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There is increasing evidence that the intestinal microbiota plays an integral role in disease pathogenesis and treatment. Specifically, the intestinal microbiota significantly influences the pharmacokinetics and pharmacodynamics of orally administered drugs through direct involvement in drug metabolism and, consequently, drug bioavailability. However, the gut microbiota also exerts immunoregulatory effects on the liver—the organ primarily responsible for drug metabolism—thereby indirectly impacting the body's capacity to metabolise and process drugs. Individual differences in this pathway substantially contribute to the variability in clinical drug treatment outcomes observed between patients. This review examines the impact of liver immune responses, as triggered by the intestinal microbiota, on the activity of drug-metabolising enzymes and discusses the implications for precision medicine. [ABSTRACT FROM AUTHOR]

Introduction: In this study, we aimed to comparatively analyse the indicators of availability to orphan drugs in South Korea, the United States of America, Europe Union, and Japan. Methods: For 169 drugs designated as orphan drugs in South Korea between 2012 and 2021, information on the drugs designated as orphan drugs from each jurisdiction was extracted by country. Then, the availability indicators (approval time, drug lag time, and designation gap) were analysed for the drugs approved in each jurisdiction. Results: The approval rate of drugs designated as orphan drugs were 11.22% and 6.31% in the USA and EU, respectively, which was lower than that of orphan drugs in South Korea and Japan. The highest number of approved drugs was in the USA (87 drugs), EU 27 drugs, Japan 22 drugs and Korea 21 drugs. Furthermore, the approval time significantly differed between South Korea and the other countries. South Korea had a significantly different drug lag time and designation gap compared with the USA and EU. Conclusion: Our findings show that to fundamentally improve the access to treatments for rare disease, a policy of regulatory science that can comprehensively support the early stages of research and development and commercialisation is needed. [ABSTRACT FROM AUTHOR]

AbstractAlzheimer’s disease (AD) impairs mental development and interrupts neurocognitive functions that escalate with time leading to death. With continuous evolution in lifestyle and progression of age, the prevalence of AD is progressively rising, leading to a significant economic burden. Thus, effective therapeutic approaches are indeed necessary to address this growing concern. Current treatment regimens primarily help to relieve the symptoms, nevertheless, with nanotechnology-based approaches the nerve damage can be regressed along with a reduction in inflammation and improved brain delivery. Researchers and healthcare professionals are working diligently to develop innovative treatments and interventions to improve the quality of life for individuals affected by AD. This review paper aims to provide comprehensive insights on disease pathogenesis, FDA-approved treatment, recent advancements in drug therapy, and innovative formulation approaches along with an update on drugs in different clinical phases. The review specifically highlights nanocrystals-based formulations and their ability to minimize side effects, improve drug bioavailability, pharmacodynamics and pharmacokinetics. The current review also prospects of role of NCs in enabling drug delivery across BBB and it dives deep to understand its potential to carve out directions in this niche area of treating AD. [ABSTRACT FROM AUTHOR]

The medicinal potential of phytoconstituents obtained from plants is widely recognized. Whole-plant extracts or isolated phytoconstituents have been shown through experiments to exhibit a variety of medicinal potentials, including antibacterial, neurologically protective, liver-protective properties, an antioxidant and skin-protective properties. Although these phytoconstituents offer potential therapeutic effects, their usage is restricted due to inadequate bioavailability, persistence in physiological fluids, and authenticity problems. These remain unresolved issues that impact the use of these priceless traditional herbal remedies in the efficient management and treatment of a range of medical ailments. Phytoconstituents' loading in phospholipid-based vesicular systems may be a way to tackle these challenging issues. The goal of this review is to summarize phyto-phospholipid vesicles and some of their relevant uses in drug delivery systems, as well as to emphasize the relationship between properties and applications, as well as the effect of phospholipid species on drug delivery efficiency. Based on the findings of various research investigations, this literature review attempts to investigate why Phyto-phospholipid vesicles are considered as the best nanotechnology in delivery systems for drugs. Optimal absorption and utilization of nutraceuticals and herbal medications can be enhanced by the process of Phyto phospholipid complexation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), is a neurodegenerative disorder that escalates with time, exerting a significant impact on physical and mental health and leading to death. The prevalence of AD is progressively rising along with its associated economic burden and necessitates effective therapeutic approaches in the near future. This review paper aims to offer an insightful overview of disease pathogenesis, current FDA-approved drugs, and drugs in different clinical phases. It also explores innovative formulations and drug delivery strategies, focusing on nanocarriers and long-acting medications (LAMs) to enhance treatment efficacy and patient adherence. The review also emphasizes preclinical evidence related to nanocarriers and their potential to improve drug bioavailability, pharmacokinetics, and pharmacodynamics parameters, while also highlighting their ability to minimize systemic side effects. By providing a comprehensive analysis, this review furnishes valuable insights into different pathophysiological mechanisms for future drug development. It aims to inform the development of treatment strategies and innovative formulation approaches for delivering existing molecules in Alzheimer's disease, ultimately striving to improve patient compliance. [Display omitted] [ABSTRACT FROM AUTHOR]

The evolution of respiratory diseases represents a considerable public health challenge, as they are among the leading causes of death worldwide. In this sense, in addition to the high prevalence of diseases such as asthma, chronic obstructive pulmonary disease, pneumonia, cystic fibrosis, and lung cancer, emerging respiratory diseases, particularly those caused by members of the coronavirus family, have contributed to a significant number of deaths on a global scale over the last two decades. Therefore, several studies have been conducted to optimize the efficacy of treatments against these diseases, focusing on pulmonary drug delivery using nanomedicine. Thus, the development of nanocarriers has emerged as a promising alternative to overcome the limitations of conventional therapy, by increasing drug bioavailability at the target site and reducing unwanted side effects. In this context, nanoparticles composed of chitosan (CS) show advantages over other nanocarriers because chitosan possesses intrinsic biological properties, such as anti-inflammatory, antimicrobial, and mucoadhesive capacity. Moreover, CS nanoparticles have the potential to enhance drug stability, prolong the duration of action, improve drug targeting, control drug release, optimize dissolution of poorly soluble drugs, and increase cell membrane permeability of hydrophobic drugs. These properties could optimize the performance of the drug after its pulmonary administration. Therefore, this review aims to discuss the potential of chitosan nanoparticles for pulmonary drug delivery, highlighting how their biological properties can improve the treatment of pulmonary diseases, including their synergistic action with the encapsulated drug. [ABSTRACT FROM AUTHOR]

Ulcerative colitis is a chronic inflammatory bowel disease that strongly affects patient quality of life. Side effects of current therapies necessitate new treatment strategies that maximise the drug concentration at the site of inflammation, while minimizing systemic exposure. Capitalizing on the biocompatible and biodegradable structure of lipid mesophases, we present a temperature-triggered in situ forming lipid gel for topical treatment of colitis. We show that the gel is versatile and can host and release drugs of different polarities, including tofacitinib and tacrolimus, in a sustained manner. Further, we demonstrate its adherence to the colonic wall for at least 6 h, thus preventing leakage and improving drug bioavailability. Importantly, we find that loading known colitis treatment drugs into the temperature-triggered gel improves animal health in two mouse models of acute colitis. Overall, our temperature-triggered gel may prove beneficial in ameliorating colitis and decreasing adverse effects associated with systemic application of immunosuppressive treatments. Treatment of the chronic disease ulcerative colitis is impeded by systemic side effects of orally administered drugs. Here the authors develop a gel that uses the rectal temperature as a mechanism to trigger solidification for localized delivery of colitis therapeutics. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases are a major global health burden particularly with the increasing ageing population. Hereditary predisposition and environmental risk factors contribute to the heterogeneity of existing pathological phenotypes. Traditional clinical interventions focused on the use of small drugs have often led to failures due to the difficulties in crossing the blood–brain barrier and reaching the brain. In this regard, nanosystems can specifically deliver drugs and improve their bioavailability, overcoming some of the major challenges in neurodegenerative disease treatment. This review focuses on the use of nanosystems as an encouraging therapeutic approach targeting molecular pathways involved in localized and systematic neurodegenerative diseases. Among the latter, Friedreich's ataxia is an untreatable complex multisystemic disorder and the most widespread type of ataxia; it represents a test case to validate the clinical potential of therapeutic strategies based on nanoparticles with pleiotropic effects. [ABSTRACT FROM AUTHOR]

