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The oral route is the most preferred route of drug administration. Tablets are the most prominent oral dosage form as they can provide greater dose precision, higher stability, simplicity and lower cost of manufacturing and suitability for large-scale production. Compressed tablets, which are the most widely used tablets, consist of a blend of one or more active pharmaceutical ingredients (APIs) with suitable excipients. The excipients in tablets, in particular dissolution enhancing excipients, play a vital role in ensuring an efficient oral drug delivery (i.e., high oral bioavailability). These excipients are usually utilized as a part of a solubilization strategy to enhance the drug solubility, and thus its oral bioavailability. However, various excipients in tablets are associated with instability issues, hence, a comprehensive, costly, and time-consuming investigation of excipients is essential to develop stable and efficient tablets. SmartFilms technology is an innovative strategy which enhances the drug aqueous solubility via embedding the drug within a matrix of cellulose-based paper in an amorphous state. Despite its proven effectiveness, smartFilms technology remains unrecognized by the pharmaceutical industry due to the difficulty of large-scale production of paper tablets from paper cut outs with limited flowability. The inadequate flowability might obstruct the compression process due to the adherence of the paper to the tablet press, which might result in dose variation of the tablets. In addition, the influence of the smartFilm tablets on the bioactivity of the loaded drug is still ambiguous. In this thesis, smartFilm tablets were investigated as a potential, industrially feasible approach for an improved solubility and bioactivity of poorly water-soluble APIs. The first part of the thesis investigated the possibility of transforming unloaded smartFilms (i.e., paper) into a flowable physical form and the influence of sucrose as a binder (i.e., amounts and forms) on the behavior of the material under compression as well as the properties of the obtained tablets. Cellulose-based paper utilized in this work was successfully transformed into granules via a wet granulation process. The obtained unloaded paper granules exhibited a slightly elongated shape, demonstrated good flowability and allowed the production of tablets in a continuous mode. The results also showed that using sucrose as a dry powder during the granulation process was the most suitable for obtaining paper granules that can be compressed in large scale into tablets with good pharmaceutical properties (i.e., in accordance with the European Pharmacopoeia). Investigating the mechanical behavior of paper granules under compression indicated that the compaction behavior of these granules was comparable to the behavior of classical binders and compression enhancers. These findings indicate that the obtained paper granules have good flowability, a suitable compression behavior and propose paper granules as suitable intermediate products for the production of tablets made from paper on a large, industrial scale. The second and the third part of the thesis studied the impact of smartFilm tablets on the oral delivery and bioactivity of two poorly water-soluble APIs (i.e., curcumin and norfloxacin) using an ex vivo porcine intestinal model. Curcumin-loaded smartFilms and norfloxacin-loaded smartFilms were successfully transferred into smartFilm granules and smartFilm tablets, respectively. Results also showed that the curcumin-loaded smartFilm granules and smartFilm tablets preserved the amorphous state of the incorporated drug. The obtained tablets also fulfilled the criteria according to the European Pharmacopoeia regarding hardness, friability, content uniformity, mass uniformity, and disintegration time. The incorporation of curcumin or norfloxacin into smartFilm tablets resulted in increasing the dissolution rate (approx. two-fold) especially at the beginning of the release. The ex vivo intestinal permeability of curcumin from the smartFilm tablets was also studied and compared to a physical mixture of curcumin and paper and to a classical and an innovative commercial product, respectively. The innovative product contains curcumin in a micellar form and has previously demonstrated an exceptional oral bioavailability. The findings showed an enhanced intestinal permeability of curcumin from the smartFilm tablets, as compared to the physical mixture tablet and the classical marketed product that contains curcumin as a raw powder (approx. two-fold increase). No difference in the total amount of permeated curcumin was found between the smartFilm tablets and the innovative commercial product (i.e., micellar curcumin). Nevertheless, a trend towards a deeper intestinal permeation of the curcumin from the smartFilm tablets was observed. These outcomes indicate that smartFilm tablets can be equally efficient as innovative and classical curcumin formulation approaches in improving the oral bioavailability of curcumin. The ex vivo bioactivity of norfloxacin from the smartFilm tablets was also investigated and showed a similar trend (i.e., a two-fold higher antibacterial activity of norfloxacin from the smartFilm tablets when compared to the physical mixture tablet). The findings of this thesis provide evidence that smartFilm tablets are a cost-effective, universal, industrially feasible formulation approach for improved solubility and enhanced bioactivity of poorly water-soluble APIs, i.e., BCS class II and IV drugs.

Heavy metal content has become a serious issue with increase in compost application in agricultural land. The bioavailable fraction (water soluble and diethylene triamine pentaacetic acid (DTPA) extractable) is the major concern comparing to the total concentration as it can be taken up by plants which in turn affects the human health. Thus, this study was carried out to determine the variation in bioavailable and leachable fraction of heavy metals (Cd, Cu, Fe, Ni, Pb, Cr, Zn, Hg and Mn) and to assess the influence of temperature, pH, organic matter degradation and humification during rotary drum composting of paper mill sludge (PMS) for 20 days. A total concentration of all the metals as well as nutrients increased during composting. The Hg was not detected in water soluble and DTPA extractable fraction, whereas Pb and Cr were also not detected in water soluble fraction in all the trials. A decreasing trend was observed in leachable quantity for all the metals during composting. Water extractable quantity increased for Fe and Cu during composting. Organic matter degradation and humification during composting influences the variation in bioavailability and leachability of heavy metals, which can be optimized by applying appropriate proportion of cow dung during rotary drum composting of PMS.

