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One of the possible causes of failure of the mechanochemical activation of poorly soluble drugs relies on the scarce drug wettability. Indeed, the mechanochemical process comports the disposition of drug nano-crystals and amorphous drug, generated by the destruction of original drug macro-crystals, on the surface of the carrier (acting as stabiliser), usually represented by crosslinked polymeric particles. Accordingly, the scarce drug wettability can reduce the beneficial action of mechanochemical activation (nano-crystals and amorphous drug are characterised by a higher solubility with respect to the original macro-crystals). In this light, this paper is focussed on the use of surfactants for the increase of delivery system (drug plus carrier) wettability. In particular, the surfactant-polymer systems are characterised for what concerns their bulk and surface properties. This allows to select the best surfactant and to experimentally verify its effect on the release kinetics of a poorly soluble and wettable drug. [ABSTRACT FROM AUTHOR]

Efficacy and safety of Givinostat, an oral histone deacetylase inhibitor for the treatment of Duchenne muscular dystrophy (DMD) have been assessed in the Epidys phase 3 study in ambulant boys (NCT02851797). DSC/14/2357/51 (NCT03373968) is an ongoing open label, long-term study of givinostat in 194 DMD subjects enrolled in givinostat studies and treated until marketing approval. 142 subjects from DSC/14/2357/51 were matched to 142 subjects from ImagingDMD (NCT01484678) and CINRG (NCT00468832) natural history studies (control group) using propensity score matching based on baseline results of functional tests and type of steroid. The median age at disease progression milestones, i.e., persistent loss to perform 4 stair climb (Lo4SC), loss of rise from floor (LoR), and loss of ambulation (LoA) were analyzed. Kaplan-Meier hazard ratios (HR) for givinostat vs control group and 95% CI were calculated using Cox proportional hazard model. Twenty-one (14.8%) patients showed Lo4SC in the Givinostat group vs 52 (36.6%) in the control group (HR=0.39 [0.24, 0.65], p<0.001). Median age at Lo4SC was 17.9 years (95% CI 15.65-NE) in the Givinostat group vs 13.9 (95% CI 13.50 14.88) in the control group. Forty-five (31.7%) patients show LoR in the Givinostat vs 61 (43.0%) in the control group (HR=0.66 (0.45, 0.96), p=0.028) at a median age of 14.9 years (95% CI 13.60-15.97) in the Givinostat group vs 12.9 (95% CI 12.20 14.33) in the control group. Fourteen (9.9%) subjects show LoA in the Givinostat group vs 39 (27.5%) in the control group (HR=0.42 (0.23, 0.76), p=0.004) at a median age of 18.1 years (95%CI 18.09, NE) in the givinostat group vs 15.2 (95%CI 14.70 18.31) in the control group. These results show that patients treated with givinostat, when compared with matched, steroid-treated controls, delays the occurrence of disease milestones. These results confirm givinostat efficacy demonstrated in Epidys Study with longer-term treatment. [ABSTRACT FROM AUTHOR]

Efficacy and safety of givinostat, an oral histone deacetylase inhibitor for the treatment of Duchenne Muscular Dystrophy (DMD) have been assessed in Epidys phase 3 study, a randomized double-blind, placebo-controlled trial in ambulant patients (NCT02851797). Patients enrolled in previous givinostat phase 2 and 3 studies transitioned to Study 51 (i.e., DSC/14/2357/51, NCT03373968), an ongoing open label, long-term study of DMD subjects who will be treated until marketing approval. In Study 51, at the data cut of 31st December 2023, 207 patients were enrolled and 186 are still on treatment, with a mean duration of exposure of 3.18 years and a maximum exposure of 6.1 years. Epidys phase 3 study enrolled 118 patients treated for 18 months with givinostat and 61 in control group with placebo; all of them were on stable corticosteroids. Givinostat met the primary end point in phase 3 trial, while the ongoing Study 51 is evaluating the long-term safety and efficacy. Short-term (ST) safety data (within 3 months of treatment initiation) were compared with long-term data (LT, after 3 months). Diarrhea and vomiting were less frequent in LT than ST (15.3% vs 29.7% and 14.4% vs 21.2 respectively). Abdominal pain was 8.5% in LT vs 16.1% in ST. Platelet counts drop and thrombocytopenia were less frequent in LT than ST (5.1% vs 14.4% and 6.8% vs 10.2%, respectively). These results show that patients treated with givinostat show a predictable safety profile, with adverse events appearing more frequently in the first 3 months of treatment and therefore manageable through dose management, among study population with Duchenne Muscular Dystrophy. [ABSTRACT FROM AUTHOR]

