Moxifloxacin Liposomes:Effect of Liposome Preparation Method on Physicochemical Properties and Antimicrobial Activity against Staphylococcus epidermidis

The aim of this study was the development of optimal sustained-release moxifloxacin (MOX)-loaded liposomes as intraocular therapeutics of endophthalmitis. Two methods were compared for the preparation of MOX liposomes; the dehydration–rehydration (DRV) method and the active loading method (AL). Numerous lipid-membrane compositions were studied to determine the potential effect on MOX loading and retention in liposomes. MOX and phospholipid contents were measured by HPLC and a colorimetric assay for phospholipids, respectively. Vesicle size distribution and surface charge were measured by DLS, and morphology was evaluated by cryo-TEM. The AL method conferred liposomes with higher MOX encapsulation compared to the DRV method for all the lipid compositions used. Cryo-TEM showed that both liposome types had round vesicular structure and size around 100–150 nm, while a granular texture was evident in the entrapped aqueous compartments of most AL liposomes, but substantially less in DRV liposomes; X-ray diffraction analysis demonstrated slight crystallinity in AL liposomes, especially the ones with highest MOX encapsulation. AL liposomes retained MOX for significantly longer time periods compared to DRVs. Lipid composition did not affect MOX release from DRV liposomes but significantly altered drug loading/release in AL liposomes. Interestingly, AL liposomes demonstrated substantially higher antimicrobial potential towards S. epidermidis growth and biofilm susceptibility compared to corresponding DRV liposomes, indicating the importance of MOX retention in liposomes on their activity. In conclusion, the liposome preparation method/type determines the rate of MOX release from liposomes and modulates their antimicrobial potential, a finding that deserves further in vitro and in vivo exploitation

Medical Device Development for Children and Young People—Reviewing the Challenges and Opportunities

Development of specific medical devices (MDs) is required to meet the healthcare needs of children and young people (CYP). In this context, MD development should address changes in growth and psychosocial maturation, physiology, and pathophysiology, and avoid inappropriate repurposing of adult technologies. Underpinning the development of MD for CYP is the need to ensure MD safety and effectiveness through pediatric MD-specific regulations. Contrary to current perceptions of limited market potential, the global pediatric healthcare market is expected to generate around USD 15,984 million by 2025. There are 1.8 billion young people in the world today; 40% of the global population is under 24, creating significant future healthcare market opportunities. This review highlights a number of technology areas that have led to successful pediatric MD, including 3D printing, advanced materials, drug delivery, and diagnostic imaging. To ensure the targeted development of MD for CYP, collaboration across multiple professional disciplines is required, facilitated by a platform to foster collaboration and drive innovation. The European Pediatric Translational Research Infrastructure (EPTRI) will be established as the European platform to support collaboration, including the life sciences industrial sector, to identify unmet needs in child health and support the development, adoption, and commercialization of pediatric MDs

