Pharmacokinetics of Morphine Sulfate Orodispersible Tablets and Bioequivalence with Immediate-Release Oral Morphine Sulfate Formulations in Healthy Adult Subjects Under Fasting Conditions: Single-Dose Comparative Bioavailability Studies.

BACKGROUND AND OBJECTIVE: An orodispersible tablet (ODT) formulation of morphine sulfate has been developed to provide a novel alternative for patients with severe pain requiring opioids. This formulation has been developed in a range of doses (1-30 mg), enabling relief from severe pain to be achieved and maintained with the lowest possible morphine dose for each patient. The ODT formulation is particularly suitable for patients with swallowing difficulties. OBJECTIVE: The aim of this study was to compare the pharmacokinetics and bioequivalence of the ODTs with reference formulations of morphine sulfate. METHODS: Three randomized, single-dose, laboratory-blinded, phase I, crossover studies were conducted in adult healthy volunteers under fasting conditions. The pharmacokinetics of a 30 mg morphine sulfate ODT were compared with those of equivalent doses of currently marketed oral immediate-release formulations: tablets (Sevredol®), capsules (Actiskenan®), and a solution (Oramorph®). The bioequivalence of 30 mg and 10 mg doses of the ODTs and tablets was then assessed in two further studies. Subjects were asked to complete a product appreciation questionnaire for two morphine formulations (ODT and solution). RESULTS: A total of 104 subjects were included across the three studies. The pharmacokinetics of the ODTs were assessed in 100 subjects and were found to be similar to those of the reference formulations. The time to maximum plasma concentration (Tmax) for the ODTs was 0.8 h, within the range observed for the reference formulations (0.75-1.25 h). Maximum plasma concentrations (Cmax) for the ODTs were 7.7 ± 2.7 ng/mL for the 10 mg dose and 26.1 ± 10.0 ng/mL for the 30 mg dose. These values were similar to those obtained for the 10 mg and 30 mg tablets (8.0 ± 2.9 ng/mL and 28.5 ± 11.9 ng/mL, respectively), and for the 30 mg capsule (29.9 ± 13.0 ng/mL). A higher Cmax was observed for the solution (37.9 ± 16.5 ng/mL). Plasma exposure to morphine (area under the plasma drug concentration-time curve [AUC]) after ODT administration was similar to that observed for the reference formulations: 39.8 ± 14.8 ng·h/mL and 115.5 ± 34.6 ng·h/mL for the 10 mg and 30 mg ODTs, versus 40.7 ± 13.5 ng·h/mL and 117.4 ± 31.5 ng·h/mL for the 10 mg and 30 mg tablets, and 121.8 ± 32.0 ng·h/mL and 121.0 ± 35.7 ng·h/mL for the 30 mg solution and capsule, respectively. Bioequivalence of the 30 mg and 10 mg ODTs and tablets, assessed in 83 patients across two studies, was demonstrated for both the Cmax and AUC from time zero to time t (AUC0-t). No serious or unexpected drug-related events were reported. A product appreciation questionnaire concluded that both ODTs and oral solution products were considered pleasant by most of the subjects. CONCLUSION: The ODTs were safe, well tolerated, and showed similar pharmacokinetics to those of the reference formulations. The development of a range of doses of morphine sulfate ODTs may provide a new alternative for the oral administration of immediate-release morphine for pain management in pediatric, geriatric and adult populations with swallowing problems.

Application of the Tissue Composition-Based Model to Minipig for Predicting the Volume of Distribution at Steady State and Dermis-to-Plasma Partition Coefficients of Drugs Used in the Physiologically Based Pharmacokinetics Model in Dermatology.