Background: Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy., Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (≤1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with ClinicalTrials.gov, NCT02851797, and is complete., Findings: Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1-11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17-1·37) for boys receiving givinostat and 1·48 (1·32-1·66) for those receiving placebo (ratio 0·86, 95% CI 0·745-0·989; p=0·035). The most common adverse events in the givinostat group were diarrhoea (43 [36%] of 118 boys vs 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] vs 8 [13%]); no treatment-related deaths occurred., Interpretation: Among ambulant boys with Duchenne muscular dystrophy, results of the four-stair climb assessment worsened in both groups over the study period; however, the decline was significantly smaller with givinostat than with placebo. The dose of givinostat was reduced after an interim safety analysis, but no new safety signals were reported. An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with Duchenne muscular dystrophy., Funding: Italfarmaco., Competing Interests: Declaration of interests EM declares payment or honoraria for lectures and symposia from Sarepta Therapeutics, PTC Therapeutics, and Roche; and participation on advisory boards for Sarepta Therapeutics, NS Pharma, Santhera, PTC Therapeutics, Roche, Pfizer, WAVE Life Sciences, Italfarmaco, and Dyne Therapeutics, all outside the scope of this manuscript. JJV declares grants from PTC Therapeutics; consulting fees from Santhera, Sarepta Therapeutics, and PTC Therapeutics; and payment for lectures, presentations, speakers bureaus, manuscript writing or educational events from PTC Therapeutics, all outside the scope of this manuscript. OB-T declares grants to her institution from Roche, Novartis, Biogen, Genethon, and Metafora Biosystems; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis; support for attending meetings and/or travel from Novartis; participation on a data safety monitoring board or advisory board for Minoryx Therapeutics; and unpaid leadership roles with AFM-Téléthon (scientific board president) and Société Francophone de Neurogenetique, all outside the scope of this manuscript. CMZ declares grants or contracts from Biogen and Novartis; consulting fees from Sarepta Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Sarepta Therapeutics and Optum; support for attending meetings and/or travel from Sarepta Therapeutics and Optum; and participation on a data safety monitoring board or advisory board for Sarepta Therapeutics, all outside the scope of this manuscript. JKM declares research grants to her institution from Italfarmaco, Biogen, Novartis, NS Pharma, Pfizer, PTC Therapeutics, ReveraGen Biopharma, Roche, Sarepta Therapeutics, and Alberta Children's Hospital Foundation, all outside the scope of this manuscript. NG declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biogen; and participation on a data safety monitoring board or advisory board for Pfizer, Biogen, and WAVE Life Sciences, all outside the scope of this manuscript. WM-F declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biogen, Roche, Sarepta Therapeutics, Sanofi-Aventis, and Novartis; payment to his institution for expert testimony from Astellas Pharma; participation on a data safety monitoring board or advisory board with payment to himself from PTC Therapeutics, Roche, and Novartis, and to his institution from Astellas Pharma; and unpaid leadership roles for the Deutsche Gesellschaft für Muskelkranke and Glykogenose Deutschland, all outside the scope of this manuscript. EHN declares grants to his institution from Pfizer and PTC Therapeutics; and consulting fees to his institution from Pfizer, Edgewise Therapeutics, Sarepta Therapeutics, Epirium Bio, Regenxbio, Janssen Pharmaceuticals, all outside the scope of this manuscript. US-S declares consulting fees from Santhera, PTC Therapeutics, Sarepta Therapeutics, and Pfizer, all outside the scope of this manuscript. EB declares participation on advisory boards for Pfizer, Roche, Biogen, and Novartis, all outside the scope of this manuscript. GPC declares payment for a lecture from Biogen; participation on advisory boards for PTC Therapeutics, Roche, and Sanofi Genzyme; and an unpaid leadership role (president) of the Italian Association of Myology, all outside the scope of this manuscript. KDM declares grants to her institution from Italfarmaco, Sarepta Therapeutics, PTC Therapeutics, FibroGen, Capricor Therapeutics, Pfizer, Edgewise Therapeutics, Biomarin Pharmaceutical, Centers for Disease Control and Prevention, and the National Institutes of Health; an honorarium to cover travel costs from the Muscular Dystrophy Association; reimbursement to her institution of support to attend meetings and/or travel from the Parent Project Muscular Dystrophy; participation on a data safety monitoring board or advisory board for Dyne Therapeutics, NS Pharma, TRiNDS, and Sarepta Therapeutics; and payment to her institution for participation in a grant review board for the Muscular Dystrophy Association, all outside the scope of this manuscript. LS declares grants to his institution from Roche, Novartis, Biogen, Sysnav Healthcare, Zentech, and Perkin Elmer; consulting fees from Pfizer, Santhera, Dynacure, Dyne