InnoCore Pharmaceuticals

Groningen, Netherlands

InnoCore Pharmaceuticals

Groningen, Netherlands

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Zandstra J.,University of Groningen | Hiemstra C.,InnoCore Pharmaceuticals | Petersen A.H.,University of Groningen | Zuidema J.,InnoCore Pharmaceuticals | And 7 more authors.
European Cells and Materials | Year: 2014

Biodegradable poly-(DL-lactide-co-glycolide) (PLGA) microspheres (MSP) are attractive candidate vehicles for site-specific or systemic sustained release of therapeutic compounds. This release may be altered by the host’s foreign body reaction (FBR), which is dependent on the characteristics of the implant, e.g. chemistry, shape or size. In this study, we focused on the characterisation of the influence of MSP size on the FBR. To this end we injected monodisperse MSP of defined size (small 5.8 µm, coefficient of variance (CV) 14% and large 29.8 µm, CV 4%) and polydisperse MSP (average diameter 34.1 µm, CV 51%) under the skin of rats. MSP implants were retrieved at day 7, 14 and 28 after transplantation. The FBR was studied in terms of macrophage infiltration, implant encapsulation, vascularisation and extracellular matrix deposition. Although PLGA MSP of all different sizes demonstrated excellent in vitro and in vivo biocompatibility, significant differences were found in the characteristics of the FBR. Small MSP were phagocytosed, while large MSP were not. Large MSP occasionally elicited giant cell formation, which was not observed after implantation of small MSP. Cellular and macrophage influx and collagen deposition were increased in small MSP implants compared to large MSP. We conclude that the MSP size influences the FBR and thus might influence clinical outcome when using MSP as a drug delivery device. We propose that a rational choice of MSP size can aid in optimising the therapeutic efficacy of microsphere-based therapies in vivo.


Falke L.L.,University Utrecht | van Vuuren S.H.,University Utrecht | Kazazi-Hyseni F.,University Utrecht | Ramazani F.,University Utrecht | And 10 more authors.
Biomaterials | Year: 2015

Kidney injury triggers fibrosis, the final common pathway of chronic kidney disease (CKD). The increase of CKD prevalence worldwide urgently calls for new therapies. Available systemic treatment such as rapamycin are associated with serious side effects. To study the potential of local antifibrotic therapy, we administered rapamycin-loaded microspheres under the kidney capsule of ureter-obstructed rats and assessed the local antifibrotic effects and systemic side effects of rapamycin. After 7 days, microsphere depots were easily identifiable under the kidney capsule. Both systemic and local rapamycin treatment reduced intrarenal mTOR activity, myofibroblast accumulation, expression of fibrotic genes, and T-lymphocyte infiltration. Upon local treatment, inhibition of mTOR activity and reduction of myofibroblast accumulation were limited to the immediate vicinity of the subcapsular pocket, while reduction of T-cell infiltration was widespread. In contrast to systemically administered rapamycin, local treatment did not induce off target effects such as weight loss. Thus subcapsular delivery of rapamycin-loaded microspheres successfully inhibited local fibrotic response in UUO with less systemic effects. Therapeutic effect of released rapamycin was most prominent in close vicinity to the implanted microspheres. © 2014 Elsevier Ltd.


Stankovic M.,University of Groningen | Tomar J.,University of Groningen | Hiemstra C.,InnoCore Pharmaceuticals | Steendam R.,InnoCore Pharmaceuticals | And 2 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2014

In this study, the in vitro release of proteins from novel, biodegradable phase-separated poly(ε-caprolactone-PEG)-block-poly(ε-caprolactone), [PCL-PEG]-b-[PCL]) multiblock copolymers with different block ratios and with a low melting temperature (49-55 °C) was studied. The effect of block ratio and PEG content of the polymers (i.e. 22.5, 37.5 and 52.5 wt%) as well as the effect of protein molecular weight (1.2, 5.8, 14, 29 and 66 kDa being goserelin, insulin, lysozyme, carbonic anhydrase and albumin, respectively) on protein release was investigated. Proteins were spray-dried with inulin as stabilizer to obtain a powder of uniform particle size. Spray-dried inulin-stabilized proteins were incorporated into polymeric implants by hot melt extrusion. All incorporated proteins fully preserved their structural integrity as determined after extraction of these proteins from the polymeric implants. In general, it was found that the release rate of the protein increased with decreasing molecular weight of the protein and with increasing the PEG content of the polymer. Swelling and degradation rate of the copolymer increased with increasing PEG content. Hence, release of proteins of various molecular weights from [PCL-PEG]-b-[PCL] multi-block copolymers can be tailored by varying the PEG content of the polymer. © 2014 Elsevier B.V. All rights reserved.