An increasing proportion of recycled fibers are used in paper industries due to their important environmental and economic benefits. However, removing the ink, clay, coatings and contaminants from paper waste in order to produce recycled fibers creates large amounts of de-inking paper sludge. For this reason, the preparation of biochar from pyrolysis process of this kind of waste rich in cellulose fibers, carbonates and clays, and their use in soil remediation contaminated by heavy metals can be perceived as an interesting valorization alternative. The aim of the present work is to study the influence of biochar from de-inking paper sludge (HP) pyrolysis in a Ni2+ polluted soil. Selected soil (S) was artificially contaminated with Ni2+ at 1000 mg Ni kg(-1) (S1000) and then amended at a rate of 5 wt% using HP and two biochars prepared from pyrolysis of HP at 300 degrees C (HP300) and 500 degrees C (HP500). Non-contaminated soil (S) was used as control and amended with the same rate of HP, HP300 and HP500. An incubation experiment was designed and soil CO2 emissions were measured in the different treatments during 77 days. The results have shown that CO2 emissions followed the order S = S + HP = S + HP300 > S + HP500 for the non-polluted soil and the patternS1000 + HP300 > S1000 approximate to S1000 + HP > S1000 + HP500 for the soil spiked with Ni. Finally, it was observed that HP500 addition to the polluted soil reduced the quantity of mobile, leached and bioavailable Ni.

Objective: The objective of this study was to formulate orodispersible tablets containing empagliflozin by direct compression method with sufficient hardness and rapid disintegration time and to study the effect of functionality differences of super-disintegrants on the tablet properties. Methods: A two factor three level factorial design (32) was used for the formulation optimization of orodispersible tablets of Empagliflozin and experimental trials were performed on all possible formulations, in which the amount of β-cyclodextrin, crospovidone and croscarmellose sodium were selected as independent variables (factor) varied at three different levels: low (-1), medium (0), and high (+1) levels. The drug release and disintegration time were used as dependent variables (response). All formulations were characterized for parameters such as diameter, hardness, weight, thickness, friability, disintegration time, drug release. Results: Formulation FD6 having 30 sec disintegration time, 98.84% drug release after 30 min, 2.8 kg/cm2 hardness and 0.292% friability was found best among all formulations and selected as an optimized formulation with rapid onset of action and enhanced bioavailability (more than 98% drug release within 30 min.) as compared to the oral empagliflozin tablet. Conclusion: Empagliflozin orodispersible tablets with different superdisintegrants were successfully prepared and formulation containing highest percentage of crospovidone was found best among all other formulations in terms of bioavailability and rapid onset of action.

Introduction Studies have suggested that free radicals-induced neurodegeneration is one of the many studies of Parkinson Disease (PD). Quercetin as a natural polyphenol has been regarded as a significant player in altering the progression of neurodegenerative diseases by protecting from damages caused by free radicals. Owing to its poor water solubility, preparation of its oral formulation is urgently needed. Recently, nanocrystal technique as an effective way has been introduced for oral administration of drugs. Methods This study investigated the neuroprotective effects of quercetin nanocrystals on 6-hydroxydopamine (6-OHDA)-induced Parkinson-like model in male rats. Quercetin nanocrystals were prepared by the Evaporative Precipitation of Nanosuspension (EPN) method. Results Administration of quercetin and its nanocrystals (10 and 25 mg/kg) prevented disruption of memory, increased antioxidant enzyme activities (superoxide dismutase and catalase) and total glutathione and reduced Malondialdehyde (MDA) level in the hippocampal area. Conclusion The present study results demonstrated that quercetin nanocrystals with greater bioavailability is effective than quercetin alone in treatment of Parkinson-like model in rat.

We determined the potentially algal-available P (P(aa)) in pulp and paper mill effluents by two bioassay techniques (a dual-culture assay and a batch approach) and compared it with chemically analysed P (total P, total dissolved P, reactive P, dissolved reactive P and dissolved hydrolysable P). The mean P(aa) given by the dual-culture assay was within a 40% range of that given by the batch approach. The P(aa) obtained by both bioassays differed from total P. Dissolved reactive P appeared to be the most readily available chemical P fraction, but other P fractions also contributed to P(aa). The analysis of reactive P, which involves direct staining of an unfiltered sample, best approximated the P(aa) given by the dual-culture assay (relative error 9%). The results suggest that assessment of eutrophying effluent P can be improved by analysing simple chemical P fractions in wastewater. The fractions to be analysed, however, may be site specific.

