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Background/Aims Prostacyclin analogues, although effective treatment for systemic sclerosis (SSc)-related Raynaud’s phenomenon (RP), have the disadvantage of requiring intravenous or subcutaneous (SC) infusion. Treprostinil subcutaneous depot (CAM2043) is a novel extended-release SC formulation of treprostinil. The aim of this trial was to explore the effect of a single SC dose of CAM2043 on skin temperature (indirect measure of perfusion), as evaluated by thermography following cold challenge. Methods This was an exploratory, open-label, single-dose Phase 2 trial. Ten female patients (mean age 54.9 years) with mean SSc duration of 11.5 years (all anticentromere antibody positive) and mean RP duration of 14.5 years, were recruited. To be included, patients had to experience ≥5 attacks of RP/week. Patients attended on 6 occasions: screening, baseline (Day 1), and on Days 2, 3, 8, and 15. At baseline, each patient received a single SC injection of 2.5 mg CAM2043 (except the first patient who received 5mg CAM2043). A standard cold challenge test of the hands (15 °C for one minute) was performed pre-dose and at 3-, 6-, 24-, 72-, 168- and 336-hours post-dose, with temperature responses over the subsequent 15 minutes measured by infrared thermography. The primary endpoint was the mean change from baseline to 6 hours post-dose in the area under the curve (AUCtherm) for rewarming (8 fingers). Secondary endpoints included: change from baseline in AUCtherm, maximum temperature after rewarming (MAX) and Raynaud’s Condition Score (RCS). Safety and tolerability were assessed throughout the trial. Results AUCtherm increased 6 hours post-dose, but not statistically significantly: mean increase 192.7 °C×sec (95% CI: -727.1, 1112.6). AUCtherm was significantly greater at 24 hours than at baseline (mean increase 1175.8 °C×sec (95% CI: 127.3, 2224.3)), with a trend towards mean AUCtherm values higher than baseline up to 168 hours post-dose (Day 8) and returning to baseline values at 336 hours (Day 15). A statistically significant increase from baseline was also seen for MAX at 24 hours: mean increase 1.4 °C (95% CI: 0.1, 2.7). At baseline, mean (SD) RCS was 3.7 (1.3) units (10-point scale), and was significantly improved post dosing, including Day 8 (mean reduction 1.6 units (95% CI: -2.68, -0.52)). This positive treatment effect persisted at Day 15 (mean reduction 1.6 units (95% CI: -3.33, 0.19)). Adverse events were reported by all 10 patents: all reported erythema and pain at the injection site. Conclusion Finger skin temperature rose after CAM2043 treatment (significantly at 24 hours post-dose), with significant improvements in RP symptoms (RCS) over the 15-day period following dosing indicating a positive treatment effect. Overall, the safety profile for CAM2043 was consistent with known safety profile for treprostinil, including injection site reactions. The results indicate that CAM2043 could be further investigated in clinical trials of RP. Disclosure A.L. Herrick: Consultancies; Camurus AB. A. Murray: None. G. Dinsdale: None. J. Manning: None. C. Chukwu: None. M. Alvarez Fernandez: Corporate appointments; Camurus AB (employee). J.R. Seibold: Corporate appointments; Medical Lead, Prometheus Biosciences. Consultancies; Camurus AB, Alexion, GlaxoSmithKline, Mitenyi. Shareholder/stock ownership; Prometheus Biosciences. Other; Advisory Committee/Boards: CSL Behring, Prometheus Biosciences, Mitenyi. F. Tiberg: Corporate appointments; President & CEO Camurus AB. Shareholder/stock ownership; Camurus AB. Other; Board Member Camurus AB and Amniotics AB.

Background: The aim of this study was to analyze how Swedish courts describe persons sentenced for purchasing illicit drugs online. Methods: Qualitative analysis of naturally occurring data through 201 sentences that included 248 individuals sentenced for having purchased drugs online between January 1 2010 and January 1 2020. Results: The analysis resulted in the construction of four ideal types regarding the described characteristics of the sentenced persons; the ordinary person, the recreational user, the addict and the criminal. The courts operate with a notable dichotomy between traditional drug markets and online drug markets, that can be understood in relation to descriptions of Bourdieusian capital forms, specifically street capital and digital capital. Conclusion: Descriptions relating to street capital were of larger interest to the courts compared to digital capital, although there were examples of when the courts argued that uses of digital capital should be viewed as an aggravating circumstance. The courts largely held a dichotomous view of online and offline drug markets that focus on street-based criminality, which may have implications for how emerging digital drug markets are responded to by drug law enforcement and judicial systems.

