was a significant increase in the plasma levels of IL-2, IL-12, and IFN-γ [ P = 0.001, P = 0.006, and P = 0.029; respectively], while there was a significant decrease in IL-6, VEGF-α, LDH, and Alpha-fetoprotein (AFP) after CPT administration compared to the baseline levels [P < 0.001, P < 0.001, P = 0.020, and P = 0.004; respectively]. The expression level of miRNA-21 was significantly decreased after CPT administration compared to the baseline level [5.5±0.88, 4.1±0.78, 3±0.75, and 2.5±0.76; respectively, P<0.001]. Though there was a noticeable decrease in the FOXP3 expression after each cycle, however, it didn't reach a significant level [5.3±0.8, 4.2±0.76, 3.2±0.67, and 2.5±0.79; respectively, P=0.184]. CONCLUSION: CPT could exhibit a potential immune-stimulating effect in HCC patients. The current trial had been registered at the National Hepatology and Tropical Medicine Research Institute (NHTMRI), with a registration number of NHTMRI-IRB 2-21 on 5th January 2021.

Darifenacin Self-assembled Liquid Crystal Cubic Nanoparticles: a Sustained Release Approach for an Overnight Control of Overactive Bladder.

The current study is regarding the development and characterization of Darifenacin-loaded self-assembled liquid crystal cubic nanoparticles (LCCN). An anhydrous approach was used for the preparation of these cubic nanoparticles using a hydrotropic agent (propylene glycol), with minimal energy input. Upon dispersion in aqueous medium, the system was successfully transformed to cubosomal nanoparticles counterpart as depicted by transmission electron micrographs. A Box-Behnken design was used to optimize formulation variables, namely A: amount of GMO, B: amount of Pluronic F127, C: amount of PG, and D: amount of HPMC. The design has generated 29 formulae which were tested regarding drug content uniformity, dispersibility in water, particle size, zeta potential, polydispersity index, and in vitro release behavior. The numerical optimization algorithms have generated an optimized formula with high desirability ≈ 1. The optimized formula displayed small particle size, good homogeneity, and zeta potential along with controlled in vitro release profile and ex vivo permeation through rabbit intestine. Thus, self-assembled LCCN might offer an alternative anhydrous approach for the preparation of cubosomal nanoparticles with controlled release profile for a possibly better control of overactive bladder syndrome which tremendously affect the overall life quality.

Investigating the Targeting Power to Brain Tissues of Intranasal Rasagiline Mesylate-Loaded Transferosomal In Situ Gel for Efficient Treatment of Parkinson's Disease.

Rasagiline mesylate (RSM) is a hydrophilic drug with poor oral bioavailability (36%) because of hepatic first-pass metabolism. The present study focuses on delivering RSM directly to the brain through its inclusion within transferosomal in situ gel administered through the intranasal (IN) route. Transferosomes were formed by the thin-film hydration method with the aid of Design-Expert® software by varying the edge activator (EA) type in the absence or presence of cholesterol. By desirability calculations, the optimum formulation was composed of phosphatidylcholine and sodium deoxycholate as an EA (5:1% w/w) with no cholesterol. The optimum formulation was 198.63 ± 34.98 nm in size and displayed an entrapment efficiency of 95.73 ± 0.09%. Transmission electron microscopy revealed discrete and spherical vesicles. Optimized transferosomes were further incorporated into an in situ gel composed of 0.5% pectin, 15% Pluronic® F-127, and 5% Pluronic® F-68 and tested for the in vivo performance. The systemic as well as brain kinetics were assessed in rats by comparing the IN-administered in situ gel to the IV aqueous solution. The optimum in situ gel showed safety and biocompatibility on rats' nasal mucosa with enhanced brain bioavailability (131.17%). Drug targeting efficiency and direct transport percentage indices (304.53% and 67.16%, respectively) supported successful brain targeting offering direct nose-to-brain drug delivery.

Insights on the Dynamic Innovative Tumor Targeted-Nanoparticles-Based Drug Delivery Systems Activation Techniques.

Anti-cancer conventional chemotherapeutic drugs novel formula progress, nowadays, uses nano technology for targeted drug delivery, specifically tailored to overcome therapeutic agents' delivery challenges. Polymer drug delivery systems (DDS) play a crucial role in minimizing off-target side effects arising when using standard cytotoxic drugs. Using nano-formula for targeted localized action, permits using larger effective cytotoxic doses on a single special spot, that can seriously cause harm if it was administered systemically. Therefore, various nanoparticles (NPs) specifically have attached groups for targeting capabilities, not seen in bulk materials, which then need activation. In this review, we will present a simple innovative, illustrative, in a cartoon-way, enumeration of NP anti-cancer drug targeting delivery system activation-types. Area(s) covered in this review are the mechanisms of various NP activation techniques.