International audience; Bisphenol A (BPA) is an endocrine disrupting environmental contaminant used in a wide variety of products, and BPA metabolites are found in almost everyone's urine, suggesting widespread exposure from multiple sources. Regulatory agencies estimate that virtually all BPA exposure is from food and beverage packaging. However, free BPA is applied to the outer layer of thermal receipt paper present in very high (∼20 mg BPA/g paper) quantities as a print developer. Not taken into account when considering thermal paper as a source of BPA exposure is that some commonly used hand sanitizers, as well as other skin care products, contain mixtures of dermal penetration enhancing chemicals that can increase by up to 100 fold the dermal absorption of lipophilic compounds such as BPA. We found that when men and women held thermal receipt paper immediately after using a hand sanitizer with penetration enhancing chemicals, significant free BPA was transferred to their hands and then to French fries that were eaten, and the combination of dermal and oral BPA absorption led to a rapid and dramatic average maximum increase (Cmax) in unconjugated (bioactive) BPA of ∼7 ng/mL in serum and ∼20 µg total BPA/g creatinine in urine within 90 min. The default method used by regulatory agencies to test for hazards posed by chemicals is intra-gastric gavage. For BPA this approach results in less than 1% of the administered dose being bioavailable in blood. It also ignores dermal absorption as well as sublingual absorption in the mouth that both bypass first-pass liver metabolism. The elevated levels of BPA that we observed due to holding thermal paper after using a product containing dermal penetration enhancing chemicals have been related to an increased risk for a wide range of developmental abnormalities as well as diseases in adults.

The aim of this study was to examine the stability and bioavailability of different phosphorus fractions of pulp and paper mill effluents in order to assess the environmental benefits of reducing their phosphorus discharges. Two types of effluent were studied: activated sludge treated bleached kraft mill effluent and activated sludge treated paper mill effluent. Phosphorus was characterized on the basis of its solubility and chemical reactivity. The stability of particulate phosphorus was studied in long-term (6-8 weeks) degradation tests. The bioavailability of different phosphorus fractions was measured by algal growth potential tests. In bleached kraft mill effluent (BKME) the proportion of dissolved phosphorus in relation to the total phosphorus was on an average 80%, and of this, approximately 80-90% was reactive phosphorus. During a 6-8 week incubation period some 60-70% of the particulate phosphorus in BKME was dissolved as soluble phosphorus, and most of it was of the reactive type. Approximately 90% of the dissolved phosphorus and 45% of the particulate phosphorus in BKME was biologically available phosphorus (BAP). Altogether some 80% of the total phosphorus in activated sludge treated BKME was available for algae either immediately or after inherent degradation. The percentages of dissolved and particulate phosphorus of paper mill effluent (PME) total phosphorus were of the same order of magnitude as those of BKME, but less than 20% of the dissolved phosphorus was of the reactive type. Approximately 50-60% of the particulate phosphorus in PME was dissolved in degradation tests, and 90% of it was biologically available.

Heavy metal contamination of soil poses risks and hazards to environment and human being. Many amendments were used to remediate the contaminated soil. In this report, paper sludge was used to reduce the bioavailability of Pb in soil, and the remediation mechanism was studied by investigating the redistribution of Pb speciation after paper sludge addition. In pot experiments, significantly increased weights of shoots (from 1.6 to 3.3 mg per plant) and roots (from 0.7 to 0.8 mg per plant), as well as significantly decreased Pb content in shoots (from 153.8 to 24.4 mg kg−1) and roots (from 467.1 to 38.0 mg kg−1) of rape were observed after paper sludge was added. The addition of paper sludge resulted in redistribution of Pb from the liable fractions (carbonate-bound Pb from 58.3 to 3.7%) to the Fe–Mn oxide-bound fraction (from 29.2 to 74.9%). Paper sludge addition increased the content of organic matters and pH of soil, and induced Pb redistribution, which ultimately inhibited Pb uptake and improved...

This is an open access article under the terms of the Creative Commons Attribution-Non-Commercial-NoDerivs Licence.-- et al., Various secondary plant metabolites or phytochemicals, including polyphenols and carotenoids, have been associated with a variety of health benefits, such as reduced incidence of type 2 diabetes, cardiovascular diseases, and several types of cancer, most likely due to their involvement in ameliorating inflammation and oxidative stress. However, discrepancies exist between their putative effects when comparing observational and intervention studies, especially when using pure compounds. These discrepancies may in part be explained by differences in intake levels and their bioavailability. Prior to exerting their bioactivity, these compounds must be made bioavailable, and considerable differences may arise due to their matrix release, changes during digestion, uptake, metabolism, and biodistribution, even before considering dose- and host-related factors. Though many insights have been gained on factors affecting secondary plant metabolite bioavailability, many gaps still exist in our knowledge. In this position paper, we highlight several major gaps in our understanding of phytochemical bioavailability, including effects of food processing, changes during digestion, involvement of cellular transporters in influx/efflux through the gastrointestinal epithelium, changes during colonic fermentation, and their phase I and phase II metabolism following absorption., The EU-COST FA 1005 Infogest action is greatly acknowledged for providing funding for travel and meetings and allowing for open access.

Lab-scale tests have been conducted on the reduction of residual COD in biologically purified effluents from mills with integrated waste paper treatment plants and/or TMP lines. For this purpose, waste water samples were subjected to ozonization or a combined ozone/UV treatment at varied temperatures and pHs. The influence of ozone on the biodegradability of biologically part-treated effluents was studied by means of the Zahn-Wellens test. For specific ozone consumption rates < 2.5 g O3/g eliminated COD, COD elimination rates of up to 82% and DOC elimination rates of up to 64% were obtained. Ozone consumption was considerably higher for a combined ozone/UV treatment or treatment at pH > 9 or at elevated temperatures (40°C). For colour stripping of the waste waters and for destroying the surfactants contained in them, ozone additions of up to 80 mg O3/l waste water were required. The bioavailability of effluents that have been part-treated biologically in trickling filters or anaerobic stages to COD > 500 mg/l and BOD5/COD > 0.2 cannot be positively influenced by ozonization with up to 1.8 g O3/l waste water. On the other hand, in fully biologically treated effluents (COD < 500 mg/l), ozonization brought about a rise in the BOD5/COD ratio from an initial < 0.05 to a maximum of 0.37 - an observation which clearly demonstrates an increase in bio-degradability.