Context: There is currently no consensus regarding optimal dose or dose-range of buprenorphine (BUP) for treatment of opioid use disorder (OUD).Objective: To elucidate the relationship betw...

AimsTo assess the long‐term safety of subcutaneous buprenorphine (CAM2038) weekly and monthly depots.DesignPhase 3, open‐label, observational, multi‐centre 48‐week trial (ClinicalTrials.gov NCT02672111).SettingTwenty‐six out‐patient sites (United States, United Kingdom, Hungary, Denmark, Sweden, Germany, Australia) between 14 December 2015 and 12 April 2017.ParticipantsTwo hundred and twenty‐eight adults with opioid use disorder; 227 received CAM2038 (37 initiated onto CAM2038 and 190 converted from sublingual buprenorphine).InterventionsCAM2038 weekly (8, 16, 24 or 32 mg) or monthly (64, 96, 128 or 160 mg) with flexible dosing and individualized titration utilizing multiple CAM2038 weekly and monthly doses.MeasurementsSafety variables, urine toxicology samples and self‐reported illicit opioid use were collected at each visit. Participants were administered a patient satisfaction survey at months 6 and 12, completed by 162 of 227 (71.4%) participants.FindingsThe study treatment period was completed by 167 of 227 (73.6%) participants. At least one treatment‐emergent adverse event (TEAE) was reported by 143 of 227 (63.0%) participants, of whom 60 of 227 (26.4%) reported as being drug‐related. Most of the TEAEs, reported by 128 of 227 (56.4%) of participants, were mild or moderate in intensity. Injection‐site reactions were reported by 46 of 227 (20.3%) participants, with most [45 of 46 (97.8%)] reported as mild to moderate. Five participants (2.2%) discontinued the study drug due to a TEAE, two cases (0.9%) of which were injection‐site‐related. No serious adverse events were attributed to the study drug. At the end of the study, the percentage of opioid‐negative urine tests combined with self‐reports was 63.0% (17 of 37) in new‐to‐treatment participants and 82.8% (111 of 190) for participants converted from sublingual buprenorphine. Participants reported high levels of satisfaction with CAM2038.ConclusionsSubcutaneous buprenorphine delivered weekly or monthly (CAM2038) was well tolerated, with a systemic safety profile consistent with the known profile of sublingual buprenorphine. CAM2038 weekly and monthly was associated with high retention rates and low levels of illicit opioid use throughout this study.

Octreotide SC depot is a novel, ready-to-use formulation administered via a thin needle. In a phase 1 study in healthy volunteers, this formulation provided higher bioavailability of octreotide with faster onset and stronger suppression of IGF-1 in healthy volunteers versus long-acting intramuscular (IM) octreotide. This phase 2 study evaluated the pharmacokinetics, efficacy, and safety of octreotide SC depot in patients with acromegaly and functioning NETs, previously treated with octreotide IM.Adult patients with acromegaly or functioning NETs treated for ≥ 2 months with octreotide IM [10/20/30 mg every 4 weeks (q4w)] received the last dose of octreotide IM treatment in study period 0 and were randomized 28 days later to receive octreotide SC depot 10 mg q2w, or 20 mg q4w for 3 months (period 1). The primary objective was to characterize the PK profile of octreotide SC depot after each injection vs PK for octreotide IM (period 0).Twelve patients were randomized to receive octreotide SC depot 10 mg q2w (acromegaly n = 3; NET n = 1) or 20 mg q4w (acromegaly n = 4; NET n = 4). Plasma levels of octreotide were higher with octreotide SC depot as compared to octreotide IM. Adverse events were reported in 6 and 8 patients during period 0 and period 1, respectively; most common in period 1 were gastrointestinal disorders.Octreotide SC depot provided higher exposure (AUC) than octreotide IM, maintained biochemical control in patients with acromegaly and symptom control in patients with functioning NETs, and was well tolerated with a safety profile consistent with octreotide IM. CLINICALTRIALS.NCT02299089.