Agenda Released for Controlled Release Delivery: FDA, Janssen, GSK and Boehringer Ingelheim to Present Next April SMi is thrilled to announce the release of the highly anticipated brochure for 14th annual Controlled Release Delivery taking place on 3rd to 4th of April in London. London, United Kingdom, December 02, 2016 --( The expert speaker line-up will feature: Chairmen: - Howard Stevens, Professor, University Of Strathclyde - Sudhakar Garad, Global Head of Chemical and Pharmaceutical Profiling, Novartis Institutes for BioMedical Research Featured Speakers: - Markham Luke, Director, Division of Therapeutic Performance, FDA - René Holm, Head and Scientific Director, Liquids & Parenterals, Janssen - Mark Wilson, Director, Technology Licensing, PTS, GSK - Patrick Garidel, Associate Director Protein Science, Boehringer Ingelheim - Stephan Buchmann, Head Preformulation & Preclinical Galenics, Actelion - John Fox, Chief Executive Officer, Merrion Pharmaceuticals - and many more... Event highlights will include: 1. Listen to FDA evaluate generic drug development 2. Novartis optimise the success of biopharmaceutical approaches for controlled release delivery 3. Can lipid suspensions improve oral bioavailability? Answers from Janssen 4. Insights into the opportunities and limitations to improving solubility and bioavailability with Actelion 5. Hear InnoCore Pharmaceuticals discuss microparticles and hydrogels for parenteral drug delivery A full speaker line-up and detailed conference agenda is available to download online at http://www.controlledreleasedelivery.com/prcom. For those looking to attend, there is currently a £400 discount available which expires on 16th December 2016. Controlled Release Delivery Strengthening innovation and overcoming the challenging regulatory landscape 3rd & 4th April 2017 London, UK http://www.controlledreleasedelivery.com/prcom Contact Information: For all media enquiries contact Zoe Gale on Tel: +44 (0)20 7827 6032 / Email: zgale@smi-online.co.uk To register for the conference, visit http://www.controlledreleasedelivery.com/prcom or contact Ameenah Begum on Tel: +44 (0)20 7827 6166 / Email: abegum@smi-online.co.uk To sponsor, speak or exhibit at the conference, contact Alia Malick on Tel: +44 (0)20 7827 6168 / Email: amalick@smi-online.co.uk About SMi Group: Established since 1993, the SMi Group is a global event-production company that specializes in Business-to-Business Conferences, Workshops, Masterclasses and online Communities. We create and deliver events in the Defence, Security, Energy, Utilities, Finance and Pharmaceutical industries. We pride ourselves on having access to the world’s most forward thinking opinion leaders and visionaries, allowing us to bring our communities together to Learn, Engage, Share and Network. More information can be found at http://www.smi-online.co.uk London, United Kingdom, December 02, 2016 --( PR.com )-- Aimed at drug development experts and formulation specialists, Controlled Release Delivery 2017 will reflect on the latest innovations made within controlled release. The 2017 event will address the latest regulatory updates and how to overcome challenges within the industry. Key topics that will be explored include: innovations in drug delivery, nanoparticles/nanomedicine & QbD, CNS drug delivery and therapeutic application.The expert speaker line-up will feature:Chairmen:- Howard Stevens, Professor, University Of Strathclyde- Sudhakar Garad, Global Head of Chemical and Pharmaceutical Profiling, Novartis Institutes for BioMedical ResearchFeatured Speakers:- Markham Luke, Director, Division of Therapeutic Performance, FDA- René Holm, Head and Scientific Director, Liquids & Parenterals, Janssen- Mark Wilson, Director, Technology Licensing, PTS, GSK- Patrick Garidel, Associate Director Protein Science, Boehringer Ingelheim- Stephan Buchmann, Head Preformulation & Preclinical Galenics, Actelion- John Fox, Chief Executive Officer, Merrion Pharmaceuticals- and many more...Event highlights will include:1. Listen to FDA evaluate generic drug development2. Novartis optimise the success of biopharmaceutical approaches for controlled release delivery3. Can lipid suspensions improve oral bioavailability? Answers from Janssen4. Insights into the opportunities and limitations to improving solubility and bioavailability with Actelion5. Hear InnoCore Pharmaceuticals discuss microparticles and hydrogels for parenteral drug deliveryA full speaker line-up and detailed conference agenda is available to download online at http://www.controlledreleasedelivery.com/prcom. For those looking to attend, there is currently a £400 discount available which expires on 16th December 2016.Controlled Release DeliveryStrengthening innovation and overcoming the challenging regulatory landscape3rd & 4th April 2017London, UKhttp://www.controlledreleasedelivery.com/prcomContact Information:For all media enquiries contact Zoe Gale on Tel: +44 (0)20 7827 6032 / Email: zgale@smi-online.co.ukTo register for the conference, visit http://www.controlledreleasedelivery.com/prcom or contact Ameenah Begum on Tel: +44 (0)20 7827 6166 / Email: abegum@smi-online.co.ukTo sponsor, speak or exhibit at the conference, contact Alia Malick on Tel: +44 (0)20 7827 6168 / Email: amalick@smi-online.co.ukAbout SMi Group:Established since 1993, the SMi Group is a global event-production company that specializes in Business-to-Business Conferences, Workshops, Masterclasses and online Communities. We create and deliver events in the Defence, Security, Energy, Utilities, Finance and Pharmaceutical industries. We pride ourselves on having access to the world’s most forward thinking opinion leaders and visionaries, allowing us to bring our communities together to Learn, Engage, Share and Network. More information can be found at http://www.smi-online.co.uk Click here to view the list of recent Press Releases from SMi Group