Multi-Epitope Vaccine Design against Monkeypox Virus via Reverse Vaccinology Method Exploiting Immunoinformatic and Bioinformatic Approaches.

(1) Background: The monkeypox virus is a zoonotic orthopox DNA virus that is closely linked to the virus. In light of the growing concern about this virus, the current research set out to use bioinformatics and immunoinformatics to develop a potential vaccine against the virus. (2) Methods: A multiepitope vaccine was constructed from the B-cell and T-cell epitopes of the MPXVgp181 strain using adjuvant and different linkers. The constructed vaccine was predicted for antigenicity, allergenicity, toxicity, and population coverage. In silico immune simulation studies were also carried out. Expression analysis and cloning of the constructed vaccine was carried out in the pET-28a(+) vector using snapgene. (3) Results: The constructed vaccine was predicted to be antigenic, non-allergenic, and non-toxic. It was predicted to have excellent global population coverage and produced satisfactory immune response. The in silico expression and cloning studies were successful in E. coli, which makes the vaccine construct suitable for mass production in the pharmaceutical industry. (4) Conclusion: The constructed vaccine is based on the B-cell and T-cell epitopes obtained from the MPXVgp181 strain. This research can be useful in developing a vaccine to combat the monkeypox virus globally after performing in-depth in vitro and in vivo studies.

Tangled quest of post-COVID-19 infection-caused neuropathology and what 3P nano-bio-medicine can solve?

COVID-19-caused neurological problems are the important post-CoV-2 infection complications, which are recorded in ~ 40% of critically ill COVID-19 patients. Neurodegeneration (ND) is one of the most serious complications. It is necessary to understand its molecular mechanism(s), define research gaps to direct research to, hopefully, design new treatment modalities, for predictive diagnosis, patient stratification, targeted prevention, prognostic assessment, and personalized medical services for this type of complication. Individualized nano-bio-medicine combines nano-medicine (NM) with clinical and molecular biomarkers based on omics data to improve during- and post-illness management or post-infection prognosis, in addition to personalized dosage profiling and drug selection for maximum treatment efficacy, safety with least side-effects. This review will enumerate proteins, receptors, and enzymes involved in CoV-2 entrance into the central nervous system (CNS) via the blood-brain barrier (BBB), and list the repercussions after that entry, ranging from neuroinflammation to neurological symptoms disruption mechanism. Moreover, molecular mechanisms that mediate the host effect or viral detrimental effect on the host are discussed here, including autophagy, non-coding RNAs, inflammasome, and other molecular mechanisms of CoV-2 infection neuro-affection that are defined here as hallmarks of neuropathology related to COVID-19 infection. Thus, a couple of questions are raised; for example, "What are the hallmarks of neurodegeneration during COVID-19 infection?" and "Are epigenetics promising solution against post-COVID-19 neurodegeneration?" In addition, nano-formulas might be a better novel treatment for COVID-19 neurological complications, which raises one more question, "What are the challenges of nano-bio-based nanocarriers pre- or post-COVID-19 infection?" especially in the light of omics-based changes/challenges, research, and clinical practice in the framework of predictive preventive personalized medicine (PPPM / 3P medicine).

Iron Oxide Nanoparticles-Plant Insignia Synthesis with Favorable Biomedical Activities and Less Toxicity, in the "Era of the-Green": A Systematic Review.

In the era of favoring environment-friendly approaches for pharmaceutical synthesis, "green synthesis" is expanding. Green-based nanomedicine (NM), being less toxic and if having biomedical acceptable activities, thence, the chemical methods of synthesis are to be replaced by plants for reductive synthesis. Iron oxide nanoparticles (IONPs) exhibited remarkable anti-microbial and anti-cancer properties, besides being a drug delivery tool. However, owing to limitations related to the chemical synthetic method, plant-mediated green synthesis has been recognized as a promising alternative synthetic method. This systematic review (SR) is addressing plant-based IONPs green synthesis, characteristics, and toxicity studies as well as their potential biomedical applications. Furthermore, the plant-based green-synthesized IONPs in comparison to nanoparticles (NPs) synthesized via other conventional methods, characteristics, and efficacy or toxicity profiles would be mentioned (if available). Search strategy design utilized electronic databases including Science Direct, PubMed, and Google Scholar search. Selection criteria included recent clinical studies, available in the English language, published till PROSPERO registration. After screening articles obtained by first electronic database search, by title, abstract and applying the PICO criteria, the search results yielded a total of 453 articles. After further full text filtrations only 48 articles were included. In conclusion, the current SR emphasizes the perspective of the IONPs plant-mediated green synthesis advantage(s) when utilized in the biomedical pharmaceutical field, with less toxicity.