IMPORTANCE: Buprenorphine treatment for opioid use disorder may be improved by sustained-release formulations. OBJECTIVE: To determine whether treatment involving novel weekly and monthly subcutaneous (SC) buprenorphine depot formulations is noninferior to a daily sublingual (SL) combination of buprenorphine hydrochloride and naloxone hydrochloride in the treatment of opioid use disorder. DESIGN, SETTING, AND PARTICIPANTS: This outpatient, double-blind, double-dummy randomized clinical trial was conducted at 35 sites in the United States from December 29, 2015, through October 19, 2016. Participants were treatment-seeking adults with moderate-to-severe opioid use disorder. INTERVENTIONS: Randomization to daily SL placebo and weekly (first 12 weeks; phase 1) and monthly (last 12 weeks; phase 2) SC buprenorphine (SC-BPN group) or to daily SL buprenorphine with naloxone (24 weeks) with matched weekly and monthly SC placebo injections (SL-BPN/NX group). MAIN OUTCOMES AND MEASURES: Primary end points tested for noninferiority were response rate (10% margin) and the mean proportion of opioid-negative urine samples for 24 weeks (11% margin). Responder status was defined as having no evidence of illicit opioid use for at least 8 of 10 prespecified points during weeks 9 to 24, with 2 of these at week 12 and during month 6 (weeks 21-24). The mean proportion of samples with no evidence of illicit opioid use (weeks 4-24) evaluated by a cumulative distribution function (CDF) was an a priori secondary outcome with planned superiority testing if the response rate demonstrated noninferiority. RESULTS: A total of 428 participants (263 men [61.4%] and 165 women [38.6%]; mean [SD] age, 38.4 [11.0] years) were randomized to the SL-BPN/NX group (n = 215) or the SC-BPN group (n = 213). The response rates were 31 of 215 (14.4%) for the SL-BPN/NX group and 37 of 213 (17.4%) for the SC-BPN group, a 3.0% difference (95% CI, −4.0% to 9.9%; P

The self-assembly of lipids leads to the formation of a rich variety of nano-structures, not only restricted to lipid bilayers, but also encompassing non-lamellar liquid crystalline structures, such as cubic, hexagonal, and sponge phases. These non-lamellar phases have been increasingly recognized as important for living systems, both in terms of providing compartmentalization and as regulators of biological activity. Consequently, they are of great interest for their potential as delivery systems in pharmaceutical, food and cosmetic applications. The compartmentalizing nature of these phases features mono- or bicontinuous networks of both hydrophilic and hydrophobic domains. To utilize these non-lamellar liquid crystalline structures in biomedical devices for analyses and drug delivery, it is crucial to understand how they interact with and respond to different types of interfaces. Such non-lamellar interfacial layers can be used to entrap functional biomolecules that respond to lipid curvature as well as the confinement. It is also important to understand the structural changes of deposited lipid in relation to the corresponding bulk dispersions. They can be controlled by changing the lipid composition or by introducing components that can alter the curvature or by deposition on nano-structured surface, e.g. vertical nano-wire arrays. Progress in the area of liquid crystalline lipid based nanoparticles opens up new possibilities for the preparation of well-defined surface films with well-defined nano-structures. This review will focus on recent progress in the formation of non-lamellar dispersions and their interfacial properties at the solid/liquid and biologically relevant interfaces.

Introduction Sublingual buprenorphine is effective for opioid dependence treatment but associated with misuse, abuse, and diversion. The present Phase I/II study evaluated a novel buprenorphine subcutaneous depot formulation for once-weekly dosing (CAM2038 q1w) in patients receiving maintenance treatment for opioid use disorder with daily sublingual buprenorphine. Methods After discontinuation of buprenorphine for 48h, patients received a single CAM2038 q1w dose based on their pre-study daily sublingual maintenance dose. CAM2038 q1w doses of 7.5, 15, 22.5, and 30mg were administered in a sequential dose-escalating design. The following assessments were performed: pharmacokinetics of buprenorphine and norbuprenorphine, pharmacodynamics (evaluated using the Subjective and Clinical Opiate Withdrawal Scales), and time to intake of rescue sublingual buprenorphine medication. Results Single doses of CAM2038 q1w indicated dose-proportional buprenorphine pharmacokinetics (C max and AUC 0–7d ), with time to C max ~20h and an apparent terminal half-life of 3–5days, supporting once-weekly dosing. On average, patients showed a rapid and extended decrease in opiate-withdrawal symptoms from baseline, with zero or very low SOWS and COWS values measured at least up to 7days after dosing of CAM2038 q1w. The median time to first use of rescue buprenorphine was 10days. No dose dependence was seen in the pharmacodynamics, attributable to the selection of CAM2038 q1w doses based on patients' pre-study maintenance doses. CAM2038 q1w was safe and generally well tolerated. Conclusions Pharmacokinetics and pharmacodynamics of a novel buprenorphine subcutaneous depot formulation for once-weekly dosing was evaluated, suggesting utility in maintenance treatment of patients with opioid use disorder.