Statins (HMG-CoA reductase inhibitors) are a group of highly efficient pharmacological agents used for reducing blood cholesterol level and prevention/treatment of cardiovascular disease. Adverse reactions during statin treatment affect quite significant numbers of patients (reportedly from 5% to 20%), with more side effects occurring at higher doses. Reduced statin dosing can be achieved by improved bioavailability of statins, which is fairly low due to poor aqueous solubility, low permeability and high molecular weight of some members of the statin family. Moreover, since hepatic cholesterologenesis is a main target of statin action and extrahepatic inhibition of HMG-CoA reductase has no effect on plasma lipids, hepatic bioavailability, in our opinion, becomes a new important modality of statins maximizing their potential effect on the plasma lipid profile and diminishing their extrahepatic toxicity. Therefore efficient delivery systems of statins into hepatocytes need to be developed and introduced. Uses of nano-emulsifying statin delivery systems which may include vectors of intrahepatic transport, in particular lycopene, are discussed. As a proof of concept, some preliminary results revealing the effect of a lycopene-containing nanoformulation of simvastatin (designated as Lyco-Simvastatin) on LDL in mildly hypercholesterolemic patients are shown.

Background Interest in vegetarian diets is growing in Italy and elsewhere, as government agencies and health/nutrition organizations are emphasizing that regular consumption of plant foods may provide health benefits and help prevent certain diseases. Methods and results We conducted a Pubmed search, up to September, 2015, for studies on key nutrients (proteins, vitamin B12, iron, zinc, calcium, vitamin D, and n-3 fatty acids) in vegetarian diets. From 295 eligible publications the following emerged: Vegetarians should be encouraged to supplement their diets with a reliable source of vitamin B12 (vitamin-fortified foods or supplements). Since the plant protein digestibility is lower than that of animal proteins it may be appropriate for vegetarians to consume more proteins than recommended for the general population. Vegetarians should also be encouraged to habitually consume good sources of calcium, iron and zinc – particularly vegetables that are low in oxalate and phytate (e.g. Brassicaceae), nuts and seeds, and calcium-rich mineral water. Calcium, iron, and zinc bioavailability can be improved by soaking, germination, and sour-dough leavening that lower the phytate content of pulses and cereals. Vegetarians can ensure good n-3 fatty acid status by habitually consuming good sources of a-linolenic acid (walnuts, flaxseeds, chia seeds, and their oils) and limiting linoleic acid intake (corn and sunflower oils). Conclusions Well-planned vegetarian diets that include a wide variety of plant foods, and a reliable source of vitamin B12, provide adequate nutrient intake. Government agencies and health/nutrition organizations should provide more educational resources to help Italians consume nutritionally adequate vegetarian diets.

In organic soil fertility management, rock phosphate (RP) is gaining momentum as an acceptable phosphorus source, though much of this P is not bioavailable for plant uptake, particularly in igneous RP. This study evaluated the nutrient solubilization, biodegradation and heavy metal concentration when cow dung – waste paper mixture amended with increasing rates of igneous RP was vermicomposted with E. fetida. The cow dung was optimized to a C/N ratio of 30 using waste paper and amended with RP to provide 0%; 2%; 4% and 8% of elemental phosphorus on a dry w/w basis. Incorporation of RP at 2% and 8% P enhanced compost biodegradation resulting in a 12% and 22% significantly (P < 0.001) lower final C/N ratio, respectively, compared to the control; together with higher humification parameters. Amending the cow dung – waste paper mixture with 2%, 4% and 8% P as rock phosphate, resulted in a 39%; 50% and 65% more resin extractable P, respectively, relative to the control. Similarly, the bicarbonate extractable P, which represents the bioavailable P fraction, increased consistently by 19%; 28% and 33% following 2%, 4% and 8% RP application, respectively. Though incorporation of RP initially resulted in increased heavy metal levels, reductions of 40%; 35%; 35%; 40% and 45% for Cr, Cu, Cd, Pb and Zn, respectively, were observed in the 8% RP treatment after 8 weeks, due to the presence of earthworms. Vermicomposting with E. fetida significantly reduced heavy metals to levels below the maximum permissible concentration of potentially toxic elements in soils after 8 weeks. This study demonstrates the potential of optimized vermicomposting with igneous RP for generating nutrient rich organic fertilizers.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing cimetidine are reviewed. According to the current Biopharmaceutics Classification System (BCS), cimetidine would be assigned to Class III. Cimetidine's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA) problems were also taken into consideration. On the basis of the overall evidence, a biowaiver can be recommended for cimetidine IR products, provided that the test product contains only those excipients reported in this paper in their usual amounts, and that the test and the comparator drug products both are “rapidly dissolving” as per BCS.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing amitriptyline hydrochloride are reviewed. Its therapeutic uses, its pharmacokinetic properties, the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. Literature data indicates that amitriptyline hydrochloride is a highly permeable active pharmaceutical ingredient (API). Data on the solubility according to the current Biopharmaceutics Classification System (BCS) were not fully available and consequently amitriptyline hydrochloride could not be definitively assigned to either BCS Class I or BCS Class II. But all evidence taken together, a biowaiver can currently be recommended provided that IR tablets are formulated with excipients used in existing approved products and that the dissolution meets the criteria defined in the Guidances.

