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Groningen, Netherlands

Sandker M.J.,Erasmus Medical Center | Petit A.,InGell Labs BV | Petit A.,Utrecht Institute for Pharmaceutical science | Redout E.M.,University Utrecht | And 8 more authors.
Biomaterials | Year: 2013

Sustained intra-articular drug delivery opens up new opportunities for targeted treatment of osteoarthritis. In this study, we investigated the invitro and invivo properties and performance of a newly developed hydrogel based on acyl-capped PCLA-PEG-PCLA specifically designed for intra-articular use. The hydrogel formulation consisted of a blend of polymers either capped with acetyl, or with 2-(2',3',5',-triiodobenzoyl, TIB) moieties. TIB was added to visualize the gel using μCT, enabling longitudinal quantification of its degradation. Blends containing TIB-capped polymer degraded in vitro (37°C; pH 7.4 buffer) through dissolution over a period of ~20 weeks, and degraded slightly faster (~12 weeks) after subcutaneous injection in rats. This invivo acceleration was likely due to active (enzymatic) degradation, shown by changes in polymer composition and molecular weight as well as the presence of macrophages. After intra-articular administration in rats, the visualized gel gradually lost signal intensity over the course of 4 weeks. Good cytocompatibility of acetyl-capped polymer based hydrogel was proven invitro on erythrocytes and chondrocytes. Moreover, intra-articular biocompatibility was demonstrated using μCT-imaging and histology, since both techniques showed no changes in cartilage quality and/or quantity. © 2013 Elsevier Ltd.

Petit A.,InGell Labs BV | Petit A.,University Utrecht | Sandker M.,Erasmus Medical Center | Muller B.,InGell Labs BV | And 13 more authors.
Biomaterials | Year: 2014

In this study, we investigated the invitro and invivo properties and performance of a celecoxib-loaded hydrogel based on a fully acetyl-capped PCLA-PEG-PCLA triblock copolymer. Blends of different compositions of celocoxib, a drug used for pain management in osteoarthritis, and the acetyl-capped PCLA-PEG-PCLA triblock copolymer were mixed with buffer to yield temperature-responsive gelling systems. These systems containing up to 50mg celecoxib/g gel, were sols at room temperature and converted into immobile gels at 37°C. Invitro, release of celecoxib started after a ~10-day lag phase followed by a sustained release of ~90 days. The release was proven to be mediated by polymer dissolution from the gels. Invivo (subcutaneous injection in rats) experiments showed an initial celecoxib release of ~30% during the first 3 days followed by a sustained release of celecoxib for 4-8 weeks. The absence of a lag phase and the faster release seen invivo were likely due to the enhanced celecoxib solubility in biological fluids and active degradation of the gel by macrophages. Finally, intra-articular biocompatibility of the 50mg/g celecoxib-loaded gel was demonstrated using μCT-scanning and histology, where no cartilage or bone changes were observed following injection into the knee joints of healthy rats. In conclusion, this study shows that celecoxib-loaded acetyl-capped PCLA-PEG-PCLA hydrogels form a safe drug delivery platform for sustained intra-articular release. © 2014 Elsevier Ltd.

Petit A.,InGell Labs BV | Petit A.,University Utrecht | Muller B.,InGell Labs BV | Bruin P.,InGell Labs BV | And 6 more authors.
Acta Biomaterialia | Year: 2012

In this study, the ability to modulate rheological and degradation properties of temperature-responsive gelling systems composed of aqueous blends of poly(-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(-caprolactone- co-lactide) (PCLA-PEG-PCLA) triblock copolymers (i.e. uncapped) and their fully capped derivatives was investigated. Uncapped and capped PCLA-PEG-PCLA triblock copolymers, abbreviated as degree of modification 0 and 2 (DM0 and DM2, respectively), were composed of identical PCLA and PEG blocks but different end groups: namely hydroxyl and hexanoyl end groups. DM0 was synthesized by ring opening polymerization of l-lactide and -caprolactone in toluene using PEG as initiator and tin(II) 2-ethylhexanoate as the catalyst. A portion of DM0 was subsequently reacted with an excess of hexanoyl chloride in solution to yield DM2. The cloud point and phase behaviour of DM0 and DM2 in buffer as well as that of their blends were determined by light scattering in a diluted state and by vial tilting and rheological measurements in a concentrated state. Degradation/dissolution properties of temperature-responsive gelling systems were studied in vitro at pH 7.4 and 37 °C. The cloud points of DM0/DM2 blends were ratio-dependent and could be tailored from 15 to 40 °C for blends containing 15 to 100 wt.% DM0. Vial tilting and rheological experiments showed that, with solid contents between 20 and 30 wt.%, DM0/DM2 blends (15/85 to 25/75 w/w) had a sol-to-gel transition temperature at 10-20 °C, whereas blends with less than 15 wt.% DM0 formed gels below 4 °C and the ones with more than 25 wt.% DM0 did not show a sol-to-gel transition up to 50 °C. Complete degradation of temperature-responsive gelling systems took ∼100 days, independent of the DM0 fraction and the initial solid content. Analysis of residual gels in time by GPC and 1H-NMR showed no chemical polymer degradation, but indicated gel degradation by dissolution. Preferential dissolution of lactoyl-rich polymers induced enrichment of the residual gels in caproyl-rich polymers. To the best of our knowledge, degradation of temperature-responsive gelling systems by dissolution has not been reported or hypothesized as being the consequence of acylation of polymers. In conclusion, blending of PCLA-PEG-PCLA triblock polymers composed of identical backbones but different end groups provides for a straightforward preparation of temperature-responsive gelling systems with well-characterized rheological properties and potential in drug delivery. Furthermore, acylation of triblock copolymers may allow for the design of bioerodible systems with control over degradation by polymer dissolution. © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Petit A.,InGell Labs BV | Petit A.,University Utrecht | Redout E.M.,University Utrecht | van de Lest C.H.,University Utrecht | And 7 more authors.
Biomaterials | Year: 2015

In this study, the intra-articular tolerability and suitability for local and sustained release of an in situ forming gel composed of an acetyl-capped poly(ε-caprolactone- co-lactide)- b-poly(ethylene glycol)- b-poly(ε-caprolactone- co-lactide) (PCLA-PEG-PCLA) copolymer loaded with celecoxib was investigated in horse joints. The systems were loaded with two dosages of celecoxib, 50mg/g ('low CLB gel') and 260mg/g ('high CLB gel'). Subsequently, they were injected into the joints of five healthy horses. For 72h after intra-articular injection, they induced a transient inflammatory response, which was also observed after application of Hyonate®, a commercial formulation containing hyaluronic acid for the intra-articular treatment of synovitis in horses. However, only after administration of the 'high CLB gel' the horses showed signs of discomfort (lameness score: 1.6±1.3 on a 5-point scale) 1 day after injection, which completely disappeared 3 days after injection. Importantly, there was no indication of cartilage damage. Celecoxib Cmax in the joints was reached at 8h and 24h after administration of the 'low CLB gel' and 'high CLB gel', respectively. In the joints, concentrations of celecoxib were detected 4 weeks post administration. Celecoxib was also detected in plasma at concentrations of 150ng/ml at day 3 post administration and thereafter its concentration dropped below the detection limit. These results show that the systems were well tolerated after intra-articular administration and showed local and sustained release of celecoxib for 4 weeks with low and short systemic exposure to the drug, demonstrating that these injectable in situ forming hydrogels are promising vehicles for intra-articular drug delivery. © 2015 Elsevier Ltd.

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