Pharmacy-grade exogenous lung surfactant preparations of bovine and porcine origin, dispersed in physiological electrolyte solution have been studied. The organization and dynamics at the air/water interface at physiological temperature was analysed by neutron reflection. The results show that a well-defined surface phase is formed, consisting of a multilayer structure of lipid/protein bilayers alternating with aqueous layers, with a repetition period of about 70 A and correlation depths of 3 to >25 bilayers, depending on electrolyte composition and time. The experimental surfactant concentration of 0.15% (w/w) is far below that used in therapeutic application of exogenous surfactants and it is therefore likely that similar multilayer structures are also formed at the alveolar surface in the clinical situation during surfactant substitution therapy. Lung surfactant preparations in dry form swell in aqueous solution towards a limit of about 60% (w/w) of water, forming a lamellar liquid-crystalline phase above about 34 degrees C, which disperses into lamellar bodies at higher water concentrations. The lamellar spacings in the surface multilayers at the air/water interface are smaller than those in the saturated limit even though they are in contact with much greater water concentrations. The surface multilayers are laterally disordered in a way that is consistent with fragments of Lalpha-phase lamellae. The near surface layers of the multilayer structure have a significant protein content (only SP-B and SP-C are present in the preparations). The results demonstrate that a multilayer structure can be formed in exogenous surfactant even at very low concentrations and indicate that multilayers need to be incorporated into present interpretations of in vitro studies of similar lung surfactant preparations, which are largely based on monolayer models.

The effects of enzyme structure and activity on the degradation of model cellulose substrates were investigated by ellipsometry for the cellulase Humicola insolens GH45. The inactive variant D10N was found to adsorb at the cellulose surface but also to be incorporated into the cellulose films to an extent that depended on pH. For the native protein, the initial adsorption monitored for the inactive variant D10N was followed by enzyme-mediated degradation of the cellulose films. Again, a dependence on pH was found, such that higher pH resulted in slower enzymatic degradation. Removing the carbohydrate-binding module eliminated this pH dependence but also resulted in a decreased adsorption to the cellulose surface, and in a decreased net catalytic effect.

Synthesis of 1-glyceryl monooleyl ether (GME) has been accomplished yielding material of high purity (99.6%). The aqueous phase behavior of synthesized lipid has been investigated by using polarized microscopy and small angle X-ray diffraction. As a result, a partial temperature-composition phase diagram has been constructed. GME forms a reversed micellar solution and reversed hexagonal liquid crystalline phase at low and high hydration, respectively. The hexagonal phase coexists with excess water and is stable up to about 63 degreesC. These findings make GME an interesting alternative to glycerol monoesters in various fields of applications. (C) 2004 Elsevier B.V. All rights reserved.

The present article provides current opinion on studies of the interfacial dynamics, adsorption, and structure of surfactant layers. The physical principles and applications of physicochemical methods such as tensiometry, ellipsometry, photon correlation spectroscopy, and neutron reflectivity techniques, as well as relevant theoretical aspects related to the adsorption and desorption kinetics, interfacial structure development, wetting enhancement, and the effect of adsorbed surfactant films of the interfacial dynamics, are covered in detail. In order to make the text as self-contained as possible, essential mathematical derivations are given demonstrating how raw data, such as ellipsometric angles or neutron reflectivity, are transformed into sought layer characteristics, such as thickness or density.

We have investigated the formation of supported model membranes via the adsorption of phospholipid-surfactant mixtures at the Si water interface by specular neutron reflection. The adsorption of mixed micelles of the nonionic surfactant beta-D-dodecyl maltoside and DOPC or POPC was determined as a function of bulk concentration, and using d(25)-beta-D-dodecyl maltoside, the composition of DOPC and POPC bilayers was determined. Bilayer thicknesses of 39 +/- 3 (A) dot over for DOPC and 41 +/- 3 A for POPC agree well with data from bulk lamellar phases for both lipids, and the average area per lipid molecule can be varied from 62 to 115 (A) dot over (2) by varying the bulk concentrations used. The amount of surfactant in the bilayer is very sensitive to the bulk volume-to-surface area ratio, but it can be fully eliminated by ensuring a sufficiently large dilution/rinsing volume of the solution. (C) 2004 Elsevier B.V. All rights reserved.