Pharmaceutical nanotechnology: from the bench to the market.

BACKGROUND: Nanotechnology is considered a new and rapidly emerging area in the pharmaceutical and medicinal field. Nanoparticles, as drug delivery systems, impart several advantages concerning improved efficacy as well as reduced adverse drug reactions. MAIN BODY: Different types of nanosystems have been fabricated including carbon nanotubes, paramagnetic nanoparticles, dendrimers, nanoemulsions, etc. Physicochemical properties of the starting materials and the selected method of preparation play a significant aspect in determining the shape and characteristics of the developed nanoparticles. Dispersion of preformed polymers, coacervation, polymerization, nano-spray drying and supercritical fluid technology are among the most extensively used techniques for the preparation of nanocarriers. Particle size, surface charge, surface hydrophobicity and drug release are the main factors affecting nanoparticles physical stability and biological performance of the incorporated drug. In clinical practice, many nanodrugs have been used for both diagnostic and therapeutic applications and are being investigated for various indications in clinical trials. Nanoparticles are used for the cure of kidney diseases, tuberculosis, skin conditions, Alzheimer's disease, different types of cancer as well as preparation of COVID-19 vaccines. CONCLUSION: In this review, we will confer the advantages, types, methods of preparation, characterization methods and some of the applications of nano-systems.

Urethral instillation of chlorhexidine gel is an effective method of sterilisation.

Objective: To examine the effectiveness of preoperative urethral sterilisation with chlorhexidine gel in rendering the urethra as sterile as the skin of the genital area, with the skin sterilised as per the International Society for Sexual Medicine guidelines for penile prosthesis implantation. Patients and methods: A total of 111 male patients undergoing sterile andrological surgical procedures were divided into a control group (N = 61) and a chlorhexidine gel group (N = 50). Patients in the chlorhexidine group received urethral instillation with 6 mL of chlorhexidine preoperatively and on table. Patients from both groups received on-table skin preparation using povidone iodine and chlorhexidine povidone iodine. At the end of surgery, swabs were obtained from urethra and the penile skin. Skin and urethral swabs were compared for bacterial colonisation by culture and sensitivity. Results: Of the 111 patients, 16 had urethral colonisation and 10 had skin contamination, and they were all in the control group. The most common organism detected in both the urethral and skin samples was coagulase-negative Staphylococcus aureus. Urethral colonisation was significantly greater in the control group compared to the chlorhexidine group, at 16/61 vs 0/50 (P = 0.001). Similarly, skin colonisation was significantly greater in the control group compared to the chlorhexidine group, at 10/61 vs 0/50, (P = 0.002). Conclusion: Chlorhexidine gel is a powerful sterilising agent that will render the urethra sterile.

Industrial application of QbD and NIR chemometric models in quality improvement of immediate release tablets.

Quality by Design (QbD) and chemometric models are different sides of the same coin. While QbD models utilize experimentally designed settings for optimization of some quality attributes, these settings can also be utilized for chemometric prediction of the same attributes. We aimed to synchronize optimization of comparative dissolution results of carvedilol immediate release tablets with chemometric prediction of dissolution profile and content uniformity of the product. As an industrial application, selection of variables for optimization was done by performing risk assessment utilizing the archived product records at the pharmaceutical site. Experimental tablets were produced with 20 different settings with the variables being contents of sucrose, sodium starch glycolate, lactose monohydrate, and avicel Ph 101. Contents of the excipients were modelled with F1 dissimilarity factor and F2 similarity factor in HCL, acetate, and USP dissolution media to determine the design space. We initiatively utilized Partial Least Square based Structural Equation Modelling (PLS-SEM) to explore how the excipients and their NIR records explained dissolution of the product. Finally, the optimized formula was utilized with varied content of carvedilol for chemometric prediction of the content uniformity.

Investigating the Potential of Phosphatidylcholine-Based Nano-Sized Carriers in Boosting the Oto-Topical Delivery of Caroverine: in vitro Characterization, Stability Assessment and ex vivo Transport Studies.