Dry eye disease is a multifactorial disorder of the eye and tear film with potential damage to the ocular surface. Various treatment approaches for this disorder aim to alleviate disease symptoms and restore the normal ophthalmic environment. The most widely used dosage form is eye drops of different drugs with 5% bioavailability. The use of contact lenses to deliver drugs increases bioavailability by up to 50%. Cyclosporin A is a hydrophobic drug loaded onto contact lenses to treat dry eye disease with significant improvement. The tear is a source of vital biomarkers for various systemic and ocular disorders. Several biomarkers related to dry eye disease have been identified. Contact lens sensing technology has become sufficiently advanced to detect specific biomarkers and predict disease conditions accurately. This review focuses on dry eye disease treatment with cyclosporin A-loaded contact lenses, contact lens biosensors for ocular biomarkers of dry eye disease, and the possibility of integrating sensors in therapeutic contact lenses. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases as a primary driver of global morbidity and mortality. Despite the array of therapeutic avenues in clinical practice, predominantly pharmaceutical and surgical interventions, they often fall short of fully addressing the clinical exigencies of cardiovascular patients. In recent years, nanocarriers have shown great potential in the treatment and diagnose of cardiovascular diseases. They can enhance drug targeting and bioavailability while reducing side effects. Additionally, by improving imaging and detection technologies, they enhance early diagnosis and disease monitoring capabilities. These advancements in technology offer new solutions for precision medicine in cardiovascular diseases, advancing treatment efficacy and disease management. Crafted from biomaterials, metals, or their amalgamations, these nanocarriers approximate the dimensions of biologically active molecules like proteins and DNA. Cardiovascular nanomedicine, in its infancy, has only recently burgeoned. Yet, with continual refinement in nanocarrier architecture, drug delivery mechanisms, and therapeutic outcomes, the potential of nanomedical technologies in clinical contexts becomes increasingly evident. This review aims to consolidate the strides made in nanocarrier research concerning the treatment and diagnose of cardiovascular diseases. Fig. 1 Optimal design and function of nano-drug loading (BY Figdraw). Note: There is a wide variety of nanocarriers, each with distinct physical and chemical properties, leading to different biological effects. Nanocarriers can be modified through methods like membrane fusion, hydrogel formation, and surface protein modification to create nanomedicine systems that integrate targeting and therapy. By selecting the most suitable injection method, these carriers can achieve longer circulation times in the body and improve the function of damaged tissues or organs, thereby providing therapeutic or diagnostic benefits. [Display omitted] [ABSTRACT FROM AUTHOR]

Colonic drug delivery can facilitate access to unique therapeutic targets and has the potential to enhance drug bioavailability whilst reducing off-target effects. Delivering drugs to the colon requires considered formulation development, as both oral and rectal dosage forms can encounter challenges if the colon's distinct physiological environment is not appreciated. As the therapeutic opportunities surrounding colonic drug delivery multiply, the success of novel pharmaceuticals lies in their design. This review provides a modern insight into the key parameters determining the effective design and development of colon-targeted medicines. Influential physiological features governing the release, dissolution, stability, and absorption of drugs in the colon are first discussed, followed by an overview of the most reliable colon-targeted formulation strategies. Finally, the most appropriate in vitro , in vivo , and in silico preclinical investigations are presented, with the goal of inspiring strategic development of new colon-targeted therapeutics. [Display omitted] [ABSTRACT FROM AUTHOR]

Current research into the role of engineered nanoparticles in drug delivery systems (DDSs) for medical purposes has developed numerous fascinating nanocarriers. This paper reviews the various conventionally used and current used carriage system to deliver drugs. Due to numerous drawbacks of conventional DDSs, nanocarriers have gained immense interest. Nanocarriers like polymeric nanoparticles, mesoporous nanoparticles, nanomaterials, carbon nanotubes, dendrimers, liposomes, metallic nanoparticles, nanomedicine, and engineered nanomaterials are used as carriage systems for targeted delivery at specific sites of affected areas in the body. Nanomedicine has rapidly grown to treat certain diseases like brain cancer, lung cancer, breast cancer, cardiovascular diseases, and many others. These nanomedicines can improve drug bioavailability and drug absorption time, reduce release time, eliminate drug aggregation, and enhance drug solubility in the blood. Nanomedicine has introduced a new era for drug carriage by refining the therapeutic directories of the energetic pharmaceutical elements engineered within nanoparticles. In this context, the vital information on engineered nanoparticles was reviewed and conferred towards the role in drug carriage systems to treat many ailments. All these nanocarriers were tested in vitro and in vivo. In the coming years, nanomedicines can improve human health more effectively by adding more advanced techniques into the drug delivery system. [ABSTRACT FROM AUTHOR]

Selenium nanoparticles (SeNPs) have attracted increasing interest over the last decades because of their activities on redox balance in human body. However, the SeNPs tend to aggregate into large clusters, resulting in lower bioactivity, bioavailability and biocompatibility. Surface-capping agents on SeNPs play crucial roles in its stabilization and biological activity. Here, a green synthesis method for the preparation of Lycium barbarum polysaccharides capped SeNPs using green tea extracts as reductants under mild conditions, at room temperature, is reported. The structure, size, morphology and thermal behaviour were analyzed by various characterization techniques. The functionalized nanoparticles demonstrated high antioxidant activity, including DPPH and ABTS free radical scavenging. Moreover, the SeNPs significantly protected the H2O2-induced PC-12 cell death. Taken together, these results evidence the possible application of these SeNPs as antioxidants food supplement or ingredient and neuroprotective agent. [ABSTRACT FROM AUTHOR]

Therapeutic use of cannabinoids, the main active ingredients of Cannabis sativa L., is often hindered by their limited bioavailability and undesirable psychoactivity. We conducted an observational study in December 2016 and another one in February 2018 to investigate respectively: (i) the effectiveness of Trokie R lozenges, a standardized formulation containing cannabis extracts, to deliver cannabinoids via buccal absorption and (ii) its long-term safety. Participants were members of the Palliative Care Corporation health clinic, registered California cannabis patients, and had a diagnosis of chronic non-cancer pain. For the effectiveness study, 49 participants were asked to self-report pain perception before and after 1-12 weeks of taking Trokie R lozenges, using an 11- point pain intensity numeric rating scale (PI-NRS). A mean reduction in PI-NRS score of 4.9 ± 2.0 points was observed. Onset of analgesia typically varied between 5 and 40 min, which seems consistent with, at least partial, buccal absorption. In the safety study, 35 participants were asked to complete a questionnaire about adverse events (AEs) associated with TrokieR lozenges. AEs were reported by 16 subjects (46%), the most common being dizziness/unsteadiness (N = 7), bad taste (N = 5), and throat irritation/dry mouth (N = 4). None of the self-reported AEs resulted in a serious medical situation and most of them had limited impact on daily functions. Despite the AEs, 90% of participants reported being "satisfied" or "very satisfied" with the product. These observations suggest that buccal administration of standardized extracts via Trokie® lozenges may represent an efficacious and safe approach to cannabis administration. [ABSTRACT FROM AUTHOR]