Aims The aim was to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of octreotide subcutaneous (s.c.) depot, a novel octreotide formulation. Methods This was a phase I, randomized, open label study. After a single dose of octreotide immediate release (IR) 200 µg, subjects were randomized to one of eight groups to receive three monthly injections of octreotide s.c. depot A 10, 20 or 30 mg, B 30 mg, C 10, 20 or 30 mg or long acting octreotide (octreotide LAR) 30 mg. Results One hundred and twenty-two subjects were randomized. For all depot variants, onset of octreotide release was rapid and sustained for up to 4 weeks. The relative octreotide bioavailability of depot variants vs. octreotide IR ranged from 0.68 (90% confidence interval [CI] 0.61, 0.76) to 0.91 (90% CI 0.81, 1.02) and, vs. octreotide LAR, was approximately four- to five-fold greater: 3.97 (90% CI 3.35, 4.71) to 5.27 ng ml–1 h (90% CI 4.43, 6.27). All depot variants showed relatively rapid initial reductions of insulin-like growth factor 1 (IGF-1) compared with octreotide LAR. A trend of octreotide dose dependence was also indicated from the plasma concentrations and suppression of IGF-1. Maximum inhibition of IGF-1 at steady-state was highest for depot B and C. All depot treatments were well tolerated. The most frequent adverse events were gastrointestinal related. Conclusions Octreotide s.c. depot provides greater octreotide bioavailability with a more rapid onset and stronger suppression of IGF-1 than octreotide LAR in healthy volunteers.

The formation and structure of multilayer films containing a cationic polyelectrolyte and anionic silica nanoparticles were studied by means of ellipsometry and atomic force microscopy. Three types of silica particles of different sizes were examined. The density and thickness of the films as well as the adsorption kinetics appear to be strongly dependent on the choice of particle; smaller particles favor the formation of smooth and dense films with a higher content of the inorganic component.

In this work the effect of ionic strength on the adsorption behavior of cationic polyelectrolyte (acrylamide–acrylamidopropyltrimethylammonium chloride) and negatively charged silica particles has been studied by means of ellipsometry. The adsorption of the polyelectrolyte was observed to increase with increasing salt concentration, a behavior typical for polyelectrolytes with a screening-reduced solvency and a nonelectrostatic affinity for the surface. A similar dependence on the ionic strength was observed when studying the electrolyte effect on the nanoparticle adsorption to the preadsorbed polyelectrolyte film, suggesting that the polyelectrolyte surface conformations largely govern the binding capacity of the particles to the surface.

Buprenorphine is an efficacious, widely used treatment for opioid use disorder (OUD). Daily oral transmucosal formulations can be associated with misuse, diversion, and nonadherence; these limitations may be obviated by a sustained release formulation.To evaluate the ability of a novel, weekly, subcutaneous buprenorphine depot formulation, CAM2038, to block euphorigenic opioid effects and suppress opioid withdrawal in non-treatment-seeking individuals with OUD.This multisite, double-blind, randomized within-patient study was conducted at 3 controlled inpatient research facilities. It involved 47 adults with DSM-V moderate-to-severe OUD. The study was conducted from October 12, 2015 (first patient enrolled), to April 21, 2016 (last patient visit).A total of five 3-day test sessions evaluated the response to hydromorphone (0, 6, and 18 mg intramuscular in random order; 1 dose/session/day). After the first 3-day session (ie, qualification phase), participants were randomized to either CAM2038 weekly at 24 mg (n = 22) or 32 mg (n = 25); the assigned CAM2038 dose was given twice, 1 week apart (day 0 and 7). Four sets of sessions were conducted after randomization (days 1-3, 4-6, 8-10, and 11-13).The primary end point was maximum rating on the visual analog scale for drug liking. Secondary end points included other visual analog scale (eg, high and desire to use), opioid withdrawal scales, and physiological and pharmacokinetic outcomes.A total of 46 of 47 randomized participants (mean [SD] age, 35.5 [9] years; 76% male [n = 35]) completed the study. Both weekly CAM2038 doses produced immediate and sustained blockade of hydromorphone effects (liking maximum effect, CAM2038, 24 mg: effect size, 0.813; P .001, and CAM2038, 32 mg: effect size, 0.753; P .001) and suppression of withdrawal (Clinical Opiate Withdrawal Scale, CAM2038, 24 mg: effect size, 0.617; P .001, and CAM2038, 32 mg: effect size, 0.751; P .001). CAM2038 produces a rapid initial rise of buprenorphine in plasma with maximum concentration around 24 hours, with an apparent half-life of 4 to 5 days and approximately 50% accumulation of trough concentration from first to second dose (trough concentration = 0.822 and 1.23 ng/mL for weeks 1 and 2, respectively, with 24 mg; trough concentration = 0.993 and 1.47 ng/mL for weeks 1 and 2, respectively, with 32 mg).CAM2038 weekly, 24 and 32 mg, was safely tolerated and produced immediate and sustained opioid blockade and withdrawal suppression. The results support the use of this depot formulation for treatment initiation and stabilization of patients with OUD, with the further benefit of obviating the risk for misuse and diversion of daily buprenorphine while retaining its therapeutic benefits.Clinicaltrials.gov Identifier: NCT02611752.

