Monistrol de Montserrat, Spain
Monistrol de Montserrat, Spain

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Patent
Esteve | Date: 2017-03-08

A dry powder inhaler for a capsule containing dry powder, the inhaler comprising a base body having a capsule receptacle, two actuator buttons arranged on opposing sides of the base body and two perforation needles, each needle being fixedly connected to an actuator button and movable relative to the base body towards each other from a normal position to a perforation position along an actuation direction to perforate a capsule arranged in the capsule receptacle, wherein the capsule receptacle is arranged in an inclined angle within the range of about 40 to about 50 with respect to the actuation direction.


Patent
Esteve | Date: 2017-03-08

A dry powder inhaler for a capsule containing dry powder, the inhaler comprising a housing having a capsule receptacle, two actuator buttons arranged on opposing sides of the housing and two perforation needles, each needle being fixedly connected to an actuator button and movable relative to the housing towards each other from a normal position to a perforation position along an actuation direction to perforate a capsule arranged in the capsule receptacle, wherein a first end of each actuator button is connected to the housing at a lower portion of the housing and in that a second free end of each actuator button is movable into the perforation position such that the perforation needle is moved along a circular line.


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Nieto F.R.,University of Granada | Nieto F.R.,King's College London | Cendan C.M.,University of Granada | Canizares F.J.,University of Granada | And 4 more authors.
Molecular Pain | Year: 2014

Background: Paclitaxel, a widely-used antineoplastic drug, produces a painful peripheral neuropathy that in rodents is associated with peripheral-nerve mitochondrial alterations. The sigma-1 receptor (σ1R) is a ligand-regulated molecular chaperone involved in mitochondrial calcium homeostasis and pain hypersensitivity. This receptor plays a key role in paclitaxel-induced neuropathic pain, but it is not known whether it also modulates mitochondrial abnormalities.In this study, we used a mouse model of paclitaxel-induced neuropathic pain to test the involvement of the σ1R in the mitochondrial abnormalities associated with paclitaxel, by using genetic (σ1R knockout mice) and pharmacological (σ1R antagonist) approaches.Results: Paclitaxel administration to wild-type (WT) mice produced cold- and mechanical-allodynia, and an increase in the frequency of swollen and vacuolated mitochondria in myelinated A-fibers, but not in C-fibers, of the saphenous nerve. Behavioral and mitochondrial alterations were marked at 10 days after paclitaxel-administration and had resolved at day 28. In contrast, paclitaxel treatment did not induce allodynia or mitochondrial abnormalities in σ1R knockout mice. Moreover, the prophylactic treatment of WT mice with BD-1063 also prevented the neuropathic pain and mitochondrial abnormalities induced by paclitaxel.Conclusions: These results suggest that activation of the σ1R is necessary for development of the sensory nerve mitochondrial damage and neuropathic pain produced by paclitaxel. Therefore, σ1R antagonists might have therapeutic value for the prevention of paclitaxel-induced neuropathy. © 2014 Nieto et al.; licensee BioMed Central Ltd.


Gonzalez-Cano R.,University of Granada | Merlos M.,Esteve | Baeyens J.M.,University of Granada | Cendan C.M.,University of Granada
Anesthesiology | Year: 2013