Mutant KRAS promotes malignant pleural effusion formation

Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition

STUDIES OF BINDING AND SOLUBILITY OF DRUGS IN MILK

THE BINDING AND THE SOLUBILITY OF EIGHT DRUGS IN MILK WAS MEASURED (HYDROCHLOROTHIORIDE, CHLOROTHIORIDE, NITROFURANTOIN, PIROXICAM, INDOMETHACIN, PREDINISOLONE, DIAZEPAM, DICUMAROL). FOR THE TWO THIORIDES THE EXPERIMENTS WERE CARRIED OUTAT 5, 15, 25 AND 37 C ON BOVINE MILK SAMPLES WITH FAT CONTENTS OF 0.75, 1,70 AND 3,50%. BINDING EXPERIMENTS WITH A 2.6% SOLUTION OF CASEIN WERE ALSO CARRIED OUT AT THE SAME TEMPERATURE AND CONCENTRATION RANGE. FOR THE REST OF THE DRUGS THE EXPERIMENTS WERE CARRIED OUT AT 15, 25 AND 37 C ON BOVINE MILK SAMPLES WITHFAT CONTENTS OF 0,75 AND 3.50%. THE BINDING TO MILK (AND CASEIN) OF ALMOST ALLTHE DRUGS USED, WAS FOUND TO BE NOT DEPENDENT ON THE CONCENTRATION OF DRUGS. THE PERCENT BOUND TO MILK WAS FOUND TO DIFFER GREATLY FROM DRUG TO DRUG. THE SOLUBILITY OF ALL DRUGS EXAMINED, IN MILK WAS FOUND TO BE SIGNIFICANTLY ENHANCED, COMPARED TO THEIR SOLUBILITY IN AN AQUEOUS SOLUTION OF THE SAME TEMPERATURE. THE % BOUND OF DRUGS TO MILK WAS FOUND TO BE DEPENDENT ON SOME PHYSICAL-CHEMICAL PROPERTIES OF THE DRUGS (LOG P, PKA, PERCENT IONIZED), AND ON THE MECHANISM OF THE BINDING PROCESS (ΔΗ, ENTHALON CHANGE DURING THE BINDING PROCESS). A MULTIPLE REGRESSION ANALYSIS WAS RUN AND GOOD CORRELATIONS WERE FOUND. THE POTENTIAL SIGNIFICANCE OF THE FINDINGS IN RESPECT TO PREPARATION AND IN VIVO DELIVERY OF DRUGS FROM DRUG-MILK FORMULATIONS IS DISCUSSED.ΕΞΕΤΑΣΘΗΚΕ Η ΣΥΝΔΕΣΗ ΚΑΙ Η ΔΙΑΛΥΤΟΤΗΤΑ ΣΤΟ ΓΑΛΑ ΟΚΤΩ ΦΑΡΜΑΚΩΝ (ΥΔΡΟΧΛΩΡΟΘΕΙΑΖΙΔΙΟ, ΧΛΩΡΟΘΕΙΑΖΙΔΙΟ, ΝΙΤΡΟΦΟΥΡΑΝΤΡΙΝΗ, ΠΙΡΟΞΙΚΑΜΗ, ΙΝΔΟΜΕΘΑΚΙΝΗ, ΠΡΕΔΝΙΖΟΛΟΝΗ, ΔΙΑΖΕΠΑΜΗ, ΔΙΚΟΥΜΑΡΟΛΗ). ΓΙΑ ΤΑ ΔΥΟ ΘΕΙΑΖΙΔΙΑ ΜΕΤΡΗΘΗΚΑΝ ΤΑ ΠΟΣΟΣΤΑ ΣΥΝΔΕΣΗΣ ΣΕ ΓΑΛΑ ΜΕ ΠΕΡΙΕΚΤΙΚΟΤΗΤΑ ΣΕ ΛΙΠΑΡΑ 0,1%, 0,75%, 1,70% ΚΑΙ 3.50% ΣΤΟΥΣ 5, 15, 25 ΚΑΙ 37 C, ΕΝΩ ΧΡΗΣΙΜΟΠΟΙΗΘΗΚΕ ΚΑΙ ΔΙΑΛΥΜΑ ΚΑΖΕΙΝΗΣ (ΡΗ 6. 5, 2,6% Β/Β). ΣΤΙΣ ΙΔΙΕΣ ΣΥΝΘΗΚΕΣ ΕΓΙΝΑΝ ΚΑΙ ΜΕΤΡΗΣΕΙΣ ΔΙΑΛΥΤΟΤΗΤΑΣ ΠΟΥ ΜΕΤΡΗΘΗΚΕ ΚΑΙ ΣΕ ΥΔΑΤΙΚΟ ΠΕΡΙΒΑΛΛΟΝ ΓΙΑ ΣΥΓΚΡΙΤΙΚΟΥΣ ΣΚΟΠΟΥΣ (ΡΥΘΜΙΣΤΙΚΟ ΔΙΑΛΥΜΑ ΦΩΣΦΟΡΙΚΩΝ, ΡΗ ). ΓΙΑ ΤΑ ΥΠΟΛΟΙΠΑ ΦΑΡΜΑΚΑ ΜΕΤΡΗΘΗΚΑΝ ΤΑ ΠΟΣΟΣΤΑ ΣΥΝΔΕΣΗΣ ΚΑΙ Η ΔΙΑΛΥΤΟΤΗΤΑ ΣΕ ΓΑΛΑ ΜΕ ΠΕΡΙΕΚΤΙΚΟΤΗΤΑ ΣΕ ΛΙΠΑΡΑ 0,75% ΚΑΙ 3.50% ΣΤΟΥΣ 15, 25 ΚΑΙ 37 C. Η ΣΥΝΔΕΣΗ, ΟΛΩΝ ΣΧΕΔΟΝ ΤΩΝ ΦΑΡΜΑΚΩΝ ΠΟΥ ΜΕΛΕΤΗΘΗΚΑΝ, ΣΤΟ ΓΑΛΑ ΕΙΝΑΙ ΜΗ-ΕΞΕΙΔΙΚΕΥΜΕΝΗ ΕΝΩ ΤΑ ΠΟΣΟΤΙΚΑ ΧΑΡΑΚΤΗΡΙΣΤΙΚΑ ΔΙΑΦΕΡΟΥΝ ΑΠΟ ΦΑΡΜΑΚΟ ΣΕ ΦΑΡΜΑΚΟ. Η ΔΙΑΛΥΤΟΤΗΤΑ ΟΛΩΝ ΤΩΝ ΦΑΡΜΑΚΩΝ ΣΤΟ ΓΑΛΑ ΕΙΝΑΙ ΕΝΤΥΠΩΣΙΑΚΑ ΑΥΞΗΜΕΝΗ ΣΕ ΣΧΕΣΗ ΜΕ ΤΗΝ ΥΔΑΤΙΚΗ ΔΙΑΛΥΤΟΤΗΤΑ ΤΟΥΣ ΣΤΗΝ ΙΔΙΑ ΘΕΡΜΟΚΡΑΣΙΑ. ΒΡΕΘΗΚΕ ΟΤΙ ΤΑ ΠΟΣΟΣΤΑ ΣΥΝΔΕΣΗΣ ΣΤΟ ΓΑΛΑ ΣΥΝΔΕΟΝΤΑΙ ΓΡΑΜΜΙΚΑ, ΜΕ ΤΙΣ ΦΥΣΙΚΟΧΗΜΙΚΕΣ ΙΔΙΟΤΗΤΕΣ ΤΩΝ ΦΑΡΜΑΚΩΝ (LOG P, ΠΟΣΟΣΤΟ ΙΟΝΙΣΜΟΥ ΡΚΑ) ΚΑΙ ΤΟΝ ΜΗΧΑΝΙΣΜΟ ΤΗΣ ΔΙΕΡΓΑΣΙΑΣ ΣΥΝΔΕΣΗΣ (ΜΕΤΑΒΟΛΗ ΤΗΣ ΕΥΘΑΛΠΙΑΣ ΔΗ) ΚΑΙ ΥΠΟΛΟΓΙΣΤΗΚΕ (ΜΕ ΠΟΛΛΑΠΛΗ ΑΝΑΛΥΣΗ ΣΥΜΜΕΤΑΒΟΛΗΣ) ΕΙΔΙΚΗ ΕΞΙΣΩΣΗ. ΣΥΖΗΤΕΙΤΑΙ Η ΣΗΜΑΝΤΙΚΟΤΗΤΑ ΤΩΝ ΔΕΔΟΜΕΝΩΝ ΣΕ ΣΧΕΣΗ ΜΕ ΤΗΝ ΠΑΡΑΣΚΕΥΗ ΚΑΙ ΤΗΝ IN- VIVO ΚΑΤΑΝΟΜΗ ΤΩΝ ΦΑΡΜΑΚΩΝ ΑΠΟ ΜΟΡΦΟΠΟΙΗΣΕΙΣ ΦΑΡΜΑΚΩΝ ΣΕ ΓΑΛΑ

