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Rinderhagen H.,Bielefeld University | Rinderhagen H.,CILAG AG | Mattay J.,Bielefeld University | Nussbaum R.,University of Fribourg | Bally T.,University of Fribourg
Chemistry - A European Journal | Year: 2010

In contrast to the structurally and configurationally stable alkyl- or aryl-substituted cyclopropyl radical cations, cyclopropyl silyl ethers undergo spontaneous ring opening upon oxidation whereby the endocyclic C-C(OTMS) bond is cleaved with remarkable selectivity. DFT calculations on 1trimethylsilyloxybicyclo[4.1.0]heptane show that this selectivity arises from the topology of the potential surface of the corresponding radical cation which is initially generated in a very steep region of the potential surface from where the steepest descent leads to cleavage of the endocyclic rather than the lateral C-C(OTMS) bond. Cleavage of the lateral bond leads to interesting conformational changes which are explored in detail. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.


Cerdeira A.M.,Cilag AG | Werner I.A.,ETH Zurich | Mazzotti M.,ETH Zurich | Gander B.,ETH Zurich
Drug Development and Industrial Pharmacy | Year: 2012

Nanosuspension technology is an attractive approach for the formulation and solubility enhancement of poorly water-soluble drug compounds. The technology requires adequate excipients for stabilizing the suspensions during nanogrinding and storage. This study aimed at establishing a near-infrared (NIR) method for assaying simultaneously the two nanoparticle stabilizers, sodium dodecyl sulphate (SDS) and hydroxypropylcellulose (HPC), in miconazole nanosuspensions. Second derivative of NIR signals was used to establish calibration curves in concentration ranges of interest of SDS (0.030.3%) and HPC (0.757.5%). The suitability and applicability of the NIR method was verified by evaluating the linearity, accuracy, precision, and specificity of the obtained data. The method was then used to quantify indirectly the amount of SDS and HPC adsorbed onto miconazole nanoparticles. Within the concentration range of interest, SDS adsorption increased up to 122 g/m (4.2×10-7 mol/m) with increasing SDS concentration, and HPC adsorption was in the range of 8001000 g/m (2127×10-7 mol/m) for nanosuspensions containing nominally 5% HPC and 12.5% or 20% miconazole. Interestingly, some of the adsorbed HPC was displaced upon increase of SDS concentration and adsorption. The data were also confirmed by surface tension measurements of aqueous solutions of SDS and HPC and nanosuspension supernatants. The availability of a fast and nondestructive method for quantifying simultaneously the adsorption of two stabilizers onto nanoground particles may not only speed up nanosuspension development, but also provide insight into the mechanisms of nanoparticle stabilization regarding competitive adsorption and electrostatic versus steric stabilization. © 2012 Informa Healthcare USA, Inc.


Flutsch A.,University of Zürich | Flutsch A.,University of California at San Diego | Ackermann R.,University of Zürich | Ackermann R.,Cilag AG | And 10 more authors.
Biochemical Journal | Year: 2014

Caspases play important roles during apoptosis, inflammation and proliferation. The high homology among family members makes selective targeting of individual caspases difficult, which is necessary to precisely define the role of these enzymes. We have selected caspase-7-specific binders from a library of DARPins (designed ankyrin repeat proteins). The DARPins D7.18 and D7.43 bind specifically to procaspase 7 and active caspase 7, but not to other members of the family. Binding of the DARPins does not affect the active enzyme, but interferes with its activation by other caspases. The crystal structure of the caspase 7-D7.18 complex elucidates the high selectivity and the mode of inhibition. Combining these caspase-7-specificDARPinswith the previously reported caspase-3-inhibitory DARPin D3.4S76R reduces the activity of caspase 3 and 7 in double-transfected HeLa cells during apoptosis. In addition, these cells showed less susceptibility to TRAIL (tumour-necrosis-factor-related apoptosis-inducing ligand)-induced apoptosis in living cell experiments. D7.18 and D7.43 are therefore novel tools for in vitro studies on procaspase 7 activation as well as for clarifying the role of its activation in different cellular processes. If applied in combination with D3.4S76R, they represent an excellent instrument to increase our understanding of these enzymes during various cellular processes. © The Authors Journal compilation © 2014 Biochemical Society.


Cerdeira A.M.,Cilag AG | Mazzotti M.,ETH Zurich | Gander B.,ETH Zurich
Chemical Engineering and Technology | Year: 2011

The feasibility and efficiency of wet-nanogrinding of three drug substances (miconazole, itraconazole, etravirine) with similar elastic and plastic properties proved to depend primarily on the adequate electrostatic and steric stabilization of the nanoparticles and the specific energy input. Particle stabilization was provided by sodium dodecyl sulfate (SDS) and hydroxypropylcellulose. The specific energy input was defined by the grinding time, grinding bead size, and stirrer tip speed. Miconazole and itraconazole exhibited similar milling behavior, whereas etravirine nanosuspensions revealed agglomerates and increasing viscosity with increasing specific energy input. Agglomeration and viscosity increase were successfully counteracted by increasing the SDS concentration in the nanosuspension from 0 to 0.125%. Under the provision of proper particle stabilization, the three drug substances could be nanosized to a mean size of ~130nm, with 90% of all particles being smaller than ~250nm. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Cerdeira A.M.,Cilag AG | Mazzotti M.,ETH Zurich | Gander B.,ETH Zurich
International Journal of Pharmaceutics | Year: 2010