Ruiter M.S.,University of Amsterdam | Ruiter M.S.,Tissue Engineering Unit | Van Tiel C.M.,University of Amsterdam | Doornbos A.,InnoCore Pharmaceuticals | And 8 more authors.
PLoS ONE | Year: 2015

Background The introduction of drug-eluting stents (DES) has dramatically reduced restenosis rates compared with bare metal stents, but in-stent thrombosis remains a safety concern, necessitating prolonged dual anti-platelet therapy. The drug 6-Mercaptopurine (6-MP) has been shown to have beneficial effects in a cell-specific fashion on smooth muscle cells (SMC), endothelial cells and macrophages. We generated and analyzed a novel bioresorbable polymer coated DES, releasing 6-MP into the vessel wall, to reduce restenosis by inhibiting SMC proliferation and decreasing inflammation, without negatively affecting endothelialization of the stent surface. Methods Stents spray-coated with a bioresorbable polymer containing 0, 30 or 300 μg 6-MP were implanted in the iliac arteries of 17 male New Zealand White rabbits. Animals were euthanized for stent harvest 1 week after implantation for evaluation of cellular stent coverage and after 4 weeks for morphometric analyses of the lesions. Results Four weeks after implantation, the high dose of 6-MP attenuated restenosis with 16% compared to controls. Reduced neointima formation could at least partly be explained by an almost 2-fold induction of the cell cycle inhibiting kinase p27Kip1. Additionally, inflammation score, the quantification of RAM11-positive cells in the vessel wall, was significantly reduced in the high dose group with 23% compared to the control group. Evaluation with scanning electron microscopy showed 6-MP did not inhibit strut coverage 1 week after implantation. Conclusion We demonstrate that novel stents coated with a bioresorbable polymer coating eluting 6- MP inhibit restenosis and attenuate inflammation, while stimulating endothelial coverage. The 6-MP-eluting stents demonstrate that inhibition of restenosis without leaving uncovered metal is feasible, bringing stents without risk of late thrombosis one step closer to the patient. © 2015 Ruiter et al.