Background: Visceral pain is an important and prevalent clinical condition whose treatment is challenging. Sigma-1 (σ1) receptors modulate somatic pain, but their involvement in pure visceral pain is unexplored. Methods: The authors evaluated the role of σ1 receptors in intracolonic capsaicin-induced visceral pain (pain-related behaviors and referred mechanical hyperalgesia to the abdominal wall) using wild-type (WT) (n = 12 per group) and σ1 receptor knockout (σ1- KO) (n = 10 per group) mice, selective σ1 receptor antagonists (BD-1063, S1RA, and NE-100), and control drugs (morphine and ketoprofen). Results: The intracolonic administration of capsaicin (0.01-1%) induced concentration-dependent visceral pain-related behaviors and referred hyperalgesia in both WT and σ1-KO mice. However, the maximum number of pain-related behaviors induced by 1% capsaicin in σ1- KO mice (mean ± SEM, 22 ± 2.9) was 48% of that observed in WT animals (46 ± 4.2). Subcutaneous administration of the σ1 receptor antagonists BD-1063 (16-64 mg/kg), S1RA (32-128 mg/kg), and NE-100 (8-64 mg/kg) dose-dependently reduced the number of behavioral responses (by 53, 62, and 58%, respectively) and reversed the referred hyperalgesia to mechanical control threshold (0.53 ± 0.05 g) in WT mice. In contrast, these drugs produced no change in σ1-KO mice. Thus, the effects of these drugs are specifically mediated by σ1 receptors. Morphine produced an inhibition of capsaicin-induced visceral pain in WT and σ1-KO mice, whereas ketoprofen had no effect in either mouse type. Conclusion: These results suggest that σ1 receptors play a role in the mechanisms underlying capsaicin-induced visceral pain and raise novel perspectives for their potential therapeutic value. © 2013, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins.


Pallicer J.M.,University of Barcelona | Calvet C.,ESTEVE | Port A.,ESTEVE | Roses M.,University of Barcelona | And 2 more authors.
Journal of Chromatography A | Year: 2012

A reorted chromatographic method to determine the 1-octanol/water partition coefficient (logP o/w) has been used to estimate the lipophilicity of 33 drugs with diverse structures and functionalities, including neutral, acid, basic, and amphoteric compounds. The applicability of the chromatographic method has been extended to the UHPLC technique, and the results obtained were compared to those obtained from conventional HPLC. No significant difference between the results obtained by both techniques is noticed. Thus, the suitability of UHPLC, which involves shorter run times, for lipophilicity assessment is demonstrated. In order to show the consistency of this chromatographic method, the logP o/w values of those drugs which have acid-base properties have been also determined by potentiometry, and the final results have been compared with both values derived from the chromatographic method and the ones from the literature. © 2012 Elsevier B.V.


Bura A.S.,University Pompeu Fabra | Guegan T.,University Pompeu Fabra | Zamanillo D.,Esteve | Vela J.M.,Esteve | Maldonado R.,University Pompeu Fabra
European Journal of Pain (United Kingdom) | Year: 2013

Background: The treatment of neuropathic pain is unsatisfactory at the present moment and the sigma 1 receptor has been identified as a new potential target for neuropathic pain. The aim of this study was to use an operant self-administration model to reveal the potential interest of a new sigma 1 receptor antagonist, S1RA, in chronic pain that was developed in mice by a partial ligation of the sciatic nerve. Methods: Once that chronic pain had reached a steady state, mice were trained to maintain an operant behaviour to self-administer S1RA. The possible abuse liability of the analgesic compound was determined by evaluating operant self-administration in sham-operated mice. The influence of S1RA on the anhedonic state related to chronic pain was also evaluated by measuring the preference for palatable drink (2% sucrose solution) using a recently validated and highly sensitive behavioural device. Results: Nerve-injured mice, but not sham-operated animals, acquired the operant responding to obtain S1RA (6 mg/kg/infusion). After 10 days of S1RA self-administration, neuropathic pain was significantly reduced in nerve-injured mice. In addition, an anhedonic state was revealed in nerve-injured mice by a decreased consumption of palatable drink, which was significantly attenuated by S1RA (25 mg/kg). Conclusions: These results reveal the analgesic efficacy of the sigma antagonist, S1RA, in neuropathic pain associated with an improvement of the emotional negative state and that was devoided of reinforcing effects. The operant responses evaluated in this new mouse model can have a high predictive value to estimate the clinical benefit/risk ratio of new analgesic compounds to treat chronic pain, such as S1RA. © 2012 European Federation of International Association for the Study of Pain Chapters.