The workshop Analysis, Toxicity and Biodegradation of Organic Pollutants in Groundwater from Contaminated Land, Landfills and Sediments was held in Barcelona, Spain 8–10 November 2001. GPoll of European Science Foundation (ESF) and Consejo Superior de Investigaciones Cientificas (CSIC) organized the workshop. The analysis, fate and effects of organic pollutants in groundwater from diffuse, local, and subsurface infrastructure pollution sources were explored by the workshop. Oral and poster presentations covered various topics, including

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by joint inflammation and immune dysfunction. Although various therapeutic approaches have been utilized for the treatment of RA in clinical applications, the low responsiveness of RA patients and undesired systemic toxicity are still unresolved problems. Targeting the resolution pathway of inflammation with pro-resolving mediators would evoke the protective actions of patient for combating the inflammation. Ac2–26, a 25-amino acid peptide derived from Annexin A (a pro-resolving mediator), has shown good efficacy in the treatment of inflammatory disorders. However, the low bioavailability of Ac2–26 peptides hinders their efficacy in vivo. In this paper, we formed PEGylated lipid nanoparticles (LDNPs) by the co-assembly of l-ascorbyl palmitate (L-AP) and N-(carbonyl methoxypolyethylene glycol-2000)-1,2-distearoyl-sn‑glycero-3-phosphoethanolamine (DSPE-PEG2k) to encapsulate and deliver Ac2–26 peptides to the arthritic rats. They showed good stability and biocompatibility. After being intravenously administrated, Ac2–26 peptide-loaded PEGylated lipid nanoparticles (ADNPs) showed the prolonged in vivo circulation time and enhanced accumulation in inflamed sites. In vivo therapeutic evaluations revealed that ADNPs could attenuate synovial inflammation and improve joint pathology. Therefore, the pro-resolving therapeutic strategy using ADNPs is effective in RA treatment., Graphical abstract The fabrication of ADNPs and their in vivo performances in arthritic rats.Image, graphical abstract

Most biopharmaceutics classification system (BCS) class IV drugs, with poor solubility and inferior permeability, are also substrates of P-glycoprotein (P-gp) and cytochrome P450 (CYP450), leading to their low oral bioavailability. The objective of this study is to explore the potential of using functional polymer-lipid hybrid nanoparticles (PLHNs) to enhance the oral absorption of BCS IV drugs. In this paper, taking paclitaxel (PTX) as a drug model, PTX-loaded PLHNs were prepared by a self-assembly method. Chitosan was selected to modify the PLHN to enhance its mucoadhesion and stability. Three P-gp inhibitors (D-α-tocopherol polyethylene glycol 1000 succinate, pluronic P123 and SolutolⓇ HS15) were incorporated into selected PLHNs, and a CYP450 inhibitor (the extract of VBRB, BC0) was utilized to jointly promote the drug absorption. Properties of all the PLHNs were characterized systemically, including particle size, zeta potential, encapsulation efficiency, morphology, stability, in vitro drug release, mucoadhesion, in situ intestinal permeability and in vivo systemic exposure. It was found mucoadhesion of the CS-modified PLHNs was the strongest among all the formulations tested, with absolute bioavailability 21.95%. P-gp and CYP450 inhibitors incorporation further improved the oral bioavailability of PTX to 42.60%, 8-fold increase compared with that of PTX itself (4.75%). Taken together, our study might shed light on constructing multifunctional PLHNs based on drug delivery barriers for better oral absorption, especially for BCS IV drugs., Graphical abstract Image, graphical abstract

Ischemic stroke is often involved in the excessive production of reactive oxygen species (ROS), which aggravate ischemic injury. Edaravone (EDV) as an efficient free radical scavenger has demonstrated the effective neuroprotective effects in the therapy of ischemic stroke. Although EDV promotes ischemic recovery by inhibiting the generation of ROS, its poor safety and bioavailability limit its clinical applications. Herein, we developed plasma exosomes (EXO) containing EDV (EXO + EDV) for improving short‐term functional and histological outcomes for stroke treatment. The results showed that EXO + EDV improved brain targeting based on the transferrin–transferrin receptor interaction, and the safety and bioavailability of EDV were also significantly increased. Furthermore, compared with EDV, EXO + EDV significantly rescued ischemic damage in brain tissue by reducing infarct area and improving neurological performance in the acute stage of stroke (first 7 days).

Montmorillonite-loaded solid lipid nanoparticles with good biocompatibility, using Betaxolol hydrochloride as model drug, were prepared by the melt-emulsion sonication and low temperature-solidification methods and drug bioavailability was significantly improved in this paper for the first time to application to the eye. The appropriate physical characteristics were showed, such as the mean particle size, Zeta potential, osmotic pressure, pH values, entrapping efficiency (EE%) and drug content (DC%), all showed well suited for possible ocular application. In vitro release experiment indicated that this novel system could continuously release 57.83% drugs within 12 h owing to the dual drug controlled-release effect that was achieved by ion-exchange feature of montmorillonite and structure of solid lipid nanoparticles. Low irritability and good compatibility of nanoparticles were proved by both CAM-TBS test and cytotoxicity experiment. We first discovered from the results of Rose Bengal experiment that the hydrophilicity of the drug-loaded nanoparticles surface was increased during the loading and releasing of the hydrophilic drug, which could contribute to prolong the ocular surface retention time of drug in the biological interface membrane of tear-film/cornea. The results of in vivo pharmacokinetic and pharmacodynamics studies further confirmed that increased hydrophilicity of nanoparticles surface help to improve the bioavailability of the drug and reduce intraocular pressure during administration. The results suggested this novel drug delivery system could be potentially used as an in situ drug controlled-release system for ophthalmic delivery to enhance the bioavailability and efficacy.

Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists, which is time-consuming, high cost and waste materials. This research aims to integrate various computational tools, including machine learning, molecular dynamic simulation and physiologically based absorption modeling (PBAM), to enhance andrographolide (AG) /cyclodextrins (CDs) formulation design. The lightGBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy. AG/γ-CD inclusion complexes showed the strongest binding affinity, which was experimentally validated by the phase solubility study. The molecular dynamic simulation was used to investigate the inclusion mechanism between AG and γ-CD, which was experimentally characterized by DSC, FTIR and NMR techniques. PBAM was applied to simulate the in vivo behavior of the formulations, which were validated by cell and animal experiments. Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate (TPGS) significantly increased the intracellular uptake of AG in MDCK-MDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers. The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills, respectively. In conclusion, this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility, dissolution rate and bioavailability. The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design., Graphic abstract Image, graphical abstract

Bioflavonoids such as hesperidin and hesperetin as anticancer and antioxidant agents are widely used in the formulation of many herbal drugs. Recently, promising evidence for the prevention and treatment of COVID 19 using these compounds has been reported. Unfortunately, these compounds are often insoluble in aqueous media and have low stability in gastric acid environment. These factors reduced the bioavailability of related oral dosage forms in digestive system. Reduction of particle size and controlled release delivery system can decline the mentioned problems. In the presented research, extraction of bioflavonoids from Citrus sinensis L. (sweet orange) peels was performed using supercritical carbon dioxide. Experimental central composite design was employed for determination of optimal conditions. Qualification analysis was performed using LC–MS, and hesperidin and hesperetin were identified in herbal extract. Micronization and coating of the flavonoids nanoparticles on sugar spheres have been performed using an inhouse developed supercritical technique. Characterization of coated nanoparticles was done using FESEM and ImageJ software. The in vitro antioxidant activity of coated samples was investigated by ferrous ion chelating activity. According to the extraction results, concentration of ethanol as organic co-solvent has the greatest effect on the extraction yield. Analysis of FESEM images illustrated that nanoparticles of extract components with particle size distribution of 5–100 nm were coated successfully. The solubility and antioxidant activity of nanoparticles in aqueous media have increased significantly compared to original form. This process led to increasing dissolution rate and improving the oral bioavailability of flavonoids. Graphical abstract

The aim of the work is the scientific and practical substantiation rabbits productivity increasing while using Jerusalem artichoke pulp and the probiotic complex "Sporothermin" in the composition of biologically valuable compound feed. The introduction of intensive breeding technologies in the rabbit breeding industry, as well as an increase in the number of livestock, led to a significant increase in the technogenic and microbiological load on the rabbits' body, which in turn causes disruption of digestion, metabolism, a decrease in productivity and the occurrence of intestinal infections. The solution to this problem can be innovative developments on the application of herbal supplements and probiotic complexes in feed rations. They help to improve the bioavailability of nutrients in compound feed and increase the safety of livestock without the use of antibiotics for therapeutic and prophylactic purposes. The influence of the probiotic additive "Sporothermin" together with Jerusalem artichoke pulp on the safety, productivity, physiological status and chemical composition of rabbit meat was studied in the work. 30 rabbits aged 45 days were selected to study the effect of probiotic complexes - Jerusalem artichoke pulp. The control group of rabbits received the main diet, consisting of compound feed PK-90, the rabbits of the experimental groups received compound feed PK-90, which included the probiotic complex "Sporothermin" (0.6 g / kg and 1.0 g / kg) - Jerusalem artichoke pulp 10% by weight of compound feed. The analysis of the chemical composition of muscle tissue showed that the application of the probiotic preparation "Sporothermin" at a dosage of 1.0 g / kg and Jerusalem artichoke pulp at a dosage of 10% to the mass of compound feed increases the average daily gains and, as a result, meat productivity, improves the balance of the chemical composition. This is confirmed by the approbation of the data obtained in the industrial complex of Lipetsk Rabbit LLC and the assessment of the physicochemical, functional, technological and organoleptic characteristics of the raw meat obtained.