New drug substances from early development are often poorly water-soluble, which causes poor bioavailability upon peroral administration and hampers drug administration through other routes such as the parenteral or ocular routes. One approach to improve drug solubility and administration flexibility is by wet milling to nanosize. Particle size reduction increases the surface energy which requires adequate stabilization by excipients. In this study, the practically water-insoluble miconazole was nanoground, and a variety of surface active and polymeric excipients were tested for their stabilizing effects. For efficient milling, two preformulation criteria had to be fulfilled: a relatively low contact angle (<70°) and high dispersibility of the native drug particles in the milling medium. Hydroxypropylcellulose (HPC-LF) in combination with sodium dodecyl sulfate (SDS) stabilized best the miconazole nanosuspensions. A design of experiments was used to achieve drug particle mean sizes of 140-170. nm by varying the concentrations of miconazole (5 and 20%, w/w), SDS (0.05 and 0.2%, w/w), and HPC-LF (1.25 and 5%, w/w). Further experiments revealed that minimal 0.0125% SDS and 3.125% HPC-LF were required for miconazole nanogrinding and nanosuspension stabilisation. Storage of the nanosuspensions at 5°C for up to 6 months caused only minor changes, whereas storage at 25°C resulted in particle agglomeration and single crystal growth. Altogether the study showed that excellent wetting of drug particles as well as their electrostatic and steric stabilization by excipients is necessary to produce stable nanosuspensions by nanogrinding. © 2010 Elsevier B.V.


Gutmann B.,University of Graz | Gutmann B.,Research Center Pharmaceutical Engineering | Weigl U.,Cilag AG | Cox D.P.,Noramco Inc. | And 2 more authors.
Chemistry - A European Journal | Year: 2016

14-Hydroxymorphinone is converted to noroxymorphone, the immediate precursor of important opioid antagonists, such as naltrexone and naloxone, in a three-step reaction sequence. The initial oxidation of the N-methyl group in 14-hydroxymorphinone with in situ generated colloidal palladium(0) as the catalyst and molecular oxygen as the terminal oxidant constitutes the key transformation in this new route. This oxidation results in the formation of an unexpected oxazolidine ring structure. Subsequent hydrolysis of the oxazolidine under reduced pressure followed by hydrogenation in a packed-bed flow reactor using palladium(0) as the catalyst provides noroxymorphone in high purity and good overall yield. To overcome challenges associated with gas–liquid reactions with molecular oxygen, the key oxidation reaction was translated to a continuous-flow process. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim


PubMed | University of Graz, Cilag AG and Noramco Inc.
Type: Journal Article | Journal: Chemistry (Weinheim an der Bergstrasse, Germany) | Year: 2016

14-Hydroxymorphinone is converted to noroxymorphone, the immediate precursor of important opioid antagonists, such as naltrexone and naloxone, in a three-step reaction sequence. The initial oxidation of the N-methyl group in 14-hydroxymorphinone with in situ generated colloidal palladium(0) as the catalyst and molecular oxygen as the terminal oxidant constitutes the key transformation in this new route. This oxidation results in the formation of an unexpected oxazolidine ring structure. Subsequent hydrolysis of the oxazolidine under reduced pressure followed by hydrogenation in a packed-bed flow reactor using palladium(0) as the catalyst provides noroxymorphone in high purity and good overall yield. To overcome challenges associated with gas-liquid reactions with molecular oxygen, the key oxidation reaction was translated to a continuous-flow process.


Deng X.,Johnson and Johnson Pharmaceutical Research and Development LLC | Roessler A.,Cilag AG | Brdar I.,Cilag AG | Faessler R.,Cilag AG | And 3 more authors.
Journal of Organic Chemistry | Year: 2011

A POCl 3-mediated, direct amination reaction of heterocyclic amides/ureas with NH-heterocycles or N-substituted anilines is described. Compared to the existing methods, this operationally simple protocol provides unique reactivity and functional group compatibility because of the metal-free, acidic reaction conditions. The yields are generally excellent. © 2011 American Chemical Society.


The present invention relates to an improved process for O-demethylating methoxy substituted morphinan-6-one derivatives using AlCl3 as a demethylating agent in a reaction-inert solvent having a water content ranging from 0.1% wt to 0.8% wt. 10


PubMed | Cilag AG
Type: Journal Article | Journal: Drug development and industrial pharmacy | Year: 2012

Nanosuspension technology is an attractive approach for the formulation and solubility enhancement of poorly water-soluble drug compounds. The technology requires adequate excipients for stabilizing the suspensions during nanogrinding and storage. This study aimed at establishing a near-infrared (NIR) method for assaying simultaneously the two nanoparticle stabilizers, sodium dodecyl sulphate (SDS) and hydroxypropylcellulose (HPC), in miconazole nanosuspensions. Second derivative of NIR signals was used to establish calibration curves in concentration ranges of interest of SDS (0.03-0.3%) and HPC (0.75-7.5%). The suitability and applicability of the NIR method was verified by evaluating the linearity, accuracy, precision, and specificity of the obtained data. The method was then used to quantify indirectly the amount of SDS and HPC adsorbed onto miconazole nanoparticles. Within the concentration range of interest, SDS adsorption increased up to 122 g/m(2) (4.2 10(-7) mol/m(2)) with increasing SDS concentration, and HPC adsorption was in the range of 800-1000 g/m(2) (21-27 10(-7) mol/m(2)) for nanosuspensions containing nominally 5% HPC and 12.5% or 20% miconazole. Interestingly, some of the adsorbed HPC was displaced upon increase of SDS concentration and adsorption. The data were also confirmed by surface tension measurements of aqueous solutions of SDS and HPC and nanosuspension supernatants. The availability of a fast and nondestructive method for quantifying simultaneously the adsorption of two stabilizers onto nanoground particles may not only speed up nanosuspension development, but also provide insight into the mechanisms of nanoparticle stabilization regarding competitive adsorption and electrostatic versus steric stabilization.

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