Lutein is a kind of natural carotenoids possessing many pharmacological effects. The application of lutein was limited mainly due to its low oral bioavailability caused by poor aqueous solubility. Nanocrystal formulation of lutein was developed to improve the oral bioavailability in this study. The nanosuspension was prepared by the anti-solvent precipitation-ultrasonication method and optimized by Box-Behnken design, followed by freeze-drying to obtain lutein nanocrystals. The nanocrystals were characterized on their physical properties, in vitro dissolution and in vivo absorption performance. Lutein nanocrystals showed as tiny spheres with an average particle size of 110.7 nm. The result of diffractograms indicated that the percent crystallinity of lutein was 89.4% in coarse powder and then declined in nanocrystal formulation. The saturated solubility of lutein in water increased from 7.3 μg/ml for coarse powder up to 215.7 μg/ml for lutein nanocrystals. The dissolution rate of lutein nanocrystals was significantly higher than that of coarse powder or the physical mixture. The Cmax and AUC0-24 h of lutein nanocrystals after oral administration in rats was 3.24 and 2.28 times higher than those of lutein suspension, respectively. These results indicated that the nanocrystal formulation could significantly enhance the dissolution and absorption of lutein and might be a promising approach for improving its oral bioavailability. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the feasibility of complexing the poorly water-soluble drug atorvastatin calcium (AC) with β-cyclodextrin (β-CD) based nanosponges (NS), which offer advantages of improving dissolution rate and eventually oral bioavailability. Blank NS were fabricated at first by reacting β-CD with the cross-linker carbonyldiimidazole at different molar ratios (1:2, 1:4, and 1:8), then NS of highest solubilization extent for AC were complexed with AC. AC loaded NS (AC-NS) were characterized for various physicochemical properties. Pharmacokinetic, pharmacodynamics and histological finding of AC-NS were performed in rats. The prepared AC-NS showed particles size ranged from 408.7 ± 12.9 to 423 ± 15.9 nm while zeta potential values varied from -21.7 ± 0.90 to -22.7 ± 0.85mV. The loading capacity varied from 17.9 ± 1.21 to 34.1 ± 1.16%. DSC, FT--IR, and PXRD studies confirmed the complexation of AC with NS and amorphous state of the drug in the complex. AC-NS displayed a biphasic release pattern with increase in the dissolution rate of AC as compared to plain AC. Oral administration of AC-NS (1:4 w/w, drug: NS) to rats led to 2.13-folds increase in the bioavailability as compared to AC suspension. Pharmacodynamics studies in rats with fatty liver revealed significant reduction (p<.05) in total cholesterol, triglyceride, LDL-C and increased level of beneficial HDL-C along with improvement in the associated liver steatosis as confirmed through photomicrographs of liver sections. In this study, we confirmed that complexation of AC with NS would be a viable approach for improving oral bioavailability and in vivo performance of AC. [ABSTRACT FROM AUTHOR]

Vinblastine (VB), as a chemotherapeutic agent, is widely used in treatment of different types of cancer. However, its clinical application is limited due to its low water solubility, side effects, and multidrug resist- ance. The aim of this study was to increase the therapeutic efficacy of VB using drug delivery systems. For this purpose, a PEGylated niosomal formulation of vinblastine (Pn-VB) was prepared by thin film hydration method and physicochemically characterized. Drug release pattern was performed by dialysis diffusion method. The cytotoxicity of Pn-VB was investigated against murine lung cancer TC-1 cells using MTT assay and its tumor inhibitory effect was evaluated in lung tumor-bearing C57BL/6 mice. Mean particle size, zeta potential, entrapment, and loading efficiency of niosomes were obtained to be about 234.3 ± 11.4 nm, -34.6 ± 4.2mV, 99.92 ± 1.6%, and 2.673 ± 0.30%, respectively. While, the mean particle size and zeta potential for non-PEGylated niosomes were obtained about 212.4 nm and -31.4mV, respectively. The in vitro release pattern of drug from niosomes showed a sustained release behavior. Pn-VB indicated a significant increase in toxicity against TC-l cells as compared to free VB. In animal model, Pn-VB exhibited stronger tumor inhibitory effect and longer life time in comparison to free VB. In conclusion, Pn-VB showed appropriate stability, high-entrapment efficacy, lower releasing rate, and stronger cytotoxic activity against lung cancer TC-1 cells as compared to free drug. Thus, the Pn-VB could be a promising formulation for delivery of vinblastine to tumor cells with enhanced drug bioavailability and therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Objective: Domperidone Maleate is a dopamine - receptor (D2) antagonist, widely used in the treatment of motion sickness and used as an antiemetic. The bioavailability of domperidone maleate when administered orally is low due to the first pass metabolism in liver, drug delivery through transdermal drug delivery has the ability to deliver the drug directly to systemic circulation by passing the liver and hence increase in bioavailability of the drug. The main aim of this investigation is to develop and evaluate matrix type transdermal drug delivery systems of domperidone maleate. Methods: The matrix type transdermal patches of Domperidone Maleate were prepared by solvent evaporation technique. The tensile strength and elongation break, in vitro drug release, in vitro drug permeation and Ex vivo permeation through rat abdominal skin were studied. The physicochemical interaction between domperidone maleate and polymer were examined by Fourier Transform Infrared Spectroscopy (FTIR). Results: All the formulations showed satisfactory physicochemical and mechanical characteristics. The optimized formulation F5 (drug: polymer ratio is 1:12.5 and 5% v/w eucalyptus oil) showed maximum cumulative percentage of drug release (1832.16±60.14 µg/cm2), permeation (650.36±29.6µg/cm²) in 10 hrs. Flux (20.462 µg/hr/cm²) and permeation coefficient of 0.204×10-2cm/hr. Values of tensile strength (2.66±0.0026 kg/mm²) and elongation at break (16.57±0.26% mm²) revealed that formulation F5 was strong but not brittle. FTIR studies showed no evidence of interaction between the drug and polymers. Conclusion: Domperidone maleate matrix type transdermal therapeutic systems could be prepared with the required flux and suitable mechanical properties. [ABSTRACT FROM AUTHOR]

Zanamivir (ZA) and guanidino-oseltamivir carboxylic acid (GOC) are very potent inhibitors against influenza neuraminidase (NA). The guanidinium moiety plays an important role in NA binding; however, its polar cationic nature also hinders the use of ZA and GOC from oral administration. In this study, we investigated the use of ZA and GOC acylguanidine derivatives as possible orally available prodrugs. The acylguanidine derivatives were prepared by coupling with either n -octanoic acid or ( S )-naproxen. The lipophilic acyl substituents were verified to improve cell permeability, and may also improve the bioavailability of acylguanidine compounds. In comparison, the acylguanidines bearing linear octanoyl chain showed better NA inhibitory activity and higher hydrolysis rate than the corresponding derivatives having bulky branched naproxen moiety. Our molecular docking experiments revealed that the straight octanoyl chain could extend to the 150-cavity and 430-cavity of NA to gain extra hydrophobic interactions. Mice receiving the ZA octanoylguanidine derivative survived from influenza infection better than those treated with ZA, whereas the GOC octanoylguanidine derivative could be orally administrated to treat mice with efficacy equal to oseltamivir. Our present study demonstrates that incorporation of appropriate lipophilic acyl substituents to the polar guanidine group of ZA and GOC is a feasible approach to develop oral drugs for influenza therapy. [ABSTRACT FROM AUTHOR]

Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson’s disease. Herein we disclose the discovery of a 4-ethoxy-7 H -pyrrolo[2,3- d ]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7 , which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100 mg/kg) and mice (45 mg/kg) following oral administration. [ABSTRACT FROM AUTHOR]