Therapeutics, Audentes Therapeutics, Zentech, Sarepta Therapeutics, Roche, Novartis, Biohaven, Biogen Digital Health, Scholar Rock, Regenexbio, and Evox Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Biogen, and Novartis; payment for expert testimony from Audentes Therapeutics; participation on a data safety monitoring board or advisory board for FibroGen, Lupin Therapeutics, and Illumina; and unpaid leadership roles for the World Muscle Society, SMA Europe, and the Association Belge contre les Maladies neuro-Musculaires , all outside the scope of this manuscript. KV declares a research service agreement for the current clinical trial. Outside of this manuscript, she declares grants from the National Institutes of Health; and research service support from Sarepta Therapeutics, Catabasis Pharmaceuticals, PTC Therapeutics, Summit Therapeutics, Astellas Pharma, ML Bio/VCU, and Edgewise Therapeutics, all directed to the University of Florida, Gainesville, FL, USA. JJ declares consulting fees from Biogen, AveXis, Sarepta Therapeutics, and Roche; and receipt of travel and speaker fees from PTC Therapeutics, all outside the scope of this manuscript. SM declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Biogen, and Novartis, all outside the scope of this manuscript. SS declares payments for participation in ad-hoc advisory boards for PTC Medical, Sarepta Therapeutics, Pfizer, and Roche; and payment for chairing a symposium sponsored by Sarepta Therapeutics at the British Neuropsychiatry Association 2019 annual meeting, all outside the scope of this manuscript. LM declares study funding and payments to her institution for provision of study materials in the current clinical trial. Outside the current manuscript she declares grants to her institution from Anavex Life Sciences. KS declares grants or contracts from Biogen (principal investigator and clinical trial site for a nusinersen study), ReveraGen-Santhera (principal investigator for a vamorolone study), and PTC Therapeutics (principal investigator for an ataluren study); payment to her institution from Roche for a teaching and educational seminar on spinal muscular atrophy; an honorarium from Novartis for a TREAT NMD talk on spinal muscular atrophy; and attendance at advisory boards for Biogen and Roche (including travel), all outside the scope of this manuscript. CGL declares contracts (as principal investigator) from Sarepta Therapeutics, Dyne Therapeutics, Avidity Biosciences, FibroGen, Scholar Rock, and Biohaven; consulting fees from Sarepta Therapeutics (payments to her institution), NS Pharma (payments to herself), and Avidity (payments to her institution and to herself); payments for participation in a speakers bureau from Biogen; and support for attending meetings and/or travel from the Muscular Dystrophy Association, CureCMD, and CureSMA, all outside the scope of this manuscript. KC declares payments directly to KJC Statistics for statistical support of the current trial. SC, NC, and PB are employees of Italfarmaco, the sponsor of the current trial. CMM reports receiving grants or research support from Astellas Pharma, BioMarin Pharmaceutical, Capricor Therapeutics, Catabasis Pharmaceuticals, Edgewise Therapeutics, Italfarmaco, Pfizer, PTC Therapeutics, and Santhera Pharmaceuticals; and consulting fees from Sarepta Therapeutics, Astellas Pharma, Avidity Biosciences, BioMarin Pharmaceutical, Bristol Myers Squib, Capricor Therapeutics, Catabasis Pharmaceuticals, Edgewise Therapeutics, Eli Lilly, Epirium Bio, Entrada Therapeutics, Gilead Sciences, Halo Therapeutics, Italfarmaco, Novartis, PepGen, Pfizer, PTC Therapeutics, Prosensa, and Santhera Pharmaceuticals, all outside the scope of this manuscript. BB and GZ declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate skin absorption of cobalt powder in an in vitro system. Experiments with volunteers show that cobalt powder can permeate through the skin, but there are no data with regard to the mechanism or the amount of permeation., Methods: Skin permeation was calculated by the Franz diffusion cell method with human skin. A physiological solution was used as receiving phase and the cobalt powder was dispersed in synthetic sweat. The amount of metal passing through the skin was analysed by electro-thermal atomic absorption spectrometry (ETAAS). Parallel polarographic analysis (differential pulse polarography-DPP) allowed evaluation of cobalt present as ions (Co(2+)) in donor and receiving phases. Measurements of cobalt skin content were also performed., Results: Evaluation of metal in the receiving phase allowed us to demonstrate the permeation of cobalt through the skin. Steady-state flow of percutaneous cobalt permeation was calculated as 0.0123+/-0.0054 microg cm(-2) h(-1), with a lag time of 1.55+/-0.71 h., Conclusions: The experiments show that cobalt powder can pass through the skin when applied as a dispersion in synthetic sweat, oxidising metallic cobalt into ions, which permeate the skin. These experiments show for the first time how cobalt can permeate the skin.