Ramazani F.,University Utrecht | Ramazani F.,RWTH Aachen | Hiemstra C.,InnoCore Pharmaceuticals | Steendam R.,InnoCore Pharmaceuticals | And 9 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2015

Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor that blocks several angiogenesis related pathways. The aim of this study was to develop sunitinib-loaded polymeric microspheres that can be used as intravitreal formulation for the treatment of ocular diseases. A series of novel multi-block copolymers composed of amorphous blocks of poly-(d,l-lactide) (PDLLA) and polyethylene glycol (PEG) and of semi-crystalline poly-(l-lactide) (PLLA) blocks were synthesized. Sunitinib-loaded microspheres were prepared by a single emulsion method using dichloromethane as volatile solvent and DMSO as co-solvent. SEM images showed that the prepared microspheres (∼30 μm) were spherical with a non-porous surface. Sunitinib-loaded microspheres were studied for their degradation and in-vitro release behavior. It was found that increasing the percentage of amorphous soft blocks from 10% to 30% accelerated the degradation of the multi-block copolymers. Sunitinib microspheres released their cargo for a period of at least 210 days by a combination of diffusion and polymer erosion. The initial burst (release in 24 h) and release rate could be tailored by controlling the PEG-content of the multi-block copolymers. Sunitinib-loaded microspheres suppressed angiogenesis in a chicken chorioallantoic membrane (CAM) assay. These microspheres therefore hold promise for long-term suppression of ocular neovascularization. © 2015 Elsevier B.V. All rights reserved.


PubMed | University Utrecht, Technical University of Delft, InnoCore Pharmaceuticals, Leiden University and 2 more.
Type: | Journal: Acta biomaterialia | Year: 2016

In this study, we investigated the use of microspheres with a narrow particle size distribution (monospheres) composed of biodegradable poly(DL-lactide)-PEG-poly(DL-lactide)-b-poly(L-lactide) multiblock copolymers that are potentially suitable for local sustained drug release in articular joints. Monospheres with sizes of 5, 15 and 30m and a narrow particle size distribution were prepared by a micro-sieve membrane emulsification process. During in vitro degradation, less crystallinity, higher swelling and accelerated mass loss during was observed with increasing the PEG content of the polymer. The monospheres were tested in both a small (mice/rat) and large animal model (horse). In vivo imaging after injection with fluorescent dye loaded microspheres in mice knees showed that monospheres of all sizes retained within the joint for at least 90days, while the same dose of free dye redistributed to the whole body within the first day after intra-articular injection. Administration of monospheres in equine carpal joints caused a mild transient inflammatory response without any clinical signs and without degradation of the cartilage, as evidenced by the absence of degradation products of sulfated glycosaminoglycans or collagen type 2 in the synovial fluid. The excellent intra-articular biocompatibility was confirmed in rat knees, where CT-imaging and histology showed neither changes in cartilage quality nor quantity. Given the good intra-articular retention and the excellent biocompatibility, these novel poly(DL-lactide)-PEG-poly(DL-lactide)-b-poly(L-lactide)-based monospheres can be considered a suitable platform for intra-articular drug delivery.This paper demonstrates the great potential in intra-articular drug delivery of monodisperse biodegradable microspheres which were prepared using a new class of biodegradable multi-block copolymers and a unique membrane emulsification process allowing the preparation of microspheres with a narrow particle size distribution (monospheres) leading to multiple advantages like better injectability, enhanced reproducibility and predictability of the in vivo release kinetics. We report not only on the synthesis and preparation, but also in vitro characterization, followed by in vivo testing of intra-articular biocompatibility of the monospheres in both a small and a large animal model. The favourable intra-articular biocompatibility combined with the prolonged intra-articular retention (>90days) makes these monospheres an interesting drug delivery platform. What should also be highlighted is the use of horses; a very accurate translational model for the human situation, making the results not only relevant for equine healthcare, but also for the development of novel human OA therapies.


PubMed | University of Amsterdam, University Utrecht and InnoCore Pharmaceuticals
Type: Journal Article | Journal: PloS one | Year: 2015