PURPOSE: Drug delivery into the inner ear across the intact tympanic membrane (TM) has been a challenge in the treatment of inner ear disorders. In this study, nano-sized carriers were formulated for improving the non- invasive oto-topical delivery of caroverine for the treatment of tinnitus. METHODS: Caroverine was loaded into two types of phospholipid-containing systems, namely, nano elastic vesicles (EVs) and phosphatidylcholine-based liquid crystalline nano-particles (PC-LCNPs). The prepared formulations were characterized for their drug loading, particle size, polydispersity index, zeta potential, morphological features by transmission electron microscopy (TEM), and physicochemical stability. In addition, comparative ex vivo transport study was carried out using rabbits' TM for both types of formulations. RESULTS: The findings show a significant superiority of PC-LCNPs over the EVs formulations in the drug payload (1% and 0.25%, respectively), physical stability and the efficiency of permeation across rabbits' TM. The results showed a more than twofold increase in the cumulative drug flux values of PC-LCNPs (699.58 ± 100 µg/cm2) compared to the EVs (250 ± 45 µg/cm2) across the TM. CONCLUSION: The current study revealed the smart physicochemical properties of PC-LCNPs demonstrating the potential of this carrier as a new attractive candidate for improving the non-invasive oto-topical delivery of caroverine.

Intranasal lipid nanocapsules for systemic delivery of nimodipine into the brain: In vitro optimization and in vivo pharmacokinetic study.

Nimodipine (NM) is FDA-approved drug for treating subarachnoid haemorrhage induced vasospasm. Intravenous (IV) administration, the most common route of NM, causes several side effects such as hypotension, bradycardia, arrhythmias and inflammation at site of administration. The aim of this study was to investigate the capability of intranasal (IN) lipid nanocapsules (LNCs) for effective delivery of NM into the brain. NM LNCs were prepared by solvent free phase inversion temperature technique using D-Optimal mixture design studying the effects of three formulation variables on the properties of the prepared LNCs. The prepared particles were evaluated for particle size, drug payload, PDI, Zeta potential and in-vitro drug release. The optimized NM loaded LNC showed particle size of 35.94 ± 0.14 nm and PDI of 0.146 ± 0.045. The in-vivo pharmacokinetic behaviour of IN NM loaded LNC in blood and brain was compared with NM-solution after IV administration in rats. Results show that IN NM loaded LNC was capable to deliver the same amount of NM at brain tissue with lower drug levels in blood compared with IV administration of the NM solution which is greatly beneficial to minimize the cardiovascular side effects of NM. Contrary to most IN nanocarriers, systemic pathway rather than olfactory pathway plays the major role in brain delivery following IN administration of LNCs. The appropriate brain delivery with lower blood levels and slow elimination propose that intranasal LNCs could provide effective systemic delivery of NM into brain with lower frequency of administration and minimal side effects.

In-situ forming chitosan implant-loaded with raloxifene hydrochloride and bioactive glass nanoparticles for treatment of bone injuries: Formulation and biological evaluation in animal model.

In-situ forming implants receive great attention for repairing serious bone injuries. The aim of the present study was to prepare novel chitosan in-situ forming implants (CIFI) loaded with bioactive glass nanoparticles and/or raloxifene hydrochloride (RLX). Incorporating raloxifene hydrochloride (RLX) as a selective estrogen receptor modulator was essential to make use of its anti-resorptive properties. The prepared formulae were tested for their in-vitro gelation time, drug release, injectability, rheological properties, erosion rate and morphological properties. Results revealed that the formulation composed of 1% (w/v) chitosan with 2% (w/v) NaHCO3 and 1% (w/v) bioactive glass nanoparticles (CIFI-BG) possessed the most sustained drug release profile which extended over four months with low burst release effect compared to the same formulation lacking bioactive glass nanoparticles (CIFI). Selected formulations were tested for their ability to enhance bone regeneration in induced puncture in rate tibia. Results declared that these formulations were able to enhance bone regeneration after 12 weeks in comparison to the untreated tibial punctures and that containing bioactive glass could be considered as novel approach for treatment of serious bone injuries which require long term treatment and internal mechanical bone support during healing.

Integrated nanovesicular/self-nanoemulsifying system (INV/SNES) for enhanced dual ocular drug delivery: statistical optimization, in vitro and in vivo evaluation.