The minipig continues to build a reputation as a viable alternative large animal model to predict humans in dermatology and toxicology studies. Therefore, it is essential to describe and predict the pharmacokinetics in that species to speed up the clinical candidate selection. Essential input parameters in whole-body physiologically based pharmacokinetic models are the tissue-to-plasma partition coefficients and the resulting volume of distribution at steady-state (Vss). Mechanistic in vitro- and in silico-based models used for predicting these parameters of tissue distribution of drugs refer to the tissue composition-based model (TCM). Robust TCMs were initially developed for some preclinical species (e.g., rat and dog) and human; however, there is currently no model available for the minipig. Therefore, the objective of this present study was to develop a TCM for the minipig and to estimate the corresponding tissue composition data. Drug partitioning into the tissues was predominantly governed by lipid and protein binding effects in addition to drug solubilization and pH gradient effects in the aqueous phase on both sides of the biological membranes; however, some more complex tissue distribution processes such as drug binding to the collagen-laminin material in dermis and a restricted drug partitioning into membranes of tissues for compounds that are amphiphilic and contain sulfur atom(s) were also challenged. The model was validated by predicting Vss and the dermis-to-plasma partition coefficients (Kp-dermis) of 68 drugs. The prediction of Kp-dermis was extended to humans for comparison with the minipig. The results indicate that the extended TCM provided generally good agreements with observations in the minipig showing that it is also applicable to this preclinical species. In general, up to 86% and 100% of the predicted Vss values are respectively within 2-fold and 3-fold errors compared to the experimentally determined values, whereas these numbers are 78% and 94% for Kp-dermis when the anticipated outlier compounds are not included. Binding data to dermis are comparable between minipigs and humans. Overall, this study is a first step toward developing a mechanistic TCM for the minipig, with the aim of increasing the use of physiologically based pharmacokinetic models of drugs for that species in addition to rats, dogs, and humans because such models are used in preclinical and clinical transdermal studies.

Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis.

With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL-23-induced mouse skin inflammation model.

Controlled production of sub-millimeter liquid core hydrogel capsules for parallelized 3D cell culture.

Liquid core capsules having a hydrogel membrane are becoming a versatile tool for three-dimensional culture of micro-organisms and mammalian cells. Making sub-millimeter capsules at a high rate, via the breakup of a compound jet in air, opens the way to high-throughput screening applications. However, control of the capsule size monodispersity, especially required for quantitative bioassays, was still lacking. Here, we report how the understanding of the underlying hydrodynamic instabilities that occur during the process can lead to calibrated core-shell bioreactors. The requirements are: i) damping the shear layer instability that develops inside the injector arising from the co-annular flow configuration of liquid phases having contrasting viscoelastic properties; ii) controlling the capillary instability of the compound jet by superposing a harmonic perturbation onto the shell flow; iii) avoiding coalescence of drops during jet fragmentation as well as during drop flight towards the gelling bath; iv) ensuring proper engulfment of the compound drops into the gelling bath for building a closed hydrogel shell. We end up with the creation of numerous identical compartments in which cells are able to form multicellular aggregates, namely spheroids. In addition, we implement an intermediate composite hydrogel layer, composed of alginate and collagen, allowing cell adhesion and thus the formation of epithelia or monolayers of cells.

Quantitative analysis of ligand effects on bioefficacy of nanoemulsion encapsulating depigmenting active.

Efficient skin delivery of active molecules is the main challenge to overcome in order to achieve significant therapeutic efficiency of cosmetics or dermo-pharmaceutical products. Nanocarriers such as nanoemulsions have been envisaged to overcome main challenges of active solubilization, protection and transport to their site of biological action. Nonetheless, their skin permeation is still limited and a new approach is required to significantly improve bioavailability. We here explored the possibility of increasing the whitening activity of a model active, licorice, by implementing a targeting approach of nanoemulsions to melanocyte cells. Targeting requires particle surface modification with specific molecules favoring nanoemulsion/cells contact through ligand-receptor interactions. The uniqueness of our strategy is that unlike classical covalent chemical grafting, we propose a self-assembled strategy based on a selection of amphiphilic ligands able to localize at nanoemulsion droplets interface. Four ligand candidates were thus assayed in terms of formulation and in vitro biological evaluation: a palmitoyl-peptide (palmitoyl-GQPR), a lipidized hyaluronic acid (caproyl-HA) and two amphiphilic actives (polydatin and isopilosine). A functional analysis based on a cellular assay of melanin inhibition was realized. The intrinsic properties of ligand candidates were first evaluated. Then, nanoemulsions encapsulating a drug model, licorice, and targeted with the different ligand candidates were assayed. The use of caproyl-HA significantly improved bioefficacy of the encapsulated licorice, suggesting a better interaction with the cells. The improved value observed was not attributed to a synergetic action as caproyl-HA did not evidence intrinsic melanogenesis modulation activity. In this study, we demonstrated the feasibility of targeting nanoemulsion droplets without chemical covalent modification of nanoemulsion droplets to increase bioefficacy of encapsulated drugs in vitro.