The molecular targeted drug ATRA demands a suitable carrier that delivers to the cancer site due to its poor bioavailability and drug resistance. ATRA, being a lipid with carboxylic acid, has been nano‐formulated as a cationic lipo‐ATRA with DOTAP:cholesterol:ATRA (5:4:1) and its pH‐responsive release, intracellular drug accumulation, and anticancer effect on human lung cancer (A549) cell line analysed. The analysis of the physicochemical characteristics of the developed lipo‐ATRA (0.8 µmol) revealed that the size of 231 ± 2.35 d.nm had a zeta potential of 6.4 ± 1.19 and an encapsulation efficiency of 93.7 ± 3.6%. The ATRA release from lipo‐ATRA in vitro was significantly (p ≤ 0.05) higher at acidic pH 6 compared to pH 7.5. The intracellular uptake of ATRA into lipo‐ATRA‐treated A549 cells was seven‐fold higher (0.007 ± 0.001 mg/ml) while only three‐fold uptake was observed in free ATRA treatment (0.003 ± 0.002 mg/ml). The lipo‐ATRA treatment caused a highly significant (p ≤ 0.001) decrease in percent cell viability at 48 h when compared with the free ATRA treatment. Overall, the results proved that the developed lipo‐ATRA has suitable physicochemical properties with enhanced ATRA release at acidic pH, while maintaining stability at physiologic pH and temperature. This resulted in an increased ATRA uptake by lung cancer cells with enhanced treatment efficiency. Hence, it is concluded that DOTAP lipo‐ATRA is a suitable carrier for ATRA delivery to solid cancer cells.

Swallowing oral solid dosage forms is challenging in patients with dysphagia who are at risk of aspiration or choking. The most common method to facilitate drug administration in dysphagia patients is to mix the powdered drug with a small amount of thickened water, however little is known about the effects of this method on in vivo bioavailability of drugs. This study aimed to evaluate the impact of thickened liquids on dissolution rate and bioavailability of levetiracetam as a model drug. Powdered commercial tablets of levetiracetam, carbamazepine, atenolol and cefixime were mixed with water thickened with two commercial thickeners, modified maize starch (MS) and xanthan gam (XG), at three thickness levels: nectar, honey and pudding in test groups, and mixed with only water in the control group. At the first stage, the effects of thickened water on in vitro drug release of 4 drugs (levetiracetam, carbamazepine, atenolol and cefixime) were tested by using dialysis membrane method. Addition of both thickeners significantly reduced the release of three drugs compared to the control group, except carbamazepine. Levetiracetam which had the highest solubility was chosen as the model drug for in vivo experiments. In the second stage, New Zealand albino female rabbits (n=24) were divided into two groups as: control group (water+drug, n=6) and test group (thickened water+drug, n=18). Powdered levetiracetam tablets were mixed with water thickened with XG (n=9, 1.2%, 2.4%, 3.6%) and MS (n=9, 4%, 6%, 8%) at three thickness levels and administered to the rabbits by intragastric gavage. Blood samples were collected at 9 time points following administration. After two-weeks of wash-out, test groups were crossed over and sample collection was repeated. Blood samples were analysed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). An in vitro-in vivo correlation (IVIVC) model was developed using in vitro drug dissolution (%) and in vivo plasma concentrations of levetiracetam for control group and test groups. The peak plasma concentration (C-max) was lower and time to reach C-max (t(max)) was relatively higher in test groups compared to control group. The lowest C-max was detected at the highest thickness level, however, the differences between groups were not statistically significant (p=0.117 and p=0.495 for C-max and t(max), respectively). No significant difference in total amount of levetiracetam absorbed (AUC) was found between groups (p=0.215 and p=0.183 for AUC(infinity) and AUC(last), respectively). The comparisons according to the type of thickener also revealed that pharmacokinetic parameters did not significantly differ between groups, except for a significantly lower C-max when drug was mixed with MS-thickened water at nectar consistency (1.2%) compared to drug mixed with XG (4%) at the same thickness level (p=0.038). A good correlation was observed between in vitro and in vivo data, which was characterized by higher r(2) values as the concentration of the thickening agents was increased, but not for all thickness levels studied, indicating an inability of this in vitro model to fully predict the in vivo response. These results suggest that regardless of the thickness level, the administration of levetiracetam with two commercial thickening agents commonly used in dysphagia for safe swallowing, do not affect the pharmacokinetic efficiency and thus, the bioavailability of the drug.

Citrus pomace consists of the peel, pulp, and membrane tissues remaining after juice expression. Globally, around one million tons of citrus pomace are generated annually, which contains a variety of bioactive constituents that could be used as value-added functional ingredients in foods. However, the polyphenols in citrus pomace are not currently being utilized to their full potential, even though they can be used as nutraceuticals in functional foods and beverages. Citrus phenolics face significant roadblocks to their successful incorporation into these products. In particular, they have poor water solubility, chemical stability, and bioavailability. This review describes the diverse range of colloidal systems that have been developed to encapsulate and deliver citrus phenolics. Examples of the application of these systems for the encapsulation, protection, and delivery of polyphenols from citrus pomace are given. The use of colloidal delivery systems has been shown to improve the stability, dispersibility, and bioaccessibility of encapsulated polyphenols from citrus pomace. The selection of an appropriate delivery system determines the handling, storage, shelf life, encapsulation efficiency, dispersibility, and gastrointestinal fate of the citrus polyphenols. Furthermore, the purity, solubility, and chemical structure of the polyphenols are key factors in delivery system selection.