Lipid nanoparticles of reversed internal phase structures, such as cubic micellar (I2) structure show good drug loading ability of peptides and proteins as well as some small molecules. Due to their controllable small size and inner morphology, such nanoparticles are suitable for drug delivery using several different administration routes, including intravenous, intramuscular, and subcutaneous injection. A very interesting system in this regard, is the two component soy phosphatidylcholine (SPC)/glycerol dioleate (GDO) system, which depending on the ratio of the lipid components form a range of reversed liquid crystalline phases. For a 50/50 (w/w) ratio in excess water, these lipids have been shown to form a reversed cubic micellar (I2) phase of the Fd3m structure. Here, we demonstrate that this SPC/GDO phase, in the presence of small quantities (5-10 wt %) of Polysorbate 80 (P80), can be dispersed into nanoparticles, still with well-defined Fd3m structure. The resulting nanoparticle dispersion has a narrow size distribution and exhibit good long-term stability. In pharmaceutical applications, biodegradation pathways of the drug delivery vehicles and their components are important considerations. In the second part of the study we show how the structure of the particles evolves during exposure to a triacylglycerol lipase (TGL) under physiological-like temperature and pH. TGL catalyzes the lipolytic degradation of acylglycerides, such as GDO, to monoglycerides, glycerol, and free fatty acids. During the degradation, the interior phase of the particles is shown to undergo continuous phase transitions from the reversed I2 structure to structures of less negative curvature (2D hexagonal, bicontinuous cubic, and sponge), ultimately resulting in the formation of multilamellar vesicles.

This paper features the interfacial behavior of nonionic surfactants and surfactant−decane microemulsions at the silica−water interface from micellar solutions and water-rich tricomponent CnEm−decane−water microemulsions. The adsorption of a nonionic surfactant (pentaethyleneglycol n-dodecyl ether, C12E5) and its decane microemulsions to silica and borosilicate glass was studied by ellipsometry and direct force measurements using a bimorph surface force apparatus. The ellipsometric measurements of the adsorbed layer properties provided evidence of an initial lateral swelling of adsorbed bilayer segments with increasing bulk oil fraction. At a weight fraction of about 0.12 w/w decane-to-surfactant + decane, the surface appeared to be fully covered by a continuous bilayer with a thickness of 42 A, a refractive index of 1.448, and an mean area per surfactant of about 49 A2. Further increase of the oil content results in the swelling of the bilayer in the direction normal to the surface plane. Force measureme...

The wetting by water of the adsorbed layer of β-casein on hydrophobised silica and pure (hydrophilic) silica surface was investigated by dynamic contact angle measurements based on the Wilhelmy plate principle. The results are discussed in relation to adsorption data obtained for the protein on similar surfaces by in situ ellipsometry. β-casein adsorption on a hydrophobic surface leads to a significant decrease of the contact angle, in particular in terms of the receding contact angle, which decreased by about 70°. This indicates a strong shielding of the hydrophobic surface by the hydrophilic domain of β-casein. Adding a specific enzyme, endoproteinase Asp-N, which previously has been proposed to remove a large fraction of the hydrophilic segments, results in a significantly decreased wettability of the solid surface. The layer is now more hydrophobic and the hysterises is much smaller. The receding contact angle after the proteolysis is roughly 70°. The results are consistent with the hypothesis that β-casein adsorbs at the hydrophobic surface to form a monolayer with the hydrophobic part of the protein anchored at the surface, leaving the hydrophilic segments dangling into the solution. Less dramatic effects are observed in terms of changes of the wettability on the hydrophilic surface. The surface is still quite hydrophilic both after adsorbing β-casein and exposing the layer to endoproteinase Asp-N. These results confirm the differences in the structure of β-casein layers on the hydrophobic and hydrophilic surface.