Development and in vitro assay of oxidative stress modifying formulations for wound healing promotion.

Often presented as metabolism byproducts, reactive oxygen species are linked to detrimental effects such as chronic wound, mutagenesis, cancer and skin ageing. However, recent in vitro and in vivo observations suggest that ROS, and mainly hydrogen peroxide, interfere with cell signaling acting like second messenger and inducing adaptive responses. This is particularly observed in skin wound healing where cells are exposed to H2O2 following injury. In this study, we developed and characterized an innovative formulation producing H2O2 at low concentrations, in order to mimic physiological inflammation phase. Then, this pro-oxidative formulation (CAM-GOx) was assayed in vitro on keratinocytes cell culture, compared to the blank formulation (CAM) and the anti-oxidative formulation (CAM-CAT) to assess whether oxidative stress was implied or not in cellular responses.

Internalisation of hybrid titanium dioxide/para-amino benzoic acid nanoparticles in human dendritic cells did not induce toxicity and changes in their functions.

Nanoparticles (NPs) have been reported to penetrate into human skin through lesional skin or follicular structures. Therefore, their ability to interact with dendritic cell (DC) was investigated using DCs generated from monocytes (mono-DCs). Hybrid titanium dioxide/para-amino benzoic acid (TiO(2)/PABA) NPs did not induce any cell toxicity. NPs were internalised into DCs through macropinocytosis and not by a receptor-mediated mechanism. Confocal microscopy showed that NPs were not detected in the nucleus. These data are confirmed by electronic microscopy which demonstrated that hybrid NPs were rapidly in contact with cellular membrane and localised into cytoplasmic vesicles without colocalisation with clathrin-coated vesicles. Hybrid NPs did not induce CD86 or HLA-DR overexpression or cytokine secretion (IL-8 and TNF-α) indicating no DC activation. Internalisation of hybrid NPs did not modify DC response towards sensitisers such as nickel and thimerosal or LPS used as positive controls. Moreover, hybrid NPs did not induce any oxidative stress implicated in DC activation process. After mono-DC irradiation by ultraviolet A (UVA), hybrid NP-treated cells did not produce UVA-induced reactive oxygen species (ROS) and exhibited a better cell viability compared with UVA-irradiated control cells, suggesting a protecting effect of hybrid TiO(2)/PABA NPs against UVA-induced ROS.

Effects of glycerol on human skin damaged by acute sodium lauryl sulphate treatment.

Glycerol, widely used as humectant, is known to protect against irritants and to accelerate recovery of irritated skin. However, most studies were done with topical formulations (i.e. emulsions) containing glycerol in relatively high amounts, preventing drawing conclusions from direct effects. In this study, acute chemical irritations were performed on the forearm with application of a 10% sodium lauryl sulphate (SLS) aqueous solution under occlusion for 3 h. Then, glycerol aqueous solutions from 1 to 10% were applied under occlusion for 3 h. After elimination of moist excess consecutive to occlusive condition, in ambient air for 15 and 30 min, skin barrier function was investigated by dual measurement of skin hydration and transepidermal water loss (TEWL). Treatments with SLS solution under occlusion significantly increased TEWL and decreased skin hydration as assessed by capacitance measurements. The SLS irritant property was raised by the occlusion and the water barrier function as well as water content appeared impaired. Recovery with glycerol at low doses was remarkable through a mechanism that implies its hygroscopic properties and which is saturable. This precocious effect acts through skin rehydration by enhancing water-holding capacity of stratum corneum that would facilitate the late physiological repair of impaired skin barrier. Thus, glycerol appears to substitute for natural moisturizing factors that have been washed out by the detergent action of SLS, enhancing skin hydration but without restoring skin barrier function as depicted by TEWL values that remained high. Thus, irritant contact dermatitis treated with glycerol application compensate for skin dehydration, favouring physiological process to restore water barrier function of the impaired skin. Empirical use of glycerol added topical formulations onto detergent altered skin was substantiated in the present physicochemical approach.