Background: GSP301 is a fixed-dose combination (FDC) of the antihistamine olopatadine hydrochloride and the corticosteroid mometasone furoate developed as a single nasal spray (NS). Objective: To assess the relative bioavailability of mometasone administered as GSP301 FDC versus two mometasone monotherapy NS formulations. Methods: In this single-dose, open-label, crossover study, healthy adults (age range, 18-65 years) were randomized equally to one of six treatment sequences for three 72-hour treatment periods with GSP301 (olopatadine 665 μg-mometasone 50 μg), the mometasone furoate monotherapy component of GSP301 (MF-sponsor, 50 μg), and U.S. Food and Drug Administration- approved mometasone (MF, 50 μg); all the treatments were administered as two sprays per nostril. To evaluate the relative bioavailability of mometasone, pharmacokinetic (PK) estimates, the maximum plasma concentration (Cmax), the area under the plasma concentration time curve (AUC) from time 0 to the last time point with measurable concentration (AUC0-t), and AUC from time 0 to time infinity (AUC0-∞) were compared by analysis of variance. Safety and tolerability were also assessed. Results: A total of 30 healthy subjects were randomized. Most subjects were white men who were not obese, mean age of ~43 years. The geometric mean ratios for natural log transformed Cmax, AUC0-t, and AUC0-∞ of mometasone in GSP301 to MF-sponsor were 113.83, 118.36, and 118.50, respectively. For GSP301 and MF, geometric mean ratios for Cmax, AUC0-t, and AUC0-∞ were 141.84, 109.92, and 115.14, respectively. The percentages of subjects who reported treatment-emergent adverse events (TEAE) were 10.0%, 13.3%, and 10.3% for GSP301, MF-sponsor, and MF treatments, respectively. All TEAEs were mild, and none resulted in discontinuation. Conclusion: Mometasone bioavailability with GSP301 was comparable with MF-sponsor and MF monotherapies. A slightly higher Cmax was observed with GSP301 than with MF, but AUC was comparable. The addition of olopatadine to mometasone in GSP301 did not considerably affect the PK of mometasone. GSP301 was well tolerated, with only mild adverse events reported. [ABSTRACT FROM AUTHOR]

Background: GSP301 is a fixed-dose combination of the antihistamine olopatadine hydrochloride and the corticosteroid mometasone furoate developed as a single nasal spray. Objective: To assess the relative bioavailability of olopatadine administered as GSP301 versus two olopatadine monotherapy nasal spray formulations. Methods: In this single-dose, open-label, crossover study, healthy adults (18-65 years old) were equally randomized to one of six treatment sequences for three 48-hour treatment periods with GSP301 (olopatadine 665 μg-mometasone 50 μg), the olopatadine monotherapy component of GSP301 (OLO-sponsor; 665 μg) and U.S. Food and Drug Administration approved olopatadine (OLO; 665 μg); each treatment was administered as a single dose (two sprays in each nostril). To assess the relative bioavailability of olopatadine in the fixed-dose nasal spray versus two monotherapies, pharmacokinetic (PK) estimates, maximum plasma concentration (Cmax), area under the plasma concentration time curve (AUC) from time 0 to the last time point with measurable concentration (AUC0-t), and AUC from time 0 to time infinity (AUC0-∞) were compared by analysis of variance. Safety and tolerability were also evaluated. Results: A total of 30 healthy adults (mean age, 43.1 years) were randomized. The majority of the subjects were white men. The geometric mean ratios for natural log transformed Cmax, AUC0-t, and AUC0-∞ of olopatadine in GSP301 and OLOsponsor were 86.63, 86.92, and 92.83, respectively. For GSP301 and OLO, geometric mean ratios for Cmax, AUC0-t, and AUC0-∞ were 84.68, 87.87, and 93.80, respectively. The percentage of subjects who reported treatment-emergent adverse events (AE) for GSP301, OLO-sponsor, and OLO were 13.8, 10.3, and 10.0%, respectively, with mild AEs reported. One subject withdrew from the study due to an AE (minor oropharyngeal pain) during OLO treatment, before receiving GSP301. Conclusion: Olopatadine bioavailability with GSP301 was comparable with OLO-sponsor and OLO. The presence of mometasone in GSP301 did not considerably affect the PK of olopatadine. GSP301 was well tolerated, with only mild AEs reported. [ABSTRACT FROM AUTHOR]

Drug formulations based on lipids can enable a significantly better delivery of a pharmaceutically active substance and thus enhance their bioavailability. However, natural fats and oils usually have properties, which do not allow their direct use for drug delivery. Therefore, we have modified palm kernel oil (PKO) and shea butter (SB) via lipase‐catalyzed transesterification using either glycerol – to create a diglyceride‐enriched lipid – or using hexanoic acid via acidolysis – to alter their fatty acid composition – and hence to improve drug solubility of Celecoxib serving as model compound. The most suitable enzyme was immobilized Thermomyces lanuginosus lipase (Novozyme TL IM). The solubility of Celecoxib as determined in SB, pharmaceutical grade SB, glycerol‐modified SB, hexanoic acid‐modified SB, PKO, glycerol‐modified PKO, and hexanoic acid‐modified PKO. Incorporation of one or two equivalents of hexanoic acid enabled higher Celecoxib solubilization than the diglyceride rich oil. Although structured SB and PKO (15.8 ± 0.4 mg mL−1) do not differ significantly (p < 0.05) as per the amount of Celecoxib dissolved, the use of the modified oils enhanced Celecoxib solubility in SB (15.5 ± 1.3 mg mL−1) in comparison to shea butter (7.9 ± 0.5 mg mL−1). The lipase‐catalyzed modification also improved the miscibility of the oils with surfactants such as Tween 20 and resulted in reduced droplet sizes (<70 nm at oil/surfactant ratios of 1:2 and 1:1) and reduced polydispersity index values of the resulting emulsions. Practical Application: The structured triglycerides synthesized in this work on the basis of natural shea butter oils could function as suppository bases and oil phase in oral and parenteral lipid‐based formulations for improving the solubility and absorption of poorly soluble drugs. As various lipases with distinct selectivity are available for the enzymatic synthesis of structured triglycerides and useful for this purpose, further tailor‐designed formations should be accessible. With the aim of developing novel lipid drug delivery matrices palm kernel oil (PKO) and shea butter (SB) were modified via lipase‐catalyzed transesterification to alter their fatty acid composition and hence to improve drug solubility of the model compound Celecoxib. Incorporation of one or two equivalents of hexanoic acid enabled better Celecoxib solubilization than the diglyceride‐rich oil. Overall, the successful modification process yielded structured lipids with promising miscibility with selected surfactants and potential enhancement of Celecoxib solubility and thus represents a promising approach for the development of novel safe and effective lipid‐based delivery systems. [ABSTRACT FROM AUTHOR]

Venlafaxine (VLX) is a first line, dual acting and unique antidepressant drug which belong to the class of serotonin and norepinephrine reuptake inhibitors. Oral administration of VLX has many adverse effects, poor bioavailability due first-pass hepatic metabolism and low permeability shows poor antidepressant action in the brain. The aim of this present study was to formulate Venlafaxine Nanostructured lipid carrier (VLX-NLC) and deliver directly into the brain through intranasal route. VLZ-NLC were prepared by Melt-Emulsification-Ultrasonication process and characterized by particle size, polydispersity index, zeta potential, Encapsulation efficiency and analyzed by differential scanning calorimetry (DSC), X-ray diffraction (XRD), transmission electron microscope (TEM). The VLX-NLC was also evaluated for in-vitro drug release and ex-vivo sheep nasal mucosa permeation. The mean particle size of VLX-NLC was between 155 and 293 nm in diameter with entrapment efficacy was up to 74.13%. TEM gave confirm of spherical nature of NLC. The DSC result shows a sharp peak at 208°C corresponds to melting peak hence confirm the peak of Venlafaxine and X-ray diffraction 2θ scattered angle represent crystallinity nature of pure Venlafaxine whereas VLX-NLC reveals decrease intensity of peak which indicates amorphization of VLX due to solubilization in lipid. In vitro studies exhibit initial burst release and afterward prolong release, ex vivo permeation through nasal sheep mucosa showed 66.45 % of drug diffused in 24 h from VLX-NLC. [ABSTRACT FROM AUTHOR]