The aim of this work was to develop a proper mathematical model able to describe the kinetics partitioning of a drug between a polar (water buffer) and an apolar (n-octanol) liquid phase. In particular, attention is focussed on sparingly soluble drugs in one or both environments. Basically, we suppose that drug fluxes occurring between the polar and apolar phase depend also on drug solubility, and not only on both the kinetics constants and the instantaneous drug concentration in the two phases. The proposed model adequately describes the drug partitioning of sparingly water soluble drugs (piroxicam and nimesulide) as proven by the comparison of the predicted and experimental data. Moreover, it indicates the unsuitability of a previous approach (Chem. Pharm. Bull. 29 (1961) 2718) in describing the partitioning kinetics unless sink conditions in both phases are attained, this being difficult to achieve when working with sparingly soluble drugs. Consequently, the model represents a simple and reliable tool to study the drug partitioning kinetics.

The topic of this paper is the study of the drug release from a drug-loaded microemulsion by reverting to a new mathematical model overcoming some drawbacks of previously proposed models. In particular, attention is focused on the mathematical expression of the drug fluxes existing between the oil and water phases during drug release. Indeed, not only the drug release kinetics, but also the drug oil-water partition coefficient strongly depend on these fluxes. Two microemulsion are considered: the first is composed by water, Tween80 as surfactant, and Triacetin as oil phase, while the second is composed by water, Tween80 as surfactant, and a Triacetin-benzylic alcohol mixture (1 : 1) as oil phase. Both of them are loaded by Nimesulide, an oil-soluble drug of considerable industrial relevance. The drug release is performed by resorting to a permeation experiment (Franz cells apparatus) as it demonstrated to be the most reliable methodology. The good agreement between the experimental permeation data and the model best-fitting ensures that the most important phenomena ruling this kind of drug release were properly accounted for by the new proposed model. Copyright 2000 Academic Press.

A novel solid formulation for oral delivery of pH-sensitive, scarcely water-soluble etoposide has been designed, characterized, and tested in vitro. The purpose of this study was to assess the performance of the new dosage forms, in comparison to marketed, liquid-filled capsules. The solid formulation was developed by grinding the drug with a cross-linked polymeric carrier (crospovidone) under controlled process conditions (mechano-physical drug activation), and subsequently incorporating selected oil/surfactant (o/s) blends into the polymer particles. Physicochemical characterization (thermal analysis, drug dissolution kinetics, drug o/w partition studies) provided information on drug-polymer interaction at the solid state, and on the formulation performance in vitro, resulting in the enhancement and modification of the etoposide solubilization process. DSC thermograms showed the amorphous or nanocrystalline state of etoposide within the carrier, as indicated by the shifting of DSC peaks (delta T > -10 degrees C). Solubility kinetics of etoposide in oversaturation conditions were strongly affected by the chemical nature of the vehicle used: short-chain triglycerides afforded drug concentrations well above 600 micrograms ml-1 for more than 3 hr, versus a drug equilibrium solubility of approximately 150 micrograms ml-1. Drug dissolution curves under sink conditions were superimposable to those of liquid-filled capsules available on the market (Vepesid 50, Bristol-Myers Squibb), yielding 100% drug release in 10 min. The oil phase/water partition coefficient of etoposide (P) was affected by the surfactant concentration. The biphasic trend observed in P values suggested a dual mechanism in drug release from polymeric particles: the presence of oily vehicles and surfactants in the formulation could create, upon release, a favorable environment to sustain etoposide dissolution, slowing down drug reprecipitation. Such solid formulation could be considered equivalent, in vitro, to the current marketed product.