Solubility of drugs in the presence of gelatin: effect of drug lipophilicity and degree of ionization

The solubility of seven drugs (nitrofurantoin, chlorothiazide, phenobarbital, prednisolone, griseofulvin, diazepam and piroxicam) in the absence and presence of gelatin was measured, at three different pH values (3.7, 5.0 and 7.0) at 37 degreesC. Drugs studied had different physicochemical properties (log P, pK(a), aqueous solubility) and their solubility in presence of 0.1 and 0.5%, (w/v) hydrolyzed land in some cases common) gelatin was estimated. Results show that the solubility of all drugs is significantly enhanced, especially in the presence of 0.5%;, gelatin. This gelatin-induced enhancement in drug solubility is higher in the pH in which acidic drugs are less ionized, especially for the less lipophilic acidic drugs (nitrofurantoin, chlorothiazide). In all cases, drug solubility in presence of gelatin is correlated with their aqueous solubility. Therefore, the established relationships between aqueous and gelatin solubility can be employed to derive an estimate of the drug solubility in presence of gelatin once its aqueous solubility is known. With the exception of piroxicam which is highly ionized and phenobarbital which is relatively soluble, there seems to be a tendency for larger gelatin-induced increases in solubility as drug lipophilicity increases or aqueous solubility decreases