Human alveolar echinococcosis is caused by the fox tapeworm Echinococcus multilocularis and is usually fatal if left untreated. Medical treatment with albendazole (ABZ) remains an effective option. However, due to its low aqueous solubility, ABZ is poorly and erratically absorbed following oral administration resulting in low drug levels in plasma and liver distribution. Thus, there arises the need to find a simple, efficient and scalable method to produce new ABZ formulations with increased bioavailability. Bearing this in mind, ABZ nanocrystals (ABZ-NCs) appears to be a useful tool to achieve this goal. The aim of the current study was to investigate the chemoprophylactic and clinical efficacy of an ABZ-NC formulation on mice infected with E. multilocularis . In the chemoprophylactic efficacy study, mean weight of the cysts recovered from the ABZ-NC group was 50% lower than that recorded from untreated mice, whereas the treatment with ABZ suspension did not show preventive effect. The viability of protoscoleces isolated from ABZ-NC treated mice was significantly lower than control groups. In the clinical efficacy studies, both ABZ formulations resulted in a reduction in the mean weight of the cysts obtained from mice, however only the treatment with the nanosuspension revealed significant differences ( P < 0.05) compared to the control groups. Treatment with ABZ-NCs reduced the weight of the cysts by 77% and the viability of their protoscoleces to 34%. All these results coincided with the tissue damage determined at the ultrastructural level. The enhanced chemoprophylactic and clinical efficacy of ABZ-NCs observed in this study could be attributed to an increase in the oral bioavailability of the drug. In a next step, we will characterize the cyst concentration profile after the administration of ABZ-NCs in mice infected with E. multilocularis . [ABSTRACT FROM AUTHOR]

Selaginella doederleinii Hieron is a widely used as folk Chinese medicine for treatment of different cancers. Our previous investigations have confirmed that the total biflavonoids in ethyl acetate extract from S. doederleinii (SDEA) have favorable anticancer potentials. However, the in vivo process of its bioactive ingredients remains unknown. In this paper, a sensitive and reliable method was developed for simultaneous quantification of main five biflavonoids, including amentoflavone, robustaflavone, 2″,3″-dihydro-3′,3″-biapigenin, 3′,3″-binaringenin and delicaflavone in the ethyl acetate extract of S. doederleinii (SDEA extract) in rat plasma by high-performance liquid chromatography with electrospray ionization-mass spectrometry (HPLC-ESI–MS/MS). Chromatographic separation was performed using an Ultimate ® XB-C18 (100 × 2.1 mm, 3.5 μm) with gradient elution of water (0.5% acetic acid) and acetonitrile at 0.2 mL/min. All analytes with internal standard (chrysin) were detected using selective reaction monitoring (SRM) in negative ionization mode. The method showed a good linearity over a wide concentration range (r 2 > 0.99). The limits of quantification for the biflavonoids were less than 10 ng/mL. The developed method was applied to the comparatively pharmacokinetic study of the five biflavonoids after oral or intravenous administration of SDEA extract in rats. In addition, in silico assessments of permeability and solubility of these biflavonoids were also performed to understand their poor bioavailability. It is the first time to report the in vivo process profiles of the biflavonoids of SDEA extract in rats. [ABSTRACT FROM AUTHOR]

BACKGROUND Curcuminoid from Curcuma longa Linnaeus has been demonstrated to be effective in anti-cancer and anti-inflammation. The objectives of the present study were to prepare curcuminoid dispersion and nanoemulsion from C. longa and determine their oral bioavailabilities in rats. RESULTS After curcuminoid extraction using 99.5% ethanol, bisdemethoxycurcumin ( BDMC), demethoxycurcumin ( DMC) and curcumin were separated within 10 min by high-performance liquid chromatography using an Eclipse XDB-C18 column (Agilent, Palo Alto, CA, USA) and a gradient mobile phase of 0.1% aqueous formic acid and acetonitrile, with a flow rate of 1 mL min−1, column temperature of 35 °C and detection wavelength of 425 nm. Curcuminoid nanoemulsion at a particle size of 12.1 nm and encapsulation efficiency 98.8% was prepared using lecithin, Tween 80 and water. A pharmacokinetic study in rats revealed that the parameters including Tmax, Cmax, t1/2 and the area under the curve were higher for curcuminoid nanoemulsions than for curcuminoid dispersion at the same dose employed for gavage administration, whereas, for intravenous injection, an opposite trend was shown. The oral bioavailabilities of BDMC, DMC, curcumin and total curcuminoids in nanoemulsion and dispersion were 34.39 and 4.65%, 39.93 and 5.49%, 47.82 and 9.38%, and 46 and 8.7%, respectively. CONCLUSION The results of the present study demonstrate a higher oral bioavailability after incorporation of curcuminoid into nanoemulsion, facilitating its application as a botanic drug. © 2017 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Purpose: The poor bioavailability of drugs in the ocular delivery systems is an important issue and development of delivery systems with prolonged release profile could be in a major importance. This study aims to develop an ocular delivery system using electrospun nanofibers to be a candidate insert for delivery of triamcinolone acetonide. Methods: For this purpose, three different chitosan-based formulations were prepared by electrospinning method, and electrospun nanofibers were compared to a formulation comprising hydrophobic polymers (Eudragit S100 and Zein). The electrospun nanofibers were characterized by SEM and FTIR analyses. The release profile and release kinetic models of all the formulations were also examined. Results: The SEM photographs of electrospun nanofibers revealed that among the four designed formulations, formulation obtained by electrospinning of chitosan and PVP possessed the best quality and the minimum size (120 ±30 nm), which resulted the most uniform and bead-free nanofibers. This formulation also possessed the prolonged release profile of triamcinolone acetonide and was the only electrospun nanofiber following the zero-order kinetic profile. Due to the small diameter and uniformity of this formulation, the prolonged and well controlled release profile, it could be taken into account as a candidate to overcome the drawbacks of the commonly used ocular delivery systems and be used as ocular insert. Conclusion: This study confirmed the ability of electrospun nanofibers to be used as ocular inserts for delivery of ophthalmic drugs. [ABSTRACT FROM AUTHOR]

Amorphization has been widely recognized as a useful solubilization technique for poorly water-soluble drugs, such as curcumin. We have recently reported the novel finding that the membrane transport of curcumin was markedly enhanced when amorphous solid particles of curcumin came into direct contact with the lipid membrane surface, but this was not true for crystalline solid particles. The increase in the permeation of curcumin was found to be independent of the improvements in aqueous solubility brought about by amorphization. Thus, we have identified a novel membrane transport mechanism that directly involves solid particles. In addition, it might represent a novel strategy for improving the bioavailability of curcumin that does not focus on the aqueous solubility of the drug. In this study, the direct effects of the administration of amorphous nanoparticles of curcumin (ANC) on the in vivo intestinal absorption of curcumin were investigated. After the intraduodenal administration of a curcumin suspension, the area under the curve of the plasma concentration of curcumin increased in a manner that was dependent on the curcumin concentration of the suspension, while no significant absorption was observed from a saturated solution. This finding is consistent with the results from our in vitro transepithelial transport study. In the latter experiment, the bioavailability of curcumin was found to be 1–2%. The intrapulmonary insufflation of ANC powder resulted in a significant increase in the bioavailability of curcumin (it was two orders of magnitude higher than that seen after the application of a crystalline suspension). This was due to the ANC particles coming into contact with epithelial cells in a more efficient manner after the pulmonary application of the ANC powder than after the intestinal application of the ANC suspension. Therefore, the pulmonary insufflation of amorphous powder is a novel approach to improving the bioavailability of curcumin and might be a useful way of increasing the bioavailability of poorly water-soluble drugs, such as curcumin. [ABSTRACT FROM AUTHOR]