Purpose CAM2028, a vehicle that forms a bioadhesive lipid barrier when applied to the oral mucosa, was developed as a carrier system for local delivery of benzydamine, an NSAID used for pain relief in oral mucositis. This trial compared the analgesic effect of CAM2028 plus benzydamine (CAM2028-benzydamine) with unmedicated CAM2028 (CAM2028-control) for the treatment of oral mucositis in patients with head-and-neck cancer. Methods Thirty-eight study participants were enrolled during their 3rd to 4th week of radiation therapy. Participants were required to have symptomatic oral mucositis (WHO Grade 2 or above) at screening and pain scores of at least 6 on an 11-point Likert scale at screening and on each day before treatment with study medication. After undergoing radiation, patients were administered a single dose of CAM2028-control or CAM2028-benzydamine 2 days apart, in a randomized crossover fashion. Pain was assessed over the following 8 h. Results With both treatments, patients experienced a mean 40 % decrease in pain intensity at 6 h (the primary study endpoint). Both treatments resulted in significant pain relief within 5 min of application that was evident during the entire 8-h assessment period. There was no difference in pain relief between the two interventions at any time point. Both treatments were safe and well tolerated. Conclusions CAM2028-benzydamine and CAM2028-control were both efficacious in reducing pain in patients with oral mucositis related to radiation therapy for head-and-neck cancer. Analgesic effects of both medications were immediate, clinically significant, and persistent for up to 8 h.

Treatment with docetaxel is the standard of care as first line chemotherapy in castration resistant prostate cancer. Due to serious side effects from the commercially available Taxotere formulation, we aimed to develop a safe and effective nanoparticle formulation of docetaxel. Liquid crystal nanoparticles (LCNPs), based on phosphatidyl choline, glycerol dioleate and polysorbate 80 dispersed in excess aqueous solution, were produced by simple procedures as carriers of docetaxel. Their effect on tumor growth in male SCID mice inoculated with PC-3 cells was compared to the effect of Taxotere and empty LCNP vehicle. Immunohistochemistry was performed to evaluate cell proliferation, angiogenesis and apoptosis in tumor tissue. Docetaxel and lipid excipients were dispersed into well-defined LCNP, stable during long-term storage. Mice subjected to LCNP/docetaxel formulation showed a better tumor regression than mice treated with Taxotere, with an indication of better tolerability. Immunohistochemical staining showed a decreased expression of Ki-67 in tumors from LCNP/docetaxel treated animals, especially in the cores of the tumors, suggesting better penetration/absorption compared to Taxotere. A new lipid-based nanoparticle formulation has been developed as carrier for docetaxel. Treatment effects in SCID mice indicate that this may be an interesting alternative to the current marketed formulation product.

There is an increasing demand for methods to study processes at the lipid-aqueous solution interface, due to the importance of lipids and lipid self-assembly structures as regulators both for biological activity and for drug delivery vehicles. The biological membrane is one of the most important interfaces that the drug delivery vehicles encounter. The potential use of non-lamellar lipid structures delivery systems in pharmaceutical, food and cosmetic applications has invoked a number of studies of the assembly and interactions of cubic phases of these materials. One such system is a colloidal dispersion of the cubic liquid crystalline phase of glycerol monooleate. We will discuss some aspects of what happens when these liquid crystalline lipid nanoparticle encounters a lipid bilayer, consisting dioleoylphosphaticylcholine, either as supported bilayer or as a vesicle. Null ellipsometry and QCM-D provides kinetic information about the adsorption and triggerable release of the nanoparticles. Using contrast matching of the supported lipid bilayer, neutron reflectivity makes it possible to assess the exchange of material from one ordered lipid phase to another. Synchrotron Small Angle X-Ray Diffraction allowed us to in detail study the phase transition when non-lamellar glycerol monooleate based nanoparticle interact with phospholipid vesicles. Together the four techniques provide insight into the interaction mechanism and shows that the release of the particles are likely to be caused by phase transition of the lipid self-assembled structures.

Enzymatic degradation of model cellulose films prepared by a spin-coating technique was investigated by ellipsometry. The cellulose films were prior to degradation characterized by ellipsometry, contact angle measurements, ESCA (electron spectroscopy for chemical analysis) and AFM (atomic force microscopy). At enzyme addition to preformed cellulose films an initial adsorption was observed, which was followed by a total interfacial mass decrease due to enzymatic degradation of the cellulose films. The degradation rate was found to be constant during an extended time of hours, whereafter the degradation leveled off. In parallel to the decreased interfacial mass, the cellulose degradation resulted in a thinner and more dilute interfacial film. At long degradation times, however, there was an expansion of the cellulose film. The enzyme concentration affected the degradation rate significantly, with a faster degradation at a higher enzyme concentration. The effects of pH, temperature, ionic strength and stirring rate in the cuvette were also investigated.

