Prolonged subcutaneous delivery of low molecular weight heparin based on thermoresponsive hydrogels with chitosan nanocomplexes: Design, in vitro evaluation, and cytotoxicity studies.
Low molecular weight heparins (LMWHs) have risen in popularity over the past decades. Owing to their appropriate pharmacokinetic profile, they enable long-term clinical applications, e.g. prophylaxis of deep vein thrombosis. Although the administration of LMWHs is not as frequent as of heparin, it still requires once daily injection at least. In order to prolong LMWH release, and thus provide less frequent subcutaneous administration, we designed and thoroughly evaluated thermoresponsive poloxamer-based systems combined with LMWH/chitosan pH-responsive nanocomplexes. A LMWH/chitosan mass ratio of 1:2 was the most appropriate for preparation of small, homogenous and stable nanocomplexes. Thermoresponsive hydrogels were examined by gelation temperature and time, thermal analysis, gel dissolution, LMWH release, and cytotoxicity in vitro. Hydrogels' behaviour was significantly shifted by gel composition e.g. the addition of hydroxypropylmethylcellulose to poloxamer-based systems decreased gelation temperature and time (from 28.6°C to 25.1°C and from 50s to 44s, respectively), but prolonged gel dissolution and LMWH release (7 and 4 days, respectively). Prolongation of drug release was additionally achieved with incorporation of LMWH/chitosan nanocomplexes into the gelling systems. As formulations demonstrated no cytotoxicity in vitro, it may be concluded that these double-responsive platforms are promising candidates for prolonged subcutaneous LMWH delivery during long-term treatment.
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Maja
M
Radivojša Matanović
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Iztok
I
Grabnar
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Mirjam
M
Gosenca
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia. Electronic address: ahlinp@ffa.uni-lj.si.
Pegi Ahlin
PA
Grabnar
D000925:Anticoagulants / Q000008:administration & dosage*; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D048271:Chitosan / Q000737:chemistry*; D003692:Delayed-Action Preparations; D065546:Drug Liberation; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage*; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D007279:Injections, Subcutaneous; D053758:Nanoparticles / Q000737:chemistry*; D012212:Rheology; D013696:Temperature
D000925:Anticoagulants; D003692:Delayed-Action Preparations; D006495:Heparin, Low-Molecular-Weight; D020100:Hydrogels; D048271:Chitosan
Chitosan nanocomplexes; Low molecular weight heparin; Prolonged release; Subcutaneous drug delivery; Thermoresponsive hydrogels; Thrombosis