The aim of the study was to use of geochemical, chemical, ecotoxicological and biological indicators for a comprehensive assessment of ecological risks related to the mobility, ecotoxicity and bioavailability of trace elements in the bottom sediment of the Rożnów reservoir. The study found three elements deserving attention in the sediments: cadmium, nickel and chromium. Cadmium proved to be the most mobile and bioavailable, although the total cadmium content and geochemical indicators did not reveal any risk to organisms. Geochemical indicators showed that the sediments are contaminated with nickel and chromium, but both elements had a low bioaccumulation factor. Fractional analysis also revealed relatively low mobility of Cr and Ni and a higher potential risk of bioavailability for nickel. Most of the tested sediment samples had low toxicity in relation to the tested organisms. For H. incongruens, 11% of the samples were non-toxic, 50% of the samples had low toxicity, and 39% of the samples were toxic. For A. fischeri, no toxicity was found in 7% of the samples, low toxicity in 76% of the samples and toxicity in 17% of the sediment samples. The As, Cd, Cu content in the F1 fraction correlated significantly positively with the content of these metals in mussel tissues. Both biotesting and chemical analysis can reveal a potential risk to aquatic organisms. For a real assessment of the ecological risks associated with trace elements, it is necessary to use bioindicators taken from the environment and exposed to trace elements in situ.

Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Overall, BET exhibited slower clearance, similar volume of distribution, faster absorption, and longer persistence than DEX with BET acetate producing extremely slow absorption but full bioavailability of BET. Six biomarkers were assessed over a 24-h baseline period with four showing circadian rhythms with complex baselines. These baselines and the strong responses seen after drug dosing were fitted with various indirect response models using the Laplace estimation methods in NONMEM 7.4. Both the PK and six biomarker responses were well-described with modest variability likely due to the homogeneous ages, weights, and ethnicities of the women. The drugs either inhibited or stimulated the influx processes with some models requiring joint inclusion of drug effects on circadian cortisol suppression. The biomarkers and order of sensitivity (lowest IC50/SC50 to highest) were: cortisol, T-helper cells, basophils, glucose, neutrophils, and T-cytotoxic cells. DEX sensitivities were generally greater than BET with corresponding mean ratios for these biomarkers of 2.86, 1.27, 1.72, 1.27, 2.69, and 1.06. Overall, the longer PK (e.g. half-life) of BET, but lesser PD activity (e.g. higher IC50), produces single-dose response profiles that appear quite similar, except for the extended effects from BET-PA. This comprehensive population modeling effort provides the first detailed comparison of the PK profiles and six biomarker responses of five commonly used dosage forms of DEX and BET in healthy women.

Insulin, a peptide hormone, is one of the most common and effective antidiabetic drugs. Although oral administration is considered to be the most convenient and safe choice for patients, the oral bioavailability of insulin is very low due to the poor oral absorption into blood circulation. Intestinal epithelium is a major barrier for the oral absorption of insulin. Therefore, it is vital to develop intestinal permeation enhancer to increase the antidiabetic efficacy of insulin after oral administration. Methods: Charge-switchable zwitterionic polycarboxybetaine (PCB) was used to load insulin to form PCB/insulin (PCB/INS) particles through the electrostatic interaction between positively charged PCB in pH 5.0 and negatively charged insulin in 0.01 M NaOH. The opening effect of PCB/INS particles on intestinal epithelium was evaluated by detecting the changes of claudin-4 (CLDN4) protein and transepithelial electrical resistance (TEER) after incubation or removal. The mechanism was further elucidated based on the results of Western blot and fluorescence images. The PCB/INS particles were then used for type 1 diabetes mellitus therapy after oral administration. Results: PCB could load insulin with the loading efficiency above 86% at weight ratio of 8:1. PCB/INS particles achieved sustained release of insulin at pH 7.4 due to their charge-switchable ability. Surprisingly, PCB/INS particles induced the open of the tight junctions of intestinal epithelium in endocytosis-mediated lysosomal degradation pathway, which resulted in increased intestinal permeability of insulin. Additionally, the opening effect of PCB/INS particles was reversible, and the decreased expression of CLDN4 protein and TEER values were gradually recovered after particles removal. In streptozotocin-induced type 1 diabetic rats, oral administration of PCB/INS particles with diameter sub-200 nm, especially in capsules, significantly enhanced the bioavailability of insulin and achieved longer duration of hypoglycemic effect than the subcutaneously injected insulin. Importantly, there was no endotoxin and pathological change during treatment, indicating that PCB/INS particles were safe enough for in vivo application. Conclusion: These findings indicate that this system can provide a platform for oral insulin and other protein drugs delivery.

Objectives The aim of this study was to couple fused deposition modelling 3D printing with melt extrusion technology to produce core–shell-structured controlled-release tablets with dual-mechanism drug-release performance in a simulated intestinal fluid medium. Coupling abovementioned technologies for personalized drug delivery can improve access to complex dosage formulations at a reasonable cost. Compared with traditional pharmaceutical manufacturing, this should facilitate the following: (1) the ability to manipulate drug release by adjusting structures, (2) enhanced solubility and bioavailability of poorly water-soluble drugs and (3) on-demand production of more complex structured dosages for personalized treatment. Methods Acetaminophen was the model drug and the extrusion process was evaluated by a series of physicochemical characterizations. The geometries, morphologies, and in vitro drug-release performances were compared between directly compressed and 3D-printed tablets. Key findings Initially, 3D-printed tablets released acetaminophen more rapidly than directly compressed tablets. Drug release became constant and steady after a pre-determined time. Thus, rapid effectiveness was ensured by an initially fast acetaminophen release and an extended therapeutic effect was achieved by stabilizing drug release. Conclusions The favourable drug-release profiles of 3D-printed tablets demonstrated the advantage of coupling HME with 3D printing technology to produce personalized dosage formulations.