Ciprofloxacin is administered as the hydrochloride salt in immediate release formulations for the treatment of various infectious diseases in different patient populations. Due to its weakly basic properties and poor solubility, the in vivo behaviour of this compound could be influenced by both physicochemical and physiological factors. The first aim of this study was to investigate the behaviour of ciprofloxacin (Ciprobay® 500 mg tablets) in the human gastro-intestinal tract with in vitro dissolution, transfer and two-stage experiments. Ciprobay® IR tablets dissolved completely in FaSSGF-V2, but dissolution was incomplete in FaSSIF-V2 and in an achlorhydric medium (FaSSGF-achlorhydric) and slow precipitation was observed in all three media. Ciprofloxacin did not precipitate in the transfer model but in the two-stage test, a simplified version of the transfer model, some precipitation was detected. In the second part of this study the data obtained in the in vitro transfer experiment were integrated into a Physiologically Based Pharmacokinetic (PBPK) Model. Based on the in vitro results, it was concluded that precipitation of ciprofloxacin would be unlikely in vivo. When precipitation was assumed to be negligible in the PBPK model, good predictions of plasma concentration time profiles provided by Bayer Pharma AG and obtained from the open literature were attained. Parameter Sensitivity Analysis (PSA) was conducted on several parameters which may influence the in vivo behaviour of ciprofloxacin. It was shown that precipitation in the gastro-intestinal tract in humans after a dose of 500 mg is not a determinant of the PK profile. PSA further suggested that ciprofloxacin behaves in vivo as a BCS Class I drug according to the Biopharmaceutics Classification System (BCS), even though on the basis of available solubility and permeability data the compound has been categorised as a BCS II/IV drug. These findings illustrate the importance of coupling in vitro results with in silico PBPK models to better understand the in vivo behaviour of weakly basic drugs. The PBPK model of ciprofloxacin, which was set up for healthy volunteers, was also modified to predict the in vivo behaviour of ciprofloxacin in several different patient populations. It was shown on the basis of these simulations that the plasma concentration time profile may be less influenced by disease state than previously expected. [ABSTRACT FROM AUTHOR]

Purpose: Letrozole as a steroidal anticancer drug with hydrophobic nature is usually administrated by oral route for patient treatment and the injectable formulation for this drug has not still been reported. In this study, a new letrozole incorporated folate-conjugated polymer - lipid hybrid nanoparticles - is introduced for cancer treatment. Methods: Nanoparticles were fabricated via modified oil in water ionic gelation method using optimization parameters and then were coupled to folic acid using carbodiimide activation. The physicochemical characterization in vitro drug release, cytotoxicity, and then ex vivo study of obtained carrier was investigated. Results: Both thermal and crystallography studies proved the amorphous loading of drug in the nanocarrier. The cytotoxicity investigation with an average IC value of 79 ± 2.40 nM proved the efficiency of the coupled folic acid carrier for the intracellular uptake of letrozole on the breast cancer line. Ex vivo , the study proved the positive effect of the letrozole entrapment on the drug bioavailability. Conclusions: The obtained targeted nanocarrier could overcome the limitations associated with the LTZ as a potent non-steroidal drug. Both the entrapment and therapeutic efficiency of letrozole in the amphiphilic carrier were increased using the lipid nanoparticles and the surface modification, respectively. [ABSTRACT FROM AUTHOR]

Nowadays, therapeutic indications for cannabinoids, specifically Δ 9 -tetrahydrocannabinol (THC) and Cannabidiol (CBD) are widening. However, the oral consumption of the molecules is very limited due to their highly lipophilic nature that leads to poor solubility at the aqueous environment. Additionally, THC and CBD are prone to extensive first pass mechanisms. These absorption obstacles render the molecules with low and variable oral bioavailability. To overcome these limitations we designed and developed the advanced pro-nanolipospheres (PNL) formulation. The PNL delivery system is comprised of a medium chain triglyceride, surfactants, a co-solvent and the unique addition of a natural absorption enhancer: piperine. Piperine was selected due to its distinctive inhibitory properties affecting both Phase I and Phase II metabolism. This constellation self emulsifies into nano particles that entrap the cannabinoids and the piperine in their core and thus improve their solubility while piperine and the other PNL excipients inhibit their intestinal metabolism. Another clear advantage of the formulation is that its composition of materials is approved for human consumption. The safe nature of the excipients enabled their direct evaluation in humans. In order to evaluate the pharmacokinetic profile of the THC-CBD-piperine-PNL formulation, a two-way crossover, single administration clinical study was conducted. The trial comprised of 9 healthy volunteers under fasted conditions. Each subject received a THC-CBD (10.8 mg, 10 mg respectively) piperine (20 mg)-PNL filled capsule and an equivalent dose of the oromucosal spray Sativex® with a washout period in between treatments. Single oral administration of the piperine-PNL formulation resulted in a 3-fold increase in Cmax and a 1.5-fold increase in AUC for THC when compared to Sativex®. For CBD, a 4-fold increase in Cmax and a 2.2-fold increase in AUC was observed. These findings demonstrate the potential this formulation has in serving as a standardized oral cannabinoid formulation. Moreover, the concept of improving oral bioavailability described here, can pave the way for other potential lipophilic active compounds requiring enhancement of their oral bioavailability. [ABSTRACT FROM AUTHOR]

Quercetin has been widely used to treat many diseases because of its high antioxidant activity. However, it has low oral bioavailability and penetration through the skin. The aim of this research was to enhance penetration and bioavailability of quercetin using transdermal ethosomal gel. Three ethosomal formulae, E1 (1%), E2 (1.5%) and E3 (2%) with different concentration of quercetin were prepared using thin-film hydration method. Their physical properties were characterized, and then a selected ethosomal formula was incorporated into a gel dosage form. Two gels, one ethosomal and the other non-ethosomal were prepared. In vitro penetration using Franz diffusion cells and bioavailability study in Sprague Dawley male rats were carried out. Results showed that E2 was the chosen formula to be incorporated into the gel dosage form. According to the in vitro penetration study, the diffusion flux of quercetin from the ethosomal and non-ethosomal gels were 343.35±17.69 ng/cm2/h and 120.68±11.92 ng/cm2/h, respectively (P<0.05). In the bioavailability study, ethosomal gel showed higher maximum concentration (Cmax) and area under curve (AUC0-t) when compared to non-ethosomal gel and oral suspension. Cmax from the ethosomal gel, nonethosomal gel, and oral suspension were 413.49±28.64, 189.46±49.68, and 61.92±14.31 ng/ml, respectively (P<0.05). AUC0-t from the ethosomal gel, non-ethosomal gel, and oral suspension were 4035.15±560.60, 584.87±265.46, and 431.21±239.85, respectively (P<0.05). In conclusion, ethosomal gel could increase penetration and bioavailability of quercetin compared to non-ethosomal gel. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD) is a phytocannabinoid with multiple pharmacological effects and several potential therapeutic properties. Its low oral bioavailability, however, can limit its clinical use. Preliminary results indicate that fluorination of the CBD molecule increases its pharmacological potency. Here, we investigated whether HUF-101 (3, 10, and 30 mg/kg), a fluorinated CBD analogue, would induce antinociceptive effects. HUF-101 effects were compared to those induced by CBD (10, 30, and 90 mg/kg) and the cannabinoid CB 1/2 receptor agonist WIN55,212-2 (1, 3, and 5 mg/kg). These drugs were tested in male Swiss mice submitted to the following models predictive to antinociceptive drugs: hot plate, acetic acid-induced writhing, and carrageenan-induced inflammatory hyperalgesia. To evaluate the involvement of CB 1 and CB 2 receptors in HUF-101 and CBD effects, mice received the CB 1 receptor antagonist AM251 (1 or 3 mg/kg) or the CB 2 receptor antagonist AM630 (1 or 3 mg/kg) 30 min before HUF-101, CBD, or WIN55,212-2. In the hot plate test, HUF-101 (30 mg/kg) and WIN55,212-2 (5 mg/kg) induced antinociceptive effects, which were attenuated by the pretreatment with AM251 and AM630. In the abdominal writhing test, CBD (30 and 90 mg/kg), HUF-101 (30 mg/kg), and WIN55,212-2 (3 and 5 mg/kg) induced antinociceptive effects indicated by a reduction in the number of writhing. Whereas the pretreatment with AM630 did not mitigate the effects induced by any drug in this test, the pretreatment with AM251 attenuated the effect caused by WIN55,212-2. In the carrageenan-induced hyperalgesia test, CBD (30 and 90 mg/kg), HUF-101 (3, 10 and 30 mg/kg) and WIN55,212-2 (1 mg/kg) decreased the intensity of mechanical hyperalgesia measured by the electronic von Frey method. The effects of all compounds were attenuated by the pretreatment with AM251 and AM630. Additionally, we evaluated whether HUF-101 would induce the classic cannabinoid CB 1 receptor-mediated tetrad (hypolocomotion, catalepsy, hypothermia, and antinociception). Unlike WIN55,212-2, CBD and HUF-101 did not induce the cannabinoid tetrad. These findings show that HUF-101 produced antinociceptive effects at lower doses than CBD, indicating that the addition of fluoride improved its pharmacological profile. Furthermore, some of the antinociceptive effects of CBD and HUF-101 effects seem to involve the activation of CB 1 and CB 2 receptors. [ABSTRACT FROM AUTHOR]