Vela J.M.,ESTEVE | Merlos M.,ESTEVE | Almansa C.,ESTEVE
Expert Opinion on Investigational Drugs | Year: 2015

Introduction: The sigma-1 receptor (σ1R) is a ligand-regulated molecular chaperone that interacts with other proteins, including NMDA and opioid receptors, to modulate their activity. Convergent evidence indicates that σ1R antagonists exert inhibitory effects (and agonists stimulatory effects) on pain by stepping down the intracellular signaling cascades involved in transduction of noxious stimuli and plastic changes (i.e., sensitization phenomena) associated with chronic pain states. Areas covered: This review addresses three primary domains. The first focuses on mechanisms underlying the antinociceptive effects of σ1R antagonists. The second addresses evidence gained using pharmacological tools and experimental drugs in the discovery phase and clinical development. Finally, the article outlines the potential benefits of σ1R antagonists, alone or in combination, in the context of available pain therapeutics. Expert opinion: There is a critical need for new analgesics based on new mechanisms of action. Target identification requires convincing evidence relating targets to function. In turn, target validation requires confirmation of therapeutic benefits, ideally in humans. Current preclinical evidence provides strong rationale for σ1R antagonists in pain. The outcome of clinical studies with the most advanced investigational σ1R antagonist, S1RA (E-52862), will be of great interest to ascertain the potential of this new therapeutic approach to pain management. © 2015 Informa UK, Ltd.


Schlager T.,University of Munster | Schepmann D.,University of Munster | Lehmkuhl K.,University of Munster | Holenz J.,Esteve | And 3 more authors.
Journal of Medicinal Chemistry | Year: 2011

The novel class of spirocyclic σ 1 ligands 3 (6′,7′-dihydro-1′H-spiro[piperidine-4,4′-pyrano[4,3-c] pyrazoles]) was designed by the combination of the potent σ 1 ligands 1 and 2 in one molecule. Thorough structure affinity relationships were derived by the variation of the substituents in position 1′, 1, and 6′. Whereas the small electron rich methylpyrazole heterocycle was less tolerated by the σ 1 receptor protein, the introduction of a phenyl substituent instead of the methyl group led to ligands with a high σ 1 affinity. It is postulated that the additional phenyl substituent occupies a previously unrecognized hydrophobic region of the σ 1 receptor resulting in additional lipophilic interactions. The spirocyclic pyranopyrazoles are very selective against the σ 2 subtype, the PCP binding site of the NMDA receptor, and further targets. Despite high σ 1 affinity, the cyclohexylmethyl derivative 17i (K i (σ 1) = 0.55 nM) and the isopentenyl derivative 17p (K i (σ 1) = 1.6 nM) showed only low antiallodynic activity in the capsaicin assay. © 2011 American Chemical Society.


Pallicer J.M.,University of Barcelona | Pascual R.,ESTEVE | Port A.,ESTEVE | Roses M.,University of Barcelona | And 2 more authors.
European Journal of Pharmaceutical Sciences | Year: 2013

The influence of the hydrogen bond acidity when the 1-octanol/water partition coefficient (log Po/w) of drugs is determined from chromatographic measurements was studied in this work. This influence was firstly evaluated by means of the comparison between the Abraham solvation parameter model when it is applied to express the 1-octanol/water partitioning and the chromatographic retention, expressed as the solute polarity p. Then, several hydrogen bond acidity descriptors were compared in order to determine properly the log Po/w of drugs. These descriptors were obtained from different software and comprise two-dimensional parameters such as the calculated Abraham hydrogen bond acidity A and three-dimensional descriptors like HDCA-2 from CODESSA program or WO1 and DRDODO descriptors calculated from Volsurf + software. The additional HOMO-LUMO polarizability descriptor should be added when the three-dimensional descriptors are used to complement the chromatographic retention. The models generated using these descriptors were compared studying the correlations between the determined log Po/w values and the reference ones. The comparison showed that there was no significant difference between the tested models and any of them was able to determine the log Po/w of drugs from a single chromatographic measurement and the correspondent molecular descriptors terms. However, the model that involved the calculated A descriptor was simpler and it is thus recommended for practical uses. © 2012 Elsevier B.V. All rights reserved.

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