Liposomes containing cyclodextrins or meglumine to solubilize and improve the bioavailability of poorly soluble drugs

Poorly soluble drug-loaded liposomes are well known for their ability to solubilize and improve the bioavailability of the carried molecules, and may provide benefits as oral drug delivery systems. In this work, we aim to evaluate the effect of the incorporation of β-cyclodextrin (βCD), methyl-βCD (MβCD), hydroxypropil-βCD (HPβCD) and meglumine (MEG) in liposomes for the oral delivery of the poorly water-soluble drugs, sulfamerazine (SMR) and indomethacin (INM). Liposomes with egg phosphatidylcholine (PC) and cholesterol (CHO), incorporating SMR or INM as plain drug or inclusion complexes, were prepared using the thin film hydration method or dehydration-rehydration method, respectively. The systems were characterized by particle size, polydispersity and zeta potential measurements, and drug-component interaction studies were performed by 1H NMR. Liposome stability in presence of SMR, INM, CD and MEG was determined by the retention of vesicle encapsulated calcein after incubation in solutions of pH 7.4, at 37 °C for up to 48 h. Drug entrapment, as well as drug release, were estimated for all liposome types prepared. The 1H NMR studies revealed that the drugs presented interaction with lipids of the liposomes, suggesting the location of the drugs in the lipid bilayer. The liposomes presented high stability in the presence of the drugs, βCD, HPβCD or MEG. The highest entrapment values were achieved for SMR and INM with PC:CHO 3:1 liposomes when MEG and HPβCD were used, respectively (5636.28 and 439.54 mmol/mol), meaning that 18 and 43 times higher incorporation of SMR and INM were achieved in comparison with the ligand-free formulation. The in-vitro release studies showed a strong influence of the ligands on the delivery of the drugs from the liposomes.Fil: Aloisio, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Antimisiaris, Sophia G.. University of Patras; GreciaFil: Longhi, Marcela Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentin

Exosomes and Exosome-Inspired Vesicles for Targeted Drug Delivery

The similarities between exosomes and liposomes, together with the high organotropism of several types of exosomes, have recently prompted the development of engineered-exosomes or exosome-mimetics, which may be artificial (liposomal) or cell-derived vesicles, as advanced platforms for targeted drug delivery. Here, we provide the current state-of-the-art of using exosome or exosome-inspired systems for drug delivery. We review the various approaches investigated and the shortcomings of each approach. Finally the challenges which have been identified to date in this field are summarized

Stability of SUV liposomes in the presence of cholate salts and pancreatic lipases: effect of lipid composition

The effect of bile salts (sodium cholate and sodium taurocholate), and pancreatic lipases on the structural integrity of SW liposomes of different lipid compositions was studied. Liposomal membrane integrity was judged by bile salt or pancreatin-induced release of vesicle encapsulated 5,6-carboxyfluorescein, and vesicle size distribution before and after incubations. Bile salt concentration was 10 mM, while a saturated solution of pancreatin (mixed with equal volume of liposomes) was utilized. Results agree with earlier studies, demonstrating the instability of liposomes composed of lipids with low transition temperatures (PC and DMPC) in presence of cholates. Addition of cholesterol (1:1 lipid:chol molar ratio) does not substantially increase the encapsulated molecule retention. Nevertheless, liposomes composed of lipids with high transition temperatures (DPPC, DSPC and SM), retain significantly higher amounts of encapsulated material, under all conditions studied. Furthermore, the vesicles formed by mixing cholesterol with these lipids will possibly be sufficiently stable in the gastrointestinal tract for long periods of time. Sizing results reveal that in most cases release of encapsulated molecules is mainly caused by their leakage through holes formed on the Lipid bilayer. However, in stearylamine containing DPPC and DSPC vesicles, the cholate-induced drastic decrease in vesicle size suggests total liposome disruption as the possible mechanism of encapsulated material immediate release. (C) 2000 Elsevier Science B.V. All rights reserved