Liver diseases caused by viral hepatitis infections have a negative impact on global health. Approximately 30 million people in the USA and 29 million people in the European Union suffer from chronic liver disease. There are many kinds of diseases of the liver, caused by viruses, such as hepatitis A, hepatitis B and hepatitis C, or by certain drugs and poisons including excessive alcohol consumption. Many herbal medicines are used in traditional medicine for their protective and therapeutic properties against liver diseases. Among their bioactive components, flavonoids have been found to be active against liver dysfunction and damage caused by liver diseases. Extensive evidences report that quercetin (QE), a major flavonol commonly found in apple, berries, onion, citrus fruits, cruciferous vegetables, tea, pepper, tomato, whole gain, cocoa and red wine, displays a wide range of healthy properties, including anti-oxidative, anti-inflammatory, anti-apoptotic and hepatoprotective activities against various hepatic ailments. This review aims to critically analyze the available literature regarding the hepatoprotective effects of QE with special emphasis on its mechanisms of actions. To provide a complete picture of QE, its distribution, chemistry, biosynthesis and bioavailability are reported. Overall, data in literature shows that QE appears to be a promising hepatoprotective compound. [ABSTRACT FROM AUTHOR]

During the last decades, the study of the in vitro dissolution of pharmaceuticals has been strongly encouraged by the FDA in order to determine its relationship with the in vivo bioavailability of a drug. In this work immediate and extended release formulations containing diclofenac, a BCS class II drug, were studied using different dissolution methods. The release profiles obtained in USP Apparatus II and USP Apparatus IV were evaluated and compared to determine the effect of the fluid dynamic conditions on the release. The influence of the mixing conditions (i.e. the paddle rotation speed in USP Apparatus II or the inlet flow rate in USP Apparatus IV) on the drug release were evaluated, finding that, for the extended release formulations, they do not affect significantly the release profile. An in vitro device simulating the peristaltic contractions of the stomach during the digestion was used to simulate fluid dynamics closer to the real physiology. The tablets were found to behave in a completely different way if tested in the artificial stomach. Both model-independent and model-dependent approaches were used to compare and fit the dissolution profiles, respectively. Fit factors were used as indicators of similarity of two dissolution profiles; model equations (such as zero-order, first-order, or Korsmeyer-Peppas equations) were used to fit the experimental data. With the identification of the best fitting model by the use of correlation factors and Akaike Information Criterion, the transport phenomena that determine the behavior of each formulation were identified. [ABSTRACT FROM AUTHOR]

Altretamine is a synthetic drug approved for treatment of ovarian cancer. The only drawback with its formulation is poor aqueous solubility and low oral bioavailability. In the present work an attempt has been made to prepare inclusion complex of altretamine with epichlorohydrin beta cyclodextrin. The complexes were prepared by kneading, co-evaporation and freeze-drying method and were confirmed by FTIR, XRD, DSC, drug content and dissolution study. Kneaded complex possess maximum solubilizing efficiency of 82.63 in 25 mM Epi-β-CD solution. SLNs of pure altretamine and ALT complexed with Epi-β-CD were prepared by modified emulsification–ultrasonication method. The particle size and zeta potential was found to be 151.5 nm and −21.3 mV. The drug release pattern of SLNs was bi-phasic in nature; with an initial burst release followed by sustained drug release. Pharmacokinetic study showed that the average C max was found to be 0.94 μg/ml, which was 2.47 times higher as compared to the pure drug. The AUCt for SLNs was 150 min μg h/ml and 54 min μg h/ml for pure ALT suspension which proved that the SLNs exhibited greater absorption compared to the pure drug. Thus, smaller particle size, higher entrapment efficiency and enhanced aqueous solubility led to improvement in oral bioavailability of ALT. [ABSTRACT FROM AUTHOR]

Sesamol, the phenolic degradation product of sesamolin, although recognised for its anti-inflammatory effects, has low bioavailability. In this manuscript, we attempted to improve its bioavailability by encapsulation in mixed phosphatidylcholine micelles. Sesamol could be solubilised and entrapped in phosphatidylcholine mixed micelles (PCS) with 96.8% efficiency (particle size 3.0 ± 0.06 nm). Fluorescence spectra of PCS revealed lower relative fluorescence intensity (RFI 112) compared to ‘free’ sesamol (FS) (RFI 271). The bioaccessibility, transport across a monolayer of cells and cellular uptake of PCS was 8.58%, 1.5-fold and 1.2-fold better, respectively, compared to FS. The anti-inflammatory effects of FS and PCS were compared using LPS treated RAW 264.7 cell line and lipoxygenase inhibition. PCS effected downregulation of iNOS protein expression (27%), NO production (20%), ROS (32%) and lipoxygenase inhibition (IC 50 = 31.24 μM) compared to FS. [ABSTRACT FROM AUTHOR]

In the last years, casein nanoparticles have been proposed as carriers for the oral delivery of biologically active compounds. However, till now, no information about their possible specific hazards in vivo was available. The aim of this work was to assess the safety of casein nanoparticles when administered orally to animals through a 90 days dose-repeated toxicity study (OECD guideline 408), that was performed in Wistar rats under GLP conditions. After 90 days, no evidences of significant alterations in animals treated daily with 50, 150 or 500 mg/kg bw of nanoparticles were found. This safety agrees well with the fact that nanoparticles were not absorbed and remained within the gut as observed by radiolabelling in the biodistribution study. After 28 days, there was a generalized hyperchloremia in males and females treated with the highest dose of 500 mg/kg bw, that was coupled with hypernatremia in the females. These effects were related to the presence of mannitol which was used as excipient in the formulation of casein nanoparticles. According to these results, the No Observed Adverse Effect Level (NOAEL) could be established in 150 mg/kg bw/day and the Lowest Observed Effect Level (LOEL) could be established in 500 mg/kg bw/day. [ABSTRACT FROM AUTHOR]

Alectinib, an anaplastic lymphoma kinase (ALK) inhibitor, is approved for treatment of patients with ALK+ non-small cell lung cancer who have progressed, on or are intolerant to, crizotinib. This study assessed the effect of a high-fat meal and the proton pump inhibitor, esomeprazole, on the pharmacokinetics (PK) of alectinib. This was an open-label, 2-group study in healthy subjects. In group 1 (n = 18), subjects were randomly assigned to a 2-treatment (A, fasted conditions; B, following a high-fat meal), 2-sequence (AB or BA) crossover assessment, separated by a 10-day washout. In group 2 (n = 24), subjects were enrolled in a 2-period, fixed-sequence crossover assessment to evaluate the effect of esomeprazole. PK parameters were evaluated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Administration of alectinib following a high-fat meal substantially increased the combined exposure of alectinib and M4 to 331% (90%CI, 279%-393%) and 311% (90%CI, 273%-355%) for Cmax and AUC0-∞, respectively, versus fasted conditions. Coadministration of esomeprazole had no clinically relevant effect on the combined exposure of alectinib and M4. Alectinib should be administered under fed conditions to maximize its bioavailability, whereas no restrictions are required with antisecretory agents. [ABSTRACT FROM AUTHOR]