The introduction of drug-eluting stents (DES) has dramatically reduced restenosis rates compared with bare metal stents, but in-stent thrombosis remains a safety concern, necessitating prolonged dual anti-platelet therapy. The drug 6-Mercaptopurine (6-MP) has been shown to have beneficial effects in a cell-specific fashion on smooth muscle cells (SMC), endothelial cells and macrophages. We generated and analyzed a novel bioresorbable polymer coated DES, releasing 6-MP into the vessel wall, to reduce restenosis by inhibiting SMC proliferation and decreasing inflammation, without negatively affecting endothelialization of the stent surface.Stents spray-coated with a bioresorbable polymer containing 0, 30 or 300 g 6-MP were implanted in the iliac arteries of 17 male New Zealand White rabbits. Animals were euthanized for stent harvest 1 week after implantation for evaluation of cellular stent coverage and after 4 weeks for morphometric analyses of the lesions.Four weeks after implantation, the high dose of 6-MP attenuated restenosis with 16% compared to controls. Reduced neointima formation could at least partly be explained by an almost 2-fold induction of the cell cycle inhibiting kinase p27Kip1. Additionally, inflammation score, the quantification of RAM11-positive cells in the vessel wall, was significantly reduced in the high dose group with 23% compared to the control group. Evaluation with scanning electron microscopy showed 6-MP did not inhibit strut coverage 1 week after implantation.We demonstrate that novel stents coated with a bioresorbable polymer coating eluting 6-MP inhibit restenosis and attenuate inflammation, while stimulating endothelial coverage. The 6-MP-eluting stents demonstrate that inhibition of restenosis without leaving uncovered metal is feasible, bringing stents without risk of late thrombosis one step closer to the patient.


PubMed | University of Amsterdam, University Utrecht and InnoCore Pharmaceuticals
Type: Journal Article | Journal: Journal of negative results in biomedicine | Year: 2016

Drug-eluting stents (DES) have dramatically reduced restenosis rates compared to bare metal stents and are widely used in coronary artery angioplasty. The anti-proliferative nature of the drugs reduces smooth muscle cell (SMC) proliferation effectively, but unfortunately also negatively affects endothelialization of stent struts, necessitating prolonged dual anti-platelet therapy. Cell-type specific therapy may prevent this complication, giving rise to safer stents that do not require additional medication. 6-Mercaptopurine (6-MP) is a drug with demonstrated cell-type specific effects on vascular cells both in vitro and in vivo, inhibiting proliferation of SMCs while promoting survival of endothelial cells. In rabbits, we demonstrated that DES locally releasing 6-MP during 4weeks reduced in-stent stenosis by inhibiting SMC proliferation and reducing inflammation, without negatively affecting endothelialization of the stent surface. The aim of the present study was to investigate whether 6-MP-eluting stents are similarly effective in preventing stenosis in porcine coronary arteries after 3months, in order to assess the eligibility for human application.6-MP-eluting and polymer-only control stents (both n=7) were implanted in porcine coronary arteries after local balloon injury to assess the effect of 6-MP on vascular lesion formation. Three months after implantation, stented coronary arteries were harvested and analyzed.Morphometric analyses revealed that stents were implanted reproducibly and with limited injury to the vessel wall. Unexpectedly, both in-stent stenosis (6-MP: 41.110.3%; control: 29.65.9%) and inflammation (6-MP: 2.140.51; control: 1.430.45) were similar between the groups after 3months.In conclusion, although 6-MP was previously found to potently inhibit SMC proliferation, reduce inflammation and promote endothelial cell survival, thereby effectively reducing in-stent restenosis in rabbits, stents containing 300g 6-MP did not reduce stenosis and inflammation in porcine coronary arteries.


PubMed | University Utrecht, University of Twente, InnoCore Pharmaceuticals and RWTH Aachen
Type: Journal Article | Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V | Year: 2015

Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor that blocks several angiogenesis related pathways. The aim of this study was to develop sunitinib-loaded polymeric microspheres that can be used as intravitreal formulation for the treatment of ocular diseases. A series of novel multi-block copolymers composed of amorphous blocks of poly-(D,L-lactide) (PDLLA) and polyethylene glycol (PEG) and of semi-crystalline poly-(L-lactide) (PLLA) blocks were synthesized. Sunitinib-loaded microspheres were prepared by a single emulsion method using dichloromethane as volatile solvent and DMSO as co-solvent. SEM images showed that the prepared microspheres ( 30 m) were spherical with a non-porous surface. Sunitinib-loaded microspheres were studied for their degradation and in-vitro release behavior. It was found that increasing the percentage of amorphous soft blocks from 10% to 30% accelerated the degradation of the multi-block copolymers. Sunitinib microspheres released their cargo for a period of at least 210 days by a combination of diffusion and polymer erosion. The initial burst (release in 24h) and release rate could be tailored by controlling the PEG-content of the multi-block copolymers. Sunitinib-loaded microspheres suppressed angiogenesis in a chicken chorioallantoic membrane (CAM) assay. These microspheres therefore hold promise for long-term suppression of ocular neovascularization.

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