Ocular drug administration is usually problematic and suffers low bioavailability due to several physiological and biological factors that hinder their effective treatment. Terconazole (TZ) is considered as one of the effective ocular antifungal agents that is usually administrated intravitreally for higher efficacy. The aim of the work in this study is to formulate a TZ-loaded ocular drug delivery system with high efficiency and good tolerability. First, TZ-loaded bile-based nanovesicles (BBNV) were prepared and the formulation variables (namely, Span 60, cholesterol, and sodium deoxycholate levels) were optimized based on the results of the entrapment efficiency (EE%), particle size (PS), and zeta potential (ZP) using Box-Behnken statistical design. The optimized system was formulated using 73.59 mg Span 60, 1.28 mg cholesterol, and 3.11 mg sodium deoxycholate. The formulated system showed vesicles with PS of 526 nm, - 42.2 mV ZP, and 93.86% EE%. TZ release, cellular uptake, and cytotoxicity of the optimized system were evaluated in vitro. In addition, in vivo assessment of its safety was conducted histopathologically and via ocular irritation test to ensure the ocular tolerance of the system. Afterwards, the optimized TZ-loaded BBNV was integrated into a self-nanoemulsifying system (SNES) to allow faster TZ release for immediate antifungal effect, enhanced ocular residence, and improved ocular permeation. TZ release study revealed more than 2 folds increment in drug release rate from the integrated system compared to BBNV alone. Finally, this integrated system was assessed for its antifungal activity in vivo where it demonstrated higher antifungal activity against induced Candida albicans infection. Graphical abstract.

Long lasting in-situ forming implant loaded with raloxifene HCl: An injectable delivery system for treatment of bone injuries.

Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries.

Superiority of DEAE-Dx-Stabilized Cationic Bile-Based Vesicles over Conventional Vesicles for Enhanced Hepatic Delivery of Daclatasvir.

The purpose of our study was to improve the delivery of a direct-acting antiviral drug, daclatasvir, to the site of action, liver tissues, using physically and biologically stable cationic bile-based vesicles. Accordingly, cationic bile-based vesicles were prepared as pro-bile-based vesicles and diethylaminoethyl dextran (DEAE-Dx)-stabilized bile-based vesicles to increase their stability without negatively affecting their hepatic affinity. The prepared bile-based vesicles were characterized for particle size, polydispersity index, ζ-potential, in vitro daclatasvir release, and ex vivo permeation using non-everted gut sac intestine. The in vivo biodistribution was experimented after oral administration utilizing the radiolabeling assay, where the liver showed the highest accumulation of the DEAE-Dx-stabilized bile-based vesicles after 4 h, reaching a value of 4.6% ID/g of the total oral administered dose of the labeled drug compared to drug solution, pro-bile-based vesicles, and cationic bile-based vesicles where the accumulation was 0.19, 1.3, and 0.31% ID/g, respectively. DEAE-Dx-stabilized bile-based vesicles increased the drug deposition into the liver about 42-fold compared to oral solution. The high physical stability and the high resistance to opsonization and clearance show that DEAE-Dx-stabilized bile-based vesicles could be efficiently applied for enhancing daclatasvir delivery to the liver after oral administration.

Combined site-specific release retardant mini-matrix tablets (C-SSRRMT) for extended oral delivery of dexketoprofen trometamol: in vitro evaluation and single versus multiple doses pharmacokinetic study in human volunteers.

Development of extended release oral formulations of dexketoprofen trometamol (DT), a rapidly eliminated drug with high solubility, poses a great challenge especially when a portion of the dose is to be absorbed from the colon. In this study, site-specific release-retardant mini-matrix tablets (SSRRMTs) were developed and functionally coated with pH-responsive materials to achieve a site-specific delivery of DT at the duodenojejunal (DSRRMT) and ileocecal (ISRRMT) regions. Stomach-specific coated mini-tablets (SSCMTs) were manufactured for immediate release of about 16% of the daily dose of DT in the stomach. The SSCMT, DSRRMT, and ISRRMT were combined into a solid dosage form (C-SSRRMT tablets or capsules) to achieve the required linear release profile for once daily administration of DT. The SSRRMT and C-SSRRMT formulations were evaluated for the physical properties, in vitro-disintegration and in vitro dissolution and proved to be consistent with the pharmacopeial specifications. The in vitro release profiles of both C-SSRRMT tablets and capsules showed a constant release rate of about 6 mg/h and were similar to that of the theoretical target linear release profile. The pharmacokinetic study using human volunteers showed the bioequivalence of a single oral dose of C-SSRRMT capsules compared to three-successive oral doses of the immediate release market tablets with less ups and downs in the drug levels. The C-SSRRMT capsules formulation, may therefore, constitute an advance in the extended oral delivery of DT without the lack of efficacy and the adverse events frequently encountered in multiple daily dosing of the immediate release tablets.