Naloxegol is a peripherally acting μ-opioid receptor antagonist approved as an orally administered tablet for the treatment of opioid-induced constipation. Patients with swallowing difficulties may benefit from alternative approaches to the oral administration of the whole-tablet formulation of naloxegol. This open-label, randomized, 4-period, 4-treatment, crossover, single-dose study (NCT02446171) evaluated the pharmacokinetic (PK) characteristics of crushed naloxegol 25-mg tablets (suspended in water) administered orally or by nasogastric tube and a naloxegol solution compared with the commercially available 25-mg tablet formulation in healthy volunteers. The PK profiles for the crushed tablet, whether administered orally or by nasogastric tube, and the 25-mg oral solution were similar to that of the 25-mg tablet administered orally. Compared with naloxegol commercial tablets, the relative bioavailability of naloxegol using 3 alternative methods of administration was approximately 100%. For each pairwise treatment comparison of the 3 alternative methods with the approved whole tablet, the geometric least-squares mean ratio ranges were 94.37%-100.04%, 94.83%-100.44%, and 97.05%-102.05% for area under the curve (AUC), AUC0-t, and maximum plasma concentration, respectively, and their 90% confidence intervals were entirely within the predefined 80% to 125% bioequivalence limits. Naloxegol was well tolerated when administered in both liquid and solid form. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs) have rapidly become an established factor in oncology, and have been shown to be effective in a wide variety of solid and hematologic malignancies. Use of the oral administration route of TKIs offers flexibility and is convenient for the patient; however, despite these advantages, the oral route of administration also causes a highly relevant new problem. Acid-inhibitory drugs, such as proton pump inhibitors (PPIs), increase the intragastric pH, which may subsequently decrease TKI solubility, bioavailability, and treatment efficacy. Clear and practical advice on how to manage PPI use during TKI therapy is currently not available in the literature. Since PPIs are extensively used during TKI therapy, prescribers are presented with a big dilemma as to whether or not to continue the combined treatment, resulting in patients possibly being deprived of optimal therapy. When all pharmacological characteristics and data of either TKIs and PPIs are considered, practical and safe advice on how to manage this drug combination can be given. [ABSTRACT FROM AUTHOR]

Resveratrol is a common polyphenol of plant origin known for its cancer prevention and other properties. Its wider application is limited due to poor water solubility, low stability, and weak bioavailability. To overcome these limitations, a series of 13 novel resveratrol triesters were synthesized previously. In this paper, we describe the synthesis of 3 additional derivatives and the activity of all 16 against primary acute lymphoblastic leukemia cells. Of these, 3 compounds were more potent than resveratrol (IC 50 = 10.5 µM) namely: resveratryl triacetate (IC 50 = 3.4 µM), resveratryl triisobutyrate (IC 50 = 5.1 µM), and resveratryl triisovalerate (IC 50 = 4.9 µM); all other derivatives had IC 50 values of >10 µM. Further studies indicated that the active compounds caused G1 phase arrest, increased expression of p53, and induced characteristics of apoptotic cell death. Moreover, the compounds were only effective in cycling cells, with cells arrested in G1 phase being refractory. [ABSTRACT FROM AUTHOR]

Quercetin, a dietary flavonol phytoestrogen, has many health benefits but it is poorly absorbed when administered orally. To improve its bioavailability, we prepared quercetin-loaded phytosome nanoparticles (QP) using the thin film hydration method. The prepared nano-formulations were characterized using different techniques. Transmission electron microscopy revealed the homogeneously spherical, well and uniformly dispersed, nano-sized nature of QP. Dynamic light scattering measurements of QP (70 ± 7.44 nm) also confirmed this. Stability of the formed nanoparticles was established via zeta potential determination. The prepared QP exhibited very high encapsulation efficiency (98.4%). The estrogenic activity of QP, concerning inflammation, oxidative stress, bone, lipid profile, blood glucose level and weight gain, was investigated in ovariectomized rat model using 10 and 50 mg/kg/day oral doses for 4 weeks. Treatment with QP showed significant increase in serum calcium, inorganic phosphorus and glutathione content. Whereas, it significantly decreased serum alkaline phosphatase, acid phosphatase, malondialdehyde level, tumor necrosis factor-alpha and glucose level and improved lipid profile. Consequently, the results obtained confirm the superiority of QP over free quercetin at the same doses as a promising hormone replacement therapy. [ABSTRACT FROM AUTHOR]

Naringin is a bioflavonoid that is rich in citrus plants and possesses enormous health benefits. However, the use of naringin as a nutraceutical is significantly limited by its low bioavailability. In this study, a novel water-soluble ternary nanoparticle material consisting of amylose, α-linoleic acid and β-lactoglobulin was developed to encapsulate naringin to improve its bioavailability. The physicochemical characteristics of the ternary nanoparticle-naringin inclusion complex were analysed by ultraviolet-visible spectroscopy (UV), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), high-resolution transmission electron microscopy (TEM), X-ray diffractometry (XRD) and particle size distribution. The results confirmed the formation of the ternary nanoparticle-naringin inclusion complex. The encapsulation efficiency (EE) and loading content (LC) of the ternary nanoparticle-naringin inclusion complex were 78.73 ± 4.17% and 14.51 ± 3.43%, respectively. In addition, the results of the ternary nanoparticle-naringin inclusion complex in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) demonstrated that naringin can be gradually released from the complex. In conclusion, ternary nanoparticles are considered promising carriers to effectively improve the bioavailability of naringin. [ABSTRACT FROM AUTHOR]

The posaconazole tablet formulation was developed to have improved bioavailability compared to the oral suspension. Here, we compared posaconazole plasma concentration (PPC) with the posaconazole oral suspension versus the tablet in Korean patients undergoing remission induction chemotherapy for hematologic malignancies. PPC was measured at 3, 8, and 15 days of treatment with the oral suspension (174 patients) or the tablet (40 patients). At all time-points, mean PPC was significantly higher with the tablet compared to the oral suspension. Our findings suggest that posaconazole tablets generate an optimal PPC earlier and in more patients than the oral suspension among Korean patients. [ABSTRACT FROM AUTHOR]

Curcumin (Cur) has been found to be very efficacious against many different types of cancer cells. However, the major disadvantage associated with the use of Cur is its low systemic bioavailability. Our present work investigated the toxic effect of encapsulation of Cur in PLGA (poly lactic-coglycolic acid) nanospheres (NCur) on PC3 human cancer prostate cell. In the present study, we have investigated the effects of NCur on growth, autophagia, and apoptosis in PC3 cells, respectively, by MTT assay, fluorescence microscopy, and Flow cytometry. MTT assays revealed that the NCur at the concentration of 25 μg/mL for 48 h were able to exert a more pronounced effect on the PC3 cells as compared to free Cur. Apoptotic index was significantly increased in NCur-treated cells compared to free Cur. The percentage of autophagic cells (LC3-II positive cells) was also significantly increased in NCur treatment in comparison to free Cur. These data indicate that the NCur has considerable cytotoxic activity more than Cur on PC3 cell lines, which is mediated by induction of both apoptotic and autophagic processes. Thus, NCur has high potential as an adjuvant therapy for clinical application in prostate cancer. [ABSTRACT FROM AUTHOR]

Brinzolamide (BZ) is an intraocular pressure reducing agent with low bioavailability. The purpose of the present study was to overcome this issue by development of BZ containing nanoemulsions (NEs) as an ocular drug delivery system with desirable therapeutic efficacy. Brinzolamide NEs were prepared by the spontaneous emulsification method. Based on initial release studies, twelve formulations with the slowest release characteristics were subjected to further physicochemical investigations such as particle size, polydispersity index, pH, refractive index, osmolality and viscosity. The therapeutic efficacy of these formulations was assessed by measuring the intraocular pressure after instillation of the prepared NEs in normotensive albino rabbit eyes. Nanoemulsions with suitable physicochemical properties exhibited high formulation stability under different conditions. more over biological evaluations indicated that using lower drug concentrations in NE formulations (0.4%) had a similar or even better pharmacodynamic effect compared to the commercial suspension with a higher drug concentration (1%). Our findings suggest that NEs could be effectively used as carriers for enhancing the bioavailability of topically applied ophthalmic drugs. [ABSTRACT FROM AUTHOR]