The interfacial properties of a mixed system of low-charged cationic polyelectrolyte and silica nanoparticles has been studied by means of ellipsometry. Special attention was devoted to the effect that the order of addition of the two components has on the adsorption behavior of the mixed system. Adsorption on silica was in one case studied after simultaneous addition of the components to the aqueous solution. The measured adsorption rates were then much slower than expected for a mass-transfer limited process. This behavior signifies the presence of an electrosteric barrier arising due to preadsorbed polymer-particle complexes. Interfacial layers containing particles were at plateau conditions shown to be highly swollen, whereas the cationic polymer in the particle-free systems adopted a more flat surface conformation. The layer thickness was observed to monotonously increase with an increasing presence of nanoparticles in solution, while the surface excess showed a maximum at intermediate values. The finding was rationalized by the competition between particles and the surface for polymer charges leading to swelling and a decreased effective interaction between polymer and surface. In the other case studied, when polyelectrolyte and nanoparticles were added sequentially, a much more rapid concentration-dependent adsorption was observed. The kinetic adsorption barrier for nonassociated particles was clearly negligible compared with that for the polymer-particle complex. The surface excess did not exhibit an adsorption maximum as a function of added nanoparticles in this situation, indicating that the polymer layer to some degree is irreversibly anchored at the silica surface. Some implications of the above findings for practical papermaking using multicomponent retention systems are put forward. Copyright 2001 Academic Press.

In this work, we have studied the interfacial properties of cationic polyelectrolyte (PE) and silica nanoparticle (NP) systems at macroscopic silica surfaces by means of ellipsometry. The influence of adsorbed layers on the interactions between silica surfaces was also investigated using the bimorph surface force apparatus. Added nanoparticles were observed to strongly swell the interfacial polyelectrolyte layers, an effect partly related to neutralization of charged polyelectrolyte groups. The effect was more pronounced for low charged than for highly charged polyelectrolytes. Overall, the presence of nanoparticles seemed to increase the repulsive interaction measured between silica surfaces. The force measured on approach was long range and quite strongly repulsive. On separation, an attractive bridging interaction was measured for polyelectrolyte-covered surfaces. For the low charged polyelectrolyte used in the study, the force turned repulsive on addition of nanoparticles. For the highly charged polyelectrolyte used, a change from a very strong attraction (involving a jump of the surfaces out of contact) to a very long-range elastic attractive force was observed on adding nanoparticles. The long-range elastic force indicates that polymer chains and nanoparticles form a transient network in the gap between the surfaces. The observed difference in the outward force curves may explain why the addition of nanoparticles appears to improve, e.g., shear-resistance and reflocculation characteristics of polymeric flocculants. Copyright 2000 Academic Press.

This paper describes the adsorption of zwitterionic dodecyl-N,N-dimethylammonio alkanoates with polymethylene intercharge arms of different lengths on silica. The data presented were obtained by in situ ellipsometry, allowing time-resolved studies of the surface excess, the mean thickness, and the refractive index of thin interfacial films. It is shown that the mode of adsorption of zwitterionic surfactants is similar to that observed for ethylene-oxide-based nonionic surfactants. The interaction energy between single zwitterionic surfactants and silica is relatively weak and the adsorption process is best described in terms of surfactant self-assembly, promoted by the presence of the solid surface. The mode of adsorption is only weakly affected by increasing the number of intercharge methylene units. The surface aggregation behavior observed at the silica surface displays many parallels with the corresponding solution phase behavior. Finally, the adsorption of zwitterionic surfactants is relatively independent of the pH. However, as the pH is lowered to the pKa values of the terminal carboxyl group (i.e., as the surfactants become increasingly positively charged) desorption is observed.

Nonlamellar lipid liquid crystalline (LC) bulk phases and dispersions show promise as functional nanostructured materials for potential use as controlled release matrices e.g. in pharmaceuticals. Herein, methods for preparing and characterizing thin films of lipid liquid crystalline phases on solid surfaces are presented. The thickness, hydration phase structure and surface topography of spin-coated films of mixtures of soy phosphatidylcholine and glycerol dioleate are characterized by means of spectroscopic ellipsometry, small angle X-ray diffraction and atomic force microscopy. Besides being useful as bioadhesive drug delivery systems, the lipid nonlamellar LC films produced may also be exploited as model surfaces for studying properties such as bioadhesion and biodegradation.