Effects of physical and chemical treatments upon biophysical properties and micro-relief of human skin.

The aim of the present study was to determine the attendant effects of physical (tape-stripping) and chemical (three commercial hydrating formulations) treatments upon biophysical and micro-relief properties of human skin. In the first set of experiment, the effects of tape-stripping onto human stratum corneum (SC) biophysical and micro-relief properties were assessed in nine volunteers. Transepidermal water loss (TEWL), skin hydration and micro-relief parameters (including total length of the lines in mm per mm(2); total surface in %; roughness of the skin measured in gray level (Ra); maximum profile valley (Rv) depth; maximum profile peak height (Rp); maximum height (Rt), peak density (Pc) and coefficient of anisotropy) were determined by using SkinEvidence Pro after subsequent tape-stripping of SC. The relevance of roughness determination as gray level by SkinEvidence Pro was confirmed by using surface roughness standards. In the second set of experiment, the effectiveness of three commercial hydrating formulations onto human SC biophysical parameters and micro-relief properties were assessed in six volunteers. TEWL, hydration and micro-relief parameters were assessed onto pre-treated acetone skin and then treated by three commercial hydrating formulations after 2, 4 and 6 h skin exposure. A linear relation between hydration and cutaneous parameters (total length of the lines, Ra and Rp) as function of SC removed was shown. Skin barrier properties evaluated by TEWL measurements, were not modified by topical formulations. However, skin treated by topical formulations showed slightly higher hydration than the one determined in control group, while micro-relief parameters were not modified. In this study was showed that biophysical and micro-relief parameters were closely related in tape-stripping experiment. Efficiency of topical formulations was suggested upon skin hydration but not onto skin micro-relief and barrier function recovering. From both experiments, it appears that different mechanisms relating to skin hydration and potential modification of cutaneous micro-relief were suggested.

Qualitative and quantitative comparison of heat separated epidermis and dermatomed skin in percutaneous absorption studies.

Transepidermal water loss (TEWL), mainly regulated by the stratum corneum, was quantitatively correlated to percutaneous absorption of compounds in human and suggested for the ex vivo assessment of skin integrity. The present study investigated qualitatively and quantitatively the relevance of 100-microm heat separated epidermis (HSE) in percutaneous absorption studies as compared to 500-microm dermatomed skin by dual complementary approaches. Percutaneous absorption of caffeine delivered from aqueous solution through dermatomed skin or HSE specimens (n = 9) was measured using vertical static diffusion cells coupled with an unventilated evaporimeter enabling the assessment of TEWL and skin integrity for 21 h. Permeation of caffeine exhibited different finite dose-like profiles ranged according to the thickness of skin specimens (cumulative dose absorbed up to 21 h: 11.5 +/- 11.5 microg/cm(2) and 29.4 +/- 36.2 microg/cm(2) through dermatomed skin and HSE, respectively). Normalized TEWL and caffeine fluxes were similar through dermatomed skin and HSE suggesting that the intrinsic permeability properties of both models were undifferentiated over time. Interestingly, a significant relationship was shown between TEWL and caffeine fluxes, suggesting the usefulness of TEWL measurement as an element in the estimation of percutaneous drug absorption. In conclusion, the present showed that percutaneous absorption through HSE was qualitatively and quantitatively similar to dermatomed skin when TEWL as endogenous standard and skin thickness were considered in permeability data comparisons.